FKBP inhibitors

Abstract

Compounds of formula (I), their salts and solvates, wherein the substituents are as described herein, are FKBP inhibitors.

1 . A method of treating neuronal degeneration comprising administering an effective amount of a compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, or solvate thereof, wherein: 
 X is O, S, NH or N(C 1-6  alkyl);  
 R 1 , R 2 , R 3  and R 4  are each independently H, OH, OCO(C 1-6  alkyl), CO 2 (C 1-6  alkyl), CONH 2 , CONH(C 1-6  alkyl), CON(C 1-6  alkyl) 2 , halo, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  alkenyl, aryl 1 , C 1-6  alkyl optionally substituted by one or more substituents selected from halo and C 3-7  cycloalkyl, and C 1-6  alkoxy optionally substituted by one or more substituents selected from fluoro and C 3-7  cycloalkyl;  
 A is unbranched C 3-5  alkylene optionally substituted by up to three C 1-6  alkyl groups;  
 D is O or S;  
 E is O, S, NH, N(C 1-6  alkyl) or CR 11 R 12 ;  
 G is C 1-4  alkyl or C 2-14  alkenyl, each of which is optionally substituted by one or more substituents independently selected from halo, aryl, C 1-4  alkoxy, cycloalk, het and NR 5 R 6 ,  
 R 5  and R 6  are either each independently H or C 1-6  alkyl, or are taken together to form, with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring optionally containing another hetero-moiety selected from NR 7 , O and S(O) p , and which 4 to 7-membered heterocyclic ring is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl and C 1-6  alkoxy;  
 R 7  is H, C 1-6  alkyl, C 2-6  alkenyl, COR 8 , SO 2 R 8 , CONR 9 R 10 , CO 2 R 8  or SO 2 NR 9 R 10 ;  
 R 8  is C 3-7  cycloalkyl, C 2-6  alkenyl, aryl 1 , or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl 1 ;  
 R 9  and R 10  are each independently H, C 2-6  alkenyl, C 3-7  cycloalkyl, or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl;  
 R 11  and R 12  are each independently H, aryl, C 2-8  alkenyl or C 1-8  alkyl, wherein said C 2-8  alkenyl and C 1-8  alkyl groups are optionally substituted by one or more substituents independently selected from halo, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, cycloalk, OH, C 1-6  alkoxy, C 2-6  alkenyloxy, phenyloxy, benzyloxy, NH 2 , aryl and het;  
 p is 0, 1 or 2;  
 wherein “aryl” means phenyl or naphthyl, each of which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy, phenyl and NH 2 ;  
 “aryl 1 ” means phenyl, naphthyl or benzyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 1-6  alkoxy and halo;  
 “cycloalk” is C 3-8  cycloalkyl optionally substituted by up to 3 substituents independently selected from C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, and C 1-6  alkyl optionally substituted by one or more halo;  
 and “het” means a 5- or 6-membered monocyclic, or 8-, 9- or 10-membered bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from O, N and S, which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally  
 substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy and NH 2 ;  
 with the proviso that the compound is not methyl 1-(5-chloro-2-benzoxazolyl)proline.  
 
     
     
         2 . A method of promoting neuronal regeneration and outgrowth comprising administering an effective amount of a compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, or solvate thereof, wherein: 
 X is O, S, NH or N(C 1-6  alkyl);  
 R 1 , R 2 , R 3  and R 4  are each independently H, OH, OCO(C 1-6  alkyl), CO 2 (C 1-6  alkyl), CONH 2 , CONH(C 1-6  alkyl), CON(C 1-6  alkyl) 2 , halo, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  alkenyl, aryl 1 , C 1-6  alkyl optionally substituted by one or more substituents selected from halo and C 3-7  cycloalkyl, and C 1-6  alkoxy optionally substituted by one or more substituents selected from fluoro and C 3-7  cycloalkyl;  
 A is unbranched C 3-5  alkylene optionally substituted by up to three C 1-6  alkyl groups;  
 D is O or S;  
 E is O, S, NH, N(C 1-6  alkyl) or CR 11 R 12 ;  
 G is C 1-14  alkyl or C 2-14  alkenyl, each of which is optionally substituted by one or more substituents independently selected from halo, aryl, C 1-4  alkoxy, cycloalk, het and NR 5 R 6 ,  
 R 5  and R 6  are either each independently H or C 1-6  alkyl, or are taken together to form, with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring optionally containing another hetero-moiety selected from NR 7 , O and S(O) p , and which 4 to 7-membered heterocyclic ring is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl and C 1-6  alkoxy;  
 R 7  is H, C 1-6  alkyl, C 2-6  alkenyl, COR 8 , SO 2 R 8 , CONR 9 R 10 , CO 2 R 8  or SO 2 NR 9 R 10 ;  
 R 8  is C 3-7  cycloalkyl, C 2-6  alkenyl, aryl 1 , or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl 1 ;  
 R 9  and R 10  are each independently H, C 2-6  alkenyl, C 3-7  cycloalkyl, or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl;  
 R 11  and R 12  are each independently H, aryl, C 2-8  alkenyl or C 1-8  alkyl, wherein said C 2-8  alkenyl and C 1-8  alkyl groups are optionally substituted by one or more substituents independently selected from halo, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, cycloalk, OH, C 1-6  alkoxy, C 2-6  alkenyloxy, phenyloxy, benzyloxy, NH 2 , aryl and het;  
 p is 0, 1 or 2;  
 wherein “aryl” means phenyl or naphthyl, each of which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy, phenyl and NH 2 ;  
 “aryl 1 ” means phenyl, naphthyl or benzyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 1-6  alkoxy and halo;  
 “cycloalk” is C 3-8  cycloalkyl optionally substituted by up to 3 substituents independently selected from C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, and C 1-6  alkyl optionally substituted by one or more halo;  
 and “het” means a 5- or 6-membered monocyclic, or 8-, 9- or 10-membered bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from O, N and S, which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy and NH 2 ;  
 with the proviso that the compound is not methyl 1-(5-chloro-2-benzoxazolyl)proline.  
 
     
     
         3 . A method of treating a neurological disease or disorder such as a neurodegenerative disease comprising administering an effective amount of a compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, or solvate thereof, wherein: 
 X is O, S, NH or N(C 1-6  alkyl);  
 R 1 , R 2 , R 3  and R 4  are each independently H, OH, OCO(C 1-6  alkyl), CO 2 (C 1-6  alkyl), CONH 2 , CONH(C 1-6  alkyl), CON(C 1-6  alkyl) 2 , halo, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  alkenyl, aryl 1 , C 1-6  alkyl optionally substituted by one or more substituents selected from halo and C 3-7  cycloalkyl, and C 1-6  alkoxy optionally substituted by one or more substituents selected from fluoro and C 3-7  cycloalkyl;  
 A is unbranched C 3-5  alkylene optionally substituted by up to three C 1-6  alkyl groups;  
 D is O or S;  
 E is O, S, NH, N(C 1-6  alkyl) or CR 11 R 12 ;  
 G is C 1-14  alkyl or C 2-14  alkenyl, each of which is optionally substituted by one or more substituents independently selected from halo, aryl, C 1-4  alkoxy, cycloalk, het and NR 5 R 6 ,  
 R 5  and R 6  are either each independently H or C 1-6  alkyl, or are taken together to form, with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring optionally containing another hetero-moiety selected from NR 7 , O and S(O) p , and which 4 to 7-membered heterocyclic ring is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl and C 1-6  alkoxy;  
 R 7  is H, C 1-6  alkyl, C 2-6  alkenyl, COR 8 , SO 2 R 8 , CONR 9 R 10 , CO 2 R 8  or SO 2 NR 9 R 10 ;  
 R 8  is C 3-7  cycloalkyl, C 2-6  alkenyl, aryl 1 , or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl 1 ;  
 R 9  and R 10  are each independently H, C 2-6  alkenyl, C 3-7  cycloalkyl, or C 1-6  alkyl optionally substituted by C 3-7  cycloalkyl or aryl;  
 R 11  and R 12  are each independently H, aryl, C 2-8  alkenyl or C 1-8  alkyl, wherein said C 2-8  alkenyl and C 1-8  alkyl groups are optionally substituted by one or more substituents independently selected from halo, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, cycloalk, OH, C 1-6  alkoxy, C 2-6  alkenyloxy, phenyloxy, benzyloxy, NH 2 , aryl and het;  
 p is 0, 1 or 2;  
 wherein “aryl” means phenyl or naphthyl, each of which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy, phenyl and NH 2 ;  
 “aryl 1 ” means phenyl, naphthyl or benzyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 1-6  alkoxy and halo;  
 “cycloalk” is C 3-8  cycloalkyl optionally substituted by up to 3 substituents independently selected from C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, and C 1-6  alkyl optionally substituted by one or more halo;  
 and “het” means a 5- or 6-membered monocyclic, or 8-, 9- or 10-membered bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from O, N and S, which is optionally substituted by up to 3 substituents independently selected from C 1-6  alkyl optionally substituted by one or more halo or C 3-7  cycloalkyl groups, C 2-6  alkenyl, C 1-6  alkoxy, C 2-6  alkenyloxy, OH, halo, NO 2 , phenyloxy, benzyloxy and NH 2 ;  
 with the proviso that the compound is not methyl 1-(5-chloro-2-benzoxazolyl)proline  
 
     
     
         4 . A method according to  claim 3  where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease; Parkinson's disease; Huntington's disease; neurological deficits associated with stroke; a degenerative disease affecting the central or peripheral nervous system; a muscular dystrophy; progressive muscular atrophies; progressive bulbar muscular atrophy; physical or traumatic damage to the central or peripheral nervous system; a herniated, ruptured or prolapsed intervertebrae disc syndrome; cervical spondylosis; plexus disorders; thoracic outlet syndromes; diabetic and non-diabetic peripheral neuropathies; trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; an auto-immune related disease resulting in damage of the central or peripheral nervous system; AIDS related disorders of the nervous system; dapsone ticks; bulbar and retrobulbar affections of the optic nerve; hearing disorders such as tinnitus; and prion diseases.  
     
     
         5 . A method according to  claim 4 , wherein the neurological disease or disorder is a degenerative disease affecting the central or peripheral nervous system, and said degenerative disease is a cerebellar-brainstem atrophy or a syndrome of progressive ataxia.  
     
     
         6 . A method according to  claim 4 , wherein the neurological disease or disorder is a physical or traumatic damage to the spinal cord.  
     
     
         7 . A method according to  claim 4 , wherein the neurological disease or disorder is an auto-immune related disease resulting in damage of the central or peripheral nervous system, and said auto-immune related disease is multiple sclerosis, myasthenia gravis, or Guillain-Barré syndrome.  
     
     
         8 . A method according to  claim 4 , wherein the neurological disease or disorder is a bulbar or retrobulbar affection of the optic nerve, and said affection is a retinopathy or retrobulbar neuritis.  
     
     
         9 . A method according to  claim 4 , wherein the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia; amyotrophic lateral sclerosis or another form of motor neuron disease; Parkinson's disease; Huntington's disease; a neurological deficit associated with stroke; physical or traumatic damage to the central or peripheral nervous system, including physical or traumatic damage to the spinal cord; a dibetic or non-diabetic peripheral neuropathy; multiple sclerosis; or a hearing disorder such as tinnitus.  
     
     
         10 . A method of treating neuronal degeneration in a human according to  claim 1 .  
     
     
         11 . A method of promoting neuronal regeneration and outgrowth in a human according to  claim 2 .  
     
     
         12 . A method of treating a neurological disease or disorder such as a neurodegenerative disease in a human according to  claim 3 .  
     
     
         13 . A method according to  claim 12  where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease; Parkinson's disease; Huntington's disease; neurological deficits associated with stroke; a degenerative disease affecting the central or peripheral nervous system; a muscular dystrophy; progressive muscular atrophies; progressive bulbar muscular atrophy; physical or traumatic damage to the central or peripheral nervous system; a herniated, ruptured or prolapsed intervertebrae disc syndrome; cervical spondylosis; plexus disorders; thoracic outlet syndromes; diabetic and non-diabetic peripheral neuropathies; trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy; an auto-immune related disease resulting in damage of the central or peripheral nervous system; AIDS related disorders of the nervous system; dapsone ticks; bulbar and retrobulbar affections of the optic nerve; hearing disorders such as tinnitus; and prion diseases.  
     
     
         14 . A method according to  claim 13 , wherein the neurological disease or disorder is a degenerative disease affecting the central or peripheral nervous system, and said degenerative disease is a cerebellar-brainstem atrophy or a syndrome of progressive ataxia.  
     
     
         15 . A method according to  claim 13 , wherein the neurological disease or disorder is a physical or traumatic damage to the spinal cord.  
     
     
         16 . A method according to  claim 13 , wherein the neurological disease or disorder is an auto-immune related disease resulting in damage of the central or peripheral nervous system, and said auto-immune related disease is multiple sclerosis, myasthenia gravis, or Guillain-Barré syndrome.  
     
     
         17 . A method according to  claim 13 , wherein the neurological disease or disorder is a bulbar or retrobulbar affection of the optic nerve, and said affection is a retinopathy or retrobulbar neuritis.  
     
     
         18 . A method according to  claim 13 , wherein the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia; amyotrophic lateral sclerosis or another form of motor neuron disease; Parkinson's disease; Huntington's disease; a neurological deficit associated with stroke; physical or traumatic damage to the central or peripheral nervous system, including physical or traumatic damage to the spinal cord; a dibetic or non-diabetic peripheral neuropathy; multiple sclerosis; or a hearing disorder such as tinnitus.