Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof

• US 10,633,375 B2
• Filed: 08/30/2017
• Issued: 04/28/2020
• Est. Priority Date: 08/31/2016
• Status: Active Grant

• Current Assignee: Jiangsu Hengrui Medicine Company Limited, Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Original Assignee: Jinagsu Hengrui Medicine Company Limited
• Inventors: Yang, Fanglong, Wang, Weimin, Li, Xiaodong, Chen, Gang, He, Feng, Tao, Weikang
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US16/328,128
• Publication Number:
  US 20190185464A1
• Time in Patent Office: 972 Days
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/02 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to an oxopicolinamide derivative, a preparation method therefor and the pharmaceutical use thereof. In particular, the present invention relates to an oxopicolinamide derivative as shown in the general formula (AI), a preparation method therefor and a pharmaceutical composition comprising the derivative, and to the use thereof as a therapeutic agent, in particular as an inhibitor of blood coagulation factor XIa (Factor XIa, FXIa for short) and the use thereof in the preparation of a drug for treating diseases such as thromboembolism, wherein the definition of each substituent in the general formula (AI) is the same as defined in the description.

Claims

1. A compound of formula (AI):

2. The compound according to claim 1, being a compound of formula (I):

3. The compound of according to claim 2, being a compound of formula (Iaa):

4. The compound according to claim 1, wherein

5. The compound according to claim 2, being a compound of formula (II):

6. The compound according to claim 1, wherein each R⁵ is identical or different, and each is independently selected from the group consisting of alkyl, alkoxy, oxo, halogen, haloalkyl, cyano, hydroxy, —

C(O)OR⁸, —

NHC(O)OR⁸, —

C(O)NR¹⁰R¹¹, —

CH₂NHC(O)OR₉, —

CH₂NR¹⁰R¹¹, —

C(O)OCH(R¹⁰)R¹¹ and —

S(O)_mR⁸;

R⁸ is selected from the group consisting of hydrogen, alkyl, hydroxy and amino;

R¹⁰ and R¹¹ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, —

C(O)OR⁸ and —

OC(O)OR¹², wherein the cycloalkyl and heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, oxo, amino, nitro, cyano, hydroxy and hydroxyalkyl; and

R¹² is alkyl.

7. The compound of formula (AI) according to claim 1, wherein R¹ is —

C(O)R⁷;

R⁷ is selected from the group consisting of alkyl, cycloalkyl and haloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl and cycloalkyl.

8. The compound according to claim 2, being a compound of formula (III):

9. The compound according to claim 8, being a compound of formula (IV):

10. The compound according to claim 1, wherein R² is halogen;

and n is 0, 1 or 2.

11. The compound according to claim 1, wherein R³ is alkoxy, wherein the alkoxy is optionally substituted by one or more deuteriums or halogens.

12. The compound according to claim 2, wherein L¹ is —

(CR¹⁴₂)_x—

, x is an integer of 1, 2, 3, 4;

or 4;

R¹⁴ is hydrogen or deuterium;

R⁶ is selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl;

wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, —

NHC(O)R¹² and R¹³;

R¹² is alkyl or cycloalkyl;

R¹³ is aryl or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano and hydroxy.

13. The compound according to claim 2, wherein L¹ is —

CH₂—

or —

CD₂-;

R⁶ is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, —

NHC(O)R¹² and R¹³;

R¹² is alkyl or cycloalkyl;

R¹³ is aryl or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano and hydroxy.

14. The compound according to claim 2, wherein L¹ is —

CH₂CH₂—

; and

R⁶ is alkyl, alkoxy or cycloalkyloxy.

16. A process for preparing the compound of formula (AI) according to claim 1, comprising:

17. A process for preparing the compound of formula (I) according to claim 2, comprising:

18. A pharmaceutical composition comprising the compound according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. A method for preventing and/or treating a factor XIa mediated disease, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition according to claim 18.

20. A method for preventing and/or treating a cardiovascular and cerebrovascular disease, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition according to claim 18.

21. A method for inhibiting factor XIa, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition according to claim 18.

15. A compound selected from the group consisting of: