(3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists
View Patent ↗The present invention encompasses compounds of Formula I: as well as the pharmaceutically acceptable salts thereof. The compounds are S1P 1 /Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.
1. A compound represented by Formula A:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-5 alkoxy,
wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-5 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH, C 1-8 alkoxy and —CO 2 H,
and any two of R 1 , R 2 , R 3 and R 4 may be joined together with the atoms to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms optionally containing 1 or 2 oxygen atoms;
R 5 is selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy,
wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy;
R 6 is selected from the group consisting of: phenyl and pyridinyl, each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —CN, —OH, —NR 7 R 8 , —NO 2 , phenyl, thienyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 2-4 acyloxy,
wherein said phenyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy are each optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy,
R 7 and R 8 are independently selected from the group consisting of: —H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, optionally containing 1 or 2 oxygen atoms, said ring is optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy;
U, V and W are each; —C(R 9 )—;
each R 9 is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy,
wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy;
For U or V, R 9 and R 1 or R 9 and R 2 may be joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the 6-membered aromatic ring to which R 9 is attached;
the ring
J is selected from the group consisting of: —CO 2 H,
each R 14 is independently selected from the group consisting of: —H and —CH 3 .
2. A compound in accordance with claim 1 represented by Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-5 alkoxy,
wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-5 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH, C 1-8 alkoxy and —CO 2 H,
and any two of R 1 , R 2 , R 3 and R 4 may be joined together with the atoms to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms optionally containing 1 or 2 oxygen atoms;
R 5 is selected from the group consisting of: —F, —Cl, —Br, —I, —CN, —OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy,
wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy;
R 6 is selected from the group consisting of: phenyl and pyridinyl each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —CN, —OH, —NR 7 R 8 , —NO 2 , phenyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 2-4 acyloxy,
wherein said phenyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy,
C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy are each optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy
R 7 and R 8 are independently selected from the group consisting of: —H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, optionally containing 1 or 2 oxygen atoms, said ring is optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy;
U, V and W are each —C(R 9 )—;
each R 9 is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy,
wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy;
For U or V, R 9 and R 1 or R 9 and R 2 may be joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the 6-membered aromatic ring to which R 9 is attached; and
the ring
3. A compound according to claim 2 wherein R 5 is methyl.
4. A compound according to claim 2 wherein R 6 is selected from the group consisting of: phenyl and pyridinyl, each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —CN, —OH, —NR 7 R 8 , —NO 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-6 cycloalkoxy and C 1-4 acyloxy,
wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-6 cycloalkoxy and C 1-4 acyloxy are each optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy; and
R 7 and R 8 are independently selected from the group consisting of: —H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, optionally containing 1 or 2 oxygen atoms, said ring is optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy.
5. A compound according to claim 2 wherein V and W are —CH—.
6. A compound according to claim 2 of Formula Ia
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of: —H, —OH and methyl or R 1 and
R 2 may be joined together with the atoms to which they are attached to form cyclopropyl;
U and V are each —C(R 9 )—;
each R 9 is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are each optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-8 alkoxy, and
For U or V, R 9 and R 1 or R 9 and R 2 may be joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the 6-membered aromatic ring to which R 9 is attached;
A is selected from the group consisting of: —N— and —C(R 13 )—, wherein R 13 is selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —CH 3 , —OCH 3 , —CF 3 , ethynyl, —NO 2 and —NH 2 ;
R a is selected from the group consisting of: NR 7 R 8 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy are each optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: —F, —Cl, —Br, —I and —OH;
R 7 and R 8 are independently selected from the group consisting of: —H and C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, optionally containing 1 or 2 oxygen atoms, said ring is optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy; and
R b is selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —CH 3 , —OCH 3 , —CF 3 , ethynyl, —NO 2 and —NH 2 .
7. A compound according to claim 2 of Formula Ib
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of: —H, —OH and methyl;
A is selected from the group consisting of: —N— and —C(R 13 )—, wherein R 13 is selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —CH 3 , —OCH 3 , —CF 3 , ethynyl, —NOand —NH 2 ;
R a is selected from the group consisting of: NR 7 R 8 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio and C 1-4 acyloxy are each optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: —F, —Cl, —Br, —I and —OH;
R 7 and R 8 are independently selected from the group consisting of: —H and C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, optionally containing 1 or 2 oxygen atoms, said ring is optionally substituted with one to three substituents independently selected from the group consisting of: —F, —Cl, —Br, —I, —OH and C 1-5 alkoxy; and
R b is selected from the group consisting of: —H, —F, —Cl, —Br, —I, —CN, —CH 3 , —OCH 3 , —CF 3 , ethynyl, —NO 2 and —NH 2 .
8. A compound according to claim 2 selected from the following table:
Ie
Ex.
R a
R b
A
U
R 2
R 1
1
i-PrO—
—CN
—CH═
═CH—
H
H
2
i-PrO—
Cl—
—CH═
═CH—
H
H
3
i-PrO—
Br—
—CH═
═CH—
H
H
4
i-PrO—
MeO—
—CH═
═CH—
H
H
5
i-PrO—
Me—
—CH═
═CH—
H
H
6
i-PrO—
F—
—CH═
═CH—
H
H
8
i-PrO—
—CF 3
—CH═
═CH—
R 2 and R 1 joined to
form cyclopropyl
9
i-PrO—
—CF 3
—CH═
═CH—
H
Me
10
i-PrO—
—CN
—CH═
═CH—
H
Me
11
i-PrO—
—CH3
—CH═
═CH—
H
Me
12
i-PrO—
—CF 3
—CH═
═CH—
Me
H
13
i-PrO—
—CN
—CH═
═CH—
Me
H
14
i-PrO—
—CH3
—CH═
═CH—
Me
H
15
i-PrO—
Cl—
—N═
═CH—
H
H
16
i-Pr-NH—
Cl—
—N═
═CH—
H
H
17
2,2-trifluoro-1-
Cl—
—N═
═CH—
H
H
methylethoxy
18
pyrrolidinyl
Cl—
—N═
═CH—
H
H
19
morpholin-4-yl
Cl—
—N═
═CH—
H
H
20
i-Pr-N(Me)—
Cl—
—N═
═CH—
H
H
21
2,2,2-trifluoroethoxy
Cl—
—N═
═CH—
Me
H
22
2,2,2-trifluoro-1-
Cl—
—N═
═CH—
Me
H
methylethoxy
23
3,3,-difluoro
Cl—
—N═
═CH—
Me
H
piperidinyl
24
3,3,-difluoro
Cl—
—N═
═CH—
Me
H
pyrrolidinyl
25
morpholin-4-yl
—CF 3
—N═
═CH—
Me
H
26
3,3,-difluoro
Cl—
—N═
═CH—
R 2 and R 1 joined to
pyrrolidinyl
form cyclopropyl
27
2,2,2-trifluoroethoxy
Cl—
—N═
═CH—
R 2 and R 1 joined to
form cyclopropyl
28
2,2,2-trifluoro-1-
Cl—
—N═
═CH—
R 2 and R 1 joined to
methylethoxy
form cyclopropyl
29
1-Me-n-PrO—
Cl—
—N═
═CH—
R 2 and R 1 joined to
form cyclopropyl
30
i-PrO—
Cl—
—N═
═CH—
R 2 and R 1 joined to
form cyclopropyl
31
i-Bu—
Cl—
—N═
═CH—
H
H
32
i-Pr-N(Me)—
I—
—N═
═CH—
H
H
33
i-Pr-N(Me)—
—CN
—N═
═CH—
H
H
34
3,3,-difluoro
I
—N═
═CH—
H
H
pyrrolidinyl
35
3,3,-difluoro
—CN
—N═
═CH—
H
H
pyrrolidinyl
36
i-PrO—
—CN
—CH═
═CH—
R 2 and R 1 joined to
form cyclopropyl
37
2,2,2-trifluoro-1-
—CN
—CH═
═CH—
R 2 and R 1 joined to
methylethoxy
form cyclopropyl
38
i-PrO—
MeO—
—CH═
═CH—
R 2 and R 1 joined to
form cyclopropyl
39
2,2,2-trifluoroethoxy
—CN
—CH═
═CH—
R 2 and R 1 joined to
form cyclopropyl
40
2,2,2-trifluoro-
—CN
—CH═
═CH—
R 2 and R 1 joined to
1-trifluoromethyl
form cyclopropyl
ethoxy
43
1-Me-n-PrO—
—CN
—CH═
═CH—
R 2 and R 1 joined to
form cyclopropyl
44
2,2,2-trifluoro-1-
—CN
—N═
═CH—
R 2 and R 1 joined to
methylethoxy
form cyclopropyl
45
i-PrO—
I
—N═
═CH—
R 2 and R 1 joined to
form cyclopropyl
48
Ethoxy
—CN
—N═
═CH—
H
H
49
2,2,2-trifluoro-1-
—CN
—N═
═CH—
H
H
methylethoxy
50
2-Me-n-Pr—
—CN
—N═
═CH—
H
H
51
2-methyl-1,1-
H
—CH═
═CH—
H
H
difluoro-n-Propyl
52
2,2,2-trifluoro-1-
I—
—N═
═CH—
H
H
methylethoxy
53
Cyclopentyloxy
Cl—
—CH═
═CH—
H
H
54
2-Me-n-Pro—
Cl—
—CH═
═CH—
H
H
55
2,2,2-trifluoro-1-
—CN
—CH═
═CH—
H
H
methylethoxy
56
2,2,2-trifluoro-1-
Cl—
—CH═
═CH—
H
H
methylethoxy
57
i-PrO—
Cl—
—C(Cl)═
═CH—
H
H
58
cyclopropylmethoxy
Cl—
—CH═
═CH—
H
H
60
2,2,2-trifluoro-1-
—NO 2
—CH═
═CH—
H
H
methylethoxy
61
2,2,2-trifluoroethoxy
—CN
—CH═
═CH—
H
H
62
2,2,2-trifluoro-
—CN
—CH═
═CH—
H
H
1-trifluoromethyl
ethoxy
63
1-Me-n-PrO—
—CN
—CH═
═CH—
H
H
65
2,2,2-trifluoro-1-
—NH 2
—CH═
═CH—
H
H
methylethoxy
66
1-Me-n-PrO—
—CN
—CH═
═CH—
Me
H
67
2,2,2-trifluoro-
—CN
—CH═
═CH—
Me
H
1-trifluoromethyl
ethoxy
68
2,2,2-trifluoromethoxy
—CN
—CH═
═CH—
Me
H
75
i-PrO—
—CF 3
—CH═
═CH—
H
H
79
i-PrO—
—CN
—CH═
═CH—
OH
OH
80
i-PrO—
—CN
—CH═
═CH—
OH
OH
or a pharmaceutically acceptable salt of any of the compounds above.
9. A compound according to claim 2 selected from the following table:
or a pharmaceutically acceptable salt of any of the compounds above.
10. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
11. A compound according to claim 1 of Formula Ig:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from —N— or —CH—;
the group
is:
R 1 and R 2 are —H, or R 1 and R 2 may be joined together with the atoms to which they are attached to form cyclopropyl;
U and V are —C(R 9 )—;
each R 9 is —H, or
For U or V, R 9 and R 1 or R 9 and R 2 may be joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the phenyl ring to which R 9 is attached;
R a is selected from the group consisting of: thienyl, NR 7 R 8 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy and C 3-6 cycloalkoxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy and C 3-6 cycloalkoxy are each optionally substituted from one up to the maximum number of substitutable positions with fluoro;
R 7 and R 8 are independently selected from the group consisting of: —H and C 1-6 alkyl, optionally substituted with one to three fluoro groups, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, said ring is optionally substituted with one to three fluoro groups.
12. A compound according to claim 11 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the above.
13. A compound according to claim 1 of Formula Ih:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from —N— or —CH—;
the group
is:
R 1 and R 2 are —H, or R 1 and R 2 may be joined together with the atoms to which they are attached to form cyclopropyl;
R 5 is —H or —CH 3 ;
U and V are —C(R 9 )—;
each R 9 is —H, or
For U or V, R 9 and R 1 or R 9 and R 2 may be joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the phenyl ring to which R 9 is attached;
R a is selected from the group consisting of: —F, NR 7 R 8 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy and C 3-6 cycloalkoxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy and C 3-6 cycloalkoxy are each optionally substituted from one up to the maximum number of substitutable positions with fluoro;
R 7 and R 8 are independently selected from the group consisting of: —H and C 1-6 alkyl, optionally substituted with one to three fluoro groups, and
R 7 and R 8 may be joined together with the nitrogen atom to which they are attached to form a saturated monocyclic ring of 3 to 8 atoms, said ring is optionally substituted with one to three fluoro groups;
R b is Cl or I;
J is selected from the group consisting of: —CO 2 H,
and
each R 14 is independently selected from the group consisting of: —H and CH 3 .
14. A compound according to claim 13 , wherein:
For U, R 9 and R 1 are joined together with the atoms to which they are attached to form a 5 membered ring, thus forming a fused partially aromatic bicyclic ring system of 9 atoms with the phenyl ring to which R 9 is attached;
R 5 is CH 3 ;
R b is Cl; and
J is selected from the group consisting of: —CO 2 H,
wherein each R 14 is independently selected from the group consisting of: —H and —CH 3 .
15. A compound according to claim 13 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the above.