COMPOUNDS FOR INHIBITING FGFR4
Provided herein are compounds which inhibit FGFR4, compositions thereof, methods of their preparation, and methods for treating disorders mediated by FGFR4 such as cancer.
1 . A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
is 5- to 6-membered arylene or heteroarylene, each of which is optionally substituted by 1-4 halogen or C 1 -C 6 alkyl groups;
L is —OCH 2 —, —CH 2 O—, —CH 2 CH 2 —,
each Y is independently halogen or —O(C 1 -C 6 alkyl) optionally substituted by 1-5 groups independently selected from the group consisting of halogen, hydroxyl, —CN, and —NH 2 , provided that when
is 5-membered heteroarylene, then at least one Y, when present, is halogen;
n is 0-5;
V is CH 2 , O, or CH(OH);
W is CH 2 , CH 2 CH 2 , or a bond;
R 1 is H, halogen, hydroxyl, —CN, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 cycloalkyl, —CH 2 NR 2 R 3 , —CH(CH 3 )NR 2 R 3 , —O(C 1 -C 6 alkyl), —CH 2 CO 2 H, —C(O)H, or 5- to 6-membered heterocyclyl or heteroaryl,
wherein the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and each of which heterocyclyl or heteroaryl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, hydroxyl, —CN, —NH 2 , oxo, and 4- to 6-membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S;
R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or (C 1 -C 6 alkyl) 2 N—(C 1 -C 6 alkylene);
R 3 is H, C 1 -C 6 alkyl, —C(O)(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —C(O)CH 2 OH, —C(O)CH 2 O(C 1 -C 6 alkyl), —C(O)CH 2 N(C 1 -C 6 alkyl) 2 , or —S(O) 2 (C 1 -C 6 alkyl);
or R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered heterocyclyl optionally containing one additional heteroatom or heteroatom-containing moiety selected from the group consisting of N, N-oxide, O, and S, wherein the heterocyclyl is optionally substituted by 1-5 R 4 groups;
each R 4 is independently:
halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), or hydroxyl;
taken together with another R 4 group and the carbon atom or atoms to which they are attached to form a spiro or fused 4- to 6-membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S; or
taken together with another R 4 group attached to the same ring atom to form an oxo group;
R 5 is H, C 1 -C 6 alkyl, or C 1 -C 6 cycloalkyl; and
R 6 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
is phenylene or 5- to 6-membered heteroarylene containing 1-3 nitrogen atoms, each of which phenylene or heteroarylene is optionally substituted by 1-2 halogen or C 1 -C 3 alkyl groups.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
each of which is optionally substituted by 1-2 Cl or —CH 3 groups.
4 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein:
L is —OCH 2 —.
5 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein:
L is —CH 2 O—.
6 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein:
L is —CH 2 CH 2 —.
7 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein:
L is
8 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein:
L is
9 . The compound of any one of claims 1 - 8 , or a pharmaceutically acceptable salt thereof, wherein:
each Y, where present, is independently halogen or —O(C 1 -C 3 alkyl) optionally substituted by 1-3 groups independently selected from the group consisting of halogen, hydroxyl, —CN, and —NH 2 .
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
each Y is independently F, Cl, or —O(C 1 -C 2 alkyl) optionally substituted by 1-2 groups independently selected from the group consisting of Cl, hydroxyl, —CN, and —NH 2 .
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:
each Y is independently F, Cl, or —OCH 3 .
12 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein:
n is 1-5.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
n is 4.
14 . The compound of any one of claims 1 - 13 , or a pharmaceutically acceptable salt thereof, wherein:
V is CH 2 .
15 . The compound of any one of claims 1 - 13 , or a pharmaceutically acceptable salt thereof, wherein:
V is O or CH(OH).
16 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt thereof, wherein:
W is CH 2 .
17 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt thereof, wherein:
W is CH 2 CH 2 or a bond.
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halogen, hydroxyl, —CN, —NH 2 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, C 1 -C 6 cycloalkyl, —CH 2 NR 2 R 3 , —CH(CH 3 )NR 2 R 3 , —O(C 1 -C 3 alkyl), —CH 2 CO 2 H, —C(O)H, or 5- to 6-membered heterocyclyl or heteroaryl,
wherein the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and each of which heterocyclyl or heteroaryl is optionally substituted by 1-3 groups independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halogen, hydroxyl, —CN, —NH 2 , oxo, and 4- to 5-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N and O.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, Cl, —CH 3 , hydroxyl, —CN, —NH 2 , —CF 3 , —CH 2 OH, cyclohexyl, —CH 2 NR 2 R 3 , —CH(CH 3 )NR 2 R 3 , —OCH 3 , —CH 2 CO 2 H, —C(O)H, or 5- to 6-membered heterocyclyl or heteroaryl,
wherein the heterocyclyl or heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, and each of which heterocyclyl or heteroaryl is optionally substituted by 1-3 groups independently selected from the group consisting of —CH 3 , —CF 3 , Cl, F, hydroxyl, —CN, —NH 2 , oxetanyl, and oxo.
20 . The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H.
21 . The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —CH 2 NR 2 R 3 .
22 . The compound of claim 19 or 21 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, or (C 1 -C 3 alkyl) 2 N—(C 1 -C 3 alkylene); and
R 3 is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, —C(O)(C 1 -C 3 alkyl), —C(O)CH 2 OH, —C(O)CH 2 O(C 1 -C 3 alkyl), —C(O)CH 2 N(C 1 -C 3 alkyl) 2 , or —S(O) 2 (C 1 -C 3 alkyl);
or R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered heterocyclyl optionally containing one additional heteroatom or heteroatom-containing moiety selected from the group consisting of N, N-oxide, O, and S, wherein the heterocyclyl is optionally substituted by 1-5 R 4 groups.
23 . The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, —CH 3 , —CF 3 , —CH 2 OH, or (CH 3 ) 2 N—CH 2 —; and
R 3 is H, —CH 3 , —CF 3 , —CH 2 OH, —C(O)(CH 3 ), —C(O)CH 2 OH, —C(O)CH 2 OCH 3 , —C(O)CH 2 N(CH 3 ) 2 , or —S(O) 2 CH 3 ;
or R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N and O, wherein the heterocyclyl is optionally substituted by 1-5 R 4 groups.
24 . The compound of any one of claims 21 - 23 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form
wherein the nitrogen atom at the 4-position is bound to H when not substituted by R 4 .
25 . The compound of any one of claims 22 - 24 , or a pharmaceutically acceptable salt thereof, wherein:
each R 4 , where present, is independently:
halogen, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, —N(C 1 -C 3 alkyl) 2 , —C(O)(C 1 -C 3 alkyl), or hydroxyl;
taken together with another R 4 group and the carbon atom or atoms to which they are attached to form a spiro or fused 4- to 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or
taken together with another R 4 group attached to the same ring atom to form an oxo group.
26 . The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein:
each R 4 is independently:
Cl, F, —CN, —CH 3 , —N(CH 3 ) 2 , —C(O)CH 3 , or hydroxyl;
taken together with another R 4 group and the carbon atom or atoms to which they are attached to form a spiro or fused 4- to 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or
taken together with another R 4 group attached to the same ring atom to form an oxo group.
27 . The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein:
each R 4 is —CH 3 .
28 . The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein:
two R 4 groups attached to the same ring atom are taken together to form an oxo group.
29 . The compound of any one of claims 1 - 28 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is H, C 1 -C 3 alkyl, or C 3 -C 5 cycloalkyl.
30 . The compound of claim 29 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is H, —CH 3 , or cyclopropyl.
31 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is H.
32 . The compound of any one of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyl-OH.
33 . The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H, Cl, —CH 3 , —CF 3 , or —CH 2 OH.
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H or —CH 3 .
35 . A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
36 . A pharmaceutical composition comprising the compound of any one of claims 1 - 35 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
37 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 - 35 , or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 36 .
38 . The method of claim 37 , wherein the cancer is liver, colorectal, anal, breast, gastrointestinal, skin, stomach, esophageal, or pancreatic cancer.
39 . The method of claim 38 , wherein the cancer originates from the liver or spreads to the liver.
40 . The method of any one of claims 37 - 39 , wherein the cancer is hepatocellular carcinoma (HCC).
41 . The method of any one of claims 37 - 40 , further comprising administering one or more additional pharmaceutical agents.
42 . The method of claim 41 , wherein the one or more additional pharmaceutical agents is selected from the group consisting of cabozantinib-S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, ramucirumab, and regorafenib.