Substituted piperidines as bruton's tyrosine kinase inhibitors
A fused bicyclic compound having an effect in inhibition of the activity of a tyrosine kinase, and preparation and use thereof are disclosed. In particular, a compound of formula (IV) or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, a prodrug or an isotopic variation thereof, as well as a pharmaceutical composition including the same are disclosed. As a selective irreversible inhibitor of Bruton's tyrosine kinase, the described compound can be used for preventing or treating diseases such as inflammation, autoimmune diseases (such as rheumatoid arthritis), xenogeneic immune diseases and cancers.
1 . A method for inhibiting Bruton's tyrosine kinase (BTK) activity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (IV):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 3 is CR 1 ;
X 6 is N;
each R 1 is independently H;
Ar 1 is ring C of the formula:
is:
wherein * is the point of attachment to the carbon atom of the imidazo[1,5-a]pyrazine ring and # is the point of attachment to L a ;
L a is —O—;
Ar 2 is unsubstituted phenyl;
L is:
wherein * is the point of attachment to the carbon atom of the imidazo[1,5-a]pyrazine ring and # is the point of attachment to V;
V is —C(O)—; and
R is C 2 -C 4 alkenyl;
wherein the subject has a multiple sclerosis.
2 . The method of claim 1 , wherein the Bruton's tyrosine kinase is the C481S mutant form of Bruton's tyrosine kinase.
3 . The method of claim 1 , wherein the therapeutically effective amount is a daily amount in the range of from 1 mg to 500 mg.
4 . The method of claim 1 , wherein the method further comprises once, twice, or three times daily administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof.
5 . The method of claim 1 , wherein the method further comprises twice daily administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof.
6 . The method of claim 5 , wherein the method further comprises twice daily administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, at least eight hours between the first daily administration and the second daily administration.
7 . The method of claim 1 , wherein the method further comprises twice daily administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, once in the morning and once in the evening.
8 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, for a duration of at least one week.
9 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, without eating food.
10 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, within one hour prior to eating food.
11 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, along with eating food.
12 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof, in a form selected from the group consisting of an aerosol, a capsule, an elixir, a pill, a powder, a semisolid, a solution, a suspension, a sustained release formulation, and a tablet.
13 . The method of claim 1 , wherein the method further comprises orally administering to the subject in need thereof a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt or tautomer thereof.
14 . The method of claim 1 , wherein
is:
wherein * is the point of attachment to the carbon atom of the imidazo[1,5-a]pyrazine ring and # is the point of attachment to L a .
15 . The method of claim 1 , wherein R is CH═CH 2 .
16 . The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or tautomer thereof.
17 . The method of claim 1 , wherein the multiple sclerosis is progressive multiple sclerosis (PMS) or relapsing multiple sclerosis (RMS).
18 . The method of claim 1 , wherein the progressive multiple sclerosis is primary-progressive multiple sclerosis (PPMS) or secondary-progressive multiple sclerosis (SPMS).
19 . The method of claim 17 , wherein the relapsing multiple sclerosis is progressive-relapsing multiple sclerosis (PRMS) or relapsing-remitting multiple sclerosis (RRMS).