Kinase inhibitors and their uses

Patent metadata

Field	Value
Publication number	US-9834568-B2
Application number	US-201514754989-A
Country	US
Kind code	B2
Filing date	Jun 30, 2015
Priority date	Dec 15, 2005
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Ding Pingyu
• Argade Ankush
• Goff Dane
• Singh Rajinder
• Masuda Esteban
• Taylor Vanessa
• Holland Sacha

Classifications

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title