Barbituric acid derivatives as inhibitors of TNF-α converting enzyme (TACE) and/or matrix metalloproteinases

• US 7,595,317 B2
• Filed: 04/05/2007
• Issued: 09/29/2009
• Est. Priority Date: 12/20/2001
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Duan, Jingwu, Jiang, Bin, Lu, Zhonghui, Chen, Lihua, Barbosa, Joseph, Pitts, William J.
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Ward; Paul V.
• Application Number:
  US11/696,847
• Publication Number:
  US 20070167451A1
• Time in Patent Office: 908 Days
• Field of Search: 514/247, 514/256, 544/224, 544/242, 544/299
• US Class Current: 514/247
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 239/62 Barbituric acids
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

The present application describes novel barbituric acid derivatives of formula I:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, L, R¹, R², R³, R⁴, R⁵, n, W, U, X, Y, Z, U^a, X^a, Y^a, and Z^a are defined in the present specification, which are useful as TNF-α converting enzyme (TACE) and matrix metalloproteinases (MMP) inhibitors.

Claims

1. A compound of formula I:

2. A compound according to claim 1, wherein;

W is (CHR^a)_m or C_2-3 alkenylene;

U is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

X is absent or C_1-3 alkylene;

U^a is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

X^a is absent or is selected from C_1-4 alkylene, C_2-4 alkenylene, and C_2-4 alkynylene;

Y^a is absent or is selected from O and NR^a1;

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

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹ and R², together with the carbon atoms to which they are attached, combine to form a 5-6 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_p, and 0-2 double bonds, and substituted with 0-3 R^c;

R³ is selected from Q, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, C_2-6 alkynylene-Q, (CR^aR^a1)_r1OR^a1, (CR^aR^a1)_r1NR^a(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)OR^a1, (CR^aR^a1)_r1C(O)NR^aR^a1, (CR^aR^a1)_r1C(O)NR^a(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1NR^aC(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1NR^aC(O)OR^a1, (CR^aR^a1)_r1S(O)_p(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1SO₂NR^aR^a1, and (CR^aR^a1)_r1NR^aSO₂(CR^aR^a1)_r—

Q;

Q, at each occurrence, is independently selected from H, CF₃, a C_3-13 carbocycle substituted with 0-5 R^d, 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 R^d;

R⁴ is selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

R⁵ is selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

n is 0 or 1;

alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom to which they are attached, combine to form a 3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_p, and 0-2 double bonds, and substituted with 0-3 R^c;

R¹⁰, at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-2 R^c1, C_2-6 alkenyl substituted with 0-2 R^c1, C_2-6 alkynyl substituted with 0-2 R^c1, (CR^aR^a1)_sNR^aR^a1, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)₅NR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)₅NR^aSO₂R^a3, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0-2 R^c1, and (CR^aR^a1)_r-5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-2 R^c1;

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0-1 R^c1;

C_2-6 alkenyl substituted with 0-1 R^c1;

C_2-6 alkynyl substituted with 0-1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0-2 R^c1; and

(CH₂)_r-5-6 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 R^c1;

alternatively, when two R^c groups are attached to the same carbon atom, they form a spiro ring C that is a 3-8 membered carbocycle or heterocycle substituted with 0-2 R^c1 and comprising;

carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_p, and 0-2 double bonds, provided that ring C contains other than a S—

S, O—

O, or S—

O bond; and

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring D substituted with 0-2 R^c1 and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 0-3 double bonds.

3. A compound according to claim 2, wherein;

B is O;

L is O;

U is absent or is selected from;

O, NR^a1, C(O), C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

X is absent, methylene or ethylene;

Z is absent or is selected from;

a C_3-8 cycloalkyl substituted with 0-5 R^b;

a C_3-8 cycloalkenyl substituted with 0-5 R^b;

phenyl substituted with 0-5 R^b;

naphthyl substituted with 0-5 R^b; 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 R^b;

U^a is absent or is selected from;

O, NR^a1, C(O), C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

Z^a is selected from H, a C_5-10 carbocycle substituted with 0-5 R^e, 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 R^c;

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

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

provided that when Z is absent, Z^a is other than H;

R³ is selected from Q, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, C_2-6 alkynylene-Q, (CR^aR^a1)_r1OR^a1, (CR^aR^a1)_r1NR^a(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)OR^a1, (CR^aR^a1)_r1C(O)NR^aR^a1, (CR^aR^a1)_r1NR^aC(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1NR^aC(O)OR^a1, (CR^aR^a1)_r1S(O)_p(CR^aR^a1)_r—

Q, and (CR^aR^a1)_r1SO₂NR^aR^a1;

Q, at each occurrence, is independently selected from H, a C_3-10 carbocycle substituted with 0-3 R^d, 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 0-3 R^d;

R⁴ is selected from H and C_1-6 alkyl;

R⁵ is selected from H and C_1-6 alkyl;

R¹⁰, at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-1 R^c1, C_2-6 alkenyl substituted with 0-1 R^c1, C_2-6 alkynyl substituted with 0-1 R^c1, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rC_3-6 carbocycle substituted with 0-2 R^c1, and (CR^aR^a1)_r-5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-2 R^c1;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;

alternatively, R^a and R^a1, 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 0-1 additional heteroatoms selected from N, NR^a2, O, and S(O)_p;

R^a3, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, and —

(CH₂)_r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^a2, O, and S(O)_p and substituted with 0-3 R^c1;

R^c, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_3-6 carbocycle substituted with 0-2 R^c1; and

5-6 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 R^c1;

alternatively, when two R^c groups are attached to the same carbon atom, they form a spiro ring C that is a 3-8 membered carbocycle or heterocycle substituted with 0-2 R^c1 and comprising;

carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_p, and 0-2 double bonds, provided that ring C contains other than a S—

S, O—

O, or S—

O bond;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered carbocyclic or heterocyclic ring D substituted with 0-2 R^c1 and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 0-3 double bonds;

R^c1, at each occurrence, is independently selected from H, C_1-4 alkyl, OR^a, Cl, F, Br, I, ═

O, CF₃, —

CN, NO₂, C(O)OR^a, and C(O)NR^aR^a1;

R^d, at each occurrence, is independently selected from C_1-6 alkyl substituted with 0-2 R^e, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, C(O)R^a1, C(O)OR^a, C(O)NR^aR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, S(O)_pR^a3, CF₃, (CH₂)_r—

C_3-6 carbocycle substituted with 0-2 R^e, 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; and

R^e, at each occurrence, is independently selected from H, C_1-4 alkyl, OR^a, Cl, F, Br, I, ═

O, CF₃, —

CN, NO₂, C(O)OR^a, and C(O)NR^aR^a.

4. A compound according to claim 3, wherein;

W is (CH₂)_m or C_2-3 alkenylene;

Z is absent or selected from;

a C_4-8 cycloalkyl substituted with 0-3 R^b;

a C_4-8 cycloalkenyl substituted with 0-3 R^b;

phenyl substituted with 0-3 R^b;

naphthyl substituted with 0-3 R^b;

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 R^b; and

said 5-10 membered heterocycle is selected from the group;

furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;

Z^a is selected from;

H;

phenyl substituted with 0-3 R^c;

naphthyl substituted with 0-3 R^c; 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 R^c; and

said 5-10 membered heterocycle is selected from the group;

furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;

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

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

provided that when Z is absent, Z^a is other than H;

R¹ and R², together with the carbon atoms to which they are attached, combine to form a 5-6 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_p, and 0-2 double bonds, and substituted with 0-3 R^c;

R³ is selected from Q, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, (CR^aR^a1)_r1OR^a1, (CR^aR^a1)_r1NR^a(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)OR^a1, (CR^aR^a1)_r1C(O)NR^aR^a1, (CR^aR^a1)_r1NR^aC(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1NR^aC(O)OR^a1, (CR^aR^a1)_r1S(O)(CR^aR^a1)_r—

Q, and (CR^aR^a1)_r1SO₂NR^aR^a1;

Q, at each occurrence, is independently selected from H, a C_3-6 carbocycle substituted with 0-3 R^d, 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 R^d;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;

R^a3, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, and benzyl;

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

O, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, S(O)₂NR^aR^a1, S(O)_pR^a3, and CF₃;

R^c, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1 (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_3-6 carbocycle substituted with 0-2 R^c1; and

5-6 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 R^c1; and

R^d, at each occurrence, is independently selected from C_1-6 alkyl substituted with 0-1 R^e, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, C(O)R^a1, C(O)OR^a, C(O)NR^aR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, S(O)_pR^a3, CF₃, and (CH₂)_r-phenyl substituted with 0-2 R^e.

5. A compound according to claim 4, wherein;

X is absent or is methylene;

Y is absent or is O;

Z is absent or is selected from;

phenyl substituted with 0-3 R^b;

naphthyl substituted with 0-3 R^b;

thiophenyl substituted with 0-2 R^b;

oxazolyl substituted with 0-1 R^b;

isoxazolyl substituted with 0-1 R^b; and

thiazolyl substituted with 0-1 R^b;

U^a is absent or is O;

Y^a is absent or is O;

Z^a is selected from;

H;

phenyl substituted with 0-3 R^c;

pyridyl substituted with 0-3 R^c;

indolyl substituted with 0-3 R^c;

quinolinyl substituted with 0-3 R^c;

benzimidazolyl substituted with 0-3 R^c; and

1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted with 0-3 R^c;

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

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

provided that when Z is absent, Z^a is other than H;

R¹ and R², together with the carbon atoms to which they are attached, combine to form a 5-6 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_p, and 0-2 double bonds, and substituted with 0-3 R^c;

R³ is selected from Q, C_1-6 alkylene-Q, (CR^aR^a1)_r1OR^a1, (CR^aR^a1)_r1NR^a(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1C(O)OR^a1, (CR^aR^a1)_r1C(O)NR^aR^a1, (CR^aR^a1)_r1NR^aC(O)(CR^aR^a1)_r—

Q, (CR^aR^a1)_r1NR^aC(O)OR^a1, (CR^aR^a1)_r1S(O)_p(CR^aR^a1)_s—

Q, and (CR^aR^a1)_r1SO₂NR^aR^a1;

R⁴ is selected from H and C_1-4 alkyl;

R⁵ is selected from H and C_1-4 alkyl;

n is 0 or 1;

R¹⁰, at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-1 R^c1, C_2-6 alkenyl substituted with 0-1 R^c1, C_2-6 alkynyl substituted with 0-1 R^c1, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_r—

C_3-6 carbocycle substituted with 0-2 R^c1, and (CR^aR^a1)_r-5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p and substituted with 0-2 R^c1; and

R^c, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, and phenyl.

6. A compound according to claim 5, wherein;

R³ is selected from Q, C_1-6 alkylene-Q, C(O)(CR^aR^a1)_r—

Q, C(O)OR^a1, C(O)NR^aR^a1, C(O)NR^a(CR^aR^a1)_r—

Q, and S(O)_p(CR^aR^a1)_r—

Q;

Q, at each occurrence, is independently 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;

R⁴ is selected from H, methyl, and ethyl;

R⁵ is selected from H, methyl, and ethyl;

R^a2, at each occurrence, is independently selected from H, methyl, and ethyl;

R^c, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, and (CR^aR^a1)_rS(O)_pR^a3; and

r, at each occurrence, is selected from 0, 1, 2, and 3.

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

4-[(2-methyl-4-quinolinyl)methoxy]-N-(1,3,5-trioxo-2,4-diazaspiro[5.5]undec-7-yl)benzamide trifluoroacetate;

4-[(2-methyl-4-quinolinyl)methoxy]-N-(6,8,10-trioxo-7,9-diazaspiro[4.5]dec-1-yl)benzamide trifluoroacetate;

4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester;

4-[4-(1,1-dioxo-2,3-dihydro-1H-1λ

⁶-benzo[1,4]thiazin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester;

4-[4-(2-isopropyl-benzoimidazol-1-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester;

4-[4-(2-methyl-quinolin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester;

4-(2-methyl-quinolin-4-ylmethoxy)-N-(6,8,10-trioxo-2-oxa-7,9-diaza-spiro[4.5]dec-4-yl)-benzamide;

7-[4-(2-methyl-quinolin-4-ylmethoxy)-benzoylamino]-1,3,5-trioxo-2,4,9-triaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;

N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;

N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;

N-[2-(2,2-dimethyl-propionyl)-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;

4-(2-methyl-quinolin-4-ylmethoxy)-N-[6,8,10-trioxo-2-(pyridine-3-carbonyl)-2,7,9-triaza-spiro[4.5]dec-4-yl]-benzamide;

N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide;

N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide;

N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-isopropyl-benzoimidazol-1-ylmethyl)-benzamide;

4-(2-isopropyl-benzoimidazol-1-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide;

N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(1,1-dioxo-2,3-dihydro-1H-1λ

⁶-benzo[1,4]thiazin-4-ylmethyl)-benzamide;

4-(1,1-Dioxo-2,3-dihydro-1H-1λ

⁶-benzo[1,4]thiazin-4-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide; and

1-(4-phenoxy)phenyl-5,7-diazaspiro[2.5]octane-4,6,8-trione;

or a pharmaceutically acceptable salt form thereof.

8. A pharmaceutical composition, comprising:

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

13. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt form thereof.

14. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt form thereof.