Dipeptidyl peptidase inhibitors for the treatment of diabetes
View Patent ↗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. A compound having Formula I:
including pharmaceutically acceptable salts and prodrugs thereof, wherein:
X is selected from the group consisting of: CR 10 R 11 ,S, SO, SO 2 , and CR 10 R 9 , with the proviso that when X is CR 10 R 9 , Q and R 8 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 R 1 ;
R 1 is selected from the group consisting of:
(1) halogen,
(2) C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens,
(3) OC 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens, and
(4) CN;
Each R 2 is independently selected from the group consisting of H, OH, halogen and C 1-6 alkyl, wherein C 1-6 alkyl is linear or branched and is optionally substituted with 1–5 halogens, wherein the two groups R 2 can optionally be joined to form a C 3-6 cycloalkyl, which is optionally substituted with 1–3 halogens;
Each R 3 is independently selected from the group consisting of H, halogen and C 1-6 alkyl, wherein C 1-6 alkyl is linear or branched and is optionally substituted with 1–5 halogens, wherein the two groups R 3 can optionally be joined to form a C 3-6 cycloalkyl, which is optionally substituted with 1–3 halogens;
Q is selected from the group consisting of:
(1) H,
(2) C(═O)NR 4 Z, and
(3) CN;
R 4 is selected from the group consisting of
(1) H, and
(2) C 1-6 alkyl, 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 R 6 ,
(2) C 1-6 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl,
(d) phenyl,
(e) naphthyl,
(f) C 3-6 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 C 3-6 cycloalkyl, phenyl and naphthyl are optionally substituted with 1–5 substituents independently selected from halogen and R 6 , 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 R 6 ; and
(3) C 3-6 cycloalkyl, which is optionally substituted with 1–3 groups independently selected from halogen, hydroxy, CO 2 H, CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl, said CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 6 is selected from the group consisting of:
(1) OH,
(2) CN,
(3) C 3-6 cycloalkyl optionally substituted with 1–3 groups independently selected from hydroxy, halogen, CO 2 H, CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl, wherein said C 1-6 alkyl, OC 1-6 alkyl and CO 2 C 1-6 alkyl are linear or branched and are optionally substituted with 1–6 substituents independently selected from 0–5 halogens and 0–1 substituents selected from CO 2 C 1-6 alkyl, CO 2 H and OC 1-6 alkyl, said CO 2 C 1-6 alkyl and OC 1-6 alkyl substituents being linear or branched and optionally substituted with 1–5 halogens,
(4) C 1-10 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl, 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
(f) CONR 7 R 7 ,
(g) SO 2 NR 7 R 7 ,
(h) NR 7 C(O)R 7,
(i) NR 7 C(O)NR 7 R 7 ,
(j) NR 7 CO 2 R 5 ,
(k) OC(O)R 7 ,
(l) OC(O)NR 7 R 7 ,
(m) NR 7 S(O) 2 R 5 ,
(n) NR 7 R 7 ,
(o) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–6 substituents independently selected from 0–1 C3–6cycloalkyl and 0–5 halogens, and
(p) C 3-6 cycloalkyl, which is optionally substituted with 1–6 halogens;
(5) OC 1-10 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl, 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
(f) CONR 7 R 7 ,
(g) SO 2 NR 7 R 7 ,
(h) NR 7 C(O)R 7 ,
(i) NR 7 C(O)NR 7 R 7 ,
(j) NR 7 CO 2 R 5 ,
(k) OC(O)R 7 ,
(l) OC(O)NR 7 R 7 ,
(m) NR 7 S(O) 2 R 5 ,
(n) NR 7 R 7 ,
(o) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–6 substituents independently selected from 0–1 C 3-6 cycloalkyl and 0–5 halogens, and
(p) C 3-6 cycloalkyl, which is optionally substituted with 1–6 halogens;
(6) CO 2 H;
(7) CO 2 C 1-6 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally subtitued 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
(10) CONR 7 R 7 ;
(11) SO 02 NR 7 R 7 ;
(12) NR 7 C(O)R 7 ;
(13) NR 7 C(O)NR 7 R 7 ;
(14) NR 7 CO 2 R 5 ;
(15) OC(O)R 7 ;
(16) OC(O)NR 7 R 7 ;
(17) NR 7 S(O) 2 R 5 ;
(18) NR 7 R 7 ; and
(19) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 5 is selected from the group consisting of phenyl, C 3-6 cycloalkyl and C 1-6 alkyl, wherein C 1-6 alkyl 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 R 5 when R 5 is phenyl or C 3-6 cycloalkyl are optionally substituted with 1–5 substituents independently selected from halogen, OH, C 1-6 alkyl, and OC 1-5 alkyl, said C 1-5 alkyl and OC 1-5 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 7 is selected from
(1) H, and
(2) R 5 ;
R 8 is selected from
(1) H, and
(2) C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens;
R 9 is C(═O)NR 4 Z; and
R 10 and R 11 are each selected from the group consisting of H, F and C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens.
2. A compound having formula I as recited in claim 1 , wherein R 2 and R 3 are H.
3. A compound having formula I as recited in claim 1 , wherein Ar is phenyl, which is optionally substituted as in claim 1 .
4. A compound having Formula I as recited in claim 1 , wherein R 4 is H.
5. A compound having Formula I as recited in claim 1 , wherein Q is C(═O)NHZ, Z is selected from CH 2 phenyl, cyclohexyl and cyclopentyl, and R 9 is C(═O)NHCH 2 phenyl, where phenyl, cyclohexyl and cyclopentyl are optionally substituted as in claim 1 .
6. A compound having Formula I as recited in claim 1 , wherein R 8 is H.
7. A compound having Formula I as recited in claim 1 , wherein said 8–10 membered bicyclic ring system is selected from the group consisting of indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, isoquinoline, tetrahydroisoquinoline, and dihydroisoquinoline.
8. A compound having Formula I as recited in claim 1 , wherein said 5- or 6-membered heterocycle is selected from the group consisting of furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine and tetrazolidine.
9. A compound having Formula Ia:
including pharmaceutically acceptable salts and prodrugs thereof, wherein:
X is selected from the group consisting of: CR 10 R 11 , S, SO, SO 2 , and CR 10 R 9 , with the proviso that when X is CR 10 R 9 , Q and R 8 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 R 1 ;
R 1 is selected from the group consisting of:
(1) halogen,
(2) C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens,
(3) OC 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens, and
(4) CN;
Each R 2 is independently selected from the group consisting of H, OH, halogen and C 1-6 alkyl, wherein C 1-6 alkyl is linear or branched and is optionally substituted with 1–5 halogens, wherein the two groups R 2 can optionally be joined to form a C 3-6 cycloalkyl, which is optionally substituted with 1–3 halogens;
Each R 3 is independently selected from the group consisting of H, halogen and C 1-6 alkyl, wherein C 1-6 alkyl is linear or branched and is optionally substituted with 1–5 halogens, wherein the two groupsR 3 can optionally be joined to form a C 3-6 cycloalkyl, which is optionally substituted with 1–3 halogens;
Q is selected from the group consisting of:
(1) H,
(2) C(═O)NR 4 Z, and
(3) CN;
R 4 is selected from the group consisting of
(1) H, and
(2) C 1-6 alkyl, 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 R 6 ,
(2) C 1-6 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl,
(d) phenyl,
(e) naphthyl,
(f) C 3-6 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 C 3-6 cycloalkyl, phenyl and naphthyl are optionally substituted with 1–5 substituents independently selected from halogen and R 6 , 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 R 6 ; and
(3) C 3-6 cycloalkyl, which is optionally substituted with 1–3 groups independently selected from halogen, hydroxy, CO 2 H, CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl, said CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 6 is selected from the group consisting of:
(1) OH,
(2) CN,
(3) C 3-6 cycloalkyl optionally substituted with 1–3 groups independently selected from hydroxy, halogen, CO 2 H, CO 2 C 1-6 alkyl, C 1-6 alkyl, and OC 1-6 alkyl, wherein said C 1-6 alkyl, OC 1-6 alkyl and CO 2 C 1-6 alkyl are linear or branched and are optionally substituted with 1–6 substituents independently selected from 0–5 halogens and 0–1 substituents selected from CO 2 C 1-6 alkyl, CO 2 H and OC 1-6 alkyl, said CO 2 C 1-6 alkyl and OC 1-6 alkyl substituents being linear or branched and optionally substituted with 1–5 halogens,
(4) C 1-10 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl, 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being halogens;
(f) CONR 7 R 7 ,
(g) SO 2 NR 7 R 7 ,
(h) NR 7 C(O)R 7 ,
(i) NR 7 C(O)NR 7 R 7 ,
(j) NR 7 CO 2 R 5 ,
(k) OC(O)R 7 ,
(l) OC(O)NR 7 R 7 ,
(m) NR 7 S(O) 2 R 5 ,
(n) NR 7 R 7 ,
(o) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–6 substituents independently selected from 0–1 C 3-6 cycloalkyl and 0–5 halogens, and
(p) C 3-6 cycloalkyl, which is optionally substituted with 1–6 halogens;
(5) OC 1-10 alkyl, 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) CO 2 H,
(c) CO 2 C 1-6 alkyl, 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
(f) CONR 7 R 7 ,
(g) SO 2 NR 7 R 7 ,
(h) NR 7 C(O)R 7 ,
(i) NR 7 C(O)NR 7 R 7 ,
(j) NR 7 CO 2 R 5 ,
(k) OC(O)R 7 ,
( 1 ) OC(O)NR 7 R 7 ,
(m) NR 7 S(O) 2 R 5 ,
(n) NR 7 R 7 ,
(o) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–6 substituents independently selected from 0–1 C 3-6 cycloalkyl and 0–5 halogens, and
(p) C 3-6 cycloalkyl, which is optionally substituted with 1–6 halogens;
(6) CO 2 H;
(7) CO 2 C 1-6 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, C 1-6 alkyl, and OC 1-6 alkyl, said C l-6 alkyl and OC 1-6 alkyl 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, C 1-6 alkyl, and OC 1-6 alkyl, said C 1-6 alkyl and OC 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
(10) CONR 7 R 7 ;
(11) SO 2 NR 7 R 7 ;
(12) NR 7 C(O)R 7 ;
(13) NR 7 C(O)NR 7 R 7 ;
(14) NR 7 CO 2 R 5 ;
(15) OC(O)R 7 ;
(16) OC(O)NR 7 R 7 ;
(17) NR 7 S(O) 2 R 5 ;
(18) NR 7 R 7 ; and
(19) phenyl, which is optionally substituted with 1–5 groups independently selected from halogen, OH, C 1-6 alkyl, OC 1-6 alkyl, CO 2 H, and CO 2 C 1-6 alkyl, said C 1-6 alkyl, OC 1-6 alkyl, and CO 2 C 1-6 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 5 is selected from the group consisting of phenyl, C 3-6 cycloalkyl and C 1-6 alkyl, wherein C 1-6 alkyl 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 R 5 when R 5 is phenyl or C 3-6 cycloalkyl are optionally substituted with 1–5 substituents independently selected from halogen, OH, C 1-5 alkyl, and OC 1-5 alkyl, said C 1-5 alkyl and OC 1-5 alkyl being linear or branched and optionally substituted with 1–5 halogens;
R 7 is selected from
(1) H, and
(2) R 5 ;
R 8 is selected from
(1) H, and
(2) C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens;
R 9 is C(═O)NR 4 Z; and
R 10 and R 11 are each selected from the group consisting of H, F and C 1-6 alkyl, which is linear or branched and is optionally substituted with 1–5 halogens.
10. A compound having formula Ia as recited in claim 9 , wherein R 2 and R 3 are H.
11. A compound having formula Ia as recited in claim 9 , wherein Ar is phenyl, which is optionally substituted as in claim 1 .
12. A compound having Formula Ia as recited in claim 9 , wherein R 4 is H.
13. A compound having Formula Ia as recited in claim 9 , wherein Q is C(═O)NHZ, Z is selected from CH 2 phenyl, cyclohexyl and cyclopentyl, and R 9 is C(═O)NHCH 2 phenyl, where phenyl, cyclohexyl and cyclopentyl are optionally substituted as in claim 1 .
14. A compound having Formula Ia as recited in claim 9 , wherein R 8 is H.
15. A compound having Formula Ia as recited in claim 9 , wherein said 8–10 membered bicyclic ring system is selected from the group consisting of indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, isoquinoline, tetrahydroisoquinoline, and dihydroisoquinoline.
16. A compound having Formula Ia as recited in claim 9 , wherein said 5- or 6-membered heterocycle is selected from the group consisting of furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, tetrazolidine, and triazolidine.
17. A compound having Formula Ib:
including pharmaceutically acceptable salts and prodrugs thereof, wherein Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X , Q and Z are as defined in any of claims 1 – 16 .
18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
19. A method for treating, controlling, or preventing non-insulin dependent (Type 2) diabetes mellitus in a mammalian patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 1 .