Tricyclic compounds as inhibitors of mutant IDH enzymes

1. A compound of formula (I):

wherein A is —C(R 1 )═, and R 1 is hydrogen or hydroxyl;

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

B is —C(R 10 )— 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 —R a , wherein t is 0 or 1;

each occurrence of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , R 14 and R 15 is independently selected from the group consisting of:

(1) halogen,

(2) —CN, and

(3) —(C═O) t —R a , wherein t is 0 or 1;

R 8 is selected from the group consisting of:

(1) hydrogen,

(2) —CN, and

(3) C 1-6 alkyl;

R 9 is selected from the group consisting of:

(1) halogen,

(2) —CN, and

(3) —(C═O)t-R a , wherein t is 0 or 1;

R 10 is hydrogen or C 1-6 alkyl;

each occurrence of R a is independently selected from the group consisting of:

(1) hydrogen,

(2) —(O) t —R d , wherein t is 0 or 1; R d is selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-7 cycloalkyl, and (d) phenyl;

wherein each of the C 1-6 alkyl of (b) and C 3-7 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from R b ,

(3) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-6 cycloalkyl, (d) —O—C 1-6 alkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl;

wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, and heterocyclyl; and

the C 3-6 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, and C 1-4 alkyl, 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, C 1-4 alkyl, —O—C 1-4 alkyl, C 3-6 cycloalkyl, and heterocyclyl,

(4) C 2-6 alkenyl, optionally substituted with one to four substituents independently selected from R b ,

(5) C 5-6 cycloalkenyl, optionally substituted with one to four substituents independently selected from R b ,

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

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

each occurrence of R b is independently selected from the group consisting of:

(1) halogen,

(2) —CN,

(3) oxo,

(4) —(O) t —R d , wherein t is 0 or 1; R d is selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 3-7 cycloalkyl, and (d) heterocyclyl;

wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from (i) halogen, (ii) hydroxyl, (iii) —O—C 1-6 alkyl, (iv) C 3-6 cycloalkyl optionally substituted with 1-3 halogens, (v) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl optionally substituted with one to four halogens, and heterocyclyl, and (vi) heterocyclyl;

the C 3-7 cycloalkyl of (c) is optionally substituted with one to four substituents independently selected from (i) halogen, and (ii) C 1-6 alkyl, 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) C 1-6 alkyl optionally substituted with one to four halogens, (v) —O—C 1-6 alkyl, (vi) heterocyclyl optionally substituted with halogen or hydroxyl, and (vii) —NR j R k ;

wherein each of R j and R k is independently selected from the group consisting of hydrogen and C 1-6 alkyl,

(5) —(C═O) t —R c , wherein t is 0 or 1; R c is selected from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, —O—C 1-6 alkyl, —NR x R y , and heterocyclyl;

wherein each of R x and R y is independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 3-6 cycloalkyl, (e) phenyl optionally substituted with one to four halogens, and (f) heterocyclyl;

wherein the C 1-6 alkyl of (b) is optionally substituted with one to four substituents independently selected from halogen, —O—C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, and —(C═O)—NR j R k , wherein each of R j and R k is independently hydrogen or C 1-6 alkyl,

the C 3-6 cyclolkyl of (d) is optionally substituted with one to four substituents independently selected from halogen and C 1-4 alkyl, 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, C 1-6 alkyl, and —O—C 1-6 alkyl,

(6) C 2-6 alkenyl, and

(7) phenyl, optionally substituted with one to four substituents independently selected from halogen, C 1-6 alkyl, and —O—C 1-6 alkyl;

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 claim 2 having the following formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 of the following formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 having the following formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 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 claim 7 having the following formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 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 claim 1 , 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 claim 1 , wherein:

each occurrence of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 13 , R 14 and R 15 , when present, is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —O—C 1-6 alkyl, and

(4) C 1-6 alkyl;

R 12 , when present, is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —O—R d , wherein Rd is hydrogen or C 1-6 alkyl,

(5) —(C═O)—R c , wherein R c is selected from the group consisting of (a) C 1-6 alkyl, (b) —O—R d , (c) —NR j R k , and (d) heterocyclyl; wherein R d is hydrogen or C 1-6 alkyl; each of R j and R k is independently selected from the group consisting of hydrogen and C 1-6 alkyl; and the heterocyclyl of (d) is optionally substituted with one to four substituents independently selected from halogen and C 1-6 alkyl,

(6) C 1-6 alkyl, optionally substituted with one to four halogens,

(7) phenyl, and

(8) heterocyclyl, optionally substituted with one to four substituents independently selected from halogen, C 1-6 alkyl 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 claim 1 , wherein R 8 is hydrogen, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein each occurrence of R 9 , when present, is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) —O—R d , wherein R d is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 2 , wherein:

R is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, optionally substituted with —CN, and

(3) heterocyclyl, optionally substituted with one to four substituents independently selected from halogen, oxo and C 1-6 alkyl; wherein the heterocyclyl is selected from the group consisting of morpholinyl and oxazolidinyl;

or a pharmaceutically acceptable salt thereof.

17. A composition which comprises an inert carrier or excipient and a compound of claim 1 or a pharmaceutically acceptable salt thereof.