Kinase inhibitors and their uses
The present disclosure provides compounds that inhibit protein kinases, such as JAK, Axl, or Syk kinases, compositions comprising the compounds and methods of using the compounds to inhibit protein kinase and treat and/or prevent diseases associated with inappropriate kinase activity.
1. A compound according to structural formula (I):
or a salt, hydrate, solvate or N-oxide thereof, wherein:
B is
wherein R 5 and R 6 together form an unsaturated alkylene chain of 4 atoms to form structure (B. 1.a),
wherein the unsaturated alkylene chain formed by R 5 and R 6 is optionally substituted with one or more R a and/or R b ;
R 2 is selected from the group consisting of a (C 6 -C 20 ) aryl optionally substituted with one or more R 8 , a 5-20 membered heteroaryl optionally substituted with one or more R 8 , a (C 7 -C 28 ) arylalkyl optionally substituted with one or more R 8 and a 6-28 membered heteroarylalkyl optionally substituted with one or more R 8 ;
R 4 is a saturated or non-aromatic unsaturated, bridged or unbridged cycloalkyl containing a total of from 3 to 16 carbon atoms that is substituted with an R 7 group, with the proviso that when R 4 is an unsaturated unbridged cycloalkyl, or a saturated bridged cycloalkyl, the R 7 substituent is optional, wherein R 4 is further optionally substituted with one or more R f
R 7 is —C(O)OR d , —C(O)NR d R d , —C(O)NR d OR d , or —C(O)NR d NR d R d ;
each R 8 group is, independently of the others, selected from the group consisting of a water-solubilizing group, R a , R b , C 1 -C 8 alkyl optionally substituted with one or more R a and/or R b , C 3 -C 8 cycloalkyl optionally substituted with one or more R a and/or R b , heterocycloalkyl containing 3 to 12 annular atoms, optionally substituted with one or more R a and/or R b , C 1 -C 8 alkoxy optionally substituted with one or more R a and/or R b , and —O—(CH 2 ) x —R b , where x is 1-6;
each R a is, independently of the others, selected from the group consisting of hydrogen, C 1 -C 8 alkyl, bridged or unbridged C 3 -C 10 cycloalkyl, bridged or unbridged heterocycloalkyl containing 3 to 12 annular atoms, heteroaryl, (C 6 -C 14 ) aryl, and (C 7 -C 20 ) arylalkyl, wherein R a is optionally substituted with one or more R f ;
each R b is, independently of the others, a suitable group selected from the group consisting of ═O, —OR a , (C 1 -C 3 ) haloalkyloxy, ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —C 1 -C 3 haloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c ,R c ,—OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR 2 R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(O)NR a OR a , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a ,—C(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ; each R c is, independently of the others, is R a or two R c that are bonded to the same nitrogen atom taken together with the nitrogen atom to which they are both attached form a heterocycloalkyl group containing 5 to 8 annular atoms, which optionally includes from 1 to 3 additional heteroatomic groups selected from the group consisting of —O—, —S—, —N(—(CH 2 ) y —R a )—, —N(—(CH 2 ) y —C(O)R a )—, —N(—(CH 2 ) y —C(O)OR a )—, —N(—(CH 2 ) y —S(O) 2 R a )—, —N(—(CH 2 ) y —S(O) 2 OR a )— and —N(—(CH 2 ) y —C(O)NR a R a )—, where y is 0-6, wherein the heterocycloalkyl is optionally substituted with one or more R f ;
each R d is, independently of the others, selected from the group consisting of R a , R c and a chiral auxiliary group; and
each R f is independently —C 1 -C 8 alkoxy, —C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl, cyano, nitro, amino, (C 1 -C 8 alkyl)amino, di(C 1 -C 8 alkyl)amino, phenyl, benzyl, oxo, or halogen,
or any two R f bonded to adjacent atoms, taken together with the atoms to which they are each attached, form a fused saturated or unsaturated cycloalkyl or a fused saturated or unsaturated heterocycloalkyl group containing 5 to 8 annular atoms, wherein the formed cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more groups which are each independently selected from halogen, C 1 -C 8 alkyl, and phenyl, the water solubilizing group is of the formula
where Y is selected from the group consisting of CH and N, Z is selected from the group consisting of —C(H(R a ))—, —CH 2 —, —O—, —S—, —N═, ═N, —NH—, —N (—(CH 2 ) y —R a )—, —N (—(CH 2 ) y —C(O)R a )—, —N ((CH 2 ) y —C(O)OR a )—, N (—(CH 2 ) y —S(O) 2 R a )—, —N((CH 2 ) y —S(O) 2 OR a )— and —N(—(CH 2 R a —C(O)NR c R c )—, with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively, and
the chiral auxiliary is
where R 9 is hydrogen or C 1 -C 8 alkyl.
2. The compound of claim 1 in which B is optionally substituted with 1 or 2 R g , wherein each R g is independently ═O, —OH, —C 1 -C 6 alkoxy, (C 1 -C 3 ) haloalkyloxy, —NR c R c , halogen, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —CN, —NO 2 , —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 NR c R c , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(O)NR a OR a , —C(NR a ) NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O) NR c R c , —OC(NR a ) NR c R c ; aryl, or (C 7 -C 20 ) arylalkyl.
3. The compound of claim 2 in which R 2 is phenyl substituted with one or more of the same or different R 8 .
4. The compound of claim 3 in which R 2 is phenyl substituted with one R 8 group.
5. The compound of claim 4 in which the one R 8 substituent is positioned at the meta or para position.
6. The compound of claim 3 in which R 2 is phenyl substituted with two of the same or different R 8 .
7. The compound of claim 6 in which the R 8 substituents are positioned 3,4- or 3,5-.
8. The compound of claim 3 in which R 2 is phenyl substituted with three of the same or different R 8 .
9. The compound of claim 8 in which the R 8 substituents are positioned 3,4,5-.
10. The compound of claim 2 in which R 2 is of the formula
wherein one of R 11 , R 12 or R 13 is a water-solubilizing group, and the other two of R 11 , R 12 and R 13 are each, independently of one another, selected from the group consisting of hydrogen, C 1 -C 8 alkyl, halo, hydroxy, (C 1 -C 3 ) hydroxyalkyl, —O(CH 2 ) x —R b , —NR c R c , —C(O)NR c R c , and —C(O)NHR a .
11. The compound of claim 10 , wherein the water solubilizing group is of the formula,
wherein Y is selected from the group consisting of CH and N, and Z is selected from the group consisting of CH 2 , CH(R a ), O, S, N, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , provided that Y and Z are not simultaneously CH and CH 2 , respectively.
12. The compound of claim 11 , wherein one of R 11 , R 12 , and R 13 is halogen, one is hydrogen, and the other is the water-solubilizing group.
13. The compound of claim 12 , wherein one of R 11 , R 12 , and R 13 is fluoro, one is hydrogen, and the other is the water-solubilizing group.
14. The compound of claim 13 , wherein one of R 12 is the water solubilizing group, R 11 is hydrogen; and R 13 is fluoro.
15. The compound of claim 11 , wherein Y is N and Z is CH(R a ) or N—(CH 2 ) y —R a .
16. The compound of claim 15 , wherein Z is CH(R a1 ), wherein R a1 is —NR c c .
17. The compound of claim 1 in which R 2 is a heteroaryl, optionally substituted with one or more R h , wherein each R h is independently ═O, —OH, —C 1 -C 6 alkoxy, —C 1 -C 3 alkyl, (C 1 -C 3 ) haloalkyloxy, —NR c R c , Zhalogen, —C 1 -C 3 haloalkyl, —CN, —NO 2 , —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR Rc , aryl, or (C 7 -C 20 ) arylalkyl.
18. The compound of claim 1 in which R 4 is selected from the group consisting of
where s is an integer ranging from 1 to 6, and R 7 is selected from the group consisting of —C(O)OR a and —C(O)NR c R c , where R a and R c are as previously defined.
19. The compound of claim 18 , where R 4 is
20. The compound of claim 18 in which R 7 is —C(O)O(C 1 -C 8 alkyl) or —C(O)NH 2 .
21. The compound of claim 20 in which R 7 is —C(O)NH 2 .
22. A compound according to claim 1 of structural formula (XII):
or a salt, hydrate, solvate or N-oxide thereof, wherein the bond including the dotted line is a single bond or a double bond.
23. The compound of claim 22 which is enriched in the corresponding diastereomer of structural formula (XIIa):