Tricyclic compounds useful in the treatment of cancer, autoimmune and inflammatory disorders
The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases, such as cancer, autoimmune disorders, and inflammatory disorders.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each is a single or double bond;
Q is —CH 2 —, O, or NH;
X is N or C;
Y is N or C;
Z is N or CRS;
wherein when one of X and Y is N, the other of X and Y is C;
R X is hydrogen or halogen;
n is 1, 2, or 3;
R 1 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —NR A R B , or C1-C3 alkyl optionally substituted with 1-3 substituents selected from hydroxyl and C1-C3 alkoxy;
R 2 is hydrogen, halogen, amino, or C1-C3 alkyl;
each R 3 is independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl; or two R 3 together with the carbon atom to which they are attached come together to form an oxo group, a 4-8 membered heterocyclyl, or a C3-C8 cycloalkyl;
m is 0, 1, 2, or 3;
R 4 is phenyl or 5-9 membered heteroaryl; wherein each R 4 group is optionally substituted with 1-3 substituents independently selected from R 6 ;
R 5 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —NR C R D , or C1-C3 alkyl; and
each R 6 is independently selected from halogen; cyano; amino; —N=(S═O)(C1-C3 alkyl) 2 ; —S(═O) p (C1-C3 alkyl); —(C═O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; 5-6 membered heteroaryl optionally substituted with halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4-6 membered heterocyclyl, or C1-C3 alkyl optionally substituted with hydroxyl or —NR E R F ; C1-C4 alkyl optionally substituted with hydroxyl, —NR E R F , or C1-C3 alkoxy; 3-8 membered heterocyclyl; and C3-C6 cycloalkoxy;
p is 1 or 2; and
R A , R B , R C , R D , R E , and R F , are independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or
R A and R B , or R C and R D , or R E and R F , together with the nitrogen atom to which they are attached come together to form a 4-6 membered heterocyclyl optionally substituted with 1-2 halogens.
2 . The compound of claim 1 , wherein;
X is C and Y is C; or
X is N and Y is C; or
X is C and Y is N.
3 . The compound of claim 1 , wherein Z is N.
4 . The compound of claim 1 , wherein Z is CR 5 .
5 . The compound of claim 1 , wherein Q is —CH 2 —.
6 . The compound of claim 1 , wherein Q is O.
7 . The compound of claim 1 , wherein R 1 is hydrogen, halogen, cyano, hydroxyl, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with 1-3 substituents selected from hydroxyl and C1-C3 alkoxy.
8 . The compound of claim 1 , wherein R 1 is hydrogen, halogen, or C1-C3 alkyl.
9 . The compound of claim 1 , wherein n is 1 or 2.
10 . The compound of claim 1 , wherein m is 2 or 3.
11 . The compound of claim 1 , wherein each R 3 is independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy.
12 . The compound of claim 1 , wherein:
m is 2 and each R 3 is methyl; or
m is 2 and one R 3 is methyl and the other R 3 is trifluoromethyl; or
m is 2 and one R 3 is trifluoromethyl and the other R 3 is ethoxy; or
m is 2 and the two R 3 together with the carbon atom to which they are attached come together to form a 4-8 membered heterocyclyl, optionally wherein the 4-8 membered heterocyclyl is oxetanyl or tetrahydropyranyl; or
m is 2 and the two R 3 together with the carbon atom to which they are attached form a C3-C8 cycloalkyl, optionally wherein the C3-C8 cycloalkyl is cyclopropyl or cyclobutyl; or
m is 3; two R 3 are methyl, and one R 3 is selected from the group consisting of methyl and hydroxyl.
13 . The compound of claim 1 , wherein R 4 is 5-9 membered heteroaryl optionally substituted with 1-3 independently selected R 6 .
14 . The compound of claim 1 , wherein:
(i) at least one of R 6 is halogen; or
(ii) at least one of R 6 is cyano; or
(iii) at least one of R 6 is —(C═O)NR E R F , optionally wherein:
R E and R F are independently hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; or
one of R E and R F is hydrogen and the other of R E and R F is C1-C3 alkyl or C3-C6 cycloalkyl; or
one of R E and R F is C1-C3 alkyl and the other of R E and R F is C3-C6 cycloalkyl; or
R E and R F together with the nitrogen atom to which they are attached come together to form a 4-6 membered heterocyclyl optionally substituted with 1-2 halogens; or
(iv) at least one of R 6 is —N=(S═O)(C1-C3 alkyl) 2 ; or
(v) at least one of R 6 is C1-C3 alkoxy; or
(vi) at least one of R 6 is C1-C3 haloalkyl optionally substituted with hydroxyl; or
(vii) at least one of R 6 is C1-C3 haloalkoxy; or
(viii) at least one of R 6 is 5-6 membered heteroaryl optionally substituted with halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl optionally substituted with hydroxyl or —NR E R F , amino, or C1-C3 haloalkyl; or
(ix) at least one of R 6 is C1-C4 alkyl optionally substituted with hydroxyl, —NR E R F , or C1-C3 alkoxy; or
(x) at least one of R 6 is 3-8 membered heterocyclyl; or
(xi) at least one of R 6 is C3-C6 cycloalkoxy; or
(xii) at least one of R 6 is cyclopropoxy.
15 . The compound of claim 1 , wherein R 4 is 3-pyridyl or 4-pyridyl substituted with 1-3 independently selected R 6 .
16 . The compound of claim 1 ,
wherein R 4 is
wherein the wavy line crosses the bond that connects to the —C(═O)NH— moiety of Formula (I).
17 . The compound of claim 16 , wherein R 6 is selected from the group consisting of cyano, halogen, C1-C3 haloalkyl optionally substituted with hydroxyl, C1-C3 haloalkoxy, and C1-C3 alkoxy.
18 . The compound of claim 1 ,
wherein R 4 is
wherein R 6A and R 6B are independently selected from R 6 and the wavy line crosses the bond that connects to the —C(═O)NH— moiety of Formula (I).
19 . The compound of claim 18 , wherein
R 6A is selected from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; and
R 6B is selected from the group consisting of: 5-6 membered heteroaryl optionally substituted with cyano, C1-C3 alkyl optionally substituted with hydroxyl, 4-6 membered heterocyclyl, or amino; —N=(S═O)(C1-C3 alkyl) 2 ; —(C═O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; cyano; C3-C6 cycloalkoxy; and C1-C3 alkyl optionally substituted with hydroxyl.
20 . The compound of claim 1 ,
wherein R 4 is
wherein R 6A , R 6B , and R 6C are independently selected from R 6 and the wavy line crosses the bond that connects to the —C(═O)NH— moiety of Formula (I).
21 . The compound of claim 20 , wherein
R 6A is selected from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl;
R 6B is selected from the group consisting of: 5-6 membered heteroaryl optionally substituted with cyano, C1-C3 alkyl, or amino; —(C═O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 haloalkoxy; cyano; and C1-C3 alkyl; and
R 6C is selected from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl.
22 . The compound of claim 1 , wherein R 5 is hydrogen or halogen, optionally wherein the halogen is fluoro.
23 . The compound of claim 1 , wherein R X is halogen, optionally wherein the halogen is fluoro.
24 . The compound of claim 1 , wherein R X is hydrogen.
25 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
26 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
27 . A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
28 . A method of treating a MALT1-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated cancer an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
29 . The method of claim 27 , further comprising administering an additional therapy or therapeutic agent to the subject.
30 . A method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
31 . A method of treating a MALT1-associated autoimmune disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated autoimmune disorder an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
32 . A method for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
33 . A method of treating a MALT1-associated inflammatory disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated inflammatory disorder an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.