Amino-heteroaryl-containing prokineticin 1 receptor antagonists

Abstract

The present invention relates to certain novel compounds of Formula (I): and methods for preparing these compounds, compositions, intermediates and derivatives thereof and for the treatment of prokineticin 1 or prokinetin 1 receptor mediated disorders.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is hydrogen, C 1-4 alkoxy, aryl, aryloxy, optionally benzofused heterocyclyl, or an optionally benzofused heteroaryl; 
         and aryl, aryloxy, heteroaryl, heterocyclyl, the benzo portion of benzofused heterocyclyl, and benzofused heteroaryl are optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, halogen, nitro, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, hydroxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkoxycarbonylamino, C 1-6 alkylcarbonyl, C 1-6 alkylthiocarbonyl, formyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; and wherein aryl, aryloxy, heteroaryl, heterocyclyl, the benzo portion of benzofused heterocyclyl, and benzofused heteroaryl are optionally further substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, and hydroxy; provided that A 1  is other than 3,5-di-t-butyl-phenyl; 
         L 1  is —(CH 2 ) r —, —CH 2 C 2-4 alkenyl-, or —CH 2 CH 2 X(CH 2 ) s —, wherein L 1  is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and halogen; and, r is an integer of 1 to 5; such that r is greater than or equal to 4 when A 1  is C 1-4 alkoxy; 
         s is an integer of 1 to 3; 
         X is O or S; 
         D is —P-A 2 ; 
         wherein P is —(CH 2 ) 1-2 — or —CH 2 CH═CH— when A 2  is phenyl, optionally benzofused heterocyclyl, optionally benzofused heteroaryl, or C 3-8 cycloalkyl; alternatively, P is —(CH 2 ) 3-6 —, when A 2  is hydrogen, C 1-4 alkoxy, or C 1-4 alkoxycarbonyl; and wherein P is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and halogen; 
         A 2  is hydrogen; dihydrobenzofuranyl; heteroaryl other than unsubstituted pyridin-2-yl; C 3-8 cycloalkyl; or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, hydroxy, nitro, C 1-6 alkylcarbonyl, C 1-6 alkylthiocarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; wherein dihydrobenzofuranyl, heteroaryl, and C 3-8 cycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, hydroxy, nitro, C 1-6 alkylcarbonyl, C 1-6 alkylthiocarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; 
         provided that no more than two substituents on A 2  are aryl(C 1-6 )alkoxy, phenyl, or a non fused C 3-6 cycloalkyloxy; 
         such that both A 1  and A 2  are not 4-fluoro-phenyl when L 1  and L 2  are both —CH 2 — and Q is a substituent of formula Q 1 ; 
         W is C(R W ); wherein R W  is H or C 1-2 alkyl; 
         L 2  is a bivalent radical selected from the group consisting of
 pyrrolidinyl or piperidinyl attached to the W-containing ring of Formula (I) via its nitrogen atom, wherein said pyrrolidinyl or piperidinyl is substituted on a carbon atom with —(CH 2 ) 0-2 —; 
 —NH—C 5-7 cycloalkyl(CH 2 ) 0-2 —; such that when C 5-7 cycloalkyl is cyclohexyl, Q is attached at either the 2- or cis-4-position relative to the position of NH—; 
 —C(═O)NH(CR y R z ) 2-5 —; 
 and 
 —NH—CH(R x )—(CR y R z ) 1-5 —; 
 
         R x , R y , and R z  are independently H or C 1-4 alkyl; 
         and provided that L 2  in any instance does not exceed 7 atoms in length; 
         such that Q is selected from the group consisting of Q 1 , Q 2 , Q 4 , and Q 6  when L 2  is other than —NH—CH(R x )—(CR y R z ) 1-5 —; 
         Q is 
       
       
         
           
           
               
               
           
         
         
           wherein the benzo portion of Q 1 , Q 2 , Q 4  and Q 6  is optionally substituted with R 1 ; 
         
         R 1  is one to two substituents independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halogen, trifluoromethyl, and C 1-4 alkylsulfonyl; 
         R a  and R b  are independently hydrogen, trifluoromethylcarbonyl, C 1- 4alkylcarbonyl, and methyl; 
         and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1  wherein A 1  is phenyl, 2,3-dihydro-benzofuranyl wherein the point of attachment to L 1  is at the benzo ring, or 1-methyl-benzotriazol-5-yl; wherein phenyl is optionally substituted with a substituent selected from the group consisting of C 1-2 alkyl, C 1-2 alkoxy, fluoro, chloro, and C 1-2 alkylthio; and wherein phenyl is optionally further substituted with a fluoro or chloro substituent. 
     
     
         3 . The compound of  claim 1  wherein A 1  is 4-ethyl-phenyl, 3,4-dichloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methylthio-phenyl, 2,3-dihydro-benzofuran-5-yl, or 1-methyl-benzotriazol-5-yl. 
     
     
         4 . The compound of  claim 1  wherein L 1  is (CH 2 ) r — optionally substituted with a substituent selected from the group consisting of methyl and allyl, provided that r is 1 to 3 when A 1  is other than hydrogen. 
     
     
         5 . The compound of  claim 1  wherein L 1  is —CH 2 —. 
     
     
         6 . The compound of  claim 1  wherein P is —CH 2 —. 
     
     
         7 . The compound of  claim 1  wherein A 2  is hydrogen, a heteroaryl other than unsubstituted pyridin-2-yl, dihydrobenzofuranyl, or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; wherein heteroaryl other than unsubstituted pyridin-2-yl and dihydrobenzofuranyl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy;
 provided that no more than two substituents on A 2  are aryl(C 1-6 )alkoxy, phenyl, or a non fused C 3-6 cycloalkyloxy. 
 
     
     
         8 . The compound of  claim 1  wherein A 2  is furanyl, pyridin-3-yl, pyridin-4-yl, or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, halogenated C 1- 3alkoxy, C 1-3 alkylthio, hydroxy, amino, aminocarbonyl, C 1- 3alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; and wherein furanyl, pyridin-3-yl, and pyridin-4-yl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, halogenated C 1-3 alkoxy, C 1-3 alkylthio, hydroxy, amino, aminocarbonyl, C 1-3 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy;
 provided that no more than two substituents on A 2  are non fused C 3-6 cycloalkyloxy. 
 
     
     
         9 . The compound of  claim 1  wherein A 2  is pyridin-3-yl, Pyridin-4-yl, or phenyl optionally substituted at the meta and para positions with one to two substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and methylcarbonylamino; wherein pyridin-3-yl and pyridin-4-yl are optionally substituted with one to two substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and methylcarbonylamino. 
     
     
         10 . The compound of  claim 1  wherein A 2  is phenyl substituted at the para position with a substituent selected from the group consisting of methoxy, ethoxy, isopropyloxy, difluoromethoxy, hydroxy, and aminocarbonyl; or A 2  is pyridin-3-yl or pyridin-4-yl substituted with methoxy. 
     
     
         11 . The compound of  claim 1  wherein W is C(R w ) wherein R w  is H. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1  wherein L 2  is a bivalent radical selected form the group consisting of —C(═O)NH(CR y R z ) 2-5 — and —NH—CH(R x )—(CR y R z ) 1-5 —; wherein R x , R y , and R z  are independently H or C 1-4 alkyl;
 and provided that L 2  in any instance does not exceed 7 atoms in length; such that Q is selected from the group consisting of Q 1 , Q 2 , Q 4 , and Q 6  when L 2  is other than —NH—CH(R x )—(CR y R z ) 1-5 —. 
 
     
     
         14 . The compound of  claim 1  wherein L 2  is a bivalent radical selected form the group consisting of —NH—CH 2 CH 2 —; wherein R x , R y , and R z  are each H. 
     
     
         15 . The compound of  claim 1  wherein Q is 
       
         
           
           
               
               
           
         
         wherein R a  and R b  are each hydrogen. 
       
     
     
         16 . The compound of  claim 1  wherein R 1  is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro, and trifluoromethyl. 
     
     
         17 . The compound of  claim 1  wherein R 1  is a substituent selected from hydrogen, fluoro, or chloro. 
     
     
         18 . The compound of  claim 1  wherein R a  and R b  are each hydrogen. 
     
     
         19 . The compound of  claim 1  wherein
 A 1  is phenyl, benzofused heterocyclyl wherein the point of attachment to L 1  is at benzo ring, or benzofused heteroaryl; wherein phenyl, the benzo portion of benzofused heterocyclyl, and benzofused heteroaryl are optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, fluoro, chloro, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, cyano, hydroxy, aminocarbonyl, C 1-4 alkylaminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkoxycarbonylamino, C 1-4 alkylcarbonyl, C 1-4 alkylthiocarbonyl, formyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, aminosulfonyl, C 1-4 alkylaminosulfonyl, and di(C 1-4 alkyl)aminosulfonyl; and wherein phenyl, the benzo portion of benzofused heterocyclyl, and benzofused heteroaryl are optionally further substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, and hydroxy; provided that A 1  is other than 3,5-di-t-butyl-phenyl; 
 L 1  is —(CH 2 ) r —, optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and halogen; provided that when A 1  is hydrogen, r is greater than or equal to 4; 
 D is —P— A 2 ; 
 P is —CH 2 — or —CH 2 CH═CH—; 
 A 2  is hydrogen, heteroaryl other than unsubstituted pyridin-2-yl, dihydrobenzofuranyl, or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; wherein heteroaryl other than unsubstituted pyridin-2-yl and C 3-8 cycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; 
 provided that no more than two substituents on A 2  are aryl(C 1-6 )alkoxy, phenyl, or a non fused C 3-6 cycloalkyloxy; 
 W is C(R w ) wherein R w  is H; 
 L 2  is a bivalent radical selected form the group consisting of —C(═O)NH(CR y R z ) 2-6  and —NH—CH(R x )—(CR y R z ) 1-5 —; 
 wherein R x , R y , and R z  are independently H or C 1-4 alkyl; such that Q is selected from the group consisting of Q 1 , Q 2 , Q 4 , and Q 6  when L 2  is other than —NH—CH(R x )—(CR y R z ) 1-5 —; 
 and provided that L 2  in any instance does not exceed 7 atoms in length; 
 Q is 
 
       
         
           
           
               
               
           
         
         R 1  is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro, and trifluoromethyl; 
         R a  is hydrogen, trifluoromethylcarbonyl, methylcarbonyl, or t-butylcarbonyl; and R b  is hydrogen; 
         and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. 
       
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A compound of Formula (Ia) (wherein L 1  is CH 2 ) 
       
         
           
           
               
               
           
         
         selected from the group consisting of 
         a compound of Formula (Ia) wherein A 1  is 4-methoxy-phenyl, D is 4-methoxy-phenylmethyl, W is CH, L 2  is —C(O)NH(CH 2 ) 2 —, and Q is 2-amino-benzoimidazol-1-yl; 
         and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. 
       
     
     
         23 . A pharmaceutical composition comprising a compound, salt or solvate according to  claim 1  admixed with a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         24 . A pharmaceutical composition comprising a compound, salt, or solvate according to  claim 22  admixed with a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         25 . A method of treating or preventing a disease or condition in a mammal in which the disease or condition selected from the group consisting of gastrointestinal (GI) diseases, GERD and secretory diarrhea, cancers of the GI tract and reproductive organs, and pain.