IP Library › Patent Application 17998291

Patent Application

App. No. 17/998,291

METHODS OF TREATING COVID-19 USING BARDOXOLONE METHYL OR ANALOGS THEREOF

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Patent No.: US None
App. No.: 17/998,291

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Abstract

The present invention provides methods of treating patients infected with a coronavirus. In particular, provided are methods of treating or preventing COVID-19, or symptoms or complications thereof, in patients in need thereof using bardoxolone methyl or analogs thereof, and/or preventing the onset of COVID-19 in patients infected with SARS-COV-2.

Claims (307)

1 . A method of treating a patient infected with SARS-CoV-2, comprising administering to the patient a therapeutically effective amount of a compound of the formula:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤8) , heterocycloalkyl (C≤12) , alkoxy (C≤8) , cycloalkoxy (C≤8) , aryloxy (C≤12) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , alkylthio (C≤8) , acylthio (C≤8) , alkyl sulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , or substituted versions of any of these groups;

—alkanediyl (C≤8) -R b , —alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

heteroaryl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , heteroarylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —OC(O)NH-alkyl (C≤8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and Re is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH-heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the patient has been identified as not having a history of left-sided heart failure or wherein the patient does not show evidence of left ventricular dysfunction.

3 . A method of treating a patient infected with a coronavirus, comprising administering to the patient a therapeutically effective amount of a compound of the formula:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R e is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH— heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof,

wherein the compound is not

4 . The method of claim 3 , wherein the patient has been identified as not having a history of left-sided heart failure or wherein the patient does not show evidence of left ventricular dysfunction.

5 . A method of treating a patient infected with a coronavirus, comprising administering to the patient a therapeutically effective amount of a compound of the formula:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≤4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof,

wherein the patient has been identified as not having a history of left-sided heart failure or wherein the patient does not show evidence of left ventricular dysfunction.

6 . The method of any one of claims 1 - 5 , wherein the compound is further defined as:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH-S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

heteroaryl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , heteroarylamino (C≤8) , alkyl sulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —OC(O)NH-alkyl (C≤8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R e is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH— heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof.

7 . The method of claim 6 , wherein the compound is further defined as:

wherein:

R 2 is hydrogen or methyl;

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤8) , heterocycloalkyl (C≤12) , alkoxy (C≤8) , cycloalkoxy (C≤8) , aryloxy (C≤12) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , alkylthio (C≤8) , acylthio (C≤8) , alkyl sulfonylamino (C≤8) , cycl ° alkyl sulfonylamino (C≤8) , or substituted versions of any of these groups;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

heteroaryl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , heteroarylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfylamino (C≤8) , amido (C≤8) , —OC(O)NH-alkyl (C≤8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R e is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH— heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 7 , wherein the compound is further defined as:

wherein:

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

heteroaryl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , heteroarylamino (C≤8) , alkyl sulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —OC(O)NH-alkyl (C≤8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH— heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof.

9 . The method of claim 8 , wherein the compound is further defined as:

wherein:

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

-alkanediyl (C≤8) -R b , -alkenediyl (C≤8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or mercapto; or

heteroaryl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , heteroarylamino (C≤8) , alkyl sulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —OC(O)NH-alkyl (C≤8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R e is:

hydrogen, hydroxy, halo, amino, —NHOH, or mercapto; or

alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤8) , aralkyl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , alkoxy (C≤8) , cycloalkoxy (C≤8) , alkenyloxy (C≤8) , aryloxy (C≤8) , aralkoxy (C≤8) , heteroaryloxy (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , cycloalkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , alkylsulfonylamino (C≤8) , cycloalkylsulfonylamino (C≤8) , amido (C≤8) , —NH-alkoxy (C≤8) , —NH— heterocycloalkyl (C≤8) , —NH-amido (C≤8) , or a substituted version of any of these groups;

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

or a pharmaceutically acceptable salt thereof.

10 . The method of claim 9 , wherein the compound is further defined as:

11 . The method of any one of claims 1 - 9 , wherein the compound is not

12 . The method according to any one of claims 1 - 11 , wherein the patient does not have cardiovascular disease.

13 . The method according to any one of claims 1 - 11 , wherein the patient has cardiovascular disease.

14 . The method according to either claim 12 or claim 13 , wherein the cardiovascular disease is left-sided myocardial disease.

15 . The method according to either claim 12 or claim 13 , wherein the cardiovascular disease is atherosclerosis.

16 . The method according to either claim 12 or claim 13 , wherein the cardiovascular disease is restenosis.

17 . The method according to either claim 12 or claim 13 , wherein the cardiovascular disease is thrombosis.

18 . The method according to either claim 12 or claim 13 , wherein the cardiovascular disease is pulmonary hypertension.

19 . The method of claim 18 , wherein the pulmonary hypertension is World Health Organization (WHO) Class I pulmonary hypertension (pulmonary arterial hypertension or PAH).

20 . The method of claim 19 , wherein the pulmonary hypertension is pulmonary arterial hypertension associated with connective tissue disease.

21 . The method of claim 19 , wherein the pulmonary hypertension is idiopathic pulmonary arterial hypertension.

22 . The method of claim 18 , wherein the pulmonary hypertension is WHO Class II pulmonary hypertension.

23 . The method of claim 18 , wherein the pulmonary hypertension is WHO Class III pulmonary hypertension.

24 . The method of claim 18 , wherein the pulmonary hypertension is WHO Class IV pulmonary hypertension.

25 . The method of claim 18 , wherein the pulmonary hypertension is WHO Class V pulmonary hypertension.

26 . The method according to any one of claims 1 - 25 , wherein the patient does not have endothelial dysfunction.

27 . The method according to any one of claims 1 - 25 , wherein the patient has endothelial dysfunction.

28 . The method according to any one of claims 1 - 27 , wherein the patient does not have Stage 4 or higher chronic kidney disease.

29 . The method according to any one of claims 1 - 27 , wherein the patient does not have an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2 .

30 . The method according to any one of claims 1 - 27 , wherein the patient does not have an elevated albumin/creatinine ratio (ACR) is greater than 2000 mg/g.

31 . The method according to any one of claims 1 - 30 , wherein the patient does not have diabetes.

32 . The method according to any one of claims 1 - 30 , wherein the patient has diabetes.

33 . The method of either claim 31 or claim 32 , wherein the diabetes is Type 2 diabetes.

34 . The method according to any one of claims 1 - 33 , wherein the patient does not have a complication associated with diabetes.

35 . The method according to any one of claims 1 - 33 , wherein the patient has a complication associated with diabetes.

36 . The method according to either claim 34 or claim 35 , wherein the complication associated with diabetes is diabetic nephropathy.

37 . The method according to either claim 34 or claim 35 , wherein the complication is selected from the group consisting of obesity, stroke, peripheral vascular disease, neuropathy, myonecrosis, retinopathy and metabolic syndrome (syndrome X).

38 . The method according to any one of claims 1 - 37 , wherein the patient does not have insulin resistance.

39 . The method according to any one of claims 1 - 37 , wherein the patient has insulin resistance.

40 . The method according to any one of claims 1 - 39 , wherein the patient does not have fatty liver disease.

41 . The method according to any one of claims 1 - 39 , wherein the patient has fatty liver disease.

42 . The method according to any one of claims 1 - 39 , wherein the patient does not have hepatic impairment.

43 . The method according to any one of claims 1 - 39 , wherein the patient has hepatic impairment.

44 . The method according to any one of claims 1 - 43 , wherein the patient is not overweight.

45 . The method according to any one of claims 1 - 43 , wherein the patient is overweight.

46 . The method according to either claim 44 or claim 45 , where the patient is obese.

47 . The method of claim 46 , where the obesity is class I.

48 . The method of claim 46 , where the obesity is class II.

49 . The method of claim 46 , where the obesity is class III.

50 . The method according to either claim 45 or claim 46 , where the patient's body mass index (BMI) is from 25 kg/m 2 to 30 kg/m 2 .

51 . The method according to either claim 45 or claim 46 , where the patient's BMI is from kg/m 2 to 35 kg/m 2 .

52 . The method according to either claim 45 or claim 46 , where the patient's BMI is from kg/m 2 to 40 kg/m 2 .

53 . The method according to either claim 45 or claim 46 , where the patient's BMI is from kg/m 2 to 80 kg/m 2 .

54 . The method according to any one of claims 1 - 41 , wherein the patient has cancer.

55 . The method according to any one of claims 1 - 41 , wherein the patient does not have cancer.

56 . The method of either claim 54 or claim 55 , wherein the cancer is an advanced solid tumor or lymphoid malignancy.

57 . The method of either claim 54 or claim 55 , wherein the cancer is selected from the groups consisting of breast cancer, prostate cancer, colon cancer, brain cancer, melanoma, pancreatic cancer, ovarian cancer, leukemia, or bone cancer.

58 . The method of claim 57 , wherein the cancer is an advanced malignant melanoma.

59 . The method of claim 57 , wherein the cancer is pancreatic cancer.

60 . The method according to any one of claims 1 - 59 , wherein the patient does not have chronic obstructive pulmonary disease (COPD).

61 . The method according to any one of claims 1 - 59 , wherein the patient has chronic obstructive pulmonary disease (COPD).

62 . The method according to any one of claims 1 - 61 , wherein the patient is a smoker.

63 . The method according to any one of claims 1 - 61 , wherein the patient is not a smoker.

64 . The method according to any one of claims 1 - 63 , wherein the patient has impaired renal function.

65 . The method according to any one of claims 1 - 64 , wherein the patient has elevated levels of at least one biomarker associated with renal disease.

66 . The method of claim 65 , wherein the biomarker is serum creatinine.

67 . The method of claim 65 , wherein the biomarker is cystatin C.

68 . The method of claim 65 , wherein the biomarker is uric acid.

69 . The method according to any one of claims 1 - 68 , wherein the patient has radiographic infiltrates by imaging prior to treatment.

70 . The method of claim 69 , wherein the imaging is a chest X-ray or CT scan.

71 . The method according to any one of claims 1 - 70 , wherein the patient's blood oxygen saturation, at rest, is at most 94% prior to treatment.

72 . The method according to any one of claims 1 - 71 , wherein the patient requires supplemental oxygen prior to treatment.

73 . The method according to any one of claims 1 - 72 , wherein the patient requires non-invasive ventilation prior to treatment.

74 . The method according to any one of claims 1 - 73 , wherein the patient requires mechanical ventilation for up to 2 days prior to treatment.

75 . The method according to any one of claims 1 - 68 , wherein the method is a method of treating or preventing COVID-19 in a patient in need thereof.

76 . The method according to any one of claim 1 - 68 , wherein the coronavirus is a betacoronavirus.

77 . The method according to any one of claims 1 - 68 , wherein the coronavirus is a severe acute respiratory syndrome-related (SARS) coronavirus.

78 . The method according to any one of claims 1 - 75 , wherein the coronavirus is SARS-CoV-2.

79 . The method according to any one of claims 1 - 78 , wherein the method inhibits replication of SARS-CoV-2 in the patient.

80 . The method according to any one of claims 1 - 79 , wherein the method suppresses or prevents systemic inflammation in the patient.

81 . The method of claim 80 , wherein the method suppresses or prevents a cytokine storm in the patient.

82 . The method according to any one of claims 1 - 80 , wherein the method suppresses or prevents lung inflammation in the patient.

83 . The method according to any one of claims 1 - 82 , wherein the method treats or prevents inflammation-induced liver damage in the patient.

84 . The method according to any one of claims 1 - 83 , wherein the method treats or prevents acute lung injury in the patient.

85 . The method according to any one of claims 1 - 84 , wherein the method treats or prevents kidney damage in the patient.

86 . The method according to any one of claims 1 - 85 , wherein the method treats or prevents acute kidney injury in the patient.

87 . The method according to any one of claims 1 - 86 , wherein the method improves kidney function in the patient.

88 . The method according to any one of claims 1 - 87 , wherein the method increases the patient's estimated glomerular filtration rate (eGFR).

89 . The method according to any one of claims 1 - 88 , wherein the method treats or prevents acute respiratory distress syndrome in the patient.

90 . The method according to any one of claims 1 - 89 , wherein the method treats or prevents seizures in the patient.

91 . The method according to any one of claims 1 - 90 , wherein the method treats or prevents brain inflammation in the patient.

92 . The method according to any one of claims 1 - 91 , wherein the method reduces the hospitalization time of the patient.

93 . The method according to any one of claims 1 - 92 , wherein the method reduces the time spent in the intensive care unit.

94 . The method according of any one of claims 1 - 91 , wherein the method delays the need for hospitalization of the patient.

95 . The method according of any one of claims 1 - 94 , wherein the method increases the probability of survival of the patient.

96 . The method according of any one of claims 1 - 95 , wherein the method prevents the need for non-invasive mechanical ventilation.

97 . The method according of any one of claims 1 - 96 , wherein the method prevents the need for invasive mechanical ventilation.

98 . The method according of any one of claims 1 - 97 , wherein the method prevents respiratory failure.

99 . The method according to any one of claims 1 - 98 , wherein the method lowers the patient's WHO score.

100 . The method according of any one of claims 1 - 99 , wherein the method prevents the need for renal replacement therapy.

101 . The method according to any one of claims 1 - 100 , wherein the patient exhibits microhematuria.

102 . The method of claim 101 , wherein the patient exhibits hematuria.

103 . The method according to any one of claims 1 - 102 , wherein the patient further exhibits microalbuminuria.

104 . The method of claim 103 , wherein the patient exhibits albuminuria.

105 . The method of either claim 103 or claim 104 , wherein the concentration of albumin in the urine is between 30 μg per mg of creatinine and 300 μg per mg of creatinine.

106 . The method of either claim 103 or claim 104 , wherein the concentration of albumin in the urine is greater than 300 μg per mg of creatinine.

107 . The method according to any one of claims 1 - 106 , wherein the patient further exhibits proteinuria.

108 . The method of claim 107 , wherein the patient exhibits overt proteinuria.

109 . The method of either claim 107 or claim 108 , wherein the patient's urine exhibits the presence of multiple proteins.

110 . The method according to any one of claims 107 - 109 , wherein the patient's urine exhibits a protein to creatinine ratio of greater than 0.2 mg/g.

111 . The method of claim 110 , wherein the patient's urine exhibits a protein to creatinine ratio of greater than 1.0 mg/g.

112 . The method according to any one of claims 1 - 111 , wherein the patient has an eGFR less than 45 mL/min/1.73 m 2 .

113 . The method of claim 112 , wherein the patient exhibits an ACR of less than 2000 mg/g.

114 . The method according to any one of claims 1 - 113 , wherein the patient is less than 75 years old.

115 . The method of claim 114 , wherein the patient is less than 70 years old.

116 . The method of claim 114 , wherein the patient is less than 60 years old.

117 . The method of claim 116 , wherein the patient is less than 40 years old.

118 . The method of claim 117 , wherein the patient is less than 30 years old.

119 . The method of claim 118 , wherein the patient is less than 25 years old.

120 . The method according to any one of claims 1 - 119 , wherein the patient does not have at least one of the following characteristics:

(A) a cardiovascular disease;

(B) an elevated baseline B-type natriuretic peptide (BNP) level;

(D) an elevated albumin/creatinine ratio (ACR)>2000 mg/g.

121 . The method of claim 120 , wherein the patient does not have two of the characteristics.

122 . The method of claim 120 , wherein the patient does not have three of the characteristics.

123 . The method of claim 122 , wherein the patient does not have any of said characteristics.

124 . The method according to any one of claims 1 - 123 , wherein the patient has not been intubated for three or more days at the time of treatment.

125 . The method according to any one of claims 1 - 124 , wherein the patient has not been on mechanical ventilation for three or more days at the time of treatment.

126 . The method according to any one of claims 1 - 124 , wherein the patient has not been on invasive mechanical ventilation for three or more days at the time of treatment.

127 . The method according to any one of claims 1 - 124 , wherein the patient has not been intubated for three or more days at the time of treatment.

128 . The method according to any one of claims 1 - 127 , wherein the patient is not known to have an impaired left ventricular ejection fraction, preferably wherein the patient is not known to have a left ventricular ejection fraction (LVEF) of less than 40%.

129 . The method according to any one of claims 1 - 128 , wherein the patient has not been previously hospitalized for heart failure.

130 . The method according to any one of claims 1 - 129 , wherein the patient has not previously experienced cardiac arrest.

131 . The method according to any one of claims 1 - 130 , wherein the patient has not previously experienced shock.

132 . The method according to any one of claims 1 - 131 , wherein the patient has not does not have an uncontrolled bacterial infection.

133 . The method according to any one of claims 1 - 132 , wherein the patient has not does not have an uncontrolled fungal infection.

134 . The method according to any one of claims 1 - 133 , wherein the patient has not does not have another uncontrolled viral infection in addition to the SARS-CoV-2 infection.

135 . The method according to any one of claims 1 - 134 , wherein the patient has not does not have a history of cirrhosis, chronic active hepatitis, or severe hepatic disease.

136 . The method according to any one of claims 1 - 135 , wherein the patient does not have a history of an estimated glomerular filtration rate (eGFR)<15 mL/min/1.73 m 2 .

137 . The method according to any one of claims 1 - 136 , wherein the patient does not have a history of requiring dialysis.

138 . The method according to any one of claims 1 - 137 , wherein the patient does not have an ALT level or AST level that is more than 5 times greater than the ULN.

139 . The method according to any one of claims 1 - 138 , wherein the patient is a human.

140 . The method according to any one of claims 1 - 139 , wherein the patient is male.

141 . The method according to any one of claims 1 - 139 , wherein the patient is female.

142 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 °2θ.

143 . The method of claim 142 , wherein the X-ray diffraction pattern (CuKα) is substantially as shown in FIG. 1 A or FIG. 1 B .

144 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a peak at approximately 13.5 °2θ, substantially as shown in FIG. 1 C , and a transition glass temperature (T g ).

145 . The method of claim 144 , wherein the T g value is in the range of about 120° C. to about 135° C.

146 . The method of claim 145 , wherein the T g value is in the range of about 125° C. to about 130° C.

147 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 6.2, 12.4, 15.4, 18.6 and 24.9 °2θ.

148 . The method of claim 147 , wherein the crystalline form is further characterized by one, two, three, four or five additional diffraction peaks selected from the group consisting of 8.6, 13.3, 13.7, 17.1 and 21.7 °2θ.

149 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 3.6, 7.1, 10.8, 12.4 and 16.5 °2θ.

150 . The method of claim 149 , wherein the crystalline form is further characterized by one, two, three, four or five additional diffraction peaks selected from the group consisting of 12.9, 13.9, 14.8, 18.6 and 20.6 °2θ.

151 . The method of either claim 149 or 150 , wherein the crystalline form is further characterized by a Raman spectrum having peaks at 2949, 1671, 1618 and 1464±4 cm −1 .

152 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a toluene solvate crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 9.65, 7.58, 7.18, 6.29, 6.06, 5.47, 5.21, 4.77 and 3.07 °2θ.

153 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a semi-dioxane solvate crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 10.01, 7.09, 6.84, 6.23, 5.29, 5.20, 5.10, 4.84, and 4.61 °2θ.

154 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a semi-tetrahydrofuran solvate crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 10.00, 7.14, 6.80, 6.65, 6.10, 5.62, 5.29, 4.88, and 4.50 °2θ.

155 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as a methanol solvate crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 8.86, 8.45, 8.17, 7.90, 7.26, 4.67, 6.63, 6.46, and 3.64 °2θ.

156 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present as an anhydrous crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 12.05, 8.90, 8.49, 8.13, 7.92, 7.29, 6.64, 4.67 and 3.65 °2θ.

157 . The method according to any one of claims 10 - 141 , wherein at least a portion of the compound is present a dihydrate crystalline form having an X-ray diffraction pattern (CuKα) comprising diffraction peaks at about 8.81, 8.48, 7.91, 7.32, 5.09, 4.24, 3.58, 3.36 and 3.17 °2θ.

158 . The method according to any one of claims 1 - 157 , wherein the therapeutically effective amount is a daily dose from about 0.1 mg to about 300 mg of the compound.

159 . The method of claim 158 , wherein the daily dose is from about 0.5 mg to about 200 mg of the compound.

160 . The method of claim 159 , wherein the daily dose is from about 1 mg to about 150 mg of the compound.

161 . The method of claim 160 , wherein the daily dose is from about 1 mg to about 75 mg of the compound.

162 . The method of claim 161 , wherein the daily dose is from about 1 mg to about 20 mg of the compound.

163 . The method of claim 158 , wherein the daily dose is from about 2.5 mg to about 30 mg of the compound.

164 . The method of claim 163 , wherein the daily dose is about 2.5 mg of the compound.

165 . The method of claim 163 , wherein the daily dose is about 5 mg of the compound.

166 . The method of claim 163 , wherein the daily dose is about 10 mg of the compound.

167 . The method of claim 163 , wherein the daily dose is about 15 mg of the compound.

168 . The method of claim 163 , wherein the daily dose is about 20 mg of the compound.

169 . The method of claim 163 , wherein the daily dose is about 30 mg of the compound.

170 . The method according to any of claims 1 - 157 , wherein the therapeutically effective amount is a daily dose is 0.01-100 mg of compound per kg of body weight.

171 . The method of claim 170 , wherein the daily dose is 0.05-30 mg of compound per kg of body weight.

172 . The method of claim 171 , wherein the daily dose is 0.1-10 mg of compound per kg of body weight.

173 . The method of claim 172 , wherein the daily dose is 0.1-5 mg of compound per kg of body weight.

174 . The method of claim 173 , wherein the daily dose is 0.1-2.5 mg of compound per kg of body weight.

175 . The method according to any of claims 1 - 157 , wherein the compound is administered as a single dose to the patient per day.

176 . The method according to any of claims 1 - 157 , wherein the compound is administered as two or more doses to the patient per day.

177 . The method according to any one of claims 1 - 157 , wherein the compound is administered orally, intraarterially or intravenously.

178 . The method according to any one of claims 1 - 157 , wherein the compound is formulated as a hard or soft capsule or a tablet.

179 . The method according to any one of claims 1 - 157 , wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.

180 . The method of claim 179 , wherein the excipient is a methacrylic acid-ethyl acrylate copolymer.

181 . The method of claim 180 , wherein the copolymer comprises methacrylic acid and ethyl acrylate at a 1:1 ratio.

182 . The method according to any of claims 1 - 181 , further comprising administering to patient a second therapy.

183 . The method of claim 182 , wherein the second therapy comprises administering to said patient a therapeutically effective amount of a second drug or of convalescent plasma.

184 . The method of claim 183 , wherein the second drug is an anti-platelet drug, an anti-coagulation agent, an anti-viral drug, a corticosteroid, or a human type I IFN.

185 . The method of claim 183 , wherein the second drug is remdesivir or tocilizumab.

Assignments (5)

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC

To: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

Reel/Frame 070793/0130 →

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC

To: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

Reel/Frame 070793/0228 →

AMENDED AND RESTATED PATENT SECURITY AGREEMENT Recorded Jul 12, 2023

From: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

To: BIOPHARMA CREDIT PLC

Reel/Frame 064264/0557 →

PATENT SECURITY AGREEMENT Recorded May 18, 2023

From: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

To: BIOPHARMA CREDIT PLC

Reel/Frame 063697/0461 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2023

From: REATA PHARMACEUTICALS, INC.

To: REATA PHARMACEUTICALS HOLDINGS, LLC

Reel/Frame 063444/0247 →