# US 11,440,899 B2 · Pyrimidine TBK/IKKe inhibitor compounds and uses thereof

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- Number: US 11,440,899 B2
- Document ID: US11440899B2
- Status: Granted
- Kind: B2
- Application number: 16/756,954
- Filed: 2018-10-17
- Published: 2021-07-15
- Granted: 2022-09-13
- Earliest claimed: 2017-10-17
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH; Srinivasa R. Karra; Yufang Xiao; Brian Sherer; Eugene Checkler
- Inventors: Srinivasa R. Karra; Yufang Xiao; Brian Sherer; Eugene Checkler
- Web page: https://patentgrep.com/patent/US11440899B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 419/14: containing three or more hetero rings
- C07D 498/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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

## Claims

### Claim 1

A compound of formula I,
or a pharmaceutically acceptable salt thereof; wherein
R1 is hydrogen, optionally substituted C1-6 aliphatic, —OR, or halogen;
Ring Z is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;
each R2 is independently
each R3 is independently —R, halogen, —OR, —SR, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
Ring A is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;
R4 is —R, halogen, —OR, —SR, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
each R5 is independently —R, halogen, —OR, —SR, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
each R is independently hydrogen, C1-6 aliphatic, C3-10 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 C3-10 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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is H.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ring Z is

### Claim 5 (depends on 1)

The compound of claim 1, wherein each R2 is independently —R, halogen, —OR, or —N(R)2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein each R3 is independently —R, halogen, —OR, or —N(R)2.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The compound of claim 1, wherein Ring A is

### Claim 9 (depends on 1)

The compound of claim 1, wherein R4 is —R or —OR.

### Claim 10 (depends on 1)

The compound of claim 1, wherein each R5 is independently —R, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, or —N(R)2.

### Claim 11 (depends on 1)

The compound of claim 1, wherein each R5 is independently

### Claim 12 (depends on 1)

The compound of claim 1, of formula II,
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, of formula VI,
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, selected from
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 17)

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, Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, and Cancer.

### Claim 19 (depends on 1)

A method for treating Systemic Lupus Erythematosus in a subject, comprising a step of administering to said subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.