cGAS ANTAGONIST COMPOUNDS
AssigneesImmuneSensor Therapeutics, Inc., Board of Regents, The University of Texas System
InventorsBoyu Zhong, Lijun Sun, Heping Shi, Jing Li, Chuo Chen, Zhijian Chen
Life of this patent
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Abstract
Disclosed are novel compounds of Formula I that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.
Claims61
A compound of Formula Ta, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof,
- wherein:
- X is NH or S;
- Y is O or S;
- Z is O, S, CHR1a or NR1a;
- R1a is hydrogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- G is N or C;
- if G is N, R1 is hydrogen C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups,
- if G is N and if Z includes Ra, R1—R1a is connected as a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH— or —CH═C(CH3)— group;
- and
- if G is C and if Z includes R1a, R1—R1a is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;
- R1 is hydrogen or C1-6alkyl, or R1—R1a are connected form a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH—, or —CH═C(CH3)— group or together with carbon or nitrogen atoms to which they are attached form a pyridine, pyrimidine or pyrazine ring;
- R2 is hydrogen, halogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- R2a is phenyl or a heteroaryl group selected from the group consisting of imidazolyl, pyridyl, pyridizinyl, pyrimidinyl, and pyrazinyl, wherein the phenyl or heterocyclic group is optionally substituted with 1-4 substituents independently selected from halothe group consisting of halogen, —SR3a, —S(O)R3a —OR3a, —OCH2R3b, —OCH(CH3)R3b, —OC(O)NHR3a, —NR3aR4a—NHSO2R3a, azido, —CHO, —CO2R3a, cyano, C1-6alkyl or —CR5aR6aR7a, C2-6alkenyl, —C(R5a)═C(R8a)(R9a), C2-6alkynyl, and —C≡CR8a;
- R3a, R3b, and R4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl;
- wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkenyl, and C2-6alkynyl group;
- and the C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;
- and
- R5a, R6a, R7a, R8a and R9a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, cyclic —(C1-8alkoxyl)-, cyclic —(C1-6oxaalkoxyl)-, cyclic —(C1-6azaalkoxyl)-;
- wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, or thiazolyl, tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkenyl, and C2-6alkynyl group, and the C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups.
A compound of Formula Ib, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof,
- wherein:
- X is NH or S;
- Y is O or S;
- Z is O, S, CHR1a or NR1a;
- R1a is hydrogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- G is N or C;
- if G is N, R1 is hydrogen C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups, or R1-R1a is connected as a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH— or —CH═C(CH3)— group;
- and if G is C, R1—R1a is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;
- R1 is hydrogen or C1-6alkyl, or R1—R1a are connected form a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH—, or —CH═C(CH3)— group or together with carbon or nitrogen atoms to which they are attached form a pyridine, pyrimidine or pyrazine ring;
- R2 is hydrogen, halo, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- R3, R5, and R6 are independently hydrogen, halogen, —SR3a, —S(O)R3a —OR3a, —OCH2R3b, —OCH(CH3)R3b, —OC(O)NHR3a, —NR3aR4a—NHSO2R3a, azido, —CHO, CO2R3a, cyano, C1-6alkyl or —CR5aR6aR7a, C2-6alkeny, —C(R5a)═C(R8a)(R9a), C2-6alkynyl, —C≡CR8a, or R2-R3 are connected as a —CH2CH2— or —CH2CH2CH2— group;
- R3a, R3b, and R4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, C2-6alkynyl;
- wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkeny, and C2-6alkynyl group;
- and the C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;
- R4 is hydrogen or halogen.
A compound of Formula Ic, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof,
- wherein:
- X is NH or S;
- Y is O or S;
- Z is O, S, CHR1a or NR1a;
- R1a is hydrogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- G is N or C;
- if G is N, R1 is hydrogen C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups, or R1-R1a is connected as a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH— or —CH═C(CH3)— group;
- and if G is C, R1—R1a is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;
- W is OR10a or NHR10a;
- wherein R10a is hydrogen, C1-6alkyl, C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups, or R10a-R6 is connected as a —CH2—CH2—, —CH═CH—, —N═CH—, or —CH═N— group;
- R2 is hydrogen, halo, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- R3 and R6 are independently hydrogen, halogen, —SR3a, —S(O)R3a, —OR3a, —OCH2R3b, —OCH(CH3)R3b, —OC(O)NHR3a, —NR3aR4a—NHSO2R3a, azido, —CHO, CO2R3a, cyano, C1-6alkyl or —CR5aR6aR7a, C2-6alkeny, —C(R5a)═C(R8a)(R9a), C2-6alkynyl, —C ═CR8a, or R2—R3 are connected as a —CH2CH2— or —CH2CH2CH2— group;
- R3a, R3b, and R4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, C2-6alkynyl;
- wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkeny, and C2-6alkynyl group;
- and the C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;
- R4 is hydrogen or halogen.
A compound of Formula Id, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof,
- wherein:
- Z is O, S, CHR1a or NR1a;
- R1a is hydrogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
- G is N or C;
- if G is N, R1 is hydrogen C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups, or R1-R1a is connected as a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH— or —CH═C(CH3)— group;
- and if G is C, R1—R1a is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;
- R3 and R4 are independently hydrogen or halogen;
- R6 is hydrogen, halogen, —SR3a, —S(O)R3a, —OR3a, —OCH2R3b, —OCH(CH3)R3b, —OC(O)NHR3a, —NR3aR4a —NHSO2R3a, azido, —CHO, CO2R3a, cyano, C1-6alkyl or —CR5aR6aR7a, C2-6alkeny, —C(R5a)═C(R8a)(R9a), C2-6alkynyl, —C≡CR8a, or R2-R3 are connected as a —CH2CH2— or —CH2CH2CH2— group;
- R3a, R3b, and R4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, C2-6alkynyl;
- wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkeny, and C2-6alkynyl group;
- and the C1-6alkyl, cyclic —(C1-8alkyl)-, cyclic —(C1-6oxaalkyl)-, cyclic —(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups.
A compound selected from the group consisting of:
A compound selected from the group consisting of:
A compound selected from the group consisting of:
A compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof, for use in medical therapy.
A pharmaceutical composition comprising (a) a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or prodrug thereof, and (b) a pharmaceutically acceptable carrier, for use in medical therapy.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the modulation of cGAS activity in research, pharmaceutical and biotechnology development.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition in which modulation of cGAS activity is beneficial.
A method for treating a disease or condition for which modulation of cGAS activity is beneficial comprising:
- administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A method for treating a disease or condition for which modulation of cGAS is beneficial comprising:
- administering to a patient in need thereof, a therapeutically effective amount of a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.
The use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use the treatment of a disease or condition for which modulation of cGAS is beneficial.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition for which modulation of cGAS is beneficial.
A pharmaceutical composition comprising:
- a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for use in the treatment of a disease or condition for which modulation of cGAS is beneficial.
A pharmaceutical composition comprising:
- a compound of Formula I, or a pharmaceutically acceptable salt thereof, at least one further therapeutic agent, and one or more of pharmaceutically acceptable excipients, for use in the treatment of a disease or condition for which modulation of cGAS is beneficial.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory, allergic or autoimmune disease.
A method of treating an inflammatory, allergic or autoimmune disease comprising:
- administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A method for treating an inflammatory, allergic or autoimmune disease comprising:
- administering to a patient in need thereof, a therapeutically effective amount of a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of an inflammatory, allergic or autoimmune disease.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for the treatment of an inflammatory, allergic or autoimmune disease.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of an infectious disease.
A method of treating an infectious disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A method for treating an infectious disease comprising:
- administering to a patient in need thereof, a therapeutically effective amount of a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of an infectious disease.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for use in the treatment of an infectious disease.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a senescence-related disease.
A method of treating a senescence-related disease comprising:
- administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A method for treating a senescence-related disease comprising:
- administering to a patient in need thereof, a therapeutically effective amount of a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a senescence-related disease.
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for the treatment of a senescence-related disease.
Dependencies are inferred from the claim text.