Therapeutic compounds
AssigneeRegents of the University of Minnesota
InventorsSwati S. More, Robert Vince
Life of this patent
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Abstract
The invention provides methods for producing analgesia in an animal comprising administering to the animal a compound of the formula Ia′, Ib′, Ic′, and Id′: and pharmaceutically acceptable salts thereof, wherein the variables A, R6, R7, R8, R9, Rx, L, X, Y, and Z have the meaning as described herein.
Claims19
A method for producing analgesia in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′:
- or a pharmaceutically acceptable salt thereof;
- i) wherein the compound of formula Ia′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is selected from the group consisting of:
- —CH2CH2—, —CH2NH—, —CH2C(═O)—, —CH(OH)CH2—,
- RL is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C3-8 cycloalkyl;
- ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORy, —SRy, —N(Ry)2, —NO2 or —CN;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRf, —N(Rf)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- R8 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- X is ═O, ═S or ═N—Rx;
- wherein Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rc is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ry is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ry groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- ii) wherein the compound of formula Ib′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- Y is S or —NR6—;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRf, —N(Ra)2, oxo, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, Oxo, —NO2 or —CN;
- R8 is hydrogen, phenyl, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rc is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iii) wherein the compound of formula Ic′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is —CH═N—, or C1-4 alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C3-8 cycloalkyl;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- ring Z is heteroaryl or unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from oxo (═O), C1-4 alkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iv) wherein the compound of formula Id′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- and
- R9 is hydrogen or —C(═NH)—NH2.
A method for treating a condition in an animal wherein the condition is selected from the group consisting of reducing endoplasmic reticulum stress and reducing drug-induced toxicity comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′:
- or a pharmaceutically acceptable salt thereof;
- i) wherein the compound of formula Ia′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is selected from the group consisting of:
- —CH2CH2—, —CH2NH—, —CH2C(═O)—, —CH(OH)CH2—,
- RL is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C3-8 cycloalkyl;
- ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORy, —SRy, —N(Ry)2, —NO2 or —CN;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRf, —N(Rf)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- R8 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- X is ═O, ═S or ═N—Rx;
- wherein Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rc is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ry is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ry groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- ii) wherein the compound of formula Ib′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- Y is S or —NR6—;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRi, —N(Ra)2, oxo, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- R8 is hydrogen, phenyl, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rc is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iii) wherein the compound of formula Ic′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is —CH═N—, or C1-4 alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C3-8 cycloalkyl;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, Oxo, —NO2 or —CN;
- ring Z is heteroaryl or unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from oxo (═O), C1-4 alkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iv) wherein the compound of formula Id′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- and
- R9 is hydrogen or —C(═NH)—NH2;
- provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not
- or a pharmaceutically acceptable salt thereof.
(canceled)
A method for treating a disease selected from the group consisting of diabetes, viral infection, liver disease, and cancer in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′:
- or a pharmaceutically acceptable salt thereof;
- i) wherein the compound of formula Ia′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is selected from the group consisting of:
- —CH2CH2—, —CH2NH—, —CH2C(═O)—, —CH(OH)CH2—,
- RL is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C3-8 cycloalkyl;
- ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORy, —SRy, —N(Ry)2, —NO2 or —CN;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRf, —N(Rf)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- R8 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- or R6 and R8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- X is ═O, ═S or ═N—Rx;
- wherein Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each RC is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ry is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ry groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- ii) wherein the compound of formula Ib′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- Y is S or —NR6—;
- R6 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORf, —SRf, —N(Ra)2, oxo, —NO2 or —CN;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- R8 is hydrogen, phenyl, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 or —CN;
- Rx is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- or Rx and R8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rb is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rb groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rc is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rc groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rd is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Rd groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rf is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rf groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rh is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rh groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iii) wherein the compound of formula Ic′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- L is —CH═N—, or C1-4 alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C3-8 cycloalkyl;
- R7 is hydrogen, or C1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 or —CN;
- ring Z is heteroaryl or unsaturated heterocycle;
- wherein the heteroaryl and heterocycle are optionally substituted with one or more groups selected from oxo (═O), C1-4 alkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, —NO2 or —CN;
- each Ra is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Ra groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Re is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl, wherein the C1-4 alkyl and C1-4 haloalkyl are optionally substituted with aryl or heteroaryl;
- or two Re groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- each Rg is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Rg groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- and
- each Ri is independently hydrogen, C1-4 alkyl or C1-4 haloalkyl;
- or two Ri groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- iv) wherein the compound of formula Id′:
- ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, —NO2 and —CN;
- and
- R9 is hydrogen or —C(═NH)—NH2;
- provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not
- or a pharmaceutically acceptable salt thereof.
(canceled)
(canceled)
Dependencies are inferred from the claim text.