US2013244999A1PendingUtilityA1
Substituted Heterocyclic Compounds
Est. expiryDec 22, 2028(~2.4 yrs left)· nominal 20-yr term from priority
A61P 37/08A61P 37/00A61P 27/14A61P 25/00A61P 29/00C07D 405/14A61K 45/06A61K 31/506C07D 487/08A61K 31/5377A61P 17/00C07D 409/14C07D 413/14A61K 31/551C07D 417/14C07D 487/04A61P 19/02A61P 11/06C07D 471/04C07D 401/14
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Claims
Abstract
The present invention relates to substituted heterocyclic compounds of Formula I: or pharmaceutically acceptable salts or N-oxides or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or pharmaceutically acceptable salt thereof or N-oxide thereof or quaternary ammonium salt thereof, wherein:
A 1 is CH 2 , CHR 2 , C(R 2 ) 2 , NH, NR 2 , O, or S;
R 1 is NR 3 R 4 , wherein R 3 and R 4 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl group wherein each of the ring-forming atoms of the 4-10 membered heterocycloalkyl group is independently selected from C, N, O, and S, and wherein the 4-10 membered heterocycloalkyl group is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 R 5 ;
each R 2 is, independently, —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 ;
or any two adjacent R 2 together with the two atoms to which they are attached form a fused 3-14 membered cycloalkyl group, a fused 3-14 membered heterocycloalkyl group, a fused aryl group, or a fused heteroaryl group, each substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
or any two R 2 together with the same carbon atom to which they are attached form carbonyl;
provided that two adjacent R 2 together with the two atoms to which they are attached form a fused 3-14 membered cycloalkyl group, a fused 3-14 membered heterocycloalkyl group, a fused aryl group, or a fused heteroaryl group, each substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
wherein —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 is other than H;
wherein —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is other than H;
each R 5 is, independently, selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 , wherein each of the C 1-6 alkyl and C 1-6 haloalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from OH, CN, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
W 1a , W 2a , W 1 , and W 2 are each, independently, selected from absent, C 1-6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, (CR 11a R 11b ) p1 O(CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 S(CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(O)(CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(S)(CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(O)O(CR 11 R 11b ) p2 , (CR 11a R 11b ) p1 C(O)NR 2 (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(S)NR e (CR 11a R 11a ) p2 , (CR 11a R 11b ) p1 S(O)(CR 11b R 11b ) p2 , (CR 11a R 11b ) p1 S(O) 2 (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 S(O)NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 S(O) 2 NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 NR e C(O)NR f (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 NR e C(S)NR f (CR 11b R 11b ) p2 , (CR 11a R 11b ) p1 NR e S(O) 2 NR f (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(═NR g )NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 NR 2 C(═NR g )NR f (CR 11a R 11b ) p2 , O(CR 11a R 11b ) q1 C(O), S(CR 11a R 11b ) q1 C(O), NR e (CR 11a R 11b ) q1 C(O), C(O)(CR 11a R 11b ) q1 C(O), NR e (CR 11a R 11b ) q1 NR f , O(CR 11a R 11b ) q1 NR f , and O(CR 11a R 11b ) q1 O, wherein each of the C 1-6 alkylenyl, C 2-6 alkenylenyl and C 2-6 alkynylenyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , and P(O)OR e OR f ;
X 1a , X 2a , X 1 , and X 2 are each, independently, selected from absent, C 1-6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said C 1-6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , SF 5 , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c n d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , and P(O)OR e OR f ;
Y 1 and Y 2 are each, independently, selected from absent, C 1-6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(S)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(S)NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O)NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e C(O)NR f (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e C(S)NR f (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e S(O) 2 NR f (CR 12a R 12b ) p4 , (cR 12a R 12b ) p3 C(═NR g )NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e C(═NR g )NR f (CR 12a R 12b ) p4 , O(CR 12a R 12b ) q2 C(O), S(CR 12a R 12b ) q2 C(O), NR e (CR 12a R 12b ) q2 C(O), NR e (CR 12a R 12b ) q2 NR f , O(CR 12a R 12b ) q2 NR f , and O(CR 12a R 12b ) q2 O, wherein each of the C 1-6 alkylenyl, C 2-6 alkenylenyl, and C 2-6 alkynylenyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, NO 2 , OR a , SR a , SF 5 , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , and P(O)OR e OR f ;
Z 1 and Z 2 are each, independently, selected from H, halo, CN, NO 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from R ZZ , halo, CN, NO 2 , OR a , SR a , SF 5 , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c S(O) 2 R b , NR c S(O) 2 NR c R d ; S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , and P(O)OR e OR f ; S(O) 2 NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , and P(O)OR e OR f ;
R 11a , R 11b , R 12a , and R 12b are each, independently, selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, CN, NO 2 , 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 g1 )NR c1 R d1 , NR c1 C(═NR g1 )NR c1 R d1 , NR c1 S(O) 2 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 , S(O) 2 NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , and P(O)OR e1 OR f1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, CN, NO 2 , OR a1 , SR a1 , SF 5 , 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 g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , NR c1 S(O) 2 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 , S(O) 2 Nr c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , and P(O)OR e1 OR f1 ;
each R XX is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, CN, NO 2 , OR a2 , SR a2 , SF 5 , 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 g2 )NR c2 R d2 , NR c2 C(═NR g2 )NR c2 R d2 , NR c2 S(O) 2 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 , S(O) 2 NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , and P(O)OR e2 OR f2 ;
each R ZZ is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, CN, NO 2 , OR a3 , SR a3 , SF 5 , 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 b3 , NR c3 C(O)OR a3 , C(═NR g3 )NR c3 R d3 , NR c3 C(═NR g2 )NR c3 R d3 , NR c3 S(O) 2 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 , S(O) 2 NR c3 R d3 , P(R f3 ) 2 , P(OR e3 ) 2 , P(O)R e3 R f3 , and P(O)OR e3 OR f3 ;
R a , R a1 , R a2 , and R a3 are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R b , R b1 , R b2 , and R b3 are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R c and R d are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
or R e and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R c1 and R d1 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R c2 and R d2 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroaryialkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
or R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R c3 and R d3 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
or R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-5 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R e , R e1 , R e2 , R e3 , R f , R f1 , R f2 , and R f3 are each, independently, selected from H, C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
R g , R g1 , R g2 , and R g3 are each, independently, selected from H, CN, and NO 2 ;
each p1 is, independently, 0, 1, or 2;
each p2 is, independently, 0, 1, or 2;
each p3 is, independently, 0, 1, or 2;
each p4 is, independently, 0, 1, or 2;
each q1 is, independently, 1 or 2;
each q2 is, independently, 1 or 2;
n1 is 0, 1, 2, or 3;
n2 is 0, 1, 2, or 3; and
m is 2, 3, 4, 5, or 6,
with the provisos:
(a) when two adjacent R 2 together with the two carbon atoms to which they are attached form a fused optionally substituted aryl group, then the fused optionally substituted aryl group is other than a fused benzo group optionally substituted with a halo group;
(b) when the moiety (QR2):
of Formula I is a moiety having the structure of
wherein m 1 is 1, 2, 3, 4, or 5, and the R 2 attached to the N atom and one of its adjacent R 2 groups together with the two atoms to which they are attached form a fused 3-14 membered heterocycloalkyl group, then the fused 3-14 membered heterocycloalkyl group is substituted with at least one W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ; and
(c) R 1 is other than a moiety having the structure of
wherein t30 is 0, 1, 2, or 3.
2 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the ring formed by R 3 and R 4 together with the N atom to which they are attached is a 5-7 membered heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 R 5 , and wherein each of the ring-forming atoms of the 5-7 membered heterocycloalkyl group is C or N.
3 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the ring formed by R 3 and R 4 together with the N atom to which they are attached is a pyrrolidine ring, a piperidine ring, or a piperazine ring, each substituted with 0, 1, 2, 3, 4, or 5 R 5 .
4 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
the ring formed by R 3 and R 4 together with the N atom to which they are attached is substituted with 0, 1, 2, or 3 R 5 ; and each R 5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 , wherein each of the C 1-6 alkyl and C 1-6 haloalkyl is substituted with 0 or 1 substituent selected from NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl).
5 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is selected from (A), (B), (C), (Q14), (Q17), (Q18), (Q19), (Q20), and (Q21):
6 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is selected from (A), (B), and (C):
7 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is (A):
8 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two atoms to which they are attached form a fused aryl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
9 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two atoms to which they are attached form a fused heteroaryl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
10 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two carbon atoms to which they are attached form a fused aryl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
11 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two carbon atoms to which they are attached form a fused heteroaryl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
12 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two carbon atoms to which they are attached form a fused benzo group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
13 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two atoms to which they are attached form a fused cycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
14 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein two adjacent R 2 together with the two atoms to which they are attached form a fused heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
15 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula I is a compound of Formula II, IIa, IIb, IIc:
wherein:
m1 is 0, 1, 2, 3, or 4;
m2 is 1, 2, 3, or 4;
n1 is 0 or 1; and
n2 is 0 or 1.
16 . The compound of claim 15 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein n1 is 1.
17 . The compound of claim 16 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein n2 is 0 or 1.
18 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is selected from absent, O, S, and NR e ; and
X 2a is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
19 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent, O, S, or NR e ; and
X 2a is aryl or heteroaryl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR C R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
20 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent, 0, 5, or NH; and
X 2a is aryl or heteroaryl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)Nr c R d , C(O)OR a , OC(O)R b , OC(O)Nr c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
21 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent; and
X 2a is aryl or heteroaryl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
22 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is 0; and
X 2a is aryl or heteroaryl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R XX , halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c (O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
23 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is NR e ; and
X 2a is aryl or heteroaryl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R XX , halo, CN, NO 2 , OR B , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .
24 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent or selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is alkyl, arylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
25 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is alkyl, arylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
26 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is alkyl, arylalkyl, aryl, or cycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 , alkoxy, C 1-6 , haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)N11-, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C j-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
27 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is heteroaryl or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
28 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is heteroaryl or heterocycloalkyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
29 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is heteroaryl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-$ dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
30 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is selected from pyridinyl, pyrazolyl, pyrrolyl, pyrimidinyl, 1,3-thiazolyl, and 3H-imidazo[4,5-b]pyridinyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), cop, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
31 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent, C(O), C(O)NH;
X 2a is heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
32 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is X 2a is selected from piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-piperazinyl, 2(1H)-oxo-pyridinyl, 1-oxo-isoindolinyl, isoindolinyl, pyrrolidinyl, and 2H-3(4H)-oxo-benzo[b][1,4]oxazinyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
33 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-3 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
34 . The compound of claim 17 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one substituent —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is a —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 wherein:
W 2a is absent;
X 2a is X 2a is selected from piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-piperazinyl, 2(1H)-oxo-pyridinyl, 1-oxo-isoindolinyl, and 2H-3(4H)-oxo-benzo[b][1,4]oxazinyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and 01-1;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
35 . The compound of claim 18 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
W 2 —is absent; X 2 is absent; Y 2 —is absent or selected from C 1-6 alkylenyl, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
36 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound is a compound of Formula III:
wherein:
R 1 is selected from (A), (B), (C), (Q14), (Q17), (Q18), (Q19), (Q20), and (Q21):
R 21 is H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein the C 1-6 alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from CN, OH, and halo;
R 22 is halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 cyanoalkyl;
W 2a is absent or selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is alkyl, arylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 ; and
m3 is 0 or 1.
37 . The compound of claim 36 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 21 is H or methyl, wherein the methyl is substituted with 0, 1, 2, or 3 substituents each independently selected from OH and halo; and R 22 is methyl, halo, or trihalomethyl.
38 . The compound of claim 36 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 1 is (A):
R 21 is H, methyl, or hydroxylmethyl;
R 22 is halo;
W 2a is selected from O, NH, N(C 1-6 alkyl), C(O), C(O)NH, C(O)N(C 1-6 alkyl), and OC(O)NH;
X 2a is alkyl, arylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)N(C 1-6 alkyl)-, X 2 is absent or selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, 6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C alkyl), and C(O)N(C 1-6 alkyl) 2 ; and
m3 is 0 or 1.
39 . The compound of claim 36 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 1 is (A):
R 21 is H, methyl, or hydroxylmethyl;
R 22 is halo;
W 2a is absent;
X 2a is heteroaryl or heterocycloalkyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH;
W 2 —is absent or selected from C 1-6 alkylenyl, C(O)NH, and C(O)N(C 1-6 alkyl);
X 2 is absent or selected from C 1-6 alkyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, CN, and OH;
Y 2 —is absent or selected from C 1-6 alkylenyl, O, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ;
Z 2 is selected from 1-1, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 ; and
m3 is 0 or 1.
40 . The compound of claim 36 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein X 2a is heteroaryl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH.
41 . The compound of claim 40 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein X 2a is selected from pyridinyl, pyrazolyl, pyrrolyl, pyrimidinyl, 1,3-thiazolyl, and 3H-imidazo[4,5-b]pyridinyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH.
42 . The compound of claim 41 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
W 2 —is absent; X 2 is absent; Y 2 —is absent or selected from C 1-6 alkylenyl, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
43 . The compound of claim 36 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein X 2a is heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH.
44 . The compound of claim 43 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein X 2a is selected from piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-piperidinyl, 2(1H)-oxo-pyridinyl, 1-oxo-isoindolinyl, and 2H-3(4H)-oxo-benzo[b][1,4]oxazinyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, halo, CN, and OH.
45 . The compound of claim 44 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
W 2 —is absent; X 2 is absent; Y 2 —is absent or selected from C 1-6 alkylenyl, C(O), C(O)O, C(O)NH, C(O)N(C 1-6 alkyl), and S(O) 2 ; and Z 2 is selected from H, halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C(O)NH 2 , C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 alkyl) 2 .
46 . A compound selected from:
4-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-methylpyridine-2-carboxamide; N-(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-2-yl)acetamide; 4-(4-Methylpiperazin-1-yl)-6-[7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-(6-Chloro-5-fluoropyridin-3-yl)-3,4-dihydroisoquinolin-2 (1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-fluoropyridine-2-carbonitrile; tert-Butyl 4-(5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-yl)piperazine-1-carboxylate; 4-(4-Methylpiperazin-1-yl)-6-[7-(2-piperazin-1-ylpyrimidin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-{1-[(6-Ethoxypyridin-3-yl)methyl]-1H-pyrazol-4-yl}-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; [1-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)cyclopentyl]acetonitrile; tert-Butyl 4-(4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate; 4-(4-Methylpiperazin-1-yl)-6-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-(4-Chloro-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidine; {(3S)-2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-3-yl}methanol; 2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(6-methylpyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine; 4-[7-(2-Chlorophenoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-(pyridin-2-ylmethyl)pyridine-2-carboxamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-(trans-4-hydroxycyclohexyl)pyridine-2-carboxamide; 1-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroquinolin-7-ol; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)-2-chlorobenzonitrile; 2-[2-Amino-6-(4-methylpiperazin-1-y 1)pyrimidin-4-yl]-1,4-dihydroisoquinolin-3 (21-1)-one; 4-(4-Methylpiperazin-1-yl)-6-[7-[(3-phenylpyrrolidin-1-yl)carbonyl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(3-fluorobenzyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide; 4-[7-(1,3-Dihydro-2H-isoindol-2-ylcarbonyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide; 2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide; 4-(4-Methylpiperazin-1-yl)-6-[7-(pyrrolidin-1-ylcarbonyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; Ethyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperazine-1-carboxylate; 4-[7-(4-Acetylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{7-[4-(2-Furoyl)piperazin-1-yl}-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)primidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-(4-chlorophenyl)piperazine-1-carboxamide; Ethyl {2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}carbamate; N-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-1-carboxamide; 1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-4-carbonitrile; 1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-4-phenylpiperidin-4-ol; 4-(4-Methylpiperazin-1-yl)-6-[7-(4-pyridin-4-ylpiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)-N-methylbenzamide; 4-(1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydro isoquinol in-7-yl}piperidin-4-yl)benzamide; 4-(1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydro isoquinol in-7-yl}piperidin-4-yl)-1-methylpyridin-2(1H)-one; 5-(1-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)-1-methylpyridin-2(1H)-one; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methylpyridin-2(1H)-one; 6-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-oxopiperazin-1-yl)-N-methylnicotinamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,3-dimethylpyridine-2-carboxamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N,3-trimethylpyridine-2-carboxamide; 2-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-methyl-1,3-thiazole-4-carboxamide; 4-(4-Methylpiperazin-1-yl)-6-[7-[4-(pyrrolidin-1-ylcarhonyl)-1,3-thiazol-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-methylpyridine-2-carboxamide; 5-(2-(2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N,N-dimethylpicolinamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-[(1R)-2-hydroxy-1-methylethyl]pyridine-2-carboxamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N[2-(dimethylamino)ethyl]-N-methylpyridine-2-carboxamide; 4-[7-[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 1-[(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-2-yl)carbonyl]azetidine-3-carbonitrile; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[6-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; (3R)-1-[(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl}-3-methyl-1,2,3,4-tetrahydro isoquinolin-7-yl) pyridin-2-yl)carbonyl]pyrrolidin-3-ol; 4-[7-(6-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-3-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[3-Methyl-7-{6-[(4-methylpiperazin-1-yl)carbonyl]pyridin-3-yl}-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-(2-hydroxyethyl)pyridine-2-carboxamide; 1-[(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-2-yl)carbonyl]azetidin-3-ol; 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylpyridine-2-carboxamide; 4-[7-[2-(Azetidin-1-ylcarbonyl)pyridin-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 1-[(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}pyridin-2-yl)carbonyl]azetidine-3-carbonitrile; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; (3S)-1-[(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-2-yl)carbonyl]pyrrolidin-3-ol; 4-[7-(2-{[(3S)-3-Fluoropyrrolidin-1-yl]carbonyl}pyridin-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-(2-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-[2-(dimethylamino)ethyl]-N-methylpyridine-2-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-[(1R)-2-hydroxy-1-methylethyl]pyridine-2-carboxamide; 4-[3-Methyl-7-{2-[(4-methylpiperazin-1-yl)carbonyl]pyridin-4-yl}-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}-N-ethylnicotinamide; 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylnicotinamide; 1-[(6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}pyridin-3-yl)carbonyl]azetidin-3-ol; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylnicotinamide; 1-[(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-3-yl)carbonyl]azetidin-3-ol; 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylpyridine-2-carboxamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-ethylpyrimidine-2-carboxamide; 1-[(5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-yl)carbonyl]azetidin-3-ol; 2-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)-N-methylacetamide; 2-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-1-yl}-N,N-dimethylacetamide; 5-[2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-N-methylpyridine-2-carboxamide; (3-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)acetonitrile; 3-(3-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)propanenitrile; 2-(3-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)ethanol; 4-[3-Methyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-(1-Ethyl-1H-pyrazol-3-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,1-dimethyl-1H-pyrrole-2-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-ethyl-1-methyl-1H-pyrrole-2-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N,1-trimethyl-1H-pyrrole-2-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-isopropyl-1-methyl-1H-pyrrole-2-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydro isoquinolin-7-yl}-N-cyclopropyl-1-methyl-1H-pyrrole-2-carboxamide; 4-[7-[5-(azetidin-1-ylcarbonyl)-1-methyl-1H-pyrrol-3-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-[2-(dimethylamino)ethyl]-N,1-dimethyl-1H-pyrrole-2-carboxamide; 4-[7-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 3-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)propanenitrile; 1-[(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)methyl]cyclopropanecarbonitrile; 4-[7-[1-(1,1-Dioxidotetrahydro-3-thienyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(tetrahydrofuran-2-ylmethyl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-[1-(2-Fluoroethyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 3-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)-2-methylpropanenitrile; 4-[7-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 3-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}-1H-pyrazol-1-yl)butanenitrile; 4-[3-Methyl-7-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-(1-Isopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-[1-(Cyclobutylmethyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-(1-Ethyl-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-[1-(Cyclopentylmethyl)-1H-pyrazol-4-yl]-3-methy 1-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 2-[4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl]ethanol; 2-[4-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)piperidin-1-yl]ethanol; 4-[7-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 2-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)acetamide; 3-(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)propanamide; 4-[7-(1-Cyclopentyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[3-Methyl-7-(2-methyl-1,3-thiazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[7-(2-Ethoxy-1,3-thiazol-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[(3S)-3-Aminopiperidin-1-yl]-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2 (1H)-yl]pyrimidin-2-amine; 4-(4-Aminopiperid in-1-yl)-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[3-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-piperazin-1-yl pyrimidin-2-amine; 4-(1,4-Diazepan-1-yl)-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(2,5-Diazabicyclo[2.2.1]hept-2-yl)-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(4-Methyl-1,4-diazepan-1-yl)-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(Hexahydropyrrolo[pyrazin-2(1H)-yl)-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-6-fluoro-1,2,3,4-tetrahydrosoquinolin-7-yl}-N-methylpyridine-2-carboxamide; 3-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylbenzamide; 5-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}-2-cyclopropylisoindolin-1-one; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,2-dimethylbenzamide; 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-2H-1,4-benzoxazin-3(4H)-one; 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-4-methyl-2H-1,4-benzoxazin-3(4H)-one; 2-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-methyl-1,3-thiazole-5-carboxamide; 2-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethyl-1,3-thiazole-5-carboxamide; 4-[7-(3H-Imidazo[4,5-b]pyridin-6-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydrosoquinolin-7-yl}-N-cyclopentyl-3,6-dihydropyridine-1(2H)-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydro-2H-bipyridine-4′-carbonitrile; 4-[7-[1-(Cyclopentylacetyl)piperidin-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; Isopropyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-1-carboxylate; 4-{2-[2-Armino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-isopropylpiperidine-1-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylpiperidine-1-carboxamide; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-[1-(Isopropylsulfonyl)piperidin-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N,N-dimethylpiperidine-1-carboxamide; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-ethylpiperidine-1-carboxamide; 4-[7-(1-Acetylpiperidin-4-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; Methyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-1-carboxylate; 4-[3-Methyl-7-[1-(methylsulfonyl)piperidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-(1-propionylpiperidin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-[7-[1-(Cyclopropylcarbonyl)piperidin-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-methylpiperidine-1-carboxamide; 4-[7-[1-(Ethylsulfonyl)piperidin-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 1[(4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridin-2-yl)carbonyl]azetidin-3-ol; 4-[7-(6-{[(3S)-3-Fluoropyrrolidin-1-yl]carbonyl}pyridin-3-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-[3-methyl-7-[1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-[1-(pyridin-4-ylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine; and 6-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-N-ethylpyridine-2-carboxamide; or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof.
47 . A composition comprising a compound of claim 1 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, and a pharmaceutically acceptable carrier.
48 . The composition of claim 47 further comprising one or more therapeutic agents.
49 . The composition of claim 47 further comprising one or more other histamine H1, H2, H3, and/or H4 receptor inhibitors/antagonists.
50 . The composition of claim 47 further comprising one or more other histamine H4 receptor inhibitors/antagonists selected from N-Cyclohexyl-4-(1H-imidazol-4-yl)piperidine-1-carbothioamide, 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole, and 5-Chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-benzimidazole.
51 . A method of modulating histamine H4 receptor comprising contacting said histamine H4 receptor with a compound of claim 1 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof.
52 . The method of claim 51 wherein said modulating comprises inhibiting or antagonizing.
53 . A method of treating a condition or disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein said condition or disease or disorder is selected from an inflammatory disease or disorder, pruritus, and pain.
54 . The method of claim 53 wherein said condition or disease or disorder is selected from allergic rhinitis, asthma, rheumatoid arthritis, atopic dermatitis, idiopathic chronic urticaria, inflammatory pain, neuropathic pain, and osteoarthrtic pain.Join the waitlist — get patent alerts
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