1. A compound of Formula (I) and Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
A1, A2, and A3 are selected from the group consisting of:
(1) CH and
(2) N;
B1 is aryl or heteroaryl;
R1 and R2 are independently selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6alkyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3alkyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) \u2014C(O)-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(9) \u2014C(O)-heterocycle, wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) \u2014NR4R5,
(11) \u2014C1-4allyl-NR4R5,
(12) \u2014C1-4allyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(13) \u2014C1-4allyl-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(14) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(15) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(16) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(17) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(18) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(19) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6, and
(20) \u2014C3-6cycloalkyl, optionally mono, di- or tri-substituted with substituents selected \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, oxo, C(O)\u2014O\u2014C(CH3)3, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN;
R3 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4alkyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014OC1-6allyl;
(6) \u2014CN,
(7) \u2014CHF2,
(8) \u2014O\u2014CF3,
(9) hydroxy,
(10) \u2014S(O)2\u2014CH3,
(11) \u2014C(O)\u2014O\u2014C1-6alkyl,
(12) \u2014C(O)\u2014NHC1-6alkyl,
(13) \u2014C(O)\u2014N(C1-6alkyl)2,
(14) \u2014C(O)\u2014O\u2014C(CH3)3,
(15) \u2014C(O)-heteroaryl,
(16) \u2014C3-6cycloalkyl,
(17) \u2014NH2,
(18) \u2014NH2\u2014C(O)\u2014CF3,
(19) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(20) \u2014NC(O)\u2014NH2,
(21) \u2014NH\u2014S(O)2\u2014CH3,
(22) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(23) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7;
R4 is selected from the group consisting of hydrogen and methyl;
R5 is selected from the group consisting of
(1) C1-4allyl, optionally mono or di-substituted, with substituents independently selected from the group consisting of C3-6cycloalkyl, \u2014CF3, heteroaryl, \u2014C1-3alkyl-CF3, CH3, hydroxy, tetrahydrofuran, and
(2) \u2014C1-3alkyl-C3-6cycloallyl, wherein the cycloalkyl is optionally mono or di-substituted with substituents independently selected from the group consisting of halo, CF3, CH3, C1-3alkyl, \u2014OC1-6alkyl, or
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6allyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6alkyl;
R6 is selected from the group consisting of \u2014CN, \u2014CH3, \u2014CF3, \u2014CHF2, \u2014CO1-6alkyl, \u2014O\u2014CF3, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6allyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6allyl)2, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, and \u2014NH\u2014S(O)2\u2014CH3, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
R7 is selected from the group consisting of \u2014CH3, hydroxy, OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014(O)\u2014O\u2014C(CH3)3, C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6allyl;
provided that when the compound is of Formula (II), and B1 is optionally substituted aryl, then R2 is other than hydrogen, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl or NR4R5 wherein both of R4 and R5 are hydrogen, or unsubstituted alkyl.
2. A compound according to claim 1 wherein
R1 is selected from the group consisting of:
(1) H
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6alkyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3alkyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(9) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(11) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(12) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(13) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6.
3. A compound according to claim 1 wherein
R2 is selected from a group consisting of:
(1) halo,
(2) \u2014CF3,
(3) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(4) \u2014C(O)\u2014NH\u2014C1-3allyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(5) \u2014C(O)-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(6) \u2014C(O)-heterocycle, wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(7) \u2014NR4R5,
(8) \u2014C1-4alkyl-NR4R5,
(9) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) \u2014C1-4alkyl-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(11) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(12) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(13) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(14) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(15) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(16) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6, and
(17) \u2014C3-6cycloalkyl, optionally mono, di- or tri-substituted with substituents selected \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6allyl)2, oxo, C(O)\u2014O\u2014C(CH3)3, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014CF3 and \u2014CN.
4. A compound according to claim 3 wherein
R2 is selected from the group consisting of:
(1) \u2014CF3,
(2) \u2014NR4R5,
(3) \u2014C1-4allyl-NR4R5,
(4) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(5) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6.
5. A compound according to claim 1 wherein
R3 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4alkyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014OC1-6alkyl;
(6) \u2014CN,
(7) \u2014CHF2,
(8) \u2014O\u2014CF3,
(9) \u2014S(O)2\u2014CH3,
(10) \u2014C(O)\u2014O\u2014C1-6alkyl,
(11) \u2014C(O)\u2014NHC1-6alkyl,
(12) \u2014C(O)\u2014N(C1-6alkyl)2,
(13) \u2014C(O)\u2014O\u2014C(CH3)3,
(14) \u2014C(O)-heteroaryl,
(15) \u2014C3-6cycloalkyl,
(16) \u2014NH2\u2014C(O)\u2014CF3,
(17) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(18) \u2014NC(O)\u2014NH2, and
(19) \u2014NH\u2014S(O)2\u2014CH3.
6. A compound according to claim 5 wherein
R3 is sleeted from a group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4alkyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014CN,
(6) \u2014S(O)2\u2014CH3,
(7) \u2014C(O)\u2014NHC1-6alkyl,
(8) \u2014C(O)\u2014N(C1-6alkyl)2,
(9) \u2014NH2\u2014C(O)\u2014CF3,
(10) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(11) \u2014NC(O)\u2014NH2, and
(12) \u2014NH\u2014S(O)2\u2014CH3.
7. A compound according to claim 1 wherein
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6alkyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6alkyl.
8. A compound according to claim 1 wherein
A1, A2, and A3 are selected from the group consisting of:
(1) CH and
(2) N;
B1 is aryl or heteroaryl;
R1 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6allyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3alkyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(9) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(11) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(12) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(13) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6;
R2 is selected from a group consisting of
(1) halo,
(2) \u2014CF3,
(3) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(4) \u2014C(O)\u2014NH\u2014C1-3alkyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(5) \u2014C(O)-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(6) \u2014C(O)-heterocycle, wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(7) \u2014NR4R5,
(8) \u2014C1-4alkyl-NR4R5,
(9) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) \u2014C1-4alkyl-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(11) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(12) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(13) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(14) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(15) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(16) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6, and
(17) \u2014C3-6cycloalkyl, optionally mono, di- or tri-substituted with substituents selected \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, oxo, C(O)\u2014O\u2014C(CH3)3, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN;
R3 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4alkyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014OC1-6alkyl;
(6) \u2014CN,
(7) \u2014CHF2,
(8) \u2014O\u2014CF3,
(9) \u2014S(O)2\u2014CH3,
(10) \u2014C(O)\u2014O\u2014C1-6alkyl,
(11) \u2014C(O)\u2014NHC1-6alkyl,
(12) \u2014C(O)\u2014N(C1-6alkyl)2,
(13) \u2014C(O)\u2014O\u2014C(CH3)3,
(14) \u2014C(O)-heteroaryl,
(15) \u2014C3-6cycloallyl,
(16) \u2014NH2\u2014C(O)\u2014CF3,
(17) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(18) \u2014NC(O)\u2014NH2, and
(19) \u2014NH\u2014S(O)2\u2014CH3;
R4 is selected from the group consisting of hydrogen and methyl;
R5 is selected from the group consisting of:
(1) C1-4alkyl, optionally mono or di-substituted, with substituents independently selected from the group consisting of C3-6cycloallyl, \u2014CF3, heteroaryl, \u2014C1-3alkyl-CF3, CH3, hydroxy, tetrahydrofuran, and
(2) \u2014C1-3alkyl-C3-6cycloalkyl, wherein the cycloalkyl is optionally mono or di-substituted with substituents independently selected from the group consisting of halo, CF3, CH3, C1-3alkyl, \u2014OC1-6alkyl, or
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6allyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6allyl;
R6 is selected from the group consisting of \u2014CN, \u2014CH3, \u2014CF3, \u2014CHF2, \u2014OC1-6alkyl, \u2014O\u2014CF3, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, and \u2014NH\u2014S(O)2\u2014CH3, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6allyl;
R7 is selected from the group consisting of \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6allyl)2, \u2014(O)\u2014O\u2014C(CH3)3, C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
provided that when the compound is of Formula (II), and B1 is optionally substituted aryl, then R2 is other than hydrogen, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl or NR4R5 wherein both of R4 and R5 are hydrogen, or unsubstituted alkyl.
9. A compound according to claim 1 wherein
A1, A2, and A3 are selected from the group consisting of:
(1) CH and
(2) N;
B1 is aryl or heteroaryl;
R1 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6alkyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3allyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(9) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(11) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(12) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(13) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6;
R2 is selected from the group consisting of:
(1) \u2014CF3,
(2) \u2014NR4R5,
(3) \u2014C1-4alkyl-NR4R5,
(4) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(5) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6;
R3 is sleeted from a group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4allyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014CN,
(6) \u2014S(O)2\u2014CH3,
(7) \u2014C(O)\u2014NHC1-6alkyl,
(8) \u2014C(O)\u2014N(C1-6alkyl)2,
(9) \u2014NH2\u2014C(O)\u2014CF3,
(10) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(11) \u2014NC(O)\u2014NH2, and
(12) \u2014NH\u2014S(O)2\u2014CH3;
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6allyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6allyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6allyl;
R6 is selected from the group consisting of \u2014CN, \u2014CH3, \u2014CF3, \u2014CHF2, \u2014OC1-6alkyl, \u2014O\u2014CF3, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, and \u2014NH\u2014S(O)2\u2014CH3, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
R7 is selected from the group consisting of \u2014CH3, \u2014O\u2014C1-6allyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6allyl)2, \u2014(O)\u2014O\u2014C(CH3)3, C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl.
10. A compound of Formula (Ia) and Formula (IIa), or a pharmaceutically acceptable salt thereof, wherein
B1 s aryl or heteroaryl;
R1 and R2 are independently selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6alkyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3allyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) \u2014C(O)-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(9) \u2014C(O)-heterocycle, wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) \u2014NR4R5,
(11) \u2014C1-4alkyl-NR4R5,
(12) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6,
(13) \u2014C1-4alkyl-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(14) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(15) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(16) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(17) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(18) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(19) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6, and
(20) \u2014C3-6cycloalkyl, optionally mono, di- or tri-substituted with substituents selected \u2014CH3, \u2014O\u2014C1-6allyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6allyl, \u2014C(O)\u2014N(C1-6alkyl)2, oxo, C(O)\u2014O\u2014C(CH3)3, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN;
R3 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4alkyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014OC1-6alkyl;
(6) \u2014CN,
(7) \u2014CHF2,
(8) \u2014O\u2014CF3,
(9) hydroxy,
(10) \u2014S(O)2\u2014CH3,
(11) \u2014C(O)\u2014O\u2014C1-6alkyl,
(12) \u2014C(O)\u2014NHC1-6alkyl,
(13) \u2014C(O)\u2014N(C1-6alkyl)2,
(14) \u2014C(O)\u2014O\u2014C(CH3)3,
(15) \u2014C(O)-heteroaryl,
(16) \u2014C3-6cycloalkyl,
(17) \u2014NH2,
(18) \u2014NH2\u2014C(O)\u2014CF3,
(19) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(20) \u2014NC(O)\u2014NH2,
(21) \u2014NH\u2014S(O)2\u2014CH3,
(22) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(23) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7;
R4 is selected from the group consisting of hydrogen and methyl;
R5 is selected from the group consisting of:
(1) C1-4alkyl, optionally mono or di-substituted, with substituents independently selected from the group consisting of C3-6cycloalkyl, \u2014CF3, heteroaryl, \u2014C1-3alkyl-CF3, CH3, hydroxy, tetrahydrofuran, and
(2) \u2014C1-3alkyl-C3-6cycloalkyl, wherein the cycloalkyl is optionally mono or di-substituted with substituents independently selected from the group consisting of halo, CF3, CH3, C1-3allyl, \u2014OC1-6alkyl, or
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6allyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6alkyl;
R6 is selected from the group consisting of \u2014CN, \u2014CH3, \u2014CF3, \u2014CHF2, \u2014OC1-6alkyl, \u2014O\u2014CF3, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, and \u2014NH\u2014S(O)2\u2014CH3, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
R7 is selected from the group consisting of \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014(O)\u2014O\u2014C(CH3)3, C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
provided that when the compound is of Formula (II), and B1 is optionally substituted aryl, then R2 is other than hydrogen, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl or NR4R5 wherein both of R4 and R5 are hydrogen, or unsubstituted alkyl.
11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein
B1 is aryl or heteroaryl;
R1 is selected from the group consisting of:
(1) H,
(2) halo,
(3) \u2014CN,
(4) \u2014CF3,
(5) \u2014C1-6alkyl,
(6) \u2014C(O)\u2014NH\u2014C1-3alkyl-CF3,
(7) \u2014C(O)\u2014NH\u2014C1-3alkyl-heteroaryl, wherein the heteroaryl is optionally mono, di or tri-substituted with substituents independently selected from R6,
(8) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(9) heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6,
(10) aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(11) O-aryl, optionally mono, di- or tri-substituted with substituents independently selected from R7,
(12) \u2014O-heteroaryl, optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(13) \u2014NH-heteroaryl, wherein the heteroaryl is optionally mono, di- or tri-substituted with substituents independently selected R6;
R2 is selected from the group consisting of:
(1) \u2014CF3,
(2) \u2014NR4R5,
(3) \u2014C1-4allyl-NR4R5,
(4) \u2014C1-4alkyl-heterocycle, wherein the alkyl is optionally substituted with hydroxyl and wherein the heterocycle is optionally mono, di- or tri-substituted with substituents independently selected from R6, and
(5) heterocycle, optionally mono, di- or tri-substituted with substituents independently selected from R6;
R3 is sleeted from a group consisting of:
(1) H,
(2) halo,
(3) \u2014C1-4allyl, optionally substituted with hydroxyl,
(4) \u2014CF3, and
(5) \u2014CN,
(6) \u2014S(O)2\u2014C1-13,
(7) \u2014C(O)\u2014NHC1-6allyl,
(8) \u2014C(O)\u2014N(C1-6alkyl)2,
(9) \u2014NH2\u2014C(O)\u2014CF3,
(10) \u2014NH2\u2014C(O)\u2014N(CH3)2,
(11) \u2014NC(O)\u2014NH2, and
(12) \u2014NH\u2014S(O)2\u2014CH3;
R4 and R5 are joined together so that along with the nitrogen to which they are attached, there is formed a heterocycle, wherein said heterocycle is optionally mono, di or tri-substituted with substituents independently selected from the group consisting of \u2014OC1-6allyl, \u2014NH\u2014C(O)\u2014O\u2014C(CH3)3, hydroxy, \u2014CH3, \u2014CF3, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014N(CH3)2, oxo, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloallyl, \u2014NH2, \u2014NH\u2014C(O)\u2014CF3, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014S\u2014CH3, and wherein the heteroaryl portion of \u2014C(O)-heteroaryl is optionally mono- di- or tri-substituted with substituents selected from the group consisting of halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014O\u2014C1-6alkyl;
R6 is selected from the group consisting of \u2014CN, \u2014CH3, \u2014CF3, \u2014CHF2, \u2014OC1-6alkyl, \u2014O\u2014CF3, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, \u2014C(O)\u2014O\u2014C1-6allyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014C(O)\u2014O\u2014C(CH3)3, \u2014C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, and \u2014NH\u2014S(O)2\u2014CH3, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl;
R7 is selected from the group consisting of \u2014CH3, \u2014O\u2014C1-6alkyl, hydroxy, \u2014CH2\u2014OH, halo, \u2014S(O)2\u2014CH3, C(O)\u2014O\u2014C1-6alkyl, \u2014C(O)\u2014NHC1-6alkyl, \u2014C(O)\u2014N(C1-6alkyl)2, \u2014(O)\u2014O\u2014C(CH3)3, C(O)-heteroaryl, \u2014C3-6cycloalkyl, \u2014NH2, \u2014NH2\u2014C(O)\u2014CF3, \u2014NH2\u2014C(O)\u2014N(CH3)2, \u2014NC(O)\u2014NH2, \u2014NH\u2014S(O)2\u2014CH3, \u2014O\u2014CF3, \u2014CF3 and \u2014CN, wherein the heteroaryl portion of \u2014C(O)-heteroaryl, is optionally mono or di-substituted with substituents independently selected from halo, \u2014CH3, \u2014CF3, \u2014CN and \u2014OC1-6alkyl.
12. A compound according to claim 1 including:
2-1-(morpholin-4-ylmethyl)imidazo1,5-apyridin-3-yl-1H-benzimidazole;
1-(4,4-difluoropiperidin-1-yl)methyl-3-(4-phenyl-1H-imidazol-2-yl) imidazo1,5-apyridine;
3-4-(4-chlorophenyl)-1H-imidazol-2-yl-1-(4,4-difluoropiperidin-1-yl)methylimidazo1,5-apyridine;
3-4-(2,4-dichlorophenyl)-1H-imidazol-2-yl-1-(4,4-difluoropiperidin-1-yl)methylimidazo1,5-apyridine;
3-4-(3,4-difluorophenyl)-1H-imidazol-2-yl-1-(4,4-difluoropiperidin-1-yl)methylimidazo1,5-apyridine;
1-(4,4-difluoropiperidin-1-yl)methyl-3-{4-3-(trifluoromethyl)phenyl-1H-imidazol-2-yl}imidazo1,5-apyridine;
3-3-(4-fluorophenyl)-1H-pyrazol-5-yl-1-(morpholin-4-ylmethyl) imidazo1,5-apyridine;
3-3-(2-chlorophenyl)-1H-pyrazol-5-yl-1-(morpholin-4-ylmethyl) imidazo1,5-apyridine;
1-(morpholin-4-ylmethyl)-3-{3-3-(trifluoromethyl)phenyl-1H-pyrazol-5-yl}imidazo1,5-Apyridine;
1-(4,4-difluoropiperidin-1-yl)methyl-3-3-(trifluoromethyl)phenylimidazo1,5-apyridine;
1,1-dicyclopropyl-N-{3-(4-fluorophenyl) imidazo1,5-apyridin-1-ylmethyl}methanamine;
2,2,2-trifluoro-N-{3-(4-fluorophenyl) imidazo1,5-apyridin-1-ylmethyl}-1-pyridin-2-ylethanamine;
1-(4,4-difluoropiperidin-1-yl)methyl-3-4-(1H-pyrazol-5-yl)phenylimidazo1,5-apyridine;
3-(1-benzyl-1H-pyrazol-4-yl)-1-(4,4-difluoropiperidin-1-yl)methylimidazo1,5-apyridine;
4-(4-{1-(4,4-difluoropiperidin-1-yl)methylimidazo1,5-apyridin-3-yl}phenyl)-2-methylbutan-2-ol;
1-(4,4-difluoropiperidin-1-yl)methyl-3-3-(1H-pyrazol-1-yl)phenylimidazo1,5-apyridine;
pharmaceutically acceptable salts and enantiomers thereof
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14. A method of modulating the CB2 receptor in a patient in need of such modulation, comprising administering an effective amount of a compound according to claim 1.
15. A method of agonizing the CB2 receptor in a patient in need of such agonizing, comprising administering an effective amount of a compound according to claim 1.
16. A method of treating a disease mediated by agonizing the CB2 receptor in a patient in need of such treatment, comprising administering an effective amount of a compound according to claim 1.
17. A method of treating a disease selected from the group consisting of inflammatory pain, neuropathic pain, osteoporosis, atherosclerosis, immune disorders and arthritis comprising administering an effective amount of a compound according to claim 1.
18. A method according to claim 16, for the treatment of acute and chronic pain.
19. A method according to claim 17, for the treatment of inflammatory and neuropathic pain.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A cutting blade comprising:
a blade body having two face surfaces, a portion of each face surface being generally planar and extending generally in parallel to the other flat portion, and a cutting edge surface extending between the face surfaces;
a plurality of cutting tips located at the cutting edge surface; and
a generally planar layer of abrasive metal particles on a region of the generally flat portion of at least one of the face surfaces.
2. The blade of claim 1 wherein a generally planar layer of abrasive metal particles is located on a region of the generally flat portion of each of the face surfaces.
3. A method of making a cutting blade comprising:
providing a metal blade having a blade body that has two face surfaces, a portion of each face surface being generally planar and extending generally in parallel to the other flat portion, a cutting edge surface extending between the face surfaces, and a plurality of cutting tips located at the cutting edge surface; and
spray coating at least one region of at least one of the generally planar portions of the face surfaces with abrasive metal particles to provide an abrasive layer that is permanently secured to the blade body and that has a surface that extends generally in parallel to the face surfaces of the blade.
4. The blade of claim 3 wherein the layer of abrasive particles is no thicker than the distance to which at least one blade tip extends from the blade on the side of the blade having the layer.