Pyrimidine TBK/IKKe inhibitor compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11440899-B2
Application number	US-201816756954-A
Country	US
Kind code	B2
Filing date	Oct 17, 2018
Priority date	Oct 17, 2017
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as TBK/IKKε inhibitors.

First claim

We claim:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof; wherein
R 1 is hydrogen, optionally substituted C 1-6 aliphatic, —OR, or halogen;
Ring Z is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;
each R 2 is independently

each R 3 is independently —R, halogen, —OR, —SR, —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
Ring A is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;
R 4 is —R, halogen, —OR, —SR, —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R 5 is independently —R, halogen, —OR, —SR, —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6-12 membered spiro, fused, or bridged bicyclic carbocyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
n is 1 or 2;
p is 0, 1, or 2; and
q is 0, 1, or 2.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein Ring Z is phenyl, pyridine, or pyrimidine.

4. The compound of claim 1 , wherein Ring Z is

5. The compound of claim 1 , wherein each R 2 is independently —R, halogen, —OR, or —N(R) 2 .

6. The compound of claim 1 , wherein each R 3 is independently —R, halogen, —OR, or —N(R) 2 .

7. The compound of claim 1 , wherein Ring A is phenyl or pyridyl.

8. The compound of claim 1 , wherein Ring A is

9. The compound of claim 1 , wherein R 4 is —R or —OR.

10. The compound of claim 1 , wherein each R 5 is independently —R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, or —N(R) 2 .

11. The compound of claim 1 , wherein each R 5 is independently

12. The compound of claim 1 , of formula II,

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , of formula VI,

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

16. A method for inhibiting TBK and IKKε activity in a patient, comprising a step of administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method for treating a TBK/IKKε related disorder in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease, Crohn's Disease, Ulcerative Colitis, Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Strok

Assignees

• Merck Patent Gmbh
• Karra Srinivasa R
• Xiao Yufang
• Sherer Brian
• Checkler Eugene

Inventors

• Karra Srinivasa R
• Xiao Yufang
• Sherer Brian
• Checkler Eugene

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title