1,6-naphthyridine derivatives as CDK4/6 inhibitor

Patent metadata

Field	Value
Publication number	US-10676474-B2
Application number	US-201716470111-A
Country	US
Kind code	B2
Filing date	Dec 15, 2017
Priority date	Dec 16, 2016
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

Disclosed is a series of compounds acting as CDK4/6 inhibitors. Specifically disclosed are compounds as represented by formula (I), pharmaceutically acceptable salts or isomers thereof, pharmaceutical compositions containing same, and the use thereof in the preparation of drugs for treating cancers.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,
wherein:
ring A is a 4-11 membered heterocycloalkyl;
ring B is C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, each optionally substituted by 1, 2 or 3 R;
R 1 is H, C 1-3 alkyl, C 1-3 heteroalkyl or C(═NOH)H, wherein the C 1-3 alkyl, C 1-3 heteroalkyl and —C(═NOH)H are each optionally substituted by 1, 2 or 3 R;
each R 2 is independently H, halogen, CN, C 1-5 alkyl, C 1-5 heteroalkyl, OH, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-5 alkyl, C 1-5 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 R;
each R is independently halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , NO 2 or OH, wherein the C 1-3 alkyl and C 1-3 heteroalkyl are each optionally substituted by 1, 2 or 3 R′; and
each R′ is independently F, Cl, Br, I, CN, NH 2 or OH;
wherein each hetero in the C 1-3 heteroalkyl, C 1-5 heteroalkyl, 3-6 membered heterocycloalkyl, 4-11 membered heterocycloalkyl and 5-6 membered heteroaryl is 1, 2 or 3 heteroatom(s) or heteroatomic group(s) independently selected from the group consisting of —C(═O)—, N, —NH—, O—, —S—, —S(═O)— and —S(═O) 2 .

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein ring A is 5-9 membered heterocycloalkyl.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

is:

4. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

is

5. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

is

6. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein ring B is cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each optionally substituted by 1, 2 or 3 R.

7. The compound according to claim 6 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein ring B is cyclopentyl, cyclohexyl or phenyl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein each R is independently F, Cl, Br, CN, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , NH 2 , OH or OCH 3 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 1 is H, CH 3 , CH 2 CH 3 , —C(═O)CH 3 or —C(═NOH)H, wherein the CH 3 , CH 2 CH 3 , —C(═O)CH 3 and —C(═NOH)H are each optionally substituted by 1, 2 or 3 R.

10. The compound according to claim 9 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 1 is CH 3 , CHF 2 , —C(═O)CH 3 , —C(═NOCH 2 CH 3 )CH 3 or —C(═NOCH(CH 3 ))CH 3 .

11. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein each R 2 is independently H, F, Cl, CN, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 2 N(CH 3 ) 2 , N(CH 3 ) 2 , OH, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, piperazinyl or morpholinyl, wherein the CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 2 N(CH 3 ) 2 , N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, piperazinyl or morpholinyl are each optionally substituted by 1, 2 or 3 R.

12. The compound according to claim 11 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein each R 2 is independently H, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 2 N(CH 3 ) 2 , N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, piperazin-1-yl or morpholin-4-yl, wherein the CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 2 N(CH 3 ) 2 , N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, piperazin-1-yl and morpholin-4-yl are each optionally substituted by 1, 2 or 3 R.

13. The compound according to claim 12 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein each R 2 is independently H, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 2 F, (CH 2 ) 2 NH 2 , (CH 2 ) 2 N(CH 3 ) 2 , (CH 2 ) 20 H, N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, piperazin-1-yl or morpholin-4-yl.

14. The compound according to claim 1 , wherein the compound is formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI′):

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

15. The compound of according to claim 1 , wherein the compound is formula (VII):

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

16. The compound according to claim 1 , wherein the compound is formula (VIII):

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

18. A method for inhibiting cyclin-dependent kinase 4 activity and/or cyclin-dependent kinase 6 activity in a subject having cancer, comprising:
administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

19. A compound selected from the group consisting of:

Assignees

• Cstone Pharmaceuticals
• Medshine Discovery Inc

Inventors

• Xu Zhaobing
• Hu Lihong
• Ding Charles Z
• Chen Shuhui

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/06

  Peri-condensed systems · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title