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1. (WO2017079140) INHIBITORS OF RET
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims:

1. A com ound having the structural formula (A):


, or a pharmaceutically acceptable salt thereof, wherein:

ring A is an aryl or heteroaryl ring;

each of X1 and X2 is independently selected from N and C(R6);

each of Y 1 and Y 2 is independently selected from -CH2- and -0-, wherein no more than one of Y1 or Y2 is -0-;

1 7

each R and each R is independently selected from selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(0)R, -OC(0)R, -C(0)OR, -(Ci-Ce alkylene)-C(0)R, -SR, -S(0)2R, -S(0)2-N(R)(R), -(Ci-C6 alkylene)-S(0)2R, -(Ci-C6 alkylene)-S(0)2-N(R)(R), -N(R)(R), -C(0)-N(R)(R), -N(R)-C(0)R, -N(R)-C(0)OR, -(Ci-C6 alkylene)-N(R)-C(0)R, -N(R)S(0)2R, and -P(0)(R)(R); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or two R1 or two R are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;

each of R2, if present, R3a, R3b, R4, R8a and R8b is independently selected from hydrogen, C C6 alkyl, Ci-C6 alkoxy, halo, hydroxyl, Ci-C6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra; each of R5 and R9 is independently selected from hydrogen, Ci-C6 alkyl, and Ci-C6 heteroalkyl; wherein each alkyl and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;

each R6 is independently selected from hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;

each R is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C6 alkyl, Ci-C6 thioalkyl, Ci-C6 alkoxy, Ci-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra, or 2 R1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of

Rb;

each Ra and each Rb is independently selected from Ci-C6 alkyl, halo, hydroxyl, Ci-C6 heteroalkyl, Ci-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R'; each R' is independently selected from Ci-C6 alkyl, Ci-C6 heteroalkyl, halo, hydroxyl, cycloalkyl or cyano; or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

= represents a single or double bond;

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

each o is 0 when = is a double bond; and

each o is 1 when = is a single bond.

2. The compound of claim 1 having the structural formula (I):


(I), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as defined in claim 1.

3. The compound of claim 1 or 2, wherein m is 1; R1 is located at the 5-position; and R1 is Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.

2

4. The compound of any one of claims 1-3, wherein R is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl.

5. The compound of any one of claims 1-4, wherein each of R a, R , R a and R , if R is present, is independently selected from hydrogen and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.

6. The compound of any one of claims claim 1-5, wherein at least one pair of R a and R or

R 8a and R 8b is simultaneously hydrogen.

7. The compound of any one of claims 1-6, wherein R4 is selected from hydrogen, Ci-C4 alkyl and 0-Ci-C4 alkyl, wherein each alkyl portion of R4 is optionally substituted with 0-3 occurrences of Ra.

8. The compound of any one of claims 1-7, wherein R5 is selected from hydrogen, Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.

9. The compound of any one of claims 1-8, wherein each R6 is independently selected from hydrogen, halo, and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.

10. The compound of any one of claims 1-9, wherein ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom.

11. The compound of claim 10, wherein ring A is selected from


and

12. The compound of any one of claims 1-11, wherein n is 1 ; and R is pyrazol- l-yl an optionally substituted with 0-3 occurrences of Rb.

13. The compound of any one of claims 1-12, wherein R9 is hydrogen.

14. A compound having the structural formula (II):

(Π),

or a pharmaceutically acceptable salt thereof, wherein:

X1 is selected from N, CH and C(halo);

X is selected from N and CH;

X is selected from N and CH;

R 12 is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl;

each of R13a, R13b, R18a and R18b is independently selected from hydrogen and C C4 alkyl;

R14 is selected from hydrogen, -Ci-C4 alkyl and -0-Ci-C4 alkyl;

R15 is selected from hydrogen and -Ci-C4 alkyl;

R16 is selected from hydrogen and -Ci-C4 alkyl;

R17b is selected from hydrogen and halo; and

R17a and R17c are independently selected from hydrogen and -Ci-C4 alkyl.

15. The compound of claim 14, wherein:

XI is selected from N, CH and C(C1);

X is selected from N and CH;

X is selected from N and CH;

R 12 is selected from hydrogen, hydroxyl, fluoro and -0-CH3;

each of R13a, R13b, R18a and R18b is independently selected from hydrogen, methyl and ethyl; and wherein at least one pair of R13a and R13b or R18a and R18b is simultaneously hydrogen.;

R14 is selected from hydrogen, -CH3, -CH2CH3, -OCH3 and -OCH2CH3;

R15 is selected from hydrogen and -CH3;

R16 is selected from hydrogen and -CH3;

R17b is selected from hydrogen, chloro and fluoro;

R17a and R17c are simultaneously hydrogen or -CH3, wherein when R17a and R17c are simultaneously -CH3, R17b is hydrogen.

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15; and a pharmaceutically acceptable carrier.

17. A method for inhibiting RET activity in a cell or in a patient, comprising the step of contacting the cell or administering to the patient a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16.

18. A method for treating a subject suffering from a condition mediated by aberrant RET activity, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16.

19. A method for treating a subject who has developed resistance to a cancer treatment, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16.

20. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for inhibiting RET activity in a cell or in a patient.

21. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for treating a subject suffering from a condition mediated by aberrant RET activity.

22. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for treating a subject who has developed resistance to a cancer treatment.