Pyrrolopyrimidine itk inhibitors for treating inflammation and cancer

Abstract

wherein R1, R2, and X are as defined in the detailed description. Methods of inhibition of ITK activity in a human or animal subject are also provided.

1 .- 27 . (canceled) 
     
     
         28 . A method of treating an ITK-mediated disorder in a subject in need thereof, comprising administering to the subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof
 wherein: 
 
         R 1  is chosen from aryl and heteroaryl, and may be optionally substituted with one or more R 3  substituents; 
         R 2  is chosen from aryl or heteroaryl, and may be optionally substituted with one or more R 4  substituents; 
         each R 3  is independently chosen from hydrogen, —C 1-4 alkyl, —OC 1-4 alkyl, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , cyano, —C(O)N(R 6 ) 2 , —C(O)C 1-4 alkyl, haloalkyl, oxo, and halo; 
         each R 4  is independently chosen from hydrogen, —C 1-4 alkyl, —OC 1-4 alkyl, —OC 1-6 cycloalkyl, —OC 1-6 heterocycloalkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, halo, —NR 5 R 6 , —(CH 2 ) m CR 7 ═CR 9 C(O)Me, —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7   2 , and —(CH 2 ) m CR 7 ═CR 9 CN; 
         R 5  is chosen from hydrogen, cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7   2 , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)Me, —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7   2 , and —(CH 2 ) m CR 7 ═CR 9 CN; 
         R 6  is chosen from hydrogen, —C 1-4 alkyl, and —(CH 2 ) n C 3-7 cycloalkyl; 
         each R 7  is independently chosen from hydrogen, —CN, —C 1-4 alkyl, —C 3-7 cycloalkyl, —C 3-7 heterocycle, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ; 
         R 8  is chosen from hydrogen, —C 1-4 alkyl, —C 1-4 alkylaryl, —C 1-4 alkylheteroaryl, —C 3-7 cycloalkyl, —C 3-7 heterocycle, —OH, —OC 1-4 alkyl, —C 1-4 alkylOC 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , heterocycle, aryl and heteroaryl; 
         R 9  is chosen from hydrogen, —C 1-4  alkyl, —CN, —CF 3 , —C(O)Me, —C(O)NH 2 , and aryl; 
         R 10  is chosen from H and —C 1-4 alkyl; 
         R 11  is chosen from hydrogen and —C 1-4 alkyl, optionally substituted with —OPO(OR 12 ) 2 , —OC(O)R 13 , or an amino acid; 
         R 12  is chosen from hydrogen and —C 1-6 alkyl; 
         R 13  is —C 1-6  alkyl; 
         m is chosen from 1, 2 and 3; and 
         n is chosen from 0, 1, 2, and 3. 
       
     
     
         29 . The method according to  claim 28 , wherein the subject is a human. 
     
     
         30 . The method according to  claim 28 , wherein the ITK-mediated disorder is selected from cancer, autoimmune disorders, chronic inflammatory disorders, auto-inflammatory disorders, pain, inflammatory disorders, allergic disorders, asthma, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, contact hypersensitivity, inflammatory bowel disease, T-cell lymphomia, lymphoblastic T-cell leukemia, HIV, psoriasis, atopy, atopic dermatitis, alopecia, nonscarring alopecia, alopecia areata (AA), including patchy AA, alopecia totalis (AT), alopecia universalis (AU), androgenetic alopecia (AGA), male and female pattern AGA, ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, scarring alopecia, lichen planopilaris, central centrifugal cicatricial alopecia, frontal fibrosing alopecia; vitiligo including segmental vitiligo, unisegmental, bisegmental or multisegmental vitiligo, non-segmental vitiligo including acral, facial, or acrofacial vitiligo, centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo, mixed vitiligo (nonsegmental associated with segmental vitiligo), focal vitiligo, solitary mucosal vitiligo or vitiligo with or without leukotricia (involvement of body hair); immunobullous diseases, bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease, dermatologic drug reactions, pruritus (itch) atopic pruritus, xerotic pruritus, pruritus associated with psoriasis, acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, hepatobiliary-associated itch, renal associated itch, lichen simplex chronicus associated pruritispruritus, prurigo nodularis, and a combination thereof. 
     
     
         31 . A method of  claim 28  further comprising the sequential or co-administration of a pharmaceutical agent. 
     
     
         32 . The method according to  claim 31 , wherein the pharmaceutical agent is selected from taxanes, inhibitors of bcr-abl, inhibitors of EGFR, DNA damaging agents, antimetabolites, paclitaxel, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin, anthracyclines, AraC, 5-FU, camptothecin, doxorubicin, idarubicin, paclitaxel, docetaxel, vincristine, a MEK inhibitor, U0126, a KSP inhibitor, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab, tremelimumab, and durvalumab. 
     
     
         33 . (canceled)