# US 2022/0031685 A1 · Combination therapy for treating blood cancer

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- Number: US 2022/0031685 A1
- Document ID: US20220031685A1
- Status: Published application
- Kind: A1
- Application number: 17/276,459
- Filed: 2019-09-18
- Published: 2022-02-03
- Earliest claimed: 2018-09-18
- Assignees: Signalchem Lifesciences Corporation
- Applicants: Signalchem Lifesciences Corporation
- Inventors: Zaihui ZHANG; Xiaoyan JIANG; Katharina ROTHE; Xiaojia NIU
- Web page: https://patentgrep.com/patent/US20220031685A1

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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

Provided herein are combination therapies for treating blood cancer, in particular, acute myeloid leukemia, by concurrently targeting Axl and BCL-2.

## Claims

### Claim 1

A method for treating blood cancer in a subject in need thereof, the method comprising administering to the subject a combination of an Axl inhibitor and a BCL-2 family protein inhibitor, wherein the Axl inhibitor is a compound of Formula (I):
wherein,
A, A1 and A2 is the same or different and independently —N═, —CR5═, or —O—;
R1 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each of which may be optionally substituted;
R2 is heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl, aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each of which may be optionally substituted;
each R3 and R4 is the same or different and independently selected from hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl, each of which may be optionally substituted;
R5, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl, each of which may be optionally substituted; or
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and
the BCL-2 family protein inhibitor is a compound of Formula (II):
wherein
n is 0 or 1;
R6 is optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heteroalkyl;
R7 is optionally substituted heterocyclylalkyl;
R8 is optionally substituted heteroaryl, or optionally substituted aryl;
Y1 is an electron-withdrawing group,
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein the Axl inhibitor is a compound of:

### Claim 3 (depends on 1)

The method of claim 1 wherein the Axl inhibitor is 3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

### Claim 4 (depends on 1)

The method of claim 1 wherein the BCL-2 family protein inhibitor is a compound of Formula (IIa) or (IIb):
wherein.
X1 is H, F, Cl, Br, or I;
X2 and X3 are independently hydrogen or alkyl; and
X4 is —O—, —C(R9)2—, or —CH2CH2—;
Y1 is —CN, —NO2, —SO2C(X5)3, —CF3, F, Cl, or Br; wherein each X5 is, at each occurrence, independently, H, F or Cl.
R9 is hydrogen or alkyl.

### Claim 5 (depends on 4)

The method of claim 4 wherein Y1 is —NO2, or —SO2CF3.

### Claim 6 (depends on 5)

The method of claim 5 wherein the BCL-2 family protein inhibitor is:

### Claim 7 (depends on 1)

The method of claim 1 wherein the Axl inhibitor is 3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; and the BCL-2 family protein inhibitor is venetoclax.

### Claim 8 (depends on 1)

The method of claim 1 wherein the Axl inhibitor is 3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; and the BCL-2 family protein inhibitor is Navitoclax.

### Claim 9 (depends on 1)

The method of claim 1 wherein the blood cancer is acute myeloid leukemia (AML).

### Claim 10 (depends on 1)

The method of claim 1 wherein the Axl inhibitor is administered at a lower dose than a monotherapy using the same Axl inhibitor.

### Claim 11 (depends on 1)

The method of claim 1 wherein the BCL-2 family protein inhibitor is administered at a lower dose than a monotherapy using the same BCL-2 family protein inhibitor.