US2011098275A1PendingUtilityA1

5-alkynyl-pyridines

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Assignee: BOEHRINGER INGELHEIM INTPriority: Apr 21, 2009Filed: Apr 20, 2010Published: Apr 28, 2011
Est. expiryApr 21, 2029(~2.7 yrs left)· nominal 20-yr term from priority
Inventors:Tobias WunbergSiegfried SchneiderLars Van Der Veen
A61P 37/06A61P 37/00A61P 43/00A61P 35/02A61P 29/00A61P 35/00A61P 31/00C07D 213/73C07D 471/04C07D 401/14C07D 405/14C07D 487/08C07D 413/14C07D 401/06A61K 31/496
42
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Claims

Abstract

The present invention encompasses compounds of general formula (1) wherein R 1 to R 4 , m and n are defined as in the specification, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a medicament having the above-mentioned properties.

Claims

exact text as granted — not AI-modified
1 . A compound of the formula (1), 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 4  independently from one another denotes a group selected from among R a , R b  and R a  substituted by one or more identical or different R b  and/or R c ; or 
 one R 1  together with the pyridine form a 9-10 membered heteroaryl ring, which is optionally substituted with one or more identical or different R b  and/or R c  and R 2  and R 3  independently from one another denotes a group selected from among C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl, optionally substituted by one or more identical or different R 5  and 
 each R 5  denotes a group selected from among R a , R b  and R a  substituted by one or more identical or different R b  and/or R c ; and 
 each R a  independently of one another denotes a group optionally substituted by one or more identical or different R b  and/or R c , selected from among C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl, 
 each R b  denotes a suitable group and is selected independently of one another from among ═O, —OR c , C 1-3 haloalkyloxy, —OCF 3 , ═S, —SR c , ═NR c , ═NOR c , ═NNR c R c , ═NN(R g )C(O)NR c R c , —NR c R c , —ONR c R c , —N(OR c )R c , —N(R g )NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R c , —S(O)OR c , —S(O) 2 R c , —S(O) 2 OR c , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R c , —OS(O) 2 R c , —OS(O) 2 OR c , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R c , —C(O)OR c , —C(O)SR c , —C(O)NR c R c , —C(O)N(R g )NR c R c , —C(O)N(R g )OR c , —C(NR g )NR c R c , —C(NOH)R c , —C(NOH)NR c R c , —OC(O)R c , —OC(O)OR c , —OC(O)SR c , —OC(O)NR c R c , —OC(NR g )NR c R c , —SC(O)R c , —SC(O)OR c , —SC(O)NR c R c , —SC(NR g )NR c R c , —N(R g )C(O)R c , —N[C(O)R C ] 2 , —N(OR g )C(O)R c , —N(R g )C(NR g )R c , —N(R g )N(R g )C(O)R c , —N[C(O)R c ]NR c R c , —N(R g )C(S)R c , —N(R g )S(O)R c , —N(R g )S(O)OR c , —N(R g )S(O) 2 R c , —N[S(O) 2 R c ] 2 , —N(R g )S(O) 2 OR c , —N(R g )S(O) 2 NR c R c , —N(R g )[S(O) 2 ] 2 R c , —N(R g )C(O)OR c , —N(R g )C(O)SR c , —N(R g )C(O)NR c R c , —N(R g )C(O)NR g NR c R c , —N(R g )N(R g )C(O)NR c R c , —N(R g )C(S)NR c R c , —[N(R g )C(O)] 2 R c , —N(R g )[C(O)] 2 R c , —N{[C(O)] 2 R c } 2 , —N(R g )[C(O)] 2 OR c , —N(R g )[C(O)] 2 NR c R c , —N{[C(O)] 2 OR c } 2 , —N{[C(O)] 2 NR c R c } 2 , —[N(R g )C(O)] 2 OR c , —N(R g )C(NR g )OR c , —N(R g )C(NOH)R c , —N(R g )C(NR g )SR c , —N(R g )C(NR g )NR c R c  and —N═C(R g )NR c R c  and 
 each R c  independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R d  and/or R e , selected from among C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and 
 each R d  denotes a suitable group and is selected independently of one another from among ═O, —OR e , C 1-3 haloalkyloxy, —OCF 3 , ═S, —SR e , ═NR e , ═NOR e , ═NNR e R e , ═NN(R g )C(O)NR e R e , —NR e R e , —ONR e R e , —N(R g )NR e R e , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R e , —S(O)OR e , —S(O) 2 R e , —S(O) 2 OR e , —S(O)NR e R e , —S(O) 2 NR e R e , —OS(O)R e , —OS(O) 2 R e , —OS(O) 2 OR e , —OS(O)NR e R e , —OS(O) 2 NR e R e , —C(O)R e , —C(O)OR e , —C(O)SR e , —C(O)NR e R e , —C(O)N(R g )NR e R e , —C(O)N(R g )OR e , —C(NR g )NR e R e , —C(NOH)R e , —C(NOH)NR e R e , —OC(O)R e , —OC(O)OR e , —OC(O)SR e , —OC(O)NR e R e , —OC(NR g )NR e R e , —SC(O)R e , —SC(O)OR e , —SC(O)NR e R e , —SC(NR g )NR e R e , —N(R g )C(O)R e , —N[C(O)R e ] 2 , —N(OR g )C(O)R e , —N(R g )C(NR g )R e , —N(R g )N(R g )C(O)R e , —N[C(O)R e ]NR e R e , —N(R g )C(S)R e , —N(R g )S(O)R e , —N(R g )S(O)OR e —N(R g )S(O) 2 R e , —N[S(O) 2 R e ] 2 , —N(R g )S(O) 2 OR e , —N(R g )S(O) 2 NR e R e , —N(R g )[S(O) 2 ] 2 R e , —N(R g )C(O)OR e , —N(R g )C(O)SR e , —N(R g )C(O)NR e R e , —N(R g )C(O)NR g NR e R e , —N(R g )N(R g )C(O)NR e R e , —N(R g )C(S)NR e R e , —[N(R g )C(O)] 2 R e , —N(R g )[C(O)] 2 R e , —N{[C(O)] 2 R e } 2 , —N(R g )[C(O)] 2 OR e , —N(R g )[C(O)] 2 NR e R e , —N{[C(O)] 2 OR e } 2 , —N{[C(O)] 2 NR e R e } 2 , —[N(R g )C(O)] 2 OR e , —N(R g )C(NR g )OR e , —N(R g )C(NOH)R e , —N(R g )C(NR g )SR e , —N(R g )C(NR g )NR e R e  and —N═C(R g )NR e R e    
 each R e  independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R f  and/or R g , selected from among C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and 
 each R f  denotes a suitable group and in each case is selected independently of one another from among ═O, —OR g , C 1-3 haloalkyloxy, —OCF 3 , ═S, —SR g , ═NR g , ═NOR g , ═NNR g R g , ═NN(R h )C(O)NR g R g , —NR g R g , —ONR g R g , —N(R h )NR g R g , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R g , —S(O)OR g , —S(O) 2 R g , —S(O) 2 OR g , —S(O)NR g R g , —S(O) 2 NR g R g , —OS(O)R g , —OS(O) 2 R g , —OS(O) 2 OR g , —OS(O)NR g R g , —OS(O) 2 NR g R g , —C(O)R g , —C(O)OR g , —C(O)SR g , —C(O)NR g R g , —C(O)N(R h )NR g R g , —C(O)N(R h )OR g , —C(NR h )NR g R g , —C(NOH)R g , —C(NOH)NR g R g , —OC(O)R g , —OC(O)OR g , —OC(O)SR g , —OC(O)NR g R g , —OC(NR h )NR g R g , —SC(O)R g , —SC(O)OR g , —SC(O)NR g R g , —SC(NR h )NR g R g , —N(R h )C(O)R g , —N[C(O)R 9 ] 2 , —N(OR h )C(O)R g , —N(R h )C(NR h )R g , —N(R h )N(R h )C(O)R g , —N[C(O)R g ]NR g R g , —N(R h )C(S)R g , —N(R h )S(O)R g , —N(R h )S(O)OR g , —N(R h )S(O) 2 R g , —N[S(O) 2 R g ] 2 , —N(R h )S(O) 2 OR g , —N(R h )S(O) 2 NR g R g , —N(R h )[S(O) 2 ] 2 R g , —N(R h )C(O)OR g , —N(R h )C(O)SR g , —N(R h )C(O)NR g R g , —N(R h )C(O)NR h NR g R g , —N(R h )N(R h )C(O)NR g R g , —N(R h )C(S)NR g R g , —[N(R h )C(O)] 2 R g , —N(R h )[C(O)] 2 R g , —N{[C(O)] 2 R g } 2 , —N(R h )[C(O)] 2 OR g , —N(R h )[C(O)] 2 NR g R g , —N{[C(O)] 2 OR g } 2 , —N{[C(O)] 2 NR g R g } 2 , —[N(R h )C(O)] 2 OR g , —N(R h )C(NR h )OR g , —N(R h )C(NOH)R g , —N(R h )C(NR h )SR g , —N(R h )C(NR h )NR g R g ; and —N═C(R h )NR h R h ; and 
 each R g  independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R h , selected from among C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and 
 each R h  is selected independently of one another from among hydrogen, C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and 
 m denotes 0, 1 or 2; and 
 n denotes 0, 1, 2 or 3; and 
 or a tautomer or salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein R 3  denotes C 6-10 aryl or 5-12 membered Heteroaryl, optionally substituted by one or more identical or different R 5 . 
     
     
         3 . A compound according to  claim 2 , wherein R 3  denotes phenyl, optionally substituted by one or more identical or different R 5 . 
     
     
         4 . A compounds according to  claim 2 , wherein R 3  denotes pyridyl, optionally substituted by one or more identical or different R 5 . 
     
     
         5 . A compound according to  claim 2 , wherein R 3  denotes pyrazolyl, optionally substituted by one or more identical or different R 5 . 
     
     
         6 . A compound according to  claim 1 , wherein R 2  denotes methyl or ethyl. 
     
     
         7 . A compound according to  claim 1 , wherein n denotes 1 or 2. 
     
     
         8 . A compound according to  claim 1 , wherein R 1  denotes methyl, ethyl, or —NR c R c . 
     
     
         9 . A compound according to  claim 1 , wherein R 1  is —NH 2 , —NH—CH 3  or —N(CH 3 ) 2 . 
     
     
         10 . A compound according to  claim 1 , wherein R a  is hydrogen, methyl, ethyl or cyclopropyl. 
     
     
         11 . A compound according to  claim 1 , wherein R b  is —F, —Cl, —CH 3 , —OCH 3 , —CF 3 , —C(O)—R c , —C(O)NR c R c , —C(O)OH, —C(O)OCH 3 , —C(O)—NH 2 , —C(O)—NHCH 3 , —C(O)—N(CH 3 ) 2 , —S(O) 2 CH 3 , or -2-propyl-R c . 
     
     
         12 . A compound according to  claim 1 , wherein R c  is —H, —CN, -methyl, -ethyl, —(CH 2 ) 2 —OCH 3 , piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl. 
     
     
         13 . A compound according to  claim 1 , wherein R 3  is phenyl substituted with one or more R 5 , wherein at least one of R 5  is —C(O)R c  and wherein R c  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound according to  claim 1 , wherein R d  is —H, -methyl, -ethyl, -propyl, —OH, —OCH 3 , or —C(O)CH 3 . 
     
     
         15 . A compound according to  claim 1 , wherein R e  is -cyclopropyl, cyclopentyl, oxiranyl, tetrahydropyranyl, or morpholinyl. 
     
     
         16 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A compound selected from the group consisting of:
 2-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-phenyl}-2-methyl-propionitrile,   5-(2,2′-Diethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine,   5-(2-Ethyl-2′,6′-dimethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine,   5-(6-Cyclopropyl-2′-ethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine,   5-(2′-Ethyl-6-trifluoromethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-morpholin-4-yl-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-piperazin-1-yl-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,   {4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-methyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,   {4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone,   {4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone,   {4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone,   1-(4-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoyl}-piperazin-1-yl)-ethanone, and   4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-N-(2-methoxy-ethyl)-N-methyl-benzamide,   or a salt thereof.   
     
     
         18 . A pharmaceutically acceptable salt of a compound according to any one of  claims 1  to  17 . 
     
     
         19 . A pharmaceutical composition comprising a compound according to one of  claims 1  to  17  or a pharmaceutically acceptable salt thereof, in combination with a carrier or diluent.

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