Aldosterone synthase inhibitors
The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W, Y, m and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
1. A compound of the formula I
wherein:
R 1 is selected from —NH 2 , —NHCH 3 and —CH 3 ;
m is 0;
n is 1; and
X is selected from C and O; or
m is 0;
n is 0; and
X is C; or
m is 1;
n is 1; and
X is O;
Y and W are selected from C and N, wherein if Y is N, then W is C and R 4 is an electron pair and if W is N, then Y is C and R 5 is an electron pair;
R 2 and R 3 are independently selected from —H, —F, —OH and C 1-4 alkyl, when X is C;
R 2 and R 3 is an electron pair when X is O;
R 4 is the group of —(CR a R b ) p (A) 0-1 (CR a R b ) q B, wherein:
p and q are independently selected from integers between 0 and 5, but p+q is always equal or less than 6;
A is selected from O, S and NR e ;
B is selected from:
—H;
—OH;
—CN;
halogen;
—SO 2 R c ;
—C(O)R c ;
—CO 2 R c ;
—NR c SO 2 R d ;
—SO 2 NR c R d ;
—CONR c R d ;
—NR c COR d ;
—NR c R d ;
-Phenyl, optionally substituted with 1 to 3 groups selected from halogen, —CN, —CH 2 CN, —NR c C(O)R d , —SO 2 C 1-3 alkyl, —C(O)NR c R d , C 1-4 alkoxy, —SO 2 NR c R d , —CO 2 R c , —NR c SO 2 R d —(CH 2 ) 0-3 SO 2 C 1-3 alkyl and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with —OH, halogen or —OCH 3 ;
-heteroaryl optionally substituted with 1 to 2 groups independently selected from, —OH, C 1-3 alkoxy, —(CH 2 ) 0-2 morpholin-4-yl and C 1-6 alkyl wherein said C 1-6 alkyl is optionally substituted with —OH, —CN, C 1-3 alkoxy-N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 or halogen; and
—C 3-7 cycloalkyl, optionally partially unsaturated, wherein up to 3 ring constituting carbons of the cycloalkyl can be optionally replaced with a group selected from O, S, N, NR e , SO, SO 2 and CO; and wherein the resulting cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 groups selected from —OH, oxo, —CN, C 1-3 alkoxy, —N(R e ) 2 , —CON(R e ) 2 , —CO 2 C 1-4 alkyl, —C(O)C 1-3 alkyl, —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 , halogen and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with —OH;
R 5 is selected from
—H;
—C 1-6 alkyl optionally substituted with —OH, oxo, —OC 1-6 alkyl or —OCH 2 phenyl;
—C 3-6 cycloalkyl, wherein up to 3 ring constituting carbons can be optionally replaced with a group selected from O, S, N, NR e , SO, SO 2 or CO and wherein the resulting cycloalkyl or heterocyclyl is optionally substituted with —OH, —CN, halogen or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with —OH;
—CO 2 R c ;
—CN;
—CF 3 ;
-halogen;
—(CR a R b ) 0-2 OC 1-3 alkyl;
—C(O)NR c R d ;
—CH 2 Ophenyl, wherein the phenyl is optionally substituted with halogen;
-Phenyl, optionally substituted with halogen or SO 2 C 1-3 alkyl;
—CR a R b NHR e ; and
-heteroaryl, optionally substituted with C 1-3 alkyl;
R 6 and R 7 are independently selected from H, —Cl, —F, —CN and —CH 3 ;
wherein at least one of R 6 or R 7 is H;
R a and R b are independently selected from
—H;
—C 1-6 alkyl;
—C 3-7 cycloalkyl wherein up to 3 ring constituting carbons can be optionally replaced with a group selected from O, S, NR e , SO, SO 2 and CO;
—OH;
—CN;
-halogen; and
—OC 1-3 alkyl; or
R a and R b , attached to the same or different atom, along with the atoms that they are attached to can form a C 3-7 cycloalkyl ring in which up to 3 ring constituting carbon atoms can be optionally replaced with a group selected from O, S, NR e , SO, SO 2 and CO;
R c and R d are independently selected from:
—H;
—C 1-6 alkyl optionally substituted with —OH, oxo, —CN, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 , halogen, heterocyclyl or heteroaryl;
—C 3-7 cycloalkyl optionally substituted with —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 or halogen; wherein up to 3 ring constituting carbon atoms of the ring can be optionally replaced with a group selected from O, S, NR e , SO, SO 2 and CO;
—(CH 2 ) 0-1 phenyl, optionally substituted with 1 to 3 groups selected from —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 and halogen;
-heteroaryl optionally substituted with 1 to 2 groups independently selected from —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 and halogen;
—SO 2 C 1-3 alkyl; and
—CO 2 C 1-3 alkyl; or
R c and R d along with the atoms that they are attached to can form a C 3-7 cycloalkyl ring in which up to 3 ring constituting carbon atoms can be optionally replaced by O, S, N, NR e , SO, SO 2 or CO, wherein the cycloalkyl or heterocyclyl ring formed can be optionally substituted with one to three groups selected from —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 and halogen, wherein if the ring is substituted with two groups on the same carbon, the groups may join to form a spiro ring;
each R e is independently selected from:
—H;
—C 1-6 alkyl optionally substituted with —OH, —CN or halogen;
—COC 1-3 alkyl;
—CO 2 C 1-4 alkyl; and
—SO 2 C 1-3 alkyl;
or a salt thereof.
2. The compound according to claim 1 , wherein
R 5 is selected from
—H;
—C 1-6 alkyl optionally substituted with —OH;
—C 3-6 cycloalkyl, wherein up to 3 ring constituting carbons can be optionally replaced with a group selected from O, S, NR e , SO, SO 2 and CO and wherein the resulting cycloalkyl or heterocyclyl is optionally substituted with —OH, —CN, halogen or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with —OH;
—CO 2 R c ;
—CN;
—CF 3 ;
-halogen;
—(CR a R b ) 0-2 OC 1-3 alkyl;
—C(O)NR c R d ;
—CH 2 Ophenyl, wherein the phenyl is optionally substituted with halogen;
-Phenyl, optionally substituted with halogen or SO 2 C 1-3 alkyl;
—CR a R b NHR e ; and
-heteroaryl, optionally substituted with C 1-3 alkyl;
R 6 is H;
R 7 is H;
R c and R d are independently selected from:
—H;
—C 1-6 alkyl optionally substituted with —OH, oxo, —CN, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 or halogen;
—C 3-7 cycloalkyl optionally substituted with —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 or halogen; wherein up to 3 ring constituting carbon atoms of the ring can be optionally replaced with a group selected from O, S, NR e , SO, SO 2 and CO;
—(CH 2 ) 0-1 phenyl, optionally substituted with 1 to 3 groups selected from —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 and halogen;
-heteroaryl optionally substituted with 1 to 2 groups independently selected from —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 and halogen;
—SO 2 C 1-3 alkyl; and
—CO 2 C 1-3 alkyl; or
R c and R d along with the atoms that they are attached to can form a C 3-7 cycloalkyl ring in which up to 3 ring constituting carbon atoms can be optionally replaced by O, S, NR e , SO, SO 2 or CO, wherein the cycloalkyl or heterocyclyl ring formed can be optionally substituted with —OH, —CN, C 1-6 alkyl, C 1-3 alkoxyl, —N(R e ) 2 , —CON(R e ) 2 , —SO 2 C 1-3 alkyl, —SO 2 N(R e ) 2 or halogen;
or a salt thereof.
3. The compound according to claim 1 , wherein:
R 1 is selected from —NH 2 and —CH 3 ;
R 2 and R 3 are independently selected from —H, —F and —OH, when X is C; R 2 and R 3 is an electron pair when X is O;
R 4 is selected from
—H;
—OH;
—(CH 2 ) 0-1 CN;
—C 1-6 alkyl, optionally substituted with one to seven groups independently selected from halogen, —OH or —OCH 3 ;
—OC 1-4 alkyl, optionally substituted with —OH;
-halogen;
—CF 3 ;
—(CH 2 ) 0-1 (O) 0-1 (CH 2 ) 0-3 SO 2 C 1-3 alkyl;
—C(O)C 1-3 alkyl;
—CO 2 R c ;
—C 0-2 alkyl-NHSO 2 C 1-3 alkyl;
—C 0-2 alkyl-NHC(O)NHC 1-3 alkyl;
—(O) 0-1 (CH 2 ) 0-1 (O) 0-1 C(O)NR c R d ;
—(CH 2 ) 0-1 NR c R d ;
—(O) 0-1 (CH 2 ) 0-1 (O) 0-1 phenyl, optionally substituted with 1 to 3 groups selected from halogen, —CN, —CH 2 CN, —NHC(O)C 1-3 alkyl, —SO 2 C 1-3 alkyl, —C(O)NR c R d , hydroxyC 2-4 alkoxy, C 1-3 alkoxy, C(O)morphilin-4-yl, —SO 2 NH(CH 2 ) 2-3 OH, —SO 2 NR c R d and C 1-3 alkyl optionally substituted with —OH or —OCH 3 ;
—(O) 0-1 (CH 2 ) 0-2 heteroaryl selected from indolyl, pyridinyl, pyrazolyl, pyrazinyl, and pyrimidinyl, wherein said heteroaryl is optionally substituted with one to two groups independently selected from C 1-3 alkyl, —OH, C 1-3 alkoxy, hydroxymethyl, —CO 2 C 1-4 alkyl, —C(O)C 1-3 alkyl and —(CH 2 ) 0-2 morpholin-4-yl;
—O 0-1 (CH 2 ) 0-2 (O) 0-1 heterocyclyl, wherein the heterocyclyl is selected from 3,6-dihydro-2H-thiopyranyl,3,6-dihydro-2H-pyranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-thiopyranyl-1,1-dioxide, tetrahydrothiopyranyl-1,1-dioxide, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl;
wherein said heterocyclyl is optionally substituted with a group selected from —C(O)C 1-3 alkyl, —OH, oxo, —(CH 2 ) 1-2 morpholin-4-yl, —CO 2 C 1-4 alkyl and C 1-3 alkyl optionally substituted with —OH or —OCH 3 ;
—C(O)heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidinyl and piperidin-1-yl; and
—(CH 2 ) 0-1 O(CH 2 ) 1-2 heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidinyl and piperidin-1-yl; and
—C 3-6 cycloalkyl, optionally substituted 1 to 3 groups selected from OH—CN, C 1-6 alkyl, C 1-3 alkoxyl, and halogen;
R 5 is selected from
—H;
—C 1-3 alkyl;
—CO 2 C 1-3 alkyl;
—CN;
—CF 3 ;
-halogen;
—OC 1-3 alkyl;
—CH 2 OC 1-3 alkyl;
—C(O)NH 2 ;
—C 1-2 alkyl-OH;
—CH(OH)C 1-3 alkyl;
—CH 2 Ophenyl, wherein the phenyl is optionally substituted with halogen;
-Phenyl, optionally substituted with halogen or SO 2 C 1-3 alkyl;
—CH 2 NHR c ; and
-pyrazolyl, optionally substituted with C 1-3 alkyl;
R 6 is H;
R 7 is H; and
R c and R d are independently selected from
H, C 1-6 alkyl, —C(O)C 1-3 alkyl, —(CH 2 ) 1-3 OH, —(CH 2 ) 2-3 NHC(O)C 1-3 alkyl, —CH 2 phenyl, and —SO 2 C 1-2 alkyl;
or a salt thereof.
4. The compound according to claim 1 , wherein:
R 1 is —NH 2 ;
X is C;
Y and W are C;
R 2 and R 3 are H;
R 4 is selected from
—H;
—OH;
—(CH 2 ) 0-1 CN;
—C 1-6 alkyl, optionally substituted with one to four groups independently selected from —F, —OH or —OCH 3 ;
-halogen selected from —F and —Cl;
—CF 3 ;
—C(O)C 1-3 alkyl;
—C 0-2 alkyl-NHSO 2 C 1-3 alkyl;
—(O) 0-1 (CH 2 ) 0-1 (O) 0-1 C(O)NR c R d ;
—O 0-1 (CH 2 ) 0-2 (O) 0-1 heterocyclyl, wherein the heterocyclyl is selected from 3,6-dihydro-2H-thiopyranyl, 3,6-dihydro-2H-pyranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-thiopyranyl-1,1-dioxide, tetrahydrothiopyranyl-1,1-dioxide, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl;
wherein said heterocyclyl is optionally substituted with a group selected from —C(O)C 1-3 alkyl, —OH, oxo, —(CH 2 ) 1-2 morpholin-4-yl, —CO 2 C 1-4 alkyl and C 1-3 alkyl optionally substituted with —OH or —OCH 3 ; and
—(CH 2 ) 0-1 C(O)heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidinyl and piperidin-1-yl; and
R 5 is selected from
—H;
—Cl — 3 alkyl;
—CN;
—CF 3 ;
-halogen;
—CH(OH)C 1-3 alkyl;
-Phenyl, optionally substituted with halogen or SO 2 C 1-3 alkyl; and
—CH 2 NHR c ;
R 6 is H;
R 7 is selected from —H and —CH 3 ; and
R c and R d are independently selected from
H, C 1-6 alkyl, —C(O)C 1-3 alkyl, —(CH 2 ) 1-3 OH, —(CH 2 ) 2-3 NHC(O)C 1-3 alkyl, —CH 2 phenyl, and —SO 2 C 1-2 alkyl;
m is 0; and
n is 1;
or a salt thereof.
5. The compound according to claim 1 , wherein:
R 4 is H;
R 6 is H; and
R 7 is H;
or a salt thereof.
6. The compound according to claim 1 , wherein:
R 5 is H;
R 6 is H; and
R 7 is H;
or a salt thereof.
7. The compound according to claim 1 , wherein:
n is 1;
R 6 is H; and
R 7 is H;
or a salt thereof.
8. The compound according to claim 1 , wherein:
m=0;
R 6 is H; and
R 7 is H;
or a salt thereof.
9. The compound according to claim 1 , wherein:
W and Y are C;
R 6 is H; and
R 7 is H;
or a salt thereof.
10. The compound according to claim 1 , wherein:
X is C;
R 6 is H; and
R 7 is H;
or a salt thereof.
11. The compound according to claim 1 , wherein:
R 1 is —NH 2 ;
R 6 is H; and
R 7 is H;
or a salt thereof.
12. The compound according to claim 1 , wherein:
R 6 is selected from H, —Cl, —F, and —CH 3 ; and
R 7 is selected from H, —CH 3 and —CN,
wherein at least one of R 6 or R 7 is H;
or a salt thereof.
13. The compound according to claim 1 , wherein
R 1 is —NH 2 ;
X is C;
Y and W are C;
R 2 and R 3 are H;
R 6 is selected from H, —Cl, —F, and —CH 3 ;
R 7 is selected from H, —CH 3 and —CN,
wherein at least one of R 6 or R 7 is H;
m is 0; and
n is 1;
or a salt thereof.
14. The compound according to claim 1 selected from the group consisting of
Cpd
No
STRUCTURE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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31
32
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35
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301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
and the pharmaceutically acceptable salts thereof.
15. The compound according to claim 14 selected from the group consisting of compound numbers 1-3, 5-11, 14-20, 22-25, 27-29, 31-35, 38, 40-43, 45, 46, 48, 50-57, 59, 60, 62-68, 70-88, 90-102, 105-107, 109, 110, 112, 116, 117, 121, 126-131, 133-137, 141-144, 147-153, 155-162, 164, 165, 167-182, 184-193, 195-199, 202, 204, 205, 207-213, 216-218, 220-243, 245-250, 252-255, 257-262, 264-270, 272, 274-298, 300, 302, 304-307 and 309-316 and the pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.