Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer

Abstract

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R1, R2, R3 and X have meanings provided in the description, which compounds are useful in the treatment of cancers.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         L represents —S(O) n —; 
         n represents 2 or 1; 
         X represents C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl each optionally substituted by one or more groups independently selected from Y; 
         R 1  represents halo, —N(R j1 )R k1 , —OR l1  or —SR m1 ; 
         R 2  and R 3  each independently represent H, halo, R a1 , —CN, -A a1 -C(Q a1 )R b1 , -A b1 -C(Q b1 )N(R c1 )R d1 , -A c1 -C(Q c1 )OR e1 , -A d1 -S(O) p R f1 , -A e1 -S(O) p N(R g1 )R h1 , -A f1- -S(O) p OR i1 , —N 3 , —N(R j1 )R k1 , —N(H)CN, —NO 2 , —ONO 2 , —OR l1  or —SR m1 , 
         each A a1  to A f1  independently represents a single bond, —N(R p1 )— or —O—; 
         each Q a1  to Q c1  independently represents ═O, ═S, ═NR a1  or ═N(OR o1 ); 
         each R a1  and R f1  independently represents C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more groups independently selected from G 1a , heterocyclyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; 
         each R b1 , R c1 , R d1 , R e1 , R g1 , R h1 , R i1 , R j1 , R k1 , R l1 , R m1 , R n1 , R o1  and R p1  independently represents H, C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more groups independently selected from G 1a , heterocyclyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; 
         any of R c1  and R d1 , R g1  and R h1  and/or R j1  and R k1  are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from G 1b , C 1-3  alkyl, C 2-3  alkenyl or C 2-3  alkynyl each optionally substituted by one or more G 1a , and ═O; 
         each G 1a  and G 1b  independently represents halo, —CN, —N(R a2 )R b2 , —OR c2 , —SR d2  or ═O; 
         each R a2 , R b2 , R c2  and R d2  independently represents H, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more fluoro; or 
         R a2  and R b2  are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro and C 1-3  alkyl, C 2-3  alkenyl or C 2-3  alkynyl each optionally substituted by one or more fluoro; 
         each Y independently represents halo, R a3 , —CN, -A a2 -(Q a2 )R b3 , -A b2 -(Q b2 )N(R c3 )R d3 , -A c2 -(Q c2 )OR e3 , -A d2 -S(O) q R f3 , -A e2 -S(O) q N(R g3 )R h3 , -A f2 -S(O) q OR i3 , —N 3 , —N(R j3 )R k3 , —N(H)CN, —NO 2 , —ONO 2 , —OR l3 , —SR m2  or ═O; 
         each Q a2  to Q c2  independently represents ═O, ═S, ═NR a3  or ═N(OR o3 ); 
         each A a2  to A f2  independently represents a single bond, —N(R p3 )— or —O—; 
         each R a3  independently represents heterocyclyl optionally substituted by one or more groups independently selected from G 2b , aryl optionally substituted by one or more groups independently selected from G 2c , or heteroaryl optionally substituted by one or more groups independently selected from G 2d ; 
         each R f3  independently represents C 1-6  alkyl optionally substituted by one or more groups independently selected from G 2a , heterocyclyl optionally substituted by one or more groups independently selected from G 2b , aryl optionally substituted by one or more groups independently selected from G 2c , or heteroaryl optionally substituted by one or more groups independently selected from G 2d ; 
         each R b3 , R c3 , R d3 , R e3 , R g3 , R h3 , R i3 , R j3 , R k3 , R l3 , R m3 , R n3 , R o3  and R p3  independently represents H, C 1-6  alkyl optionally substituted by one or more groups independently selected from G 2a , heterocyclyl optionally substituted by one or more groups independently selected from G 2b , aryl optionally substituted by one or more groups independently selected from G 2c , or heteroaryl optionally substituted by one or more groups independently selected from G 2d ; or 
         any two R c3  and R d3 , R g3  and R h3  and/or R j3  and R k3  are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from heterocyclyl optionally substituted by one or more groups independently selected from G 2b , aryl optionally substituted by one or more groups independently selected from G 2c , or heteroaryl optionally substituted by one or more groups independently selected from G 2d , and ═O; 
         each G 2a  independently represents halo, —CN, —N(R j4 )R k4 ; —OR l4 ; —SR m4  or ═O; 
         each G 2b  independently represents halo, R a4 , —CN, —N(R j4 )R k4 ; —OR l4 ; —SR m4  or ═O; 
         each G 2c  and G 2d  independently represents halo, R a4 , —CN, -A a3 -(Q a4 )R b4 , -A b3 -C(Q b3 )N(R c4 )R d4 , -A c3 -C(Q c3 )OR e4 , -A d3 -S(O) q R f4 , -A e3 -S(O) q N(R g4 )R h4 , -A f3 -S(O) q OR i4 , —N 3 , —N(R j4 )R k4 , —N(H)CN, —NO 2 , —ONO 2 , —OR l4  or —SR m4 ; 
         each Q a3  to Q c3  independently represents ═O, ═S, ═NR n4  or ═N(OR o4 ); 
         each A a3  to A f3  independently represents a single bond, —N(R p4 )— or —O—; 
         each R a4  and R f4  independently represents C 1-6  alkyl optionally substituted by one or more groups independently selected from G 3a , heterocyclyl optionally substituted by one or more groups independently selected from G 3b , aryl optionally substituted by one or more groups independently selected from G 3c , or heteroaryl optionally substituted by one or more groups independently selected from G 3d ; 
         each R b4 , R c4 , R d4 , R e4 , R g4 , R h4 , R i4 , R k4 , R l4 , R m4 , R n4 , R o4  and —R p4  independently represents H, C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more groups independently selected from G 3a  or heterocyclyl optionally substituted by one or more groups independently selected from G 3b , aryl optionally substituted by one or more groups independently selected from G 3c , or heteroaryl optionally substituted by one or more groups independently selected from G 3d ; or 
         any of R c4  and R d4 , R g4  and R h4  and/or R j4  and R k4  are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected G 3b ; 
         each G 3a  and G 3b  independently represents halo, R a5 , —CN, —N(R b5 )R c5 , —OR d5 , —SR e5  or ═O; 
         each R a5  independently represents C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more groups independently selected from G 4 ; 
         each R b5 , R c5 , R d5  and R e5  independently represents H, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more groups independently selected from G 4 ; or 
         each R b5  and R c5  are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from G 4 ; 
         each G 4  independently represents halo, R a6 , —CN, —N(R b6 )R c6 ; —OR d6  or ═O; 
         each R a6  independently represents C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more fluoro; 
         each R b6 , R c6  and R d6  independently represents H, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more fluoro; and 
         each p and q independently represents 1 or 2, 
         with the provisos that the compound of formula I does not represent: 
         (A) 
         2-((1-chloropropan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine, 
         2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonamide, 
         2-((2-chloroethyl)sulfonyl)-6-methoxy-3-nitropyridine, 
         2((4-chlorobutan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine, 
         2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonyl chloride, 
         2-((3-chloro-2-methylpropyl)sulfonyl)-6-methoxy-3-nitropyridine, 
         2-((3-chloropropyl)sulfonyl)-6-methoxy-3-nitropyridine, 
         6-methoxy-3-nitro-2-(vinyl sulfonyl)pyridine, 
         6-methoxy-2-(methyl sulfonyl)-3-nitropyridine, 
         6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(methylsulfonyl)-3-nitropyridine, 
         6-(2,6-dichloro-4-(trifluoromethoxy)phenoxy)-2-(methylsulfonyl)-3-nitropyridine, or 
         6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(ethylsulfonyl)-3-nitropyridine; 
         or 
         (B) 
         2-(butylsulfinyl)-3-nitro-pyridine; 
         or 
         (C) 
         3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid methyl ester, 
         3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid ethyl ester, 
         6-[(2-methylpropyl)sulfinyl]-5-nitro-2-methanesulfonate-2-pyridinol, 
         3-chloro-2-[(6-chloro-3-nitro-2-pyridinyl)sulfinyl]-benzoic acid ethyl ester, 
         3-nitro-2-[(4-piperidinylmethyl)sulfinyl]-pyridine, 
         3-nitro-2-[(3-pyrrolidinylmethyl)sulfinyl]-pyridine, 
         3-nitro-2-[(3-piperidinylmethyl)sulfinyl]-pyridine, 
         3-nitro-2-[(2-pyrrolidinylmethyl)sulfinyl]-pyridine, 
         3-nitro-2-[(2-piperidinylmethyl)sulfinyl]-pyridine, 
         4-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 
         3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 
         3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 
         2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester, 
         2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 
         6-[2,6-dichloro-4-(trifluoromethoxy)phenoxy]-2-(methylsulfinyl)-3-nitro-pyridine, or 
         6-[2,6-dichloro-4-(trifluoromethyl)phenoxy]-2-(ethylsulfinyl)-3-nitro-pyridine. 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein X represents C 1-8  alkyl, C 2-8  alkenyl or C 2-8  alkynyl. 
     
     
         3 . A compound as claimed in  claim 1 , wherein when X represents C 1  alkyl X is substituted with at least one Y group. 
     
     
         4 . A compound as claimed in  claim 1 , wherein each Y independently represents halo, R a3 , —CN, —C(O)N(R c3 )R d3 , —N(R p3 )C(O)R b3 , —C(O)OR e3 , —N(R j3 )R k3 , —OR l3 , —SR m3  or ═O. 
     
     
         5 . A compound as claimed in  claim 1 , wherein each Y independently represents halo, R a3 , —C(O)N(R c3 )R d3 , —N(H)C(O)R b3 , —C(O)OR e3 , —N(R j3 )R k3  or —OR l3 . 
     
     
         6 . A compound as claimed in  claim 1 , wherein:
 R 1  represents halo, —N(R j1 )R k1 , —OR l1  or —SR m1 ; and/or   R 2  and R 3  each independently represent H, halo, R a1 , —N(R j1 )R k1 , —OR l1  or —SR m1 .   
     
     
         7 . A compound as claimed in  claim 1 , wherein each R a1 , R h1 , R k1 , R l1  and R m1  independently represent C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl each optionally substituted by one or more fluoro. 
     
     
         8 . A compound as claimed in  claim 1 , wherein:
 R 1  represents halo, —N(R j1 )R k1  or —OR l1 ; and/or   R 2  and R 3  each independently represent H, halo, R a1 , —N(R j1 )R k1  or —OR l1 .   
     
     
         9 . A compound as claimed in  claim 1 , wherein each R a1 , R j1 , R k1 , R l1  and R m1  independently represent C 1-6  alkyl optionally substituted by one or more fluoro. 
     
     
         10 . A compound as claimed in  claim 1 , wherein:
 R 1  represents halo, —N(R j1 )R k1  or —OR l1 ;   R 2  and R 3  each independently represent H, halo (e.g. chloro), —N(R j1 )R k1  or —OR l1 ;   each R l1  independently represents C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl (e.g. C 1-6  alkyl) optionally substituted by one or more fluoro (such as methyl, difluoromethyl, trifluoromethyl group); and/or (e.g. and)   each and R k1  independently represent C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl (e.g. C 1-6  alkyl) optionally substituted by one or more fluoro (such as a methyl group).   
     
     
         11 . A compound as claimed in  claim 1 , wherein R 1  represents a group other than H. 
     
     
         12 . A compound as claimed in  claim 1 , wherein:
 R 2  and R 3  represent H; and/or   R 1  represents halo, —N(CH 3 ) 2  or —OCH 3 .   
     
     
         13 - 15 . (canceled) 
     
     
         16 . A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 1  but without provisos (A) and (C). 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from the group consisting of:
 soft tissue cancers, such as sarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma;   lung cancers, such as bronchogenic carcinoma, alveolar or bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;   gastrointestinal cancers: such as esophageal cancers, stomach cancers, pancreatic cancers, small bowel cancers, large bowel cancers;   genitourinary tract cancers, such as cancer of the kidney, bladder and urethra, prostate, testis;   liver cancers, such as hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;   bone cancers, such as osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;   cancers of the head and/or nervous system, such as cancer of the skull, meninges, brain, spinal cord;   gynecological cancers, such as cancers of the uterus, cervix, ovaries, cancers of the vulva, vagina, fallopian tubes;   haematologic cancers, such as cancers of the blood and bone marrow, Hodgkin's disease, non-Hodgkin's lymphoma;   skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and adrenal glands; and   neuroblastomas.   
     
     
         18 . The method of  claim 16 , wherein the cancer is a solid tumor cancer. 
     
     
         19 . A pharmaceutical composition comprising a compound as defined in  claim 1  but without provisos (A) and (C), and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier. 
     
     
         20 . A combination product comprising:
 (A) a compound as defined in  claim 1  but without provisos (A) and (C); and   (B) one or more other therapeutic agent that is useful in the treatment of cancer,   wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.   
     
     
         21 . A kit-of-parts comprising:
 (a) a pharmaceutical formulation as defined in  claim 19 ; and   (b) one or more other therapeutic agent that is useful in the treatment of cancer, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier,   which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.   
     
     
         22 . A process for the preparation of a compound as defined in  claim 1 , which process comprises:
 (i) where n represents 2, reaction of a compound of formula IIA   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 1  and LG 1  represents a suitable leaving group, with a compound of formula IIIA 
       
       
         
           
           
               
               
           
         
         wherein X is as defined in  claim 1  and M represents an alkali metal ion, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst; 
         (ii) where n represents 2, reaction of a compound of formula IIB 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 1  and M represents an alkali metal ion, with a compound of formula TIM 
       
       
         
           
           
               
               
           
         
         wherein X is as defined in  claim 1  and LG 2  represents a suitable leaving group, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst; 
         (iii) where n represents 2, reaction of a compound of formula IIA with a compound of formula IIIA, in the presence of a suitable metal halide and in the presence of a suitable solvent; 
         (iv) where n represents 2, reaction of a compound of formula IIB with a compound of formula IIIB, in the presence of a suitable metal halide and in the presence of a suitable solvent; 
         (v) reaction of a compound of formula IV 
       
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  and X are as defined in  claim 1 , with a suitable oxidising agent in the presence of a suitable solvent, and optionally in the presence of water; 
         (vi) where n represents 2, reaction of a compound of formula V 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 1  and LG 3  represents a suitable leaving group with a compound of formula VI 
       
       
         
           
           
               
               
           
         
         wherein X is as defined in  claim 1 , in the presence of a suitable Lewis acid and in the presence of a suitable solvent. 
       
     
     
         23 . (canceled)