# US 12,760,036 B2 · Inhibitors of KIF18A and uses thereof

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- Number: US 12,760,036 B2
- Document ID: US12760036B2
- Status: Granted
- Kind: B2
- Application number: 19/272,410
- Filed: 2025-07-17
- Published: 2025-11-06
- Granted: 2026-10-13
- Earliest claimed: 2023-01-20
- Assignees: Insilico Medicine IP Limited
- Applicants: Insilico Medicine IP Limited
- Inventors: Xiao Ding; Xiaoyu Ding; Feng Gao; Feng Ren; Min Zheng; Wei Zhu
- Web page: https://patentgrep.com/patent/US12760036B2

## CPC

- C07D 498/18: Bridged systems
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4995: Pyrazines or piperazines forming part of bridged ring systems
- A61K 31/504: forming part of bridged ring systems
- A61K 31/529: forming part of bridged ring systems
- A61K 31/537: spiro-condensed or forming part of bridged ring systems
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- C07D 471/18: Bridged systems
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 491/22: in which the condensed system contains four or more hetero rings
- C07D 498/08: Bridged systems
- C07D 498/22: in which the condensed system contains four or more hetero rings
- C07D 513/22: in which the condensed system contains four or more hetero rings
- 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)

## Abstract

Described herein are KIF18A inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with KIF18A.

## Claims

### Claim 1

A compound of Formula (Ib), or a pharmaceutically acceptable salt thereof:
wherein,
ring A is 4- to 6-membered heterocycloalkyl, which is optionally substituted with one or more Ra;
L1 is C1-C6alkylene, C1-C6heteroalkylene, -heterocycloalkyl-C1-C6alkylene-, -heterocycloalkyl-C1-C6heteroalkylene-, -cycloalkyl-C1-C6alkylene-, -cycloalkyl-C1-C6heteroalkylene, —C1-C6alkylene-heterocycloalkyl-, —C1-C6heteroalkylene-heterocycloalkyl-, —C1-C6alkylene-cycloalkyl-, —C1-C6heteroalkylene-cycloalkyl-, —C1-C6heteroalkylene-cycloalkyl-C1-C6heteroalkylene, —C1-C6alkylene-cycloalkyl-C1-C6alkylene, C1-C6heteroalkylene-cycloalkyl-C1-C6alkylene, C1-C6alkylene-cycloalkyl-C1-C6heteroalkylene, —C1-C6heteroalkylene-heterocycloalkyl-C1-C6heteroalkylene, —C1-C6heteroalkylene-heterocycloalkyl-C1-C6alkylene, —C1-C6alkylene-heterocycloalkyl-C1-C6heteroalkylene, or —C1-C6alkylene-heterocycloalkyl-C1-C6alkylene, wherein each of the cycloalkyl, heterocycloalkyl, alkylene and heteroalkylene is optionally substituted with one or more Rc;
L2 is a bond;
X2 is N or CR2;
X4 is N or CR4;
Y1 is N or CH;
Y2 is N or CH;
Rb1 is hydrogen, C1-C6alkyl or C1-C6haloalkyl;
Rb2 is hydrogen, C1-C6alkyl or C1-C6haloalkyl;
R2 is hydrogen, halogen, or C1-C3alkyl;
R4 is hydrogen or C1-C3alkyl;
R3 is —Z—R5, and Z—R5 is selected from the group consisting of: —NHSO2CH2CH2OH, —NHSO2CH2CH3, —NHSO2CH3, —NHC(CH3)2CH2OH, and
each of Ra is independently selected from halogen, —CN, —NO2, C1-C6alkyl, C1-C6haloalkyl, and C3-C6 cycloalkyl;
each Rc is independently selected from halogen, oxo, —OH, —OR7, C1-C6haloalkyl, C1-C6alkyl, and cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more R;
R7 is C1-C3alkyl; and
each R is halogen, —CN, —OH, oxo, —SF5, —SH, —NH2, —NHC1-C3alkyl, —N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from the group consisting of: —OCH2CH2OCH2—, —OCH2CH2CH2OCH2—, —OCH2CH2CH2CH2CH2—, —OCH(CH3)CH2CH2OCH2—, —OCH2CH(CH3)CH2OCH2—, —OCH2CH(CH3)OCH2CH2—, —OCH(CH3)CH2OCH2CH2—, —CH2OCH2—, —CH2CH2OCH2—, —CH2CH2CH2CH2OCH2—, —CH2OCH(CH3)CH2OCH2—, —CH2OCH2CH2—, —N(CH3)CH2CH2OCH2—, —N(cyclopropyl)CH2CH2CH2OCH2—, —N(CH3)CH2CH2CH2OCH2—, —NHCH2CH2OCH2—, —NHCH2CH2CH2OCH2—, —NHCH2CH(CH3)CH2OCH2—, —N(CH3)CH2CH2OCH2CH2—, —NHCH2CH2OCH2CH2—, —NH(CH2)4—, —NH(CH2)5—, —NHCH2CH(CH3)(CH2)3—, —N(CH3)(CH2)4—, —N(CH3)(CH2)5—, —NHCH2CH2CH2CH2O—, —NHCH2C(═O)N(CH3)CH2CH2—, —NHCH2CH2CH2NHCH2—, —NHCH(CH3)CH2OCH2CH2—, —NHCH2CH(CH3)OCH2CH2—, —N(CH3)CH2CH(CH3)OCH2CH2—, —NHCH2CF2CH2OCH2—, —N(CH3)CH2CF2CH2OCH2—, —NHCH2CH(CH3)CH2OCH2—, —N(CH3)CH2CH(CH3)CH2OCH2—, —NHCH(CH3)CH2CH2OCH2—, —NHCH2CH2CH(CH3)OCH2—, —NHCH2CH(CH3)CH2OCH2—, —NHCH2CHFCH2OCH2—, —NHCH2CH(OCH3)CH2OCH2—, —NHCH2CH(CF3)CH2OCH2—, —NHCH2CF2CH2OCH2—, —NHCH2CH(OH)CH2OCH2—, —N(CH3)CH2CH(CH3)CH2OCH2—, —N(CH3)CH2CHFCH2OCH2—, —N(CH3)CH2CH(OCH3)CH2OCH2—, —N(CH3)CH2CH(CF3)CH2OCH2—, —N(CH3)CH2CF2CH2OCH2—, —N(CH3)CH2CH(OH)CH2OCH2—, —C(═O)N(CH3)CH2CH2OCH2—, —C(═O)N(CH3)CH2CH2CH2OCH2—, and —C(═O)N(CH3)CH2CH2CH2CH2—.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl of L1 is
each of which is optionally substituted with one or more R.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein-L1 is

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of:

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is-heterocycloalkyl-C1-C6alkylene-, -heterocycloalkyl-C1-C6heteroalkylene-, —C1-C6alkylene-heterocycloalkyl-, —C1-C6heteroalkylene-heterocycloalkyl-, —C1-C6heteroalkylene-heterocycloalkyl-C1-C6heteroalkylene, —C1-C6heteroalkylene-heterocycloalkyl-C1-C6alkylene, —C1-C6alkylene-heterocycloalkyl-C1-C6heteroalkylene, or —C1-C6alkylene-heterocycloalkyl-C1-C6alkylene, wherein each of the heterocycloalkyl, alkylene and heteroalkylene is optionally substituted with one or more Rc.

### Claim 21 (depends on 20)

The compound of claim 20, wherein the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from N and O, which is optionally substituted with one or more R.

### Claim 22 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is

### Claim 23 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is

### Claim 24 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is
or

### Claim 25 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is

### Claim 26 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is