Compounds useful as RET inhibitors

1. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, having the structural formula Ia shown below:

wherein:

HET is selected from:

wherein

denotes the point of attachment;

R 1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy and a group of the formula:

-L-Y-Q

wherein:

L is absent or is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

Y is absent or is O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), N(R a )C(O)O, OC(O)N(R a ), S(O) 2 N(R a ), or N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen and (1-4C)alkyl; and

Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, or monocyclic saturated heterocyclyl; wherein Q is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c where y is 0, 1 or 2, SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R d )(R c )R e and (CH 2 ) z NR d R c where z is 1, 2 or 3; wherein R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl and (3-6C)cycloalkyl; or R e and R d are linked such that, together with the nitrogen atom to which they are attached, they form a monocyclic saturated 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano and hydroxy; or

Q is optionally substituted by a group of the formula:

-L 1 -L Q1 -Z 1

wherein:

L 1 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

L Q1 is absent or is selected from O, S, SO, SO 2 , N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O), N(R g )C(O)N(R f ), N(R f )C(O)O, OC(O)N(R f ), S(O) 2 N(R f ), and N(R f )SO 2 , wherein R f and R g are each independently selected from hydrogen and (1-2C)alkyl; and

Z 1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, or monocyclic saturated heterocyclyl; wherein Z 1 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, monocyclic saturated heterocycyl, (3-6C)cycloalkyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) y R h where y is 0, 1 or 2, SO 2 N(R i )R h , N(R i )SO 2 R h and (CH 2 ) z NR i R h where z is 1, 2 or 3; wherein R h and R l are each independently selected from hydrogen, (1-4C)alkyl and (3-6C)cycloalkyl;

R 1a and R 1b are each selected from H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and mercapto;

W is O, S or NR 1 , wherein R 1 is selected from H and (1-2C)alkyl;

bonds a, b, c and d are independently selected from a single and double bond;

X 1 and X 2 are each independently N or CR, when bond a is a double bond, or

NR k or CR j R k when bond a is a single bond;

wherein

R j is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R j1 , C(O)OR j1 , OC(O)R j1 , C(O)N(R j2 )R j1 , N(R j2 )C(O)R j1 , S(O) y R j1 where y is 0, 1 or 2, SO 2 N(R j2 )R j1 , N(R j2 )SO 2 R j1 and (CH 2 ) z NR j1 R j2 where z is 1, 2 or 3; wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy and halo;

R k and R j are independently selected from hydrogen and (1-4C)alkyl; and

R j1 and R j2 are each independently selected from hydrogen and (1-4C)alkyl;

X 3 is N or CR l when bond b is a double bond, or NR m or CR l R m when bond b is a single bond;

wherein:

R l is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R l1 , C(O)OR l1 , OC(O)R l1 , C(O)N(R l2 )R l1 , N(R l2 )C(O)R l1 , S(O) y R l1 where y is 0, 1 or 2, SO 2 N(R l2 )R l1 , N(R l2 )SO 2 R l1 and (CH 2 ) z NR l2 R l2 where z is 1, 2 or 3; wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy and halo;

R l and R m are independently selected from hydrogen and (1-4C)alkyl; and

R l1 and R l2 are each independently selected from hydrogen and (1-4C)alkyl;

X 4 is N or CR n when bond d is a double bond, or NR o or CR n R o when bond d is a single bond;

wherein:

R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R n1 , C(O)OR n1 , OC(O)R n1 , C(O)N(R n2 )R n1 , N(R n2 )C(O)R n1 , S(O) y R n1 where y is 0, 1 or 2, SO 2 N(R n2 )R n1 , N(R n2 )SO 2 R n1 and (CH 2 ) z NR n1 R n2 where z is 1, 2 or 3; wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy and halo;

R n and R o are independently selected from hydrogen and (1-4C)alkyl; and

R n1 and R n2 are each independently selected from hydrogen and (1-4C)alkyl;

R 2 is selected from hydrogen, (1-4C)alkyl and a group of the formula:

-L 2 -Y 2 -Q 2

wherein:

L 2 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

Y 2 is absent or is C(O), C(O)O, or C(O)N(R p ), wherein R p is selected from hydrogen and (1-4C)alkyl; and

Q 2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q 2 is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR q R r , and OR q , wherein R q and R r are each independently selected from hydrogen, (1-4C)alkyl and (3-6C)cycloalkyl;

R s is selected from hydrogen and (1-2C)alkyl;

Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q 3 is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR t R u , and OR t , wherein R t and R u are each independently selected from hydrogen, (1-4C)alkyl and (3-6C)cycloalkyl; or Q 3 is optionally substituted by a group of the formula:

-L 4 -L Q4 -Z 4

wherein:

L 4 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

L Q4 is absent or is selected from O, S, SO, SO 2 , N(R v ), C(O), C(O)O, OC(O), C(O)N(R v ), N(R v )C(O), N(R v )C(O)N(R v ), N(R v )C(O)O, OC(O)N(R v ), S(O) 2 N(R v ), and N(R v )SO 2 , wherein R v and R w are each independently selected from hydrogen and (1-2C)alkyl; and

Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR x R y , OR x , C(O)R x , C(O)OR x , OC(O)R x , C(O)N(R y )R x , N(R y )C(O)R x , S(O) y R x where y is 0, 1 or 2, SO 2 N(R y )R x , N(R y )SO 2 R x and (CH 2 ) z NR x R y where z is 1, 2 or 3; wherein R x and R y are each independently selected from hydrogen, (1-4C)alkyl and (3-6C)cycloalkyl;

with the proviso that only one or two of X 1 , X 2 , X 3 or X 4 can be N.

2. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein HET is selected from:

3. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein the compound has the structural formula Ib shown below:

4. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein X 1 and X 2 are each independently N or CR j , and bond a is a double bond, wherein R j is selected from hydrogen, halo, (1-4C)alkyl and amino.

5. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein X 3 is N or CR l , and bond b is a double bond, wherein R l is selected from hydrogen, halo, (1-4C)alkyl and amino.

6. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein X 4 is N or CR n , and bond d is a double bond, wherein R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, and (2C)alkynyl.

7. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein the compound has the structural formula Id shown below:

8. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 7 , wherein X 4 is CR n , and R n is selected from hydrogen, halo, (1-4C)alkyl and amino.

9. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein R l is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy and a group of the formula:

-L-Y-Q

wherein:

L is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

Y is absent or is C(O), C(O)O, OC(O), C(O)N(R a ) or N(R a )C(O), wherein R a and R b are each independently selected from hydrogen and (1-4C)alkyl; and

Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, or monocyclic saturated heterocyclyl; wherein Q is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c where y is 0, 1 or 2, SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R d )(R c )R e and (CH 2 ) z NR d R c where z is 1, 2 or 3; wherein R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl and (3-6C)cycloalkyl.

10. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein R 1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, or monocyclic saturated heterocyclyl; wherein each of said substituents is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c where y is 0, 1 or 2, SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R d )(R c )R e and (CH 2 ) z NR d R c where z is 1, 2 or 3; wherein R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl and (3-6C)cycloalkyl.

11. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein R 1 is selected from hydrogen, (1-6C)alkyl and (3-10C)cycloalkyl; wherein each of said substituents is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NR c R d , OR c and Si(R d )(R c )R e ; wherein R c , R d and R e are each independently selected from hydrogen and (1-4C)alkyl.

12. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein R 2 is selected from hydrogen, (1-4C)alkyl and a group of the formula:

—Y 2 -Q 2

wherein:

Y 2 is C(O)N(R p ), wherein R p is selected from hydrogen and (1-4C)alkyl; and

Q 2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q 2 is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano and hydroxy.

13. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein R 2 is hydrogen.

14. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q 3 is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR t R u , and OR t , wherein R t and R u are each independently selected from hydrogen, (1-4C)alkyl and (3-6C)cycloalkyl; or Q 3 is optionally substituted by a group of the formula:

-L 4 -L Q4 -Z 4

wherein:

L 4 is absent or is (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo;

L Q4 is absent or is selected from O, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v ), N(R v )C(O), S(O) 2 N(R v ), and N(R v )SO 2 , wherein R v and R w are each independently selected from hydrogen and (1-2C)alkyl; and

Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR x R y , and OR 1 ; wherein R x and R y are each independently selected from hydrogen and (1-4C)alkyl.

15. The compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 , wherein Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q 3 is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, amino, cyano, hydroxy, NR t R u , and OR t , wherein R t and R u are each independently selected from hydrogen and (1-4C)alkyl; or Q 3 is optionally substituted by a group of the formula:

-L 4 -L Q4 -Z 4

wherein:

L 4 is absent or is (1-2C)alkylene;

L Q4 is absent or is O; and

Z 4 is hydrogen, (1-6C)alkyl, or (3-8C)cycloalkyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, amino, hydroxy, (3-6C)cycloalkyl, NR x R y , and OR 1 ; wherein R x and R y are each independently selected from hydrogen and (1-4C)alkyl.

16. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, which is selected from:

6-(4-Amino-1-cyclopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-ethyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,5-dimethylpyrazol-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclobutyl-1H-indole-2-carboxamide;

6-(4-Amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-hydroxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-pyridyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-pyridyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-fluoroethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-ethylpyrazol-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylthiazol-2-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isoxazol-4-yl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-5-yl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-thienyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethoxy)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethoxy)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2-difluoroethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenethyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-benzyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methoxy-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-propyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-butyl-1H-indole-2-carboxamide;

6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-1H-indole-2-carboxamide;

6-[4-amino-1-(3-hydroxy-3-methyl-cyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

6-[4-amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

6-(4-amino-1-cyclobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide; and

tert-butyl 3-[4-amino-3-[2-(methylcarbamoyl)-1H-indol-6-yl]pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carboxylate.

17. A pharmaceutical formulation comprising the compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

18. A method for treatment of a cancer in which RET kinase activity is implicated in a subject in need thereof, said method comprising administering a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, to the subject.

19. The method according to claim 18 , wherein said cancer is leukemia, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, medullary thyroid cancer or non-small cell lung cancer.

20. The method according to claim 18 , wherein said cancer is a malignant neoplasm, a malignant tumor, or a solid tumor.

21. The method according to claim 18 , wherein said cancer comprises a RET mutation.

22. The method according to claim 21 , wherein the RET mutation is a RET fusion translocation, optionally wherein the RET fusion translocation is KIF5B-RET or CCDC6-RET.