Processing

Please wait...

Settings

Settings

Goto Application

1. WO2020118206 - BUTENOLIDE ANTAGONISTS OF THE CGAS/STING PATHWAY

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WE CLAIM:

1. A compound of formula (I- A), or pharmaceutically acceptable salt thereof:


wherein

R1 is H or (CI-C6)alkyl;

R2 is H, (Cl -C6)alkyl, (Cl-C6)alkoxyl, or (C6-C10)aryl that is optionally substituted with one or more substituents selected from -CN, -hydroxy, halo, (Cl-C6)alkyl, and (Cl- C6)alkoxyl ;

R3 is H, (Cl-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl;

R4 is (Cl-C6)aikyi or (Cl-C6)alkoxyl;

R5 is (Cl-C6)alkyl or (C6-C10)aryl that is optionally substituted with one or more

substituents selected from -CN, -hydroxy, halo, (Cl-C6)alkyl, and (Cl-C6)alkoxyl; wherein R1 and R2 together with the atoms to which they are bonded can form a 5- to 7- membered cycloalkenyl ring; and

wherein R2 and R3 together with the atoms to which they are bonded can form a 5- to 7- membered cycloalkyl ring;

provided that the compound of formula (I-A) is not of formula

compound 12.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I);


wherein

R1 is H or (Cl-C4)alkyl;

R2 is H, (Cl-C4)alkyl, (Cl-C4)aikoxyl, or substituted or unsubstituted aryl;

R3 is H, (Cl-C6(alkyl), (C2-C6)alkenyl, (C3-C7)cycloalkyl;

R4 is (Cl -C4)alkyl or (Cl-C4)alkoxyl; and

Rs is (Cl-C4)alkyl, substituted or unsubstituted aryl

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt


4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,

5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 - 4 and a pharmaceutically acceptable carrier.

6. A method of inhibiting the cGAS/STING pathway in a patient, in a pathway-specific manner at non-toxic concentrations, comprising administering to the patient an effective dose of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 -4

7. A method of treating a medical condition in a patient wherein i nhibition of the cGAS/STING is medically indicated, comprising administering to the patient an effective dose of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 - 4.

8. The method according to claim 7, wherein the medical condition is selected from the group consisting of chronic interferon (IFN)-associated autoimmune diseases and

inflammatory diseases.

9. The method according to claim 7 or 8, wherein the medical condition is a chronic interferon (IFN)-associated autoimmune disease selected from the group consisting of Systemic Lupus Erythematosus (SLE), type 1 diabetes, multiple sclerosis, rheumatoid arthritis, Sjogren syndrome, dermatomyositis, polymysitis, systemic sclerosis, familial Chilblain lupus, and Aicardi-Goutieres syndrome.

1(3. The method according to claim 7 or 8, wherein the medical condition is an inflammatory' disease.

1 1. The method according to any one of claims 7, 8, or 10, wherein the medical condition is inflammatory bowel disease.

12. A method of synthesis of a compound of formula (I- A):


wherein

R! is H or (Cl-C6)alkyl;

R2 is H, (Cl~C6)alkyl, (CI-C6)alkoxyl, or (C6-C10)aryl that is optionally substituted with one or more substituents selected from -CN, -hydroxy, halo, (Cl-C6)alkyl, and (Cl - C6)alkoxyl;

R3 is H, (Cl-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl;

R4 is (Cl-C6)alkyl or (Cl-C6)alkoxyl;

Rs is (Cl-C6)alkyl or (C6~C10)aryl that is optionally substituted with one or more

substituents selected from -CN, -hydroxy, halo, (Cl-C6)alkyl, and (Cl-C6)aJkoxyl;

wherein R1 and R2 together with the atoms to which they are bonded can form a 5- to 7- membered cycloalkenyl ring; and

wherein R2 and R3 together with the atoms to which they are bonded can form a 5- to 7- membered cycloalkyl ring;

comprising contacting a conjugate base of the nucleophile according to formula (II)


with an electrophile according to formula (III)


in an aprotic solvent.

13. The method according to claim 12, wherein the compound of formula (I- A) is a compound of formula (I):


wherein

R1 is H or (Cl-C4)alkyl;

R2 is H, (Cl-C4)alkyl, (Cl-C4)alkoxyl, or substituted or unsubstituted aryl;

R3 is H, (Cl-C6(alkyl), (C2-C6)alkenyl, (C3-C7)cycloalkyl;

R4 is (Cl-C4)alkyl or (Cl-C4)alkoxyl; and

Rs is (Cl-C4)alkyl, substituted or unsubstituted aryl.