US 7,442,716 B2 · 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors

Abstract

The invention encompasses novel compounds of Formula I or pharmaceutically acceptable salts thereof. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful to treat pain and/or inflammation from a variety of diseases or conditions, such as osteoarthritis, rheumatoid arthritis and acute or chronic pain. Methods of treating diseases or conditions mediated by the mPGES-1 enzyme and pharmaceutical compositions are also encompassed.

A compound represented by Formula I

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, wherein:
J is selected from the group consisting of —C(X2)— and —N—,
K is selected from the group consisting of —C(X3)— and —N—,
L is selected from the group consisting of —C(X4)— and —N—, and
M is selected from the group consisting of —C(X5)— and —N—,
with the proviso that at least one of J, K, L or M is other than —N—;
X2, X3, X4 and X5 are independently selected from the group consisting of:
(1) H;
(2) —CN;
(3) F;
(4) Cl;
(5) Br;
(6) I;
(7) —OH;
(8) —N3;
(9) C1-6alkyl, C2-6alkenyl or C2-6alkynyl, wherein one or more of the hydrogen atoms attached to said C1-6alkyl, C2-6alkenyl or C2-6alkynyl may be replaced with a fluoro atom, and said C1-6alkyl, C2-6alkenyl or C2-6alkynyl may be optionally substituted with a hydroxy group;
(10) C1-4alkoxy;
(11) NR9R10—C(O)—C1-4alkyl-O—;
(12) C1-4alkyl—S(O)k—;
(13) —NO2;
(14) C3-6cycloalkyl, (15) C3-6cycloalkoxy;
(16) phenyl, (17) carboxy;
and (18) C1-4alkyl-O—C(O)—;
R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from the group consisting of:
(1) H;
(2) F;
(3) Cl;
(4) Br;
(5) I;
(6) —CN;
(7) C1-10alkyl or C2-10alkenyl, wherein one or more of the hydrogen atoms attached to said C1-10alkyl or C2-10alkenyl may be replaced with a fluoro atom, or two hydrogen on adjacent carbon atoms may be joined together and replaced with —CH2— to form a cyclopropyl group, or two hydrogen atoms on the same carbon atom may be replaced and joined together to form a spiro C3-6cycloalkyl group, and wherein said C1-10alkyl or C2-10alkenyl may be optionally substituted with one to three substituents independently selected from the group consisting of:
—OH, acetyl, methoxy, ethenyl, R11—O—C(O)—, R35—N(R36)—, R37—N(R38)—C(O)—, cyclopropyl, pyrrolyl, imidiazolyl, pyridyl and phenyl, said pyrrolyl, imidiazolyl, pyridyl and phenyl optionally substituted with C1-4alkyl or mono-hydroxy substituted C1-4alkyl;
(8) C3-6cycloalkyl;
(9) R12—O—;
(10) R13—S(O)k—, (11) R14—S(O)k—N(R15)—;
(12) R16—C(O)—;
(13) R17—N(R18)—;
(14) R19—N(R20)—C(O)—;
(15) R21—N(R22)—S(O)k—;
(16) R23—C(O)—N(R24)—;
(17) Z-C≡C;
(18) —(CH3)C═N—OH or —(CH3)C═N—OCH3;
(19) R34—O—C(O)—;
(20) R39—C(O)—O—;
and (21) phenyl, naphthyl, pyridyl, pyradazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl or furyl, each optionally substituted with a substituent independently selected from the group consisting of:
F, Cl, Br, I, C1-4alkyl, phenyl, methylsulfonyl, methylsulfonylamino, R25—O—C(O)— and R26—N(R27)—, said C1-4alkyl optionally substituted with 1 to 3 groups independently selected from halo and hydroxy;
each Z is independently selected from the group consisting of:
(1) H;
(2) C1-6alkyl, wherein one or more of the hydrogen atoms attached to said C1-6alkyl may be replaced with a fluoro atom, and wherein
C1-6alkyl is optionally substituted with one to three substituents independently selected from:
hydroxy, methoxy, cyclopropyl, phenyl, pyridyl, pyrrolyl, R28—N(R29)— and R30—O—C(O)—;
(3) —(CH3)C═N—OH or —(CH3)C═N—OCH3;
(4) R31—C(O)—;
(5) phenyl;
(6) pyridyl or the N-oxide thereof;
(7) C3-6cycloalkyl, optionally substituted with hydroxy;
(8) tetrahydropyranyl, optionally substituted with hydroxy;
and (9) a five-membered aromatic heterocycle containing 1 to 3 atoms independently selected from O, N or S and optionally substituted with methyl;
each R9, R10, R15, R24 and R32 is independently selected from the group consisting of:
(1) H;
and (2) C1-4alkyl;
each R11, R12, R13, R14, R16, R23, R25, R30, R31, R34 and R39 is independently selected from the group consisting of:
(1) H;
(2) C1-4alkyl, (3) C3-6cycloalkyl;
(4) C3-6cycloalkyl-C1-4alkyl- (5) phenyl, (6) benzyl;
and (7) pyridyl;
said C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, phenyl, benzyl and pyridyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
OH, F, Cl, Br and I, and wherein said C1-4alkyl may be further substituted with oxo or methoxy or both;
each R17, R18, R19, R20, R21, R22, R26, R27, R28, R29, R35, R36, R37 and R38 is independently selected from the group consisting of:
(1) H;
(2) C1-6alkyl;
(3) C1-6alkoxy;
(4) OH and (5) benzyl or 1-phenylethyl;
and R17 and R18, R19 and R20, R21 and R22, R26 and R27, and R28 and R29, R35 and R36, and R37 and R38 may be joined together with the nitrogen atom to which they are attached to form a monocyclic ring of 5 or 6 carbon atoms, optionally containing one or two atoms independently selected from —O—, —S(O)k— and —N(R32)—;
and
each k is independently 0, 1 or 2.

73 more elements

2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors

Life of this patent

2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors

Life of this patent

Abstract

Claims27