Mlk inhibitors and methods of use

Abstract

Provided are compounds having an inhibitory effect on Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.

What is claimed is: 
     
         1 . A compound of structural Formula II 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 dashed lines indicate that a second bond may alternatively be present or absent; 
 X 1  is chosen from CH and N; 
 X 2  is chosen from C and N; 
 Y 1 , Y 2 , and Y 3  are independently chosen from a bond, lower alkyl, lower carboxyl, and lower heteroalkyl; 
 Y 4  is chosen from —(CH 2 ) m , C(O), —(CH 2 ) m O—, and —(CH 2 ) m N—; 
 m is an integer from 0 to 2; 
 R 1 , R 2 , and R 3  are independently chosen from lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, amido, amino, alkoxy, hydroxy, cyano, and nitro, any of which may be optionally substituted; or R 1  and R 2  may each additionally be heteroalkyl, and may be joined together such that R 1  and R 2  together form an alkylene, alkenylene, or heteroalkyl bridge comprising from 3 to 5 atoms, which may be optionally substituted; 
 R 4  is chosen from hydrogen, (O), and (S); 
 R 5  is chosen from hydrogen, hydroxy, cyano, lower alkyl, lower cycloalkyl, and lower alkoxy, any of which may be optionally substituted; 
 R 13  is chosen from hydrogen, halogen, hydroxy, cyano, nitro, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, and lower alkoxy, any of which may be optionally substituted; and additionally, R 13  and R 3  may be joined together to form a lower spiro-cycloalkyl or spiro-phenyl comprising from 3 to 6 atoms, which may be optionally substituted; and 
 R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted. 
 
     
     
         2 . The compound as recited in  claim 1 , wherein R 4  is (O), the second bond linking R 4  and the fused bicyclic core is present, and the second bond in the five-membered portion of the fused bicyclic core is absent. 
     
     
         3 . The compound as recited in  claim 1 , wherein R 4  is hydrogen, the second bond linking R 4  and the fused bicyclic core is absent, and the second bond in the five-membered portion of the fused bicyclic core is present. 
     
     
         4 . The compound as recited in  claim 1 , wherein compounds have structural Formula III 
       
         
           
           
               
               
           
         
       
       wherein:
 dashed lines indicate that a second bond may alternatively be present or absent; 
 X 1  and X 2  are independently chosen from CH and N; 
 Y 3  is chosen from a bond, lower alkyl, lower carboxyl, and lower heteroalkyl; 
 Y 4  is chosen from C(O), —(CH 2 ) m —, —(CH 2 ) m O—, and —(CH 2 ) m N—; 
 m is an integer from 0 to 1; 
 R 2  and R 3  are independently chosen from lower cycloalkyl, heterocycloalkyl, lower aryl, and lower heteroaryl, any of which may be optionally substituted; 
 R 4  is chosen from hydrogen, (O), and (S); 
 R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted. 
 
     
     
         5 . The compound as recited in  claim 4 , having a structural Formula chosen from Formula IV and Formula V: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 X 1  and X 2  are independently chosen from CH and N; 
 Y 3  is chosen from a bond, lower alkyl, lower carboxyl, and lower heteroalkyl; 
 Y 4  is chosen from C(O), —(CH 2 ) m —, —(CH 2 ) m O—, and —(CH 2 ) m N—; 
 m is an integer from 0 to 1; 
 R 2  and R 3  are independently chosen from lower cycloalkyl, lower heterocycloalkyl, lower aryl, and lower heteroaryl, any of which may be optionally substituted; and 
 R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted. 
 
     
     
         6 . The compound as recited in  claim 5 , wherein Y 3  is chosen from a bond, C(O), and lower alkyl. 
     
     
         7 . The compound as recited in  claim 6 , wherein R 3  is chosen from lower cycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted. 
     
     
         8 . The compound as recited in  claim 7 , wherein R 2  is chosen from phenyl and lower heteroaryl, any of which may be optionally substituted. 
     
     
         9 . The compound as recited in  claim 7 , wherein R 2  is chosen from phenyl, 6-membered monocyclic heteroaryl, and 5/6-fused bicyclic heteroaryl, any of which may be optionally substituted. 
     
     
         10 . The compound as recited in  claim 9 , wherein R 2  is chosen from phenyl, pyridinyl, pyrimidinyl, and indolyl, any of which may be optionally substituted. 
     
     
         11 . The compound as recited in  claim 10 , wherein R 2  is substituted with one or more substituents chosen from halogen, hydroxy, lower amino, C 1 -C 3  alkoxy and C 1 -C 3  alkyl. 
     
     
         12 . The compound as recited in  claim 11 , wherein R 2  is substituted with one or more substituents chosen from fluorine, hydroxy, NH 3 , NH(CH 3 ), N(CH 3 ) 2 , methoxy, and methyl. 
     
     
         13 . The compound as recited in  claim 9 , wherein compounds have a structural Formula chosen from Formula VI, Formula VII, Formula VIII, and Formula IX: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 Y 3  is chosen from a bond, lower alkyl, lower carboxyl, and lower heteroalkyl; 
 Y 4  is chosen from C(O), —(CH 2 ) m —, —(CH 2 ) m O—, and —(CH 2 ) m N—; 
 m is an integer from 0 to 1; 
 R 2  is chosen from phenyl, 6-membered monocyclic heteroaryl, and 5/6-fused bicyclic heteroaryl, any of which may be optionally substituted; 
 R 3  is chosen from lower cycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted; 
 R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted. 
 
     
     
         14 . The compound as recited in  claim 13 , wherein R 2  is chosen from phenyl, pyridinyl, pyrimidinyl, and indolyl, any of which may be optionally substituted. 
     
     
         15 . The compound as recited in  claim 14 , wherein Y 4  is chosen from C(O), O, N, and —CH 2 —. 
     
     
         16 . The compound as recited in  claim 13 , wherein R 2  is chosen from 
       
         
           
           
               
               
           
         
       
       wherein
 u is an integer from 0 to 3; 
 Y 4  is chosen from C(O), —(CH 2 ) m —, —(CH 2 ) m O—, and —(CH 2 ) m N—; 
 m is an integer from 0 to 1; 
 R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted; and 
 each R 15  is independently chosen from halogen, hydroxy, cyano, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, lower amino, lower amido, lower sulfonamido, and lower sulfonyl. 
 
     
     
         17 . The compound as recited in  claim 16 , wherein R 14  is chosen from null, lower heterocycloalkyl, phenyl, and monocyclic lower heteroaryl, any of which may be optionally substituted. 
     
     
         18 . The compound as recited in  claim 17 , wherein
 Y 4  is —(CH 2 ) m —;   m is 0;   R 14  is null;   u is an integer from 1 to 3; and   each R 15  is independently chosen from fluorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NS(O) 2 CH 3 , methoxy, and methyl.   
     
     
         19 . The compound as recited in  claim 17 , wherein
 Y 4  is —(CH 2 ) m —;   m is 1;   R 14  is chosen from null, lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, any of which may be optionally substituted;   u is an integer from 0 to 2; and   each R 15  is independently chosen from fluorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NS(O) 2 CH 3 , methoxy, and methyl.   
     
     
         20 . The compound as recited in  claim 17 , wherein each R 15  is independently chosen from halogen, hydroxy, lower amino C 1 -C 3  alkoxy and C 1 -C 3  alkyl. 
     
     
         21 . The compound as recited in  claim 20 , wherein Y 4  is chosen from C(O), O, N, and —CH 2 —. 
     
     
         22 . The compound as recited in  claim 21 , wherein Y 3  is chosen from a bond and lower alkyl. 
     
     
         23 . The compound as recited in  claim 22 , wherein R 14  is chosen from null and lower heterocycloalkyl, either of which may be optionally substituted. 
     
     
         24 . The compound as recited in  claim 23 , wherein Y 3  is chosen from a bond and methyl. 
     
     
         25 . The compound as recited in  claim 24 , wherein R 3  is substituted with one or more substituents chosen from halogen, hydroxy, lower amino, lower amido, lower phenylamido, lower phenylalkylamido, lower heterocycloalkyl, lowerheterocycloalkyl, loweralkylheterocycloalkyl, C 1 -C 3  alkoxy and C 1 -C 3  alkyl. 
     
     
         26 . The compound as recited in  claim 25 , wherein Y 4  is —CH 2 —. 
     
     
         27 . The compound as recited in  claim 26 , wherein R 3  is chosen from benzothiazolyl, pyrrolopyridinyl, indanyl, cyclopropyl, cyclopentyl, phenyl, pyridinyl, pyrimidinyl, and indolyl, any of which may be optionally substituted. 
     
     
         28 . The compound as recited in  claim 27 , wherein Y 3  is a bond. 
     
     
         29 . The compound as recited in  claim 28 , each R 15  is independently chosen from fluorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , methoxy, and methyl. 
     
     
         30 . The compound as recited in  claim 29 , wherein R 3  is substituted with one or more substituents chosen from fluorine, chlorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , C(O)NH 2 , C(O)NHCH 3 , morpholino, piperazinyl, methylpiperazinyl, acetamido, methylacetamido, methylpropionamido, phenylacetamidomethylene, benzamidomethylene, phenylpropanamidomethylene, methoxy and methyl. 
     
     
         31 . A compound of structural Formula III 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 dashed lines indicate that a second bond may alternatively be present or absent; 
 X 1  and X 2  are independently chosen from CH and N; 
 Y 3  is a bond; 
 Y 4  is chosen from C(O), CH 2 , CHF, and CF 2 ; 
 R 2  is chosen from phenyl and 6-membered monocyclic heteroaryl, either of which may be optionally substituted; 
 R 3  is optionally substituted bicyclic heteroaryl; 
 R 4  is chosen from hydrogen, (O), and (S); 
 R 14  is optionally substituted monocyclic heterocycloalkyl. 
 
     
     
         32 . The compound as recited in  claim 31 , wherein R 3  is an optionally substituted 5/6-fused bicyclic heteroaryl. 
     
     
         33 . The compound as recited in  claim 32 , wherein Y 4  is CH 2 . 
     
     
         34 . The compound as recited in  claim 33 , wherein R 14  is optionally substituted piperazinyl. 
     
     
         35 . The compound as recited in claim compound chosen from Examples 1 to 167. 
     
     
         36 . A compound as recited in  claim 1  for use as a medicament. 
     
     
         37 . A compound as recited in  claim 1  for use as a medicament for the treatment of an MLK-mediated disease. 
     
     
         38 . The compound as recited in  claim 37 , for use as a medicament for the treatment of an MLK3-mediated disease. 
     
     
         39 . The compound as recited in  claim 38 , wherein said disease is chosen from diabetes mellitus, hyperglycemia, retinopathy, nephropathy, neuropathy, ulcers, micro- and macroangiopathies, gout and diabetic foot disease, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, peripheral inflammation, cancer and hepatitis. 
     
     
         40 . The use of a compound as recited in  claim 1  in the manufacture of a medicament for the treatment of an MLK-mediated disease. 
     
     
         41 . The use as recited in  claim 40 , wherein said MLK is MLK3. 
     
     
         42 . The use as recited in  claim 41 , wherein said disease is chosen from diabetes mellitus, hyperglycemia, retinopathy, nephropathy, neuropathy, ulcers, micro- and macroangiopathies, gout and diabetic foot disease, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, peripheral inflammation, cancer and hepatitis. 
     
     
         43 . A pharmaceutical composition comprising a compound as recited in  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         44 . A pharmaceutical composition comprising a compound as recited in  claim 43  together with a pharmaceutically acceptable carrier. 
     
     
         45 . A method of inhibition of MLK comprising contacting MLK with a compound as recited in  claim 1 . 
     
     
         46 . The method as recited in  claim 45 , wherein said MLK is MLK3. 
     
     
         47 . The method as recited in  claim 46  wherein said inhibition is selective over other kinases. 
     
     
         48 . A method of treatment of a MLK-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient in need thereof. 
     
     
         49 . The method as recited in  claim 48  wherein said disease is an inflammatory disease or a metabolic disease. 
     
     
         50 . The method as recited in  claim 49  wherein said disease is chosen from diabetes mellitus, hyperglycemia, retinopathy, nephropathy, neuropathy, ulcers, micro- and macroangiopathies, gout and diabetic foot disease, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, and peripheral inflammation. 
     
     
         51 . The method as recited in  claim 50  wherein said disease is an autoimmune disease. 
     
     
         52 . The method as recited in  claim 51  wherein said disease is chosen from cancer and hepatitis. 
     
     
         53 . A method of treatment of a MLK-mediated disease comprising the administration of:
 a. a therapeutically effective amount of a compound as recited in  claim 1 ; and   b. another therapeutic agent.   
     
     
         54 . A method of achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient, wherein the effect is chosen from:
 increased survival of heart cells; 
 suppression of neuroinflammation or peripheral inflammation; 
 suppression of activation of immune cells; 
 suppression of proliferation of hepatocytes following injury; and 
 suppression of proliferation of cancer cells. 
 
     
     
         55 . The method as recited in  claim 54 , wherein said immune cells are chosen from monocytes, macrophages and microglia. 
     
     
         56 . A method of treatment of a neuropsychiatric disorder in a patient, comprising the step of administering to said patient an MLK inhibitor. 
     
     
         57 . The method as recited in  claim 56 , wherein said MLK is MLK3. 
     
     
         58 . A method of treatment of a neuropsychiatric in a patient, comprising the step of administering to said patient a compound as recited in  claim 1 . 
     
     
         59 . The method as recited in  claim 58  wherein said disorder a psychological disorder. 
     
     
         60 . The method as recited in  claim 59  wherein said disease is chosen from depression, bipolar disorder, and post-traumatic stress disorder (PTSD). 
     
     
         61 . The method as recited in  claim 58  wherein said disorder is a traumatic brain injury. 
     
     
         62 . The method as recited in  claim 61  wherein said traumatic brain injury is stroke. 
     
     
         63 . The method as recited in  claim 58  wherein said disorder is chosen from Alzheimer's Disease (AD), Parkinson's Disease, and HIV associated neurocognitive disorder (HAND). 
     
     
         64 . The method as recited in  claim 58  wherein said disorder is a neurologic disorder of hearing or vision. 
     
     
         65 . The method as recited in  claim 64  wherein said disorder is chosen from ototoxicity, hearing loss, acute injury to the inner ear, acoustic trauma, and injury resulting from blast noise. 
     
     
         66 . The method as recited in  claim 2 , additionally comprising the administration of a second therapeutic agent. 
     
     
         67 . The method as recited in  claim 66  wherein said second therapeutic agent is a selective serotonin reuptake inhibitor (SSRI). 
     
     
         68 . The method as recited in  claim 66  wherein said second therapeutic agent is CRP 1347. 
     
     
         69 . A method of achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient, wherein the effect is chosen from:
 increased survival of cells of the nervous system, cochlear cells, vestibular cells or retinal cells; 
 promotion of neurogenesis; 
 promotion of synaptogenesis; 
 prevention or reduction of neuronal damage; and 
 restoration or improvement of neuronal function. 
 
     
     
         70 . A method of achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient, wherein the effect is chosen from:
 increased survival of cells of the nervous system, cochlear cells, vestibular cells or retinal cells; 
 increased survival of heart cells; 
 promotion of neurogenesis; 
 promotion of synaptogenesis; 
 prevention or reduction of neuronal damage; 
 restoration or improvement of neuronal function; 
 suppression of neuroinflammation or peripheral inflammation; 
 suppression of activation of immune cells; 
 suppression of proliferation of hepatocytes following injury; and 
 suppression of proliferation of cancer cells. 
 
     
     
         71 . The method as recited in  claim 70 , wherein said immune cells are chosen from monocytes, macrophages and microglia.