# US 12,600,719 B2 · Salt inducible kinase inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,600,719 B2
- Document ID: US12600719B2
- Status: Granted
- Kind: B2
- Application number: 18/019,527
- Filed: 2021-08-05
- Published: 2024-01-25
- Granted: 2026-04-14
- Earliest claimed: 2020-08-05
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: Marc Nathan Wein; William J. Greenlee
- Web page: https://patentgrep.com/patent/US12600719B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/497: containing further heterocyclic rings
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 498/10: Spiro-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application provides compounds that modulate the activity of one or more salt inducible kinases (SIKs). Pharmaceutical composition and methods of treating diseases associated with abnormal expression and/or activity of one or more SIKs are also provided.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
V, X, and Z are each C, and W and Y are each N; or
V, Y, and Z are each C, and W and X are each N; or
V and Y are each C, and W, X, and Z are each N;
U is CR3 or N;
U′ is CR5 or N;
U″ is CR6 or N;
R1 is selected from 5 membered heteroaryl, ORa1, C(O)NRc1Rd1, and NRc1C(O)Rb1, wherein the 5 membered heteroaryl is optionally substituted with 1 or 2 independently selected R1A substituents;
Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents;
or Rc1 and Rd1, together with the nitrogen to which they are attached, come together to form a 10-14 membered heterocycloalkyl or 10-14 membered heteroaryl group, wherein the 10-14 membered heterocycloalkyl and 10-14 membered heteroaryl group are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents;
each R1A is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, NO2, CN, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with C1-4 alkoxy;
R2 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
R3 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
R4 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, NO2, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)N(Rc4)NRc4Rd4, NRc4C(O)Rb4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, and NRc4C(O)ORa4, wherein the C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4A substituents;
Ra4, Rb4, Rc4, and Rd4 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
each R4A is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
R5 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
or R4 and R5, together with the carbon atoms to which they are attached, come together to form a 5-6 membered aryl ring which is optionally substituted with 1, 2, 3, or 4 independently selected R7 substituents;
R6 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 alkoxy;
each R7 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, NO2, CN, and ORa7, wherein the C6-10 aryl, C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R7A substituents;
each Ra7 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl; and each R7A is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl) amino, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with amino or C1-4 alkoxy.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl, wherein the 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1 or 2 independently selected R1A substituents; or
Rc1 and Rd1, together with the nitrogen to which they are attached, come together to form a 10-14 membered heterocycloalkyl or 10-14 membered heteroaryl group.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
each R1A is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and CN, wherein each C1-6 alkyl is optionally substituted with C1-4 alkoxy.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R2 is selected from H and C1-6 alkoxy;
R3 is selected from H, halo, and C1-6 alkoxy;
R4 is selected from H, 5-10 membered heteroaryl, CN, and C(O)NRc4Rd4, wherein the 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R4A substituents;
R5 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
R6 is selected from H and C1-6 alkoxy.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R4 and R5 together with the carbon atoms to which they are attached, come together to form a 6-membered aryl ring which is optionally substituted with 1 or 2 independently selected R7 substituents.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
each R7 is independently selected from C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, and ORa7, wherein the C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 independently selected RA substituents.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl, wherein the 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1 or 2 independently selected R1A substituents;
or Rc1 and Rd1, together with the nitrogen to which they are attached, come together to form a 10-14 membered heterocycloalkyl or 10-14 membered heteroaryl group;
each R1A is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and CN, wherein each C1-6 alkyl is optionally substituted with C1-4 alkoxy;
R2 is H or C1-6 alkoxy;
U is CR3 or N;
U′ is CR5 or N;
U″ is CR6 or N;
R3 is selected from H, halo, and C1-6 alkoxy;
R4 is selected from H, 5-10 membered heteroaryl, CN, and C(O)NRc4Rd4, wherein the 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R4A substituents;
Rc4 and Rd4 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
each R4A is an independently selected C1-6 alkyl group;
R5 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
or R4 and R5 together with the carbon atoms to which they are attached, come together to form a 5-6 membered aryl ring which is optionally substituted with 1, 2, 3, or 4 independently selected R7 substituents;
R6 is selected from H and C1-6 alkoxy;
each R7 is independently selected from C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, and ORa7, wherein the C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R7A substituents;
each Ra7 is an independently selected 4-10 membered heterocycloalkyl group; and
each R7A is independently selected from C1-6 alkyl, amino, C3-6 cyclopropyl and 4-6 membered heterocycloalkyl, wherein each C1-6 alkyl is optionally substituted with amino or C1-4 alkoxy.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl, wherein the 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl, and (5-10 membered heteroaryl)-C1-6 alkyl are each optionally substituted with 1 or 2 independently selected R1A substituents;
or Rc1 and Rd1, together with the nitrogen to which they are attached, come together to form a 10-14 membered heterocycloalkyl or 10-14 membered heteroaryl group;
each R1A is independently selected from C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and CN, wherein each C1-6 alkyl is optionally substituted with C1-4 alkoxy;
R2 is H or C1-6 alkoxy;
U is CR3 or N;
U′ is CR5 or N;
U″ is CR6 or N;
R3 is selected from H, halo, and C1-6 alkoxy;
R4 is selected from H, 5-6 membered heteroaryl, CN, and C(O)NRc4Rd4, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 independently selected R4A substituents;
Rc4 and Rd4 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
each R4A is an independently selected C1-6 alkyl group;
R5 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
or R4 and R5 together with the carbon atoms to which they are attached, come together to form a 6-membered aryl ring which is optionally substituted with 1 or 2 independently selected R7 substituents;
each R7 is independently selected from C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, and ORa7, wherein the C3-10 cycloalkyl, 4-14 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R7A substituents;
each Ra7 is an independently selected 4-10 membered heterocycloalkyl group; and each R7A is independently selected from C1-6 alkyl, amino, C3-6 cyclopropyl and 4-6 membered heterocycloalkyl, wherein each C1-6 alkyl is optionally substituted with amino or C1-4 alkoxy.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, methyl, pyrazolyl, pyridinylmethyl, pyridinylethyl, imidazo [1,2-a]pyridinylmethyl, benzoimidazolylmethyl, imidazo [4,5-c]pyridinylmethyl, benzoxazolylmethyl, oxetanylmethyl, oxetanylethyl, thietanyl-(1,1-dioxide) methyl, 2-oxaspiro [3.3]heptanyl, and 2-oxaspiro [3.5]nonanyl, wherein the methyl, pyrazolyl, pyridinylmethyl, pyridinylethyl, imidazo [1,2-a]pyridinylmethyl, benzoimidazolylmethyl, imidazo [4,5-c]pyridinylmethyl, benzoxazolylmethyl, oxetanylmethyl, oxetanylethyl, thietanyl-(1,1-dioxide) methyl, 2-oxaspiro [3.3]heptanyl, and 2-oxaspiro [3.5]nonanyl are each optionally substituted with 1 or 2 independently selected R1A substituents;
or Rc1 and Rd1, together with the nitrogen to which they are attached, come together to form 1,2,3,4-tetrahydrobenzo [4,5]imidazo [1,2-a] pyrazinyl;
each R1A is independently selected from methyl, ethyl, methoxymethyl, and CN;
R2 is H or C1-6 alkoxy;
U is CR3 or N;
U′ is CR5 or N;
U″ is CR6 or N;
R3 is selected from H, halo, and C1-6 alkoxy;
R4 is selected from H, 5-6 membered heteroaryl, CN, and C(O)NRc4Rd4, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 independently selected R4A substituents;
Rc4 and Rd4 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
each R4A is an independently selected C1-6 alkyl group;
R5 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
or R4 and R5 together with the carbon atoms to which they are attached, come together to form a 6-membered aryl ring which is optionally substituted with 1 or 2 independently selected R7 substituents;
each R7 is independently selected from bicyclo[1.1.1]pentanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazolyl, azaspiro [3.3]heptanyl, diazaspiro [3.5]nonanyl, oxadiazaspiro[5.5]undecanyl, diazaspiro [4.4]nonanyl, and azetidinyloxy, wherein the bicyclo[1.1.1]pentanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazolyl, azaspiro [3.3]heptanyl, diazaspiro [3.5]nonanyl, oxadiazaspiro[5.5]undecanyl, and diazaspiro [4.4]nonanyl are each optionally substituted with 1 or 2 R7A substituents; and each R7A is independently selected from methyl, methoxyethyl, aminomethyl, amino, cyclopropyl, and oxetanyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is a compound of Formula V:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

A method of inhibiting an activity of a salt inducible kinase (SIK), the method comprising contacting the salt inducible kinase (SIK) with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 18

A compound, which is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

A pharmaceutical composition comprising a compound of claim 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 18)

A method of inhibiting an activity of a salt inducible kinase (SIK), the method comprising contacting the salt inducible kinase (SIK) with a compound of claim 18, or a pharmaceutically acceptable salt thereof.