Substituted quinolin-4-ylamine analogues

Abstract

Substituted quinolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
     
     at least one of Y and Z is N; and the other of Y and Z is N or CR 1 ; 
     R 1  is hydrogen, halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or mono- or di-(C 1 -C 4 alkyl)amino; 
     R 2  is: (i) hydrogen, halogen or cyano;
 (ii) a group of the formula —R c -M-A-R y , wherein:
 R c  is C 0 -C 3 alkyl or is joined to R y  or R z , to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 2 substituents independently chosen from R b ; 
 M is a single covalent bond, O, S, SO 2 , C(═O), OC(═O), C(═O)O, O—C(═O)O, C(═O)N(R z ), OC(═O)N(R z ), N(R z )C(═O), N(R z )SO 2 , SO 2 N(R z ) or N(R z ); 
 A is a single covalent bond or C 1 -C 8 alkyl substituted with from 0 to 3 substituents independently chosen from R b ; and 
 R y  and R z , if present, are:
 (a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 2 -C 8 alkenyl, a 4-to 10-membered carbocycle or heterocycle, or joined to R c  to form a 4- to 10-membered carbocycle or heterocycle, wherein each non-hydrogen R y  and R z  is substituted with from 0 to 6 substituents independently chosen from R b ; or 
 (b) joined to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 6 substituents independently chosen from R b ;
 such that R 2  is not —NH 2 ; or 
 
 
 
 (iii) taken together with R 7  to form a fused 5- to 7-membered ring that is substituted with from 0 to 3 substituents independently chosen from oxo and C 1 -C 4 alkyl; 
 
     R 7  is hydrogen, COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl or taken together with R 2  to form a fused, optionally substituted ring; 
     Ar 1  is phenyl or 6-membered heteroaryl, each of which is unsubstituted or substituted ortho to the point of attachment with 1 or 2 substituents independently chosen from groups of the formula LR a ; 
     Ar 2  is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from oxo and groups of the formula LR a ; 
     L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O) m , N(R x ), C(═O)N(R x ), N(R x )C(═O), N(R x )S(O) m , S(O) m N(R x ) and N[S(O) m R w ]S(O) m ; wherein m is independently selected at each occurrence from 0, 1 and 2; R x  is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl and C 1 -C 6 alkylsulfonyl; and R w  is hydrogen or C 1 -C 6 alkyl; 
     R a  is independently selected at each occurrence from:
 (i) hydrogen, halogen, cyano and nitro; and 
 (ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkyl ether, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 0 -C 6 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R b ; and 
 
     R b  is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkanoyl, C 1 -C 8 alkanoyloxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl ether, C 1 -C 8 hydroxyalkyl, C 1 -C 8 haloalkyl, phenylC 0 -C 8 alkyl, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, C 1 -C 8 alkylsulfonyl and (4- to 7-membered heterocycle)C 0 -C 8 alkyl. 
   
   
       2 . A compound or salt according to  claim 1 , wherein Z is N. 
   
   
       3 . A compound or salt according to  claim 1 , wherein Y is N. 
   
   
       4 . A compound or salt according to  claim 2 , wherein Y is CH. 
   
   
       5 . A compound or salt according to  claim 1 , wherein Y and Z are N. 
   
   
       6 . A compound or salt according to  claim 1 , wherein Ar 2  is phenyl or a 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently selected from (a) groups of the formula LR a  and (b) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from R b . 
   
   
       7 . (canceled) 
   
   
       8 . (canceled) 
   
   
       9 . A compound or salt according to  claim 6 , wherein Ar 1  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is unsubstituted or substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy. 
   
   
       10 . A compound or salt according to  claim 9 , wherein:
 Ar 1  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl substituted with halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and   Ar 2  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is substituted with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkanoyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkylsulfonyl or C 1 -C 4 haloalkylsulfonyl.   
   
   
       11 . A compound or salt according to  claim 1 , wherein R 2  is:
 (i) hydrogen, hydroxy or halogen; or   (ii) C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 -aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl or (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl C 1 -C 6 alkoxy and C 1 -C 6 haloalkyl.   
   
   
       12 .- 16 . (canceled) 
   
   
       17 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       Y and Z are each independently N or CR 1 ; 
       R 1  is independently selected at each occurrence from hydrogen, halogen, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy and mono- and di-(C 1 -C 6 alkyl)amino; 
       R 2  is: (i) hydrogen, halogen or cyano;
 (ii) a group of the formula —R c -M-A-R Y , wherein:
 R c  is C 0 -C 3 alkyl or is joined to R y  or R z , to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 2 substituents independently chosen from R b ; 
 M is a single covalent bond, O, S, SO 2 , C(═O), OC(═O), C(═O)O, O—C(═O)O, C(═O)N(R z ), OC(═O)N(R z ), N(R z )C(═O), N(R z )SO 2 , SO 2 N(R z ) or N(R z ); 
 A is a single covalent bond or C 1 -C 8 alkyl substituted with from 0 to 3 substituents independently chosen from R b ; and 
 R y  and R z , if present, are:
 (a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 2 -C 8 alkenyl, a 4-to 10-membered carbocycle or heterocycle, or joined to R c  to form a 4- to 10-membered carbocycle or heterocycle, wherein each non-hydrogen R y  and R z  is substituted with from 0 to 6 substituents independently chosen from R b ; or 
 (b) joined to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 6 substituents independently chosen from R b ; or 
 
 
 (iii) taken together with R 7  to form a fused 5- to 7-membered ring that is substituted with from 0 to 3 substituents independently chosen from oxo and C 1 -C 4 alkyl; 
 
       R 7  is hydrogen, COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl or taken together with R 2  to form a fused, optionally substituted ring; 
       Ar 1  is phenyl or 6-membered heteroaryl, each of which is unsubstituted or substituted ortho to the point of attachment with 1 or 2 substituents independently chosen from groups of the formula LR a ; 
       Ar 2  is 5- to 10-membered heteroaryl that is substituted with from 0 to 6 substituents independently chosen from oxo and groups of the formula LR a ; 
       L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O) m , N(R x ), C(═O)N(R x ), N(R x )C(═O), N(R x )S(O) m , S(O) m N(R x ) and N[S(O) m R w ]S(O) m ; wherein m is independently selected at each occurrence from 0, 1 and 2; R x  is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl and C 1 -C 6 alkylsulfonyl; and R w  is hydrogen or C 1 -C 6 alkyl; 
       R a  is independently selected at each occurrence from:
 (i) hydrogen, halogen, cyano and nitro; and 
 (ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkyl ether, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 0 -C 6 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R b ; and 
 
       R b  is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkanoyl, C 1 -C 8 alkanoyloxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl ether, C 1 -C 8 hydroxyalkyl, C 1 -C 8 haloalkyl, phenylC 0 -C 8 alkyl, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, C 1 -C 8 alkylsulfonyl and (4- to 7-membered heterocycle)C 0 -C 8 alkyl. 
     
   
   
       18 .- 26 . (canceled) 
   
   
       27 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       Y and Z are each independently N or CR 1 ; 
       R 1  is independently selected at each occurrence from hydrogen, halogen, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy and mono- and di-(C 1 -C 6 alkyl)amino; 
       R 2  is: (i) halogen or cyano;
 (ii) a group of the formula —R c -M-A-R y , wherein:
 R c  is C 0 -C 3 alkyl or is joined to R y  or R z , to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 2 substituents independently chosen from R b ; 
 M is a single covalent bond, O, S, SO 2 , C(═O), OC(═O), C(═O)O, O—C(═O)O, C(═O)N(R z ), OC(═O)N(R z ), N(R z )C(═O), N(R z )SO 2 , SO 2 N(R z ) or N(R z ); 
 A is a single covalent bond or C 1 -C 8 alkyl substituted with from 0 to 3 substituents independently chosen from R b ; and 
 R y  and R z , if present, are:
 (a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 2 -C 8 alkenyl, a 4-to 10-membered carbocycle or heterocycle, or joined to R c  to form a 4- to 10-membered carbocycle or heterocycle, wherein each non-hydrogen R y  and R z  is substituted with from 0 to 6 substituents independently chosen from R b ; or 
 (b) joined to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 6 substituents independently chosen from R b ; 
  such that R 2  is not —NH 2 ; or 
 
 
 (iii) taken together with R 7  to form a fused 5- to 7-membered ring that is substituted with from 0 to 3 substituents independently chosen from oxo and C 1 -C 4 alkyl; 
 
       R 7  is hydrogen, COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl or taken together with R 2  to form a fused, optionally substituted ring; 
       Ar 1  is phenyl or 6-membered heteroaryl, each of which is unsubstituted or substituted ortho to the point of attachment with 1 or 2 substituents independently chosen from groups of the formula LR a ; 
       Ar 2  is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from oxo and groups of the formula LR a ; 
       L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O) m , N(R x ), C(═O)N(R x ), N(R x )C(═O), N(R x )S(O) m , S(O) m N(R x ) and N[S(O) m R w ]S(O) m ; wherein m is independently selected at each occurrence from 0, 1 and 2; R x  is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl and C 1 -C 6 alkylsulfonyl; and R w  is hydrogen or C 1 -C 6 alkyl; 
       R a  is independently selected at each occurrence from:
 (i) hydrogen, halogen, cyano and nitro; and 
 (ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkyl ether, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 0 -C 6 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R b ; and 
 
       R b  is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkanoyl, C 1 -C 8 alkanoyloxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl ether, C 1 -C 8 hydroxyalkyl, C 1 -C 8 haloalkyl, phenylC 0 -C 8 alkyl, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, C 1 -C 8 alkylsulfonyl and (4- to 7-membered heterocycle)C 0 -C 8 alkyl. 
     
   
   
       28 . A compound or salt according to  claim 27 , wherein at least one of Y and Z is N. 
   
   
       29 . A compound or salt according to  claim 27 , wherein Y and Z are both CH. 
   
   
       30 . A compound or salt according to  claim 27 , wherein Ar 2  is phenyl or a 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently selected from (a) groups of the formula LR a  and (b) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from R b . 
   
   
       31 . (canceled) 
   
   
       32 . (canceled) 
   
   
       33 . A compound or salt according to  claim 27 , wherein Ar 1  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is unsubstituted or substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy. 
   
   
       34 .- 46 . (canceled) 
   
   
       47 . A compound or salt according to  claim 27 , wherein the compound has the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 Ar 1  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is unsubstituted or substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; 
 Ar 2  is phenyl or a 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently selected from (a) groups of the formula LR a  and (b) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from R b ; 
 R 3  is selected from:
 (i) hydrogen; and 
 (ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, and 5- to 10-membered heterocycleC 0 -C 8 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R b ; 
 
 R 5  and R 6  are, independently at each occurrence:
 (i) each independently selected from hydrogen, hydroxy and C 1 -C 6 alkyl; or 
 (ii) taken together to form a keto group; and
 n is 1, 2 or 3. 
 
 
 
   
   
       48 . A compound or salt according to  claim 47 , wherein Ar 2  is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is substituted with 0, 1 or 2 substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, amino, mono- and di-(C 1 -C 6 alkyl)amino. 
   
   
       49 .- 59 . (canceled) 
   
   
       60 . A pharmaceutical composition, comprising at least one compound or salt according to  claim 1  in combination with a physiologically acceptable carrier or excipient. 
   
   
       61 . A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt according to  claim 1 , and thereby reducing calcium conductance of the capsaicin receptor. 
   
   
       62 .- 70 . (canceled) 
   
   
       71 . A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in vitro, the method comprising contacting capsaicin receptor with at least one compound or salt according to  claim 1 , in an amount sufficient to detectably inhibit vanilloid ligand binding to capsaicin receptor. 
   
   
       72 . A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in a patient, the method comprising contacting cells expressing capsaicin receptor with at least one compound or salt according to  claim 1 , in an amount sufficient to detectably inhibit vanilloid ligand binding to cells expressing a cloned capsaicin receptor in vitro, and thereby inhibiting binding of vanilloid ligand to the capsaicin receptor in the patient. 
   
   
       73 . (canceled) 
   
   
       74 . A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a capsaicin receptor modulatory amount of a compound or salt according to  claim 1 , and thereby alleviating the condition in the patient. 
   
   
       75 . (canceled) 
   
   
       76 . (canceled) 
   
   
       77 . A method for treating pain in a patient, comprising administering to a patient suffering from pain a capsaicin receptor modulatory amount of at least one compound or salt according to  claim 1 , and thereby alleviating pain in the patient. 
   
   
       78 .- 80 . (canceled) 
   
   
       81 . A method according to  claim 77 , wherein the patient is suffering from neuropathic pain. 
   
   
       82 . A method according to  claim 77 , wherein the patient is afflicted with a condition selected from: postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal cord injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina, labor, hemorrhoids, dyspepsia, Charcot's pains, intestinal gas, menstruation, cancer, venom exposure, irritable bowel syndrome, inflammatory bowel disease and trauma. 
   
   
       83 . (canceled) 
   
   
       84 . A method for treating a condition selected from the group consisting of itch, cough, hiccup, urinary incontinence or overactive bladder in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt according to  claim 1 , and thereby alleviating the condition in the patient. 
   
   
       85 . (canceled) 
   
   
       86 . (canceled) 
   
   
       87 . A method promoting weight loss in an obese patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt according to  claim 1 , and thereby promoting weight loss in the patient. 
   
   
       88 .- 91 . (canceled) 
   
   
       92 . A packaged pharmaceutical preparation, comprising:
 (a) a pharmaceutical composition according to  claim 60  in a container; and   (b) instructions for using the composition to treat pain.   
   
   
       93 .- 97 . (canceled)