Heteroaryl linked quinolinyl modulators of RORγt
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Abstract
The present invention comprises compounds of Formula I.
wherein:
R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification.
The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Citations
24 Claims
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1. A compound of Formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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2. A compound of claim 1 wherein:
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R1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl;
wherein said piperidinyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, or quinolinyl are optionally substituted with C(O)C(1-4)alkyl, C(O)NH2, C(1-4)alkyl, CF3, CH2CF3, Cl, F, —
CN, OC(1-4)alkyl, N(C(1-4)alkyl)2, —
(CH2)3OCH3, SC(1-4)alkyl, OH, CO2H, CO2C(1-4)alkyl, OCF3, OCHF2, SO2CH3, SO2NH2, or OCH2OCH3; and
optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, C(1-2)alkyl, SCH3, OC(1-2)alkyl, CF3, —
CN, and F; and
wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO2CH3, SO2NH2, C(O)NH2, —
CN, OC(1-2)alkyl, (CH2)(2-3)OCH3, SCH3, CF3, F, Cl, and C(1-2)alkyl; and
said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO2CH3, SO2NH2, C(O)NH2, —
CN, OC(1-4)alkyl, (CH2)(2-3)OCH3, SC(1-4)alkyl, CF3, F, Cl, and C(1-4)alkyl;R2 is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—
C(1-3)alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C(1-2)alkyl imidazolyl;
wherein said 1-C(1-2)alkyl imidazolyl is optionally substituted with up to two additional substituents independently selected from the group consisting of C(1-2)alkyl, SCH3, OC(1-2)alkyl, CF3, —
CN, F, and Cl; and
said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO2CH3, SO2NH2, C(O)NH2, —
CN, OC(1-2)alkyl, (CH2)(2-3)OCH3, SCH3, CF3, F, Cl, and C(1-2)alkyl; and
said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO2CH3, SO2NH2, C(O)NH2, —
CN, OC(1-2)alkyl, (CH2)(2-3)OCH3, SCH3, CF3, F, Cl, and C(1-2)alkyl; and
said 1-methyl pyrazolyl is optionally substituted with up to two additional CH3 groups;R6 is —
O-phenyl, —
NHphenyl, —
N(C(1-3)alkyl)phenyl, —
N(CO2C(CH3)3)phenyl, N(COCH3)phenyl, —
O-pyridyl, —
NHpyridyl, —
N(C(1-3)alkyl)pyridyl, N(CO2C(CH3)3)pyridyl, N(COCH3)pyridyl, —
O-pyrimidinyl, —
NHpyrimidinyl, —
N(C(1-3)alkyl)pyrimidinyl, N(CO2C(CH3)3)pyrimidinyl, N(COCH3)pyrimidinyl, —
O-pyridazyl, —
NHpyridazyl, —
N(C(1-3)alkyl)pyridazyl, N(CO2C(CH3)3)pyridazyl, N(COCH3)pyridazyl, —
O-pyrazinyl, —
NHpyrazinyl, —
N(C(1-3)alkyl)pyrazinyl, N(CO2C(CH3)3)pyrazinyl, or N(COCH3)pyrazinyl;
wherein said phenyl or said pyridyl is optionally substituted with OCF3, SO2C(1-4)alkyl, CF3, CHF2, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, C(1-4)alkyl, C(3-4)cycloalkyl, OC(1-4)alkyl, N(CH3)2, SO2NH2, SO2NHCH3, SO2N(CH3)2, CONH2, CONHCH3, CON(CH3)2, Cl, F, —
CN, CO2H, OH, CH2OH, NHCOC(1-2)alkyl, COC(1-2)alkyl, or SCH3;R7 is H, Cl, —
CN, C(1-4)alkyl, OC(1-4)alkylCF3, OCH2CH2OC(1-4)alkyl, CF3, SCH3, CH2NA1A2, CH2OC(2-3)alkylNA1A2, NA1A2, C(O)NA1A2, N(CH3)C(2-4)alkylNA1A2, OC(2-4)alkylNA1A2, OC(1-4)alkyl, OCH2-(1-methyl)-imidazol-2-yl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl;
wherein said imidazolyl or pyrazolyl is optionally substituted with one CH3 group;A1 is H, or C(1-4)alkyl; A2 is H, C(1-4)alkyl, C(1-4)alkylOC(1-4)alkyl, C(1-4)alkylOH, C(O)C(1-4)alkyl, or OC(1-4)alkyl;
or A1 and A2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of;
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3. A compound of claim 2 wherein:
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R1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl;
wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with C(O)C(1-4)alkyl, C(O)NH2, C(1-4)alkyl, CF3, CH2CF3, Cl, F, —
CN, OC(1-4)alkyl, N(C(1-4)alkyl)2,-(CH2)3OCH3, SC(1-4)alkyl, OH, CO2H, CO2C(1-4)alkyl, OCF3, OCHF2, SO2CH3, SO2NH2, or OCH2OCH3; and
optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH3, and CH3; and
wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH3 groups;R2 is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—
C(1-2)alkyl-piperidinyl, thiazolyl, pyridazyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C(1-2)alkyl imidazolyl;
wherein said 1-C(1-2)alkyl imidazolyl is optionally substituted with up to two additional CH3 groups, or one substituent selected from the group consisting of SCH3, and Cl; and
said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two subsitutents independently selected from the group consisting of SO2CH3, SO2NH2, C(O)NH2, —
CN, OCH3, CF3, Cl, and CH3; and
said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two CH3 groups; and
said 1-methyl pyrazolyl is optionally substituted with up to two additional CH3 groups;R6 is —
O-phenyl, —
NHphenyl, —
N(C(1-3)alkyl)phenyl, —
N(CO2C(CH3)3)phenyl, N(COCH3)phenyl, —
O-pyridyl, —
NHpyridyl, —
N(C(1-3)alkyl)pyridyl, N(CO2C(CH3)3)pyridyl, N(COCH3)pyridyl, —
O-pyrimidinyl, —
NHpyrimidinyl, —
N(C(1-3)alkyl)pyrimidinyl, N(CO2C(CH3)3)pyrimidinyl, N(COCH3)pyrimidinyl, —
O-pyridazyl, —
NHpyridazyl, —
N(C(1-3)alkyl)pyridazyl, N(CO2C(CH3)3)pyridazyl, N(COCH3)pyridazyl, —
O-pyrazinyl, —
NHpyrazinyl, —
N(C(1-3)alkyl)pyrazinyl, N(CO2C(CH3)3)pyrazinyl, or N(COCH3)pyrazinyl wherein said phenyl or said pyridyl is optionally substituted with OCF3, SO2CH3, CF3, CHF2, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, CH3, OCH3, N(CH3)2, SO2NH2, CONH2, Cl, F,—
CN, CO2H, OH, CH2OH, NHCOCH3, or COCH3;R7 is H, Cl, —
CN, C(1-4)alkyl, OC(1-4)alkylCF3, OCH2CH2OC(1-4)alkyl, CF3, SCH3, NA1A2, C(O)NA1A2, N(CH3)C(2-4)alkylNA1A2, OC(2-4)alkylNA1A2, OC(1-4)alkyl, OCH2-(1-methyl)-imidazol-2-yl, imidazolyl, furyl, pyrazolyl, pyridyl, or pyrimidinyl;
wherein said imidazolyl or pyrazolyl is optionally substituted with one CH3 group;A1 is H, or C(1-4)alkyl; A2 is H, C(1-4)alkyl, C(1-4)alkylOC(1-4)alkyl, C(1-4)alkylOH, C(O)C(1-4)alkyl, or OC(1-4)alkyl;
or A1 and A2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of;
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4. A compound of claim 3 wherein:
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R1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl;
wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with SO2CH3, C(O)CH3, C(O)NH2, CH3, CH2CH3, CF3, Cl, F, —
CN, OCH3, N(CH3)2, —
(CH2)3OCH3, SCH3, OH, CO2H, CO2C(CH3)3, or OCH2OCH3; and
optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH3, and CH3;and wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH3 groups; R2 is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—
C(1-2)alkyl-piperidinyl, thiazol-5-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C(1-2)alkyl imidazol-5-yl;
wherein said 1-C(1-2)alkyl imidazol-5-yl is optionally substituted with up to two additional CH3 groups, or one substituent selected from the group consisting of SCH3, and Cl; and
said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH2, —
CN, OCH3, CF3, Cl, and CH3; and
said thiazol-5-yl, and said isoxazolyl are optionally substituted with up to two CH3 groups; and
said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH3 groups;R5 is H, Cl, —
CN, CF3, SCH3, OC(1-3)alkyl, OH, C(1-4)alkyl, N(CH3)OCH3, NH(C(1-2)alkyl), N(C(1-2)alkyl)2, or 4-hydroxy-piperidinyl;R6 is —
O-phenyl, —
NHphenyl, —
N(C(1-3)alkyl)phenyl, —
N(CO2C(CH3)3)phenyl, —
O-pyridyl, —
NHpyridyl, —
N(C(1-3)alkyl)pyridyl, or —
N(CO2C(CH3)3)pyridyl wherein said phenyl or said pyridyl is optionally substituted with OCF3, SO2CH3, CF3, CHF2, imidazol-l-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH3, OCH3, Cl, F, or —
CN;R7 is H, Cl, —
CN, C(1-4)alkyl, OCH2CF3, OCH2CH2OCH3, CF3, SCH3, NA1A2, C(O)NHCH3, N(CH3)CH2CH2NA1A2, OCH2CH2NA1A2, OC(1-3)alkyl, OCH2-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl;
wherein said imidazolyl or pyrazolyl is optionally substituted with one CH3 group;A1 is H, or C(1-4)alkyl; A2 is H, C(1-4)alkyl, C(1-4)alkylOC(1-4)alkyl, C(1-4)alkylOH, C(O)C(1-2)alkyl, or OCH3;
or A1 and A2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of;
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5. A compound of claim 4 wherein:
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R1 is thiazolyl, pyridyl, or phenyl;
wherein said pyridyl, and said phenyl, are optionally substituted with CF3, Cl, or OCH3;R2 is pyrid-3-yl, or 1-methyl imidazol-5-yl; R3 is OH; R4 is H; R5 is Cl, —
CN, CF3, or OC(1-2)alkyl;R6 is —
O-phenyl, —
NHphenyl, —
N(C(1-3)alkyl)phenyl, or —
N(CO2C(CH3)3)phenyl;
wherein said —
O-phenyl is optionally substituted with Cl, F, or —
CN;R7 is Cl, —
CN, NA1A2, or OC(1-2)alkyl;A1 is C(1-2)alkyl; A2 is C(1-2)alkyl, or CH2CH2OCH3;
or A1 and A2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of;
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6. A compound of claim 1 selected from the group consisting of:
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7. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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8. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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9. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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10. A method for treating or ameliorating a RORγ
- t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1, wherein the disease is selected from the group consisting of;
rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn'"'"'s disease, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis.
- t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1, wherein the disease is selected from the group consisting of;
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11. The method of claim 10, wherein the disease is psoriasis.
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12. The method of claim 10, wherein the disease is rheumatoid arthritis.
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13. The method of claim 10, wherein the disease is ulcerative colitis.
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14. The method of claim 10, wherein the disease is Crohn'"'"'s disease.
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15. The method of claim 10, wherein the disease is multiple sclerosis.
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16. The method of claim 10, wherein the disease is neutrophilic asthma.
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17. The method of claim 10, wherein the disease is steroid resistant asthma.
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18. The method of claim 10, wherein the disease is psoriatic arthritis.
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19. The method of claim 10, wherein the disease is ankylosing spondylitis.
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20. The method of claim 10, wherein the disease is systemic lupus erythematosus.
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21. The method of claim 10, wherein the disease is chronic obstructive pulmonary disorder.
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22. A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of:
- rheumatoid arthritis, and psoriasis.
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23. A method for treating or ameliorating a RORγ
- t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 6, wherein the disease is selected from the group consisting of;
rheumatoid arthritis and psoriasis.
- t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 6, wherein the disease is selected from the group consisting of;
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24. A method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
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2. A compound of claim 1 wherein:
Specification
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Current AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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Original AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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InventorsLeonard, Kristi A., Barbay, Kent, Edwards, James P., Kreutter, Kevin D., Kummer, David A., Maharoof, Umar, Nishimura, Rachel, Urbanski, Maud, Venkatesan, Hariharan, Wang, Aihua, Wolin, Ronald L., Woods, Craig R., Fourie, Anne, Xue, Xiaohua
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Primary Examiner(s)Seaman, D M
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Application NumberUS14/053,682Publication NumberTime in Patent Office903 DaysField of Search546/159, 514/312US Class Current1/1CPC Class CodesA61K 31/4709 Non-condensed quinolines an...A61K 45/06 Mixtures of active ingredie...A61P 1/02 Stomatological preparations...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 13/08 of the prostateA61P 13/10 of the bladderA61P 13/12 of the kidneysA61P 15/08 for gonadal disorders or fo...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 25/00 Drugs for disorders of the ...A61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/04 Antibacterial agentsA61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...C07D 401/06 : linked by a carbon chain co...C07D 401/14 : containing three or more he...C07D 417/14 : containing three or more he...