US2013296327A1PendingUtilityA1
Substituted heterocylic compounds
Est. expiryMar 20, 2029(~2.6 yrs left)· nominal 20-yr term from priority
A61P 37/08A61P 29/00A61P 17/02A61P 11/02A61K 45/06C07D 403/12C07D 401/06C07D 239/84A61P 17/04A61K 31/517C07D 401/14C07D 405/12A61P 19/02A61P 11/06A61K 31/506A61P 17/00C07D 417/12C07D 239/95C07D 409/12C07D 239/48
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Claims
Abstract
The present invention relates to substituted heterocyclic compounds of Formula I or XI: 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 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 XI:
or pharmaceutically acceptable salt thereof or N-oxide thereof or quaternary ammonium salt thereof, wherein:
ring A is an aryl or a 5- or 6-membered heteroaryl group wherein ring A is linked to the pyrimidine ring through a carbon atom of ring A, wherein each of the ring-forming atoms of the 5- or 6-membered heteroaryl group is independently selected from C, N, O, and S, and wherein ring A is substituted with 0, 1, 2, or 3 —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 ;
wherein —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 is other than H;
ring B is a 4-20 membered cycloalkyl or heterocycloalkyl group that is fused to ring A, wherein each of the ring-forming atoms of the 4-20 membered heterocycloalkyl group is independently selected from C, N, O, and S, wherein ring B is substituted with 0, 1, 2, 3, 4, 5, or 6 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
wherein —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 is other than H;
ring C is an aryl or a 5- or 6-membered heteroaryl group fused to the pyrimidine ring, wherein each of the ring-forming atoms of the 5- or 6-membered heteroaryl group is independently selected from C, N, O, and S, and wherein ring C is substituted with —C(O)NR 9 R 10 and with 0, 1, 2, or 3 R 8 ;
R 1 is NR 2 R 3 , wherein R 2 and R 3 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 4 ;
each R 4 is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OH, oxo, C 1-6 alkoxy, C 1-6 haloalkoxy, NH 2 , NH(C 1-4 alkyl), NH(C 3-7 cycloalkyl), and N(C 1-4 alkyl) 2 , wherein each of the C 1-6 alkyl and C 3-7 cycloalkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from halo, OH, CN, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
each R 8 is independently selected from selected from halo, CN, NO 2 , OR a4 , SR a4 , SF 5 , 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 a4 C(O)R b4 , NR a4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR g4 )NR c4 R d4 , NR a4 C(═NR g4 )NR c4 R d4 , NR a4 S(O) 2 NR a4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , S(O) 2 NR c4 R d4 , 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, or 5 substituents each independently selected from R 8a , halo, CN, NO 2 , oxo, OR a4 , SR a4 , SF 5 , 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 d4 , NR c4 C(O)OR a4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ;
R 9 and R 10 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, heteroaryl, cycloalkyl, 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, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from R 10a , halo, CN, NO 2 , oxo, 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 9 and R 10 together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from R 10a , halo, CN, NO 2 , oxo, 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ;
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 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(O)NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 C(S)NR e (CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 S(O)(CR 11a R 11b ) p2 , (CR 11a R 11b ) p1 S(O) 2 (CR 11 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 11a 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 e 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 , and S(O) 2 NR c R d ;
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 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 ;
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 ) 2 C(O), S(CR 12a R 12b ) 2 C(O), NR e (CR 12a R 12b ) 2 C(O), NR e (CR 12a R 12b ) 2 NR f , O(CR 12a R 12b )NR f , and O(CR 12a R 12b ) 2 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 , and S(O) 2 NR c R d ;
Z 1 and Z 2 are each, independently, selected from H, 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 , 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 7 , 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 , and S(O) 2 NR c R d ;
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 , and S(O) 2 NR c1 R d1 , 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 , and S(O) 2 NR c1 R d1 ;
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 , and S(O) 2 NR c2 R d2 ;
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 3 , 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 g3 )NR c3 R d3 , NR c3 C(═NR g3 )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 , and S(O) 2 NR c3 R d3 ;
each R 8a 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 , oxo, OR a4 , SR a4 , SF 5 , 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 g4 )NR c4 R d4 , NR c4 C(═NR g4 )NR c4 R d4 , NR c4 S(O) 2 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 ;
each R 10a 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 , oxo, OR a5 , SR a5 , SF 5 , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 a , R a1 , R a2 , R a3 , R a4 , and R a5 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 , R b3 , R b4 , and R b5 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, 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 c and R d are 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, heteroaryl, cycloalkyl, 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, 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, CN, 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 c 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, CN, 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 1-6 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 1-6 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, CN, 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, CN, 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 1-6 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 1-6 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, CN, 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, CN, 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 1-6 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 1-6 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, CN, 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 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, CN, 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 c4 and R d4 are 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, heteroaryl, cycloalkyl, 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, 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, CN, 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 c4 and R d4 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, CN, 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 c5 and R d5 are 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, heteroaryl, cycloalkyl, 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, 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, CN, 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 c5 and R d5 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, CN, 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 e , R e1 , R e2 , R e3 , R e4 , and R e5 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, heteroaryl, cycloalkyl, 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, 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, CN, 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 g , R g1 , R g2 , R g3 , R g4 , and R g5 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; and
each q2 is, independently, 1 or 2,
provided that the moiety of
is other than a moiety of
2 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the ring formed by R 2 and R 3 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 4 , 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 2 and R 3 together with the N atom to which they are attached is a pyrrolidine ring or a piperazine ring, each substituted with 0, 1, 2, 3, 4, or 5 R 4 .
4 . The compound of claim 3 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
the ring formed by R 2 and R 3 together with the N atom to which they are attached is substituted with 0, 1, 2, or 3 R 4 ; and each R 4 is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, NH 2 , NH(C 1-4 alkyl), NH(C 3-7 cycloalkyl), and N(C 1-4 alkyl) 2 , wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl is substituted with 0 or 1 substituent selected from halo, NH 2 , NH(C 1-4 alkyl), C 3-7 cycloalkyl and N(C 1-4 alkyl) 2 .
5 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is selected from formula (A1), (B1), (C1), (D1), and (E1):
6 . The compound of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is 4-methyl-piperazin-1-yl.
7 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring A is phenyl substituted with 0, 1, 2, or 3 —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 .
8 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring A is phenyl substituted with 0 or 1 —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 .
9 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring A is a 6-membered heteroaryl group substituted with 0, 1, 2, or 3 —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 .
10 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring A is a 5-membered heteroaryl group substituted with 0, 1, or 2 —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 .
11 . The compound of Formula I claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each —W 1a —X 1a —W 1 —X 1 —Y 1 —Z 1 is independently selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy.
12 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the fused ring B is a 5-7 membered heterocycloalkyl 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 Formula I of claim 12 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein at least one of the ring-forming atoms of ring B is N.
14 . The compound of Formula I claim 13 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each of the ring-forming atoms of ring B is independently selected from C and N.
15 . The compound of Formula I of claim 14 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring B is substituted with 1 or 2 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
16 . The compound of Formula I claim 14 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein ring B is substituted with 1 —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
17 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the moiety of
is a moiety of
wherein:
R 5 is H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
T 100 is CH 2 , CH(—W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ), C(—W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ) 2 , S, S(O) or —S(O) 2 ;
p20 is 0, 1, or 2; and
p30 is 0 or 1.
18 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the moiety of
is a moiety selected from:
wherein:
each R 5 is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
each R 6 is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
each R 7 is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
each R 5a is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
T 200 is CH 2 , CH(—W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ), C(—W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ) 2 , S, S(O) or S(O) 2 ;
each p101 is 0, 1, or 2; and
each p201 is 0, 1, or 2.
19 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof wherein:
R 1 is selected from formulas (A1), (B1), (C1), (D1), and (E1):
and the moiety of
is a moiety of:
wherein:
p101 is 0, 1, or 2;
p201 is 0, 1, or 2; and
R 5 is H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 .
20 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 1 is 4-methyl-piperazin-1-yl.
21 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof is a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17, III-18, III-19, III-20, III-21, III-22, III-23, III-24, III-25, III-26, III-27, III-28, or III-29:
or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each R 5 is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
each R 7 is independently H or —W 2a —X 2a —W 2 —X 2 —Y 2 —Z 2 ;
T 200 is CH 2 , S, S(O) or S(O) 2 ; and
p201 is 0, 1, or 2.
22 . The compound of Formula I of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof is a compound of Formula III-0-a, III-0-b, or III-1:
wherein R 47 is H, C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, or CN.
23 . The compound of claim 22 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, each R 5 is independently selected from H, Z 2 , —C(O)Z 2 , —C(S)Z 2 , —C(O)NHZ 2 , —C(O)N(C 1-6 alkyl)Z 2 , —C(S)NHZ 2 , —C(S)N(C 1-6 alkyl)Z 2 , —C(O)OZ 2 , —S(O)Z 2 , —S(O)NHZ 2 , —S(O)N(C 1-6 alkyl)Z 2 , —S(O) 2 Z 2 , —S(O) 2 NHZ 2 , and —S(O) 2 N(C 1-6 alkyl)Z 2 ; and each Z 2 is independently selected from 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, each substituted with 0, 1, 2 or 3 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 , and S(O) 2 NR c R d .
24 . The compound of claim 22 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, each R 5 is independently selected from Z 2 , —C(O)Z 2 , —C(S)Z 2 , —C(O)NHZ 2 , —C(O)N(C 1-6 alkyl)Z 2 , —C(S)NHZ 2 , —C(S)N(C 1-6 alkyl)Z 2 , —C(O)OZ 2 , —S(O)Z 2 , —S(O)NHZ 2 , —S(O)N(C 1-6 alkyl)Z 2 , —S(O) 2 Z 2 , —S(O) 2 NHZ 2 , and —S(O) 2 N(C 1-6 alkyl)Z 2 ; and each Z 2 is independently selected from 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, each substituted with 0, 1, 2 or 3 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 , and S(O) 2 NR c R d .
25 . The compound of claim 22 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, each R 5 is independently selected from:
(1) H; (2) aryl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, C(O)OR a , C(O)R b , OR a , C(O)NR c R d , NR c C(O)R d , NR c C(O)OR a , and S(O) 2 R b ; (3) heteroaryl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, Ar, CN, C(O)OR a , C(O)R b , OR a , C(O)NR c R d , NR c C(O)R d , NR c C(O)OR a , and S(O) 2 R b ; (4) —C(O)Z 21 , wherein Z 21 is selected from C 1-6 alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, —OR a , C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ; (5) —S(O) 2 Z 22 , wherein Z 22 is selected from aryl and arylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, —O—Ar, C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ; (6) —C(O)OZ 23 ; wherein Z 23 is selected from C 1-6 alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, —OR a , C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ; (7) —C(O)NZ 24 Z 25 wherein Z 24 and Z 25 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 or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, Ar, HetAr; and (8) —C(O)NZ 26 Z 27 ;
wherein:
Z 26 is selected from H and C 1-6 alkyl;
Z 27 is selected from C 1-6 alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, Ar, HetAr, —OR a , C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
26 . The compound of claim 22 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, each R 5 is independently selected from:
(1) H; (2) phenyl or naphthyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (3) pyradinyl, pyrazinyl, pyrazolyl, 1,3-thiazolyl, 1,3-benzothiazolyl, furanyl, benzofuranyl, thienyl, quinoxalinyl, and 2,1,3-benzothiadiazolyl, each substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, Ar, CN, and C(O)NR c R d ; (4) —C(O)Z 21 , wherein Z 21 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, —OAr, and NR c C(O)OR a ; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, and haloalkyl; (c) phenyl and naphthyl, each substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (d) aryalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, and CN; (e) cycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, NR c C(O)OR a , and CN; (f) heteroarylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , and CN; and (g) heterocycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , CN, C(O)R b , C(O)OR a , and S(O) 2 R b ; (5) —S(O) 2 Z 22 , wherein Z 22 is selected from phenyl, naphthyl, benzyl, phenylethyl, and phenylpropyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, —O—Ar, C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ; (6) —C(O)OZ 23 ; wherein Z 23 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, —OAr, and NR c C(O)OR a ; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, and C 1-6 haloalkyl; (c) phenyl and naphthyl, each substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (d) cycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, NR c C(O)OR a , and CN; and (e) heterocycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , CN, C(O)NR c R d , C(O)R b , C(O)OR a , and S(O) 2 R b ; (7) —C(O)NZ 24 Z 25 wherein Z 24 and Z 25 together with the N atom to which they are attached form a pyrrolidinyl or piperidinyl group, each substituted with 0, 1, 2 or 3 substituents each independently selected from C 1-6 alkyl, Ar, HetAr; and (8) —C(O)NZ 26 Z 27 ;
wherein:
Z 26 is selected from H and C 1-3 alkyl;
Z 27 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, and CN; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, OR a , C(O)R b , C(O)NR c R d , and C(O)OR a ; (c) phenyl and naphthyl, each substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, OR a , HetAr, and CN; (d) arylakyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C(O)NR c R d , halo, and CN; (e) heteroaryl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, OR a , C(O)OR a , halo, NR c R d , Ar, and CN; and (f) heterocycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, C(O)R b , C(O)OR a , Ar, and HetAr;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
27 . The compound of any one of claim 22 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, each R 5 is independently selected from:
(1) H; (2) phenyl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (3) pyrdinyl substituted with 0, 1, 2, or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, Ar, CN, and C(O)NR c R d ; (4) —C(O)Z 21 , wherein Z 21 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, —OAr, and NR c C(O)OR a ; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, and C 1-6 haloalkyl; (c) phenyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (d) arylakyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, and CN; (e) cycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, NR c C(O)OR a , and CN; (f) heteroarylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , and CN; and (g) heterocycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , CN, C(O)R b , C(O)OR a , and S(O) 2 R b ; (5) —S(O) 2 Z 22 , wherein Z 22 is selected from phenyl and benzyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, CN, —O—Ar, C(O)R b , C(O)NR c R d , C(O)OR a , S(O) 2 R b , NR c R d , NR c C(O)R b , and NR c C(O)OR a ; (6) —C(O)OZ 23 ; wherein Z 23 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, —OAr, and NR c C(O)OR a ; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, and C 1-6 haloalkyl; (c) phenyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from 6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, and CN; (d) cycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, NR c C(O)OR a , and CN; and (e) heterocycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, NR c R d , CN, C(O)NR c R d , C(O)R b , C(O)OR a , and S(O) 2 R b ; (7) —C(O)NZ 24 Z 25 wherein Z 24 and Z 25 together with the N atom to which they are attached form a pyrrolidinyl or piperidinyl group, each substituted with 0, 1, 2 or 3 substituents each independently selected from C 1-6 alkyl, Ar, HetAr; and (8) —C(O)NZ 26 Z 27 ;
wherein:
Z 26 is selected from H and C 1-3 alkyl;
Z 27 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, and CN; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, OR a , C(O)R b , C(O)NR c R d , and C(O)OR a ; (c) phenyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, OR a , HetAr, and CN; (d) arylakyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C(O)NR c R d , halo, and CN; (e) heteroaryl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, OR a , C(O)OR a , halo, NR c R d , Ar, and CN; and (f) heterocycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, C(O)R b , C(O)OR a , Ar, and HetAr;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
28 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each W 2a is independently absent, C(O), S(O) 2 , C(O)O, or C(O)NH; and each X 2a is independently C 1-6 alkylenyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, or 6 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 .
29 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each W 2a is independently absent, C(O), S(O), S(O) 2 , C(O)O, C(O)NH, S(O) 2 NH, S(O) 2 N(C 1-6 alkyl), or C(O)N(C 1-6 alkyl); and each —X 2a —W 2 —X 2 —Y 2 —Z 2 is independently C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, or 6 substituents each independently selected from R XX , halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy.
30 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each W 2a is independently absent, C(O), S(O) 2 , C(O)O, or C(O)NH; and each —X 2a —W 2 —X 2 —Y 2 —Z 2 is independently C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, or 6 substituents each independently selected from R XX , halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy.
31 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each W 2a is independently absent, C(O), S(O), S(O) 2 , C(O)O, C(O)NH, S(O) 2 NH, S(O) 2 N(C 1-6 alkyl), or C(O)N(C 1-6 alkyl); and each —X 2a —W 2 —X 2 —Y 2 —Z 2 is independently C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, or 6 substituents each independently selected from R XX , halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy; and each R XX is independently selected from 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 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy.
32 . The compound of claim 19 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
each W 2a is independently absent, C(O), S(O) 2 , C(O)O, or C(O)NH; and each —X 2a —W 2 —X 2 —Y 2 —Z 2 is independently C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with 0, 1, 2, 3, 4, 5, or 6 substituents each independently selected from R XX , halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy; and each R XX is independently selected from 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 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl, —C(O)—(C 1-4 alkyl), —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 2-8 alkoxyalkoxy.
33 . A compound selected from:
4-(4-Methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine; 4-[2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[2-(Cyclobutylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclopentyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-(4-Methylpiperazin-1-yl)-6-[2-(phenylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; Cyclopentyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-(4-Methylpiperazin-1-yl)-6-[2-(pyrrolidin-1-ylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; Isobutyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; Isopropyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-isopropyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-{7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}benzonitrile; 4-{7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}-2-fluorobenzonitrile; 6-{7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}nicotinonitrile; 5-{7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}-N-methylpyridine-2-carboxamide; 4-{6-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyridin-3-yl}benzonitrile; 4-{6-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]pyridin-3-yl}-N-methylbenzamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(3-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-[2-(3-Chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(3-chloro-2-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-[2-(Cyclopentylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[1-(3-methylpyridin-2-yl)piperidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(5-cyanopyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(6-cyanopyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; Methyl 6-({[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}amino)nicotinate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(6-methoxypyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(1-methylcyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(trans-2-phenylcyclopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(1-phenylethyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; Ethyl 4-({[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}amino)piperidine-1-carboxylate; Ethyl cis-2-({[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}amino)cyclohexanecarboxylate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-{4-[(dimethylamino)carbonyl]cyclohexyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(cis-2-methoxycyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(trans-4-methoxycyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-1-Adamantyl-7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1R)-1-benzyl-2-(dimethylamino)-2-oxoethyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-{2-[Difluoro(phenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[2-(4,4,4-trifluoro-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4,4-difluorocyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[4-(trifluoromethyl)cyclohexyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-{2-[(4-Fluorophenyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[(3-Chlorophenoxy)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 1-(Cyclopentylcarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 1-(Isopropoxycarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 1-[(Cyclopentyloxy)carbonyl]piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 1-[(Cyclopentylamino)carbonyl]piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; Isopropyl 4-{2-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}piperidine-1-carboxylate; 4-(2-{[1-(Cyclopropylcarbonyl)piperidin-4-yl]acetyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[(1-Benzoylpiperidin-4-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(2-{[1-(Ethylsulfonyl)piperidin-4-yl]acetyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4-chlorophenyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclohexyl-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4-chlorophenyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclohexyl-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; Tetrahydrofuran-3-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-benzyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclohexyl-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2,3-dihydro-1H-inden-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(3R)-tetrahydrofuran-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(cis)-2-ethoxycyclohexyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(cis)-2-(cyclopropylmethoxy)cyclohexyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-1,3-thiazol-2-yl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 1-(Cyclopentylsulfonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-1,3-benzothiazol-2-yl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(5-phenylpyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4-isopropoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[4-(1H-pyrazol-1-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[1-(methoxymethyl)cyclopentyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(4-phenoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1S)-1,2-dimethylpropyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[(1R)-1,2-dimethylpropyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 4-[2-(3-Methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[2-(3-phenylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; 4-[2-(2-Cyclohexylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-{2-[(4-phenylpiperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-amine; 4-{2[(4,4-Difluoropiperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[2-(Cyclohexylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[2-(Cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-{2-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}benzonitrile; 4-{2-[(6-Chloropyridin-3-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-[2-(Cyclobutylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[2-(tetrahydro-2H-pyran-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; 4-[2-(3-Methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(4-Methylpiperazin-1-yl)-6-[2-(1H-pyrazol-1-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine; Methyl {3-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-1-methyl-3-oxopropyl}carbamate; Methyl {3-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-1-cyclohexyl-3-oxopropyl}carbamate; 1-(Methoxycarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 1-(Ethoxycarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate; 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[1-(trifluoromethyl)cyclopropyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; Methyl 3-{2-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}pyrrolidine-1-carboxylate; Isopropyl 3-{2-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}pyrrolidine-1-carboxylate; 1-{2-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}cyclobutanecarbonitrile; 4-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2,2-dimethyl-4-oxobutanenitrile; 1-{2-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}cyclopentanecarbonitrile; 4-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-cyclopropyl-2-methyl-4-oxobutanenitrile; 4-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxo-2-phenylbutanenitrile; 5-{2-[7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}nicotinonitrile; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(1-pyridin-3-ylethyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 7-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-[1-(1-methyl-1H-pyrazol-3-yl)ethyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; and 4-(4-Methylpiperazin-1-yl)-6-{2-[(6-pyrrolidin-1-ylpyridin-3-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-amine; or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof.
34 . The compound of Formula XI of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the fused ring C is an aryl group substituted with —C(O)NR 9 R 10 and with 0, 1, 2, or 3 R 8 .
35 . The compound of Formula XI of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the fused ring C is a phenyl group substituted with —C(O)NR 9 R 10 and with 0, or 1 R 8 .
36 . The compound of Formula XI of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the fused ring C is a 5- or 6-membered heteroaryl group substituted with —C(O)NR 9 R 10 and with 0, 1, 2, or 3 R 8 .
37 . The compound of Formula XI of claim 1 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each R 8 is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OR a4 , SR a4 , SF 5 , 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 d4 , NR c4 C(O)OR a4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 , wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from 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 d4 , NR c4 C(O)OR a4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 .
38 . The compound of Formula XI of claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each R 8 is independently selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy.
39 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is selected from H and C 1-6 alkyl; R 10 is selected from H, C 1-6 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 1-6 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 R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ; and
40 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is selected from H and C 1-6 alkyl; and R 10 is selected from C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
41 . The compound of Formula XI of claim 38 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is selected from H and C 1-6 alkyl; and
R 10 is selected from arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
42 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is selected from H and C 1-6 alkyl; and R 10 is selected from arylalkyl and cycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
43 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is H; and R 10 is —(CR 10b R 10c ) p33 R 10d ; R 10b and R 10c are each, independently, H or C 1-3 alkyl; R 10d is aryl or cycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ; and p33 is 0, 1, 2, 3, or 4.
44 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein:
R 9 is H; and R 10 is —(CR 10b R 10c ) p33 R 10d ; R 10b and R 10c are each, independently, H or methyl; R 10d is aryl or cycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ; and p33 is 0, 1, 2, 3, or 4.
45 . The compound of Formula XI of claim 38 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein R 9 and R 10 together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from R 10a , halo, CN, NO 2 , oxo, 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
46 . The compound of Formula XI of claim 44 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each R 10a 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 a5 , SR a5 , SF 5 , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
47 . The compound of Formula XI of claim 45 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein each R 10a 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 halo, CN, NO 2 , OR a5 , SR a5 , SF 5 , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 .
48 . The compound of Formula XI of claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula XI is a compound of Formula XI-1:
wherein:
R 1 is selected from formulas (A1), (B1), (C1), (D1), and (E1):
R 8 is selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 9 is selected from H and C 1-6 alkyl;
R 10 is selected from arylalkyl and cycloalkylalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10a , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 NR 6 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 ;
each R 10a 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 a5 , SR a5 , SF 5 , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ; and
p31 is 0 or 1.
49 . The compound of Formula XI claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula XI is a compound of Formula XI-1:
wherein:
R 1 is selected from formulas (A1), (B1), (C1), (D1), and (E1):
R 8 is selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 9 is H; and
R 10 is —(CR 10b R 10c ) p33 R 10d ;
R 10b and R 10c are each, independently, H or methyl;
R 10d is aryl or cycloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from R 10 CN, OR a5 , Se, 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ;
p33 is 0, 1, 2, 3, or 4;
each R 10a 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 a5 , SR a5 , SF 5 , 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 g5 )NR c5 R d5 , NR c5 C(═NR g5 )NR c5 R d5 , NR c5 S(O) 2 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 ; and
p31 is 0 or 1.
50 . The compound of claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula XI-1 is a compound of Formula XI-2 or XI-2a:
wherein:
R 8 is selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 9 is H or C 1-4 alkyl;
R 10 is selected from (a) C 1-6 alkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, C(O)OR a , —OAr, and NR c C(O)OR a ; (b) C 3-10 cycloalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from halo, CN, Ar, HetAr, —O—Ar, —O-HetAr, —O-L d -Ar, —O-L 1 -HetAr, C 1-6 alkyl, and C 1-6 haloalkyl; (c) aryl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, and CN; (d) arylakyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, Ar, HetAr, halo, CN, —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr; (e) cycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, NR c C(O)OR a , and CN; and (f) heteroarylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)NR c R d , Ar, NR c C(O)OR a , halo, NR c R d , and CN; and (g) heterocycloalkylalkyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c C(O)OR a , halo, Ar, NR c R d , CN, —C(O)NR c R d , C(O)R b , C(O)OR a , and S(O) 2 R b ;
or R 9 and R 10 together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group that is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, Ar, HetAr, halo, CN, —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
L d is selected from C 1-4 alkylenyl and —C(O)NH—, wherein the C 1-4 alkylenyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, and CN;
p31 is 0 or 1;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
51 . The compound of claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula XI-1 is a compound of Formula XI-2 or XI-2a:
wherein:
R 8 is selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 3-7 cycloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy;
the moiety of
is a moiety of M1, M2, M3, M4, M5, M6, M7, or M8:
R 12 is C 1-4 alkyl;
R 13 is C 1-4 alkyl;
R 14 is Ar or HetAr;
R 21 is C 1-4 alkyl;
R 22 is C 1-4 alkyl;
R 118 is selected from C 3-10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, each substituted with substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, Ar, HetAr, halo, CN, NR c C(O)OR a , NR c R d , C(O)R b , S(O) 2 R b , —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
R 119 is selected from Ar, HetAr, —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
R 120 is selected from Ar, HetAr, —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
L d is selected from C 1-4 alkylenyl and —C(O)NH—, wherein the C 1-4 alkylenyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, and CN;
p31 is 0 or 1;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
52 . The compound of claim 35 , or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, wherein the compound of Formula XI-1 is a compound of Formula XI-2 or XI-2a:
wherein:
R 8 is selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
the moiety of
is a moiety of M1, M2, M3, M4, M5, M6, M7, or M8:
R 12 is C 1-4 alkyl;
R 13 is C 1-4 alkyl;
R 14 is Ar or HetAr;
R 21 is C 1-4 alkyl;
R 22 is C 1-4 alkyl;
R 118 is selected from aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each substituted with substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, Ar, HetAr, halo, CN, NR c C(O)OR a , NR c R d , C(O)R b , S(O) 2 R b , —OR a , —OC(O)NR c R d , —C(O)OR a , —C(O)NR c R d , —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
R 119 is selected from —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
R 120 is selected from —O—Ar, —O-HetAr, —O-L d -Ar, and —O-L d -HetAr;
p31 is 0 or 1;
L d is selected from C 1-4 alkylenyl and —C(O)NH—, wherein the C 1-4 alkylenyl is substituted with 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from C 1-4 alkyl and halo;
each Ar is independently aryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a , and
each HetAr is independently heteroaryl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C(O)OR a .
53 . A compound selected from:
(R)-2-amino-4-(4-methylpiperazin-1-yl)-N-(1-(naphthalen-2-yl)ethyl)quinazoline-7-carboxamide; (S)-2-amino-4-(4-methylpiperazin-1-yl)-N-(1-(naphthalen-2-yl)ethyl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(1-phenylethyl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(1-phenylethyl)quinazoline-7-carboxamide; 2-amino-N-(cyclopropylmethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-methyl-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-(3-chlorophenyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-[1-(4-isobutylphenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-[1-(4-henoxyphenyl)ethyl]quinazoline-7-carboxamide; 2-amino-N-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-[1-(4-bromophenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-[(1S)-1-(4-methylphenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(4-phenoxyphenyl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(4-phenoxybenzyl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(4-phenoxyphenyl)quinazoline-7-carboxamide; 2-amino-N-(3-chloro-4-methylbenzyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(2-phenylethyl)quinazoline-7-carboxamide; 2-amino-4-(4-methylpiperazin-1-yl)-N-(3-phenylpropyl)quinazoline-7-carboxamide; 2-Amino —N-[cyano(phenyl)methyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Ethyl (2S)-2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-4-phenylbutanoate; 2-Amino —N-(3,4-dichlorobenzyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Benzyl ({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7yl]carbonyl}amino)acetate; Methyl (2S)-2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-3-(4-isopropoxyphenyl)propanoate; (S)-Methyl 2-(2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamido)-3-(4-(isopropylcarbamoyloxy)phenyl)propanoate; (S)-2-Amino —N-(1-(dimethylamino)-3-(4-isopropoxyphenyl)-1-oxopropan-2-yl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-1-cyano-2-(4-isopropoxyphenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl (2S)-2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-3-biphenyl-4-ylpropanoate; 2-Amino —N-[(1S)-1-(biphenyl-4-ylmethyl)-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl (2S)-2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7yl]carbonyl}amino)-3-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propanoate; 2-Amino —N-[2-(1-benzofuran-2-yl)-1-methylethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-methyl-2-(4-phenoxyphenyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{2-[4-(cyclopentyloxy)phenyl]-1-methylethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-(1,3-benzothiazol-2-ylmethyl)-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[2-(dimethylamino)-2-oxo-1-(3-phenoxybenzyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{2-(dimethylamino)-2-oxo-1-[(5-phenyl-2-thienyl)methyl]ethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{(1S)-2-(dimethylamino)-2-oxo-1-[4-(2-thienyl)benzyl]ethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[2-(dimethylamino)-1-(4-isopropylbenzyl)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{2-(dimethylamino)-2-oxo-1-[4-(trifluoromethyl)benzyl]ethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-amino-N-[2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{(1S)-2-(dimethylamino)-1-[(2′-methoxybiphenyl-4-yl)methyl]-2-oxoethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-{(1S)-2-(dimethylamino)-1-[4-(6-methoxypyridin-2-yl)benzyl]-2-oxoethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-1-[(3′-cyanobiphenyl-4-yl)methyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-1-[4-(5-cyanopyridin-2-yl)benzyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-1-[4-(5-cyanopyridin-3-yl)benzyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[(1S)-1-{4-[3-cyano-6-(trifluoromethyl)pyridin-2-yl]benzyl}-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 4′-[(2S)-2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-3-(dimethylamino)-3-oxopropyl]biphenyl-3-carboxylate; 2-Amino —N-((1S)-2-(dimethylamino)-1-{[4′-fluoro-3′-(trifluoromethyl)biphenyl-4-yl]methyl}-2-oxoethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-2-(dimethylamino)-2-oxo-1-(4-pyridin-2-ylbenzyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-((1S)-2-(dimethylamino)-2-oxo-1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzyl}ethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[(1S)-1-[(2′,3′-dichlorobiphenyl-4-yl)methyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-{[6-(2,3-difluorophenyl)pyridin-3-yl]methyl}-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-(-2-(dimethylamino)-1-{[6-(4-methoxyphenyl)pyridin-3-yl]methyl}-2-oxoethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 4-[(2S)-2-({[2-Amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-3-(dimethylamino)-3-oxopropyl]phenyl (3-chlorophenyl)carbamate; 2-Amino —N-{2-(dimethylamino)-1-[3-(4-methoxyphenoxy)benzyl]-2-oxoethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-[3-(3,5-dichlorophenoxy)benzyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[1-{3-[(4-chloro-1,2,5-thiadiazol-3-yl)oxy] benzyl]-2-(dimethylamino)-2-oxoethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 4-{3-[2-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)-3-(dimethylamino)-3-oxopropyl]phenoxy} benzoate; 2-Amino —N-[1-[3-(2-cyano-5-methoxyphenoxy)benzyl]-2-(dimethylamino)-2-oxo ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[1-{3-[5-cyano-2-(trifluoromethyl)phenoxy]benzyl}-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[1-[3-(4-chloro-2-cyanophenoxy)benzyl]-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[1-{3-[(3-cyano-6-methylpyridin-2-yl)oxy]benzyl}-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-(3-(3-(3-cyanophenoxy)phenyl)-1-(dimethylamino)-1-oxopropan-2-yl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[1-{3-[(3-cyanobenzyl)oxy]benzyl}-2-(dimethylamino)-2-oxoethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[2-(dimethylamino)-2-oxo-1-(3-{1-[3-(trifluoromethyl)phenyl]ethoxy}benzyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[2-(dimethylamino)-2-oxo-1-(3-{[4-(trifluoromethoxy)benzyl]oxy} benzyl)ethyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[3-(4-methoxyphenoxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 4-{3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}benzoate; 2-Amino —N-[3-(2-cyano-5-methoxyphenoxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[3-(isoquinolin-1-yloxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-4-(4-methylpiperazin-1-yl)-N-{3-[(4-methylpyridin-2-yl)oxy]benzyl}quinazoline-7-carboxamide; 2-Amino —N-{3-[(4-cyanopyridin-2-yl)oxy]benzyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Ethyl 2-{3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}nicotinate; Ethyl 2-{3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}-4-methyl-1,3-thiazole-5-carboxylate; Ethyl 2-{3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}-3-cyano-6-methylisonicotinate; 2-Amino —N-{3-[(3,6-dimethylpyrazin-2-yl)oxy]benzyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-4-(4-methylpiperazin-1-yl)-N-[3-(quinoxalin-2-yloxy)benzyl]quinazoline-7-carboxamide; 2-Amino-N-[3-(2-cyano-3-methylphenoxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-[3-(2-cyano-3-methoxyphenoxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 2-{3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}benzoate; 2-amino-N-(3-(3-cyanobenzyloxy)benzyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 4-({3-[({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)methyl]phenoxy}methyl)benzoate; 2-Amino-N-{3-[(3,5-dimethoxybenzyl)oxy]benzyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-[3-(2,1,3-benzothiadiazol-4-ylmethoxy)benzyl]-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-4-(4-methylpiperazin-1-yl)-N-(3-{1-[3-(trifluoromethyl)phenyl]ethoxy} benzyl)quinazoline-7-carboxamide; 2-Amino —N-{1-[3-(4-chloro-2-cyanophenoxy)phenyl]ethyl}-4-(4-methylpiperazin-1-yl)quinazoline-7-c arboxamide; 2-Amino-N-(1-{3-[(3-cyano-6-methylpyridin-2-yl)oxy]phenyl}ethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino-N-(1-{3-[(3-cyanopyridin-2-yl)oxy]phenyl}ethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 3-({3-[1-({[2-amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl]carbonyl}amino)ethyl]phenoxy}methyl)benzoate; 2-Amino-N-(1-{3-[(3-cyanobenzyl)oxy]phenyl}ethyl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; 2-Amino —N-(7-(3-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(4-methylpiperazin-1-yl)quinazoline-7-c arboxamide; 2-Amino —N-(7-(3-methoxybenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamide; Methyl 3-((8-(2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)benzoate; 2-Amino —N-(7-(4-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(4-methylpiperazin-1-yl)quinazoline-7-c arboxamide; Methyl 4-((8-(2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)benzoate; 3-((2-(2-Amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl)benzonitrile; (2-Amino-4-(4-methylpiperazin-1-yl)quinazolin-7-yl)(5-(3-methoxybenzyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; Methyl 3-((2-(2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl)benzoate; 4-((2-(2-Amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl)benzonitrile; and Methyl 4-((2-(2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl)benzoate; or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof.
54 . 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.
55 . A composition comprising a compound of claim 25 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, and a pharmaceutically acceptable carrier.
56 . A composition comprising a compound of claim 50 or pharmaceutically acceptable salt or N-oxide or quaternary ammonium salt thereof, and a pharmaceutically acceptable carrier.
57 . The composition of claim 54 further comprising one or more therapeutic agents.
58 . The composition of claim 54 further comprising one or more other histamine H1, H2, H3, and/or H4 receptor inhibitors/antagonists.
59 . The composition of claim 54 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.
60 . 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.
61 . The method of claim 60 wherein said modulating comprises inhibiting or antagonizing
62 . 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.
63 . The method of claim 62 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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