Phenyl amino pyrimidine bicyclic compounds and uses thereof
The present invention relates to phenyl amino pyrimidine bicyclic compounds formula I which are inhibitors of protein kinases including JAK kinases. In particular the compounds are active against JAK1, JAK2, JAK3 and TYK2 kinases. The kinase inhibitors can be used in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
1. A compound of formula I
wherein
R 1 is a substituted or unsubstituted bicyclic heterocyclyl;
R 2 is selected from H, halogen, substituted or unsubstituted C 1-4 alkyl, CF 3 substituted or unsubstituted C 1-4 alkoxy, CON(R) 2 , CN and CO 2 R;
R is selected from H and substituted or unsubstituted C 1-4 alkyl,
or an enantiomer thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein the compound of formula I has the formula Ia:
wherein,
R 1 and R 2 are as defined in claim 1 ,
or an enantiomer thereof or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein the compound of formula I has the formula Ib
wherein R 1 and R 2 are as defined in claim 1 ,
or an enantiomer thereof or a pharmaceutically acceptable salt thereof.
4. A compound selected from
4-(2-((4-(1-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
4-(2-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
(S)-4-(2-((4-(1-oxa-6-azaspiro[3.4]octan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
(R)-4-(2-((4-(1-oxa-6-azaspiro[3.4]octan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
(R)-4-(2-((4(4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
(S)-4-(2-((4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
4-(2-((4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
4-(2-((4-(6-oxa-3-azabicyclo [3.1.1]heptan-3-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
4-(2-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
4-(2-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide; and
4-(2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide;
or an enantiomer thereof or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein the compound is a kinase inhibitor.
6. The compound according to claim 5 , wherein the kinase inhibitor is a JAK1, JAK2, JAK3 and/or TYK2 inhibitor.
7. A process for the preparation of the compound of formula I according to claim 1 which comprises the step of coupling a compound of formula II
wherein
R 2 is defined in claim 1 and X is a leaving group with a compound of formula III
wherein
R 1 is defined in claim 1 ; and
M is B or a metal; or
coupling a compound of formula IV
wherein
R 2 , X and R are as defined above with a compound of formula III as defined above to prepare a compound of formula V
wherein
R 1 , R 2 , X and R are as defined in claim 1 ; and
coupling the compound of formula V defined above with
8. The process according to claim 7 wherein X in the compound of formula II is chloro which is then converted into iodo prior to coupling with the compound of formula III.
9. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
10. An implant which comprises the compound according to claim 1 .
11. A method for the treatment of an immunological or inflammatory disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, polymyalgia rheumatica, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, which comprises administering an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt or a pharmaceutical composition thereof to a subject in need thereof.
12. A method for the treatment of a myeloproliferative disease selected from the group consisting of polycythemia vera, primary myelofibrosis, thrombocythemia, essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia, systemic mastocystosis, chronic neutrophilic leukemia, myelodisplastic syndrome, and systemic mast cell disease, which comprises administering an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a subject in need thereof.
13. A method of inhibiting a kinase in a cell comprising contacting the cell with the compound according to claim 1 .
14. A compound of formula V:
wherein
R 1 is a substituted or unsubstituted bicyclic heterocyclyl;
R 2 is selected from H, halogen, substituted or unsubstituted C 1-4 alkyl, CF 3 substituted or unsubstituted C 1-4 alkoxy, CON(R) 2 , CN and CO 2 R;
R is selected from H and substituted or unsubstituted C 1-4 alkyl,
or an enantiomer thereof or a pharmaceutically acceptable salt thereof.