Substituted condensed thiophenes as modulators of sting

Abstract

A compound of formula (I): wherein: R 1 is selected from (i) H, (ii) C 3-6 cycloalkyl, (iii) C 3-7 heterocyclyl optionally substituted with a group selected from: methyl and ester, and (iv) linear or branched C 1-4 alkyl optionally substituted with a group selected from: alkoxy, amino, amido, acylamido, acyloxy, alkyl carboxyl ester, alkyl carbamoyl, alkyl carbamoyl ester, phenyl, phosphonate ester, C 3-7 heterocyclyl optionally substituted with a group selected from methyl and oxo, and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A 1 is CR A or N; A 2 is CR B or N; A 3 is CR C or N; A 4 is CR D or N; where no more than two of A 1 , A 2 , A 3 , and A 4 may be N; one or two of R A , R B , R C , and R D , (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and CH 2 NMe 2 ; the remainder of R A , R B , R C , and R D , (if present) are H; Y is O, NH or CH 2 ; R Y is selected from: (RYA) and (RYB).

1 - 23 . (canceled) 
     
     
         24 . A method of treatment of a disease, disorder and/or condition selected from cancer, an autoimmune disease, inflammation, cellular proliferation, a neurodegenerative disease and an infectious disease, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         W is O or NH; 
         R 1  is selected from:
 (i) H; 
 (ii) C 3-6  cycloalkyl; 
 (iii) 3-7 membered heterocyclyl optionally substituted with a group selected from:
 methyl; and 
 C(═O)OR, wherein R is selected from a C 1-4  alkyl group, a 3-7 membered heterocyclyl, or a phenyl group; and 
 
 (iv) linear or branched C 1-4  alkyl optionally substituted with a group selected from:
 alkoxy; 
 amino; 
 C(═O)N(R″)R′ wherein R′ and R″ are independently selected from H and C 1-4  alkyl; 
 —N(R″)C(═O)R′ wherein R′ and R″ are independently selected from H and C 1-4  alkyl; 
 OC(═O)R, wherein R is selected from a C 1-4 alkyl group, a 3-7 membered heterocyclyl, and a phenyl group; 
 OC(═O)O—C 1-4  alkyl; 
 —NHC(═O)O—C 1-4  alkyl; 
 OC(═O)NR′R″ wherein R′ and R″ are independently selected from H and C 1-4  alkyl; 
 phenyl; 
 P(O)(OC 1-4 alkyl) 2 ; 
 3-7 membered heterocyclyl optionally substituted with a group selected from methyl and oxo; and 
 a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, —C(O)—CH 3  and boc; 
 
 A 1  is CR A  or N; 
 A 2  is CR B  or N; 
 A 3  is CR C  or N; 
 A 4  is CR D  or N; 
 
         where no more than two of A 1 , A 2 , A 3 , and A 4  may be N; 
         one or two of R A , R B , R C , and R D , (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH; 
         the remainder of R A , R B , R C , and R D , (if present) are H; 
         Y is O, NH or CH 2 ; 
         R Y  is selected from: 
         (a) 
       
       
         
           
           
               
               
           
         
         
           wherein:
 Z 1  is CR Z1  or N; 
 Z 2  is CR Z2  or N; 
 Z 4  is CR Z4  or N; 
 Z 5  is CR Z5  or N; 
 
         
         where no more than two of Z 1 , Z 2 , Z 4  and Z 5  may be N; 
         one or two of R Z1 , R Z2 , R Z4  and R Z5 , (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4  alkenyl, and 5-membered heterocyclyl; 
         the remainder of R Z1 , R Z2 , R Z4  and R Z5 , (if present) are H; 
         (b) 
       
       
         
           
           
               
               
           
         
         where R 12  is selected from H, F, Cl, Br, OMe, cyano and CF 3 ; 
         wherein each heterocyclyl comprises 1 or 2 heteroatoms selected from N and O; 
         with the proviso that when A 1  is CF; A 2 , A 3  and A 4  are CH; Y is O or NH; R Y  is RYA, where Z 1 , Z 2 , Z 4  and Z 5  are CH; R 1  is not Et; and 
         when A 1  is CF; A 2 , A 3  and A 4  are CH; Y is NH; R Y  is RYA, where Z 1  and Z 5  are CH, one of Z 2  and Z 4  is CF, and the other of Z 2  and Z 4  is CH; R 1  is not Et. 
       
     
     
         25 . The method of  claim 24 , wherein:
 the cancer is selected from cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumors; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hamartoma; mesothelioma; Hodgkin's Disease or a combination of one or more of the foregoing cancers;   the autoimmune disease is selected from STING associated vasculitis with onset at infancy (SAVI), Aicardi Goutieres syndrome (AGS), chilblain lupus, ataxia telanogiectasia (also referred to as Louis-Bar Syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis, diabetes mellitus including insulin-dependent diabetes mellitus (IDDM), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma), and Sjogren's syndrome (SS), rheumatoid arthritis, psoriatic arthritis, polyarthritis, myasthenia gravis, polyarteritis nodosa, vasculitis, cutaneous vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Henoch-Schonlein purpura, autoimmune hepatitis, primary sclerosing cholangitis, Wegener's granulomatosis, microscopi polyangiitis, Behcet's disease, spondylitis, giant cell arteritis, polymyalgia rheumatic, Raynaud's phenomenon, primary biliary cirrhosis, primary angiitis of the central nervous system microscopic polyangiitis, neuromyelitis optica and mixed connective tissue disease;   the inflammatory disease is selected from musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, autoimmune conditions having an inflammatory component. Such conditions include acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, STING associated vasculitis with onset at infancy (SAVI), Aicardi Goutieres syndrome (AGS), chilblain lupus, ataxia telangiectasia (also referred to as Louis-Bar Syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), ANCA)-associated vasculitis, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease), appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xenografts, serum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sezary syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphomas in adults, acute leukemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis). In one embodiment, the compounds of this invention may be used to treat asthma;   the neurodegenerative disease is selected from multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS);   the cellular proliferation is selected from arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, proliferative retinopathies, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing; and   the infectious disease is derived from a bacterial infection, parasitic protozoan infection, or an infection of a DNA or RNA virus.   
     
     
         26 . The method according to  claim 24 , wherein W is O. 
     
     
         27 . The method according to  claim 24 , wherein R 1  is H. 
     
     
         28 . The method according to  claim 24 , wherein R 1  is selected from C 3-6 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, and optionally substituted linear or branched C 1-4  alkyl. 
     
     
         29 . The method according to  claim 24 , wherein R 1  is optionally substituted linear or branched C 1-4  alkyl. 
     
     
         30 . The method according to  claim 29 , wherein R 1  is selected from optionally substituted methyl, optionally substituted ethyl and optionally substituted iso-butyl. 
     
     
         31 . The method according to  claim 29 , wherein R 1  is substituted with —OC(═O)R, wherein R is selected from a C 1-4 alkyl group, a 3-7 membered heterocyclyl group, and a phenyl group. 
     
     
         32 . The method according to  claim 29 , wherein R 1  is pivaloyloxymethyl or propanoyloxyisobutyl. 
     
     
         33 . The method according to  claim 24 , wherein A 1  is CR A , A 2  is CR B , A 3  is CR C , and A 4  is CR D . 
     
     
         34 . The method according to  claim 24 , wherein the compound is selected from compounds of formulae IIIb, IIIc, IIId and IIIe: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method according to  claim 24 , wherein:
 R A  (if present) is selected from Cl and Br;   R B  (if present) is H;   R C  (if present) is H;   R D  (if present) is selected from H, Me, F, Br, OMe.   
     
     
         36 . The method according to  claim 24 , wherein A 1 , A 2 , A 3  and A 4  are selected from combinations 1-7: 
       
         
           
                 
                 
                 
                 
                 
               
                     
                 
                   combination 
                   A 1   
                   A 2   
                   A 3   
                   A 4   
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
               
                   1 
                   CCl 
                   CH 
                   CH 
                   CH 
                 
                   2 
                   CCl 
                   CH 
                   CH 
                   CCH 3   
                 
                   3 
                   CCl 
                   CH 
                   CH 
                   CBr 
                 
                   4 
                   CBr 
                   CH 
                   CH 
                   CH 
                 
                   5 
                   CCl 
                   CH 
                   CH 
                   CF 
                 
                   6 
                   CCl 
                   CH 
                   CH 
                   COCH 3   
                 
                   7 
                   CBr 
                   CH 
                   CH 
                   CF 
                 
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         37 . The method according to  claim 36 , wherein Y is O. 
     
     
         38 . The method according to  claim 36 , wherein R Y  is RYA; and
 Z 1  is CR Z1 , Z 2  is CR Z2 , Z 4  is CR Z4  and Z 5  is CR Z5 .   
     
     
         39 . The method according to  claim 36 , wherein:
 R Z1  is selected from H, F, and CH 2 OH;   R Z2  is H;   R Z4  is H;   R Z5  is selected from H, F, and CH 2 OH.   
     
     
         40 . The method according to  claim 36 , wherein:
 R Z1  is F, R Z2  is H, R Z4  is H and R Z5  is F; or   one of R Z1  and R Z5  is CH 2 OH, R Z2  is H, R Z4  is H and the other of R Z1  and R Z5  is F.   
     
     
         41 . The method according to  claim 24 , comprising administering to the subject a pharmaceutical composition comprising the compound, and a pharmaceutically acceptable excipient.