IP Library Granted Patent US 9,278,950
Granted Patent B2
US 9,278,950 · App. 14/155,134 · Granted Mar 8, 2016

Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors

Inventors: Yun-Long Li (Chadds Ford, PA); David M. Burns (Glen Mills, PA); Hao Feng (Glen Mills, PA); Chu-Biao Xue (Hockessin, DE); Anlai Wang (Wilmington, DE); Jun Pan (Media, PA)
Assignees: Incyte Corporation; Incyte Holdings Corporation
C07D401/12C07D401/14C07D405/14C07D413/14C07D471/04C07D491/048C07D498/04
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Quick Facts
Patent No.
US 9,278,950
App. No.
14/155,134
Granted
Mar 8, 2016
Kind
B2
Abstract

The present disclosure describes bicyclic aromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.

Claims (162)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy is a group of the following formula (Cy-1):

wherein:

R x is H;

R y is H;

a is 1; and

b is 1;

wherein the substituted piperidin-1-yl ring forming Cy is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, R Cy1 , C 1-6 haloalkyl, CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 ,

wherein each R Cy1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, R Cy2 , C 1-6 haloalkyl, CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 , and

wherein each R Cy2 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 and S(O) 2 NR c1 R d1 ;

A 1 is CR 1 ;

R 1 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 or S(O) 2 NR c2 R d2 ; and

R 2 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 or S(O) 2 NR c2 R d2 ;

or A 1 and R 2 in combination, together with the carbon atom to which R 2 is attached, form a 5, 6 or 7-membered unsaturated or partially saturated carbocyclic or heterocyclic ring containing 3 to 7 ring carbon atoms and 0, 1 or 2 ring heteroatoms, each independently selected from N, O and S, wherein the ring formed by the combination of A 1 and R 2 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 (O)OR a2 and oxo;

R 3 is H, halogen or NH 2 ;

R 4 is H or halogen;

A 5 is N or CR 5 ;

A 6 is N or CR 6 ;

A 7 is N or CR 7 ;

A 8 is N or CR 8 ;

provided that 0, 1 or 2 of A 5 , A 6 , A 7 and A 8 are N;

R 5 is H or halogen;

R 6 is H or halogen;

R 7 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 7 , -L 7 -Cy 7 , CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 or S(O) 2 NR c3 R d3 ,

wherein said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl forming R 7 are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ;

Cy 7 is unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-6 cycloalkyl or unsubstituted or substituted 4-7 membered heterocycloalkyl,

wherein the substituted C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl forming Cy 7 is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, R Cy7 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ,

wherein each R Cy7 is C 1-6 alkyl, each of which is independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ;

L 7 is unsubstituted C 1-6 alkylene or C 1-6 alkylene substituted with 1, 2 or 3 substituents independently selected from F, Cl, CN, OH, O(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;

R 8 is H, halogen, CN or C 1-6 alkyl;

R a1 , R b1 , R c1 and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a1 , R b1 , R c1 and R d1 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 and S(O) 2 NR c4 R d4 ;

or R c1 and R d1 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 and S(O) 2 NR c4 R d4 ;

R a2 , R b2 , R c2 and R d2 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a2 , R b2 , R c2 , and R d2 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 and S(O) 2 NR c5 R d5 ;

or R c2 and R d2 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a5 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 and S(O) 2 NR c5 R d5 ;

R a3 , R b3 , R c3 and R d3 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a3 , R b3 , R c3 and R d3 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, halo, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)NR c6 R d6 , NR c6 C(O)OR a6 , C(═NR e6 )NR c6 R d6 , NR c6 C(═NR e6 )N c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 and S(O) 2 NR c6 R d6 ;

or R c3 and R d3 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)NR c6 R d6 , NR c6 C(O)OR a6 , C(═NR e6 )NR c6 R d6 , NR c6 C(═NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 and S(O) 2 NR c6 R d6 ;

R a4 , R b4 , R c4 and R d4 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a4 , R b4 , R c4 and R d4 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

or R c4 and R d4 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

R a5 , R b5 , R c5 and R d5 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a5 , R b5 , R c5 and R d5 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

or R c5 and R d5 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

R a6 , R b6 , R c6 and R d6 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a6 , R b6 , R c6 and R d6 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

or R c6 and R d6 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; and

R e1 , R e2 , R e3 , R e4 , R e5 and R e6 are each, independently, H, CN or NO 2 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is a group of the following formula (Cy-2)

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, halogen or C 1-6 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halogen, CN, C 1-6 alkyl or C 1-6 alkoxy.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 and R 2 in combination, together with the carbon atom to which R 2 is attached, form a 5, 6 or 7-membered unsaturated or partially saturated carbocyclic or heterocyclic ring containing 3 to 7 ring carbon atoms and 0, 1 or 2 ring heteroatoms, each independently selected from N, O and S; wherein the ring formed by the combination of A 1 and R 2 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, CN, OR a2 , OC(O)R a2 and oxo.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 in combination form a C 3-5 alkylene that is unsubstituted or substituted by OR a2 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 in combination form a C 3-5 alkylene that is unsubstituted or substituted by OH.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is NH 2 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 5 is CR 5 .

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 6 is N.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 6 is CR 6 .

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 7 is N.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 7 is CR 7 .

21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 or S(O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl forming R 7 are each unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl forming R 7 are each unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a3 , OC(O)R b3 , NR c3 R d3 and NR c3 C(O)R b3 .

23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen or C 1-6 alkyl, wherein said C 1-6 alkyl forming R 7 is unsubstituted or substituted with a substituent selected from halogen, CN, OR a3 , OC(O)R b3 , NR c3 R d3 and NR c3 C(O)R b3 .

24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen, C 1-6 alkyl, (C 1-6 alkylene)-CN, (C 1-6 alkylene)-OH, (C 1-6 alkylene)-O(C 1-6 alkyl) or (C 1-6 alkylene)-NR c3 R d3 .

25. The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen, methyl, ethyl, isopropyl, CH 2 CN, CH(OH)CH 3 , C(OH)(CH 3 ) 2 , CFCH 3 or CH 2 N(CH 3 ) 2 .

26. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 7 is Cy 7 or -L 7 -Cy 7 .

27. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted C 6-10 aryl or C 6-10 aryl substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

28. The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted phenyl or phenyl substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

29. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted phenyl, 2,6-difluorophenyl, 2-carbamylphenyl, 2-carbamyl-6-fluorophenyl, 2-cyanophenyl, 2-cyano-6-fluorophenyl.

30. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

31. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted pyrazolyl or pyrazolyl substituted with 1, 2 or 3 C 1-6 alkyl substituents.

32. The compound claim 26 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted C 3-7 cycloalkyl or C 3-7 cycloalkyl substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

33. The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted C 3-7 cycloalkyl.

34. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted 4-7 membered heterocycloalkyl or 4-7 membered heterocycloalkyl substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 .

35. The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is unsubstituted 4-7 membered heterocycloalkyl.

36. The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein Cy 7 is morpholinyl, piperidinyl, pyrrolidinyl or tetrahydropyranyl.

37. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 7 is -L 7 -Cy 7 and L 7 is unsubstituted C 1-6 alkylene.

38. The compound of claim 37 , or a pharmaceutically acceptable salt thereof, wherein L 7 is CH 2 .

39. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 7 is -L 7 -Cy 7 and L 7 is C 1-6 alkylene substituted with 1, 2 or 3 substituents independently selected from F, Cl, CN, OH, O(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 .

40. The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein L 7 is C 1-6 alkylene substituted with 1 substituent selected from CN, OH, O(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 or 1, 2 or 3 substituents independently selected from F and Cl.

41. The compound of claim 40 , or a pharmaceutically acceptable salt thereof, wherein L 7 is —CH(OH)—.

42. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 8 is N.

43. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 8 is CR 8 .

44. The compound of claim 43 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

45. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 are each independently selected from H and C 1-6 alkyl and R e1 , R e2 , R e3 , R e4 , R e5 and R e6 are each H.

46. A compound selected from the following compounds, or a pharmaceutically acceptable salt thereof:

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-piperidin-4-ylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-5-yl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;

3-amino-7-[2-(aminocarbonyl)phenyl]-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2-cyano-6-fluorophenyl)quinoline-2-carboxamide;

3-amino-7-[2-(aminocarbonyl)-6-fluorophenyl]-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-bromoquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(cyanomethyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethyl-6-fluoroquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-hydroxyethyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-hydroxy-1-methylethyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-[hydroxy(phenyl)methyl]quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-fluoroethyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(pyrrolidin-1-ylmethyl)quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-[(dimethylamino)methyl]quinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide; and

3-amino-N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-[4-(3-aminocyclohexyl)pyridin-3-yl]-7-ethylquinoline-2-carboxamide;

3-amino-N-(4-(3-aminopiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethoxy-1,8-naphthyridine-2-carboxamide;

3-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethoxy-1,8-naphthyridine-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethyl-1,6-naphthyridine-2-carboxamide;

3-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-5-methylpyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]-5-methylpyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[3-aminopiperidin-1-yl]-6-methoxypyridin-3-yl}-7-ethylquinoline-2-carboxamide; and

3-amino-N-{4-[3-aminopiperidin-1-yl]-5-cyanopyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-piperidin-4-ylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-5-yl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;

3-amino-7-[2-(aminocarbonyl)phenyl]-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(2-cyano-6-fluorophenyl)quinoline-2-carboxamide;

3-amino-7-[2-(aminocarbonyl)-6-fluorophenyl]-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-bromoquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(cyanomethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethyl-6-fluoroquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-hydroxyethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-hydroxy-1-methylethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-[hydroxy(phenyl)methyl]quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(1-fluoroethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(pyrrolidin-1-ylmethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-[(dimethylamino)methyl]quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-[4-(3-aminocyclohexyl)pyridin-3-yl]-7-ethylquinoline-2-carboxamide;

(S)-3-amino-N-(4-(3-aminopiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl)-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethoxy-1,8-naphthyridine-2-carboxamide;

3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethoxy-1,8-naphthyridine-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl}-7-ethyl-1,6-naphthyridine-2-carboxamide;

3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-5-methylpyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5-methylpyridin-3-yl}-7-ethylquinoline-2-carboxamide;

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-6-methoxypyridin-3-yl}-7-ethylquinoline-2-carboxamide; and

3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5-cyanopyridin-3-yl}-7-ethylquinoline-2-carboxamide.

47. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

48. A method of inhibiting Pim1, Pim2 or Pim3 enzyme in vitro comprising contacting the enzyme with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 5 is CR 5 and A 7 is CR 7 .

50. The compound of claim 49 , or a pharmaceutically acceptable salt thereof, wherein R 3 is NH 2 .

51. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 5 is CR 5 , A 6 is CR 6 and A 7 is CR 7 .

52. The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 3 is NH 2 .

53. A compound which is 3-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methylpiperidin-4-yl)quinoline-2-carboxamide, or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising the compound of claim 53 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

55. A method of inhibiting Pim1, Pim2 or Pim3 enzyme in vitro comprising contacting the enzyme with a compound of claim 53 , or a pharmaceutically acceptable salt thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 2, 2015
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 035970/0267 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2014
From: LI, YUN-LONG; BURNS, DAVID M.; FENG, HAO; XUE, CHU-BIAO; WANG, ANLAI; PAN, JUN
To: INCYTE CORPORATION
Reel/Frame 033730/0385 →
Continuity (3)
Provisional Application 61791275 · Mar 15, 2013
Provisional Application 61752249 · Jan 14, 2013
Related Publication 20140200216A1 · Jul 17, 2014