US2016193216A1PendingUtilityA1
Irak inhibitors and uses thereof
Est. expiryJan 10, 2032(~5.5 yrs left)· nominal 20-yr term from priority
Inventors:Geraldine C. HarrimanRonald T. WesterDonna L. RomeroShaughnessy RobinsonMee ShelleyMatthew David WesselJeremy Robert GreenwoodCraig E. MasseRosana Kapeller-Libermann
A61P 37/02A61P 7/00A61P 35/02A61P 37/00A61P 7/02A61P 9/04A61P 9/00A61P 3/10A61P 43/00A61P 37/04A61P 37/08A61P 3/06A61P 9/12A61P 35/00A61P 37/06A61P 9/10A61P 7/06A61P 5/00A61P 25/04A61P 25/08A61P 25/16A61P 3/04A61P 25/28A61P 29/00A61P 27/06A61P 3/00A61P 27/14A61P 27/02A61P 27/12A61P 25/14A61P 31/12A61P 31/00A61P 27/16A61P 19/00A61P 1/04A61P 13/10A61P 17/06A61P 11/04A61P 21/02A61P 19/02A61K 31/519A61P 19/06A61P 21/00A61P 17/00A61P 11/00C07D 495/14A61P 11/02A61P 13/02A61P 1/02A61P 21/04A61P 13/12A61K 31/4365A61P 1/16A61K 31/5377A61P 17/14C07D 495/04A61P 1/18A61P 25/00A61P 13/08A61P 15/00A61P 11/06Y02A50/30
43
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Claims
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same.
Claims
exact text as granted — not AI-modified1 - 29 . (canceled)
30 . A method of inhibiting an IRAK protein kinase in a patient or biological sample comprising administering to said patient, or contacting said biological sample, with a compound or a pharmaceutical composition thereof, wherein the compound is of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-4;
each R 1 is independently —R, halogen, —CN, —NO 2 , —OR, —CH 2 OR, —SR, —N(R) 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R) 2 , Cy, or —NRSO 2 R; or R 1 is selected from one of the following formulas:
two R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
m is 1-4;
p is 0-2;
W is N or —C(R 3 )—;
R z is R, CN, NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH—[Ar], —N(R)C(O)OR, —NRC(O)N(R) 2 , —OR, or —SO 2 N(R) 2 ;
[Ar] is an optionally substituted phenyl or heteroaromatic ring:
R 3 is hydrogen, halogen, —CN, C 1-4 aliphatic, C 1-4 haloaliphatic, —OR, —C(O)R, or —C(O)N(R) 2 ;
L 1 is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
each L 2 is independently a covalent bond or a C 1 -6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
each R 4 is independently halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O) 2 N(R) 2 , —NRSO 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L 2 (R 4 ) p —R 4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein said compound is not selected from the group consisting of:
31 . The method of claim 30 , wherein the IRAK protein kinase is an IRAK-4 protein kinase.
32 . The method of claim 30 , wherein the IRAK protein kinase is an IRAK-1 protein kinase.
33 . A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound, or a pharmaceutical composition thereof, wherein the compound is of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-4;
each R 1 is independently —R, halogen, —CN, —NO 2 , —OR, —CH 2 OR, —SR, —N(R) 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R) 2 , Cy, or —NRSO 2 R; or R 1 is selected from one of the following formulas:
two R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C 1 -6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
m is 1-4;
p is 0-2;
W is N or —C(R 3 )—;
R z is R, CN, NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH—[Ar], —N(R)C(O)OR, —NRC(O)N(R) 2 , —OR, or —SO 2 N(R) 2 ;
[Ar] is an optionally substituted phenyl or heteroaromatic ring;
R 3 is hydrogen, halogen, —CN, C 1-4 aliphatic, C 1 -4 haloaliphatic, —OR, —C(O)R, or —C(O)N(R) 2 ;
L 1 is a covalent bond or a C 1 -6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
each L 2 is independently a covalent bond or a C 1 -6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
each R 4 is independently halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O) 2 N(R) 2 , —NRSO 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L 2 (R 4 ) p —R 4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein said compound is not selected from the group consisting of:
34 . The method of claim 33 , wherein the IRAK-mediated disorder, disease or condition is selected from the group consisting of a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.
35 . The method of claim 34 , wherein the cancer or proliferative disorder is selected the group consisting of a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, Smoldering or indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma).
36 . The method of claim 35 , wherein the MyD88 driven disorder is selected from the group consisting of ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia.
37 . The method of claim 35 , wherein the IL-1 driven disorder is Smoldering or indolent multiple myeloma.
38 . The method of claim 34 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.
39 . The method of claim 34 , wherein the inflammatory disorder is selected from the group consisting of conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis; diseases affecting the nose including allergic rhinitis; and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.
40 . The method of claim 30 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof.
41 . The method of claim 40 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt thereof.
42 . The method of claim 41 , wherein the compound is of formula IV:
or a pharmaceutically acceptable salt thereof.
43 . The method of claim 42 , wherein the compound is of formula V:
or a pharmaceutically acceptable salt thereof.
44 . The method of claim 30 , wherein the compound is of formulae VII or VIII:
wherein each of W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are each independently hydrogen or deuterium;
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 30 , wherein the compound is of formula IX:
or a pharmaceutically acceptable salt thereof.
46 . The method of claim 45 , wherein the compound is of formulae X or XI:
or a pharmaceutically acceptable salt thereof.
47 . The method of claim 41 , wherein the compound is of formula XII:
or a pharmaceutically acceptable salt thereof.
48 . The method of claim 47 , wherein the compound is of formula XIII:
or a pharmaceutically acceptable salt thereof.
49 . The method of claim 48 , wherein the compound is of formula XIV:
or a pharmaceutically acceptable salt thereof.
50 . The method of claim 49 , wherein R 4 is —OH or F, or a pharmaceutically acceptable salt thereof.
51 . The method of claim 41 , wherein the compound is of formula XVII:
or a pharmaceutically acceptable salt thereof.
52 . The method of claim 51 , wherein the compound is of formula XVIII:
or a pharmaceutically acceptable salt thereof.
53 . The method of claim 52 , wherein the compound is of formula XIX:
or a pharmaceutically acceptable salt thereof.
54 . The method of claim 30 , wherein the compound is of formula XXII:
or a pharmaceutically acceptable salt thereof.
55 . The method of claim 54 , wherein the compound is of formula XXIII:
or a pharmaceutically acceptable salt thereof.
56 . The method of claim 40 , wherein the compound is of formula XXIV:
or a pharmaceutically acceptable salt thereof.
57 . The method of claim 56 , wherein the compound is of formula XXV:
or a pharmaceutically acceptable salt thereof.
58 . The method of claim 57 , wherein the compound is of formula XXVI:
or a pharmaceutically acceptable salt thereof.
59 . The method of claim 30 , wherein n is 1 and R 1 is —N(R) 2 or Cy, or a pharmaceutically acceptable salt thereof.
60 . The method of claim 30 , wherein n is 1 and R 1 is morpholino, or a pharmaceutically acceptable salt thereof.
61 . The method of claim 30 , wherein n is 1 and R 1 is —N(CH 3 ) 2 , or a pharmaceutically acceptable salt thereof.
62 . The method of claim 30 , wherein n is 1 and Ring A is a 1,4-trans-substituted cyclohexyl ring, or a pharmaceutically acceptable salt thereof.
63 . The method of claim 30 , wherein R z is hydrogen, or a pharmaceutically acceptable salt thereof.
64 . The method of claim 30 , wherein L 1 is —O—, or a pharmaceutically acceptable salt thereof.
65 . The method of claim 30 , wherein L 1 is —NH—, or a pharmaceutically acceptable salt thereof.
66 . The method of claim 30 , wherein said compound is selected from any one of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
67 . The method of claim 30 , wherein a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle is administered to the patient.
68 . The method of claim 33 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof.
69 . The method of claim 68 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt thereof.
70 . The method of claim 69 , wherein the compound is of formula IV:
or a pharmaceutically acceptable salt thereof.
71 . The method of claim 70 , wherein the compound is of formula V:
or a pharmaceutically acceptable salt thereof.
72 . The method of claim 33 , wherein the compound is of formulae VII or VIII:
wherein each of W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are each independently hydrogen or deuterium;
or a pharmaceutically acceptable salt thereof.
73 . The method of claim 33 , wherein the compound is of formula IX:
or a pharmaceutically acceptable salt thereof.
74 . The method of claim 73 , wherein the compound is of formulae X or XI:
or a pharmaceutically acceptable salt thereof.
75 . The method of claim 69 , wherein the compound is of formula XII:
or a pharmaceutically acceptable salt thereof.
76 . The method of claim 75 , wherein the compound is of formula XIII:
or a pharmaceutically acceptable salt thereof.
77 . The method of claim 76 , wherein the compound is of formula XIV:
or a pharmaceutically acceptable salt thereof.
78 . The method of claim 77 , wherein R 4 is —OH or F, or a pharmaceutically acceptable salt thereof.
79 . The method of claim 69 , wherein the compound is of formula XVII:
or a pharmaceutically acceptable salt thereof.
80 . The method of claim 79 , wherein the compound is of formula XVIII:
or a pharmaceutically acceptable salt thereof.
81 . The method of claim 80 , wherein the compound is of formula XIX:
or a pharmaceutically acceptable salt thereof.
82 . The method of claim 33 , wherein the compound is of formula XXII:
or a pharmaceutically acceptable salt thereof.
83 . The method of claim 82 , wherein the compound is of formula XXIII:
or a pharmaceutically acceptable salt thereof.
84 . The method of claim 68 , wherein the compound is of formula XXIV:
or a pharmaceutically acceptable salt thereof.
85 . The method of claim 84 , wherein the compound is of formula XXV:
or a pharmaceutically acceptable salt thereof.
86 . The method of claim 85 , wherein the compound is of formula XXVI:
or a pharmaceutically acceptable salt thereof.
87 . The method of claim 33 , wherein n is 1 and R 1 is —N(R) 2 or Cy, or a pharmaceutically acceptable salt thereof.
88 . The method of claim 33 , wherein n is 1 and R 1 is morpholino, or a pharmaceutically acceptable salt thereof.
89 . The method of claim 33 , wherein n is 1 and R 1 is —N(CH 3 ) 2 , or a pharmaceutically acceptable salt thereof.
90 . The method of claim 33 , wherein n is 1 and Ring A is a 1,4-trans-substituted cyclohexyl ring, or a pharmaceutically acceptable salt thereof.
91 . The method of claim 33 , wherein R z is hydrogen, or a pharmaceutically acceptable salt thereof.
92 . The method of claim 33 , wherein L 1 is —O—, or a pharmaceutically acceptable salt thereof.
93 . The method of claim 33 , wherein L 1 is —NH—, or a pharmaceutically acceptable salt thereof.
94 . The method of claim 33 , wherein said compound is selected from any one of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
95 . The method of claim 33 , wherein a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle is administered to the patient.Cited by (0)
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