IP Library › Granted Patent US 8,623,871

Granted Patent B2

US 8,623,871 · App. 11/698,781 · Granted Jan 7, 2014

Substituted biaryl compounds for inflammation and immune-related uses

Inventors: Shoujun Chen (Bedford, MA); Lijun Sun (Harvard, MA); Jun Jiang (Norwood, MA); Yu Xie (Natick, MA)

Assignee: Synta Pharmaceuticals Corp.

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Quick Facts

Patent No.: US 8,623,871
App. No.: 11/698,781
Granted: Jan 7, 2014
Kind: B2

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Abstract

The invention relates to compounds of structural formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein A, Y, L, R 1 , W 1 and W 2 are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

Claims (130)

1. A compound represented by formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

Y′ 1 is an optionally substituted C 1 -C 6 alkyl or optionally substituted cycloalkyl, wherein the optional substituents are 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, —C(O)NR 1 R 2 ,—NR 4 C(O)R 5 , halo, —OR 4 ,cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 ,—SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 ,and —S(O) p NR 1 R 2 ;

X 3 and X 4 are each, independently, CH or CZ 1 ,;

L′ is —NHCH 2 —, —CH 2 NH—, —NHC(O)—, C(S)—, or —NHC(S)—;

Z 1 and Z 2 are each, independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ;

Z 3 is a substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl with no more than two heteroatoms, wherein the substituents are selected from the group consisting of an optionally substituted C 2 -C 6 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , and —S(O) p NR 1 R 2 ;

R, for each occurrence, is independently —H alkyl, —C(O)R 7 , or —C(O)OR 7 ;

R 1 and R 2 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 1 and R 2 are taken together with the nitrogen to which they are attached to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

R 4 , R 5 , R 7 , and R 8 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 6 , for each occurrence, is —H or alkyl;

n is 0, 1, or 2; and

p is 0, 1, or 2.

2. The compound of claim 1 , wherein Z 3 is a substituted phenyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, or an optionally substituted furanyl.

3. The compound of claim 1 , wherein Z 2 is halo, a lower alkyl, or a lower alkoxy.

4. The compound of claim 1 , wherein n is 0.

5. The compound of claim 1 , wherein:

Y′ 1 is an optionally substituted C 1 -C 6 alkyl or optionally substituted cycloalkyl, wherein the optional substituents are 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , and —S(O) p NR 1 R 2 ;

L′ is —NHC(O)—;

X 3 and X 4 are each CH;

Z 2 is halo, a lower alkyl, or a lower alkoxy;

Z 3 is a substituted phenyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, an optionally substituted furanyl; and

n is 0.

6. The compound of claim 5 , wherein Y′ is methyl, ethyl, n-propyl, or isopropyl.

7. A compound represented by formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

Y′ 1 is an optionally substituted C 1 -C 6 alkyl or optionally substituted cycloalkyl, wherein the optional substituents are 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ;

X 3 and X 4 are each, independently, CH or CZ 1 ;

L″ is —NHCH 2 —, —CH 2 NH—, —NHC(O)—, —C(O)NH—, —C(O)—, C(S)—, or —NH—C(S)—;

Z′ 3 is a substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl with no more than two heteroatoms, wherein the substituents are selected from the group consisting of an optionally substituted C 2 -C 6 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , and —S(O) p NR 1 R 2 ;

R, for each occurrence, is independently —H alkyl, —C(O)R 7 , or —C(O)OR 7 ;

R 6 , for each occurrence, is —H or alkyl;

n is 0, 1, or 2;

p is 0, 1, or 2; and

provided that when L″ is —C(O)NH—, Z′ 3 is not thienyl.

8. A compound represented by formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

Y 1 is an optionally substituted alkyl or optionally substituted cycloalkyl, an optionally substituted alkenyl, or —C(O)OR′ 5 , wherein the optional substituents are 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ;

Z 7 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , or —S(O) p R 4 ;

Z 8 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl with no more than two heteroatoms, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —OR 10 , cyano, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 11 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , or —S(O) p R 4 , wherein the substituents are selected from the group consisting of an optionally substituted C 2 -C 6 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , and —S(O) p NR 1 R 2 ;

L′ 1 is —NRCH 2 —, —CH 2 NR—, —NRC(O)—, —C(O)NR—, C(S)—, or —NRC(S)—;

R, for each occurrence, is independently —H alkyl, —C(O)R 7 , or —C(O)OR 7 ;

R′ 5 , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 6 , for each occurrence, is —H or alkyl;

R 10 is an optionally substituted C 2 -C 10 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 11 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

p is 0, 1, or 2; and

provided that when L′ 1 is —C(O)NH—, Z 7 is —Cl and Z 8 is —C(O)OCH 3 , Y 1 is not substituted with a cyano group;

provided that when L′ 1 is —C(O)NH— or —NHC(O), Z 8 is not an isoquinoline;

provided that when L′ 1 is —NHC(O) and Y 1 is methyl, Z 7 is not —OCH 3 ; and

provided that when L′ 1 is —C(O)NH— and Z 7 is methyl, Z 8 is not 5-methyl-1,3,4-oxadiazol-2-yl.

9. The compound of claim 8 , wherein Z 8 is a haloalkyl, an optionally substituted phenyl, —C(O)OR 11 , an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, or an optionally substituted furanyl.

10. The compound of claim 8 , wherein Z 7 is halo, a lower alkyl, or a lower alkoxy.

11. A compound selected from the group consisting of:

N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-acetamide;

N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-isobutyramide;

2-Dimethylamino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide Hydrochloride;

2-Amino-4-methyl-pentanoic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide;

2-Amino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-acetamide;

2-Amino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

2-Amino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-4-methylsulfanyl-butyramide;

2-Amino-3-methyl-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

2-Amino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

3-Dimethylamino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

3-Amino-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

2-Amino-3-methyl-pentanoic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide;

N-(2′-Methyl-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Chloro-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Chloro-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

4′-Butyrylamino-6-methyl-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Bromo-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-lodo-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Bromo-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

6-Bromo-4′-butyrylamino-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Ethyl-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Methoxy-5′-thiazol-2-yl-biphenyl-4-yl)-butyramide;

N-(2′-Ethyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

4′-Butyrylamino-6-ethyl-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Methyl-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Chloro-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Chloro-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

6-Methyl-4′-propionylamino-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Bromo-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-lodo-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Bromo-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

6-Bromo-4′-propionylamino-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Ethyl-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Methoxy-5′-thiazol-2-yl-biphenyl-4-yl)-propionamide;

N-(2′-Ethyl-5′-oxazol-2-yl-biphenyl-4-yl)-propionamide;

6-Ethyl-4′-propionylamino-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Methyl-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-Chloro-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-Chloro-5′-oxazol-2-yl-biphenyl-4-yl)-isobutyramide;

4′-lsobutyrylamino-6-methyl-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Bromo-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-lodo-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-Bromo-5′-oxazol-2-yl-biphenyl-4-yl)-isobutyramide;

6-Bromo-4′-isobutyrylamino-biphenyl-3-carboxylic acid methyl ester;

N-(2′-Ethyl-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-Methoxy-5′-thiazol-2-yl-biphenyl-4-yl)-isobutyramide;

N-(2′-Ethyl-5′-oxazol-2-yl-biphenyl-4-yl)-isobutyramide;

6-Ethyl-4′-isobutyrylamino-biphenyl-3-carboxylic acid methyl ester;

2-Amino-3-methyl-N-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-butyramide;

N-((2′-methyl-5′-(oxazol-2-yl)biphenyl-4-yl)methyl)butan-1-amine;

N-((2′-methyl-5′-(oxazol-2-yl)biphenyl-4-yl)methyl)prop-2-en-1-amine;

N-((2′-methyl-5′-(oxazol-2-yl)biphenyl-4-yl)methyl)propan-1-amine;

methyl 4′-(butylamino)-6-methylbiphenyl-3-carboxylate;

N-butyl-2′-chloro-5′-(trifluoromethyl)biphenyl-4-amine;

N-isobutyl-2′-methyl-5′-(oxazol-2-l)biphenyl-4-amine;

2-(2′-methyl-5′-(oxazol-2-yl)biphenyl-4-ylamino)ethanol; and

ethyl 2-(2′-methyl-5′-(oxazol-2-yl)biphenyl-4-ylamino)acetate; or

a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of:

Cyclopropanecarboxylic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide;

Cyclobutanecarboxylic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide;

N-(2′-methyl-5′-(oxazol-2-yl)biphenyl-4-yl)cyclohexanecarboxamide;

N-(2′-chloro-5′-(trifluoromethyl)biphenyl-4-yl)cyclohexanecarboxamide;

N-(2′-chloro-5′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxamide;

N-(2′-chloro-5′-(trifluoromethyl)biphenyl-4-yl)cyclohexanecarboxamide;

N-(2′-chloro-5′-(trifluoromethyl)biphenyl-4-yl)cyclopropanecarboxamide; and

N-(2′-chloro-5′-(trifluoromethyl)biphenyl-4-yl)-2-methylcyclohexanecarboxamide; or

a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or claim 7 , or claim 8 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2007

From: CHEN, SHOUJUN; SUN, LIJUN; JIANG, JUN; XIE, YU

To: SYNTA PHARMACEUTICALS CORP.

Reel/Frame 019565/0478 →

Continuity (3)

Provisional Application 60761932 · Jan 25, 2006

Provisional Application 60762167 · Jan 25, 2006

Related Publication 20070254363A1 · Nov 1, 2007