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US 2004/0176428 A1Published application
Dipeptidyl peptidase inhibitors for the treatment of diabetes
AssigneeMerck & Co., Inc.
InventorsScott D. Edmondson, Emma Parmee, Ann E. Weber, Jinyou Xu
Life of this patent
Estimating the term…
Abstract
Compounds having Formula I, including pharmaceutically acceptable salts and prodrugs thereof: (Formula I) are inhibitors of the dipep tidyl peptidase-IV enzyme (DP-IV), and are useful in the treatment of DP-IV mediated diseases and conditions, such as non-insulin dependent diabetes mellitus. 1
Claims43
A compound having Formula I:
- 161
- including pharmaceutically acceptable salts and prodrugs thereof, wherein:
- X is selected from the group consisting of:
- CR10R11, S, SO, SO2, and CR10R9, with the proviso that when X is CR10R9, Q and R8 are both H;
- Ar is selected from the group consisting of:
- (1) phenyl,
- (2) naphthyl,
- (3) thienyl, and
- (4) benzothiophenyl;
- wherein Ar is optionally substituted with 1-5 groups R1;
- R1 is selected from the group consisting of:
- (1) halogen,
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens,
- (3) OC1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens, and
- (4) CN;
- Each R2 is independently selected from the group consisting of H, OH, halogen and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-5 halogens, wherein the two groups R2 can optionally be joined to form a C3-6cycloalkyl, which is optionally substituted with 1-3 halogens;
- Each R3 is independently selected from the group consisting of H, halogen and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-5 halogens, wherein the two groups R3 can optionally be joined to form a C3-6cycloalkyl, which is optionally substituted with 1-3 halogens;
- Q is selected from the group consisting of:
- (1) H,
- (2) C(═O)NR4Z, and
- (3) CN;
- R4 is selected from the group consisting of
- (1) H, and
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens;
- Z is selected from the group consisting of:
- (1) phenyl, which is optionally substituted with 1-5 substituents independently selected from halogen and R6,
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-7 substituents independently selected from (a) 0-5 halogens, and (b) 0-2 substituents selected from the group consisting of
- (a) hydroxy,
- (b) CO2H,
- (c) CO2C1-6alkyl,
- (d) phenyl,
- (e) naphthyl,
- (f) C3-6 cycloalkyl,
- (g) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O;
- and
- (h) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (a) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms selected from N, S and O, or (b) a benzene ring fused to a 5- or 6-membered heterocycle having 1-3 heteroatoms;
- wherein said C3-6cycloalkyl, phenyl and naphthyl are optionally substituted with 1-5 substituents independently selected from halogen and R6, and said 5 or 6-membered heterocycle and said 8-10 membered bicyclic ring system are each optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, and R6;
- and
- (3) C3-6cycloalkyl, which is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, CO2H, CO2C1-6alkyl, C1-6alkyl, and OC1-6alkyl, said CO2C1-6alkyl, C1-6alkyl, and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R6 is selected from the group consisting of:
- (1) OH,
- (2) CN,
- (3) C3-6 cycloalkyl optionally substituted with 1-3 groups independently selected from hydroxy, halogen, CO2H, CO2C1-6alkyl, C1-6 alkyl, and OC1-6alkyl, wherein said C1-6alkyl, OC1-6alkyl and CO2C1-6alkyl are linear or branched and are optionally substituted with 1-6 substituents independently selected from 0-5 halogens and 0-1 substituents selected from CO2C1-6alkyl, CO2H and OC1-6alkyl, said CO2C1-6alkyl and OC1-6alkyl substituents being linear or branched and optionally substituted with 1-5 halogens,
- (4) C1-10alkyl, which is linear or branched and is optionally substituted with 1-7 substituents independently selected from 0-5 halogen atoms and 0-2 groups independently selected from
- (a) OH,
- (b) CO2H,
- (c) CO2C1-6alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens,
- (d) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (e) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (i) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (ii) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, wherein said bicyclic ring system is optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (f) CONR7R7,
- (g) SO2NR7R7,
- (h) NR7C(O)R7,
- (i) NR7C(O)NR7R7,
- (j) NR7CO2R5,
- (k) OC(O)R7,
- (l) OC(O)NR7R7,
- (m) NR7S(O)2R5,
- (n) NR7R7,
- (o) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-6 substituents independently selected from 0-1 C3-6cycloalkyl and 0-5 halogens, and
- (p) C3-6 cycloalkyl, which is optionally substituted with 1-6 halogens;
- (5) OC1-10alkyl, which is linear or branched and is optionally substituted with 1-7 groups independently selected from 0-5 halogen atoms and 0-2 substituents selected from
- (a) OH,
- (b) CO2H,
- (c) CO2C1-6alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens,
- (d) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (e) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (i) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (ii) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, wherein said bicyclic ring system is optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (f) CONR7R7,
- (g) SO2NR7R7,
- (h) NR7C(O)R7,
- (i) NR7C(O)NR7R7,
- (j) NR7CO2R5,
- (k) OC(O)R7,
- (l) OC(O)NR7R7,
- (m) NR7S(O)2R5,
- (n) NR7R7,
- (o) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-6 substituents independently selected from 0-1 C3-6cycloalkyl and 0-5 halogens, and
- (p) C3-6cycloalkyl, which is optionally substituted with 1-6 halogens;
- (6) CO2H;
- (7) CO2C1-6 alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens;
- (8) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, said heterocycle being optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (9) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (a) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (b) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, said bicyclic ring system being optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (10) CONR7R7;
- (11) SO2NR7R7;
- (12) NR7C(O)R7;
- (13) NR7C(O)NR7R7;
- (14) NR7CO2R5;
- (15) OC(O)R7;
- (16) OC(O)NR7R7;
- (17) NR7S(O)2R5;
- (18) NR7R7;
- and
- (19) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R5 is selected from the group consisting of phenyl, C3-6cycloalkyl and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-6 substituents independently selected from 0-5 halogens and 0-1 phenyl, wherein said optional phenyl substituent and said R5 when R5 is phenyl or C3-6cycloalkyl are optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-5alkyl, and OC1-5alkyl, said C1-5alkyl and OC1-5alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R7 is selected from
- (1) H, and
- (2) R5;
- R8 is selected from
- (1) H, and
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens;
- R9 is C(═O)NR4Z;
- and
- R10 and R11 are each selected from the group consisting of H, F and C1-6 alkyl, which is linear or branched and is optionally substituted with 1-5 halogens.
99 more elements
A compound having Formula Ia:
- 162
- including pharmaceutically acceptable salts and prodrugs thereof, wherein:
- X is selected from the group consisting of:
- CR10R11, S, SO, SO2, and CR10R9, with the proviso that when X is CR10R9, Q and R8 are both H;
- Ar is selected from the group consisting of:
- (1) phenyl,
- (2) naphthyl,
- (3) thienyl, and
- (4) benzothiophenyl;
- wherein Ar is optionally substituted with 1-5 groups R1;
- R1 is selected from the group consisting of:
- (1) halogen,
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens,
- (3) OC1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens, and
- (4) CN;
- Each R2 is independently selected from the group consisting of H, OH, halogen and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-5 halogens, wherein the two groups R2 can optionally be joined to form a C3-6cycloalkyl, which is optionally substituted with 1-3 halogens;
- Each R3 is independently selected from the group consisting of H, halogen and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-5 halogens, wherein the two groups R3 can optionally be joined to form a C3-6cycloalkyl, which is optionally substituted with 1-3 halogens;
- Q is selected from the group consisting of:
- (1) H,
- (2) C(═O)NR4Z, and
- (3) CN;
- R4 is selected from the group consisting of
- (1) H, and
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens;
- Z is selected from the group consisting of:
- (1) phenyl, which is optionally substituted with 1-5 substituents independently selected from halogen and R6,
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-7 substituents independently selected from (a) 0-5 halogens, and (b) 0-2 substituents selected from the group consisting of
- (a) hydroxy,
- (b) CO2H,
- (c) CO2C1-6alkyl,
- (d) phenyl,
- (e) naphthyl,
- (f) C3-6 cycloalkyl,
- (g) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O;
- and
- (h) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (a) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms selected from N, S and O, or (b) a benzene ring fused to a 5- or 6-membered heterocycle having 1-3 heteroatoms;
- wherein said C3-6cycloalkyl, phenyl and naphthyl are optionally substituted with 1-5 substituents independently selected from halogen and R6, and said 5 or 6-membered heterocycle and said 8-10 membered bicyclic ring system are each optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, and R6;
- and
- (3) C3-6cycloalkyl, which is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, CO2H, CO2C1-6alkyl, C1-6alkyl, and OC1-6alkyl, said CO2C1-6alkyl, C1-6alkyl, and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R6 is selected from the group consisting of:
- (1) OH,
- (2) CN,
- (3) C3-6 cycloalkyl optionally substituted with 1-3 groups independently selected from hydroxy, halogen, CO2H, CO2C1-6alkyl, C1-6 alkyl, and OC1-6alkyl, wherein said C1-6alkyl, OC1-6alkyl and CO2C1-6alkyl are linear or branched and are optionally substituted with 1-6 substituents independently selected from 0-5 halogens and 0-1 substituents selected from CO2C1-6alkyl, CO2H and OC1-6alkyl, said CO2C1-6alkyl and OC1-6alkyl substituents being linear or branched and optionally substituted with 1-5 halogens,
- (4) C1-10alkyl, which is linear or branched and is optionally substituted with 1-7 substituents independently selected from 0-5 halogen atoms and 0-2 groups independently selected from
- (a) OH,
- (b) CO2H,
- (c) CO2C1-6alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens,
- (d) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (e) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (i) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (ii) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, wherein said bicyclic ring system is optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being halogens;
- (f) CONR7R7,
- (g) SO2NR7R7,
- (h) NR7C(O)R7,
- (i) NR7C(O)NR7R7,
- (j) NR7CO2R5,
- (k) OC(O)R7,
- (l) OC(O)NR7R7,
- (m) NR7S(O)2R5,
- (n) NR7R7,
- (o) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-6 substituents independently selected from 0-1 C3-6cycloalkyl and 0-5 halogens, and
- (p) C3-6cycloalkyl, which is optionally substituted with 1-6 halogens;
- (5) OC1-10alkyl, which is linear or branched and is optionally substituted with 1-7 groups independently selected from 0-5 halogen atoms and 0-2 substituents selected from
- (a) OH,
- (b) CO2H,
- (c) CO2C1-6alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens,
- (d) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (e) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (i) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (ii) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, wherein said bicyclic ring system is optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (f) CONR7R7,
- (g) SO2NR7R7,
- (h) NR7C(O)R7,
- (i) NR7C(O)NR7R7,
- (j) NR7CO2R5,
- (k) OC(O)R7,
- (l) OC(O)NR7R7,
- (m) NR7S(O)2R5,
- (n) NR7R7,
- (o) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-6 substituents independently selected from 0-1 C3-6cycloalkyl and 0-5 halogens, and
- (p) C3-6cycloalkyl, which is optionally substituted with 1-6 halogens;
- (6) CO2H;
- (7) CO2C1-6 alkyl, which may be linear or branched and is optionally substituted with 1-5 halogens;
- (8) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, said heterocycle being optionally substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (9) an 8-10 membered bicyclic ring system which may be saturated or unsaturated comprising (a) two fused heterocyclic rings, each heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, or (b) a 5- or 6-membered heterocycle having 1-3 heteroatoms independently selected from N, S and O fused to a benzene ring, said bicyclic ring system being optionally substituted with 1-5 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, said C1-6alkyl and OC1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- (10) CONR7R7;
- (11) SO2NR7R7;
- (12) NR7C(O)R7;
- (13) NR7C(O)NR7R7;
- (14) NR7CO2R5;
- (15) OC(O)R7;
- (16) OC(O)NR7R7;
- (17) NR7S(O)2R5;
- (18) NR7R7;
- and
- (19) phenyl, which is optionally substituted with 1-5 groups independently selected from halogen, OH, C1-6alkyl, OC1-6alkyl, CO2H, and CO2C1-6alkyl, said C1-6alkyl, OC1-6alkyl, and CO2C1-6alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R5 is selected from the group consisting of phenyl, C3-6cycloalkyl and C1-6alkyl, wherein C1-6alkyl is linear or branched and is optionally substituted with 1-6 substituents independently selected from 0-5 halogens and 0-1 phenyl, wherein said optional phenyl substituent and said R5 when R5 is phenyl or C3-6cycloalkyl are optionally substituted with 1-5 substituents independently selected from halogen, OH, C1-5alkyl, and OC1-5alkyl, said C1-5alkyl and OC1-5alkyl being linear or branched and optionally substituted with 1-5 halogens;
- R7 is selected from
- (1) H, and
- (2) R5;
- R8 is selected from
- (1) H, and
- (2) C1-6alkyl, which is linear or branched and is optionally substituted with 1-5 halogens;
- R9 is C(═O)NR4Z;
- and
- R10 and R11 are each selected from the group consisting of H, F and C1-6 alkyl, which is linear or branched and is optionally substituted with 1-5 halogens.
99 more elements
A compound as recited in any one of Examples 1-162, or a pharmaceutically acceptable salt or prodrug thereof.
A compound that has one or more functional groups that are easily changed or removed under physiological conditions during or after administration to a mammalian patient to yield a compound having Formula I, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.