# US 11,999,725 B2 · HPK1 inhibitors, preparation method and application thereof

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- Number: US 11,999,725 B2
- Document ID: US11999725B2
- Status: Granted
- Kind: B2
- Application number: 17/049,380
- Filed: 2019-04-19
- Published: 2021-09-09
- Granted: 2024-06-04
- Earliest claimed: 2018-04-25
- Assignees: Zhuhai Yufan Biotechnologies Co., Ltd.
- Applicants: Zhuhai Yufan Biotechnologies Co., Ltd
- Inventors: Xuebin Liao
- Web page: https://patentgrep.com/patent/US11999725B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- G01N 2500/10: involving cells
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Disclosed are HPK-1 inhibitors having a structure represented by Formula (X), pharmaceutical compositions comprising the HPK-1 inhibitors, methods of using the HPK-1 inhibitors, such as treating cancers, methods of preparing the HPK-1 inhibitors, and the synthetic intermediates.

## Claims

### Claim 1

A compound of Formula Y or Z, or a pharmaceutically acceptable salt thereof,
wherein:
A is CH;
Ar is an optionally substituted phenyl or an optionally substituted 5 or 6-membered heteroaryl selected from thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl,
wherein:
(i) the optionally substituted 5 or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100, —NR101R102, —C(═O)—R103, —NR101—C(═O)—R103, —NR101—SO2—R104, —SO2—R104, —NR101—POR105R106, —POR105R106, —SR107, halogen, and —CN,
wherein each R100 is independently selected from hydrogen, an oxygen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
each R101 or R102 is independently selected from hydrogen, a nitrogen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
each R103 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
each R104 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
each R105 or R106 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—R100 and —NR101R102;
each R107 is independently selected from hydrogen, a thiol protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents each independently selected from 1) C1-7 alkyl optionally substituted with 1-3 substituents each independently selected from halogen, oxo, —OH or protected OH, optionally substituted C1-4 alkoxy, —NH2 or protected NH2, —N(C0-4 alkyl)(C0-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 4-8 membered heterocyclyl; 2) halogen; 3) —OH or protected OH; 4) optionally substituted C1-4 alkoxy; 5) —NH2 or protected NH2; 6) —N(C0-4 alkyl)(C0-4 alkyl), wherein the alkyl is optionally substituted; 7) optionally substituted C3-6 cycloalkyl; 8) optionally substituted phenyl; 9) optionally substituted 5- or 6-membered heteroaryl; and 10) optionally substituted 4-8 membered heterocyclyl; or
(ii) when applicable, two adjacent substituents of the optionally substituted 5 or 6-membered heteroaryl form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring;
L is a linker of formula J1-J2-J3, wherein each of J1, J2, and J3 is independently null, O, S, SO, SO2, C═O, NH, optionally substituted C1-4 alkylene, provided that L does not contain O—O, O—N, S—S, N—S, O—S, or N—N bond, and at most one of J1, J2, and J3 is SO, SO2, or C═O;
ring B is an aryl or heteroaryl ring;
n is 0, 1, 2, or 3, as valance permits,
each RA is independently selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, CN, OH, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, wherein when applicable, two adjacent RA can form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring,
RB and RC are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or RB and RC together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl,
RD is hydrogen, optionally substituted C1-5 alkyl, optionally substituted C3-10 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl,
wherein the triple bond in Formula Y or Z is meta to the linker L; and
wherein unless otherwise indicated,
(A) the above optionally substituted non-aromatic group is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, —OH, oxo (as applicable), C1-7 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C1-7 alkyl and C1-4 alkoxy; and
(B) the above optionally substituted aromatic group is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, —OH, —CN, C1-7 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, —OH, oxo (as applicable), C1-7 alkyl and C1-4 alkoxy.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is substituted with one or two substituents, wherein one substituent is selected from
and the other substituent, when exists, is selected from halogen, methyl, ethyl, NH2, or protected NH2.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is
wherein R1 is selected from
and R0 is selected from hydrogen, methyl, ethyl, NH2, or protected NH2, provided that in
R1 is not a moiety with an N, S, or O attaching point.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is —O—(C1-4 alkylene), —S—(C1-4 alkylene), or C1-4 alkylene, wherein each of the C1-4 alkylene is optionally substituted with 1-3 substituents selected from F, methyl or fluorine substituted methyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is —O—CH2—, wherein the CH2 is directly attached to ring B.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl or pyridinyl ring.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having the Formula Y.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring B in Formula Y is selected from:

### Claim 9 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring B in Formula Y is a 5,5-bicyclic or 5,6-bicyclic heteroaryl ring.

### Claim 10 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, RB and RC are each methyl.

### Claim 11 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y,

### Claim 12 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, n is 0.

### Claim 13 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, n is 1, and RA is halogen, C1-7 alkyl optionally substituted with one or more substituents each independently selected from halogen and —OH, —CN, —OH, C1-4 alkoxyl optionally substituted with 1-3 fluorine, C3-6 cycloalkyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl, and C3-6 cycloalkoxyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl.

### Claim 14 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, L is —O—CH2—, with the CH2 directly attached to ring B.

### Claim 15

A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

A method of inhibiting HPK1 activity, comprising administering to a subject in need thereof the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A method of treating a disease or disorder associated with aberrant activity of HPK1, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease or disorder is cancer, metastasis, inflammation, or an autoimmune disease.

### Claim 20 (depends on 1)

A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer is breast cancer, colorectal cancer, hematological malignancy, lung cancer, melanoma, ovarian cancer, pancreatic cancer, and/or kidney cancer.

### Claim 22 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, Ar is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is substituted with one or two substituents, wherein one substituent is an optionally substituted 5 or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S, O, and N, wherein the S and N are optionally oxidized, and the other substituent, if present, is selected from halogen, C1-7 alkyl, and —NR101R102;
wherein the 5 or 6-membered heterocyclic ring, when substituted, is substituted with 1-3 substituents each independently selected from 1) halogen; 2) C1-7 alkyl optionally substituted with 1-3 fluorine; and 3) 5 or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S, O, and N, wherein the S and N are optionally oxidized, which is optionally substituted with 1-3 substituents each independently selected from halogen and C1-7 alkyl optionally substituted with 1-3 fluorine.

### Claim 23 (depends on 22)

The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5 or 6-membered heterocyclic ring is a ring selected from:
which is unsubstituted or substituted with 1-3 substituents each independently selected from halogen and C1-7 alkyl optionally substituted with 1-3 fluorine.

### Claim 24 (depends on 22)

The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5 or 6-membered heterocyclic ring is a ring selected from:
which is unsubstituted or substituted with 1-3 substituents each independently selected from halogen and C1-7 alkyl optionally substituted with 1-3 fluorine.

### Claim 25 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ar is
wherein R1 is selected from
and R0 is selected from hydrogen, methyl, ethyl, NH2, or protected NH2.

### Claim 26 (depends on 22)

The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein L in Formula Y is —O—(C1-4 alkylene), wherein the C1-4 alkylene is optionally substituted with 1-3 substituents selected from F, methyl or fluorine substituted methyl, wherein the C1-4 alkylene is directly attached to ring B.

### Claim 27 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein L in Formula Y is —O—CH2—, with the CH2 directly attached to ring B.

### Claim 28 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein ring B in Formula Y is selected from:

### Claim 29 (depends on 28)

The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein RB and RC in Formula Y are each independently selected from hydrogen,

### Claim 30 (depends on 28)

The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, n is 0.

### Claim 31 (depends on 28)

The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, n is 1, and RA is halogen, C1-7 alkyl optionally substituted with one or more substituents each independently selected from halogen and —OH, —CN, —OH, C1-4 alkoxyl optionally substituted with 1-3 fluorine, C3-6 cycloalkyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl, and C3-6 cycloalkoxyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl.

### Claim 32

A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula Y,
wherein:
Ar is
wherein R1 is selected from
and R0 is selected from hydrogen, methyl, ethyl, NH2, or protected NH2;
L is —O—(C1-4 alkylene), wherein the C1-4 alkylene is optionally substituted with 1-3 substituents selected from F, methyl or fluorine substituted methyl, wherein the C1-4 alkylene is directly attached to ring B;
ring B is selected from:
RB and RC are each independently selected from hydrogen,
A is CH;
n is 0,
or n is 1, and RA is halogen, C1-7 alkyl optionally substituted with one or more substituents each independently selected from halogen, —OH, and NH2, —CN, —OH, C1-4 alkoxyl optionally substituted with 1-3 fluorine, C3-6 cycloalkyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl, and C3-6 cycloalkoxyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl.

### Claim 33 (depends on 32)

The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein L is —O—CH2—, wherein the CH2 is directly attached to ring B.

### Claim 34

A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula Z:
wherein in Formula Z,
Ar is
wherein R1 is selected from
and R0 is selected from hydrogen, methyl, ethyl, NH2, or protected NH2;
L is —O—(C1-4 alkylene), wherein the C1-4 alkylene is optionally substituted with 1-3 substituents selected from F, methyl or fluorine substituted methyl, wherein the C1-4 alkylene is directly attached to ring B;
ring B is selected from:
RD is hydrogen,
A is CH;
n is 0 or
n is 1, and RA is halogen, C1-7 alkyl optionally substituted with one or more substituents each independently selected from halogen, —OH, and NH2, —CN, —OH, C1-4 alkoxyl optionally substituted with 1-3 fluorine, C3-6 cycloalkyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl, and C3-6 cycloalkoxyl optionally substituted with 1 or 2 substituents each independently selected from F and C1-7 alkyl.

### Claim 35 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

### Claim 36 (depends on 35)

A pharmaceutical composition comprising the compound of claim 35 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

### Claim 37 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein in Formula Y, RB and RC are each independently selected from hydrogen,