Sulfinylpyridines and their use in the treatment of cancer

Abstract

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R 1 , R 2 , R 3 , R 4 and n 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 represents 0 to 5; 
         R 1 , 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 e1 -C(Q e1 )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 n1  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 ; or 
         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 halo, C 1-3  alkyl, C 2-3  alkenyl or C 2-3  alkynyl each optionally substituted by one or more halo, and =0; 
         each R 4  independently represents halo, R a2 , —CN, -A a2 -C(Q a2 )R b2 , -A b2 -C(Q b2 )N(R c2 )R d2 , -A c2 -C(Q c2 )OR e2 , -A d2 -S(O) q R f2 , -A e2 -S(O) q N(R g2 )R h2 , -A f2 -S(O) q OR i2 , —N 3 , —N(R 2 )R k2 , —N(H)CN, —NO 2 , —ONO 2 , —OR l2  or —SR m2 ; 
         each Q a2  to Q c2  independently represents ═O, ═S, ═NR n2  or ═N(OR o2 ); 
         each A a2  to A f2  independently represents a single bond, —N(R p2 )— or —O—; 
         each R a2  and R f2  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 2 a, 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 2 c, or heteroaryl optionally substituted by one or more groups independently selected from G 2d ; 
         each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 , R o2  and R p2  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 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 c2  and R d2 , R g2  and R h2  and/or R j2  and R k2  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 halogen, C 1-3  alkyl, C 2-3  alkenyl or C 2-3  alkynyl each optionally substituted by one or more halogens, and =0; 
         each G 1a , G 1b , G 1c , G 1d , G 2a , G 2b , G 2c  and G 2d  independently represents halo, —CN, —N(R a3 )R b3 , —OR c3 , —SR d3  or ═O; 
         each R a3 , R b3 , R c3  and R d3  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 a3  and R b3  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, C 1-3  alkyl optionally substituted by one or more fluoro, and ═O; and 
         each p and q independently represents 1 or 2, 
         but with the proviso that the compound of formula I does not represent: 
         3-nitro-2-(phenylsulfinyl)pyridine, 
         3-nitro-2-(p-tolylsulfinyl)pyridine, 
         2-((4-bromophenyl)sulfinyl)-3-nitropyridine, 
         2-((3-chlorophenyl)sulfinyl)-3-nitropyridine, or 
         3-nitro-2-((3-(trifluoromethyl)phenyl)-sulfinyl)pyridine. 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein each R 4  independently represents halo, —N(R j2 )R k2 , —OR l2 , or R a2 . 
     
     
         3 . A compound as claimed in  claim 1 , wherein each R 1 , R 2  and R 3  each independently represents H, halo, R a1 , —N(R j1 )R k1 , —OR l1  or —SR m1 . 
     
     
         4 . A compound as claimed in  claim 1 , wherein each R a2  independently represents C 1-6  alkyl (e.g. methyl) optionally substituted by one or more fluoro, and each R j2 , R k2  and R l2  independently represents H or C 1-6  alkyl optionally substituted by one or more fluoro. 
     
     
         5 . A compound as claimed in  claim 1 , wherein n represents 0 or 1. 
     
     
         6 . A compound as claimed in  claim 1 , wherein n represents at least 1 and one R 4  group is present in the 4-position. 
     
     
         7 . A compound as claimed in  claim 1 , wherein each R 4  independently represents halo. 
     
     
         8 . A compound as claimed in  claim 1 , wherein R 1 , 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 , R 2  and R 3  each independently represent H, halo, —N(R j1 )R k1  or —OR l1 . 
     
     
         11 . A compound as claimed in  claim 1  to  10 , wherein:
 R 2  and R 3  represent H; and/or 
 R 1  represents H, chloro, —N(C 1-6  alkyl)C 1-6  alkyl or —OC 1-6  alkyl, wherein the latter two groups are optionally substituted by one or more fluoro. 
 
     
     
         12 . A compound as claimed in  claim 1 , wherein:
 R 2  and R 3  represent H; and/or   R 1  represents —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 the proviso. 
     
     
         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 17 , wherein the cancer is a solid tumor cancer. 
     
     
         19 . A pharmaceutical composition comprising a compound as defined in  claim 1  but without the proviso, 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 the proviso; 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  but without the proviso; 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:
 reaction of a compound of formula II   
       
         
           
           
               
               
           
         
         wherein R 1  to R 4  and n are as defined in  claim 1 , with a suitable oxidising agent in the presence of a suitable solvent.