Claims for Patent: 8,653,260

Summary for Patent: 8,653,260

Title:	Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
Abstract:	The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of .beta.3-adrenoceptor. ##STR00001##
Inventor(s):	Berger; Richard (Princeton, NJ), Chang; Lehua (Ramsey, NJ), Edmondson; Scott D. (Clark, NJ), Goble; Stephen D. (Edison, NJ), Ha; Sookhee Nicole (Warren, NJ), Kar; Nam Fung (Brooklyn, NY), Kopka; Ihor E. (Hampton, NJ), Li; Bing (Towaco, NJ), Morriello; Gregori J. (Randolph, NJ), Moyes; Chris R. (Westfield, NJ), Shen; Ding-Ming (Edison, NJ), Wang; Liping (Dayton, NJ), Zhu; Cheng (Edison, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	13/527,934
Patent Claims:	1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof: ##STR00542## wherein m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; t is 0, 1, 2, 3, 4, or 5; X is --CO-- or --SO.sub.2--; Y is selected from the group consisting of: (1) C.sub.1-C.sub.5 alkanediyl, C.sub.2-C.sub.5 alkenediyl, and C.sub.2-C.sub.5 alkynediyl, wherein each of alkanediyl, alkenediyl and alkynediyl is optionally substituted with one to three groups independently selected from halogen, --ORa, --S(O).sub.p--C.sub.1-C.sub.3 alkyl; (2) --(CR.sup.aR.sup.a).sub.j-Q-(CR.sup.aR.sup.a).sub.k, wherein j and k are integers independently selected from 0, 1 and 2, (3) a bond, and (4) phenylene optionally substituted with one to three groups independently selected from R.sup.1; Z is selected from the group consisting of: (1) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and (2) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C.sub.5-C.sub.10 carbocyclic ring; R.sup.1 is selected from the group consisting of: (1) C.sub.1-C.sub.5 alkyl optionally substituted with 1 to 5 halogen atoms, (2) C.sub.3-C.sub.6 cycloalkyl, (3) halogen, (4) nitro, (5) cyano, (6) --C(O)R.sup.a, (7) --C(O).sub.2R.sup.a, (8) --C(O)NR.sup.aR.sup.b, and (9) -QR.sup.b; R.sup.2 is selected from the group consisting of halogen and C.sub.1-C.sub.5 alkyl; R.sup.3 is selected from the group consisting of: (1) C.sub.1-C.sub.6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, --ORa, --CO.sub.2R.sup.a, and --CONR.sup.aR.sup.b, (2) --(CH.sub.2).sub.t-phenyl or --(CH.sub.2).sub.t--O-phenyl, and wherein said phenyl in each is optionally substituted with 1 to 3 groups independently selected from halogen, C.sub.1-C.sub.5 alkyl optionally substituted with 1 to 5 halogen atoms, and --OR.sup.a, (3) oxo, (4) thioxo, (5) halogen, (6) --CN, (7) C.sub.3-C.sub.6 cycloalkyl, (8) --(CH.sub.2).sub.t-heterocyclic ring or --(CH.sub.2).sub.t--O-heterocyclic ring, and wherein the heterocyclic ring in each is a 5- or 6-membered ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and wherein said heterocyclic ring is optionally ortho-fused to a benzene ring, and optionally substituted with 1 to 3 groups independently selected from halogen, C.sub.1-C.sub.5 alkyl optionally substituted with 1 to 5 halogen atoms, and --OR.sup.a, (9) --OR.sup.a, (10) --C(O)ORa, (11) --C(O)Ra, (12) --C(O)NR.sup.aR.sup.b, (12) --NR.sup.aR.sup.b, (13) --NR.sup.aC(O)R.sup.b, (14) --NR.sup.aC(O)OR.sup.b, and (15) --NR.sup.aC(O)NR.sup.aR.sup.b; R.sup.a is selected from the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl optionally substituted with 1 to 5 halogen atoms; R.sup.b is selected from the group consisting of: (1) hydrogen, (2) C.sub.1-C.sub.6 alkyl optionally substituted with 1 to 5 groups selected from the group consisting of: (a) hydroxy, (b) halogen, (c) --CO.sub.2R.sup.a, (d) --S(O).sub.p--C.sub.1-C.sub.3 alkyl; (e) C.sub.3-C.sub.8 cycloalkyl, (f) C.sub.1-C.sub.6 alkoxy optionally substituted with 1 to 5 halogens, and (g) phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, nitro, --NR.sup.aR.sup.a, trifluoromethyl, trifluoromethoxy, C.sub.1-C.sub.5 alkyl and --OR.sup.a, (3) C.sub.3-C.sub.8 cycloalkyl, and (4) phenyl optionally substituted with 1 to 5 groups selected from the group consisting of: (a) halogen, (b) nitro, (c) --NR.sup.aR.sup.a, (d) --OH, (e) C.sub.1-C.sub.6 alkoxy optionally substituted with 1 to 5 halogens, (f) --S(O).sub.p--C.sub.1-C.sub.6 alkyl; and (g) C.sub.1-C.sub.6 alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, trifluoromethyl, cyano, --CO.sub.2R.sup.a, C.sub.3-C.sub.8 cycloalkyl, and -QR.sup.c; R.sup.c is selected from the group consisting of: (1) Z optionally substituted with up to 5 groups selected from halogen, trifluoromethyl, cyano, C.sub.1-C.sub.5 alkyl and C.sub.1-C.sub.5 alkoxy, and (2) C.sub.1-C.sub.6 alkyl; and Q is selected from the group consisting of: (1) --N(R.sup.a)--, (2) --O--, and (3) --S(O).sub.p--. 2. The compound of claim 1 wherein Y is methylene, --CH(CH.sub.3)-- or a bond. 3. The compound of claim 1 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C.sub.5-C.sub.6 carbocyclic ring, and wherein said heterocyclic ring is a 5-membered heterocycle having one nitrogen ring atom and 0 to 3 additional heteroatoms independently selected from N, O and S, or a 6-membered heterocycle having 1, 2 or 3 ring nitrogen atoms, or 1 ring nitrogen atom and a ring oxygen or sulfur atom. 4. The compound of claim 1 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein said fused ring has 2 to 5 heteroatoms, at least one of which is nitrogen. 5. The compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof: ##STR00543## wherein Y, Z, R.sup.3 and n are as defined in claim 1. 6. The compound of claim 5 wherein Y is methylene, --CH(CH.sub.3)-- or a bond. 7. The compound of claim 5 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C.sub.5-C.sub.6 carbocyclic ring, and wherein said heterocyclic ring is a 5-membered heterocycle having one nitrogen ring atom and 0 to 3 additional heteroatoms independently selected from N, O and S, or a 6-membered heterocycle having 1, 2 or 3 ring nitrogen atoms, or 1 ring nitrogen atom and a ring oxygen or sulfur atom. 8. The compound of claim 5 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein said fused ring has 2 to 5 heteroatoms, at least one of which is nitrogen. 9. The compound of claim 8 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and wherein the fused ring has 2 to 4 nitrogen atoms and no other heteroatoms. 10. The compound of claim 5 wherein Z is selected from the group consisting of: ##STR00544## wherein r is 1 or 2. 11. The compound of claim 5 wherein R.sup.3 is selected from the group consisting of: (1) C.sub.1-C.sub.6 alkyl optionally substituted with halogen or --OR.sup.a, (2) oxo, (3) halogen, (4) --OR.sup.a, (5) --C(O)NR.sup.aR.sup.b, and (6) --NR.sup.aR.sup.b; wherein R.sup.a and R.sup.b is as defined in claim 1.