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1. WO2020112905 - METHODS OF TREATING DISEASE WITH MAGL INHIBITORS

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CLAIMS

We Claim:

1. A method for treating a disease or a condition in a patient wherein the disease or condition is selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, Tourette syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, neuropathy, osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I) having the structure:


wherein:

R1 is -C(O)OR15 or -C(O)NR10R11;

R2 is H, halogen, C1-6alkyl, or C1-6haloalkyl;

A is N or C(H);

X is -O-, -N(R16)-, or -CH2N(R16)CH2-;

Y is -CH2- or -C(O)-;

Z is -S-, -O-, or -N(R18)-;

R4 is H, halogen, -OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C(O)NR8R9, C3-8cycloalkyl, C2-9heterocycloalkyl, -C1-6alkyl-C2-9heterocycloalkyl, C6-10aryl, or C1- 9heteroaryl, wherein C3-8cycloalkyl, C2-9heterocycloalkyl, -C1-6alkyl-C2.

9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl are optionally substituted with 1 or 2

R14;

R5 is H, halogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, or phenyl;

R6 is H, halogen or C1-6alkyl;

R7 is H, C1-6alkyl, C1-6haloalkyl, -C1-6alkyl-OH, C2-9heterocycloalkyl, C6-10aryl, or C1- 9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl are optionally substituted with 1 or 2 R14;

each R8 and each R9 are independently selected from H and C1-6alkyl; or R8 and R9

together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R10 and R11 are each independently H or C1-6alkyl;

R12 is H, halogen, or C1-6alkyl;

R13 is H or C1-6alkyl;

each R14 is independently selected from halogen, -OH, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, -C1-6alkyl-OH, C3-8cycloalkyl, -C(O)0H, -C(O)NR8R9, -SO2-C1-6alkyl, and - N(R17)C(O)-C1-6alkyl;

R15 is H or C1-6alkyl;

R16 is H, C1-6alkyl, -C(O)-C1-6alkyl, -C1-6alkyl-OH, or -CH2CO2H;

R17 is H or C1-6alkyl;

R18 is H or C1-6alkyl;

v is 0 or 1;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, or 2; and

q is 0, 1 or 2;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

2. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or


3. The method of claim 1 or 2, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2.

4. The method of any one of claims 1-3, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -CH2- and A is

C(H).

5. The method of any one of claims 1-4, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R12 is H and R13 is H.

6. The method of any one of claims 1-5, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R4 is halogen, -OR7, C1-6haloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein C2- 9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl are optionally substituted with 1 or 2 R14.

7. The method of any one of claims 1-6, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R4 is halogen or R4 is C2-9heterocycloalkyl optionally substituted with 1 or 2 R14.

8. The method of any one of claims 1-7, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R2 is H, R6 is H, and R5 is H, halogen, C1-6alkyl, C1-6haloalkyl, or C1-6haloalkoxy.

9. The method of any one of claims 1-8, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is -C(O)OR15 and R15 is H.

10. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or

pharmaceutically acceptable salt thereof, wherein the compound is


solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

11. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is


solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

12. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is


solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

13. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is


solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

14. The method of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is


solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

15. The method of claim 1, wherein the compound is selected from:


or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.