Thieno [ 3,2-b] pyridine-6-carbonitriles and thieno [2,3-b] pyridine-5-carbonitriles as protein kinase inhibitors

Abstract

This invention provides compounds of Formula (1a)-(1f), II wherein: X, m, n, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y, Q, Z, Z′, Z′″, Z″ and J are defined hereinbefore in the specification, which are useful in the treatment of cancer, stroke, myocardial infarction, neuropathic pain, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid arthritis, and transplant rejection and process for producing said compounds.

1 - 4 . (canceled)  
     
     
         5 . A method of treating or inhibiting a pathological condition or disorder responsive to inhibition of a tyrosine kinase in a mammal, the method comprising providing to said mammal an effective amount of a compound of Formula Ia or Ib, or an S-oxide, an S-dioxide, or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is —NH—, —NR 4 —, —O—, —S(O) m —, or —NHCH 2 —;  
 m is 0, 1, or 2;  
 n is 2, 3, 4, or 5;  
 q is 0, 1, 2, 3, 4, or 5;  
 R 1  is a phenyl ring optionally substituted with one to four substituents selected from -J, —NO 2 , —CN, —N 3 , —CHO, —CF 3 , —OCF 3 , —R 4 , —OR 4 , S(O) m R 4 , —NR 4 R 4 , —NR 4 S(O) m R 4 , —OR 6 OR 4 , —OR 6 NR 4 R 4 , —N(R 4 )R 6 OR 4 , —N(R 4 )R 6 NR 4 R 4 , —NR 4 C(O)R 4 , —C(O)R 4 , —C(O)OR 4 , —C(O)NR 4 R 4 , —OC(O)R 4 , —OC(O)OR 4 , —OC(O)NR 4 R 4 , —NR 4 C(O)R 4 , —NR 4 C(O)OR 4 , —NR 4 C(O)NR 4 R 4 , —R 5 OR 4 , —R 5 NR 4 R 4 —R 5 S(O) m R 4 , —R 5 C(O)R 4 , —R 5 C(O)OR 4 , —R 5 C(O)NR 4 R 4 , —R 5 OC(O)R 4 , —R 5 OC(O)OR 4 , —R 5 OC(O)NR 4 R 4 , —R 5 NR 4 C(O)R 4 , —R 5 NR 4 C(O)OR 4 —R 5 NR 4 C(O)NR 4 R 4 , and —YR 7 ;  
 R 2  is —H, —R 3 , -J, —C(O)XR 3 , or —CHO, wherein the R 3  group is optionally substituted with one or more groups selected from —C(O)XR 8 , —CHO, —C(O)Q, 1,3-dioxolane, —R 8 , —(C(R 9 ) 2 ) q XR 8 , —(C(R 9 ) 2 ) q Q, —X(C(R 9 ) 2 ) n XR 8 , —X(C(R 9 ) 2 ) n Q, and —X(C(R 9 ) 2 ) q R 8 ;  
 R 3  is an alkyl of 1 to 6 carbon atoms, a cis-alkenyl of 2-6 carbon atoms, a trans-alkenyl of 2-6 carbon atoms, an alkynyl of 2-6 carbon atoms, or an aryl or heteroaryl ring;  
 R 4  is H, an alkyl of 1-6 carbon atoms, a cis-alkenyl of 2-6 carbon atoms, a trans-alkenyl of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;  
 R 5  is a divalent group comprising an alkyl of 1-6 carbon atoms, an alkenyl of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;  
 R 6  is a divalent alkyl group of 2-6 carbon atoms;  
 R 7  is a cycloalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, or an aryl or heteroaryl ring fused to one to three aryl or heteroaryl rings, wherein each of the aryl rings, the cycloalkyl rings, and the heteroaryl rings is optionally substituted with one to four substituents selected from an aryl ring, —CH 2 -aryl, —NH-aryl, —O-aryl, —S(O) m -aryl, -J, —NO 2 , —CN, —N 3 , —CHO, —CF 3 , —OCF 3 , —R 4 , —OR 4 , —S(O) m R 4 , —NR 4 R 4 , —NR 4 S(O) m R 4 , —OR 6 OR 4 , —OR 6 NR 4 R 4 , —N(R 4 )R 6 OR 4 , —N(R 4 )R 6 NR 4 R 4 , —NR 4 C(O)R 4 , —C(O)R 4 , —C(O)OR 4 , —C(O)NR 4 R 4 , —OC(O)R 4 , —OC(O)OR 4 , —OC(O)NR 4 R 4 , —NR 4 C(O)R 4 , —NR 4 C(O)OR 4 , —NR 4 C(O)NR 4 R 4 , —R 5 OR 4 , —R 5 NR 4 R 4 , R 5 S(O) m R 4 , —R 5 C(O)R 4 , —R 5 C(O)OR 4 , —R 5 C(O)NR 4 R 4 , —R 5 C(O)R 4 , —R 5 C(O)OR 4 , —R 5 C(O)NR 4 R 4 , —R 5 OC(O)R 4 , —R 5 OC(O)OR 4 , —R 5 OC(O)NR 4 R 4 , —R 5 NR 4 C(O)R 4 , —R 5 NR 4 C(O)OR 4 , and —R 5 NR 4 C(O)NR 4 R 4 ;  
 R 8  is H, an alkyl of 1 to 6 carbon atoms, a cis-alkenyl of 2-6 carbon atoms, a trans-alkenyl of 2-6 carbon atoms, an alkynyl of 2-6 carbon atoms, or an aryl or heteroaryl ring;  
 R 9  is —R 4  or —F;  
 Y is —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO 2 —, —SO 2 NH—, —C(OH)H—, —X(C(R 9 ) 2 ) q —, —(C(R 9 ) 2 ) q —, —(C(R 9 ) 2 ) q X—, —C≡C—, cis- and trans- —CH═CH— or a divalent cycloalkyl of 3-10 carbon atoms;  
 Q is NZZ′, wherein Z and Z′ are the same or different and are independently H, an alkyl of 1 to 6 carbon atoms, an alkenyl of 2-6 carbon atoms, an alkynyl of 2-6 carbon atoms, an aryl or heteroaryl ring, or alternatively, Z and Z′ taken together with the nitrogen to which they are attached form a heterocyclic ring which optionally has an additional heteroatom selected from nitrogen, oxygen, and sulfur, and the heterocyclic ring is optionally substituted with —R 4  on a carbon or a nitrogen, with —(C(R 9 ) 2 ) n XR 4  or —(C(R 9 ) 2 ) n NZ″Z′″ on a nitrogen, or with —(C(R 9 ) 2 ) q XR 4  or —(C(R 9 ) 2 ) q NZ″Z′″ on a carbon, wherein:  
 Z″ and Z′″ taken together with the nitrogen to which they are attached form a heterocyclic ring which optionally has an additional heteroatom selected from nitrogen, oxygen, and sulfur, or alternatively, Z″ and Z′″ are independently H, an alkyl of 1 to 6 carbon atoms, an alkenyl of 2-6 carbon atoms, an alkynyl of 2-6 carbon atoms, or an aryl or heteroaryl ring; and  
 J is fluoro, chloro, bromo, or iodo.  
 
     
     
         6 - 17 . (canceled)  
     
     
         18 . The method of  claim 5 , wherein the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The method of  claim 5 , wherein X is —NH—, —NR 4 —, or —NHCH 2 —.  
     
     
         20 . The method of  claim 5 , wherein R 1  is a phenyl ring optionally substituted with one to four substituents selected from -J, —CF 3 , —OCF 3 , —R 4 , and —OR 4 .  
     
     
         21 . The method of  claim 5 , wherein R 2  is R 3 , wherein R 3  is an aryl or heteroaryl ring substituted with —(C(R 9 ) 2 ) q Q.  
     
     
         22 . The method of  claim 5 , wherein R 2  is R 3 , wherein R 3  is an aryl or heteroaryl ring substituted with —CH 2 Q.  
     
     
         23 . The method of  claim 22 , wherein Q is selected from a morpholinyl group, a piperazinyl group, and a piperidinyl group, each of which optionally is substituted with —R 4  on a carbon or a nitrogen, with —(C(R 9 ) 2 ) n XR 4  or —(C(R 9 ) 2 ) n NZ″Z′″ on a nitrogen, or with —(C(R 9 ) 2 ) n XR 4  or —(C(R 9 ) 2 ) q NZ″Z′″ on a carbon.  
     
     
         24 . The method of  claim 5 , wherein the compound is selected from: 
 (21E)-3-(6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)prop-2-enoate;    2-(1-benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-(4-formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-(4-formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile;    2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine]-6-carbonitrile;    2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile;    2-[4-(hydroxymethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-[4-(morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine]-6-carbonitrile;    2-{4-[(butylamino)methyl]phenyl}-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-{4-[(dimethylamino)methyl]phenyl}-1,1-dioxo-7-[(3,4,5-trimethoxyphenyl)amino]-1H-thieno[3,2-b]pyridine-6-carbonitrile.    2-{4-[(dimethylamino)methyl]phenyl}-1-oxo-7-[(3,4,5-trimethoxyphenyl)amino]-1H-thieno[3,2-b]pyridine-6-carbonitrile;    2-{4-[(dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-{4-[(dimethylamino)methyl]phenyl}7-[(5-methoxy-2-methylphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile;    2-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile;    2-bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    2-iodo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-ylmethyl)phenyl]thieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-carbonitrile;    4-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile;    4-[(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile;    4-[5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid methyl ester;    4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzoic acid;    4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzamide;    4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}-N,N-dimethylbenzamide;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-ylbut-1-ynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[3-(diethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-iodothieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({5-[(dimethylamino)methyl]pyridin-2-yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({6-[(dimethylamino)methyl]pyridin-2-yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrrol-3-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(2-methoxyethyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4{[(2R,5S)-2,5-dimethylpiperazin-1-l]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-hydroxypropyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-methylbutyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(pyridin-4-ylmethyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[3-(dimethylamino)propyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(pyridin-2-ylmethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-morpholin-4-ylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-2-furyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-3-furyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-2-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(6-morpholin-4-ylpyridin-3-yl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(1E)-3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(1-methyl-1H-imidazol-5-yl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[3,2-b]pyridine]-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-({[2-(methylthio)ethyl]amino}methyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-1-oxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-1,1-dioxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(thiomorpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)-2-furyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-2-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(4-methylpiperazin-1-ylmethyl)furan-3-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)pyridin-2-l]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[6-(4-methylpiperazin-1-ylmethyl)pyridin-3-yl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{1-[2-(dimethylamino)ethyl]-1H-pyrrol-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{1-methyl-2-[(4-methylpiperazin-1-yl)methyl]-1H-imidazol-5-yl}thieno[3,2-b]pyridine]-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{2-[(4-methylpiperazin-1-yl)methyl]thien-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1-oxidothiomorpholin-4-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-phenylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyridin-2-ylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}-1-oxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}-1,1-dioxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[2-(dimethylamino)ethyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-furyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(diethylamino)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]furan-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]-2-furyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethylamino)methyl]pyridin-3-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethylamino)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichlorphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2-chloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2-chloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(4-phenoxyphenyl)amino]-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(5-methoxy-2-methylphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile; and    tert-butyl(2E)-3-{6-cyano-7-[(2,4dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}prop-2-enoate;    or a pharmaceutical acceptable salt thereof.    
     
     
         25 . The method of  claim 5 , wherein the pathological condition or disorder is selected from stroke, cancer, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid arthritis, transplant rejection, and neuropathic pain.  
     
     
         26 . The method of  claim 5 , wherein the pathological condition or disorder is cancer.  
     
     
         27 . The method of  claim 5 , wherein the pathological condition or disorder is selected from breast cancer, kidney cancer, bladder cancer, mouth cancer, larynx cancer, esophagus cancer, stomach cancer, prostate cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, liver cancer, and ovarian cancer.  
     
     
         28 . The method of  claim 5 , wherein the pathological condition or disorder is breast cancer.  
     
     
         29 . The method of  claim 5 , wherein the pathological condition or disorder is chronic myeloid leukemia.  
     
     
         30 . The method of  claim 5 , wherein the pathological condition or disorder is abnormal cellular proliferation.  
     
     
         31 . A method of treating or inhibiting a pathological condition or disorder responsive to inhibition of a tyrosine kinase in a mammal, the method comprising providing to said mammal an effective amount of a compound of Formula Ia or Ib, or an S-oxide, an S-dioxide, or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is —NH—;  
 q is 1, 2, or 3;  
 R 1  is a phenyl ring optionally substituted with one to four substituents selected from -J, —R 4 , and —OR 4 ;  
 R 2  is R 3 , wherein R 3  is an aryl or heteroaryl ring substituted with one or more groups selected from —(C(R 9 ) 2 ) q Q;  
 R 4  is an alkyl of 1-6 carbon atoms;  
 R 9  is H;  
 Q is NZZ′, wherein Z and Z′ are the same or different, and are independently H or an alkyl of 1 to 6 carbon atoms, or alternatively, Z and Z′ taken together with the nitrogen to which they are attached form a heterocyclic ring which optionally has an additional heteroatom selected from nitrogen and oxygen, and the heterocyclic ring is optionally substituted with —R 4  or —(CH 2 ) 2 OH on a carbon or a nitrogen; and  
 J is fluoro, chloro, bromo, or iodo.  
 
     
     
         32 . The method of  claim 31 , wherein the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof.  
     
     
         33 . The method of  claim 32 , wherein Q is a piperazinyl group optionally substituted with —R 4  or —(CH 2 ) 2 OH on a carbon or a nitrogen.  
     
     
         34 . The method of  claim 31 , wherein the compound is selected from: 
 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile; and    7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethylamino)methyl]pyridin-2-yl}thieno[3,2-b]pyridine-6-carbonitrile;    or a pharmaceutical acceptable salt thereof.    
     
     
         35 . The method of  claim 31 , wherein the pathological condition or disorder is selected from stroke, cancer, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid arthritis, transplant rejection, and neuropathic pain.  
     
     
         36 . The method of  claim 31 , wherein the pathological condition or disorder is cancer.  
     
     
         37 . The method of  claim 31 , wherein the pathological condition or disorder is selected from breast cancer, kidney cancer, bladder cancer, mouth cancer, larynx cancer, esophagus cancer, stomach cancer, prostate cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, liver cancer, and ovarian cancer.  
     
     
         38 . The method of  claim 31 , wherein the pathological condition or disorder is breast cancer.