Novel quinoline derivatives and their use in neurodegenerative diseases

Abstract

The present invention relates to quinoline compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of P2X7, and for the treatment of P2X7-related disorders.

1 - 16 . (canceled) 
     
     
         17 . A method for treating a P2X7-mediated disease or disorder in a subject in need thereof, comprising the step of administering to said subject a compound of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen, C 1-6  aliphatic, C 5-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused 7-10 membered bicyclic saturated, partially unsaturated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of R A ; or R 1  is —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         each R A  is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         wherein when R 1  is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, then R A  is —R, halogen, -haloalkyl, -hydroxyalkyl, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         wherein when R 1  is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, and R A  is —OR, then at least one R 2  is halogen; 
         Z is O, S, SO 2 , SO, C(O), CO 2 , C(O)N(R), NRC(O), NRC(O)N(R), NRSO 2 , or N(R); 
         Ring A is a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R 2  is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or two R 2  groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         each R is independently hydrogen, C 1-6  aliphatic, C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         m is 0, 1, or 2; and 
         n is 1, 2, 3, 4, or 5; 
         wherein, at least one of R A  or R 2  is halogen or haloalkyl, or at least one R 2  is —OR; and 
         wherein, the following compounds are excluded: 
         6-chloro-N-{[(1S,3 S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3S)-3-hydroxypyrrolidin-1-yl]quinoline-5-carboxamide; 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3R)-3-hydroxypyrrolidin-1-yl]quinoline-5-carboxamide; 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-(4-hydroxypiperidin-1-yl]quinoline-5-carboxamide; and 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-(3-hydroxy-3-methylpyrrolidin-1-yl]quinoline-5-carboxamide. 
       
     
     
         18 . The method of  claim 17 , wherein the disease or disorder is Parkinson's disease, multiple sclerosis (MS); Alzheimer's disease, traumatic brain injury, encephalitis; depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders, cognition disorders; epilepsy, seizure disorders; urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy, inflammatory bowel disease; allergic rhinitis, asthma, reactive airway disease, chronic obstructive pulmonary disease; rheumatoid arthritis, osteoarthritis, myocardial infarction, uveitis, atherosclerosis; or psoriasis. 
     
     
         19 . A method for treating multiple sclerosis in a subject, comprising the step of administering to said subject a compound of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen, C 1-6  aliphatic, C 5-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused 7-10 membered bicyclic saturated, partially unsaturated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of R A ; or R 1  is —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         each R A  is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         wherein when R 1  is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, then R A  is —R, halogen, -haloalkyl, -hydroxyalkyl, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         wherein when R 1  is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, and R A  is —OR, then at least one R 2  is halogen; 
         Z is O, S, SO 2 , SO, C(O), CO 2 , C(O)N(R), NRC(O), NRC(O)N(R), NRSO 2 , or N(R); 
         Ring A is a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R 2  is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or two R 2  groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         each R is independently hydrogen, C 1-6  aliphatic, C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         m is 0, 1, or 2; and 
         n is 1, 2, 3, 4, or 5; 
         wherein, at least one of R A  or R 2  is halogen or haloalkyl, or at least one R 2  is —OR; and 
         wherein, the following compounds are excluded: 
         6-chloro-N-{[(1S,3 S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3S)-3-hydroxypyrrolidin-1-yl]quinoline-5-carboxamide; 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3R)-3-hydroxypyrrolidin-1-yl]quinoline-5-carboxamide; 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-(4-hydroxypiperidin-1-yl]quinoline-5-carboxamide; and 
         6-chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-(3-hydroxy-3-methylpyrrolidin-1-yl]quinoline-5-carboxamide. 
       
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 17 , wherein at least one of R A  or R 2  is F, or at least one of R 2  is OH. 
     
     
         22 . The method of  claim 17 , wherein R 1  is hydrogen. 
     
     
         23 . The method of  claim 17 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 17 , wherein R 1  is C 5-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused 7-10 membered bicyclic saturated, partially unsaturated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of R A . 
     
     
         25 . The method of  claim 17 , wherein R 1  is —OR, —SR, —SO 2 R, —SOR, —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 . 
     
     
         26 . The method of  claim 17 , wherein Z is C(O)N(R). 
     
     
         27 . The method of  claim 17 , wherein Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, oxetanyl, or azetidinyl. 
     
     
         28 . The method of  claim 17 , wherein Ring A is cyclohexyl or cycloheptyl. 
     
     
         29 . The method of  claim 17 , wherein each R 2  is independently H. 
     
     
         30 . The method of  claim 17 , wherein each R 2  is independently methyl, F, CF 3 , or OH. 
     
     
         31 . The method of  claim 17 , wherein the compound is formula II, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . The method of  claim 17 , wherein the compound is formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 17 , wherein the compound is selected from Table 1.