Modulators of Rho-associated protein kinase
This invention relates to novel compounds and pharmaceutical compositions comprising. Compounds of the invention useful as modulators of Rho-associated protein kinase (ROCK), for example ROCK1 and/or ROCK2 inhibitors. Methods of treatment employing the compounds are also contemplated by the present invention. The compounds of the invention are useful in treating ROCK mediated diseases.
1. A compound of formula (I) and pharmaceutically acceptable salts thereof:
wherein
A 1 , A 2 or A 3 are each independently selected from the group consisting of C—H, C—F, C—Cl, C-Me, C-Et, C-i-Pr, C-cyclopropyl, C-ethenyl, C-propenyl, C—CN, C—CF 3 , and N;
B represents a 5 or 6 membered carbocyclic ring which is aromatic or unsaturated, a 5 or 6 membered heterocyclic ring which is aromatic or unsaturated, a 9 or 10 membered carbocyclic bicyclic ring system, or a 9 or 10 membered heterocyclic bicyclic ring system; wherein the bicyclic ring system is either aromatic or one of the rings within the bicyclic ring system is aromatic or unsaturated and the other ring is saturated;
R 1 is L-R 2 , wherein
L is a bond or -L 1 -L 2 -,
wherein L 1 is selected from the group consisting of a bond, —(CR A R B ) 1-3 —, —O(CR A R B ) 1-3 —, —(CR A R B ) 0-3 O—, and —NR C (CR A R B ) 1-3 —; and
L 2 is selected from the group consisting of a bond, —(CR A R B ) 1-3 —, —O—, —NR D —, —C(O)NR D —, —NR D C(O)—, —C(O)O—, —OC(O)—, —C(O)—, —S(O) 2 NR D —, —NR D S(O) 2 —, —S(O) 2 —, —S(O)(NR D )—, —NR D C(O)NR E —, —OC(O)NR D —, and —C(O)NR D S(O) 2 —; and
R 2 is selected from the group consisting of H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl substituted with —OR F , C 1-6 alkyl substituted with —NR F R G , C 1-4 haloalkyl substituted with —OR F , C 3-8 cycloalkyl substituted with OH, C 1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl, C 1-4 alkyl substituted with 6 membered heteroaryl, —(CR H R I ) 1-3 OR F , —(CR H R I ) 1-3 NR F R G , —(CR N R O ) 1-3 C(O)OR F , —(CR N R O ) 1-3 C(O)NR F R G , C 3-10 carbocyclic ring system, and 3 to 10 membered heterocyclic ring system; wherein the carbocyclic ring or heterocyclic ring system is unsubstituted or substituted with: ═O, —NR F R G , —C(O)R F , halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkyl substituted with —OR F ;
R 4 is independently selected at each occurrence from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, —CN, C 1-4 alkyl substituted with —OR J , C 1-4 alkyl substituted with —NR J R K , and 3 to 8 membered heterocycloalkyl;
R 5 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkyl substituted with —OR F , C 1-4 alkyl substituted with —NR L R L , C 3-8 cycloalkyl, substituted or unsubstituted phenyl, C 1-4 alkyl substituted with a 3 to 8 membered heterocycloalkyl, and substituted or unsubstituted 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl group may be substituted by 1 or 2 R 9 ;
R 6 is selected from the group consisting of H and methyl;
R 8 is selected from the group consisting of H, Cl, F, CN, and Me;
R 9 is selected from the group consisting of halo and C 1-4 alkyl;
n is 0, 1, or 2;
R A and R B are selected from the group consisting of H, C 1-4 alkyl, and C 1-4 haloalkyl; or R A and R B together with the atom to which they are attached form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring;
R C , R D , R E , R F and R G are each independently selected from the group consisting of H, C 1-4 alkyl, and C 1-4 haloalkyl;
R H and R I are each H except one pair of R H and R I on the same carbon atom, together with that carbon atom, form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring; and
R J , R K , R L , R M , R N and R O are each independently at each occurrence selected from the group consisting of H and C 1-4 alkyl.
2. The compound of claim 1 , wherein A 1 is selected from the group consisting of C—H, C—F, C—Cl, C-Me, C-Et, C-i-Pr, C-cyclopropyl, C—CN, C—CF 3 , and N.
3. The compound of claim 1 , wherein A 2 is selected from the group consisting of C—H and C—F.
4. The compound of claim 1 , wherein A 3 is C—H.
5. The compound of claim 1 , wherein R 8 is selected from the group consisting of H and Me.
6. The compound of claim 1 wherein R 6 is H.
7. The compound of claim 1 , wherein
is selected from the group consisting of
8. The compound of claim 1 , wherein the compound is represented by formula (Ia):
wherein m is 1 or 2; and
R 7 is selected independently for each occurrence from the group consisting of H, F, Cl, Me, Et, i-Pr, cyclopropyl, ethenyl, propenyl, CN and CF 3 .
9. The compound of claim 1 , wherein
is selected from the group consisting of
10. The compound of claim 1 , wherein B is selected from the group consisting of a 6 membered carbocyclic ring, and a 10 membered heterocyclic fused bicyclic ring system.
11. The compound of claim 1 , wherein B is selected from the group consisting of phenyl, pyrazole, pyridyl, piperidyl, azaindole, isoindoline, tetrahydroisoquionoline, tetrahydroisoquinolone, furan, indazole, benzpyrazole, pyrimidine, pyridone, tetrahydropyridine, dihydropyran, cyclopentene, cyclohexenyl, chromane, chromanone, benzodioxan, tetrahydronapthalene, dihydrobenzoxazine, benzomorpholine, tetrahydroquinoline, napthyridine, quinoline, isoquinoline, and dihydroisobenzofuran; or B is:
12. The compound of claim 1 , wherein
is selected from the group consisting of
13. The compound of claim 1 , wherein L 1 is selected from the group consisting of a bond, —(CR A R B ) 1-3 —, and —O(CR A R B ) 1-3 —.
14. The compound of claim 1 , wherein L 2 is selected from the group consisting of a bond, —NR D —, —C(O)NR D —, —NR D C(O)—, —C(O)O—, —C(O)—, —NR D C(O)NR E —, and —OC(O)NR D —.
15. The compound of claim 1 , wherein R A and R B are independently selected from the group consisting of H, C 1-4 alkyl, and C 1-4 haloalkyl; and/or R C and R D are independently selected from H and methyl.
16. The compound of claim 1 , wherein R 2 is selected from the group consisting of H, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, sec-butyl, tert-pentyl, allyl, propargyl, difluoroethyl, difluoropropyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, isopropanol, n-butanol, sec-butanol, propanol, tert-butanol, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, aziridinyl, N-acetylaziridinyl, N-alkylaziridinyl, azetidinyl, N-acetylazetidinyl, N-alkylazetidinyl, 2-methylpropan-2-amine, phenyl, chlorophenyl, pyrrolidinyl, difluoropyrrolidinyl, trifluoroethylpyrrolidinyl, N-methylpyrrolidinyl, tetrahydrofuranyl, sulfolanyl, dihydropyran, tetrahydropyranyl, tetrahydropyranoimidazolyl, morpholinyl, imidazolyl, ethyltetrahydroimidazopyridine, methylimidazolyl, piperazinyl, N-methylpiperazinyl, trifluoromethylpiperazinyl, oxadiazolyl, dimethyldihydrooxazolyl, pyrazolyl, N-methylpyrazolyl, ethylpyrazolyl, 4-pyridone, 2-pyridone, pyridyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with —NMe 2 , ethyl substituted with OMe, and ethyl substituted with OH; or R 2 is selected from the group consisting of
17. The compound of claim 1 , wherein R 4 is selected from the group consisting of F, Cl, methyl, CF 3 , Et, iPr, CN, OH, OMe, Oi-Pr, ═O, CH 2 OH, CH 2 OMe, NH 2 , NMe 2 , CH 2 NH 2 , CH 2 NMe 2 , and morpholinyl.
18. The compound of claim 1 , wherein R 5 is selected from H and methyl.
19. A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 , further comprising an additional pharmaceutically active agent.