Cyclobutyl amine derivatives

Abstract

Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

1 . A compound of formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
 one of R 1  and R 2  is a group of the formula -L 2 -R 6a -L 3 -R 6b ; 
 the other of R 1  and R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy; 
 R 3 , R 3a , and R 3b  are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy; 
 R 4  and R 5  are each independently selected from the group consisting of alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, or R 4  and R 5  taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula: 
 
     
       
         
         
             
             
         
       
       R 7 , R 8 , R 9 , and R 10  at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; 
       R 11 , R 12 , R 13 , and R 14  are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; 
       R 6a  is selected from the group consisting of a 5- to 6-membered heteroaryl ring, cyanophenyl, an 8- to 10-membered bicyclic heteroaryl ring, and a 4- to 8-membered heterocyclic ring; 
       R 6b  is selected from the group consisting of hydrogen, a 5- to 6-membered heteroaryl ring, phenyl, an 8- to 10-membered bicyclic heteroaryl ring, and a 4- to 8-membered heterocyclic ring; 
       Q is O or S; 
       L is —[C(R 16 )(R 17 )] k ; 
       L 2  is selected from the group consisting of a bond, —O—, —C(═O)—, —S—, —NH—, —N(R 16 )C(═O)—, —C(═O)N(R 16 ), and —N(alkyl)-; 
       L 3  is selected from the group consisting of a bond, —O—, —C(═O)—, —S—, —N(R 16 )C(═O)—, —C(═O)N(R 16 ), and —N(R 15 )—; 
       R 15  is selected from the group consisting of hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and formyl; 
       R 16  and R 17  at each occurrence are independently selected from the group consisting of hydrogen and alkyl; 
       R x  and R y  at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; 
       k is 0, 1, or 2; 
       m is an integer from 1 to 5; and 
       n is 0 or 1. 
     
   
   
       2 . The compound of  claim 1 , wherein R 1  is -L 2 -R 6a -L 3 -R 6b , wherein L 2  is a bond, R 6b  is hydrogen, L 3  is a bond, and R 6a  is selected from a 5- or 6-membered heteroaryl ring. 
   
   
       3 . The compound of  claim 2 , wherein R 6a  is an unsubstituted or substituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, pyridazinonyl, pyridonyl, and pyrimidinonyl. 
   
   
       4 . The compound of  claim 2 , wherein R 6a  is an unsubstituted or substituted ring selected from the group consisting of pyrimidinyl, pyridazinonyl, pyridinyl, and pyrazolyl. 
   
   
       5 . The compound of  claim 1 , wherein R 1  is -L 2 -R 6a -L 3 -R 6b , wherein L 2  is a bond, R 6b  is hydrogen, L 3  is a bond, and R 6a  is selected from a 8- to 10-membered bicyclic heteroaryl ring. 
   
   
       6 . The compound of  claim 5 , wherein R 6a  is an unsubstituted or substituted ring selected from the group consisting of indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, and pyrrolopyrimidinyl. 
   
   
       7 . The compound of  claim 6 , wherein R 6a  is unsubstituted or substituted benzothiazolyl. 
   
   
       8 . The compound of  claim 1 , wherein one of R 3 , R 3a , and R 3b  is halogen and the others are hydrogen. 
   
   
       9 . The compound of  claim 1 , wherein R 4  and R 5  taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a). 
   
   
       10 . The compound of  claim 9 , wherein at least one substituent represented by R 7 , R 8 , R 9 , and R 10  is selected from the group consisting of alkyl, fluoroalkyl, and hydroxyalkyl or at least one substituent represented by R x  or R y  is alkyl, fluoro, or hydroxy. 
   
   
       11 . The compound of  claim 1 , wherein R 4  and R 5  are taken together with the nitrogen atom to which each is attached to form a (2R)-methylpyrrolidine ring or (2S)-methylpyrrolidine ring. 
   
   
       12 . The compound of  claim 1 , wherein the compound has the formula 
     
       
         
         
             
             
         
       
     
     wherein L, n, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , and R 5  are each as defined in  claim 1 . 
   
   
       13 . The compound of  claim 12 , wherein R 1  is -L 2 -R 6a -L 3 -R 6b , wherein L 2  is a bond, R 6b  is hydrogen, L 3  is a bond, R 6a  is selected from a 5- or 6-membered heteroaryl ring, and R 4  and R 5  taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a). 
   
   
       14 . The compound of  claim 1 , wherein the compound has the formula 
     
       
         
         
             
             
         
       
     
     wherein L, n, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , and R 5  are each as defined in  claim 1 . 
   
   
       15 . The compound of  claim 14 , wherein R 1  is -L 2 -R 6a -L 3 -R 6b , wherein L 2  is a bond, R 6b  is hydrogen, L 3  is a bond, R 6a  is selected from a 5- or 6-membered heteroaryl ring, and R 4  and R 5  taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a). 
   
   
       16 . The compound of  claim 1 , selected from the group consisting of 
     4′-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbonitrile; 
     4′-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitrile; 
     4′-[3-(2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile; 
     4′-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carbonitrile; 
     5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimidine; 
     2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyridine; 
     2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine; 
     2,6-dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine; 
     2,6-dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine; 
     4′-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitrile; 
     5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     2-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-2H-pyridazin-3-one; 
     4′-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbonitrile; 
     5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     2,4-dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotinonitrile; 
     2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-benzothiazole; 
     2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine; 
     1,3,5-trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-1H-pyrazole; 
     5-{2-fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; 
     4′-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-carbonitrile; 
     4′-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4-carbonitrile; 
     4′-{3-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-carbonitrile; 
     2,6-difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyridine; 
     5-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine; 
     4′-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-4-carbonitrile; 
     1,3,5-trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-1H-pyrazole; 
     2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-pyridazin-3-one; 
     2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine; 
     2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine; and 
     4′-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-carbonitrile. 
   
   
       17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable carrier. 
   
   
       18 . A method of selectively modulating the effects of histamine-3 receptors in a mammal comprising administering an effective amount of a compound of  claim 1 . 
   
   
       19 . A method of treating a condition or disorder modulated by the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of  claim 1 . 
   
   
       20 . The method according to  claim 19 , wherein the condition or disorder is selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, and diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, and asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, including neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, and medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome.