INHIBITORS OF BRUTON'S TYROSINE KINASE
Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.
1 . A compound having the structure of Formula (IV) having the structure:
wherein:
T is a bond, C 1 -C 6 alkylene, or C 3 -C 6 cycloalkylene;
Y and Z are each independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 4 -C 10 heterocycloalkenyl and C 2 -C 10 heterocycloalkyl, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 4 -C 10 heterocycloalkenyl and C 2 -C 10 heterocycloalkyl are optionally substituted with at least one R 1 ; or
Y and Z together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, C 4 -C 10 heterocycloalkenyl, aryl, or heteroaryl, wherein C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, C 4 -C 10 heterocycloalkenyl, aryl, or heteroaryl, are optionally substituted with at least one X;
wherein when Y and Z together with the carbon atom to which they are attached form a nitrogen atom-containing C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl, the nitrogen atom of the C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl is optionally substituted with W and the carbon atoms of the C 2 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkenyl are optionally substituted with at least one X;
W is selected from J, C(═O)-J, C(═O)O-J, C(═O)NR 2 -J, C(═NR 2 )-J, —C(═NR 2 )NR 2 -J, C(═N—OR 3 )-J, C(═S)-J, S(═O) v -J, S(═O) v O-J;
X is F, Cl, Br, I, —CN, —NO 2 , —OR 3 , —N(R 2 ) 2 , —SR 2 , —C 1 -C 6 alkyl, —C(═O)R 2 , —OC(═O)R 2 , —NR 2 C(═O)R 5 , —NR 2 C(═O)N(R 2 ) 2 , —C(═O)N(R 2 ) 2 , —C(═NR 2 )N(R 2 ) 2 , —C(═N—OR 2 )N(R 2 ) 2 , —C(═S)R 2 , —S(═O) v R 2 , —OS(═O) v R 2 , —NR 2 C(═O)OR 2 , —NR 2 S(═O) v R 2 ;
J is —C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 2 -C 6 alkene, C 2 -C 6 heterocycloalkyl, aryl, or heteroaryl optionally substituted with at least one R 1 ;
v is 1 or 2;
R b is NH 2 , OH, OSO 3 H or NHSO 3 H, halogen, —CN, —NO 2 , —SR 2 , optionally substituted C 1 -C 6 alkyl; N(R 2 ) 2 or NHR 7 ;
R 1 is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, heteroaryl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —N(R 2 ) 2 , wherein optionally the two R 2 groups of N(R 2 ) 2 and the nitrogen atom to which they are attached form a C 2 -C 6 heterocycloalkyl ring, —NR 2 C(═O)R 2 , —NR 2 C(═O)R 8 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —C(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , —SO 3 H, and at least one amino acid fragment;
R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 6 cycloalkyl;
R 3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or SO 3 H;
R 6 is selected from H, F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —N(R 2 ) 2 , wherein optionally the two R 2 groups of N(R 2 ) 2 and the nitrogen atom to which they are attached form a C 2 -C 6 heterocycloalkyl ring, —NR 2 C(═O)R 2 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —C(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , —SO 3 H, and at least one amino acid fragment; wherein each R 6 cannot all be H;
R 7 is an amino protecting group;
R 8 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, or an optionally substituted C 3 -C 6 cycloalkyl; or a pharmaceutically acceptable salt, solvate, or metabolite thereof.
2 . The compound of claim 1 wherein Y and Z together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl or C 2 -C 10 heterocycloalkyl.
3 . The compound of claim 2 wherein Y and Z together with the carbon atom to which they are attached form a C 2 -C 10 heterocycloalkyl.
4 . The compound of claim 1 wherein W is C(═O)J.
5 . The compound of claim 4 wherein J is —C 1 -C 6 alkyl or —C 2 -C 6 alkene.
6 . The compound of claim 5 wherein J is substituted with at least one R 1 .
7 . The compound of claim 6 wherein R 1 is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, heteroaryl, or phenyl.
8 . The compound of claim 3 wherein C 2 -C 10 heterocycloalkyl is selected from:
9 . The compound of claim 8 wherein C 2 -C 10 heterocycloalkyl is
10 . The compound of claim 5 wherein C 1 -C 6 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
11 . The compound of claim 10 wherein C 1 -C 6 alkyl is substituted with one R 1 .
12 . The compound of claim 10 wherein C 1 -C 6 alkyl is substituted with two R 1 .
13 . The compound of claim 11 wherein R 1 is selected from F, Cl, Br, I, —CN, NO 2 , —OR 3 , and at least one amino acid fragment.
14 . The compound of claim 5 wherein J is C 2 -C 6 alkene.
15 . The compound of claim 14 wherein C 2 -C 6 alkene is C 2 H 3 .
16 . The compound of claim 15 wherein C 2 -C 6 alkene is substituted with at least one R 1 selected from F, Cl, Br, I, —CN, NO 2 , OH, and —OSO 3 H.
17 . A pharmaceutical formulation comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
18 . The compound of claim 1 wherein the compound forms a covalent bond with a Cys 481 residue of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase.
19 . A method for treating an autoimmune disease or inflammatory disease or condition comprising administering to a patient in need the compound of claim 1 .
20 . A method for treating a cancer comprising administering to a patient in need the compound of claim 1 .
21 . A method for treating an inflammatory disease or condition comprising administering to a patient in need the compound of claim 1 .