Quinazolines useful as modulators of ion channels

Abstract

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or derivative thereof, wherein: 
       R 1  and R 2 , taken together with the nitrogen atom, form a substituted ring selected from: 
     
     
       
         
         
             
             
         
       
       
         wherein, in ring (A): 
         each of m 1  and n 1  is independently 0-3, provided that m 1 +n 1  is 2-6; 
         z 1  is 0-4; 
         Sp 1  is —O—, —S—, —NR′—, or a C1-C6 alkylidene linker, wherein up to two methylene units are optionally and independently replaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO 2 —, —OCO—, —NR′CO 2 —, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO 2 —, —NR′—, —SO 2 NR′—, NR′SO 2 —, or —NR′SO 2 NR′—, provided that Sp 1  is attached to the carbonyl group through an atom other than carbon; 
       
       ring B 1  is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B 1  is optionally substituted with w 1  independent occurrences of —R 11 , wherein w 1  is 0-4; 
       wherein, in ring (B):
 G 2  is —N—, or CH; 
 each of m 2  and n 2  is independently 0-3, provided that m 2 +n 2  is 2-6; 
 p 2  is 0-2; provided that when G 2  is N, then p 2  is not 0; 
 q 2  is 0 or 1; 
 z 2  is 0-4; 
 Sp 2  is a bond or a C1-C6 alkylidene linker, wherein up to two methylene units are optionally and independently replaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO 2 —, —OCO—, —NR′CO 2 —, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO 2 —, —NR′—, —SO 2 NR′—, NR′SO 2 —, or —NR′SO 2 NR′—; 
 
       ring B 2  is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B 2  is optionally substituted with w 2  independent occurrences of —R 12 , wherein w 2  is 0-4; 
       wherein, in ring (C) or ring (D):
 G 3  is —N—, —CH—NH—, or —CH—CH 2 —NH—; 
 each of m 3  and n 3  is independently 0-3, provided that m 3 +n 3  is 2-6; 
 p 3  is 0-2; 
 z 3  is 0-4; 
 each R XX  is hydrogen, C 1-6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R XX  is optionally substituted with w 3  independent occurrences of —R 13 , wherein w 3  is 0-3; 
 
       provided that both R XX  are not simultaneously hydrogen;
 R YY  is hydrogen, —COR′, —CO 2 R′, —CON(R′) 2 , —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —COCOR′, —COCH 2 COR′, —P(O)(OR′) 2 , —P(O) 2 OR′, or —PO(R′); 
 wherein, in ring (E): 
 each of m 4  and n 4  is independently 0-3, provided that m 4 +n 4  is 2-6; 
 p 4  is 1-2; 
 z 4  is 0-4; 
 R YZ  is C 1 -C 6  aliphatic group, optionally substituted with w 4  independent occurrences of —R 14 , wherein w 4  is 0-3; 
 x and y, each, is independently 0-4; 
 each occurrence of R 11 , R 12 , R 13 , R 14 , R 3 , R 4 , and R 5  is independently Q-R X ; wherein Q is a bond or is a C 1 -C 6  alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO 2 NR—, —SO—, —SO 2 —, —PO—, —PO 2 —, —OP(O)(OR)—, or —POR—; and each occurrence of R X  is independently selected from —R′, halogen, ═O, ═NR′, —NO 2 , —CN, —OR′, —SR′, —N(R′) 2 , —NR′COR′, —NR′CON(R′) 2 , —NR′CO 2 R′, —COR′, —CO 2 R′, —OCOR′, —CON(R′) 2 , —OCON(R′) 2 , —SOR′, —SO 2 R′, —SO 2 N(R) 2 , —NR′SO 2 R′, —NR′SO 2 N(R′) 2 , —COLOR′, —COCH 2 COR′, —OP(O)(OR′) 2 , —P(O)(OR′) 2 , —OP(O) 2 OR′, —P(O) 2 OR′, —PO(R′) 2 , or —OPO(R′) 2 ; and 
 each occurrence of R is independently hydrogen or C 1-6  aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C 1-6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
     
   
   
       2 . The compound according to  claim 1 , wherein x is 1 and R 3  is present at the 6- or 7-position of the quinazoline ring. 
   
   
       3 . The compound according to  claim 1 , wherein x is 1 and R 3  is present at the 7-position of the quinazoline ring. 
   
   
       4 . The compound according to  claim 3 , wherein R 3  is selected from —Cl, —CH 3 , —CH 2 CH 3 , —F, —CF 3 , —OCF 3 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONH(cyclopropyl), —OCH 3 , —NH 2 , —OCH 2 CH 3 , or —CN. 
   
   
       5 - 9 . (canceled) 
   
   
       10 . The compound according to  claim 1 , wherein said compound has formula I-A: 
     
       
         
         
             
             
         
       
     
   
   
       11 . (canceled) 
   
   
       12 . The compound according to  claim 10 , wherein each of m 1  and n 1  is 2. 
   
   
       13 . The compound according to  claim 10 , wherein ring B 1  is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B 1  is optionally substituted with w 1  independent occurrences of —R 11 , wherein w 1  is 0-4. 
   
   
       14 - 15 . (canceled) 
   
   
       16 . The compound according to  claim 10 , wherein:
 n 1  and m 1  each is 2;   y is 0 or 1 and R 5  is fluoro;   x is 1 and R 3  is Me at 7-position or fluoro at 6-position;   z 1  is 0;   Sp 1  is —O—CH 2 —;   w 1  is 0; and   ring B 1  is tetrahydrofuran-3-yl, pyridine-3-yl, pyridine-4-yl, or tetrahydro[2H]-pyran-4-yl.   
   
   
       17 . The compound according to  claim 1 , wherein said compound has formula I-B: 
     
       
         
         
             
             
         
       
     
   
   
       18 - 22 . (canceled) 
   
   
       23 . The compound according to  claim 17 , wherein ring B 2  is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B 2  is optionally substituted with w 2  independent occurrences of —R 12 , wherein w 2  is 0-4. 
   
   
       24 . (canceled) 
   
   
       25 . The compound according to  claim 17 , wherein
 Sp 2  is a bond, O, or —O—CH 2 —;   p 2  is 1;   R is hydrogen; and   n 2  is 1 and m 2  is 2 or 3   
   
   
       26 . The compound according to  claim 17 , wherein said compound has formula I-B-i or formula I-B-ii: 
     
       
         
         
             
             
         
       
       wherein:
 m 2  is 2 or 3; and 
 Sp 2  is —O— or —O—CH 2 . 
 
     
   
   
       27 - 29 . (canceled) 
   
   
       30 . The compound according to  claim 1 , wherein said compound has formula I-C or formula I-D: 
     
       
         
         
             
             
         
       
     
   
   
       31 - 37 . (canceled) 
   
   
       38 . The compound according to  claim 30 , wherein said compound has formula I-C-i or formula I-D-i: 
     
       
         
         
             
             
         
       
     
   
   
       39 - 44 . (canceled) 
   
   
       45 . The compound according to  claim 30 , wherein said compound has formula I-C-ii: 
     
       
         
         
             
             
         
       
     
   
   
       46 - 47 . (canceled) 
   
   
       48 . The compound according to  claim 1 , wherein said compound has formula I-E: 
     
       
         
         
             
             
         
       
     
   
   
       49 - 58 . (canceled) 
   
   
       59 . The compound according to  claim 1 , wherein said compound is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       60 . A pharmaceutical composition comprising a compound according to  claim 1 . 
   
   
       61 . A method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain comprising the step of administering to said patient an effective amount of a composition according to  claim 60 . 
   
   
       62 . (canceled) 
   
   
       63 . The method of  claim 61 , wherein the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. 
   
   
       64 - 65 . (canceled)