Aminopyrimidines as Syk inhibitors

• US 8,735,417 B2
• Filed: 12/16/2010
• Issued: 05/27/2014
• Est. Priority Date: 12/17/2009
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Canada Incorporated (Merck & Co., Inc.), Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Altman, Michael D., Arrington, Kenneth L., Burch, Jason, Cote, Bernard, Fournier, Jean-Francois, Gauthier, Jacques Yves, Kattar, Solomon, Knowles, Sandra Lee, Lim, Jongwon, Machacek, Michelle R., Northrup, Alan B., Reutershan, Michael H., Robichaud, Joel S., Schell, Adam J., Spencer, Kerrie B.
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US13/515,941
• Publication Number:
  US 20120309735A1
• Time in Patent Office: 1,258 Days
• Field of Search: 544/242, 544/322, 544/331, 514/247, 514/256, 514/275
• US Class Current: 514/275
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

The present invention provides novel pyrimidine amines of formula (I) which are potent inhibitors of spleen tyrosine kinase, and are useful in the treatment and prevention of diseases mediated by said enzyme, such as asthma, COPD and rheumatoid arthritis.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

2. A compound of claim 1 having the formula (Ia) or a pharmaceutically acceptable salt thereof:

3. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R^3a and R^3b are independently selected from (a) H, (b) C_1-6alkyl optionally substituted with one or two groups independently selected from (i) OR^a, (ii) phenyl optionally substituted with OR^a, C_1-3 alkyl or CF₃, (iii) 5- or 6-membered heterocyclyl optionally substituted with one or two groups selected from oxo, C_1-3 alkyl, OR^a and NR^bR^c, (iv) 5- or 6-membered heteroaryl optionally substituted with one or two methyl groups, (v) C_3-6cycloalkyl, (vi) CO₂H, (vii) NR^bR^c, and (viii) SR^a, (c) C_1-6haloalkyl optionally substituted with OH, (d) C_3-6cycloalkyl optionally substituted with OH, and (e) phenyl optionally substituted with CO₂H or CO₂C_1-4alkyl.

4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R^3a is H and R^3b is selected from (a) C_1-6alkyl optionally substituted with one or two groups independently selected from (i) OR^a, (ii) phenyl optionally substituted with OR^a, C_1-3 alkyl or CF₃, (iii) 5- or 6-membered heterocyclyl optionally substituted with one or two groups selected from oxo, C_1-3alkyl, OR^a and NR^bR^c, (iv) 5- or 6-membered heteroaryl optionally substituted with one or two methyl groups, (v) C_3-6cycloalkyl, (vi) CO₂H, (vii) NR^bR^c, and (viii) SR^a, and (b) C_1-6haloalkyl optionally substituted with OH.

5. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b and the nitrogen atom to which they are both attached together form a 5- or 6-membered heterocyclic ring having 0-1 additional heteroatom selected from N—

R^x and O, wherein said ring is optionally substituted with one or two groups independently selected from (a) oxo, (b) C_1-3alkyl optionally substituted with OH, CO₂H, CONH₂, or NHCOCH₃, (c) CF₃, (d) OH, (e) CONH₂, (f) CO₂H, and (g) NH₂.

6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b and the nitrogen atom to which they are both attached together form a pyrrolidinyl or piperidinyl ring, each being optionally substituted with one or two groups independently selected from (a) oxo, (b) C_1-3alkyl optionally substituted with OH, CO₂H, CONH₂, or NHCOCH₃, (c) CF₃, (d) OH, (e) CONH₂, (f) CO₂H, and (g) NH₂.

7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula (Ib) or a pharmaceutically acceptable salt thereof:

8. A compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R^x is H.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is trifluoromethyl.

11. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R¹ is trifluoromethyl.

12. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R¹ is trifluoromethyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one.