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1. WO2015027021 - DÉRIVÉS IMIDE ET ACYLURÉE UTILISÉS COMME MODULATEURS DU RÉCEPTEUR DE GLUCOCORTICOÏDES

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[ EN ]

WHAT IS CLAIMED IS:

1. A compound according to formula I,


I,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

X is selected from N and CRi;

Ri, R2, R3, R5, R5, R7, and Rg are the same or different and at each occurrence are

independently selected from hydrogen, halogen, Ci_galkyl, substituted Ci_galkyl, C2_galkenyl, substituted C2-galkenyl, C2-galkynyl, C2_gsubstituted alkynyl, nitro, cyano, dialkylaminoalkoxy, alkoxyalkyloxyalkyloxy, C3_7cycloalkyl,

C3_7cycloalkenyl, C3_7cycloalkynyl, heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl are each substituted with zero to three halogen, Ci_6alkyl, C ^hydroxy alky 1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -ORi2, =0, -NRi2Ri3, -C(=0)Ri2, -C(=0)ORi2, -C(=0)NRi2Ri3, -OC(=0)NRi2,Ri3, -NRi2C(0)NRi2Ri3, -OC(=0)Ri2, -NRi2C(=0)Ri3,

-NRi2C(0)ORi3, -NRi2C(S)ORi3, -S(0)pRi4, -NRi2S02Ri4, S02NRi2Ri3, C3_7cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with Ci_3alkyl, Ci_3hydroxyalkyl, Ci_3haloalkyl, Ci_3alkoxy, or Ci_3haloalkoxy;


R9 and Rio are the same or different and at each occurrence are independently Ci_6alkyl; or

R9 and Rio are taken together with the atom to which they are attached to form a

C3_7cycloalkyl, C3_7cycloalkenyl, or heterocyclo group;

R11 at each occurrence is independently selected from Ci_6alkyl, -OR15, -NR15R16,

C3_7cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered

heteroaryl optionally substituted with Ci_3alkyl, Ci_3hydroxyalkyl, Ci_3haloalkyl,

Ci_3alkoxy, or Ci_3haloalkoxy;

Ri2 and R13 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_8alkyl, substituted Ci_8alkyl, C2_8alkenyl, substituted C2_8alkenyl, C2-salkynyl, substituted C2-salkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R12 is taken together with

Ri3 to form a heteroaryl or heterocyclo ring each optionally substituted with OH, oxo, Ci_4alkoxy, Ci_4alkyl, halogen, and Ci_4haloalkyl;

Ri4 at each occurrence is independently selected from Ci.galkyl, substituted Ci_galkyl, C2_8alkenyl, substituted C2-salkenyl, C2-salkynyl, substituted C2-salkynyl,

C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo;

Ri5 and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_galkyl, substituted Ci_galkyl, C2_8alkenyl, substituted

C2_8alkenyl, C2-salkynyl, substituted C2-salkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R15 is taken together with

Ri6 to form a heteroaryl or heterocyclo ring; p is 0,1 and 2; and

provided the following compounds are excluded:


The compound as defined in Claim 1, having formula II,


n,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri, R2, and R3 are the same or different and at each occurrence are independently selected from halogen, Ci_galkyl, cyano, C3-7cycloalkyl, 3- to 10-membered heterocyclo, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl are each substituted with zero to three substituents independently selected from halogen, Ci_6alkyl,

Ci_6hydroxyalkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -ORi2, -NRi2Ri3, -C(=0)R12, -C(=0)OR12, -C(=0)NR12R13, -OC(=0)NR12,R13, -NR12C(0)NR12R13, -OC(=0)Ri2, -NRi2C(=0)Ri3, -NRi2C(0)ORi3, -NRi2C(S)ORi3, -S(0)pRi4, -NRi2S02Ri4, S02NRi2Ri3, C3_7cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with Ci_3alkyl,

Ci_3hydroxyalkyl, Ci_3haloalkyl, Ci_3alkoxy, or Ci_3haloalkoxy;

R5, Re, R7, and Rg are the same or different and at each occurrence are independently

selected from hydrogen, halogen, and Ci_6alkyl;

R11 at each occurrence is independently selected from Ci_6alkyl, -NR15R16, C3_7cycloalkyl, and 3- to 6-membered heterocycle;

Ri2 and Ri3 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_6alkyl, Ci_6hydroxyalkyl, Ci_6haloalkyl, Ci_6alkoxy,

Ci_6haloalkoxy, C3_7cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclo; or (ii) where possible, Ri2 is taken together with Ri3 to form a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclo ring optionally substituted with OH, oxo, Ci_4alkoxy, Ci_4alkyl, halogen, and

Ci_4haloalkyl;

Ri4 at each occurrence is independently selected from Ci_6alkyl, Ci_6hydroxyalkyl,

Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, C3_7cycloalkyl, phenyl, 5- to

6-membered heteroaryl, and 5- to 6-membered heterocycle; and

, and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_galkyl, substituted Ci_galkyl, C2_galkenyl, substituted C2_8alkenyl, C2_galkynyl, substituted C2_galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, Ri5 is taken together with Ri6 to form a heteroaryl or heterocyclo ring.

3. The compound as defined in Claim 2 havin the following formula III,


or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is independently selected from 5- to 10-membered aryl and 5- to 10-membered

heteroaryl, wherein said aryl and heteroaryl group are each substituted with zero to three substituents independently selected from halogen, Ci_6hydroxyalkyl, -ORi2, -NR12R13, -C(=0)Ri2, -C(=0)OR12, -C(=0)NR12,R13, -NR12C(=0)R13,

-S(0)2Ri4, -NRi2S02Ri4, phenyl, and 5- to 6-membered heteroaryl optionally substituted with Ci_3alkyl;

R5 is independently selected from is hydrogen and halogen;

R9 and Rio are Ci_3alkyl;

Ri2 and Ri3 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_6alkyl, Ci_6haloalkyl, and 5- to 6-membered heterocyclo; or (ii) where possible, Ri2 is taken together with Ri3 to form a 4- to 6-membered heterocyclo ring optionally substituted with Ci_3alkyl and oxo; and

Ri4 at each occurrence is independently Ci_6alkyl.

4. The compound as defined in Claim 3, or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Rii at each occurrence is independently selected from Ci_6alkyl, C3_7cycloalkyl, and

Ri5, and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_8alkyl, substituted Ci_8alkyl wherein the substituent is selected from OH and aryl optionally substitute with Ci_4alkoxy, C3_7Cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R15 is taken together with Ri6 to form a heteroaryl or heterocyclo ring.

5. A compound as defined in Claim 4, or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is phenyl, pyridyl or pyrimidinyl, each of which is substituted with zero to three

substituents independently selected from halogen, Ci_6hydroxyalkyl, -OR12, - R12R13, -C(=0)Ri2, -C(=0)ORi2, -C(=0)NRi2,Ri3, -NRi2C(=0)Ri3, -S(0)2Ri4, -NR12SO2R14, and 5- to 6-membered heteroaryl substituted with Ci_3alkyl group.

6. The compound as defined in Claim 5, or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is phenyl, pyridyl or pyrimidinyl, each of which is substituted with zero to three

substituents independently selected from F, CI, -OCF3, CH,



7. The compound as defined in Claim 3 or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is phenyl, pyridyl or pyrimidinyl, each of which is substituted with zero to three

substituents independently selected from halogen, Ci_6hydroxyalkyl, -OR12, - R12R13, -C(=0)Ri2, -C(=0)ORi2, -C(=0)NR12,R13, -NR12C(=0)R13, -S(0)2R14, -NRi2S02Ri4, and 5- to 6-membered heteroaryl substituted with Ci_3alkyl; and R11 at each occurrence is independently selected from Ci_6alkyl, and C3_7Cycloalkyl.

8. The compound as defined in Claim 3, or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is phenyl, pyridyl or pyrimidinyl, each of which is substituted with zero to three

substituents independently selected from halogen, Ci_6hydroxyalkyl, -ORi2, - R12R13, -C(=0)R12, -C(=0)OR12, -C(=0)NR12,R13, -NR12C(=0)R13, -S(0)2R14,

-NRi2S02Ri4, and 5- to 6-membered heteroaryl substituted with Ci_3alkyl;

R11 at each occurrence is independently selected from -NR15R16 and 3- to 6-membered heterocycle; and

Ri5, and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_galkyl, substituted Ci_galkyl wherein the substituent is selected from OH and aryl optionally substitute with Ci_4alkoxy, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R15 is taken together with Ri6 to form a heteroaryl or heterocyclo ring.

9. The compound as defined in Claim 8, having formula IV,

IV,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri is phenyl, pyridyl or pyrimidinyl, each of which is substituted with zero to three

substituents independently selected from F, CI, -OCF3, O CH3


R5 is independently selected from hydrogen and halogen;

R9 and Rio are Ci_3alkyl; and

Ri5 and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, methyl, ethyl, propyl, butyl, Ci_3alkyl substituted with OH or phenyl optionally substitute with methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and heteroaryl; or (ii) where possible, R15 is taken together

N


defined in Claim 9, wherein:


Rb is H, F, or CI; and


1 1. The compound as defined in Claim 1 , having formula V,


v,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:

Ri at each occurrence are independently selected from hydrogen, halogen, Ci_8alkyl, substituted Ci_8alkyl, C2_8alkenyl, substituted C2_8alkenyl, C2_8alkynyl,

C2_8substituted alkynyl, nitro, cyano, dialkylaminoalkoxy,

alkoxyalkyloxyalkyloxy, C3_7cycloalkyl, C3_7cycloalkenyl, C3_7cycloalkynyl, heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl are each substituted with zero to three halogen, Ci_6alkyl, Ci_6hydroxyalkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -ORi2, =0, - R12R13, -C(=0)R12, -C(=0)OR12, -C(=0)NR12R13, -OC(=0)NR12,R13,

-NRi2C(0)NRi2Ri3, -OC(=0)Ri2, -NRi2C(=0)Ri3, -NRi2C(0)ORi3,

-NRi2C(S)ORi3, -S(0)pRi4, -NRi2S02Ri4, S02NRi2Ri3, C3-7cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with Ci_3alkyl, Ci_3hydroxyalkyl, Ci_3haloalkyl, Ci_3alkoxy, or

Ci_3haloalkoxy;

R9 and Rio are the same or different and at each occurrence are independently Ci_6alkyl; or

R9 and Rio are taken together with the atom to which they are attached to form a

C3_7cycloalkyl, C3_7cycloalkenyl, or heterocyclo group;

Ri2 and R13 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_galkyl, substituted Ci_galkyl, C2_galkenyl, substituted C2_galkenyl, C2_galkynyl, substituted C2_galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, Ri2 is taken together with Ri3 to form a heteroaryl or heterocyclo ring each optionally substituted with OH, oxo, Ci_4alkoxy, Ci_4alkyl, halogen, and Ci_4haloalkyl;

Ri4 at each occurrence is independently selected from Ci_8alkyl, substituted Ci_galkyl, C2_8alkenyl, substituted C2_8alkenyl, C2_8alkynyl, substituted C2_8alkynyl,

C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo;

Ri5 and Ri6 are the same or different and at each occurrence are independently selected from (i) hydrogen, Ci_8alkyl, substituted Ci_8alkyl, C2_8alkenyl, substituted C2_8alkenyl, C2_8alkynyl, substituted C2_8alkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R15 is taken together with Ri6 to form a heteroaryl or heterocyclo ring; p is 0,1 and 2.

12. The compound as defined in Claim 1, or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein said compound is selected from Examples 1-84.

13. A pharmaceutical composition comprising a compound as defined in

Claim 1 and a pharmaceutically acceptable carrier therefor.

14. A method of treating a disease or disorder selected from an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, immune disease, neoplastic disease and metabolic disease, which comprise administering to a patient in need of treatment, a therapeutically effective amount of a compound as defined in Claim 1.

15. The method as defined in Claim 14 wherein the disease or disorder is an inflammatory or autoimmune disease selected from transplant rejection of kidney, liver, heart, lung, pancreas, bone marrow, cornea, small bowel, skin allografts, skin homografts, heart valve xenograft, serum sickness, and graft vs. host disease, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pyoderma gangrenum, systemic lupus erythematosis, myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Graves' disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjogren's syndrome, pernicious or

immunohaemolytic anemia, atherosclerosis, Addison's disease, idiopathic adrenal insufficiency, autoimmune polyglandular disease, glomerulonephritis, scleroderma, morphea, lichen planus, vitiligo, alopecia areata, autoimmune alopecia, autoimmune hypopituitarism, Guillain-Barre syndrome, and alveolitis; contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis, urticaria, skin allergies, respiratory allergies, hay fever, allergic rhinitis and gluten-sensitive enteropathy, osteoarthritis, acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sezary's syndrome, restenosis, stenosis and atherosclerosis, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer, juvenile rheumatoid arthritis,

Ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, psoriasis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemias and lymphomas in adults, acute leukemia of childhood, ulcerative colitis, regional enteritis, Crohn's disease, Sjogren's syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis, sepsis, and chronic obstructive pulmonary disease.

16. The method as defined in Claim 15 wherein the disease or disorder is selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, asthma, inflammatory bowel disease, systemic lupus, erythematosis, and psoriasis.