IP Library › Granted Patent US 7,737,152

Granted Patent B2

US 7,737,152 · App. 11/722,612 · Granted Jun 15, 2010

6-carboaryl-oxy-pyrazin-2-yl-carboaryl-amines and compositions comprising said compounds

Assignee: The Wellcome Trust Limited

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Quick Facts

Patent No.: US 7,737,152
App. No.: 11/722,612
Granted: Jun 15, 2010
Kind: B2

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Abstract

The present invention pertains to certain 6-carboaryloxy-pyrazin-2-yl-carboaryl-amines of the following formula, and pharmaceutically acceptable salts thereof, which, inter alia, inhibit RAF (e.g., B-RAF) activity, inhibit cell proliferation, treat cancer, etc., wherein Q is independently —N═; R P3 is independently a group of the formula -J 1 -L 1 -Z; -J 1 L 1 -Z is independently —NH—Z; Z is independently C 6-14 carboaryl and is independently unsubstituted or substituted; R P2 is independently —H; R P5 is independently a group of the formula —W—Y; W is independently —O—; Y is independently C 6-14 carboaryl and is independently unsubstituted or substituted; and R P6 is independently —H. The present invention also pertains to pharmaceutical compositions comprising such compounds.

Claims (103)

1. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

wherein:

Q is independently —N═;

R P3 is independently a group of the formula -J 1 L 1 -Z;

-J 1 -L 1 -Z is independently —NH—Z;

R P2 is independently —H;

R P5 is independently a group of the formula —W—Y;

W is independently —O—;

R P6 is independently —H;

Z is independently C 6-14 carboaryl and is independently unsubstituted or substituted with one or more of the following substituents:

—C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —C(═O)N(CH 2 CH 2 OH) 2 , —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr) 2 , —OPh-Me, —OPh-OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —OC(═O)NH 2 , —OC(═O)NHMe, —OC(═O)NMe 2 , —OC(═O)NHEt, —OC(═O)NEt 2 , —OC(═O)NHPh, —OC(═)NCH 2 Ph, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NMe(C═O)nPr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═O)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 Ph-Cl, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazoyl, pyrazolyl, oxazoyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , and —CH 2 F 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ; and

Y is independently C 6-14 carboaryl and is independently unsubstituted or substituted with one or more of the following substituents:

(1) —C(═O)OH;

(2) —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu); —C(═O)O(cPr); —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 OMe, —C(═O)OCH 2 CH 2 OEt; —C(═O)OPh, —C(═O)OCH 2 Ph;

(3) —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)N(CH 2 CH 2 OH) 2 ; —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph;

(4) —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph; —(C═O)CH 2 Ph;

(5) —F, —Cl, —Br, —I;

(6) —CN;

(7) —NO 2 ;

(8) —OH;

(9) —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph; —OCF 3 , —OCH 2 CF 3 ; —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 Et; —OPh-Me, —OPh-OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I;

(10) —SH;

(11) —SMe, —SEt, —SPh, —SCH 2 Ph;

(12) —OC(═C)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu); —OC(═O)(cPr); —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt; —OC(═O)Ph, —OC(═O)CH 2 Ph;

(13) —OC(═O)NH 2 , —OC(═O)NHMe, —OC(═O)NMe 2 , —OC(═O)NHEt; —OC(═O)NEt 2 , —OC(═O)NCHPh, —OC(═O)NCH 2 Ph;

(14) —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 ; —NHPh, —NHCH 2 Ph; piperidino, piperazino, morpholino;

(15) —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)nPr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph;

(16) —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═O)NPh, —NH(C═O)NHCH 2 Ph; —NH(C═S)NH 2 , —NH(C═S)NHMe, —NH(C═S)NHEt, —NH(C═O)NPh, —NH(C═S)NHCH 2 Ph;

(17) —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph , —NHSO 2 PhMe, —NHSO 2 CH 2 Ph; —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph;

(18) —SO 2 Me, —SO CF 3 , —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph;

(19) —OSO 2 Me, —OSO 2 CF 3 , —OSO 2 Et, —OSO 2 Ph, —OSO 2 PhMe, —OSO 2 CH 2 Ph;

(20) —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph;

(21) —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 -Ph-Cl;

(22) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I; pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl;

(23) pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl;

(24) -Me, -Et, -nPr, iPr, -nBu, iBu, -sBu, -tBu, -nPe; -cPr, -cHex; —CH═CH 2 , —CH 2 —CH═CH 2 ; —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , and —CH 2 CF 3 ; —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 ; —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 NMe 2 ;

(25) ═O;

(26) ═NH, ═NMe; ═NEt;

(27) ═NOH, ═NOMe, ═NOEt, ═NO(nPn), ═NO(iPr), ═NO(cPr), ═NO(CH 2 -cPr);

(28) —OP(═O)(OH) 2 , —P(═O)(OH) 2 , —OP(═O)(OMe) 2 , —P(═O)(OMe) 2 ;

(29) —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —O—, —O—CF 2 —O—, and —O—CF 2 —CF 2 —O—.

2. A compound according to claim 1 , wherein Z is independently C 6-14 carboaryl and is independently unsubstituted or substituted with one or more of the following substituents:

—F, —Cl, —Br, —I,

—OMe, —OEt, —OCF 3 ,

-Ph, pyridyl, furanyl, pyrrolyl, oxazolyl, thiadiazolyl,

-Me, -Et, -tBu, —CF 3 , and —CH 2 OH.

3. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

wherein:

Q is independently —N═;

R P3 is independently a group of the formula -J 1 -L 1 -Z;

-J 1 -L 1 -Z is independently —NH—Z;

Z is independently C 6-14 carboaryl and is independently unsubstituted or substituted with one or more of the following substituents:

(1) carboxylic acid; (2) carboxylic acid ester; (3) amido or thioamido; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) carbamate; (14) amino; (15) acylamino or thioacylamino; (16) aminoacylamino or aminothioacylamino; (17) sulfonamino; (18) sulfonyl; (19) sulfonate; (20) sulfonamido; (21) C 5-20 aryl-C 1-7 alkyl; (22) C 5-20 aryl; (23) C 3-20 heterocyclyl; (24) C 1-7 alkyl; (25) oxo; (26) imino; (27) hydroxyimino; (28) phosphate; and (29) bi-dentate di-oxy groups;

R P2 is independently —H;

R P5 is independently a group of the formula —W—Y;

W is independently —O—;

Y is independently C 6-14 carboaryl and is independently unsubstituted or substituted with one or more of the following substituents:

R P6 is independently —H.

4. A compound according to claim 3 , wherein Y is independently naphthyl; and is independently unsubstituted or substituted.

5. A compound according to claim 3 , wherein Y is independently phenyl; and is independently unsubstituted or substituted.

6. A compound according to claim 3 , wherein Z is independently naphthyl; and is independently unsubstituted or substituted.

7. A compound according to claim 3 , wherein Z is independently phenyl; and is independently unsubstituted or substituted.

8. A compound according to claim 3 , wherein the compound has a molecular weight of 275 to 1000.

9. A composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier or diluent.

10. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

wherein:

Q is independently —N═;

R P3 is independently a group of the formula -J 1 -L 1 -Z;

-J 1 -L 1 -Z is independently —NH—Z;

Z is independently phenyl, and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr), —C(═O)N(CH 2 CH 2 OH) 2 , —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —O(tBu), 13 OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr), —OPh-Me, —OPh-OH, —OPh-OMe, —OPh-F, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —OC(═O)NH 2 , —OC(═O)NHMe, —OC(═O)NMe 2 , —OC(═O)NHEt, —OC(═O)NEt 2 , —OC(═O)NHPh, —OC(═O)NCH 2 Ph, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)nPr, —NH(C═O)Ph, —NCH(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 Ph-Cl, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ;

R P2 is independently —H;

R P5 is independently a group of the formula —W—Y;

W is independently —O—;

Y is independently phenyl or naphthyl, and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)N(CH 2 CH 2 OH) 2 , —C(═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —C(═O)Me, —C(═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —(C═O)Pr, —NH(C═O)Ph, —NCH(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═O)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═S)NHEt, —NH(C═S)NPh, —NH(C═S)NHCH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ; and

R P6 is independently —H.

11. A compound according to claim 10 , wherein Z is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr) 2 , —OPh, -Me, —OPh, —OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 .

12. A compound according to claim 10 , wherein Z is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —F, —Cl, —Br, —I, —OMe, —OEt, —OCF 3 , —SO 2 -morpholino, -Ph, pyridyl, furanyl, pyrrolyl, oxazolyl, thiadiazolyl, -Me, -Et, -tBu, —CF 3 , and —CH 2 OH.

13. A compound according to claim 10 , wherein Y is independently phenyl and is independently, unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(tBu), —(C═O)NH 2 , —C(═O)H, —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —NHPh, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)Pr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NHC(═O)CH(Me)Ph, —NHC(═O)(thiophenyl), —NHC(═O)CH 2 (thiophenyl), —NHC(═O)furanyl, —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═O)NPh, —NH(C═O)NHCH 2 Ph, —NH(C═S)NH 2 , —NH(C═S)NHMe, —NH(C═S)NHEt, —NH(C═S)NPh, —NH(C═S)NHCH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NHSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, and —CH 2 OH.

14. A compound according to claim 13 , wherein Y is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —NH 2 , —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)Pr, —NH(C═O)Ph, and —NHC(═O)CH 2 Ph.

15. A composition comprising a compound according to claim 10 and a pharmaceutically acceptable carrier or diluent.

16. A composition comprising a compound according to claim 14 and a pharmaceutically acceptable carrier or diluent.

17. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

wherein:

Q is independently —N═;

R P3 is independently a group of the formula -J 1 -L 1 -Z;

-J 1 -L 1 -Z is independently —NH—Z;

Z is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)N(CH 2 CH 2 OH) 2 , —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr) 2 , —OPh-Me, —OPh-OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —OC(═O)NH 2 , —OC(═O)NHMe, —OC(═O)NMe 2 , —OC(═O)NHEt, —OC(═O)NEt 2 , —OC(═O)NHPh, —OC(═O)NCH 2 Ph, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)nPr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═O)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 Ph-Cl, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ;

R P2 is independently —H;

R P5 is independently a group of the formula —W—Y;

W is independently —O—;

Y is independently naphthyl and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)N(CH 2 CH 2 OH) 2 , —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)Pr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═O)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═O)NPh, —NH(C═O)NHCH 2 Ph, —NH(C═S)NH 2 , —NH(C═S)NHMe, —NH(C═S)NHEt, —NH(C═S)NPh, —NH(C═S)NHCH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ; and

R P6 is independently —H.

18. A compound according to claim 17 , wherein Z is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr) 2 , —OPh -Me, —OPh —OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —SO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 .

19. A compound according to claim 17 , wherein Y is independently naphthyl and is independently unsubstituted or substituted with one or more substituents selected from: —C(═O)OMe, —C(═O)OEt, —C(═O)O(tBu), —(C═O )NH 2 , —C(═O)H, —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —NHPh, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)Pr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NHC(═O)CH(Me)Ph, —NHC(═O)(thiophenyl), —NHC(═O)CH 2 (thiophenyl), —NHC(═O)furanyl, —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═O)NPh, —NH(C═O)NHCH 2 Ph, —NH(C═S)NH 2 , —NH(C═S)NHMe, —NH(C═S)NHEt, —NH(C═S)NPh, —NH(C═S)NHCH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, and —CH 2 OH.

20. A composition comprising a compound according to claim 17 and a pharmaceutically acceptable carrier or diluent.

21. A compound according to claim 17 , wherein Z is independently phenyl and is independently unsubstituted or substituted with one or more substituents selected from: —F, —Cl, —Br, —I, —OMe, —OEt, —OCF 3 , —SO 2 -morpholino, -Ph, pyridyl, furanyl, pyrrolyl, oxazolyl, thiadiazolyl, -Me, -Et, -tBu, —CF 3 , and —CH 2 OH.

22. A compound according to claim 21 , wherein Y is independently naphthyl and is independently unsubstituted or substituted with one or more substituents selected from: —NH 2 , —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)Pr, —NH(C═O)Ph, and —NHC(═O)CH 2 Ph.

23. A composition comprising a compound according to claim 22 and a pharmaceutically acceptable carrier or diluent.

24. A compound selected from the following compounds and pharmaceutically acceptable salts thereof:

25. A composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier or diluent.

26. A compound selected from the following compounds and pharmaceutically acceptable salts thereof:

27. A composition comprising a compound according to claim 26 and a pharmaceutically acceptable carrier or diluent.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2007

From: SPRINGER, CAROLINE JOY; NICULESCU-DUVAZ, ION; VELA, ESTABAN ROMAN; GILL, ADRIAN LIAM; TAYLOR, RICHARD DAVID; MARAIS, RICHARD MALCOLM

To: THE WELLCOME TRUST LIMITED

Reel/Frame 019814/0189 →

Priority Claims (1)

GB 0428082.2 · Dec 22, 2004 · national

Continuity (2)

Provisional Application 6063789200 · Dec 22, 2004

Related Publication 20080015191A1 · Jan 17, 2008