Organic Compounds as Smo Inhibitors

Abstract

The present invention relates generally to novel compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders. The present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action involve methods of inhibiting tumorigenesis, tumor growth and tumor survival using agents that inhibit the Hedgehog and Smo signaling pathway.

1 . A compound of Formula I: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R1 is a C 6-14  aryl group, or a 5-14 membered heteroaryl group, each of which may be unsubstituted or substituted by one or more of C 1-8  alkyl, a C 6-14  aryl group, C 1-8  haloalkyl, C 1-8  alkoxy, halo, NH 2 , CN, OCF 3 , OH, C(O)NR6R8, C(O)R6, NR6R8, NHC(O)R6, SO 2 R6, SO 2 NR6R8; 
 R2 and R3 are independently C 1-8  alkyl, C 1-8 alkylOH, or R2 and R3 form C 3-14  cycloalkyl group; 
 L is a bond, C 1-8  alkylene, —C(O)O—, —CONR9-, —C 1-8  alkylOH—, C 1-8  haloalkyl, —C(O)—, —NH— or —O—; 
 X and W are independently N, or CR5 and at least one of X and W is N; 
 R7 is a C 6-14  aryl group, a 5-14 membered heteroaryl group, or a 3-14 membered cycloheteroalkyl group; 
 R4 is C 1-8  alkyl, C 2-8  alkenyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8  alkoxy, halo, NR6R8, C(O)OR6, C(O)NR6R8, C 1-8 haloalkyl, formyl, carbalkoxy, C 1-8 alkylOH, C(O)R6, SO 2 R6, C(O)NHC 1-8 alkylR6, NR6R8, SO 2 NR6R8, OCF 3 , NHC(O)R6, CH 2 OC(O)NR6R8, CH 2 NR6R8, NHC(O)OR6, NHC(O)NR6R8, CH 2 NHSO 2 R6, CH 2 NHC(O)OR6, OC(O)R6, or NHC(O)R6, which may be substituted or unsubstituted; 
 Z is C 1-8  alkyl, CN, OH, or halogen; 
 m and p are independently 0-3; 
 Y is a bond, C 1-8  alkylene, —C(O)—, —C(O)O—, —CH(OH)—, or —C(O)N(R10)-; 
 R5 is H, halogen, CN, lower alkyl, OH, OCH 3  or OCF 3 ; 
 R9 and R10 are independently C 1-8  alkyl or H; 
 R6 and R8 are independently H, C 1-8  alkyl, C 2-8  alkenyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8 haloalkyl, C 1-8 alkylOH, C 1-8 alkoxy, or R6 and R8 on one atom can form a heteroatom containing ring; and 
 Wherein R4, R6, and R8 can be unsubstituted or substituted by one or more of C 1-8  alkyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8  alkylOH, OH, oxo, C 1-8  haloalkyl, carboxC 1-8  alkyl, or SO 2 C 1-8 alkyl, halo, —OCH 3 , —OCF 3 , —OH, —NH 2 . 
 
     
   
   
       2 . The compound of formula (I) according to  claim 1  wherein R7 is 
     
       
         
         
             
             
         
       
     
   
   
       3 . The compound of formula (I) according to  claim 1  wherein R1 is 
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound of formula (I) according to  claim 1  wherein R7 is 
     
       
         
         
             
             
         
       
       R1 is 
     
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound of formula (I) according to  claim 1  wherein R4 is C(O)OC 1-8  alkyl, CF 3 , C(O)OR6, C(O)NR6R8, C 1-8 haloalkyl, C 1-8 alkylOH, C(O)R6, SO 2 R6, C(O)NHC 1-8  alkylR6, C(CH 3 )(CH 3 )(OH), C(O)CH 3 , CH 2 —CH 2 —CH 3 , or C(CH 3 )(CH 2 OH)OH; and
 R6 and R8 are independently H, C 1-8  alkyl, C 1-8  alkenyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, or a 3-14 membered cycloheteroalkyl group.   
   
   
       6 . The compound of formula (I) according to  claim 1  wherein R1 may be unsubstituted or substituted with one or more of methyl, ethyl, isopropyl, Cl, F, CN, methoxy, or CF 3 ;
 R4 is C(O)CH 3 , C(O)NH-phenyl, C(O)OH, CF 3 , C(CH 3 )(CH 3 )OH, C(O)OCH 3 , CF 3 , C(O)OCH 2 CH 3 , or C(O)NCH 2 CH 3 , optionally substituted with piperazinyl, morpholinyl, or pyridinyl; and   p is 0, 1, or 2.   
   
   
       7 . The compound of formula (I) according to  claim 1  wherein R4 is methyl, phenyl, pyridinyl, methoxy, Cl, F, C(O)OC 1-8 alkyl, C(O)OH, C(O)NHC 6-14 aryl, C(O)NC 6-14 arylC 1-8 alkyl, C(O)-5-14membered heteroaryl group, C(O)-3-14membered cycloheteroalkyl group, CF 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 )(CH 3 )OH, C(O)CH 3 , C(O)CH 2 CH 3 , SO 2 C 1-8 alkyl, SO 2 CF 3 , C(O)NHC 1-8 alkylOH, C(O)NHC 1-8 alkylCF 3 . SO 2 NHC 1-8 alkyl, OCF 3 , NHC(O)CH 3 , or CH 2 OC(O)NHCH 3 . 
   
   
       8 . The compound of formula (I) according to  claim 1  wherein R4 is 
     
       
         
         
             
             
         
       
     
     which may be unsubstituted or substituted. 
   
   
       9 . The compound of formula (I) according to  claim 1  wherein R2 and R3 are C 1-8  alkyl. 
   
   
       10 . The compound of formula (I) according to  claim 1  wherein R2 and R3 are CH 3 . 
   
   
       11 . The compound of formula (I) according to  claim 1  wherein L is —O—, —NH—, —C(O)—, —CH(OH)—, —CH 2 —, —CF 2 —, —CHF—, —C(OH)—, or a bond. 
   
   
       12 . The compound of formula (I) according to  claim 1  wherein L is —CH 2 —. 
   
   
       13 . The compound of formula (I) according to  claim 1  wherein both X and W are N, and Z is CH 3 , and m is 1. 
   
   
       14 . The compound of formula (I) according to  claim 1  wherein R7 is 
     
       
         
         
             
             
         
       
       R4 is C(O)CH 3 , C(O)NH-phenyl, C(O)OH, CF 3 , C(CH 3 )(CH 3 )OH, C(O)OCH 3 , CF 3 , or C(O)OCH 2 CH 3 . 
     
   
   
       15 . A compound of formula (Ia): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R11 is C 1-8  alkyl, C 2-8  alkenyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8  alkoxy, halo, NR13R14, C(O)OR13, C(O)NR13R14, C 1-8 haloalkyl, formyl, carbalkoxy, C 1-8 alkylOH, C(O)R13, SO 2 R13, C(O)NHC 1-18 alkylR13, NR13R14, SO 2 NR13R14, OCF 3 , NHC(O)R13, CH 2 OC(O)NR13R14, CH 2 NR13R14, NHC(O)OR13, NHC(O)NR13R14, CH 2 NHSO 2 R13, CH 2 NHC(O)OR13, OC(O)R13, or NHC(O)R13, which may be substituted or unsubstituted; 
 R12 is H, C 1-8  alkyl, a C 6-14  aryl group, C 1-8  haloalkyl, C 1-8  alkoxy, halo, NH 2 , CN, OCF 3 , OH, C(O)NR13R14, C(O)R13, NR13R14, NHC(O)R13, SO 2 R13, SO 2 NR13R14; 
 R13 and R14 are independently H, C 1-8  alkyl, C 2-8  alkenyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8 haloalkyl, C 1-8  alkylOH, C 1-8 alkoxy, or R13 and R14 on one atom can form a heteroatom containing ring; and 
 Wherein R11, R13, and R14 can be unsubstituted or substituted by one or more of C 1-8  alkyl, C 3-14  cycloalkyl, a C 6-14  aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloheteroalkyl group, C 1-8  alkylOH, OH, oxo, C 1-8  haloalkyl, carboxC 1-8  alkyl, or SO 2 C 1-8 alkyl, halo, —OCH 3 , —OCF 3 , —OH, —NH 2 . 
 
     
   
   
       16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (Ia) according to  claim 1 . 
   
   
       17 . A method of treating a disease, disorder or syndrome associated with Smoothened inhibition, said method comprising administering a compound of formula (I) or (Ia) according to  claim 1  or its prodrug or pharmaceutical composition comprising the compound of formula I or its prodrug and pharmaceutically acceptable excipients to a subject in need thereof. 
   
   
       18 . The method of treating as claimed in  claim 17 , wherein the disease, disorder or syndrome is hyperproliferative in a subject, wherein subject is an animal including humans, selected from a group comprising cancer and inflammation. 
   
   
       19 . A compound according to  claim 1  for use in the prophylaxis or treatment of a disease state as described herein. 
   
   
       20 . The use of a compound according to  claim 1  for the manufacture of a medicament, wherein the medicament is for any one or more of the uses defined herein. 
   
   
       21 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       22 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier in a form suitable for oral administration. 
   
   
       23 . The compounds of formula (I) according to  claim 1  wherein said compound is selected from:
 2-[(R)-4-(4,5-Dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-{(R)-4-[6-(Hyrdoxy)-phenyl-methyl0-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-yl]-propan-2-ol;   2-[(R)-4-(4,5-Dimethyl-6-pyridin-4-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[(R)-4-(4,5-Dimethyl-6-pyridin-2-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′ ]bipyrazinyl-5′yl]-propan-2-ol;   2-[(S)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[4-(4-Benzyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   2-[(R)-4-(4-Benzyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol;   1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-ethanone; and   2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propane-1,2-diol.