Inhibitors of activin receptor-like kinase
Described herein are compounds, such as compounds of formula (I) and pharmaceutically acceptable salts thereof, that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl or heteroaryl, wherein ring A is optionally substituted with 1, 2, or 3 independently selected substituents selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR e , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl in addition to R 2 ;
R 1 is selected from NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C(O)—C 1 -C 4 alkyl, carbocyclyl, heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —NH—(C 0 -C 4 alkylene)-carbocyclyl, —NH-aryl, —NH—O—(C 1 -C 4 alkyl), —S-heterocyclyl, —S—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), and —NH—(C 0 -C 4 alkylene)-heterocyclyl, wherein each alkyl, alkylene, carbocyclyl, and heterocyclyl portion of R 1 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR e , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; or
R 1 is taken together with one R 3 to form a saturated ring fused to the piperazine ring in formula (I), and wherein the ring formed by R 1 and R 3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR(C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR(C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR e , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
if ring A is phenyl, then R 2 is selected from halo, C 1 -C 6 alkyl, heterocyclyl, cycloalkyl, —NH—(C 0 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-NH-heterocyclyl, and —O—(C 0 -C 4 alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion of R 2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR e , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)N R d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR(C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR(C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; or R 2 is taken together with any ring atom in ring A to form a cycloalkyl or saturated heterocyclyl ring that is fused to ring A, and wherein the ring formed by R 2 and the ring atom in ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR e , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR(C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
if ring A is heteroaryl, then R 2 is selected from halo, C 1 -C 6 alkyl, heterocyclyl, cycloalkyl, —NH—(C 0 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-NH-heterocyclyl, and —O—(C 0 -C 4 alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion of R 2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c C(C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR(C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; or R 2 is taken together with any saturated ring atom in ring A to form a cycloalkyl or saturated heterocyclyl ring that is fused, spirofused, or bridged to ring A, and wherein the ring formed by R 2 and the ring atom in ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c C(C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R e , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
each R 3 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;
each R c is selected from hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, or (C 1 -C 6 -heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each R d and R e are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
each k is independently 0, 1, or 2; and
n is 0, 1, 2, or 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
n is 0; or
n is 1 and R 3 is selected from methyl, ethyl, and CHF 2 .
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:
wherein:
“1” represents a portion of ring A bound to a pyrrolo[1,2-b]pyridazine moiety;
“2” represents a portion of ring A bound to R 2 ; and
ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR(C═O)NR d R e , —NR c C(C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl in addition to R 2 .
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with 1 or 2 substituents in addition to R 2 , wherein each optional substituent is independently selected from cyano, halo, methyl, and OCHF 2 .
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from —C(O)—(C 1 -C 3 alkyl), C 1 -C 3 alkyl, —O—(C 1 -C 5 alkyl), —NH(C 1 -C 5 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH—(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl, —O—(C 3 -C 6 cycloalkyl), —O—(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), —O—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), —NH—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), an O-containing heterocyclyl, an N-containing heterocyclyl, —O—(C 0 -C 3 alkylene)-(N-containing heterocyclyl), —S—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), —NH—O—(C 1 -C 3 alkyl), and —NH-phenyl, wherein:
any alkyl, cycloalkyl, phenyl, or heterocyclyl portion of R 1 is optionally substituted with 1, 2, or 3 substituents, wherein each optional substituent is independently selected from deuterium, halo, cyano, acetyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkylene-O—C 1 -C 4 alkyl, heteroaryl, phenyl, cycloalkyl, —COOH, and —OH, wherein each of said heteroaryl, phenyl, and cycloalkyl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; or
R 1 is taken together with any ring atom in the piperazine moiety of formula (I) to form a carbocyclyl or heterocyclyl ring fused to the piperazine moiety.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from halo, cycloalkyl, heterocyclyl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —(C 1 -C 3 alkylene)-heterocyclyl, —(C 1 -C 3 alkylene)-NH—(C 1 -C 3 alkyl), -(hydroxy-substituted C 1 -C 3 alkylene)-NH—(C 1 -C 3 alkyl), C 1 -C 4 alkyl substituted with both hydroxy and one or more of amino, C 1 -C 4 alkylamino or di-C 1 -C 4 alkylamino cyano-substituted C 1 -C 4 alkyl, hydroxy, —S(O) 2 —C 1 -C 4 alkyl, and -(amino substituted C 1 -C 3 alkylene)-heterocyclyl; or
R 2 is taken together with a ring atom in ring A to form a heterocyclyl or a carbocyclyl that is fused to ring A, wherein any heterocyclyl or carbocyclyl is optionally substituted with 0, 1, 2, or 3 substituents, wherein:
each optional substituent is independently selected from halo, cyano, hydroxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH—C(O)—O—(C 1 -C 4 alkyl), ═O, —C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkyl, deuterated C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, hydroxy-substituted —C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —O—C 1 -C 4 haloalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), -(amino substituted C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 haloalkyl), —C(O)—O—C 1 -C 4 alkyl, —COOH, C 3 -C 6 cycloalkyl, heterocyclyl, and —NH-heterocyclyl, wherein each said heterocyclyl is optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl.
8. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 13 ) or N;
R 11 is selected from: —NH—(C 3 -C 4 cycloalkyl); —NH—C 1 -C 3 alkyl; —O—C 3 -C 4 cycloalkyl; —O—(C 1 -C 3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R 12 is selected from:
piperidin-3-yl optionally 3-substituted with C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, or cyano; and
piperidin-4-yl optionally 4-substituted with C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano, wherein:
R 12 is additionally optionally 1-substituted with C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 ;
R 13 is selected from hydrogen, cyano, and fluoro; and
R 14 is fluoro.
9. The compound of claim 8 , wherein the compound is a compound of formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 13 ) or N;
R 11 is selected from: —NH—(C 3 -C 4 cycloalkyl); —NH—C 1 -C 3 alkyl; —O—C 3 -C 4 cycloalkyl; —O—(C 1 -C 3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R 13 is selected from hydrogen, cyano, and fluoro;
R 14 is fluoro;
R 15 is selected from hydrogen, C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano; and
R 16 is hydrogen or C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 .
10. The compound of claim 8 , wherein the compound is a compound of formula (IIb):
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 13 ) or N;
R 11 is selected from: —NH—(C 3 -C 4 cycloalkyl); —NH—C 1 -C 3 alkyl; —O—C 3 -C 4 cycloalkyl; —O—(C 1 -C 3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R 13 is selected from hydrogen, cyano, and fluoro;
R 14 is fluoro;
R 15 is selected from hydrogen, C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano; and
R 16 is hydrogen or C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 .
11. The compound of claim 10 , wherein the compound is a compound of formula (IIb-1):
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 10 , wherein the compound is a compound of formula (IIb-2):
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 14 is absent.
14. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen.
15. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from:
—NH—C 1 -C 3 alkyl;
—O—C 1 -C 3 alkyl optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium;
oxetan-3-yloxy; and
tetrahydrofuran-3-yloxy.
16. A compound selected from any one of the following compounds and pharmaceutically acceptable salts thereof:
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17. A pharmaceutical composition comprising:
at least one compound of claim 1 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
18. A compound
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising:
the compound of claim 18 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
20. A compound
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising:
the compound of claim 20 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
22. A compound
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising:
the compound of claim 22 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
24. A compound
or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising:
the compound of claim 24 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
26. A compound
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising:
the compound of claim 26 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
28. A compound
or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising:
the compound of claim 28 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
30. A compound
or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising:
the compound of claim 30 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
32. A compound
or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition comprising:
the compound of claim 32 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
34. A compound
or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition comprising:
the compound of claim 34 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
36. A compound
or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition comprising:
the compound of claim 36 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
38. A compound
or a pharmaceutically acceptable salt thereof.
39. A pharmaceutical composition comprising:
the compound of claim 38 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
40. A compound
or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising:
the compound of claim 40 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
42. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
43. The method of claim 42 , wherein said subject has a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having one or more amino acid modifications selected from L196P, PF197-8L, R202I, R206H, Q207E, R258S, R258G, G328A, G328W, G328E, G328R, G356D, and R375P.
44. The method of claim 42 , wherein the ALK2 enzyme has the amino acid modification R206H.
45. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 18 or a pharmaceutically acceptable salt thereof.
46. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof.
47. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 22 or a pharmaceutically acceptable salt thereof.
48. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 24 or a pharmaceutically acceptable salt thereof.
49. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 26 or a pharmaceutically acceptable salt thereof.
50. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 28 or a pharmaceutically acceptable salt thereof.
51. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 30 or a pharmaceutically acceptable salt thereof.
52. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 32 or a pharmaceutically acceptable salt thereof.
53. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 34 or a pharmaceutically acceptable salt thereof.
54. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 36 or a pharmaceutically acceptable salt thereof.
55. A method of treating or ameliorating fibrodysplasia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 38 or a pharmaceutically acceptable salt thereof.
56. A method of treating or ameliorating fibrodyspalia ossificans progressiva in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of the compound of claim 40 or a pharmaceutically acceptable salt thereof.