Modulators of Rho-associated protein kinase
This invention relates to novel compounds and pharmaceutical compositions comprising the same. 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 CH, CR 7 or N;
B represents a 5 to 10 membered carbocyclic ring system or a 5 to 10 membered heterocyclic ring system;
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 1-6 haloalkyl, —CN, —OR J , ═O, C 1-4 alkyl substituted with —OR J , —NR J R K , C 1-4 alkyl substituted with —NR J R K , C 3-8 cycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl and C 1-4 alkyl substituted with 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 L , C 1-4 alkyl substituted with —NR L R L , C 3-8 cycloalkyl, substituted or unsubstituted phenyl, 3 to 8 membered heterocycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with 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 C 1-4 alkyl;
R 7 is selected from the group consisting of H, halo, —OR M , C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkenyl, —CN, and C 3-8 cycloalkyl;
R 8 is selected from the group consisting of H, halo, C 1-4 alkyl, C 1-6 haloalkyl, —CN, and C 3-8 cycloalkyl;
R 9 is selected from the group consisting of halo or 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, or 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 or C 1-4 alkyl.
2. The compound of claim 1 , wherein A 1 , A 2 and 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 or N.
3. The compound of claim 1 , wherein R 8 is selected from the group consisting of H, Cl, F, CN or Me.
4. The compound of claim 1 wherein R 6 is selected from the group consisting of H or methyl.
5. The compound of claim 1 , wherein
is selected from the group consisting of
6. The compound of claim 1 , wherein
is selected from the group consisting of
7. The compound of claim 1 , wherein the compound is represented by formula (Ia):
wherein m is 1 or 2.
8. The compound of claim 1 , wherein R 5 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkyl substituted with —OR L , 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 .
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 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.
11. 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.
12. 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:
13. The compound of claim 1 , wherein
is selected from the group consisting of
14. 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 —.
15. 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 —.
16. 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 is independently selected from H and methyl.
17. 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, ethyl substituted with OH; or selected from the group consisting of
18. 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 , or morpholinyl.
19. The compound of claim 1 , wherein the compound is selected from the group consisting of
20. A pharmaceutical composition comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
21. The pharmaceutical composition of claim 20 , further comprising an additional pharmaceutically active agent.
22. A method of treating a condition which is modulated by ROCK1 and/or ROCK2, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of formula (I):
wherein
A 1 , A 2 or A 3 are each independently selected from the group consisting of CH, CR 7 or N;
B represents a 5 to 10 membered carbocyclic ring system or a 5 to 10 membered heterocyclic ring system;
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 G ) 1-3C (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 1-6 haloalkyl, —CN, —OR J , ═O, C 1-4 alkyl substituted with —OR J , —NR J R K , C 1-4 alkyl substituted with —NR J R K , C 3-8 cycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl and C 1-4 alkyl substituted with 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 L , C 1-4 alkyl substituted with —NR L R L , C 3-8 cycloalkyl, substituted or unsubstituted phenyl, 3 to 8 membered heterocycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with 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 C 1-4 alkyl;
R 7 is selected from the group consisting of H, halo, —OR M , C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkenyl, —CN, and C 3-8 cycloalkyl;
R 8 is selected from the group consisting of H, halo, C 1-4 alkyl, C 1-6 haloalkyl, —CN, and C 3-8 cycloalkyl;
R 9 is selected from the group consisting of halo or 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, or 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 or C 1-4 alkyl.
23. The method of claim 22 , wherein the condition is treatable by inhibition of ROCK1 and/or ROCK2.
24. A method of treating a condition selected from the group consisting of fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of formula (I):
wherein
A 1 , A 2 or A 3 are each independently selected from the group consisting of CH, CR 7 or N;
B represents a 5 to 10 membered carbocyclic ring system or a 5 to 10 membered heterocyclic ring system;
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 G ) 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 1-6 haloalkyl, —CN, —OR J , ═O, C 1-4 alkyl substituted with —OR J , —NR J R K , C 1-4 alkyl substituted with —NR J R K , C 3-8 cycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl and C 1-4 alkyl substituted with 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 L , C 1-4 alkyl substituted with —NR L R L , C 3-8 cycloalkyl, substituted or unsubstituted phenyl, 3 to 8 membered heterocycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with 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 C 1-4 alkyl;
R 7 is selected from the group consisting of H, halo, —OR M , C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkenyl, —CN, and C 3-8 cycloalkyl;
R 8 is selected from the group consisting of H, halo, C 1-4 alkyl, C 1-6 haloalkyl, —CN, and C 3-8 cycloalkyl;
R 9 is selected from the group consisting of halo or 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, or 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 or C 1-4 alkyl.
25. The method of claim 22 wherein the condition is selected from the group consisting of Idiopathic Pulmonary Fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; Nonalcoholic Steatohepatitis (NASH); Nonalcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia/reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, stenosis of the bowel, disorders involving neuronal degeneration or physical injury to neural tissue, Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.