Indazole acetylene derivatives
The invention provides novel compounds having the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 2′ , R 3 , R 4 and R 5 are as described herein. The compound of formula (I) can be used as a medicament.
1 . A compound of formula (I)
wherein
R 1 is hydrogen or halogen;
R 2 and R 2′ are independently selected from hydrogen and alkyl;
or R 2 and R 2′ , together with the carbon atom to which they are attached, form cycloalkyl;
R 3 is hydrogen or halogen;
R 4 is alkyl; and
R 5 is hydroxyalkyl(heterocycloalkyl)alkyl;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or fluoro.
3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 2′ are independently selected from hydrogen or methyl; or R 2 and R 2′ , together with the carbon atom to which they are attached, form cyclopropyl.
5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 2′ are both alkyl at the same time; or R 2 and R 2′ , together with the carbon atom to which they are attached, form cycloalkyl.
6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 2′ are both methyl; or R 2 and R 2′ , together with the carbon atom to which they are attached, form cyclopropyl.
7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or fluoro.
8 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
9 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydroxyalkyl(piperidinyl)alkyl.
10 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydroxymethyl(piperidinyl)methyl.
11 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , wherein the compound of formula (I) is
18 . The compound of claim 1 , wherein the compound of formula (I) is
19 . The compound of claim 1 , wherein the compound of formula (I) is
20 . The compound of claim 1 , wherein the compound of formula (I) is
21 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 1 and a therapeutically inert carrier.
22 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof,
comprising contacting a compound of formula (B1)
with a compound of formula (B2)
in the presence of a base, a Pd(II) catalyst and a Cu(I) salt,
wherein
R 1 is hydrogen or halogen;
R 2 and R 2′ are independently selected from hydrogen and alkyl;
or R 2 and R 2′ , together with the carbon atom to which they are attached, form cycloalkyl;
R 3 is hydrogen or halogen;
R 4 is alkyl; and
R 5 is hydroxyalkyl(heterocycloalkyl)alkyl; and
X is halogen.
23 . A method for treating a non-small cell lung cancer (NSCLC) comprising one or more Epidermal Growth Factor Receptor (EGFR) mutations selected from T790M, L858R and C797S in a patient in need thereof, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 1 .