Modulators of muscarinic receptors

Abstract

The modulator compounds described herein modulate muscarinic receptors and are useful for treating muscarinic receptor mediated diseases.

1 . A compound of Formula I, 
     
       
         
         
             
             
         
       
     
     wherein:
 Ring A is aryl or heteroaryl; 
 One of V, W, Y or Z is nitrogen and the other of V, W, Y and Z are —C(R 5 )—; 
 Each R 1  is independently selected from H, aliphatic, cycloaliphatic, heteroaliphatic and heterocycle, wherein each of the aliphatic, cycloaliphatic, heteroaliphatic and heterocycle is optionally substituted with 1-3 Ra; 
 Each R 2  is independently selected from H, aryl, heteroaryl, aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, —C(O)Rc, and —S(O) 2 Rc, wherein each aliphatic, cycloaliphatic, heteroaliphatic and heterocycle is optionally substituted with 1-3 Ra, and wherein each aryl and heteroaryl is optionally substituted with 1-3 Rb, or
 R 1  and R 2  together with the nitrogen to which they are attached may form a heterocyclic ring or a heteroaryl ring each optionally substituted with 1-3 Ra; 
 
 Each R 3  is independently H, halo, haloaliphatic, aliphatic, —ORd, or —S(O) i Rd; 
 Each R 4  is independently selected from H, halogen, —CN, —OH, —NO 2 , —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —N(Rd)C(O)Rd, —N(Rd)C(O)ORd, —OC(O)ORd, —OC(O)NRd, —N(Rd)S(O) 2 Rd, aliphatic optionally substituted with 1-3 Ra, and any two adjacent R 4  on Ring A together with the atoms to which they are attached may be taken together to form a heterocyclic or carbocyclic ring; 
 Each R 5  is independently selected from H, halogen, —CN, —OH, —NO 2 , —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —N(Rd)C(O)Rd, —N(Rd)C(O)ORd, —OC(O)ORd, —OC(O)NRd, —N(Rd)S(O) 2 Rd, aliphatic optionally substituted with 1-3 of Ra, and any two adjacent R 5  together with the atoms to which they are attached may be taken together to form a heterocyclic or carbocyclic ring; 
 Each Ra is independently selected from aryl, heteroaryl, halogen, —CN, —OH, —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —NRdC(O)Rd, —N(Rd)C(O)ORd, —N(Rd)C(O)N(Rd) 2 , —OC(O)ORd, —OC(O)N(Rd) 2 , ═N—OH, ═NORd, ═N═N(Rd) 2 , ═O, ═S, —S(O) 2 N(Rd) 2 , —N(Rd)S(O) 2 Rd, —N(Rd)S(O) 2 N(Rd) 2  and —S(O) i Rd; 
 Each Rb is independently selected from halo, aryl, —OH, —ORd, —S(O) i Rd, —N(Rd) 2 , —NRdC(O)Rd, —NRdC(O)ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —S(O) i N(Rd) 2 , —CN, and —NO 2 ; 
 Each Rc is independently selected from H, aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, —ORd, and —N(Rd) 2 , wherein the aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, aryl, and heteroaryl are optionally substituted with 1-3 of Ra; 
 Each Rd is independently selected from H, aliphatic, heteroaliphatic, heterocycle, cycloaliphatic, aryl, heteroaryl, wherein each of aliphatic, heteroaliphatic, heterocycle, cycloaliphatic, aryl, heteroaryl may be optionally substituted with 1-3 of halo, aryl, —OH, —Oaliphatic, —Oaryl, —Oacyl, —NH 2 , —N(aliphatic) 2 , —N(aryl) 2 , —S(O) i aliphatic, or —S(O) i aryl; 
 n is 0 to 3; and 
 i is 0 to 2; and provided 
 (i) when A is 2-trifluoromethylphenyl, one of Z or Y is N and the remaining of W, V, Y, or Z is —C(H)—, R 3  is H, and R 1  is H, then R 2  is not indazolyl, pyrazolyl, or triazolyl each optionally substituted with aliphatic, phenyl, and —C(O)O-aliphatic; 
 (ii) when A is phenyl, V is N and W, Y and Z are —C(H)—, R 3  is H, that R 1  and R 2  together with the nitrogen to which they are bound do not form piperidine optionally substituted with —C(O)O-aliphatic, —C(O)N(H)-aliphatic, or —C(O)OH; 
 (iii) when A is phenyl, V is N and W, Y and Z are —C(H)—, R 3  is H, and R 1  is H, that R 2  is not —CH 2 -piperidine; 
 (iv) when A is phenyl optionally substituted with one R 4 , Z is N, V and W are —C(H)—, and R 3  is H, that Y is other than —C(aliphatic)-; 
 (v) when A is phenyl optionally substituted with one R 4 , Z is N, Y and V are —C(H)—, and R 3  is H, that W is other than —C(aliphatic)-; and 
 (vi) when A is pyridinyl, Z is N, R 1  is H, R 3  is H, and V, W, and Y are —C(H)—, that R 2  is not —(CH 2 ) 2 —N(aliphatic) 2 . 
 
   
   
       2 . The compound of  claim 1 , wherein one of W, Y, Z and V is N and the other of W,Y,Z and V is C—R. 
   
   
       3 . The compound of  claim 2 , wherein W is N and Y, Z and V are C—R 5 . 
   
   
       4 . The compound of  claim 3 , wherein one of R 1  and R 2  is H. 
   
   
       5 . The compound of  claim 4 , wherein both of R 1  and R 2  are H. 
   
   
       6 . The compound of  claim 4 , wherein A is aryl. 
   
   
       7 . The compound of  claim 5 , wherein R 4  is selected from the group consisting of halogen,
 —ORd, and aliphatic optionally substituted with 1-3 of Ra.   
   
   
       8 . The compound of  claim 7 , wherein R 4  is —Oaliphatic or haloaliphatic. 
   
   
       9 . A compound selected from the group consisting of 
     2-Phenyl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-Benzo[1,3]dioxol-5-yl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Chloro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-m-Tolyl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Trifluoromethyl-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Fluoro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Chloro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Methoxy-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-p-Tolyl-[1,6]naphthyridin-4-ylamine, 
     2-(4-Trifluoromethyl-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(3-Fluoro-phenyl)-[1,6]naphthyridin-4-ylamine, and 
     2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[1,6]naphthyridin-4-ylamine. 
   
   
       10 . The compound of  claim 2 , wherein Y is N and W, Z and V are C—R 5 . 
   
   
       11 . The compound of  claim 10 , wherein R 1 , R 2  and R 5  are H. 
   
   
       12 . The compound of  claim 9 , wherein A is aryl. 
   
   
       13 . The compound of  claim 13 , wherein R 4  is selected from the group consisting of halogen, —ORd, and aliphatic optionally substituted with 1-3 of Ra. 
   
   
       14 . The compound of  claim 13 , wherein R 4  is —Oaliphatic or haloaliphatic. 
   
   
       15 . A compound selected from the group consisting of 
     2-Phenyl-[1,7]naphthyridin-4-ylamine, 
     2-(3-Chloro-phenyl)-[1,7]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,7]naphthyridin-4-ylamine, and 
     2-Benzo[1,3]dioxol-5-yl-[1,7]naphthyridin-4-ylamine. 
   
   
       16 . The compound of  claim 2 , wherein Z is N and Y,W and V are C—R 5 . 
   
   
       17 . The compound of  claim 16 , wherein R 1  and R 2  are H. 
   
   
       18 . The compound of  claim 17 , wherein A is aryl. 
   
   
       19 . The compound of  claim 16 , wherein R 4  is selected from the group consisting of halogen,
 —ORd, and aliphatic optionally substituted with 1-3 of Ra.   
   
   
       20 . The compound of  claim 19 , wherein R 4  is —Oaliphatic or haloaliphatic. 
   
   
       21 . A compound selected from the group consisting of 
     2-Phenyl-[1,8]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,8]naphthyridin-4-ylamine, 
     2-Benzo[1,3]dioxol-5-yl-[1,8]naphthyridin-4-ylamine, and 
     2-(3-Chloro-phenyl)-[1,8]naphthyridin-4-ylamine. 
   
   
       22 . The compound of  claim 1 , wherein A is heteroaryl. 
   
   
       23 . A compound selected from the group comprising 
     2-Pyridin-2-yl-[1,6]naphthyridin-4-ylamine, 
     2-Pyridin-2-yl-[1,7]naphthyridin-4-ylamine, and 
     2-Pyridin-2-yl-[1,8]naphthyridin-4-ylamine. 
   
   
       24 . A method of modulating activity of a muscarinic receptor, comprising the step of contacting said receptor with a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 Ring A is aryl or heteroaryl; 
 One of V, W, Y or Z is nitrogen and the other of V, W, Y and Z are —C(R 5 )—; 
 Each R 1  is independently selected from H, aliphatic, cycloaliphatic, heteroaliphatic and heterocycle, wherein each of the aliphatic, cycloaliphatic, heteroaliphatic and heterocycle is optionally substituted with 1-3 Ra; 
 Each R 2  is independently selected from H, aryl, heteroaryl, aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, —C(O)Rc, and —S(O) 2 Rc, wherein each aliphatic, cycloaliphatic, heteroaliphatic and heterocycle is optionally substituted with 1-3 Ra, and wherein each aryl and heteroaryl is optionally substituted with 1-3 Rb, or
 R 1  and R 2  together with the nitrogen to which they are attached may form a heterocyclic ring or a heteroaryl ring each optionally substituted with 1-3 Ra; 
 
 Each R 3  is independently H, halo, haloaliphatic, —CN, aliphatic, —ORd, or —S(O) i Rd; 
 Each R 4  is independently selected from H, halogen, —CN, —OH, —NO 2 , —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —N(Rd)C(O)Rd, —N(Rd)C(O)ORd, —OC(O)ORd, —OC(O)NRd, —N(Rd)S(O) 2 Rd, aliphatic optionally substituted with 1-3 Ra, and any two adjacent R 4  on Ring A together with the atoms to which they are attached may be taken together to form a heterocyclic or carbocyclic ring; 
 Each R 5  is independently selected from H, halogen, —CN, —OH, —NO 2 , —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —N(Rd)C(O)Rd, —N(Rd)C(O)ORd, —OC(O)ORd, —OC(O)NRd, —N(Rd)S(O) 2 Rd, aliphatic optionally substituted with 1-3 of Ra, and any two adjacent R 5  together with the atoms to which they are attached may be taken together to form a heterocyclic or carbocyclic ring; 
 Each Ra is independently selected from aryl, heteroaryl, halogen, —CN, —OH, —ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —N(Rd) 2 , —NRdC(O)Rd, —N(Rd)C(O)ORd, —N(Rd)C(O)N(Rd) 2 , —OC(O)ORd, —OC(O)N(Rd) 2 , ═N—OH, ═NORd, ═N═N(Rd) 2 , ═O, ═S, —S(O) 2 N(Rd) 2 , —N(Rd)S(O) 2 Rd, —N(Rd)S(O) 2 N(Rd) 2  and —S(O) i Rd; 
 Each Rb is independently selected from halo, aryl, —OH, —ORd, —S(O) i Rd, —N(Rd) 2 , —NRdC(O)Rd, —NRdC(O)ORd, —C(O)Rd, —C(O)ORd, —C(O)N(Rd) 2 , —S(O) i N(Rd) 2 , —CN, and —NO 2 ; 
 Each Rc is independently selected from H, aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, —ORd, and —N(Rd) 2 , wherein the aliphatic, cycloaliphatic, heteroaliphatic, heterocycle, aryl, and heteroaryl are optionally substituted with 1-3 of Ra; 
 Each Rd is independently selected from H, aliphatic, heteroaliphatic, heterocycle, cycloaliphatic, aryl, heteroaryl, wherein each of aliphatic, heteroaliphatic, heterocycle, cycloaliphatic, aryl, heteroaryl may be optionally substituted with 1-3 of halo, aryl, —OH, —Oaliphatic, —Oaryl, —Oacyl, —NH 2 , —N(aliphatic) 2 , —N(aryl) 2 , —S(O) i aliphatic, or —S(O) i aryl; 
 n is 0 to 3; and 
 i is 0 to 2. 
 
   
   
       25 . The method of  claim 24 , wherein W is N and Y, Z and V are C—R 5 . 
   
   
       26 . The method of  claim 24 , wherein one of R 1  and R 2  is H. 
   
   
       27 . The method of  claim 26 , wherein both of R 1  and R 2  are H. 
   
   
       28 . The method of  claim 24 , wherein R 4  is selected from the group consisting of halogen, —ORd, and aliphatic optionally substituted with 1-3 of Ra. 
   
   
       29 . The method of  claim 28 , wherein R 4  is —Oaliphatic or haloaliphatic. 
   
   
       30 . The method of  claim 24 , wherein Ring A is aryl optionally substituted with 1-4 of R 4 . 
   
   
       31 . The method of  claim 24 , wherein Ring A is heteroaryl optionally substituted with 1-4 of R 4 . 
   
   
       32 . The method of  claim 24 , wherein the compound is selected from the group consisting of 
     2-Phenyl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-Benzo[1,3]dioxol-5-yl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Chloro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-m-Tolyl-[1,6]naphthyridin-4-ylamine, 
     2-(3-Trifluoromethyl-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Fluoro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Chloro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(4-Methoxy-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-p-Tolyl-[1,6]naphthyridin-4-ylamine, 
     2-(4-Trifluoromethyl-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(3-Fluoro-phenyl)-[1,6]naphthyridin-4-ylamine, 
     2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[1,6]naphthyridin-4-ylamine. 
     2-Phenyl-[1,7]naphthyridin-4-ylamine, 
     2-(3-Chloro-phenyl)-[1,7]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,7]naphthyridin-4-ylamine, 
     2-Benzo[1,3]dioxol-5-yl-[1,7]naphthyridin-4-ylamine, 
     2-Phenyl-[1,8]naphthyridin-4-ylamine, 
     2-(3-Methoxy-phenyl)-[1,8]naphthyridin-4-ylamine, 
     2-Benzo[1,3]dioxol-5-yl-[1,8]naphthyridin-4-ylamine, 
     2-(3-Chloro-phenyl)-[1,8]naphthyridin-4-ylamine. 
     2-Pyridin-2-yl-[1,6]naphthyridin-4-ylamine, 
     2-Pyridin-2-yl-[1,7]naphthyridin-4-ylamine, and 
     2-Pyridin-2-yl-[1,8]naphthyridin-4-ylamine. 
   
   
       33 . A pharmaceutical composition comprising a compound a compound according to  claim 1  and a pharmaceutical carrier. 
   
   
       34 . A method of treating or reducing the severity of a muscarinic receptor mediated disease in a mammal, comprising the step of administering to said mammal a compound as described in  claim 1  or a composition according to  claim 33 . 
   
   
       35 . The method of  claim 34 , wherein said receptor is M 1 . 
   
   
       36 . A method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis associated with CNS disorders including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances, and wound healing, wherein said method comprises the step of contacting said patient with a compound as described in  claim 1  or a composition according to  claim 33 .