IP Library › Patent Application 12523192

Patent Application

App. No. 12/523,192

DECAHYDROQUINOLINE ANALOGS AS CB2 RECEPTOR MODULATORS, USEFUL IN THE TREATMENT OF PAIN, RESPIRATORY AND NON-RESPIRATORY DISEASES

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App. No.: 12/523,192

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Abstract

The present invention relates to compounds represented by Formula (I): and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising the instant compounds. This invention further provides methods to treat and prevent pain, respiratory and non-respiratory diseases.

Claims (382)

1 . A compound of Formula (I):

or pharmaceutically acceptable salts and N-oxides thereof, wherein.

m is 1, 2, 3 or 4;

n and k are each independently selected from 0, 1 and 2;

R 1 is independently selected from

(1) H,

(2) OH,

(3) —NH 2 ,

(4) —NHR 4 ,

(5) —NR 4 R 5 ,

(6) —CF 3 ,

(7) —CN,

(8) —C 1-6 alkyl,

(9) —C 2-6 alkenyl,

(10) —C 2-6 alkynyl,

(11) —C 3-6 cycloalkyl,

(12) heterocycle,

(13) heteroaryl,

(14) aryl,

wherein the alkyl, cycloalkyl, alkenyl and alkynyl of choices (8), (9), (10) and (11) are each independently optionally mono- or di-substituted with substituents independently selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , and

the heterocycle, heteroaryl and aryl of choices (12), (13), and (14), are each optionally mono- or di-substituted with substituents selected from halo, —CN, hydroxy, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —CH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—C 1-3 alkyl-CF 3 , -hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —C 1-2 alkyl-heterocycle, —NR 6 R 7 , —NH—C(O)—R 6 , —NH—(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —NH—C 1-4 alkyl-aryl, and —S—C 1-4 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (12), (13) and (14) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl;

R 2 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 2-6 alkynyl,

(4) —C 3-6 cycloalkyl,

(5) carbocycle,

(6) -aryl,

(7) (CH 2 )m-carbocycle,

(8) —(CH 2 )m-aryl,

(9) —(CH 2 )m-heterocycle,

(10) —(CH 2 )m-heteroaryl,

(11) —NHR 4 ,

(12) —O—C 1-6 alkyl,

(13) —N(R 4 )C 1-6 alkyl,

(14) —O—C 2-6 alkenyl,

(15) —N(R 4 )C 2-6 alkenyl,

(16) —O—C 2-6 alkenyl,

(17) —N(R 4 )C 2-6 alkynyl,

(18) —O—C 3-6 cycloalkyl,

(19) —NR 4 )—C 3-6 cycloalkyl,

(20) —O-carbocycle,

(21) N(R 4 )-carbocycle,

(22) -heterocycle,

(23) —O-heterocycle,

(24) —N(R 4 )-heterocycle,

(25) -heteroaryl,

(26) —O-heteroaryl,

(27) —N(R 4 )-heteroaryl,

(28) —O-aryl,

(29) —N(aryl)R 4 ,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), (5), (7), (12), (13), (14), (15), (16), (17), (18), (19), (20), and (21) are each optionally mono- or di-substituted with substituents independently selected from hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl and

wherein the aryl, heteroaryl and heterocycle of choices (6), (8), (9), (10), (22), (23), (24), (25), (26), (27), (28), and (29) are optionally mono-, di- or tri-substituted with substituents independently selected from —CN, hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —C 1-4 alkyl-OH, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl; or

R 1 and R 2 are joined so that together with the carbon to which they are attached there is formed a cycloalkyl, carbocyclic or heterocyclic ring, said ring being optionally mono- or di-substituted with a substituent selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , heteroaryl, aryl, heterocycle;

R 3 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C(O)H,

(3) —S(O) 2 H,

(4) —C(O)NHR 5 ,

(5) —C(O)—C 1-6 alkyl,

(6) —S(O) 2 —C 1-6 alkyl,

(7) —C(O)N(R 5 )—C 1-6 alkyl,

(8) —CH 2 —C 2-6 alkenyl,

(9) —C(O)—C 2-6 alkenyl,

(10) —S(O) 2 —C 2-6 alkenyl,

(11) —C(O)N(R 5 )—C 2-6 alkenyl,

(12) —CH 2 —C 2-6 alkynyl,

(13) —C(O)—C 2-6 alkynyl,

(14) —S(O) 2 —C 2-6 alkynyl,

(15) —C(O)N(R 5 )—C 2-6 alkynyl,

(16) C 3-6 cycloalkyl,

(17) —CH 2 —C 3-6 cycloalkyl,

(18) —C(O)—C 3-6 cycloalkyl,

(19) —S(O) 2 —C 3-6 cycloalkyl,

(20) —C(O)N(R 5 )—C 3-6 cycloalkyl,

(21) heterocycle,

(22) —CH 2 -heterocycle,

(23) —C(O)-heterocycle,

(24) —C(O)—C 1-2 alkyl-heterocycle,

(25) —S(O) 2 -heterocycle,

(26) —C(O)N(R 5 )-heterocycle,

(27) heteroaryl,

(28) —CH 2 -heteroaryl,

(29) —C(O)-heteroaryl,

(30) —C(O)—C 1-2 alkyl-heteroaryl,

(31) —S(O) 2 -heteroaryl,

(32) —C(O)N(R 5 )-heteroaryl,

(33) aryl,

(34) —CH 2 -aryl,

(35) —C(O)-aryl,

(36) —C(O)—C 1-2 alkyl-aryl,

(37) —S(O) 2 -aryl,

(38) —C(O)N(R 5 )-aryl,

(39) carbocycle,

(40) —CH 2 -carbocycle,

(41) —C(O)-carbocycle,

(42) —S(O) 2 -carbocycle,

(43) —C(O)N(R 5 )-carbocycle,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17) (18) (19), (20), (39), (40), (41), (42) and (43) are each optionally mono- or di-substituted with substituents independently selected from halo, oxo, hydroxy, —CN, —C 1-6 alkyl, —CF 3 , —CHF 2 , CH 2 F, —C 1-4 alkyl-CF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —C 1-4 alkylCF 3 , hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NH—C(O)—R 6 , —NH—C(O)—C 3-6 cycloalkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —S-heteroaryl, —S-heterocycle, aryl, —C(O)-aryl, heteroaryl, —C(O)-heteroaryl, heterocycle, and —C(O)heterocycle, wherein the aryl, heteroaryl, heteroaryl and heterocycle portion of substituents on choices (5) to (19) and (35) to (38) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-6 alkyl, and

wherein the aryl, heteroaryl and heterocycle of choices (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37) and (38) is optionally mono-, di- or tri-substituted with substituents independently selected from —CN, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —OC 1-6 alkyl, —O—CF 3 , —O—CH 2 —CF 3 , hydroxy, -hydroxyC 1-6 alkyl, halo, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —CH 2 -heterocycle, —NR 6 R 7 , —NH—C(O)—R 6 , —NH—C(O)—N(CH 3 ) 2 , —NH—S(O) 2 —R 6 , —NH—C 1-2 alkyl-aryl, and —S—C 1-3 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37) and (38) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl;

R 4 and R 5 are each independently selected from

(1) H,

(2) —CF 3 ,

(3) —CN,

(4) —C1-6alkyl,

(5) —C2-6alkenyl,

(6) —C2-6alkynyl,

(7) —C 3-6 cycloalkyl,

(8) heterocycle,

(9) heteroaryl,

(10) aryl,

wherein the alkyl, cycloalkyl, alkenyl and alkynyl of choices (4), (5), (6) and (7) (8) are each independently optionally mono- or di-substituted with substituents independently selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, —C 1-4 alkyl-OH, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NHR 4 , —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , and

the heterocycle, heteroaryl and aryl of choices (8), (9) and (10), is each optionally mono- or di-substituted with substituents selected from halo, —CN, hydroxy, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —CH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—C 1-3 alkyl-CF 3 , -hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —C 1-2 alkyl-heterocycle, —NR 6 R 7 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —NH—C 1-4 alkyl-aryl, and —S—C 1-4 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (9), (10) and (11) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl;

R 6 is selected from hydrogen, CF 3 , C 1-4 alkyl, C 3-6 cycloalkyl, carbocycle, aryl, heterocycle and heteroaryl;

R 7 is selected from hydrogen and C 1-4 alkyl;

with the proviso that when R 1 is choice (2), (3), (4) or (5), then R 2 is other than choice (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), or (29).

2 . A compound of claim 1 wherein

R 1 is independently selected from

(1) H,

(2) OH,

(3) —NH 2 ,

(4) —NHR 4 ,

(5) —NR 4 R 5 ,

(6) —CF 3 ,

(7) —CN,

(8) heterocycle,

(9) heteroaryl,

(10) aryl,

wherein

the heterocycle, heteroaryl and aryl of choices (8), (9), and (10), are each optionally mono- or di-substituted with substituents selected from halo, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —OC 1-6 alkyl, —O—CF 3 , —O—C 1-3 alkyl-CF 3 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 .

3 . A compound of claim 1 wherein

R 1 is independently selected from

(1) H,

(2) OH,

(3) —NH 2 ,

(6) —CF 3 ,

(7) —CN.

4 . A compound of claim 1 wherein

R 2 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 2-6 alkynyl,

(4) —C 3-6 cycloalkyl,

(5) carbocycle,

(6) -aryl,

(7) CH 2 -carbocycle,

(8) —CH 2 -aryl,

(9) —CH 2 -heterocycle,

(10) —CH 2 -heteroaryl,

(11) —NHR 4 ,

(12) —O—C 1-6 alkyl,

(13) —N(R 4 )C 1-6 alkyl,

(14) —O—C 2-6 alkenyl,

(15) —N(R 4 )C 2-6 alkenyl,

(16) —O—C 2-6 alkenyl,

(17) —N(R 4 )C 2-6 alkynyl,

(18) —O—C 3-6 cycloalkyl,

(19) —N(R 4 )—C 3-6 cycloalkyl,

(20) —O-carbocycle,

(21) N(R 4 )-carbocycle,

(22) -heterocycle,

(23) —O-heterocycle,

(24) —N(R 4 )heterocycle,

(25) -heteroaryl,

(26) —O-heteroaryl,

(27) —N(R 4 )-heteroaryl,

(28) —O-aryl,

(29) —N(aryl)R 4 ,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), (5), (7), (12), (13), (14), (15), (16), (17), (18), (19), (20), and (21) are each optionally mono- or di-substituted with substituents independently selected from hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl and

wherein the aryl, heteroaryl and heterocycle of choices (6), (8), (9), (10), (22), (23), (24), (25), (26), (27), (28), and (29) are optionally mono-, di- or tri-substituted with substituents independently selected from —CN, hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, —C 1-4 alkyl-OH, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl; or

R 1 and R 2 are joined so that together with the carbon to which they are attached there is formed a cycloalkyl, carbocyclic or heterocyclic ring, said ring being optionally mono- or di-substituted with a substituent selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , heteroaryl, aryl, heterocycle.

5 . A compound of claim 1 wherein

R 2 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 2-6 alkynyl,

(4) —C 3-6 cycloalkyl,

(5) carbocycle,

(6) -aryl,

(7) CH 2 -carbocycle,

(8) —CH 2 -aryl,

(9) —CH 2 -heterocycle,

(10) —CH 2 -heteroaryl,

(11) heterocycle,

(12) heteroaryl,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), (5) and (7), are each optionally mono- or di-substituted with substituents independently selected from hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl and

wherein the aryl, heteroaryl and heterocycle of choices (6), (8), (9), (10), (11) and (12) are optionally mono-, di- or tri-substituted with substituents independently selected from —CN, hydroxy, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, —C 1-4 alkyl-OH, —S(O) 2 —R 6 , —NR 4 R 5 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl; or

R 1 and R 2 are joined so that together with the carbon to which they are attached there is formed a cycloalkyl, carbocyclic or heterocyclic ring, said ring being optionally mono- or di-substituted with a substituent selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , heteroaryl, aryl, heterocycle.

6 . A compound of claim 1 wherein

R 2 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 3-6 cycloalkyl,

(3) carbocycle,

(4) -aryl,

(5) heterocycle,

(6) heteroaryl,

wherein the alkyl, cycloalkyl, and carbocycle of choices (1), (2) and (3), are each optionally mono- or di-substituted with substituents independently selected from hydroxy, —CF 3 , C 1-4 alkylCF 3 , aryl, heteroaryl, and

wherein the aryl, heteroaryl and heterocycle of choices (4), (5) and (6) are optionally mono-, di- or tri-substituted with substituents independently selected from —CN, halo, —CF 3 , —CO 2 H, CO 2 R 4 , —C(O)NR 4 R 5 , aryl, heteroaryl, C 3-6 cycloalkyl; or

R 1 and R 2 are joined so that together with the carbon to which they are attached there is formed a cycloalkyl, carbocyclic or heterocyclic ring, said ring being optionally mono- or di-substituted with a substituent selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , heteroaryl, aryl, heterocycle.

7 . A compound of claim 1 wherein

R 3 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C(O)H,

(3) —C(O)NHR 5 ,

(4) —C(O)—C 1-6 alkyl,

(5) —C(O)N(R 5 )—C 1-6 alkyl,

(6) —CH 2 —C 2-6 alkenyl,

(7) —C(O)—C 2-6 alkenyl,

(8) —C(O)N(R 5 )—C 2-6 alkenyl,

(9) —CH 2 —C 2-6 alkynyl,

(10) —C(O)—C 2-6 alkynyl,

(11) —C(O)N(R 5 )—C 2-6 alkynyl,

(12) C 3-6 cycloalkyl,

(13) —CH 2 —C 3-6 cycloalkyl,

(14) —C(O)—C 3-6 cycloalkyl,

(15) —C(O)N(R 5 )—C 3-6 cycloalkyl,

(16) heterocycle,

(17) —CH 2 -heterocycle,

(18) —C(O)-heterocycle,

(19) —C(O)—C 1-2 alkyl-heterocycle,

(20) —C(O)N(R 5 )-heterocycle,

(21) heteroaryl,

(22) —CH 2 -heteroaryl,

(23) —C(O)-heteroaryl,

(24) —C(O)—C 1-2 alkyl-heteroaryl,

(25) —C(O)N(R 5 )-heteroaryl,

(26) aryl,

(27) —CH 2 -aryl,

(28) —C(O)-aryl,

(29) —C(O)—C 1-2 alkyl-aryl,

(30) —C(O)N(R 5 )-aryl,

(31) carbocycle,

(32) —CH 2 -carbocycle,

(33) —C(O)-carbocycle,

(34) —C(O)N(R 5 )-carbocycle,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (31), (32), (33), and (34) are each optionally mono- or di-substituted with substituents independently selected from halo, oxo, hydroxy, —CN, —C 1-6 alkyl, —CF 3 , —CHF 2 , CH 2 F, —C 1-4 alkyl-CF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F,—OC 1-6 alkyl, —O—CF 3 , —C 1-4 alkylCF 3 , hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NH—C(O)—R 6 , —NH—C(O)—C 3-6 cycloalkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —S-heteroaryl, —S-heterocycle, aryl, —C(O)-aryl, heteroaryl, —C(O)-heteroaryl, heterocycle, and —C(O)heterocycle, wherein the aryl, heteroaryl, heteroaryl and heterocycle portion of substituents on choices (1), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (31), (32), (33), and (34) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-6 alkyl, and

wherein the aryl, heteroaryl and heterocycle of choices (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29) and (30), is optionally mono-, di- or tri-substituted with substituents independently selected from —CN, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —OC 1-6 alkyl, —O—CH 2 —CF 3 , hydroxy, -hydroxyC 1-6 alkyl, halo, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —CH 2 -heterocycle, —NR 6 R 7 , —NH—C(O)—R 6 , —NH—C(O)—N(CH 3 ) 2 , —NH—S(O) 2 —R 6 , —NH—C 1-2 alkyl-aryl, and —S—C 1-3 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29) and (30) is each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl.

8 . A compound of claim 7 wherein

R 3 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C(O)—C 1-6 alkyl,

(3) —CH 2 —C 2-6 alkenyl,

(4) —C(O)—C 2-6 alkenyl,

(5) —CH 2 —C 2-6 alkynyl,

(6) —C(O)—C 2-6 alkynyl,

(7) C 3-6 cycloalkyl,

(8) —C(O)—C 3-6 cycloalkyl,

(9) —C(O)N(R 5 )—C 3-6 cycloalkyl,

(10) heterocycle,

(11) —CH 2 -heterocycle,

(12) —C(O)-heterocycle,

(13) —C(O)—C 1-2 alkyl-heterocycle,

(14) heteroaryl,

(15) —CH 2 -heteroaryl,

(16) —C(O)-heteroaryl,

(17) —C(O)—C 1-2 alkyl-heteroaryl,

(18) aryl,

(19) —CH 2 -aryl,

(20) —C(O)-aryl,

(21) —C(O)—C 1-2 alkyl-aryl,

(22) carbocycle,

(23) —CH 2 -carbocycle,

(24) —C(O)-carbocycle,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), (5), (6), (7), (8), (9), (22), (23) and (24) are each optionally mono- or di-substituted with substituents independently selected from halo, oxo, hydroxy, —CN, C 1-6 alkyl, —CF 3 , —CHF 2 , CH 2 F, —C 1-4 alkyl-CF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —C 1-4 alkylCF 3 , hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NH—C(O)—R 6 , —NH—C(O)—C 3-6 cycloalkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —S-heteroaryl, —S-heterocycle, aryl, —C(O)-aryl, heteroaryl, —C(O)-heteroaryl, heterocycle, and —C(O)heterocycle, wherein the aryl, heteroaryl, heteroaryl and heterocycle portion of substituents on choices (1), (2), (3), (4), (5), (6), (7), (8), (9), (22), (23) and (24) is each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-6 alkyl, and

wherein the aryl, heteroaryl and heterocycle of choices (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20) and (21) is optionally mono-, di- or tri-substituted with substituents independently selected from —CN, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —OC 1-6 alkyl, —O—CF 3 , —O—CH 2 —CF 3 , hydroxy, -hydroxyC 1-6 alkyl, halo, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —CH 2 -heterocycle, —NR 6 R 7 , —NH—C(O)—R 6 , —NH—C(O)—N(CH 3 ) 2 , —NH—S(O) 2 —R 6 , —NH—C 1-2 alkyl-aryl, and —S—C 1-3 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20) and (21) is each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl.

9 . A compound of claim 8 wherein

R 3 is selected from the group consisting of:

(1) —C(O)—C 1-6 alkyl,

(2) —C(O)—C 2-6 alkenyl,

(3) —C(O)—C 2-6 alkynyl,

(4) —C(O)—C 3-6 cycloalkyl,

(5) —C(O)-heterocycle,

(6) —C(O)—C 1-2 alkyl-heterocycle,

(7) —C(O)-heteroaryl,

(8) —C(O)—C 1-2 alkyl-heteroaryl,

(9) —C(O)-aryl,

(10) —C(O)—C 1-2 alkyl-aryl,

(11) —C(O)-carbocycle,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), and (11), is each optionally mono- or di-substituted with substituents independently selected from oxo, hydroxy, —CN, —CF 3 , —C 1-4 alkyl-CF 3 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , and

wherein the aryl, heteroaryl and heterocycle of choices (5), (6), (7), (8), (9) and (10) is optionally mono-, di- or tri-substituted with substituents independently selected from —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , halo, —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —NR 6 R 7 , —NH—C(O)—R 6 , —NH—C(O)—N(CH 3 ) 2 .

10 . A compound of claim 1 wherein

R 4 and R 5 are each independently selected from

(1) H,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) heterocycle,

(5) heteroaryl,

(6) aryl,

wherein the alkyl, cycloalkyl, alkenyl and alkynyl of choices (2) and (3) is each independently optionally mono- or di-substituted with substituents independently selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, —C 1-4 alkyl-OH, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NHR 4 , —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , and

the heterocycle, heteroaryl and aryl of choices (4), (5), and (6), are each optionally mono- or di-substituted with substituents selected from halo, —CN, hydroxy, oxo, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —CH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—C 1-3 alkyl-CF 3 , -hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NHC 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C(O)—O—C(CH 3 ) 3 , aryl, —C(O)aryl, —C 1-2 alkyl-aryl, heteroaryl, —C(O)-heteroaryl, —C 1-2 alkyl-heteroaryl, —C 3-6 cycloalkyl, heterocycle, —C(O)-heterocycle, —C 1-2 alkyl-heterocycle, —NR 6 R 7 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —NH—C 1-4 alkyl-aryl, and —S—C 1-4 alkyl, wherein the aryl, heteroaryl and heterocycle portion of the substituents on choices (9), (10) and (11) are each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-4 alkyl.

11 . A compound of claim 1 wherein

R 6 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, and aryl.

12 . A compound of claim 1 of formula I wherein

R 1 is independently selected from

(1) H,

(2) OH,

(3) —NH 2 ,

(4) —NHR 4 ,

(5) —NR 4 R 5 ,

(6) —CF 3 ,

(7) —CN,

(8) heterocycle,

(9) heteroaryl,

(10) aryl,

wherein

R 2 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 3-6 cycloalkyl,

(3) carbocycle,

(4) -aryl,

(5) heterocycle,

(6) heteroaryl,

R 1 and R 2 are joined so that together with the carbon to which they are attached there is formed a cycloalkyl, carbocyclic or heterocyclic ring, said ring being optionally mono- or di-substituted with a substituent selected from hydroxy, oxo, halo, —C 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —C 1-4 alkylCF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —OC 1-6 alkyl, —O—CF 3 , —O—CHF 2 , —O—CH 2 F, —O—C 1-4 alkyl-CF 3 , —O—C 1-4 alkylCHF 2 , —O—C 1-4 alkylCH 2 F, -hydroxyC 1-4 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NR 4 R 5 , —NH—C(O)—R 6 , —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , heteroaryl, aryl, heterocycle;

R 3 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C(O)—C 1-6 alkyl,

(3) —CH 2 —C 2-6 alkenyl,

(4) —C(O)—C 2-6 alkenyl,

(5) —CH 2 —C 2-6 alkynyl,

(6) —C(O)—C 2-6 alkynyl,

(7) C 3-6 cycloalkyl,

(8) —C(O)—C 3-6 cycloalkyl,

(9) —C(O)N(R 5 )—C 3-6 cycloalkyl,

(10) heterocycle,

(11) —CH 2 -heterocycle,

(12) —C(O)-heterocycle,

(13) —C(O)—C 1-2 alkyl-heterocycle,

(14) heteroaryl,

(15) —CH 2 -heteroaryl,

(16) —C(O)-heteroaryl,

(17) —C(O)—C 1-2 alkyl-heteroaryl,

(18) aryl,

(19) —CH 2 -aryl,

(20) —C(O)-aryl,

(21) —C(O)—C 1-2 alkyl-aryl,

(22) carbocycle,

(23) —CH 2 -carbocycle,

(24) —C(O)-carbocycle,

wherein the alkyl, cycloalkyl, carbocycle, alkenyl and alkynyl of choices (1), (2), (3), (4), (5), (6), (7), (8), (9), (22), (23) and (24) are each optionally mono- or di-substituted with substituents independently selected from halo, oxo, hydroxy, —CN, —C 1-6 alkyl, —CF 3 , —CHF 2 , CH 2 F, —C 1-4 alkyl-CF 3 , —C 1-4 alkylCHF 2 , —C 1-4 alkylCH 2 F, —O—CF 3 , —C 1-4 alkylCF 3 , hydroxyC 1-6 alkyl, —S(O) 2 —R 6 , —C(O)—O—C 1-6 alkyl, —C(O)—NR 6 R 7 , —C(O)—O—C(CH 3 ) 3 , —C 3-6 cycloalkyl, —NH 2 , —NH—C(O)—R 6 , NH—C(O)—C 3-6 cycloalkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)—NR 6 R 7 , —NH—S(O) 2 —R 6 , —S-heteroaryl, —S-heterocycle, aryl, —C(O)-aryl, heteroaryl, —C(O)-heteroaryl, heterocycle, and —C(O)heterocycle, wherein the aryl, heteroaryl, heteroaryl and heterocycle portion of substituents on choices (1), (2), (3), (4), (5), (6), (7), (8), (9), (22), (23) and (24) is each optionally mono or di-substituted with substituents independently selected from halo, —CH 3 , —CF 3 , —CN, hydroxy and —OC 1-6 alkyl, and

R 4 and R 5 are each independently selected from

(1) H,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) heterocycle,

(5) heteroaryl,

(6) aryl,

R 6 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, and aryl.

13 . A compound of claim 12 wherein

R 1 is independently selected from

(1) H,

(2) OH,

(3) —NH 2 ,

(6) —CF 3 ,

(7) —CN;

R 3 is selected from the group consisting of:

(1) —C(O)—C 1-6 alkyl,

(2) —C(O)—C 2-6 alkenyl,

(3) —C(O)—C 2-6 alkynyl,

(4) —C(O)—C 3-6 cycloalkyl,

(5) —C(O)-heterocycle,

(6) —C(O)—C 1-2 alkyl-heterocycle,

(7) —C(O)-heteroaryl,

(8) —C(O)—C 1-2 alkyl-heteroaryl,

(9) —C(O)-aryl,

(10) —C(O)—C 1-2 alkyl-aryl,

(11) —C(O)-carbocycle,

14 . A compound according to claim 1 selected from the group consisting of

15 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

16 . 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 .

17 . 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 .

18 . 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 .

19 . A method of treating a disease selected from the group consisting inflammatory pain, osteoporosis, atheroschlerosis, immune disorders and arthritis comprising administering an effective amount of a compound according to claim 1 .

20 . A method according to claim 19 , for the treatment of the acute and chronic pain.

21 . A method according to claim 21 , for the treatment of the pain of rheumatoid arthritis or osteoarthritis.

Assignments (2)

CHANGE OF NAME Recorded Jan 27, 2010

From: MERCK & CO., INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 023852/0595 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2009

From: LINDSLEY, CRAIG

To: MERCK & CO., INC.

Reel/Frame 023485/0819 →