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1. WO2020110056 - COMPOSÉS UTILES DANS LA THÉRAPIE DU VIH

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

. 1. A compound represented by the Formula (I):

 

 

a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R, R’, R” and R’’’ are independently selected from H and CH3;

X1 and X2 are independently selected from the group consisting of O and S; and L is a linker selected from the group consisting of:

wherein:

  Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar13, Ar14 , Ar15 , Ar16, Ar17, Ar18, Ar19, Ar21, Ar22, Ar23, Ar24 , Ar25 and Ar26 are each independently selected from (C6-C14)aryl;

Alk, Alk2 and Alk3 are each independently selected from:

;

R1, is C3-C6 cycloalkyl or C1-C6 heterocycle;

R2 is selected from the group consisting of -(CH2)a- , -(CH2)b-O--(CH2)c- , -(CH2)d-(C6-C14)aryl-(CH2)e– and -(CH2)f-(C1-C6)heteroaryl-(CH2)g-;

R3 is selected from the group consisting of -(CH2)h- ; -(CH2)i-O--(CH2)j- , -(CH2)k-(C6-C14)aryl-(CH2)l– and -(CH2)m’-(C1-C6)heteroaryl-(CH2)m’’-;

R4 is C3-C6 cycloalkyl, (C6-C14)aryl or (CH2)n’-(C6-C14)aryl -(CH2)n’’, (CH2)n’’’-Alk-(CH2)n’’’’ , wherein n’, n’’, n’’’ and n’’’’ are independently selected from 1 to 8

R5 is C3-C6 cycloalkyl;

R6 is selected from the group consisting of (CH2)z,

a, b, c, d, e, f, g, h, i, j, k, l, m, m’, m’’. n, p, q, r, s, t, u, v, x, y and z are each independently selected from 1 to 12.

2. The compound according to Claim 1, wherein each of Alk, Alk2 and Alk3 is selected from:

;

 

3. The compound according to Claim 1, wherein each of Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11,Ar21, Ar22, Ar23 , Ar24 , Ar25 and Ar26 is C6 aryl.

4. The compound according to Claim 1, wherein each of Ar12, Ar13, Ar14 and Ar15 Ar16, Ar17, Ar18 and Ar19 is C9 aryl.

5. The compound according to Claim 1, wherein each of Ar16, Ar17, Ar18 and Ar19 is C10 aryl.

6. The compound according to Claim 1, wherein the linker (L) is selected from the group consisting of:

 

 

 

 

 

 


          ; 

 

     ;   

  ;   

     ;   

   ;   

   


 ;   

           ; 

 

 

 

 

 


 

 

   


 

7. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

8. A compound represented by the formula (Ia):

 

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R, R’, R” and R’’’ are independently selected from H and CH3;

X1 and X2 are independently selected from the group consisting of O and S; and L is a linker selected from the group consisting of:

wherein:

  Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar13, Ar14 , Ar15 , Ar16, Ar17, Ar18, Ar19, Ar21, Ar22, Ar23, Ar24 , Ar25 and Ar26 are each independently selected from (C6-C14)aryl;

Alk, Alk2 and Alk3 are each independently selected from:

;

R1, is C3-C6 cycloalkyl or C1-C6 heterocycle;

R2 is selected from the group consisting of -(CH2)a- , -(CH2)b-O--(CH2)c- , -(CH2)d-(C6-C14)aryl-(CH2)e– and -(CH2)f-(C1-C6)heteroaryl-(CH2)g-;

R3 is selected from the group consisting of -(CH2)h- ; -(CH2)i-O--(CH2)j- , -(CH2)k-(C6-C14)aryl-(CH2)l– and -(CH2)m’-(C1-C6)heteroaryl-(CH2)m’’-;

R4 is C3-C6 cycloalkyl, (C6-C14)aryl or (CH2)n’-(C6-C14)aryl -(CH2)n’’, (CH2)n’’’-Alk-(CH2)n’’’’ , wherein n’, n’’, n’’’ and n’’’’ are independently selected from 1 to 8

R5 is C3-C6 cycloalkyl;

R6 is selected from the group consisting of (CH2)z,

a, b, c, d, e, f, g, h, i, j, k, l, m, m’, m’’. n, p, q, r, s, t, u, v, x, y and z are each independently selected from 1 to 12.

9. A compound of the formula (Ib):


 

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R, R’, R” and R’’’ are independently selected from H and CH3;

X1 and X2 are independently selected from the group consisting of O and S; and L is a linker selected from the group consisting of:

wherein:

  Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar13, Ar14 , Ar15 , Ar16, Ar17, Ar18, Ar19, Ar21, Ar22, Ar23, Ar24 , Ar25 and Ar26 are each independently selected from (C6-C14)aryl;

Alk, Alk2 and Alk3 are each independently selected from:

;

R1, is C3-C6 cycloalkyl or C1-C6 heterocycle;

R2 is selected from the group consisting of -(CH2)a- , -(CH2)b-O--(CH2)c- , -(CH2)d-(C6-C14)aryl-(CH2)e– and -(CH2)f-(C1-C6)heteroaryl-(CH2)g-;

R3 is selected from the group consisting of -(CH2)h- ; -(CH2)i-O--(CH2)j- , -(CH2)k-(C6-C14)aryl-(CH2)l– and -(CH2)m’-(C1-C6)heteroaryl-(CH2)m’’-;

R4 is C3-C6 cycloalkyl, (C6-C14)aryl or (CH2)n’-(C6-C14)aryl -(CH2)n’’, (CH2)n’’’-Alk-(CH2)n’’’’ , wherein n’, n’’, n’’’ and n’’’’ are independently selected from 1 to 8

R5 is C3-C6 cycloalkyl;

R6 is selected from the group consisting of (CH2)z,

a, b, c, d, e, f, g, h, i, j, k, l, m, m’, m’’. n, p, q, r, s, t, u, v, x, y and z are each independently selected from 1 to 12.

10. The compounds of any of Claims 1 and 8-9, wherein each of Alk, Alk2 and Alk3 is:


.

11. The compounds of any of Claims 1 and 8-9, wherein X1 and X2 are each O.

12. The compounds of any of Claims 1 and 8-9, wherein in said linker (L), each of Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar20, Ar21, Ar22, Ar23, and Ar24 is C6 aryl.

13. The compounds of any of Claims 1 and 8-9, wherein each of m, n, p, and q is 1 and each (CH2)0-3 group in formula (v) is represented by (CH2).

14. The compounds of any of Claims 1 and 8-9, wherein each of Ar12 and Ar14 is


and each of Ar13 and Ar15 is where the wavy lines represent points of attachment.

15. The compounds of any of Claims 1 and 8-9 wherein the linker (L) is selected from the group consisting of:


16. A compound selected from the group consisting of:

 


.         

 

 

;    

    ; and pharmaceutically acceptable salts thereof.

17. A compound represented by the Formula (II):

 

 

wherein

R, R’, R” and R’’’ are independently selected from H and CH3;

X1 and X2 are independently selected from the group consisting of O and S; and

L’ is a linker of the formula:

wherein:

Ar27 and Ar28 are each independently selected from C6-C14 aryl,

R7 is selected from the group consisting of

 ,  C6 aryl and -(CH2)4-15-; and

a’ and b’ are independently selected from 0 to 6.

18. A compound represented by the formula (III):

 

 

wherein

R, R’, R” and R’’’ are independently selected from H and CH3;

X1 and X2 are independently selected from the group consisting of O and S; and L’’ is a linker of the formula:

wherein Ar29 and Ar30 are independently selected from C6-C10 aryl and R8 is selected from the group consisting of:

 , -(CH2)6-15-,- and -(CH2)d’-(C6-C10)aryl-(CH2)e’–; wherein d’ and e’ are independently selected and ranging from 1 to 6.

19. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

20. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

21. The compound according to Claim 20, wherein the compound is present as a hydrochloride salt.

22. The compound according to Claim 21, wherein the hydrochloride salt is a dihydrochloride salt.

23. A pharmaceutical composition comprising a compound according to any of Claims 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. The composition of Claim 23, wherein the compound is present in

an amorphous form.

25. The composition of Claim 23, wherein the composition is in a

tablet form.

26. The composition of Claim 23, wherein the compound is present as a spray dried dispersion.

27. A method of treating an HIV infection in a subject comprising administering to the subject a compound of any of Claims 1-22, or a pharmaceutically acceptable salt thereof.

28. A method of treating an HIV infection in a subject comprising

administering to the subject a pharmaceutical composition according to any of Claims 23-26.

29. A compound according to any of Claims 1-22, for use in treating an

HIV infection.

30. Use of a compound according to any of Claims 1-22, in the

manufacture of a medicament for treating an HIV infection.

31. A method of treating cancer and pre-cancerous syndromes, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound as described in any one of Claims 1-22.

32. The method of claim 31 wherein the mammal is a human.

33. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of

a) a compound of any one of Claims 1-22; and

b) at least one anti-neoplastic agent.

 

  34. The method of Claim 33, wherein the at least one anti-neoplastic agent is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

 

  35. The method according to any one of Claims 31-33 wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, metastatic melanoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

 

36. The method of claim 35 wherein the mammal is a human.

37. The method according to any one of Claims 31-33 wherein said pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

38. A combination comprising:

i) a compound according to any of Claims 1-22; and

ii) one or more additional agents active against HIV.

39. The combination of Claim 38, wherein the one or more additional agents is selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inbhibitors, and antibodies for clearance therapy.

40. The combination of Claim 38, wherein the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, dolutegravir,cabotegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepin, valpronic acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, disulforam, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, and neutralizing antibodies.

41. A method of depleting latent HIV infected cells comprising administering to a subject a compound of any of Claims 1-22 or a pharmaceutically acceptable salt thereof.

42.. The method of Claim 41, wherein each of Alk, Alk2 and Alk3 is


.

43. The method of Claim 41, wherein each of Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar20, Ar21, Ar22, Ar23 Ar24, Ar25, and Ar26 is C6 aryl.

44. The method of Claim 41, wherein each of Ar12, Ar13, Ar14 and Ar15, Ar16, Ar17, Ar18, and Ar19 is C9 aryl.

45. The method of Claim 41, wherein each of Ar16, Ar17, Ar18 and Ar19 is C10 aryl.

46. The method of Claim 41, wherein the linker (L) is selected from the group consisting of:

 

 

   

 


 

 


 

         ;   

    ;   

      ;   

         ;   

 


 

       

 


 


47. The method of Claim 41, wherein the compound is selected from the group consisting of:

(S,4S,4'S,7S,7'S,9aS,9a'S)‐N,N'‐

 

oxooctahydropyrrolo[2,1‐

b][1,3]thiazepine‐7‐carboxamide)  (S,4S,4'S,7S,7'S,9aS,9a'S)‐N,N'‐ ((1R,1'R,2R,2'R)‐(((1,4‐

phenylenebis(methylene))bis(azanediyl))

oxooctahydropyrrolo[2,1‐

b][1,3]thiazepine‐7‐carboxamide)  (S,4S,4'S,7S,7'S,9aS,9a'S)‐N,N'‐

((1R,1'R,2R,2'R)‐(((1R,4R)‐cyclohexane‐

(methylamino)propanethioamido)‐5‐ 4‐((S)‐2‐

(methylamino)propanethioamido)‐5‐ oxooctahydropyrrolo[2,1‐ b][1,3]thiazepine‐7‐carboxamide)   

.

48. The method of Claim 41, wherein the linker (L) is selected from the group consisting of:

49. The method of Claim 41, wherein said linker (L) is selected from the group consisting of (vi) and (vii), and each of Ar12, Ar13, Ar14 and Ar15 is C9 aryl.

50. The method of Claim 41, wherein each of Ar12 and Ar14 is


and each of Ar13 and Ar15 is where the wavy lines represent points of attachment.

51. The method of Claim 41 wherein the linker (L) is selected from the group consisting of:

52. A method of depleting latent HIV infected cells comprising administering to a subject a compound of Claim 20 or a pharmaceutically acceptable salt thereof.

53. The method according to Claim 52, wherein the compound is present as a hydrochloride salt.

….

54. The method according to Claim 53, wherein the hydrochloride salt is a dihydrochloride salt.