Substituted pyrimidinone and azapyrimidinone compounds, compositions, and uses thereof

Abstract

Substituted pyrimidinone and azapyrimidinone compounds of Formula (I) and methods of use are disclosed.

Description

Substituted pyrimidinone and azapyrimidinone compounds of formula (I) and their methods of use are disclosed. Abstract

Claims

LAK13-200 What is claimed is:

1. A compound having the formula:or a pharmaceutically acceptable salt thereof, wherein R1 is (C1-C8)straight-chain alkyl, (C3-C8)branched-chain alkyl, (C3-C8)cycloalkyl, phenylalkyl, alkylcycloalkyl, hydroxy(C1-C8)straight-chain alkyl, hydroxy(C3-C8)branched-chain alkyl, alkoxy(C1-C8)straight-chain alkyl, alkoxy(C3-C8)branched-chain alkyl, halo(C1- C8)straight-chain alkyl, or halo(C3-C8)branched-chain alkyl; R2, R3, and R4 are each independently H, OH, oxy(C1-C8)straight-chain alkyl, oxy(C1- C8)branched-chain alkyl, CF3, or F; X is N or C-R5; R5 and R6 are each independently H, F, Cl, CF3, or CH3; and R7and R8are each independently H, (C1to C5)straight-chain alkyl, (C1to C5)branched- chain alkyl, or are bound to one another through a C-C bond to form a C3-C8 cycloalkyl.

2. The compound according to claim 1, wherein R1 is octyl.

3. The compound according to claim 1, wherein R1is hexyl.

4. The compound according to claim 1, wherein R1 is butyl.

5. The compound according to claim 1, wherein R1is 2-methylpropyl.

6. The compound according to claim 1, wherein R1 is 2-methylbutyl.

7. The compound according to claim 1, wherein R1 is 1,1,1-trifluorobutyl.

8. The compound according to any one of claims 1 to 7, wherein X is N.LAK13-200 9. The compound according to any one of claims 1 to 7, wherein X is C-R5.

10. The compound according to claim 9, wherein R5 is H.

11. The compound according to any one of claims 1 to 10, wherein R2is H.

12. The compound according to any one of claims 1 to 10, wherein R2 is OH.

13. The compound according to any one of claims 1 to 12, wherein R3and R4are both H.

14. The compound according to any one of claims 1 to 12, wherein R3 and R4 are both F.

15. The compound according to any one of claims 1 to 12, wherein R3 is OCH3 and R4is H.

16. The compound according to any one of claims 1 to 12, wherein R3 is H and R4 is OCH3.

17. The compound according to any one of claims 1 to 16, wherein R6is H.

18. The compound according to any one of claims 1 to 17, wherein R6 and R7 are both H.

19. The compound according to any one of claims 1 to 17, wherein R6 and R7 are both CH3.

20. The compound according to any one of claims 1 to 17, wherein one of R6and R7is H and the other of R6 and R7 is CH3.

21. A compound having the formula:LAK13-200or a pharmaceutically acceptable salt thereof.

22. A compound having the formula:or a pharmaceutically acceptable salt thereof.

23. A compound having the formula:or a pharmaceutically acceptable salt thereof.

24. A compound having the formula:or a pharmaceuticallyLAK13-200 25. A compound having the formula:or a pharmaceutically acceptable salt thereof.

26. A compound having the formula: or a pharmaceutically27. A compound having the formula:or a pharmaceutically acceptable salt thereof.

28. A compound having the formula:or a pharmaceuticallyLAK13-200 29. A compound having the formula: or a pharmaceutically30. A compound having the formula:or a pharmaceutically acceptable salt thereof.

31. A compound having the formula: or a pharmaceutically32. A compound having the formula:LAK13-200 or a pharmaceutically33. A compound having the formula: or a pharmaceutically34. A compound having the formula: or a pharmaceutically35. A compound having the formula:or a pharmaceuticallyLAK13-200 36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, diluents, or a mixture of two or more thereof.

37. A method of treating an infection in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

38. A method of treating an infection of at least one of a wound or an ulcer in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

39. A method of treating an infection of a diabetic foot ulcer in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

40. A method of treating a bladder and / or a urinary tract infection in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

41. A method of treating a lung infection in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

42. The method of claim 41, wherein the lung infection arises from a pulmonary condition.

43. The method of claim 42, wherein the pulmonary condition is selected from the group consisting of genetic conditions, acquired conditions, primary conditions, secondaryLAK13-200 conditions, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiestasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory diseases, croup, high altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, stridor, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis infection, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and conditions caused by any one or combination of the above.

44. The method of claim 42, wherein the pulmonary condition arises from a coronavirus.

45. The method of claim 44, wherein the coronavirus is selected from the group consisting of an alphacoronavirus, a betacoronavirus, a gammacoronavirus, a deltacoronavirus, and an omicroncoronavirus, or combinations thereof.

46. The method of claim 44, wherein the coronavirus is selected from the group consisting of porcine epidemic diarrhea virus (PEDv), scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-Alpha-CoV HuB-2013, bat coronavirus HKU10, miniopterus bat coronavirus HKU8, miniopterus bat coronavirus 1, Nyctalus velutinus alphacoronavirus SC- 2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alphacoronavirus Sax-2011, HumCoV 229E, 229E-related bat coronavirus, camel alphacoronavirus, alpaca respiratory coronavirus,LAK13-200 HumCoV NL63, NL63-related Bat-CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus2, FIPV, TGEV, PRCV, alphacoronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus Parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rousettus bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS- CoV, badger SARS-CoV, bat-SL-CoV RsSHC014, bat-SL-CoV Rs3367, bat-SL-CoV WIV1, HKU3, bat-SL-CoV ZC45, bat-SL-CoV ZXC21, bat-CoV RaTG13, bat-CoV RmYN02, human SARS-CoV-2, cat-CoV, tiger-CoV, dog-CoV, mink-CoV, GD pangolin-CoV, bat Hp- betacoronavirus Zhejiang2013, peafowl IBV, avian coronavirus 9203, fowl IBV, avian coronavirus, duck-CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21,HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, or combinations thereof.

47. The method of claim 44, wherein the coronavirus is a betacoronavirus selected from the group consisting of HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus Parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rousettus bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, bat-SL-CoV RsSHC014, bat-SL-CoV Rs3367, bat-SL-LAK13-200 CoV WIV1, HKU3, bat-SL-CoV ZC45, bat-SL-CoV ZXC21, bat-CoV RaTG13, bat-CoV RmYN02, human SARS-CoV-2, cat-CoV, tiger-CoV, dog-CoV, mink-CoV, GD pangolin-CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof.

48. A method of treating cystic fibrosis in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

49. A method of treating pneumonia in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

50. The method of claim 49, wherein the pneumonia is ventilator acquired pneumonia.

51. A method of treating an infection in a burn wound in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

52. A method of treating otitis externa in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

53. A method of treating bacterial vaginosis in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.

54. A method of treating impetigo in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.LAK13-200 55. A method of treating oral mucositis in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, to the patient.