# US 9,434,741 B2 · Thieno[2,3-d]pyrimidine derivatives, preparation method and use thereof

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- Number: US 9,434,741 B2
- Document ID: US9434741B2
- Status: Granted
- Kind: B2
- Application number: 14/241,056
- Filed: 2012-09-19
- Published: 2015-03-19
- Granted: 2016-09-06
- Earliest claimed: 2012-09-19
- Assignees: Fujian Institute of Research On the Structure of Matter, Chinese Academy of Sciences
- Applicants: Canzhong Lu; Jianping Yong
- Inventors: Canzhong Lu; Jianping Yong
- Web page: https://patentgrep.com/patent/US9434741B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure provides thieno[2,3-d]pyrimidine compounds containing isoxazole heterocycle represented by formula (I), or pharmaceutically acceptable salts thereof. Such compounds are useful for the treatment of diseases including tumors and cancers.

## Claims

### Claim 1

A thieno[2,3-d]pyrimidine compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R1 and R2 are the same or different and are independently selected from H, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, hydroxyl substituted C1-6 alkyl, aryl group optionally substituted by R7, or heteroaryl group optionally substituted by R8;
Z is —NR5—, C(R6)2, —S—, or —O—, in which R5 is H or C1-6 alkyl, and R6 is the same or different, selected from H, C1-6 alkyl, halo-C1-6 alkyl, or hydroxyl substituted C1-6 alkyl;
R3 is selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, or hydroxyl substituted C1-6 alkyl;
n is an integer of 0-5;
R4 is selected from H, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, aryl group optionally substituted by R9, or heteroaryl group optionally substituted by R10; and
R7, R8, R9, and R10 are independently selected from H, hydroxy, mercapto, cyano, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, carboxy, halo-C1-6 alkyl, halo-C1-6 alkoxy or halo-C1-6 alkylthio,
wherein the following compounds are disclaimed:

### Claim 2 (depends on 1)

The thieno[2,3-d]pyrimidine compound, or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein
R1 and R2 are the same or different and is independently selected from H, C1-3 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, halo-C1-6 alkoxy, phenyl, or R7-substituted phenyl group, and
R4 is selected from H, C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkyl, phenyl, or R9-substituted phenyl group.

### Claim 3 (depends on 1)

The thieno[2,3-d]pyrimidine compound, or the pharmaceutically acceptable salt or solvate according to claim 1, wherein
R1 and R2 are independently selected from H, C1-3 alkyl, phenyl, or R7-substituted phenyl group,
Z is —NH—, CH2, or —O—;
R3 is selected from H, fluoro, chloro, bromo, methyl, methoxy, or trifluoromethyl;
n is 1-4; and
R4 is selected from H, C1-6 alkyl, C1-6 alkoxy or halo-C1-6 alkyl, phenyl, or R9-substituted phenyl group.

### Claim 4 (depends on 1)

The thieno[2,3-d]pyrimidine compound, or the pharmaceutically acceptable salt or solvate of claim 1, wherein said thieno[2,3-d]pyrimidine compound is selected from:

### Claim 5 (depends on 1)

A pharmaceutical composition comprising:
the thieno[2,3-d]pyrimidine compound and/or the pharmaceutically acceptable salt or solvate thereof according to claim 1, and at least one pharmaceutically acceptable, inert, non-toxic excipient or carrier or diluent.

### Claim 6 (depends on 5)

The pharmaceutical composition according to claim 5, wherein said pharmaceutical composition is a formulation selected from tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, hydro-acupuncture for injection, lyophilized powder for injection, large volume infusion, or small volume infusion.

### Claim 7 (depends on 1)

A method for treating tumors or cancers in a human subject comprising administering to the subject an effective amount of the thieno[2,3-d]pyrimidine compound, and/or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the tumors or cancers is lung cancer or colon cancer.

### Claim 8 (depends on 1)

A method for inhibiting an overexpression and/or overactivity of EGFR, comprising preparing an inhibitor comprising an effective amount of the thieno[2,3-d]pyrimidine compound, and/or the pharmaceutically acceptable salt or solvate thereof according to claim 1.

### Claim 9 (depends on 1)

A preparation method of the thieno[2,3-d]pyrimidine compound of formula (I) according to claim 1, comprising:
reacting 2,5,6-trisubstituted-4-chloro-thieno[2,3-d]pyrimidine (formula II) and 3-substituted phenyl-5-hydroxymethyl-isoxazole (formula III) or 3-substituted phenyl-5-aminomethyl-isoxazole (formula VI) in a system comprising a dry organic solvent and an alkaline acid binding agent;
obtaining a compound of formula I-1 or I-2, respectively,
wherein the reaction is schematically represented as follows:

### Claim 10 (depends on 3)

The thieno[2,3-d]pyrimidine compound, or the pharmaceutically acceptable salt or solvate thereof according to claim 3, wherein:
R1 is selected from H, methyl, or phenyl and R2 is selected from H, methyl, ethyl or tert-butyl;
Z is —NH— or —O—;
R3 is at the ortho- or para-position in the isoxazole ring, and is selected from 4-fluoro, 4-chloro, 2-chloro, 4-bromo, 2,4-dichloro, 4-methyl, 4-methoxy, H, 4-trifluoromethyl, or 2,4-dimethoxy; and
R4 is selected from H, methyl, or phenyl.

### Claim 11 (depends on 5)

The pharmaceutical composition of claim 5, further comprising one or more pharmaceutically acceptable auxiliary materials selected from fillers, disintegrants, lubricants, glidants, effervescents, flavoring agents, preservatives, or coating materials.