Chiral diaryl macrocycles and uses thereof

Abstract

This disclosure relates to the use of certain diaryl macrocycle compounds, specifically (7S13R)-11-fluoro-7,13-di-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one in the treatment of disease in mammals. This disclosure also relates to compositions including such compounds, and to methods of using such compositions in the treatment of diseases in mammals, especially in humans.

1 . A method of treating disease in a patient comprising, administering to the patient a therapeutically effective amount of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the disease is mediated by a tyrosine kinase selected from the group consisting of ALK, ROS1, TRKA, TRKB, TRKC, JAK2, SRC, FYN, LYN, YES, FGR, FAK, ARK5, and combinations thereof. 
     
     
         3 .- 7 . (canceled) 
     
     
         8 . The method of  claim 1   7 , wherein the disease is cancer. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the disease is a cancer mediated by a genetically altered ALK. 
     
     
         11 . The method of  claim 1 , wherein the disease is a cancer mediated by a fusion protein comprising a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN AL017 and MYH9. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 10 , wherein the genetically altered ALK is one or more of an EML4-ALK fusion protein, an NPM-ALK fusion protein, or a TPR-ALK fusion protein. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 13 , wherein the one or more of an EML4-ALK fusion protein, an NPM-ALK fusion protein, or a TPR-ALK fusion protein comprises at least one resistance mutation. 
     
     
         16 . The method of  claim 13 , wherein the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, D1203R, L1152P/R, F1174C/L/V, C1156Y, I1171N, G1123S, S106Y, G1269S/A, and 1151T insertion. 
     
     
         17 .- 30 . (canceled) 
     
     
         31 . The method of  claim 13 , wherein the TPR-ALK fusion protein comprises a L1196M point mutation. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the disease is a cancer mediated by ALK having one or more point mutations selected from the group consisting of R1050H, F1174C/I/L/S/V, F1245C/I/L/V, R1275L/Q, T1151M, M1166R, I1170N, I1170S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, G1286R, and T13431. 
     
     
         34 .- 39 . (canceled) 
     
     
         40 . The method of  claim 1 , wherein the disease is a cancer mediated by a genetically altered ROS1. 
     
     
         41 . The method of  claim 1 , wherein the disease is a cancer mediated by a fusion protein comprising a fragment of a protein encoded by an ROS1 gene and a fragment of a protein encoded by a gene selected from the group consisting of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, and LRIG3. 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 40 , wherein the genetically altered ROS1 is one or more of a CD74-ROS1 fusion protein, a SDC4-ROS1 fusion protein, or a SLC34A2-ROS1fusion protein. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 43 , wherein the one or more of a CD74-ROS1 fusion protein, a SDC4-ROS1 fusion protein, or a SLC34A2-ROS1fusion protein comprises at least one resistance mutation. 
     
     
         46 . The method of  claim 43 , wherein the CD74-ROS1 fusion protein comprises a G2032R, L2026M or D2033N point mutation. 
     
     
         47 .- 49 . (canceled) 
     
     
         50 . The method of  claim 43   4 - 7 , wherein the SDC4-ROS1 fusion protein comprises a G2032R point mutation. 
     
     
         51 .- 53 . (canceled) 
     
     
         54 . The method of  claim 43 , wherein the SLC34A2-ROS1 fusion protein comprises a G2032R point mutation. 
     
     
         55 .- 56 . (canceled) 
     
     
         57 . The method of  claim 1 , wherein the disease is a cancer mediated by TRKA, TRKB or TRKC. 
     
     
         58 . The method of  claim 1 , wherein the disease is a cancer mediated by a genetically altered TRKA, TRKB or TRKC. 
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 58 , wherein the genetically altered TRKA is a TPM3-TRKA or LMNA-TRKA fusion protein. 
     
     
         61 .- 69 . (canceled) 
     
     
         70 . The method of  claim 1 , wherein the disease is a cancer mediated by JAK1, JAK2 or JAK3. 
     
     
         71 . The method of  claim 1 , wherein the disease is a cancer mediated by a genetically altered JAK2. 
     
     
         72 . (canceled) 
     
     
         73 . The method of  claim 71 , wherein the genetically altered JAK2 is a TEL-JAK2 fusion protein, or a PCM1-JAK2 fusion protein. 
     
     
         74 . (canceled) 
     
     
         75 . The method of  claim 71 , wherein the genetically altered JAK2 comprises a V617F point mutation. 
     
     
         76 . The method of  claim 1 , wherein the disease is a cancer mediated by SRC. 
     
     
         77 .- 78 . (canceled) 
     
     
         79 . The method of  claim 1 , wherein the disease is pain mediated by TRKA, TRKB or TRKC. 
     
     
         80 .- 82 . (canceled) 
     
     
         83 . The method of  claim 1  wherein the disease is selected from the group consisting of psoriasis, rheumatoid arthritis, polycythemia vera, essential thrombocythemia, ulcerative colitis, and myeloid metaplasia with myelofibrosis. 
     
     
         84 . (canceled) 
     
     
         85 . A method of treating cancer in a patient previously shown to express a genetically altered tyrosine or serine/threonine kinase comprising, administering to the patient a therapeutically effective amount of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one, or a pharmaceutically acceptable salt thereof. 
     
     
         86 . The method of  claim 85 , wherein the genetically altered tyrosine kinase is selected from the group consisting of a genetically altered ALK, genetically altered ROS1, genetically altered TRK and genetically altered JAK. 
     
     
         87 . The method of  claim 86 , wherein the genetically altered ALK is a fusion protein comprising a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN ALO17 and MYH9. 
     
     
         88 . (canceled) 
     
     
         89 . The method of  claim 86 , wherein the genetically altered ALK is one or more of an EML4-ALK fusion protein, an NPM-ALK fusion protein, or a TPR-ALK fusion protein. 
     
     
         90 .- 100 . (canceled) 
     
     
         101 . The method of  claim 85 , wherein the bypass resistance mechanism is mediated by SRC. 
     
     
         102 .- 103 . (canceled) 
     
     
         104 . The method of  claim 86 , wherein the genetically altered ROS1 is a fusion protein comprising a fragment of a protein encoded by an ROS1 gene and a fragment of a protein encoded by a gene selected from the group consisting of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, and LRIG3. 
     
     
         105 . (canceled) 
     
     
         106 . The method of  claim 104 , wherein the genetically altered ROS1 is a CD74-ROS1 fusion protein, a SDC4-ROS1 fusion protein, or a SLC34A2-ROS1fusion protein. 
     
     
         107 .- 120 . (canceled) 
     
     
         121 . The method of  claim 86 , wherein the genetically altered TRK is a TPM3-TRKA or LMNA-TRKA fusion protein. 
     
     
         122 .- 127 . (canceled) 
     
     
         128 . The method of  claim 86 , wherein the genetically altered JAK is a TEL-JAK2 fusion protein or a PCM1-JAK2 fusion protein. 
     
     
         129 . (canceled) 
     
     
         130 . A method of treating cancer in a patient comprising;
 i. identifying a genetically altered tyrosine or serine/threonine kinase in the patient, and   ii. administering to the patient a therapeutically effective amount of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one, or a pharmaceutically acceptable salt thereof.   
     
     
         131 . The method of  claim 130 , wherein the step of identifying comprises subjecting a patient sample to a test selected from the group consisting of FISH, IHC, PCR and gene sequencing. 
     
     
         132 . A method of identifying a patient for treatment with (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-j][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one, or a pharmaceutically acceptable salt thereof, comprising diagnosing the patient with a cancer mediated by a genetically altered tyrosine or serine/threonin kinase. 
     
     
         133 .- 143 . (canceled)