Compounds and methods for treatment of viral infections
Compounds and methods of using said compounds, singly or in combination with additional agents, and salts, crystalline forms, pharmaceutical compositions of said compounds for the treatment of viral infections are disclosed.
1. A crystalline form of the compound of Formula:
wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.5°, 22.1°, and 23.8°.
2. The crystalline form of claim 1 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.4°, 16.9°, and 28.1°.
3. The crystalline form of claim 1 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8° and 28.1°.
4. The crystalline form of claim 1 , wherein the XRPD pattern comprises degree 2θ-reflections (+1-0.2 degrees 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1°.
5. The crystalline form of claim 1 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
8.5
74
10.5
9
11.8
4
14.1
6
15.4
17
16.9
100
17.5
23
17.6
13
20.3
7
22.1
20
23.8
17
24.1
8
25.0
4
25.7
3
26.2
4
26.5
7
27.5
7
28.1
20
30.1
2
30.8
3
32.1
3
34.7
1
35.4
3
36.5
3
38.0
3.
6. The crystalline form of claim 1 , wherein the crystalline form displays one endothermic transition at about 169° C.
7. The crystalline form of claim 1 , wherein the crystalline form is unsolvated.
8. A crystalline form of the compound of Formula:
wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.4°, 13.7°, and 16.3°.
9. The crystalline form of claim 8 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 18.4°, 20.8°, and 23.3°.
10. The crystalline form of claim 8 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°.
11. The crystalline form of claim 10 , wherein the XRPD pattern further comprises a degree 2θ-reflection at 25.4°.
12. The crystalline form of claim 8 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
6.4
100
13.7
4
16.3
25
18.4
2
20.8
3
23.3
2
25.4
3.
13. The crystalline form of claim 8 , wherein the crystalline form exhibits two endothermic events around 165° C. and 176° C. and an exothermic event around 169° C.
14. The crystalline form of claim 8 , wherein the crystalline form is unsolvated.
15. A xinafoate salt of a compound of Formula:
16. A crystalline form of the xinafoate salt of claim 15 , wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 12.2°, and 14.8°.
17. The crystalline form of claim 16 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.2°, 12.9° and 26.6°.
18. The crystalline form of claim 16 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8° and 26.6°.
19. The crystalline form of claim 16 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6°.
20. The crystalline form of claim 16 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
3.1
5
4.0
31
5.3
8
6.2
100
7.8
18
9.3
5
10.3
16
10.6
11
11.7
4
12.2
20
12.9
13
13.5
3
14.5
6
14.8
41
15.7
7
16.3
5
16.8
5
17.1
3
18.1
5
18.5
5
18.7
4
20.9
8
22.6
7
23.6
3
25.1
3
26.6
22.
21. The crystalline form of claim 16 , wherein the crystalline form one endothermic event at about 154° C.
22. The crystalline form of claim 16 , wherein the crystalline form is unsolvated.
23. A HCl salt of a compound of Formula:
24. A crystalline form of the HCl salt of claim 23 , wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3°.
25. The crystalline form of claim 24 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°.
26. The crystalline form of claim 24 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°.
27. The crystalline form of claim 24 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9°, and 24.3°.
28. The crystalline form of claim 24 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
5.9
100
11.7
81
13.5
3
14.0
21
14.2
8
15.6
3
16.7
6
17.2
4
18.4
4
18.9
3
19.7
20
20.7
2
22.4
6
22.8
4
23.9
10
24.3
14
25.1
4
25.9
5
26.5
3
29.4
4
30.9
5.
29. The crystalline form of claim 24 , wherein the crystalline form displays two endothermic transitions at about 115° C. and 187° C. and an exothermic event at about 140° C.
30. The crystalline form of claim 24 , wherein the crystalline form shows a weight loss even of about 1.1% by weight starting between about 20° C. and 100° C., a weight loss even of about 3.4% by weight starting between about 100° C. and 135° C., and a weight loss even of about 31% by weight starting between about 135° C. and 265° C.
31. A crystalline form of the HCl salt of claim 23 , wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 15.0°, and 25.8°.
32. The crystalline form of claim 31 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.6°, 16.3°, and 26.7°.
33. The crystalline form of claim 31 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°.
34. The crystalline form of claim 31 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5°.
35. The crystalline form of claim 31 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
4.0
100
8.0
1
10.6
4
12.2
5
13.5
5
15.0
12
15.7
12
16.3
18
17.6
12
18.7
9
20.4
8
23.4
17
25.8
9
26.7
7
27.7
11
29.5
3
31.5
8
33.5
4
37.1
2
38.0
2.
36. The crystalline form of claim 31 , wherein the crystalline form displays two endothermic transitions at about 155° C. and 195° C.
37. The crystalline form of claim 31 , wherein the crystalline form shows a weight loss of about 35% by weight starting between about 100° C. and 260° C.
38. A crystalline form of the HCl salt of claim 23 , wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 15.9°, and 26.6°.
39. The crystalline form of claim 38 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.1°, 16.8°, and 25.7°.
40. The crystalline form of claim 38 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°.
41. The crystalline form of claim 38 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0°.
42. The crystalline form of claim 38 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
4.3
100
7.1
52
12.8
8
13.5
34
14.3
45
14.6
36
15.9
72
16.8
26
18.7
58
19.5
38
21.0
16
22.8
13
25.7
48
26.6
44
27.0
48
30.6
14
33.2
8.
43. The crystalline form of claim 38 , wherein the crystalline forms displays one endothermic transition at about 178° C.
44. The crystalline form of claim 38 , wherein the crystalline form shows a weight loss of about 1.2% by weight starting between about 20° C. and 100° C. and a weight loss of about 28% by weight starting between about 100° C. and 240° C.
45. A crystalline form of the HCl salt of claim 23 , wherein the crystalline form is characterized by an XRPD pattern having degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 14.7°, and 31.4°.
46. The crystalline form of claim 45 , wherein the XRPD pattern further comprises one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.8°, 17.3°, and 35.1°.
47. The crystalline form of claim 45 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°.
48. The crystalline form of claim 45 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1°.
49. The crystalline form of claim 45 , wherein the XRPD pattern comprises degree 2θ-reflections (+/−0.2 degrees 2θ) at:
Pos. [º2Th.]
Rel. Int. [%]
4.3
100
7.1
3
12.8
19
14.4
3
14.7
11
15.9
6
16.6
8
17.3
77
18.6
32
19.5
9
20.7
21
21.0
8
22.8
19
23.9
8
24.9
34
27.0
4
27.2
16
27.6
6
28.1
4
30.0
7
30.6
4
31.4
25
32.4
4
33.3
5
33.6
4
35.1
48
36.1
9
38.1
5
39.0
3.
50. The crystalline form of claim 45 , wherein the crystalline form displays one endothermic transition at about 186° C.
51. The crystalline form of claim 45 , wherein the crystalline form a weight loss of about 30% by weight starting between about 100° C. and 250° C.
52. A pharmaceutical composition comprising:
(a) the crystalline forms of claim 1 ; and
(b) a pharmaceutically acceptable excipient.
53. The pharmaceutical formulation of claim 52 , wherein the pharmaceutical formulation is for oral administration.
54. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline form of claim 1 .
55. The method of claim 54 , wherein the viral infection is a coronavirus infection.
56. The method of claim 54 , wherein the viral infection is SARS-CoV-2 infection (COVID-19).
57. The method of claim 54 , wherein the viral infection is a pneumoviridae virus infection, picornaviridae virus infection, flaviviridae virus infection, Filoviridae virus infection, orthomyxovirus infection, or paramyxoviridae virus infection.
58. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 8 .
59. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the xinafoate salt of claim 15 .
60. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 16 .
61. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the HCl salt of claim 23 .
62. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 24 .
63. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 31 .
64. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 38 .
65. A method of treating a viral infection in a human in need thereof, wherein the method comprises administering to the human the crystalline forms of claim 45 .