Arylpyrrolopyridine derived compounds as LRRK2 inhibitors

Abstract

The present invention is directed to arylpyrrolopyridine derivatives of formula (A) The compounds are considered useful for the treatment of diseases associated with LRRK2 such as Lewy body dementia, Parkinson's disease or cancer.

1 . A compound of formula A 
       
         
           
           
               
               
           
         
         wherein 
         R1 is H or a NHR2 group, 
         R2 is H or a 5 or 6 membered heteroaromatic ring with 1 or 2 N, which heteroaromatic ring is optionally substituted with 1 or 2 groups each independently selected from the group comprising CF 3 , halogen, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkylamine or C 1 -C 3  alkoxy amine, 
         R3 is a 5 or 6 membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2 heteroatoms(s) selected from S or N, which aromatic ring or heteroaromatic ring is optionally substituted with H, OH, 1 or 2 C 1 -C 3  alkyl, 1 or 2 C 1 -C 3  alkoxy or a trifluoromethyl, 
         L is absent or represents (CH 2 ) n , n=1 or 2, 
         R4 is H, NH 2  or a 5 or 6 membered heterocylic ring with 1 or 2 heteroatom(s) selected from N or O, which heterocyclic ring is optionally substituted with 1 or 2 C 1 -C 3  alkyl, 1 or 2 C 2 -C 3  alkoxy, 1 or 2 C 1 -C 3  alkyl amine or 1 or 2 C 2 -C 3  alkoxy amine; 
         or a pharmaceutically acceptable salt thereof; 
         with the proviso that the compound is not selected from 
         4-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 
         4-(3-Hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile or 
         4-(2,4-Dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. 
       
     
     
         2 . The compound according to  claim 1 , wherein R2 is H or a 5 or 6 membered heteroaromatic ring with 1 or 2 N, which heteroaromatic ring is optionally substituted with 1 or 2 C 1 -C 3  alkyl, 1 or 2 C 1 -C 3  alkoxy, 1 or 2 C 1 -C 3  alkylamine or 1 or 2 C 1 -C 3  alkoxy amine. 
     
     
         3 . The compound according to  claim 1 , wherein R2 is a heteroaromatic ring selected from the group consisting of 
       
         
           
           
               
               
           
         
         optionally substituted with 1 or 2 groups each independently selected from the group consisting of CF 3 , halogen, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkylamine and C 1 -C 3  alkoxy amine, and * denotes the attachment point. 
       
     
     
         4 . The compound according to  claim 1 , wherein R3 is an aromatic ring selected from the group consisting of 
       
         
           
           
               
               
           
         
         R5 represent H, C 1 -C 3  alkyl or C 1 -C 3  alkoxy; and 
         * denotes the attachment point. 
       
     
     
         5 . The compound according to  claim 1 , wherein R3-L-R4 is selected from the group consisting of 
       
         
           
           
               
               
           
         
         R5 and R6 are each independently H, C 1 -C 3  alkyl or C 1 -C 3  alkoxy; and 
         * denotes the attachment point. 
       
     
     
         6 . The compound according to  claim 1 , wherein R4 is 
       
         
           
           
               
               
           
         
       
       and
 * denotes the attachment point. 
 
     
     
         7 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of
 4-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-(3-Methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-(3-Ethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-(Thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[4-(Morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[1-(Morpholin-4-ylmethyl)pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-{4-[(Dimethylamino)methyl]-3-methylphenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[3-Ethyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[3-Methoxy-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-Amino-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-Amino-4-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-[(1-Methylpyrazol-3-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-(3-Methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-[(1-Methylpyrazol-4-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   4-Phenyl-6-(pyridin-2-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   6-[(1-Methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; and   6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 1  and one or more pharmaceutically acceptable carriers or diluents. 
     
     
         9 . A method of treating a patient having a disease or disorder characterised by over-expression of LRRK2 or a mutated form of LRRK2 such as G2019S, I2020T, M1646T, G2385R, A419V, N551K, R1398H, K1423K, R1441G, R1441H, R1441C, R1628P, S1647T, Y1699C, I2020T or Y2189C comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
         10 . A method of treating a patient having Lewy body dementia comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
         11 . A method of treating a patient having Parkinson's disease comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
         12 . The method of  claim 11 , wherein the Parkinson's disease is idiopathic Parkinson's disease, sporadic Parkinson's disease or Parkinson's disease in a patient carrying a G2019S mutation in LRRK2. 
     
     
         13 . A method of treating a patient having cancer or an immune related disorder comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient, wherein the cancer or immune related disorder is characterised by over-expression of LRRK2 or a mutated form of LRRK2 such as G2019S, I2020T, M1646T, G2385R, A419V, N551K, R1398H, K1423K, R1441G, R1441H, R1441C, R1628P, S1647T, Y1699C, I2020T or Y2189C. 
     
     
         14 . The method of  claim 13 , wherein the patient has cancer in the brain, lungs, kidney, spleen or blood organs. 
     
     
         15 . The method of  claim 13 , wherein the patient has renal cancer, lung cancer, skin cancer, papillary renal and thyroid carcinomas. 
     
     
         16 . The method of  claim 9 , wherein the patient has Crohn's disease, ulcerative colitis or leprosy.