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US 2011/0212938 A1Published application
Bicyclic heterocycle derivatives and their use as modulators of the activity of gpr119
AssigneeSchering Corporation
InventorsYan Xia, Craig D. Boyle, William J. Greenlee, Samuel Chackalamannil, Charles Lee Jayne
Life of this patent
Estimating the term…
Abstract
The present invention relates to Bicyclic Heterocycle Derivatives, compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient.
Claims41
A compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl or -5- or 6-membered heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-alkyl-OH, —O-alkyl-O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)mR4, —S(O)nR4 and —S(O)mN(R4)2;
- B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, -alkylene-S(O)2-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)mR4, —S(O)nR4 and —S(O)mN(R4)2, wherein a cycloalkyl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group;
- W is a bond, alkylene, —C(O)—, —C(O)—O—, —C(O)—S—, —S(O)—, —S(O)2—, —S(O)2—N(R10)— or —C(O)—N(R10)—;
- X is —C(R1)2—, —O—, —N(R10)— or —S—;
- Y is —O-(alkylene)t-, —N(R10)-(alkylene)t-, or —S—;
- Z is a single bond, a double bond, —C(O)—, —C═NOR12, —C═C(R14)2, —C(R14)2, —C(R1)2—, —O—, —N(R10)— or —S(O)n—, such that when q is 0, Z is other than a double bond;
- each occurrence of R1 is independently H, alkyl, cycloalkyl, halo or —OR7;
- wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups:
- —O-alkyl, —OH or —N(R4)2;
- and wherein any two geminal R1 groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycloalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group;
- and wherein any two R1 groups present on separate ring carbon atoms can join to form a cycloalkyl or heterocycloalkyl bridge;
- and wherein when any R1 group is —OH, then the carbon atom to which the R1 group is attached is not also attached to another oxygen atom or to a nitrogen or halogen atom;
- each occurrence of R2 is independently H or alkyl;
- R3 is alkyl, -(alkylene)talkenyl, -(alkylene)t-alkynyl, -(alkylene)t-C(O)R4, -(alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene)t-aryl, -alkylene-S-aryl, -alkylene-N(R4)C(O)O-alkyl, —CH(cycloalkyl)2, —CH(heterocycloalkyl)2, -(alkylene)t-aryl, -(alkylene)t-cycloalkyl, -(alkylene)t-cycloalkenyl, -(alkylene)t-heterocycloalkyl, -(alkylene)theterocycloalkenyl or -(alkylene)theteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9;
- each occurrence of R4 is H, alkyl, cycloalkyl or -(alkylene)talkenyl, wherein an alkyl group is unsubstituted or optionally substituted with halo, —OH or —O-alkyl;
- R7 is H or alkyl;
- R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, —CN, —NO2, —O-(alkylene)t-R13, —S-(alkylene)t-R13, —N(R13)-(alkylene)t-R13, -(alkylene)t-R13, —C(O)-(alkylene)t-R13, —C(O)O-(alkylene)t-R13, —N(R7)C(O)-(alkylene)t-R13, —C(O)N(R7)-(alkylene)t-R13, —OC(O)-(alkylene)t-R13, —N(R7)C(O)N(R7)-(alkylene)t-R13, —N(R7)C(O)O-(alkylene)t-R13, —S(O)-(alkylene)t-R13 or —S(O)2(alkylene)t-R13;
- R10-is H, alkyl, aryl, or —C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with —OH or —O-alkyl;
- R12 is H, alkyl or aryl;
- each occurrence of R13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl;
- each occurrence of R14 is independently H, alkyl or aryl, or both R14 groups, and the carbon atom to which they are attached, combine to form a cycloalkyl or heterocycloalkyl group;
- each occurrence of m is independently 1 or 2;
- each occurrence of n is independently 0, 1 or 2;
- p is 0, 1 or 2;
- q is 0, 1 or 2;
- r is 0, 1 or 2;
- s is 0, 1 or 2;
- each occurrence of t is independently 0 or 1;
- and
- u is 0, 1 or 2.
30 more elements
-5. (canceled)
-8. (canceled)
-11. (canceled)
(canceled)
-18. (canceled)
-21. (canceled)
(canceled)
-29. (canceled)
-33. (canceled)
-38. (canceled)
(canceled)
A compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- W is a bond, —C(O)—O— or —S(O)2—;
- X is —O— or —NH—;
- Y is —O—, such that the group —Y-A-X—B can be in an exo- or endo-configuration with respect to the bicyclic ring to which variable Y is attached;
- Z is a bond, —CH2— or —O—;
- A is a heteroaryl, which is unsubstituted or optionally substituted with up to 2 groups, which can be the same or different, and are selected from alkyl, halo and —O-alkyl, such that when Y is —O—, A is other than pyridyl;
- B is aryl or a -5- or 6-membered heteroaryl group, each of which can be unsubstituted or optionally substituted with up to 3 groups, which can be the same or different, and are selected from:
- alkyl, heteroaryl, halo, —CN, —S(O)2-alkyl and —S(O)2-cycloalkyl;
- R3 is alkyl, -alkylene-aryl, -cycloalkyl, -alkylene-O-alkyl or haloalkyl, wherein a cycloalkyl group can be unsubstituted or substituted with an alkyl group;
- R7 is H;
- p is 0, 1 or 2;
- q is 0, 1 or 2;
- r is 0, 1 or 2;
- s is 0, 1 or 2;
- and
- u is 0, 1 or 2.
13 more elements
(canceled)
-47. (canceled)
A compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl or -5- or 6-membered heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-alkyl-OH, —O-alkyl-O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)mR4, —S(O)nR4 and —S(O)mN(R4)2, such that when Y is —O—, A is other than phenyl or pyridyl;
- B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)mR4, —S(O)nR4 and —S(O)mN(R4)2, wherein a cycloalkyl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group, wherein the 4 to 7-membered cycloalkyl group or cycloalkanoyl group can be unsubstituted or optionally substituted with R9;
- W is a bond, alkylene, —C(O)—, —C(O)—O—, —S(O)—, —S(O)2—, —S(O)2—N(R10)— or —C(O)—N(R10)—;
- X is —C(R1)2—, —O—, —N(R10)— or —S—;
- Y is —O-(alkylene)t-, —N(R10)-(alkylene)t-, or —S—;
- such that the group —Y-A-X—B can be in an exo- or endo-configuration with respect to the bicyclic ring to which variable Y is attached;
- R is R1 when Y is —C(R1)2—, and R is R4 when Y is other than —C(R1)2—;
- each occurrence of R1 is independently H, alkyl, cycloalkyl, halo or —OR7;
- or any two geminal R1 groups, together with the common carbon atom to which they are attached, join to form a spirocyclic 3- to 6-membered cycloalkyl group or a spirocyclic 3- to 6-membered heteroaryl group;
- or any two R1 groups present on adjacent carbon atoms, together with the adjacent carbon atoms to which they are attached, join to form a fused 3- to 6-membered cycloalkyl group, a fused 3- to 6-membered heteroaryl group or a fused aryl group;
- and wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups:
- —O-alkyl, —OH or —N(R4)2;
- and wherein an optional endocyclic double bond can be present between any two adjacent ring carbon atoms;
- R3 is alkyl, -(alkylene)t-alkenyl, -(alkylene)t-alkynyl, -(alkylene)t-C(O)R4, -(alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene)t-aryl, -alkylene-S-aryl, -alkylene-N(R4)C(O)O-alkyl, —CH(cycloalkyl)2, —CH(heterocycloalkyl)2, -(alkylene)t-aryl, -(alkylene)t-cycloalkyl, -(alkylene)t-cycloalkenyl, -(alkylene)t-heterocycloalkyl, -(alkylene)t-heterocycloalkenyl or -(alkylene)t-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9;
- each occurrence of R4 is H, alkyl, cycloalkyl or -(alkylene)t-alkenyl, wherein an alkyl group is unsubstituted or optionally substituted with halo, —OH or —O-alkyl;
- each occurrence of R5 is independently H, alkyl, -(alkylene)t-aryl, heterocycloalkyl, heteroaryl or cycloalkyl;
- each occurrence of R7 is independently H or alkyl;
- R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, —CN, —NO2, —O-(alkylene)t-R13, —S-(alkylene)t-R13, —N(R13)-(alkylene)t-R13, -(alkylene)t-R13, —C(O)-(alkylene)t-R13, —C(O)O-(alkylene)t-R13, —N(R7)C(O)-(alkylene)t-R13, —C(O)N(R7)-(alkylene)t-R13, —OC(O)-(alkylene)tR13, —N(R7)C(O)N(R7)-(alkylene), —R13, —N(R7)C(O)O-(alkylene)t-R13, —S(O)-(alkylene)t-R13 or —S(O)2(alkylene)t-R13;
- R10 is H, alkyl, aryl, or —C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with —OH or —O-alkyl;
- each occurrence of R13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl;
- each occurrence of m is independently 1 or 2;
- each occurrence of n is independently 0, 1 or 2;
- p is an integer ranging from 0 to 3, such that the sum of p and q is at least 1;
- q is an integer ranging from 0 to 3;
- r is an integer ranging from 0 to 3, such that the sum of r and s is at least 1;
- s is an integer ranging from 0 to 3;
- and
- each occurrence of t is independently 0 or 1.
28 more elements
-61. (canceled)
A compound having the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl or -5- or 6-membered heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-alkyl-OH, —O-alkyl-O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)mR4, —S(O)nR4 and —S(O)mN(R4)2, such that when Y is —O—, A is other than phenyl or pyridyl;
- B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from:
- alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R4)2, —C(O)H, —C(O)R4, —C(O)OR4, —C(O)N(R4)2, —NHC(O)R4, —NHS(O)m, R4, —S(O)nR4 and —S(O)mN(R4)2, wherein a cycloalkyl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group, wherein the 4 to 7-membered cycloalkyl group or cycloalkanoyl group can be unsubstituted or optionally substituted with R9;
- W is a bond, alkylene, —C(O)—, —C(O)—O—, —S(O)—, —S(O)2—, —S(O)2—N(R10)— or —C(O)—N(R10)—;
- X is —C(R1)2—, —O—, —N(R10)— or —S—;
- Y is —O-(alkylene)t-, —N(R10)-(alkylene)t-, or —S—;
- such that the group —Y-A-X—B can be in an exo- or endo-configuration with respect to the bicyclic ring to which variable Y is attached;
- R is R1 when Y is —C(R1)2—, and R is R4 when Y is other than —C(R1)2—;
- each occurrence of R1 is independently H, alkyl, cycloalkyl, halo or —OW;
- or any two geminal R1 groups, together with the common carbon atom to which they are attached, join to form a spirocyclic 3- to 6-membered cycloalkyl group or a spirocyclic 3- to 6-membered heteroaryl group;
- or any two R1 groups present on adjacent carbon atoms, together with the adjacent carbon atoms to which they are attached, join to form a fused 3- to 6-membered cycloalkyl group, a fused 3- to 6-membered heteroaryl group or a fused aryl group;
- and wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups:
- —O-alkyl, —OH or —N(R4)2;
- and wherein an optional endocyclic double bond can be present between any two adjacent ring carbon atoms;
- each occurrence of R2 is independently H, alkyl, halo or —OH;
- R3 is alkyl, -(alkylene)t-alkenyl, -(alkylene)t-alkynyl, -(alkylene)t-C(O)R4, -(alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene)t-aryl, -alkylene-S-aryl, -alkylene-N(R4)C(O)O-alkyl, —CH(cycloalkyl)2, —CH(heterocycloalkyl)2, -(alkylene)t-aryl, -(alkylene)t-cycloalkyl, -(alkylene)t-cycloalkenyl, -(alkylene)t-heterocycloalkyl, -(alkylene)t-heterocycloalkenyl or -(alkylene)t-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9;
- each occurrence of R4 is H, alkyl, cycloalkyl or -(alkylene)t-alkenyl, wherein an alkyl group is unsubstituted or optionally substituted with halo, —OH or —O-alkyl;
- each occurrence of R5 is independently H, alkyl, -(alkylene)t-aryl, heterocycloalkyl, heteroaryl or cycloalkyl;
- each occurrence of R7 is independently H or alkyl;
- R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, —CN, —NO2, —O-(alkylene)t-R13, —S-(alkylene)t-R13, —N(R13)-(alkylene)t-R13, -(alkylene)t-R13, —C(O)-(alkylene)t-R13, —C(O)O-(alkylene)t-R13, —N(R7)C(O)-(alkylene)t-R13, —C(O)N(R7)-(alkylene)t-R13, —OC(O)-(alkylene)t-R13, —N(R7)C(O)N(R7)-(alkylene)t-R13, —N(R7)C(O)O-(alkylene)t-R13, —S(O)-(alkylene)t-R13 or —S(O)2(alkylene)t-R13;
- R10 is H, alkyl, aryl, or —C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with —OH or —O-alkyl;
- each occurrence of R13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl;
- each occurrence of m is independently 1 or 2;
- each occurrence of n is independently 0, 1 or 2;
- p is 0, 1 or 2;
- q is 0, 1 or 2;
- r is 0, 1 or 2;
- s is 0, 1 or 2;
- and
- each occurrence of t is independently 0 or 1.
29 more elements
-75. (canceled)
A compound being any compound numbered from 1-611 in the above specification, or a pharmaceutically acceptable salt thereof.
-97. (canceled)
-102. (canceled)
-108. (canceled)
-126. (canceled)
Dependencies are inferred from the claim text.