Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2016089833 - NOUVEAUX COMPOSÉS TRICYCLIQUES COMME INHIBITEURS D'ENZYMES IDH MUTANTES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A compound of formula (I):


wherein A is -C(R1)= or -N=, and R1 is hydrogen or hydroxyl

X is a bridged ring moiety selected from the group consisting of:


B is -C(R10)- or -N-;

a is 0 or 1; b is 0 or 1

m is 0, 1 or 2; p is 0 or 1; r is 0, 1 or 2; with the proviso that when r is 2, m is 0;

R is selected from the group consisting of:

(1) halogen,

(2) -CN, and

(3) -(C=O)t-Ra, wherein t is 0 or 1;

each occurrence of R2, R3, R4, R5, R6, R7, R11, R12, R13, R14 and R15 is independently selected from the group consisting of:

(1) halogen,

(2) -CN, and

(3) -(C=O)t-Ra, wherein t is 0 or 1;

R8 is selected from the group consisting of:

(1) hydrogen,

(2) -CN, and

(3) C1-6alkyl;

R9 is selected from the group consisting of:

(1) halogen,

(2) -CN, and

(3) -(C=O)t-Ra, wherein t is 0 or 1;

R10 is hydrogen or C1-6alkyl;

each occurrence of Ra is independently selected from the group consisting of:

(1) hydrogen,

(2) -(O)t-Rd, wherein t is 0 or 1; Rd is selected from the group consisting of (a) hydrogen, (b) C1-6alkyl, (c) C3-7cycloalkyl, and (d) phenyl;

wherein each of the C1-6alkyl of (b) and C3-7Cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from Rb,

(3) -NRxRy, wherein each of Rx and Ry is independently selected from the group consisting of (a) hydrogen, (b) C1-6alkyl, (c) C3-6cycloalkyl, (d) -O-C1-6alkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl; wherein the C1-6alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, -O-C1-4alkyl, C3-6cycloalkyl, and heterocyclyl; and

the C3-6cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from halogen, -O-C1-4alkyl, C3-6cycloalkyl, heterocyclyl, and C1-4alkyl, which is optionally substituted with one to four halogens, the heterocyclyl of (f) is optionally substituted with one to four substituents independently selected from halogen, C1-4alkyl, -O-C1-4alkyl, C3-6cycloalkyl, and heterocyclyl,

(4) C2-6alkenyl, optionally substituted with one to four substituents independently selected from Rb,

(5) C5-6cycloalkenyl, optionally substituted with one to four substituents independently selected from Rb,

(6) aryl, optionally substituted with one to four substituents independently selected from Rb, and

(7) heterocyclyl, optionally substituted with one to four substituents independently selected from Rb;

each occurrence of Rb is independently selected from the group consisting of:

(1) halogen,

(2) -CN,

(3) oxo,

(4) -(O)t-Rd, wherein t is 0 or 1 ; Rd is selected from the group consisting of (a) hydrogen, (b) C1-6alkyl, (c) C3-7cycloalkyl, and (d) heterocyclyl;

wherein the C1-6alkyl of (b) is optionally substituted with one to four substituents independently selected from (i) halogen, (ii) hydroxyl, (iii) -O-C1-6alkyl, (iv) C3- 6cycloalkyl optionally substituted with 1-3 halogens, (v) -NRxRy, wherein each of Rx and Ry is independently selected from the group consisting of hydrogen, C1- 6alkyl, C3-6cycloalkyl, phenyl optionally substituted with one to four halogens, and heterocyclyl, and (vi) heterocyclyl;

the C3-7cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from (i) halogen, and (ii) C1-6alkyl, which is optionally substituted with one to four halogens, and (iii) -CN; and

the heterocyclyl of (d) is optionally substituted with one to four substituents independently selected from (i) halogen, (ii) hydroxyl, (iii) oxo, (iv) C1-6alkyl optionally substituted with one to four halogens, (v) -O-C1-6alkyl, (vi) heterocyclyl optionally substituted with halogen or hydroxyl, and (vii) -NRjRk; wherein each of Rj and Rk is independently selected from the group consisting of hydrogen and C1 -6alkyl,

(5) -(C=O)t-Rc, wherein t is 0 or 1; Rc is selected from the group consisting of hydrogen, hydroxyl, C1-6alkyl, C2-6alkenyl, -O-C1-6alkyl, -NRxRy, and heterocyclyl;

wherein each of Rx and Ry is independently selected from the group consisting of (a) hydrogen, (b) C1-6alkyl, (c) C2-6alkenyl, (d) C3-6cycloalkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl; wherein the C1-6alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, -O-C1-4alkyl, C3-6cycloalkyl, heterocyclyl, and -(C=O)-NR'Rk, wherein each of Rj and Rk is independently hydrogen or C1- 6alkyl,

the C3-6Cyclolkyl of (d) is optionally substituted with one to four substituents independently selected from halogen and C1-4alkyl, which is optionally substituted with one to four halogens, and

the heterocyclyl of (f) is optionally substituted with one to four substituents independently selected from halogen, -CN, C1-6alkyl, and -O-C1-6alkyl,

(6) C2-6alkenyl, and

(7) phenyl, optionally substituted with one to four substituents independently selected from halogen, C1-6alkyl, and -O-C1-6alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 having the following formula:


or a pharmaceutically acceptable salt thereof.

3. The compound of any of Claims 1-2 having the following formula:


or a pharmaceutically acceptable salt thereof.

4. The compound of any of Claims 1-3 of the following formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of any of Claims 1-2 having the following formula:


or a pharmaceutically acceptable salt thereof.

6. The compound of any of Claims 1-2 having the following formula:


or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1 having the following formula:

or a pharmaceutically acceptable salt thereof.

8. The compound of any of Claims 1 and 7 having the following formula:


or a pharmaceutically acceptable salt thereof.

9. The compound of any of Claims 1 and 7 having the following formula:


or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 having the following formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1 having the following formula:


or a pharmaceutically acceptable salt thereof.

12. The compound of any of Claims 1-11, wherein:

each occurrence of the heterocyclyl is independently selected from the group consisting of: 8-azabicyclo[3.2.1]octanyl,

2-azaspiro[3.3]heptanyl,

azaindolyl,

azetidinyl,

2,5-diazabicyclo[2.2.2]octanyl,

1,6-diazaspiro[3.3]heptanyl,

2,6-diazaspiro[3.3]heptanyl,

2,3-dihydro-1,4-dioxinyl,

3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,

5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl,

1,4-dioxanyl,

hexahydro-1H-furo[3,4-c]pyrrolyl,

1,2,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrolyl, imidazolyl,

1H-imidazo[4,5-b]pyridinyl,

isoindolinyl,

isoxazolyl,

morpholinyl, octahydrocyclopenta[1,4]oxazinyl, octahydro-1H-imidazo[4,5-c]pyridinyl,

2-oxa-5-azabicyclo[2.2.1]heptanyl,

3-oxa-6-azabicyclo[3.2.0]heptanyl,

6-oxa-3-azabicyclo[3.1.1]heptanyl,

2-oxa-5-azabicyclo[2.2.2]octanyl,

3-oxa-8-azabicyclo[3.2.1]octanyl,

8-oxa-3-azabicyclo[3.2.1]octanyl,

1-oxa-8-azaspiro[4.5]decanyl,

2-oxa-6-azaspiro[3.3]heptanyl,

4-oxa-7-azaspiro[2.5]octanyl,

6-oxa-2-azaspiro[3.4]octanyl,

7-oxa-2,5-diazaspiro[3.4]octanyl,

3-oxa-1,7-diazaspiro[4.4]nonanyl,

1,4-oxazepanyl,

oxazolidinyl,

oxetanyl,

piperazinyl,

piperidinyl,

pyrazolo[1,5-b]pyridazinyl,

pyrazolyl,

pyridazinyl,

pyridinyl,

pyrimidinyl,

pyrrolidinyl,

pyrrolyl,

tetrahydrofuranyl,

5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl,

tetrahydropyranyl,

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,

4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl,

1,2,3,6-tetrahydropyridinyl,

1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinyl,

4.5.6.7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazinyl,

5.6.7.8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,

5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,

thiazolyl, and

thiophenyl;

or a pharmaceutically acceptable salt thereof.

13. The compound of any of Claims 1-12, wherein:

each occurrence of R2, R3, R4, R5, R6, R7, R11, R13, R14 and R15, when present, is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) -O-C1-6alkyl, and

(4) C1-6alkyl;

R12, when present, is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) -CN,

(4) -O-Rd, wherein Rd is hydrogen or C1-6alkyl,

(5) -(C=O)-Rc, wherein Rc is selected from the group consisting of (a) C1-6alkyl, (b) - O-Rd, (c) -NRjRk, and (d) heterocyclyl; wherein Rd is hydrogen or C1-6alkyl; each of Rj and Rk is independently selected from the group consisting of hydrogen and C1-6alkyl; and the heterocyclyl of (d) is optionally substituted with one to four substituents independently selected from halogen and C1-6alkyl,

(6) C1-6alkyl, optionally substituted with one to four halogens,

(7) phenyl, and

(8) heterocyclyl, optionally substituted with one to four substituents independently selected from halogen, C1-6alkyl and -CF3;

wherein each occurrence of the heterocyclyl of (5) and (8) is independently selected from the group consisting of azaindolyl, azetidinyl, 1,4-dioxanyl, imidazolyl, isoindolinyl, isoxazolyl, morpholinyl, oxazolidinyl, piperidinyl, pyridinyl, pyrazolyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl;

or a pharmaceutically acceptable salt thereof.

14. The compound of any of Claims 1-13, wherein R8 is hydrogen, or a pharmaceutically acceptable salt thereof.

15. The compound of any of Claims 1-14, wherein each occurrence of R9, when present, is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) -O-Rd, wherein Rd is hydrogen or C1-6alkyl;

or a pharmaceutically acceptable salt thereof.

16. The compound of any of Claims 1-15, wherein:

R is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) -O-C1-4alkyl,

(4) -NRxRy, wherein each of Rx and Ry is independently selected from the group consisting of hydrogen, and C1-6alkyl,

(5) -(C=O)-Ra, wherein Ra is selected from the group consisting of hydrogen, C1- 6alkyl, and heterocyclyl;

(6) C1-6alkyl, optionally substituted with one to four substituents independently selected from halogen, hydroxyl, -CN, -O-C1-6alkyl, and

(7) heterocyclyl, optionally substituted with one to four substituents independently selected from halogen, hydroxyl, oxo, -CN, -O-C1-6alkyl, and C1-6alkyl; wherein wherein each occurrence of the heterocyclyl of (5) and (7) is independently selected from the group consisting of azaindolyl, azetidinyl, 1,4-dioxanyl, imidazolyl,

isoindolinyl, isoxazolyl, morpholinyl, oxazolidinyl, piperidinyl, pyridinyl, pyrazolyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl;

or a pharmaceutically acceptable salt thereof.

17. The compound of any of Claims 1-16, wherein:

R is selected from the group consisting of:

(1) hydrogen,

(2) C1-6alkyl, optionally substituted with -CN, and

(3) heterocyclyl, optionally substituted with one to four substituents independently selected from halogen, oxo and C1-6alkyl; wherein the heterocyclyl is selected from the group consisting of morpholinyl and oxazolidinyl;

or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 selected from the group consisting of

the compounds in Examples 1-2, 6-8, 15-17, 22, 24-33, 57-61, 67, 73-78, 93, and 101, or a pharmaceutically acceptable salt thereof.

19. A composition which comprises an inert carrier or excipient and a compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof.

20. Use of a compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with mutant IDH enzyme activity.

21. A method for treating a disease or disorder associated with mutant IDH enzyme activity in a mammalian subject which comprises administering to the subject an effective amount of the compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof.

22. A method for treating a disease or disorder associated with mutant IDH enzyme activity in a mammalian subject which comprises administering to the subject an effective amount of the compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof in combination with another anti-cancer agent.

23. The method of any of Claims 21 and 22, wherein the disease or disorder associated with mutant IDH enzyme activity is a cancer selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia (AML), breast cancer, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma.

24. The method of any of Claims 23, wherein the cancer is selected from glioma, glioblastoma multiforme, acute myeloid leukemia, and breast cancer.

25. A compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof for use in medicine.