# US 10,308,654 B2 · Preparation and use of kinase inhibitor

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- Number: US 10,308,654 B2
- Document ID: US10308654B2
- Status: Granted
- Kind: B2
- Application number: 15/566,872
- Filed: 2016-04-15
- Published: 2018-05-10
- Granted: 2019-06-04
- Earliest claimed: 2015-04-17
- Assignees: Changzhou Longthera Pharmaceuticals Inc.
- Applicants: Changzhou Longthera Pharmaceuticals Inc
- Inventors: Peng Cheng; Wenjie Cao
- Web page: https://patentgrep.com/patent/US10308654B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/52: Purines, e.g. adenine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 35/02: specific for leukemia
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 473/28: Oxygen atom
- C07D 473/32: Nitrogen atom
- C07D 473/36: Sulfur atom
- 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

Disclosed are a preparation method for a kinase inhibitor and a use thereof. The kinase inhibitor is a compound represented by formula (I) wherein the groups are defined as described in the description. The compound of formula (I) has a kinase inhibitory activity and therefore can be used for the preparation of medicines for treating kinase activity-related diseases.

## Claims

### Claim 1

A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein,
R1 and R2 can be connected with adjacent N atom to form a ring structure, said ring structure includes a substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycle or a bridged ring or a spiro ring; wherein said heterocycle refers to a ring structure containing 0-3 heteroatoms selected from the group consisting of N, O or S, in addition to the nitrogen atom attached to the parent nucleus;
R3 is selected from a substituted or unsubstituted C1-C8 alkyl, CN, C(O)OR12, CONR13R14, C(O)R15, a substituted or unsubstituted 5-8 membered aryl, a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycle or carbocycle; wherein said heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O or S; said heterocycle contains 1-3 heteroatoms selected from the group consisting of N, O or S;
R4 is selected from H, a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a halogen, OH, CN, C(O)OR12, CONR13R14,C(O)R15, a substituted or unsubstituted 5-8 membered aryl, a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycle or carbocycle; wherein said heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O or S; said heterocycle contains 1-3 heteroatoms selected from the group consisting of N, O or S;
R5 is selected from H or C1-C4 alkyl;
X is CR16;
A and B are each independently selected from N or CR16;
Z is N;
R16 is H, C1-C4 alkyl or C1-C4 haloalkyl;
L is selected from the group consisting of none, C1-C6 alkylene, C(O), CONR17 or S(O)2;
Y is H, R18, NR19R20, OH, or Y is selected from part of the group consisting of:
wherein,
R6 is none, H, a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a substituted or unsubstituted C2-C6 acyl, a substituted or unsubstituted C2-C6 sulfonyl, a substituted or unsubstituted C1-C6 alkylenehydroxy, CONR22R23 or C(O)R24;
R7 may be 0-3 substituents and R7 is a substituted or unsubstituted C1-C8 alkyl, an oxygen or a halogen, or two or more R7 form a bridged cycloalkyl;
W is CR21, N or O (when W is O, R6 is absent);
Ya is CR21 or N;
R21 is H or a halogen;
R8, R9, R10, R11, R12, R13, R14, R15, R17, R18, R19, R20, R22, R23 and R24 are each independently selected from H, a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a substituted or unsubstituted C1-C6 alkyleneamino, a substituted or unsubstituted C1-C6 alkylenehydroxy, a substituted or unsubstituted 5-8 membered aryl, a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 3-12 membered saturated heterocycle or carbocycle; wherein said heteroaryl contains at least one heteroatom selected from the group consisting of N, O or S, said heterocycle contains at least one heteroatom selected from the group consisting of N, O or S;
n and t are 0, 1 or 2, respectively;
any one of the above mentioned “substituted” means that one or more hydrogen atoms on the group are substituted with substituent(s) selected from the group consisting of a halogen, OH, NH2, CN, an unsubstituted or halogenated C1-C8 alkyl, C1-C8 alkoxy, an unsubstituted or halogenated C2-C6 alkenyl, an unsubstituted or halogenated C2-C6 alkynyl, an unsubstituted or halogenated C2-C6 acyl, an unsubstituted or halogenated 5-8 membered aryl, an unsubstituted or halogenated 5-8 membered heteroaryl, an unsubstituted or halogenated 3-12 membered saturated heterocycle or carbocycle; wherein said heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O or S, said heterocycle contains 1-3 heteroatoms selected from the group consisting of N, O or S.

### Claim 2 (depends on 1)

The compound of formula I of claim 1, wherein the compound of formula I is the compound selected from the group consisting of:

### Claim 3 (depends on 1)

A process for the preparation of the compound of formula I of claim 1, wherein the process comprises the following step:
a) a compound of formula I-6 reacts with a compound of formula I-7 in an inert solvent to form the compound of formula I, wherein each group is defined as in claim 1.

### Claim 4 (depends on 3)

The process of claim 3, wherein the inert solvent is selected from the group consisting of toluene, xylene, glycol dimethyl ether, dioxane, THF, DMF, DMSO, NMP, or a combination thereof.

### Claim 5 (depends on 3)

The process of claim 3, wherein the process has one or more following characteristics:
the reaction is carried out in the presence of a palladium catalyst, and the palladium catalyst is selected from the group consisting of Pd(PPh3)4, Pd2(dba)3, Pd(dba)2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(dppe)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, or a combination thereof;
the reaction is carried out in the presence of a ligand, and the ligand is a monodentate phosphine ligand or bidentate phosphine ligand; and the ligand is selected from the group consisting of triphenylphosphine, trimethylphenylphosphine, tricyclohexylphosphine, Tri-tert-butylphosphine, X-Phos, S-Phos, Binaphthyl diphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, Xant-Phos, or a combination thereof; and / or
the reaction is carried out in the presence of a base, and the base is selected from the group consisting of Na2CO3, K2CO3, Cs2CO3, LiHMDS, NaHMDS, KHMDS, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, or a combination thereof.

### Claim 6 (depends on 1)

A pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) an effective amount of the compound of formula I set forth in claim 1, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A method of inhibiting CDK kinase activity, wherein the method comprises steps: administering a subject an inhibitory effective amount of the compound of formula I of claim 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I or a pharmaceutical acceptable salt thereof.

### Claim 8 (depends on 1)

A method of inhibiting tumor cells or treating cancer, wherein the method comprises: administering a subject an inhibitory effective amount of the compound of formula I of claim 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I or the pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, gastric cancer, bladder cancer, lymphoma, head and neck cancer, melanoma, non-small cell lung cancer, liver cancer, glioma, and colon cancer.

### Claim 9 (depends on 7)

The method of claim 7, wherein the CDK kinase is CDK4, CDK6, or a combination thereof.

### Claim 10 (depends on 8)

The method of claim 8, wherein the tumor cell is a leukemic cell line.

### Claim 11 (depends on 10)

The method of claim 10, wherein the leukemic cell line is a myeloid leukemia cell line.

### Claim 12 (depends on 11)

The method of claim 11, wherein the myeloid leukemia cell line is an acute myeloid leukemia cell line KG1.

### Claim 13 (depends on 1)

The compound of formula I of claim 1, wherein A is N, and B is CH.