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1. WO2020118133 - MODULATORS OF TREX1

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

Listing of Claims:

1. A compound having the Formula I:


or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, (Ci-C alkyl, halo(Ci-C4)alkyl, 3- to 4-membered cycloalkyl, -OR f , -SRf, or -NReRf;

R is hydrogen, (Ci-COalkyl, halo(Ci-C4)alkyl, or 3- to 4-membered cycloalkyl;

X is a bond, NR , O, S, or (Ci-C4)alkylene, wherein said (Ci-C4)alkylene is optionally substituted with 1 to 2 groups selected from R4;

R3 is hydrogen, (Ci-C4)alkyl, -C(0)Rd, or -C(S)Rd;

R4 is halo, (Ci-C4)alkyl, phenyl, -NHC(0)0Ra, -NHC(S)ORa, -C(0)Rb,-NHC(0)NHRg, -NHC(S)NHRg, -NHS(0)2NHRg, -C(S)Rb, S(0)2Rc, S(0)Rc, -C(0)0Rd, -C(S)ORd, -C(0)NHRe, -C(S)NHRe, -NHC(0)Rd, -NHC(S)Rd, -ORe, -SRe, -0(Ci-C4)alkylORe, or -NReRf, wherein said phenyl for R4 is optionally substituted with 1 or 2 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;

Ring A is phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, or 3-to 7-membered cycloalkyl, each of which are optionally and independently substituted with 1 or 2 groups selected from R5;

R5 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo(Ci-C4)afkoxy, halo, phenyl, -NHC(0)0Ra, -NHC(S)ORa, -C(0)Rb,-NHC(0)NHRg, -NHC(S)NHRg, -NHS(0)2NHRg, -C(S)Rb, S(0)2Rc, S(0)Rc, -C(0)0Rd, -C(S)ORd, -C(0)NReRf, -C(S)NHRe, -NHC(0)Rd, -NHC(S)Rd, -ORe, -SRe, -0(Ci-C4)alkyl0Re, -NReRf, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said phenyl for R5 is optionally substituted with 1 or 2 groups selected from Rg, said (Ci-C4)alkyl for R5 is optionally substituted with 1 or 2 groups selected from ORh, -NRJRk, phenyl, and 5- to 6-membered heteroaryl, said 4- to 7-membered heterocyclyl and 4- to 6-membered heteroaryl are each optionally and independently substituted with 1 or 2 groups selected from Rm, and wherein said phenyl and 5- to 6-membered heteroaryl of the optional substituents listed for (Ci-C alkyl in R5 are each optionally and independently substituted with 1 or 2 groups selected from Rg;

Rg, Rh, R1, Rk, and Rm are each independently hydrogen, halo, (Ci-C alkyl, halo(Ci-C alkyl, (Ci-C alkoxy, halo(Ci-C4)alkoxy, phenyl, -(Ci-C alkylphenyl, 3- to 4-membered cycloalkyl, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, and wherein said 4- to 7-membered heterocyclyl for Rg, Rh, R1 and Rkis further optionally substituted with =0.

Ra, Rb, Rc, Rd, Re and Rfare each independently hydrogen, halo, (Ci-C alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, phenyl, 3- to 4-membered cycloalkyl, 4-to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein i) said (Ci-C4)alkyl for Ra, Rb, Rc, Rd, Re and Rfis optionally substituted with 1 or 2 groups selected from phenyl, -ORh, -NRJRk; ii) said phenyl, 4- to 6-membered heteroaryl, and 4- to 7-membered

heterocyclyl for Ra, Rb, Rc, Rd, Re, and Rfare each optionally and independently substituted with 1 or 2 groups selected from Rg, and iii) said 4- to 7-membered heterocyclyl for Ra, Rb, Rc, Rd, Re, and Rf is further optionally substituted with =0.

2. The compound of Claim 1, wherein the compound is of the Formula II:


or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, wherein R is (C1-C4) alkyl.

4. The compound of any one of Claims 1 to 3, wherein the compound is of the Formula

III:


(ill);

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of Claims 1 to 4, wherein ring A is phenyl, pyridyl, pyrazolyl, cyclopropyl, cyclobutyl, azetidinyl, or piperidinyl, each of which being optionally and independently substituted with one or two R5.

6. The compound of any one of Claims 1 to 4, wherein ring A is triazolyl, pyrrolidinyl, diazepanyl, or piperazinyl, each of which being optionally and independently substituted with one or two R5.

7. The compound of any one of Claims 1 to 6, wherein R5 is (Ci-C4)alkyl, halo(Ci-C4) alkyl, halo(Ci-C4)alkoxy, halo, phenyl, -NHC(0)0Ra, -C(0)Rb, S(0)2Rc, S(0)Rc, -C(0)0Rd, -C(0)NReRf, -NHC(0)Rd, -ORe, -0(Ci-C4)alkylORe, -NReRf, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said phenyl for R5 is optionally substituted with 1 or 2 groups selected from Rg, said (Ci-C4)alkyl for R5 is optionally substituted with 1 or 2 groups selected from -ORh, -NRJRk, phenyl, and 5- to 6-membered heteroaryl, said 4- to 6-membered heteroaryl and 4- to 7-membered heterocyclyl are each optionally and independently substituted with 1 or 2 groups selected from Rm, and wherein said phenyl and 5- to 6-membered heteroaryl of the optional substituents listed for (Ci-C4)alkyl in R5 are each optionally and independently substituted with 1 or 2 groups selected from Rg;

Ra is (Ci-C4)alkyl optionally substituted with phenyl;

Rb is (Ci-C4)alkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 7-membered heterocyclyl, wherein said (Ci-C4)alkyl is optionally substituted with 1 or 2 groups selected from phenyl, -ORh, and -NRJRk, wherein said phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl are each optionally and independently substituted with 1 or 2 groups selected from Rg, and wherein said 4- to 7-membered heterocyclyl is further optionally substituted with =0;

each Rc is independently phenyl or (Ci-C4)alkyl;

each Rd is hydrogen or (Ci-C4)alkyl;

each Re is independently hydrogen or (Ci-C4)alkyl optionally substituted with ORh; each R is independently hydrogen, (Ci-C4)alkyl, phenyl 3- to 4-membered cycloalkyl, 4- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein said phenyl, 3- to 4-membered cycloalkyl, 4- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl are each optionally and independently substituted with Rg;

each Rg is independently (Ci-C alkyl, halo(Ci-C4)alkyl, (Ci-C alkoxy, halo(Ci-C4)alkoxy, or halo;

each Rh is hydrogen, (Ci-C4)alkyl, or -(Ci-C4)alkylphenyl;

each RJ is independently hydrogen or (Ci-C4)alkyl;

each Rk is independently hydrogen, (Ci-C4)alkyl, or 3- to 4-membered cycloalkyl; and each Rm is (Ci-C4)alkyl.

8. The compound of any one of Claims 1 to 7, wherein R5 is (Ci-C4)alkyl, halo(Ci-C4) alkyl, halo, phenyl, -NHC(0)0Ra, -C(0)Rb, S(0)2Rc, -C(0)0Rd, -C(0)NReRf, -NHC(0)Rd, -0(Ci-C4)alkyl0Re, -NReRf, 4- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein said (Ci-C4)alkyl for R5 is optionally substituted with -ORh, phenyl, or 5- to 6-membered heteroaryl, said 4- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl are each optionally and independently substituted with 1 or 2 groups selected from Rm, and wherein said phenyl and 5- to 6-membered heteroaryl of the optional substituents listed for (Ci-C4)alkyl in R5 are each optionally and independently substituted with 1 or 2 groups selected from Rg.

9. The compound of any one of Claims 1 to 8, wherein R5 is (Ci-C4)alkyl, halo(Ci-C4) alkyl, halo, phenyl, -NHC(0)0Ra, -C(0)Rb, S(0)2Rc, -C(0)0Rd, -C(0)NReRf, -NHC(0)Rd, or -0(Ci-C4)alkyl0Re, -NReRf, morpholinyl, piperazinyl, or pyrazolyl, wherein said morpholinyl, piperazinyl, and pyrazolyl are each optionally substituted with 1 or 2 groups selected from Rm, said (Ci-C4)alkyl for R5 is optionally substituted with -ORh, phenyl, pyrazolyl, pyrimidinyl, or pyridinyl, and wherein said phenyl, pyrazolyl, pyrimidinyl, and pyridinyl of the optional substituents listed for (Ci-C4)alkyl in R5 are each optionally and independently substituted with 1 or 2 groups selected from Rg.

10. The compound of any one of Claims 1 to 9, wherein each R is independently hydrogen, (Ci-C4)alkyl, phenyl pyrazolyl, pyridinyl, tetrahydropyranyl, piperidinyl, wherein said phenyl pyrazolyl, pyridinyl, tetrahydropyranyl, and piperidinyl are each optionally and independently substituted with (Ci-C4)alkyl.

11. The compound of any one of Claims 1 to 10, wherein each Rg is independently (Ci-C4)alkyl, (Ci-C4)alkoxy, or halo.

12. The compound of any one of Claims 1 to 11, wherein Rb is (Ci-C alkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 7-membered heterocyclyl, wherein said phenyl and 5- to 6-membered heteroaryl for Rb are each optionally and independently substituted with 1 or 2 groups selected from halo and (Ci-C alkoxy, wherein said 4- to 7-membered heterocyclyl for Rbis optionally substituted with =0, and wherein said (Ci-C alkyl for Rbis optionally substituted with 1 or 2 groups selected from phenyl, -ORh, and -NRJRk.

13. The compound of any one of Claims 1 to 12, wherein each Rk is independently hydrogen or (Ci-C alkyl.

14. The compound of any one of Claims 1 to 13, wherein Rb is (Ci-C alkyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, or piperidinyl, wherein said phenyl, pyridinyl, pyrazolyl, and pyrimidinyl for Rb are each optionally and independently substituted with 1 or 2 groups selected from halo and (Ci-C alkoxy, wherein said (Ci-C alkyl for Rbis optionally substituted with 1 or 2 groups selected from phenyl, OH, and NMe2, and wherein said piperidinyl for Rbis optionally substituted with =0.

15. The compound of any one of Claims 1 to 14, wherein R is hydrogen.

16. The compound of any one of Claims 1 to 15, wherein X is an unsubstituted (Ci- COalkylene.

17. The compound of any one of Claims 1 to 16, wherein R4 is phenyl or -NHC(0)0Ra.

18. The compound of any one of Claims 1 to 15, wherein X is a bond or CH2.

19. A pharmaceutical composition comprising the compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

20. A method of treating a disease responsive to the inhibition of TREX1 in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, or the composition of Claim 17.

21. The method of Claim 20, wherein the disease is cancer.