WO2013169704A2 - TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE - Google Patents
TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE Download PDFInfo
- Publication number
- WO2013169704A2 WO2013169704A2 PCT/US2013/039839 US2013039839W WO2013169704A2 WO 2013169704 A2 WO2013169704 A2 WO 2013169704A2 US 2013039839 W US2013039839 W US 2013039839W WO 2013169704 A2 WO2013169704 A2 WO 2013169704A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkylene
- compound
- halogen
- group
- Prior art date
Links
- 0 CC(c1c(*)cccc1*)=O Chemical compound CC(c1c(*)cccc1*)=O 0.000 description 16
- VJRKNJLMLJSHIC-UHFFFAOYSA-N CC(C)(C)OC(NC(C1)COc(ncc(NC(c(c(Cl)ccc2)c2Cl)=O)c2)c2N1S(c1cc(C)ccc1)(=O)=O)=O Chemical compound CC(C)(C)OC(NC(C1)COc(ncc(NC(c(c(Cl)ccc2)c2Cl)=O)c2)c2N1S(c1cc(C)ccc1)(=O)=O)=O VJRKNJLMLJSHIC-UHFFFAOYSA-N 0.000 description 1
- PSAPYSPPENBSMA-JTQLQIEISA-N CC(C)(C)OC(NC[C@@H](C(Nc1c2)=O)Oc1ncc2C(OC)=O)=O Chemical compound CC(C)(C)OC(NC[C@@H](C(Nc1c2)=O)Oc1ncc2C(OC)=O)=O PSAPYSPPENBSMA-JTQLQIEISA-N 0.000 description 1
- WAQZCUQPLHTOFP-CQSZACIVSA-N CC(C)(C)OC(Nc(cc12)cnc1O[C@@H](CO)CN2S(c1cccc(Cl)c1)(=O)=O)=O Chemical compound CC(C)(C)OC(Nc(cc12)cnc1O[C@@H](CO)CN2S(c1cccc(Cl)c1)(=O)=O)=O WAQZCUQPLHTOFP-CQSZACIVSA-N 0.000 description 1
- NRPRHQAJUMNAPV-UHFFFAOYSA-N CC(COc(c1c2)ncc2NC(c(c(Cl)ccc2)c2F)=O)N1S(c(cc1)ccc1F)(=O)=O Chemical compound CC(COc(c1c2)ncc2NC(c(c(Cl)ccc2)c2F)=O)N1S(c(cc1)ccc1F)(=O)=O NRPRHQAJUMNAPV-UHFFFAOYSA-N 0.000 description 1
- SUVVHNSNWRBFIJ-HHXXYDBFSA-N C[C@@H](C(C)(C)C)C(Nc1cnc(C[C@@H](CN(CC2)C[C@@H]2O)CN2S(c3c[n](C(F)F)nc3C)(=O)=O)c2c1)=O Chemical compound C[C@@H](C(C)(C)C)C(Nc1cnc(C[C@@H](CN(CC2)C[C@@H]2O)CN2S(c3c[n](C(F)F)nc3C)(=O)=O)c2c1)=O SUVVHNSNWRBFIJ-HHXXYDBFSA-N 0.000 description 1
- SUVVHNSNWRBFIJ-SZVBFZGTSA-N C[C@@H](C(C)(C)C)C(Nc1cnc(C[C@H](CN(CC2)C[C@@H]2O)CN2S(c3c[n](C(F)F)nc3C)(=O)=O)c2c1)=O Chemical compound C[C@@H](C(C)(C)C)C(Nc1cnc(C[C@H](CN(CC2)C[C@@H]2O)CN2S(c3c[n](C(F)F)nc3C)(=O)=O)c2c1)=O SUVVHNSNWRBFIJ-SZVBFZGTSA-N 0.000 description 1
- GIPFRXCGMNSSPR-AWEZNQCLSA-N C[C@@H](CN(c1c2)S(c3cc(C4CC4)ccc3)(=O)=O)Oc1ncc2NC(OC(C)(C)C)=O Chemical compound C[C@@H](CN(c1c2)S(c3cc(C4CC4)ccc3)(=O)=O)Oc1ncc2NC(OC(C)(C)C)=O GIPFRXCGMNSSPR-AWEZNQCLSA-N 0.000 description 1
- HOKPQFNSXUUFGL-AWEZNQCLSA-N C[C@@H](CN(c1c2)S(c3cc(C4CC4)ccc3)(=O)=O)Oc1ncc2NC(c(c(Cl)ccc1)c1Cl)=O Chemical compound C[C@@H](CN(c1c2)S(c3cc(C4CC4)ccc3)(=O)=O)Oc1ncc2NC(c(c(Cl)ccc1)c1Cl)=O HOKPQFNSXUUFGL-AWEZNQCLSA-N 0.000 description 1
- YSOTXIWBUMUMLC-QMMMGPOBSA-N C[C@@H](CNc1c2)Oc1ncc2NC(OC(C)(C)C)=O Chemical compound C[C@@H](CNc1c2)Oc1ncc2NC(OC(C)(C)C)=O YSOTXIWBUMUMLC-QMMMGPOBSA-N 0.000 description 1
- KCVGGFSEOSVOQH-UHFFFAOYSA-N Cc(c([N+]([O-])=O)c1)ncc1[N+]([O-])=O Chemical compound Cc(c([N+]([O-])=O)c1)ncc1[N+]([O-])=O KCVGGFSEOSVOQH-UHFFFAOYSA-N 0.000 description 1
- AAWMSTYRLNOBBJ-UHFFFAOYSA-N Cc1cccc(S(N(C2)c(cc(cn3)NC(c(c(Cl)ccc4)c4F)=O)c3OCC2N(C)C)(=O)=O)c1 Chemical compound Cc1cccc(S(N(C2)c(cc(cn3)NC(c(c(Cl)ccc4)c4F)=O)c3OCC2N(C)C)(=O)=O)c1 AAWMSTYRLNOBBJ-UHFFFAOYSA-N 0.000 description 1
- VXTWBRLTCSARQO-UHFFFAOYSA-N Cc1cccc(S(N2c3cc(C(OC)=O)cnc3C=CC2)(=O)=O)c1 Chemical compound Cc1cccc(S(N2c3cc(C(OC)=O)cnc3C=CC2)(=O)=O)c1 VXTWBRLTCSARQO-UHFFFAOYSA-N 0.000 description 1
- VIKCCAXUQAEAKE-UHFFFAOYSA-N Cc1cccc(S(Nc2cc(C(OC)=O)cnc2C=C)(=O)=O)c1 Chemical compound Cc1cccc(S(Nc2cc(C(OC)=O)cnc2C=C)(=O)=O)c1 VIKCCAXUQAEAKE-UHFFFAOYSA-N 0.000 description 1
- CNQZRCRYDVJGLJ-SECBINFHSA-N Cc1n[n](C(F)F)cc1S(N1c2cc(N)cnc2C[C@@H](CO)C1)(=O)=O Chemical compound Cc1n[n](C(F)F)cc1S(N1c2cc(N)cnc2C[C@@H](CO)C1)(=O)=O CNQZRCRYDVJGLJ-SECBINFHSA-N 0.000 description 1
- FNNJXDDADNXSKB-UHFFFAOYSA-N Nc(cc1[N+]([O-])=O)ncc1Cl Chemical compound Nc(cc1[N+]([O-])=O)ncc1Cl FNNJXDDADNXSKB-UHFFFAOYSA-N 0.000 description 1
- DJVWHVOIZRUYJM-SFHVURJKSA-N O=C(c(c(Cl)ccc1)c1Cl)Nc(cc1)cc2c1O[C@@H](CN(CCC1)C1=O)CN2S(c1cccc(Cl)c1)(=O)=O Chemical compound O=C(c(c(Cl)ccc1)c1Cl)Nc(cc1)cc2c1O[C@@H](CN(CCC1)C1=O)CN2S(c1cccc(Cl)c1)(=O)=O DJVWHVOIZRUYJM-SFHVURJKSA-N 0.000 description 1
- NPYZHHNTAPQXEC-HNNXBMFYSA-N O=C(c(c(Cl)ccc1)c1Cl)Nc(cc12)cnc1O[C@@H](CN(C(CO1)=O)C1=O)CN2S(c1cc(Cl)ccc1)(=O)=O Chemical compound O=C(c(c(Cl)ccc1)c1Cl)Nc(cc12)cnc1O[C@@H](CN(C(CO1)=O)C1=O)CN2S(c1cc(Cl)ccc1)(=O)=O NPYZHHNTAPQXEC-HNNXBMFYSA-N 0.000 description 1
- LAMRJSOLOKETRI-INIZCTEOSA-N O=C(c(c(Cl)ccc1)c1Cl)Nc1cc(N(C[C@H](C2)N(CCO3)C3=O)S(c3cccc(C(F)(F)F)c3)(=O)=O)c2nc1 Chemical compound O=C(c(c(Cl)ccc1)c1Cl)Nc1cc(N(C[C@H](C2)N(CCO3)C3=O)S(c3cccc(C(F)(F)F)c3)(=O)=O)c2nc1 LAMRJSOLOKETRI-INIZCTEOSA-N 0.000 description 1
- ONCAZCNPWWQQMW-UHFFFAOYSA-N O=S(c1cccc(C(F)(F)F)c1)(Cl)=O Chemical compound O=S(c1cccc(C(F)(F)F)c1)(Cl)=O ONCAZCNPWWQQMW-UHFFFAOYSA-N 0.000 description 1
- RWWPFTSMFSNMAL-UHFFFAOYSA-N [O-][N+](c1cc([nH]nc2)c2nc1)=O Chemical compound [O-][N+](c1cc([nH]nc2)c2nc1)=O RWWPFTSMFSNMAL-UHFFFAOYSA-N 0.000 description 1
- GJGOMJQJFHCDAS-UHFFFAOYSA-N [O-][N+](c1cnc(cn[n]2S(c3cccc(C(F)(F)F)c3)(=O)=O)c2c1)=O Chemical compound [O-][N+](c1cnc(cn[n]2S(c3cccc(C(F)(F)F)c3)(=O)=O)c2c1)=O GJGOMJQJFHCDAS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the invention provides tetrahydronaphthyridine and related compounds, methods of inhibiting RORy activity and/or reducing the amount of IL-17 in a subject, and therapeutic uses of the tetrahydronaphthyridine and related compounds.
- the invention provides 1-sulfonyl-tetrahydronaphthyridine and related compounds, methods of using such compounds to inhibit RORy activity and/or reduce the amount of IL-17 in a subject, and treat immune disorders and inflammatory disorders.
- Retinoid-related orphan receptors are reported to have an important role in numerous biological processes. See, for example, Dussault et al. in Mech. Dev. (1998) vol. 70, 147-153; and Andre et al. in EMBO J. (1998) vol. 17, 3867-3877. Scientific
- RORy has been reported to be expressed in high concentration in various tissues, such as thymus, kidney, liver, muscle, and certain fat tissue. See, for example, Hirose et al. in Biochem. Biophys. Res. Commun. (1994) vol. 205, 1976-1983; Medvedev et al. in Gene
- RORyt plays a critical role in regulating differentiation of Thl7 cells, a subset of T helper lymphocytes.
- a number of inflammatory cytokines, such as IL-17, IL-22, and IL-23, are synthesized in Thl7 cells. These cytokines are important pathogenic factors for many immune and inflammatory diseases.
- Compounds capable of modulating RORyt activity are contemplated to provide a therapeutic benefit in the treatment of multiple medical disorders, including immune and inflammatory disorders.
- Psoriasis is a T cell-mediated inflammatory disease that affects approximately 2% to 3% of adults and has a substantial adverse impact on the quality of life for patients suffering from this disorder. Plaques resulting from psoriasis can be painful and are visually unappealing. Various therapeutics have been developed in an attempt to treat psoriasis. However, the traditional therapies for psoriasis often have toxic adverse effects.
- rheumatoid arthritis An exemplary inflammatory disorder in need of better treatment is rheumatoid arthritis. This form of arthritis is characterized by inflammation in the synovial membrane and results in destruction of bone. Numerous therapeutics have been developed in an attempt to treat this disorder. Exemplary therapeutics for treating rheumatoid arthritis include glucocorticoids, methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.
- the invention provides tetrahydronaphthyridine and related compounds
- compositions methods of inhibiting RORy activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such compounds.
- one aspect of the invention provides a collection of
- tetrahydronaphthyridine and related compounds such as Formulae II- VI, I-A, II-A, and III-A, are described in the detailed description.
- Another aspect of the invention provides a method of treating a subject suffering from a medical disorder.
- the method comprises administering to the subject a therapeutically effective amount of one or more tetrahydronaphthyridine or related compounds described herein, e.g., a compound of Formula I, II, III, IV, V, VI, I-A, II-A, or III-A, wherein
- the compounds described herein can be used to treat an immune disorder or inflammatory disorder, such as rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, epidermal hyperplasia, and other medical disorders described herein.
- the disorder is rheumatoid arthritis.
- Another aspect of the invention provides a method of inhibiting the activity of RORy.
- the method comprises exposing a RORy to an effective amount of one or more
- tetrahydronaphthyridine or related compounds described herein e.g., a compound of Formula I, II, III, IV, V, VI, I-A, II-A, or III-A, or a pharmaceutical composition described herein.
- Another aspect of the invention provides a method of reducing the amount of IL-17 in a subject.
- the method comprises administering to a subject an effective amount of one or more tetrahydronaphthyridine or related compounds described herein, e.g., a compound of Formula I, II, III, IV, V, VI, I-A, II-A, or III-A, or a pharmaceutical composition described herein, to reduce the amount of IL-17 in the subject.
- the invention provides tetrahydronaphthyridine and related compounds
- compositions methods of inhibiting RORy activity and/or reducing the amount of IL-17 in a subject, and therapeutic uses of the tetrahydronaphthyridine and related compounds.
- the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in "Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); "Handbook of experimental immunology” (D.M. Weir & C.C.
- alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer.
- cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and includes bicycloalkyls such as where two saturated carbocyclic rings are fused together. In certain embodiments, the cycloalkyls have about 5, 6 or 7 carbons in the ring structure.
- Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and cyclobutyl.
- alkylene refers to a diradical of an alkyl group.
- alkylene groups include .
- cycloalkylene refers to a diradical of a cycloalkyl group.
- Exemplary cycloalkylene groups
- haloalkyl refers to an alkyl group that is substituted with at least one halogen.
- exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
- hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl group.
- exemplary hydroxyl alkyl groups include -CH 2 OH, -
- aralk refers to an alkyl group substituted with an aryl group.
- exemplary aralkyl groups include
- heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
- alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
- aryl is art-recognized and refers to a carbocyclic aromatic group.
- aryl groups include phenyl, naphthyl, anthracenyl, and the like. Unless specified otherwise, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -C0 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,
- aryl also includes polycyclic aromatic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein all of the fused rings are aromatic rings, e.g., in a naphthyl group.
- heteroaryl is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
- the heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -C0 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, - CF 3 , -CN, or the like.
- heteroaryl also includes polycyclic aromatic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein all of the fused rings are heteroaromatic, e.g., in a naphthyridinyl group.
- ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
- 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
- heterocyclic and “heterocyclyl” represent, for example, an aromatic or nonaromatic ring (e.g., a monocyclic or bicyclic ring) containing one or more heteroatoms.
- the heteroatoms can be the same or different from each other. Examples of heteratoms include, but are not limited to nitrogen, oxygen and sulfur.
- Aromatic and nonaromatic heterocyclic rings are well-known in the art. Some nonlimiting examples of aromatic heterocyclic rings include, but are not limited to, pyridine, pyrimidine, indole, purine, quinoline and isoquinoline.
- Nonlimiting examples of nonaromatic heterocyclic compounds include, but are not limited to, piperidine, piperazine, morpholine, pyrrolidine and pyrazolidine.
- oxygen containing heterocyclic rings include, but are not limited to, furan, oxirane, 2H-pyran, 4H-pyran, 2H-chromene, benzofuran, and 2,3- dihydrobenzo[b][l,4]dioxine.
- sulfur-containing heterocyclic rings include, but are not limited to, thiophene, benzothiophene, and parathiazine.
- nitrogen containing rings include, but are not limited to, pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, indole, purine, benzimidazole, quinoline, isoquinoline, triazole, and triazine.
- heterocyclic rings containing two different heteroatoms include, but are not limited to, phenothiazine, morpholine, parathiazine, oxazine, oxazole, thiazine, and thiazole.
- the heterocyclic ring is optionally further substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -C0 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,
- heterocyclyl aryl or heteroaryl moieties, -CF 3 , -CN, or the like.
- the heterocyclyl group is a 3-7 membered ring that, unless specified otherwise, is substituted or unsubstituted.
- heterocycloalkyl refers to a saturated heterocyclyl group having, for example, 3-7 ring atoms.
- amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
- R 50 , R 51 , R 52 and R 53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R 61 , or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
- R 61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
- only one of R 50 or R 51 may be a carbonyl, e.g., R 50 , R 51 and the nitrogen together do not form an imide.
- R 50 and R 51 (and optionally R 52 ) each independently represent a hydrogen, an alkyl, an alkenyl, or - (CH 2 ) m -R 61 .
- alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
- Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
- An “ether” is two
- an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of - O-alkyl, -O-alkenyl, -O-alkynyl, and -0-(CH 2 ) m -R 61 , where m and R 61 are described above.
- a cyclopentane susbsituted with an oxo group is cyclopentanone.
- substituted means that one or more hydrogens on the atoms of the designated group are replaced with a selection from the indicated group, provided that the atoms' normal valencies under the existing circumstances are not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- stable compound' or stable structure refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
- “Hydrate” is a solvate wherein the solvent molecule is H 2 0.
- Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. Further, certain compounds described herein may be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
- the compounds may contain one or more stereogenic centers. For example, asymmetric carbon atoms may be present in a substituent such as an alkyl group.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g. , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- a particular enantiomer of a compound of the present invention may be prepared by reacting chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- the terms "subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention.
- Such organisms preferably include, but are not limited to, mammals ⁇ e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
- EC50 is art-recognized and refers to the concentration of a compound that is required for 50% maximal effect.
- an effective amount refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result).
- An effective amount can be administered in one or more
- treating includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
- the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
- pharmaceutically acceptable carrier refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions ⁇ e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
- the compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants.
- the term "pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
- salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
- acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene -2-sulfonic, benzenesulfonic acid, and the like.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their
- bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is Ci_ 4 alkyl, and the like.
- salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
- flucoheptanoate glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate (also known as toluenesulfonate), undecanoate, and the like.
- tosylate also known as toluenesulfonate
- salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group), and the like.
- a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci_ 4 alkyl group)
- Further examples of salts include, but are not limited to: ascorbate, borate, nitrate, phosphate, salicylate, and sulfate.
- acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S.
- Additional exemplary basic salts include, but are not limited to: ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
- Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g.
- dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
- long chain halides e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides
- aralkyl halides e.g., benzyl and phenethyl bromides
- salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
- salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
- a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions ("inner salts") may be formed.
- acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
- Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
- the present invention includes the compounds of the invention in all their isolated forms (such as any solvates, hydrates, stereoisomers, and tautomers thereof). Further, the invention includes compounds in which one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
- different isotopic forms of hydrogen (H) include protium (iH) and deuterium (3 ⁇ 4). Protium is the predominant hydrogen isotope found in nature.
- Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- SEA Syndrome refers to Seronegativity, Enthesopathy, Arthropathy Syndrome.
- compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
- THF tetrahydrofuran
- DCM dichloromethane
- DMF dimethylformamide
- DMA dimethylacetamide
- DTT dithiothreitol
- EDTA is art-recognized and refers to
- ethylenediaminetetraacetic acid ethylenediaminetetraacetic acid.
- TFA trifluoroacetic acid.
- compositions specifying a percentage are by weight unless otherwise specified.
- One aspect of the invention provides a compound represented by Formula I:
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 8 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ghaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, d_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl,
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, C ⁇ hydroxy alky 1, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_6haloalkoxy;
- R 8 is hydrogen, Ci_ 6 alkyl, or -C(0)-Ci_ 6 alkyl
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_ 6 alkylene N(R 4 )C(0)-Ci_ 6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and m and p each represent independently for each occurrence 0, 1, or 2.
- Another aspect of the invention provides a compound represented by Formula I:
- substituents independently selected from the group consisting of halogen, hydroxyl, Ci_galkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ehaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R is hydrogen or Ci_ 6 alkyl
- R 2 is -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(0)-[C(R 6 ) 2 ] m - heterocyclyl, -C(0)-Ci_galkyl, -C(0)-Ci_6alkylene-Ci_6alkoxyl, -C(0)-Ci_6alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(0)-Ci_ 6
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkoxy, and Ci_6haloalkoxy;
- R 8 is hydrogen, Ci_ 6 alkyl, or -C(0)-Ci_ 6 alkyl
- R 9 is hydrogen, Ci_6alkyl, Ci_6hydroxyalkyl, Ci_6alkylene N(R 4 )(R 5 ), or Ci_6alkylene
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl. In certain embodiments, at least one substituent is attached at the meta-position of the phenyl ring.
- A is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- X is -0-[C(R 6 )(R 7 )]-[C(R 6 ) 2 ] m ⁇ . In certain other embodiments, X is -C(R 6 ) 2 -[C(R 6 )(R 7 )]-[C(R 6 ) 2 ] m - ⁇
- Y 1 is N, and Y 2 is C(R 3 ). In certain other embodiments, Y 1 is C(R 3 ), and Y 2 is N. In certain other embodiments, Y 1 is N, and Y 2 is CH. In certain other embodiments, Y 1 is CH, and Y 2 is N.
- R 1 is hydrogen
- R 2 is hydrogen, -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_6haloalkoxy, Ci_ 6 alkyl, and Ci_6haloalkyl, and said substituents are located at the ortho-positions of the aromatic ring.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- each R' is independently halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, or
- R 2 is represented by:
- each R' is independently halogen, Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_6haloalkoxy, Ci_6alkyl, and Ci_6haloalkyl, and said substituents are located at the ortho-positions of the aromatic ring.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_6alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- R 2 is represented by: wherein R" is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, aryl, or heterocyclyl
- R 3 is hydrogen. [0067] In certain embodiments, R is hydrogen. In certain other embodiments, R is hydroxyl, Ci_6hydroxyalkyl, Ci_6alkyl, Ci_6haloalkyl, -C0 2 R 6 , Ci_6alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 alkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), or Ci_ 6 alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents
- Ci_ 6 alkyl independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Another aspect of the invention provides a compound represented by Formula I-A:
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ghaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, d_ 6 alkoxy, d_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ eal
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_6haloalkoxy;
- R 8 is hydrogen, Ci_ 6 alkyl, or -C(0)-Ci_ 6 alkyl
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_
- variables in Formulae I-A above encompass multiple chemical groups.
- the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where A is aryl, and R 2 is -C(O)- aryl.
- variables A, X, Y 1 , Y 2 , R 1 to R 9 , m, and p described in the preceding paragraphs in connection with Formula I are reiterated here for use in association with Formula I-A.
- Another aspect of the invention provides a compound represented by Formula II:
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ehaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, and -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, d_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ ealky
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-C(0)N(R 4 )(R 5 ), -N(R 4 )C0 2 -Ci_ 6 alkyl, or Ci_ 6 alkylene-N(R 4 )(C(0)N(R 4 )(R 5 ); or R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl,
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_ 6 alkylene N(R 4 )C(0)-Ci_ 6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and m and p each represent independently for each occurrence 0, 1, or 2.
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl.
- at least one substituent is attached at the meta-position of the phenyl ring.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N, and Y 2 is C(R 3 ). In certain other embodiments, Y 1 is C(R 3 ), and Y 2 is N. In certain other embodiments, Y 1 is N, and Y 2 is CH. In certain other embodiments, Y 1 is CH, and Y 2 is N.
- R 1 is hydrogen.
- R 2 is hydrogen, -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_6alkoxy, Ci_6haloalkoxy, Ci_ 6 alkyl, and Ci_6haloalkyl, and said substituents are located at the ortho-positions of the aromatic ring.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_6alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- R 2 is represented by:
- each R' is independently halogen, Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
- R 2 is represented by: wherein R" is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, aryl, or heterocyclyl
- R 3 is hydrogen. [0079] In certain embodiments, R is hydrogen. In certain other embodiments, R is hydroxyl, Ci_6hydroxyalkyl, Ci_6alkyl, Ci_6haloalkyl, -C0 2 R 6 , Ci_6alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is Ci_6hydroxyalkyl, Ci_6alkyl, Ci_6alkylene-C0 2 R 6 , Ci_6alkylene-N(R 4 )(R 5 ), or Ci_6alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_3hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- Another aspect of the invention provides a compound represented by Formula II-A:
- A is aryl, heteroaryl, or heterocycloalkyl; each of which is optionally substituted with
- Y 1 and Y 2 are each independently C(H) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen
- R 2 is -C(0)-phenyl substituted with 2 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, wherein the substituents are located at the ortho positions of the phenyl ring;
- R 3 is hydrogen
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, C ⁇ hydroxy alky 1, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy;
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_
- A is aryl or heteroaryl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_
- A is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl. In certain embodiments, at least one substituent is attached at the meta-position of the phenyl ring. [0082] In certain other embodiments, A is heterocycloalkyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N
- Y 2 is C(H).
- Y 1 is C(H)
- Y 2 is N.
- R 2 is represented by:
- each R' is independently fluoro, chloroo, or Ci_ 6 haloalkyl.
- R is hydrogen.
- R is Ci_ 6 hydroxyalkyl, Ci_6alkyl, Ci_6haloalkyl, -C0 2 R 6 , Ci_6alkylene-C0 2 R 6 , Ci_
- R 7 is Ci_6hydroxyalkyl, Ci_6alkyl, Ci_6alkylene-C0 2 R 6 , Ci_6alkylene-N(R 4 )(R 5 ), or Ci_6alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_3hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- Another aspect of the invention provides a compound represented by Formula III:
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci ehaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, and -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one of Y 1 is N;
- R is hydrogen or Ci_ 6 alkyl
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, d_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ ealky
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, C ⁇ hydroxy alky 1, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy;
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_ 6 alkylene N(R 4 )C(0)-Ci_ 6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and m and p each represent independently for each occurrence 0, 1, or 2.
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl.
- at least one substituent is attached at the meta-position of the phenyl ring.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N, and Y 2 is C(R 3 ). In certain other embodiments, Y 1 is C(R 3 ), and Y 2 is N. In certain other embodiments, Y 1 is N, and Y 2 is CH. In certain other embodiments, Y 1 is CH, and Y 2 is N.
- R 1 is hydrogen
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, and said substituents are located at the ortho-positions of the aromatic ring.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- each R' is independently halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, or
- R 2 is represented by:
- each R' is independently halogen, Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
- R 2 is represented by: wherein R" is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci
- R 3 is hydrogen
- R 7 is hydrogen. In certain other embodiments R 7 is hydroxyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_
- R 7 is Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 alkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- Another aspect of the invention provides a compound represented by Formula III-A:
- A is aryl, heteroaryl, or heterocycloalkyl; each of which is optionally substituted with
- substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_6haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy;
- Y 1 and Y 2 are each independently C(H) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen
- R 2 is -C(0)-phenyl substituted with 2 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl, wherein the substituents are located at the ortho positions of the phenyl ring;
- R 3 is hydrogen;
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, C ⁇ hydroxy alky 1, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy;
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_ 6 alkylene N(R 4 )C(0)-Ci_ 6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and m and p each represent independently for each occurrence 0, 1, or 2.
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl. In certain embodiments, at least one substituent is attached at the meta-position of the phenyl ring.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N, and Y 2 is C(H). In certain other embodiments, Y 1 is C(H), and Y 2 is N. [0099] In certain embodiments, R 2 is represented by:
- each R' is independently fluoro, chloroo, or Ci_ 6 haloalkyl.
- R 7 is hydrogen. In certain other embodiments, R 7 is Ci_
- Ci_6alkyl Ci_6haloalkyl, -C0 2 R 6 , Ci_6alkylene-C0 2 R 6 , Ci_
- R 7 is Ci_6hydroxyalkyl, Ci_6alkyl, Ci_6alkylene-C0 2 R 6 , Ci_6alkylene-N(R 4 )(R 5 ), or Ci_ 6 alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ehaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, and -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl;
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ ealkyl,
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy;
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_ 6 alkylene N(R 4 )C(0)-Ci_ 6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and m and p each represent independently for each occurrence 0, 1, or 2.
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl.
- at least one substituent is attached at the meta-position of the phenyl ring.
- A is heterocycloalkyl optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N
- Y 2 is C(R 3 ).
- Y 1 is C(R 3 )
- Y 2 is N.
- Y 1 is N
- Y 2 is CH.
- Y 1 is CH, and Y 2 is N.
- R 1 is hydrogen
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- R 2 is represented by:
- each R' is independently halogen, Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
- R 2 is represented by:
- R' ' is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, d_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloal
- R 3 is hydrogen
- R 7 is hydrogen. In certain other embodiments R 7 is hydroxyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 alkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), or Ci_ 6 alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ehaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, and -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl
- R 2 is hdyrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, d_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl; and m and p each represent independently for each occurrence 0, 1, or 2.
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl. In certain embodiments, at least one substituent is attached at the meta-position of the phenyl ring.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- Y 1 is N, and Y 2 is C(R 3 ). In certain other embodiments, Y 1 is C(R 3 ), and Y 2 is N. In certain other embodiments, Y 1 is N, and Y 2 is CH. In certain other embodiments, Y 1 is CH, and Y 2 is N.
- R 1 is hydrogen
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- each R' is independently halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, or
- R 2 is represented by:
- R 2 is represented by:
- R" is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, d_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 3 is hydrogen.
- R 7 is hydrogen. In certain other embodiments R 7 is hydroxyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 alkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkoxy, Ci_ ghaloalkoxy, -N(R 4 )(R 5 ), -C0 2 R 6 , -C(0)R 6 , -CN, -Ci_ 4 alkylene-Ci_ 4 alkoxy, -Ci_
- Y 1 and Y 2 are each independently C(R 3 ) or N, provided that at least one ofY 1 and Y 2 is N;
- R 1 is hydrogen or Ci_ 6 alkyl
- R 2 is hydrogen, -C(0)-aryl, -C(0)-aralkyl, -C(0)-[C(R 6 ) 2 ] m -cycloalkyl, -C(O)- [C(R 6 ) 2 ] m -heterocyclyl, -C(0)-Ci_ 8 alkyl, -C(0)-Ci_ 6 alkylene-Ci_ 6 alkoxyl, -C(0)-Ci_ 6 alkylene- cycloalkyl, or -C(0)-Ci_ 6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -
- R 3 represents independently for each occurrence hydrogen, halogen, or Ci_ 6 alkyl
- R 4 and R 5 each represent independently for each occurrence hydrogen or Ci_ 6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R 6 represents independently for each occurrence hydrogen or Ci_ 6 alkyl
- R 7 is hydrogen, hydroxyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 hydroxyalkylene-N(R 4 )(R 5 ), -N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_ 6 alkylene-N(R 4 )C(0)R 9 , Ci_
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxy alkyl, Ci_ 6 alkoxy, and Ci_6haloalkoxy;
- R 8 is hydrogen, Ci_ 6 alkyl, or -C(0)-Ci_ 6 alkyl
- R 9 is hydrogen, Ci_ 6 alkyl, Ci_ 6 hydroxyalkyl, N(R 4 )(R 5 ), Ci_ 6 alkylene N(R 4 )(R 5 ), or Ci_
- A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and Ci_ 6 haloalkyl.
- at least one substituent is attached at the meta-position of the phenyl ring.
- A is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_6alkoxy, and Ci_6haloalkoxy.
- A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy.
- X is -0-[C(R 6 )(R 7 )]-[C(R 6 ) 2 ] m - ⁇
- R 1 is hydrogen
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-aryl or -C(0)-aralkyl; each of which is substituted with 2 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_6haloalkoxy, Ci_6alkyl, and Ci_6haloalkyl, and said substituents are located at the ortho-positions of the aromatic ring.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_6alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is -C(0)-phenyl or -C(0)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 2 is represented by:
- R 2 is represented by:
- each R' is independently halogen, Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
- R 2 is represented by:
- R" is Ci_ 6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -N(R 4 )(R 5 ), -CN, -C0 2 -Ci_ 6 alkyl, -C(O)- Ci_ 6 alkyl, -C(0)N(R 4 )(R 5 ), -S(0) p Ci_ 6 alkyl, -S0 2 N(R 4 )(R 5 ), and -N(R 4 )S0 2 (Ci_ 6 alkyl).
- R" is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
- R 3 is hydrogen.
- R 7 is hydrogen. In certain other embodiments, R 7 is hydroxyl, Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -C0 2 R 6 , Ci_ 6 alkylene-C0 2 R 6 , Ci_ 4 hydroxyalkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), Ci_
- R 7 is Ci_ 6 hydroxyalkyl, Ci_ 6 alkyl, Ci_ 6 alkylene-C0 2 R 6 , -N(R 4 )(R 5 ), Ci_ 6 alkylene-N(R 4 )(R 5 ), or Ci_ 6 alkylene-N(R 4 )C(0)R 9 .
- R 7 is Ci_ 3 hydroxyalkyl, methyl, ethyl, or Ci_ 3 alkylene-N(H)C(0)-Ci_ 4 alkyl.
- R 7 is heterocycloalkyl or Ci_ 4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents
- Ci_ 6 alkyl independently selected from the group consisting of oxo, halogen, hydroxyl, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C ⁇ hydroxy alky 1, Ci_6alkoxy, and Ci_6haloalkoxy.
- variables in Formulae I-VI, I-A, II-A, and III-A above encompass multiple chemical groups.
- the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
- the compound is one of the compounds listed in Tables 1-3 herein below, Tables 4-9 in the Examples, or a pharmaceutically acceptable salt of any of the foregoing. TABLE 1
- Bromo-1,5- naphthyridine B can be converted to amino-l,5-naphthyridine C using procedures known in the art, such as (1) Ullmann CuS0 4 mediated addition of ammonia (Hauser et al. in J. Org. Chem. 1950, 15, 1224-1232); (2) Pd-mediated addition of a carbamate (Bhagwanth et al. in J. Org Chem. 2009, 74, 4634-4637) followed by deprotection; (3) Pd-mediated addition of hexamethyldisilazide (Stefko et al. in J. Org. Chem.
- a functional group that is part of R, R 1 , or R n would not be amenable to a reaction condition described in Scheme 1, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, and then the protecting group is removed after completing the desired synthetic transformation. See, for example, Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991, for further description of protecting chemistry and strategies.
- a functional group in substituent R, R 1 , and R n in tetrahydro-l,5-naphthyridine F can converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, "Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992)
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl.
- Scheme 2 illustrates an alternative general method for preparing substituted 5,6,7,8- tetrahydro-l,5-naphthyridine compounds.
- Reduction of halo-nitro-pyridine A by dissolving metal reduction provides halo-amino-pyridine B.
- Exemplary dissolving metal reduction conditions include using, for example, (1) SnCl 2 in HCl as described by Adams et al. in WO 2008/150827, or (2) Fe in HCl or NH 4 C1 as described by Carroll et al. in J. Med. Chem. 2002, 45, 4755-4761 and Oalmann et al. in WO 2010/071853.
- Reaction of halo-amino-pyridine B with a sulphonyl chloride or sulfamoyl chloride provides halo-pyridinyl sulfonamide C.
- alkene D Reaction of halo-pyridinyl sulfonamide C with a vinyl boronic acid or vinyl stannane provides alkene D, which can be allylated using, for example, an allyl halide under basic conditions or an allyl alcohol under Mitsunobu conditions to provide di-alkene E.
- Di-alkene E can be subjected to ring closing metathesis conditions to provide dihydro-l,5-naphthyridine F.
- ring closing metathesis conditions see, for example, Mitsuhiro et al. in J. Org. Chem. 2006, 71, 4255-4261.
- Reduction of dihydro-l,5-naphthyridine F provides saturated tetrahydro-l,5-naphthyridine G.
- the methyl ester on tetrahydro-l,5-naphthyridine G can be converted to a carboxylic acid under hydrolytic conditions, and the resulting carboxylic acid is subjected to reaction conditions that facilitate Curtius rearrangement (see, for example, Ninomiya in Tetrahedron 1974, 30, 2151-2157) to provide
- tetrahydronaphthyridinyl carbamate H can be converted to an amino group using standard carbamate protecting group removal procedures, and the resulting amino- tetrahydronaphthyridine can be reacted with an acid (R ⁇ CC ⁇ H) using standard amide coupling conditions (e.g., using amide coupling reagents HATU or PyBop) to provide amido- tetrahydro-l,5-naphthyridine I.
- standard amide coupling conditions e.g., using amide coupling reagents HATU or PyBop
- R I C(0)C1 an acid chloride
- R ⁇ C ⁇ H an acid chloride
- amide coupling reagent in the step used to produce amido- tetrahydro-l,5-naphthyridine I.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl
- pin _ pvi are substituents, such as methyl
- X may be, for example, halogen.
- Scheme 3 illustrates a general route to providing oxygenated 5,6,7,8-tetrahydro-l,5- naphthyridine compounds.
- Chiral osmylation of alkene A provides diol B.
- diol B For exemplary chiral osmylation procedures, see, for example, Noe et al. in Org. Reactions 2005, 66, 109.
- Reduction of diol B provides alcohol C.
- the hydroxyl group in compound C can be alkylated to provide ether D, or the hydroxyl group can be converted to other functional groups using functional group conversion procedures known in the art.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl; and R MI - R VI are substituents, such as methyl.
- Scheme 4 illustrates another general procedure for preparing 5,6,7,8-tetrahydro-l,5- naphthyridine compounds.
- Treatment of halo-nitro-pyridine A with a Negishi reagent under Pd-mediated conditions provides diester B.
- a Negishi reagent under Pd-mediated conditions.
- Dissolving metal reduction of diester B with in situ cyclization affords dihydro-l,5-naphthyridin-2(lH)-one C.
- Reaction of dihydro-l,5-naphthyridin-2(lH)-one C with a protecting group installation reagent e.g., benzylbromide (Bn-Br)
- a protecting group installation reagent e.g., benzylbromide (Bn-Br)
- Bn-Br benzylbromide
- a substituent can be installed alpha to the amide group by reaction of carbamate E with base and an electrophile (e.g., R v -halide) to provide substituted-dihydro-l,5-naphthyridin-2(lH)- one F.
- Reduction of substituted-dihydro-l,5-naphthyridin-2(lH)-one F can be performed by reaction with a hydride (e.g., a borane or lithium aluminum hydride) to provide tetrahydro- 1,5-naphthyridine G.
- a hydride e.g., a borane or lithium aluminum hydride
- protecting groups e.g., the benzyl and carbamate protecting group
- the resulting amine is reacted with a desired carbonxylic acid, acid chloride, sulphonyl chloride, and/or sulfamoyl chloride to provide the final amido-tetrahydro- 1,5-naphthyridine H.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl
- R v and R v " are substituents, such as methyl
- X may be, for example, halogen.
- Scheme 5 illustrates another procedure for preparing substituted tetrahydro-1,5- naphthyridines.
- Reacting halo-nitro-pyridine A with a Negishi reagent formed from a 2- ((fert-butoxycarbonyl)amino)-3-iodopropanoate) provides amino acid B.
- amino acid B is subjected to dissolving metal reduction conditions with in situ cyclization to provide dihydro-l,5-naphthyridin-2(lH)-one C.
- dihydro-l,5-naphthyridin-2(lH)-one C to hydrolysis conditions provides a carboxylic acid (not shown), that after in situ formation of an acyl azide followed by a Curtius rearrangement provides bis-carbamate D.
- Selective reduction of the amide group in bis-carbamate D using borane or lithium aluminum hydride provides tetrahydro-l,5-naphthyridine E.
- Reaction of tetrahydro-l,5-naphthyridine E with a sulphonyl chloride or sulfamoyl chloride provides sulfonamide F.
- the benzylcarbamate protecting group is removed from sulfonamide F to provide an amino-tetrahydro-1,5- naphthyridine (not shown) that can be subjected to amide coupling conditions using a carboxylic acid and an amide coupling agent to provide amido-tetrahydro- 1,5 -naphthyridine G.
- the remaining Boc protecting group on amido-tetrahydro- 1,5 -naphthyridine G can be removed by treatment with acid to provide amino-tetrahydro- 1,5 -naphthyridine H.
- amino group on amino-tetrahydro- 1,5 -naphthyridine H can be converted to other functional groups (e.g., by reaction with an alkylating agent(s), aldehyde (reductive alkylations), acyl halide, sulphonyl chloride, isocyanate, and the like) to afford the compound I.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl
- R v and R v " are substituents, such as methyl
- X may be, for example, halogen.
- Scheme 6 illustrates a general procedure for preparing tetrahydro-5H-pyrido[3,2- 3 ⁇ 4]azepines. Reaction of halo-nitro-pyridine A with a Negishi reagent under Pd-mediated conditions provides diester B. For additional description of related procedures, see, for example, Zhu et al. in J. Org. Chem. 1991, 56, 1445-1453. Dissolving metal reduction of diester B with in situ cyclization provides tetrahydro-5H-pyrido[3,2-£]azepine C, which can be converted to final product D using procedures described in Scheme 4 above. SCHEME 6.
- Scheme 7 illustrates a general method for preparing tetrahydro-5H-pyrido[3,2- 3 ⁇ 4]azepines having an amino group at the 7-position.
- Reacting halo-nitro-pyridine A with a Negishi reagent formed from a 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate) provides amino acid B.
- amino acid B is subjected to dissolving metal reduction conditions with in situ cyclization to provide tetrahydro-5H-pyrido[3,2-£]azepine C, which can be converted to final product D using procedures described in Scheme 5 above.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl
- R VI - R VM are substituents, such as methyl
- X may be, for example, halogen.
- Scheme 8 illustrates a general method for preparing substituted tetrahydro-1,6- naphthyridines.
- Acylation of pyridyl-amine A provides pyridyl-amide B, which is treated with an allylic alcohol under Heck conditions to afford compound C.
- exemplary description of such Heck reaction conditions see, for example, Colbon et al. in J. Org. Letters 2011, 13, 5456-5459.
- Subjecting compound C to reductive cyclization followed by treatment with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-tetrahydro- 1,6-naphthyridine D.
- R and R may be, for example, a cyclic group, such as phenyl; and R IV and R v may be, for example, H or a substituent, such as methyl.
- Scheme 9 illustrates another general method for preparing substituted tetrahydro-1,5- naphthyridines.
- Acylation of amino-pyridine A provides amido-pyridine B, which is treated with an allylic alcohol under Heck conditions to provide compound C.
- Heck reaction conditions see, for example, Colbon et al. in J. Org.
- R' and R" may be, for example, a cyclic group, such as phenyl; and R IV and R v may be, for example, H or a substituent, such as methyl.
- Scheme 10 illustrates a general method for preparing 2-substituted-2,3-dihydro-lH- pyrido[2,3-3 ⁇ 4]oxazines. Reaction of chloro-pyridine A with hydroxy-ketone B provides nitro- pyridyl ether C. Exhaustive reduction (e.g., using Raney Nickel) of compound C provides amino-dihydro-lH-pyrido[2,3-3 ⁇ 4]oxazine D.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl; and R IV is a substituent, such as methyl.
- Scheme 11 illustrates a general method for preparing substituted-2,3-dihydro-lH- pyrido[2,3-3 ⁇ 4]oxazines. Reacting chloro-pyridine A with protected hydroxyketone (or a protected hydroxyaldehyde) B provides an aryl-alkyl ether intermediate (not shown) that upon acid hydrolysis provides dinitropyridyl-ketone (or dinitropyridyl-aldehyde) C.
- Exhaustive reduction (e.g., using Raney Nickel) of compound C provides amino-dihydro-lH- pyrido[2,3-3 ⁇ 4]oxazine D.
- Acylation of the amino group in compound D affords amido- dihydro-lH-pyrido[2,3-£]oxazine E, which is treated with a sulphonyl chloride or a sulfamoyl chloride to afford the final compound F.
- a protected chiral hydroxyketone B can be used as starting material.
- R, R , and R v may be, for example, hydrogen or a substituent, such as methyl;
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl
- R v " is, for example, alkyl.
- Scheme 12 illustrates another general method for preparing substituted-2,3-dihydro- lH-pyrido[2,3-3 ⁇ 4]oxazines.
- Reaction of halo-pyridine A with a 2-hydroxyester provides nitro- carboxypyridine B.
- Subjecting nitro-carboxypyridine B to dissolving metal reduction conditions with in situ cyclization affords lH-pyrido[2,3-£][l,4]oxazin-2(3H)-one C.
- the carbamate protecting group is removed from sulfonamide F to provide amino-dihydro-lH-pyrido[2,3-3 ⁇ 4]oxazine G that can be subjected to amide coupling conditions using a carboxylic acid and a coupling agent to provide amido-dihydro-lH-pyrido[2,3-£]oxazine H.
- Scheme 13 illustrates an alternate general method for preparing substituted-2,3- dihydro-lH-pyrido[2,3-3 ⁇ 4]oxazines.
- Reaction of halo-nitropyridine A with a hydroxyalkyl- epoxide provides nitro-pyridyl ether B.
- Subjecting nitro-pyridyl ether B to dissolving metal reduction conditions with in situ cyclization affords a bicyclic alkoxide intermediate (not shown) that is reacted with an alcohol protecting group reagent (e.g., a trialkylsilylchloride or with an alkyl halide if the final target is an ether) to provide bicyclic ether C.
- an alcohol protecting group reagent e.g., a trialkylsilylchloride or with an alkyl halide if the final target is an ether
- Reaction of bicyclic ether C with a sulphonyl chloride or sulfamoyl chloride provides sulfonamide - pyrido-oxazine D.
- the methyl ester on sulfonamide-pyrido-oxazine D can be converted to a carboxylic acid using hydrolytic conditions to provide an intermediate carboxylic acid compound (not shown), that is converted to an acyl azide followed by a Curtius
- the carbamate protecting group may be removed using standard deprotection conditions to provide a bicyclic amine (not shown) that can be subjected to amide coupling conditions using a carboxylic acid and an amide coupling agent to provide amide-substituted 5,6,7,8-tetrahydro-l,5-naphthryridine F.
- R is protecting group (e.g., a trialkylsilyl group)
- R may be removed using standard deprotection conditions (e.g., using tetra-n-butylammonium fluoride) to provide alcohol G.
- R may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl
- R v - R v " are substituents, such as methyl
- R IX is a protecting group or alkyl
- X may be, for example, halogen.
- Scheme 14 illustrates a general method for preparing substituted 1,2,3,4- tetrahydropyrido[2,3-b][l,4]oxazepines. SCHEME 14.
- R and R v - R v " may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R" may be, for example, a cyclic group, such as phenyl
- X may be, for example, halogen.
- Scheme 15 illustrates a general method for preparing substituted 2,3-dihydro-lH- pyrido[3,4-3 ⁇ 4]oxazines.
- Alkylation of halo-hydroxypyridine A provides pyridinyl-ether B.
- Oxidation of pyridinyl-ether B followed by nitration provides nitro-pyridine C, which after reductive cyclization affords 1H- pyrido[3,4-£][l,4]oxazin-2(3H)-one D.
- Selective hydride reduction provides amine E, which is treated with a sulphonyl chloride or sulfamoyl chloride to provide dihydro-lH-pyrido[3,4- 3 ⁇ 4]oxazine F.
- the chloride can be aminated (such as using procedures shown in Scheme 1) to provide amine G, which allows functionalization with an acyl moiety to provide the final amide-substituted 2,3-dihydro-lH-pyrido[3,4-£]oxazine H.
- R and R v - R v " may be, for example, hydrogen or a substituent, such as methyl; and R 1 and R" may be, for example, a cyclic group, such as phenyl.
- Scheme 16 illustrates a general method for preparing amido-dihydro-5H- pyridazino[3,4-3 ⁇ 4][l,4]oxazines. Reaction of halo-nitro-pyridazine A with a 2-hydroxyester provides pyridazine ether B. Reductive cyclization of pyridazine ether B affords 5H- pyridazino[3,4-£][l,4]oxazin-6(7H)-one C.
- Reaction of a protected amine (Pg-NH 2 , such as NH 2 COOtBu) with oxazinone C in the presence of a palladium catalyst provides protected amino-dihydro-5H-pyridazino[3,4-3 ⁇ 4][l,4]oxazine D.
- Selective hydride reduction affords amino-oxazine E, and treatment of amino-oxazine E with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-dihydro-5H-pyridazino[3,4-3 ⁇ 4][l,4]oxazine F.
- the amino protecting group (Pg) can be removed using standard protecting group removal procedures, and the resulting amine can be used in an amide coupling reaction (such as with a carboxylic acid an amide coupling reagent) to provide final oxazine G. SCHEME 16.
- R and R V may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl.
- Scheme 17 illustrates another general method for preparing amido-dihydro-5H- pyridazino[3,4-3 ⁇ 4][l,4]oxazines.
- Reaction of halopyridazine A with amino alcohol B provides the halo-dihydro-5H-pyridazino[3,4-3 ⁇ 4][l,4]oxazine C.
- Nyrkova et al. in Zh. Org. Khimii 1965, 1, 1688-1691 see, for example, Nyrkova et al. in Zh. Org. Khimii 1965, 1, 1688-1691.
- Reaction of protected amine (Pg-NH 2 , such as /?ara-methoxybenzylamine (PMB-NH 2 )) with oxazine C in the presence of a palladium catalyst provides protected amino-dihydro-5H- pyridazino[3,4-3 ⁇ 4][l,4]oxazine D.
- Reaction of oxazine D with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-dihydro-5H-pyridazino[3,4-3 ⁇ 4][l,4]oxazine E.
- the /?ara-methoxybenzyl (PMB) protecting group on oxazine E can be removed using standard PMB deprotection conditions to provide an amino-oxazine (not shown), which can be used in an amide coupling reaction (such as with a carboxylic acid an amide coupling reagent) to provide oxazine F.
- PMB /?ara-methoxybenzyl
- R and R may be, for example, hydrogen or a substituent, such as methyl; and R 1 and R 11 may be, for example, a cyclic group, such as phenyl.
- Scheme 18 illustrates a general method for preparing amido-dihydro-1,5- naphthyridin-4(lH)-ones.
- Alkylation of amino-pyridine A with halo-alkyl nitrile B provides nitrile C.
- Base catalyzed intramolecular condensation of nitrile C provides dihydro-l,5-naphthyridin-4(lH)-one D.
- Reaction of dihydro-1,5- naphthyridin-4(lH)-one D with base and an alkylhalide provides nitrile E.
- Reaction of nitrile E with base provides a carboxylic acid which decarboxylates to provide dihydro-1,5- naphthyridin-4(lH)-one F.
- Reaction of dihydro-l,5-naphthyridin-4(lH)-one F with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-dihydro-l,5-naphthyridin- 4(lH)-one G.
- Metal-catalyzed coupling of amide H with sulfonamido-dihydro-1,5- naphthyridin-4(lH)-one G provides final compound I.
- R, R , and R v may be, for example, hydrogen or a substituent, such as methyl;
- R 1 and R" may be, for example, a cyclic group, such as phenyl
- X is a leaving group, such as bromide.
- Scheme 19 illustrates a general method for preparing amido-dihydro-2H- pyrazino[2,3-3 ⁇ 4][l,4]oxazines.
- Reaction of halo-nitro-pyrazine A with a 2-hydroxyester provides pyrazine ether B.
- Reductive cyclization of pyrazine ether B affords 2H- pyrazino[2,3-£][l,4]oxazin-3(4H)-one C.
- Reaction of a protected amine (Pg-NH 2 , such as NH 2 COOtBu) with oxazinone C in the presence of a palladium catalyst provides protected amino-oxazin-3(4H)-one D.
- amino-oxazinone E and treatment of amino-oxazinone E with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-dihydro-2H-pyrazino[2,3-3 ⁇ 4][l,4]oxazine F.
- the amino protecting group (Pg) can be removed using standard protecting group removal procedures, and the resulting amine can be used in an amide coupling reaction (such as with a carboxylic acid an amide coupling reagent) to provide final oxazine G.
- SCHEME 19 19.
- R and R v may be, for example, hydrogen or a substituent, such as methyl
- R 1 and R 11 may be, for example, a cyclic group, such as phenyl.
- Scheme 20 illustrates an alternative general method for preparing amido-substituted 3,4-dihydro-2H-pyrazino[2,3-3 ⁇ 4][l,4]oxazines.
- Alkylation of amino-pyrazinol A with an di- haloalkane provides chloro-dihydro-2H-pyrazino[2,3-3 ⁇ 4][l,4]oxazine B.
- WO 2011/059839 See, for example, WO 2011/059839.
- Reaction of a protected amine (Pg-NH 2 , such as /?ara-methoxybenzylamine (PMB-NH 2 )) with oxazine B in the presence of a palladium catalyst provides protected amino-dihydro-2H-pyrazino[2,3- 3 ⁇ 4][l,4]oxazine C.
- Reaction of oxazine C with a sulphonyl chloride or a sulfamoyl chloride provides sulfonamido-dihydro-2H-pyrazino[2,3-£][l,4]oxazine D.
- the protecting group (Pg) on oxazine D can be removed using standard deprotection conditions to provide an amino- oxazine (not shown), which is used in an amide coupling reaction (such as with a carboxylic acid an amide coupling reagent) to provide oxazine E. SCHEME 20.
- R and R may be, for example, hydrogen or a substituent, such as methyl; and R 1 and R 11 may be, for example, a cyclic group, such as phenyl.
- tetrahydronaphthyridine and Related Compounds provide therapeutic benefits to subjects suffering from an immune disorder or inflammatory disorder. Accordingly, one aspect of the invention provides a method of treating a disorder selected from the group consisting of an immune disorder or inflammatory disorder.
- the method comprises administering a therapeutically effective amount of a tetrahydronaphthyridine or related compound described herein, such as a compound of Formula I, I-A, II, II- A, III, III-A, IV, V, or VI, to a subject in need thereof to ameliorate a symptom of the disorder, wherein Formula I, I-A, II, II-A, III, III-A, IV, V, or VI are as described above.
- a tetrahydronaphthyridine or related compound described herein such as a compound of Formula I, I-A, II, II- A, III, III-A, IV, V, or VI
- the particular compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI is the compound defined by one of the embodiments described above.
- the disorder is an immune disorder. In certain other embodiments, the disorder is an inflammatory disorder. In certain other embodiments, the disorder is an autoimmune disorder. In certain other embodiments, the disorder is
- rheumatoid arthritis psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, or epidermal hyperplasia.
- the disorder is cartilage inflammation, bone degradation, arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyo litis, derm
- granulomatosis arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, atherosclerosis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type I diabetes mellitus, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, or an immune disorder associated with or arising from activity of pathogenic lymphocytes.
- the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, or erythrodermic psoriasis.
- the disorder is rheumatoid arthritis.
- the subject is a human.
- Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, II, II -A, III, III-A, IV, V, or VI) in the manufacture of a medicament.
- the medicament is for treating a disorder described herein, such as rheumatoid arthritis.
- Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, II, II -A, III, III-A, IV, V, or VI) for treating a medical disorder, such a medical disorder described herein (e.g., rheumatoid arthritis).
- tetrahydronaphthyridine and related compounds described herein can inhibit the activity of RORy. Accordingly, another aspect of the invention provides a method of inhibiting the activity of RORy.
- the method comprises exposing a RORyto an effective amount of a tetrahydronaphthyridine or related compound described herein, such as a compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI, to inhibit said RORy, wherein Formula I, I-A, II, II-A, III, III-A, IV, V, and VI I are as described above.
- a particular compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI is the compound defined by one of the embodiments described above.
- tetrahydronaphthyridine and related compounds described herein can reduce the amount of interleukin-17 (IL-17) in a subject.
- IL-17 is a cytokine that affects numerous biological functions, including inducing and mediating pro-inflammatory responses. Accordingly, another aspect of the invention provides a method of reducing the amount of IL-17 in a subject.
- the method comprises administering to a subject an effective amount of a tetrahydronaphthyridine or related compound described herein, such as a compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI, to reduce the amount of IL-17 in the subject, wherein Formula I, I-A, II, II-A, III, III-A, IV, V, and VI are as described above.
- the particular compound of Formula I, I-A, II, II-A, III, III- A, IV, V, or VI is the compound defined by one of the embodiments described above.
- the subject is a human. In certain embodiments,
- administering the compound reduces the amount of IL-17 produced by Th-17 cells in the subject.
- a change in the amount of IL-17 produced by, for example, Th-17 cells can be measured using procedures described in the literature, such as an ELISA assay or intracellular staining assay.
- tetrahydronaphthyridine and related compounds described herein such as a compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI, may inhibit the synthesis of IL-17 in a subject. Accordingly, another aspect of the invention provides a method of inhibiting the synthesis of IL-17 in a subject.
- the method comprises administering to a subject an effective amount of a compound described herein, e.g., a compound of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI, to inhibit the synthesis of IL-17 in the subject, wherein Formula I, I-A, II, II-A, III, III-A, IV, V, and VI are as described above.
- a compound described herein e.g., a compound of Formula I, I-A, II, II-A, III, III-A, IV, V, and VI
- the particular compound of Formula I, I-A, II, II-A, III, III- A, IV, V, or VI is a compound defined by one of the embodiments described above.
- Inhibition of RORyt in cells is determined using a reporter system in HEK293 cells employing a luciferase readout.
- the RORyt DNA binding domain (DBD) is replaced with heterologous yeast GAL4 DBD using standard recombinant DNA methods.
- the resulting GAL4-RORyt-LBD fusion construct is placed under the control of a constitutive
- CMV cytomegalovirus
- a transcriptional reporter expression construct is used to monitor GAL4-RORy activity, which contains five copies of the GAL4 binding sequence (UAS) controlling expression of a firefly luciferase reporter gene.
- This construct pGL4.31, is commercially available from Promega Corporation, Madison WI. Both constructs are transfected in bulk into HEK-293 cells using standard lipid-based transfection techniques, which allows the GAL4-RORy-LBD fusion protein to drive expression of the luciferase reporter. Control transfections are performed with an empty pCDN3.1+ vector. [0171] The next day, cells are plated into 384 well plates, test compounds are added, and the plates are incubated overnight.
- Test compounds capable of blocking the GAL4-RORg fusion protein from initiating expression of the luciferase signal are identified.
- Promega firefly assays kits are used to stabilize the luciferase signal, and the intensity of the luciferase signal is measured using an En Vision Multilabel Plate Reader (Perkin Elmer, Waltham, MA).
- En Vision Multilabel Plate Reader Perkin Elmer, Waltham, MA.
- HEK 293 cells are transfected with GAL4-RORyc-LBD construct (pcDNA3.1neo) and the pGL4.31 GAL4-luciferase reporter construct (Promega).
- GAL4-RORyc-LBD construct pcDNA3.1neo
- pGL4.31 GAL4-luciferase reporter construct Promega
- Transfection protocol is for a single T75 flask performed with Minis Trans-It 293 reagent. A 60 xL aliquot of Trans-IT reagent at room temperature is added drop wise to 1.5 mL of Optimem (Invitrogen). The resulting solution is mixed by inversion and incubated for 5-20 minutes at room temperature. This reagent mixture is added to 10 ⁇ of DNA (5 ⁇ g of each expression vector). The solution is mixed by inversion and incubated at room temperature for 20 minutes.
- TrypLE Express stable Trypsin- like reagent, Invitrogen
- the mixture is incubated at room temperature until the cells are visibly loose in the flask (approximately 2-5 minutes).
- the cells and transfection mixture are added to one T75 flask.
- the contents of the T75 flask are mixed and incubated overnight at 37 °C and 5% C0 2 .
- cells are harvested and plated for test compound screening.
- Cells may be harvested as described above.
- cells are counted and an appropriate number of cells are spun down.
- cells are aspirated and re-suspended in complete growth media at a concentration of 0.5xl0 6 cells/mL. Plate 20 [iL of the cell suspension into a white, tissue- culture treated 384 well plate. (10,000 -20,000 cells/well).
- a 10 mM stock solution of test compound in dimethylsulfoxide (DMSO) is diluted to 500x the final test concentration in DMSO, then diluted to 5x the final test concentration with complete growth medium to provide the Test Compound Solution.
- the concentration of DMSO in the Test Compound Solution is 0.2%.
- a 5 aliquot of Test Compound Solution is added to each test well in the 384 well plate previously plated with the cell suspension. Next, plates are spun briefly and incubated overnight at 37°C and 5% C0 2 .
- luciferase assay After 16-24 hours, the luciferase assay is performed. Plates and luciferase reagent (e.g. One-Glo® or Dual Glo®; Promega, Madison, WI) are brought to room temperature. Next, a 25 aliquot of luciferase reagent is added to each well. Plates are spun down briefly and incubated at room temperature for 10 minutes. The luciferase signal is measured on an Envision plate reader (Perkin Elmer) set to the ultra sensitive luminescence setting.
- luciferase reagent e.g. One-Glo® or Dual Glo®; Promega, Madison, WI
- Another aspect of the invention provides for combination therapy.
- Tetrahydronaphthyridine and related compounds e.g., a compound of Formula I, I- A, II, II- A, III, III-A, IV, V, or VI
- additional therapeutic agents to treat medical disorders, such as medical disorders associated with inappropriate IL-17 pathway activity.
- Exemplary additional therapeutic agents include, for example, (1) a TNF-a inhibitor; (2) a non-selective COX- l/COX-2 inhibitor; (3) a selective COX-2 inhibitor, such as celecoxib and rofecoxib; (4) other agents for treating inflammatory disease and autoimmune disease including, for example, methotrexate, leflunomide, sulfasalazine, azathioprine, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofm, parenteral gold, oral gold, cyclophosphamide, Lymphostat-B, a BAFF/ APRIL inhibitor, CTLA-4-Ig, or a mimetic of CTLA-4-Ig; (5) a leukotriene biosynthesis inhibitor, such as a 5 -lipoxygenase (5-LO) inhibitor, or a 5
- a NRF2 pathway activator such as the fumaric acid derivative, BG-12
- a chemokine or chemokine receptor inhibitor such as a CCR9 antagonist.
- the amount tetrahydronaphthyridine or related compound e.g., a compound of Formula I, I-A, II, II-A, III, III- A, IV, V, or VI
- additional therapeutic agent and the relative timing of administration may be selected in order to achieve a desired combined therapeutic effect.
- the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
- a tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI
- a tetrahydronaphthyridine or related compound may be administered during a time when the additional therapeutic agent(s) exerts its prophylactic or therapeutic effect, or vice versa.
- the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
- the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
- the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
- tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI
- the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
- the tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI
- the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
- the tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI
- the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
- the tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I-A, II, II-A, III, III-A, IV, V, or VI
- the additional therapeutic agent(s) may act additively or synergistically.
- a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
- a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
- kits comprising a therapeutically effective amount of the tetrahydronaphthyridine or related compound (e.g., a compound of any one of Formula I, I- A, II, II-A, III, III- A, IV, V, or VI), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
- a therapeutically effective amount of the tetrahydronaphthyridine or related compound e.g., a compound of any one of Formula I, I- A, II, II-A, III, III- A, IV, V, or VI
- a pharmaceutically acceptable carrier e.g., a compound of any one of Formula I, I- A, II, II-A, III, III- A, IV, V, or VI
- a pharmaceutically acceptable carrier e.g., a compound of any one of Formula I, I- A, II, II-A, III, III- A, IV, V, or VI
- compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
- compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
- oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.
- terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
- compositions are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
- Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
- a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
- an aforementioned formulation renders orally bioavailable a compound of the present invention.
- Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
- a compound of the present invention may also be administered as a bolus, electuary or paste.
- the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
- compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
- dosage forms can be made by dissolving or dispersing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
- Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
- compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
- antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
- Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
- the rate of drug release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
- the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
- parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
- systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
- These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
- the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
- the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
- a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
- the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
- the effective amount may be less than when the agent is used alone.
- the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
- the invention further provides a unit dosage form (such as a tablet or capsule) comprising a tetrahydronaphthyridine or related compound described herein (such as a compound of any one of Formulae I-VI, I- A, II- A, and III-A, or a specific compound described herein, such as in Tables 1-9) in a therapeutically effective amount for the treatment of an immune or inflammatory disorder, such as one of the particular disorders or inflammatory disorders described herein.
- a unit dosage form such as a tablet or capsule
- a tetrahydronaphthyridine or related compound described herein such as a compound of any one of Formulae I-VI, I- A, II- A, and III-A, or a specific compound described herein, such as in Tables 1-9
- an immune or inflammatory disorder such as one of the particular disorders or inflammatory disorders described herein.
- HPLC Method A The conditions of HPLC Method A are as follows: Waters C-18 column, 4.6 x 150 mm, 3.5 micron, 25°C, 2.0 mL/min, 1 min 25% MeCN in H 2 0 (0.1% TFA), 7 min gradient of 25%-95% MeCN in H 2 0 (0.1% TFA), 95% MeCN in H 2 0 (0.1% TFA) for 2 min, and then equilibration to 25% MeCN in H 2 0 (0.1% TFA) over 2.0 min.
- 6-Chloro-lH-pyrazolo[4,3-c]pyridine 150 mg, 1.0 mmol was dissolved in dichloromethane (2 mL) and pyridine (2 mL) to form a solution.
- 4-Fluorobenzenesulfonyl chloride 300 mg, 1.5 mmol was added to the solution and the resulting reaction mixture was stirred at 50 °C for 16 hours.
- reaction mixture was diluted with ethyl acetate (15 mL), solids were removed by filtration, and the filtrate was concentrated in the presence of silica to provide a crude product, which was purified by column chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to provide the title compound (0.68 g, 64% yield); HPLC retention time Method A: 5.46 minutes (98.9% pure).
- reaction mixture was recooled to 0°C before carefully quenching with sodium sulfate decahydrate.
- the resulting slurry was stirred at ambient temperature for two hours, and then solids were removed by filtration over celite. The solids were washed with tetrahydrofuran, and the filtrates were concentrated in the presence of silica to provide a crude product, which was purified via column chromatography eluting with a gradient of 0.5-5% methanol in dichloromethane to provide the title compound. (1.1 g, 62% yield); HPLC retention time Method A: 2.36 minutes (96.4% pure).
- reaction mixture was cooled, diluted with ethyl acetate, and the organic layer was washed with 1M hydrogen chloride (3 x 40 mL), washed with brine, dried with sodium sulfate, filtered and concentrated in the presence of silica to provide a crude product, which was purified by column chromatography eluting with a gradient of 20-70% ethyl acetate in hexanes to provide the title compound. (540 mg, 68% yield); HPLC retention time Method A: 6.46 minutes (95% pure).
- reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield title compound. (0.78 g, 47% yield).
- reaction mixture was heated to reflux under a nitrogen atmosphere for 3 hours. Then, the reaction mixture was cooled, filtered, diluted with ethyl acetate, and then washed with 1M hydrogen chloride, saturated sodium bicarbonate, and brine. The resulting organic solution was dried with sodium sulfate, filtered, and concentrated in vacuo in the presence of silica to provide the crude product that was purified by column chromatography eluting with a gradient of 30- 100% ethyl acetate in hexanes to provide the title compound. (3.1 g, 81% yield); HPLC retention time Method A: 4.55 minutes (95% pure).
- reaction mixture was shaken at ambient temperature for 2 hours, diluted with ethyl acetate, and washed with 1M hydrogen chloride and brine.
- the resulting organic solution was dried with sodium sulfate, filtered, and concentrated in the presence of silica to provide a crude product that was purified by column chromatography eluting with a gradient of 0.5-10% methanol in dichloromethane to provide the title compound. (29 mg, 51% yield); HPLC retention time Method A: 5.36 minutes (95% pure).
- reaction mixture was partitioned between ethyl acetate and brine, the organic layer was separated and dried with sodium sulfate, filtered and concentrated in vacuo to provide a crude product that was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to produce the title compound. (520 mg, 74% yield); HPLC retention time Method A: 7.43 minutes (95% pure).
- reaction vessel was evacuated and refilled with nitrogen three times before filtering the reaction mixture over celite to remove the solids.
- the solids were washed with methanol, and the organic solution was concentrated in vacuo to yield title compound as a crude mixture. (0.34 g, 88% yield); HPLC retention time Method A: 5.46 minutes (95% pure).
- reaction mixture was cooled, filtered, diluted with ethyl acetate, and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine.
- the resulting organic solution was dried with sodium sulfate, filtered, and concentrated in vacuo in the presence of silica to provide the crude product that was purified by column chromatography eluting with a gradient of 15-80% ethyl acetate in hexanes to provide the title compound. (250 mg, 54% yield); HPLC retention time Method A: 4.80 minutes (95.6% pure).HPLC: 95.6% pure @ 4.80minutes.
- reaction mixture was concentrated in vacuo in the presence of silica to provide a crude product that was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to provide the title compound. (50 mg, 47% yield); HPLC retention time Method A: 6.46 minutes (86% pure).
- reaction mixture was concentrated in vacuo in the presence of silica to provide a mixture that was purified by column chromatography eluting with a gradient of EtOAc in hexanes to provide the title compound. (5 mg, 15% yield); HPLC retention time Method A: 5.4 minutes (98% pure).
- N-(5-Bromo-2-chloro-pyridin-3-yl)-N-[3-(tert-butyl-dimethyl-silanyloxy)-2- dibenzylamino-propyl]-3-methyl-benzenesulfonamide (4.44 g, 6.09 mmol) was dissolved in THF (120 mL). Tetrabutylammonium fluoride (1M in THF, 7.3 mL, 7.3 mmol) was added and the reaction was stirred for 8 hours at 60 °C. Additional TBAF (1M in THF, 3 mL, 3 mmol) was added and the reaction was stirred for 2 hours at 70 °C.
- N 3 ,N 3 -Dibenzyl -(m-tolylsulfonyl) ,2,3,4-tetrahydropyrido[2,3-3 ⁇ 4][l,4]oxazepine- 3,8-diamine 500 mg, 0.97 mmol
- disopropylethylamine 0.60 mL, 3.4 mmol
- Trifluoroacetic anhydride 0.30 mL, 2.1 mmol
- N-[7-dibenzylamino-5-(toluene-3-sulfonyl)-5,6,7,8-tetrahydro-9-oxa-l,5- diazabenzocyclo hepten-3-yl]-2,2,2-trifluoro-acetamide (475 mg, 0.78 mmol, 1.0 equiv.) dissolved in 50 mL methanol. 10% Palladium on carbon (712 mg) was added and the resulting mixture was transferred to a Parr apparatus and hydrogenated at 80 PSI for 18 hours.
- N-[7-amino-5-(toluene-3-sulfonyl)-5,6,7,8-tetrahydro-9-oxa-l,5-diaza- benzocyclohepten-3-yl]-2,2,2-trifluoro-acetamide 200 mg, 0.46 mmol, 1.0 equiv was dissolved in /?-dioxane (2 mL), then sodium bicarbonate (98 mg, 1.2 mmol, 2.5 equiv), di- tert-butyl dicarbonate (152 mg, 0.70 mmol, 1.5 equiv), and water (1 mL) were added and the resulting mixture stirred at room temperature.
- N-[7-Amino-5-(toluene-3-sulfonyl)-5,6,7,8-tetrahydro-9-oxa-l,5-diaza- benzocyclohepten-3-yl]-2,6-dichloro-benzamide (15 mg, 0.028 mmol, 1.0 equiv) was dissolved in 1 : 1 tetrahydrofuran/ethanol (0.5 mL). Formalin (0.015 mL, 0.174 mmol, 6.3 equiv) was added and the mixture was stirred at room temperature for 15 minutes.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015511594A JP6236068B2 (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibiting RORγ activity and treating diseases |
BR112014028017A BR112014028017A2 (en) | 2012-05-08 | 2013-05-07 | compound, pharmaceutical composition, method for treating a disorder, method for reducing the amount of il-17 in an individual, and method for inhibiting ror activity |
KR20147031132A KR20150007300A (en) | 2012-05-08 | 2013-05-07 | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
US14/398,061 US9657033B2 (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
MX2014013549A MX367341B (en) | 2012-05-08 | 2013-05-07 | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE. |
CN201380024191.9A CN104812393A (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
CA2871514A CA2871514C (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of ror.gamma.activity and the treatment of disease |
EP13788167.8A EP2846804B1 (en) | 2012-05-08 | 2013-05-07 | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
RU2014149136A RU2014149136A (en) | 2012-05-08 | 2013-05-07 | TETRAHYDRONAFTHYRIDINE AND RELATED Bicyclic Compounds for Inhibition of Rorγ Activity and Treatment of a Disease |
AU2013259737A AU2013259737A1 (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
HK15108736.5A HK1207990A1 (en) | 2012-05-08 | 2015-09-08 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of rorgamma activity and the treatment of disease ror |
US15/587,934 US10377768B2 (en) | 2012-05-08 | 2017-05-05 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261644158P | 2012-05-08 | 2012-05-08 | |
US61/644,158 | 2012-05-08 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/398,061 A-371-Of-International US9657033B2 (en) | 2012-05-08 | 2013-05-07 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
US15/587,934 Division US10377768B2 (en) | 2012-05-08 | 2017-05-05 | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2013169704A2 true WO2013169704A2 (en) | 2013-11-14 |
WO2013169704A3 WO2013169704A3 (en) | 2015-05-28 |
Family
ID=49551429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2013/039839 WO2013169704A2 (en) | 2012-05-08 | 2013-05-07 | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
Country Status (12)
Country | Link |
---|---|
US (2) | US9657033B2 (en) |
EP (1) | EP2846804B1 (en) |
JP (1) | JP6236068B2 (en) |
KR (1) | KR20150007300A (en) |
CN (1) | CN104812393A (en) |
AU (1) | AU2013259737A1 (en) |
BR (1) | BR112014028017A2 (en) |
CA (1) | CA2871514C (en) |
HK (1) | HK1207990A1 (en) |
MX (1) | MX367341B (en) |
RU (1) | RU2014149136A (en) |
WO (1) | WO2013169704A2 (en) |
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014201857A1 (en) * | 2013-06-19 | 2014-12-24 | 中国科学院上海药物研究所 | Five-membered heterocyclic pyridine compounds and preparation method and use thereof |
WO2015095792A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Carbamate benzoxaxine propionic acids and acid derivatives for modulation of rorgamma activity and the treatment of disease |
WO2015095788A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | 2-ACYLAMIDOMETHYL AND SULFONYLAMIDOMETHYL BENZOXAZINE CARBAMATES FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
WO2015095795A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE, AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
US9266886B2 (en) | 2014-02-03 | 2016-02-23 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US9394315B2 (en) | 2012-05-08 | 2016-07-19 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
CN106061947A (en) * | 2014-01-06 | 2016-10-26 | 百时美施贵宝公司 | Cyclohexyl sulfone ror [gamma] modulators |
US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
WO2016179343A1 (en) * | 2015-05-05 | 2016-11-10 | Lycera Corporation | DIHYDRO-2H-BENZO[b][1,4]OXAZINE SULFONAMIDE AND RELATED COMPOUNDS FOR USE AS AGONISTS OF RORy AND THE TREATMENT OF DISEASE |
CN106132931A (en) * | 2014-01-06 | 2016-11-16 | 百时美施贵宝公司 | Carbocyclic ring sulfone ROR gamma modulators |
US9512111B2 (en) | 2010-11-08 | 2016-12-06 | Lycera Corporation | N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
US9657033B2 (en) | 2012-05-08 | 2017-05-23 | Lycera Corporation | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
WO2017127375A1 (en) * | 2016-01-20 | 2017-07-27 | Boehringer Ingelheim International Gmbh | Pyrazinedihydropyrimidinone or pyridazinedihydropyrimidinone compounds as modulators of ror gamma |
US9796710B2 (en) | 2014-10-14 | 2017-10-24 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
US9896441B2 (en) | 2014-05-05 | 2018-02-20 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
WO2018234805A1 (en) * | 2017-06-22 | 2018-12-27 | Curadev Pharma Limited | Small molecule modulators of human sting |
US10189777B2 (en) | 2014-05-05 | 2019-01-29 | Lycera Corporation | Benzenesulfonamido and related compounds for use as agonists of RORγ and the treatment of disease |
US10221142B2 (en) | 2015-02-11 | 2019-03-05 | Merck Sharp & Dohme Corp. | Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof |
US10287272B2 (en) | 2015-10-27 | 2019-05-14 | Merck Sharp & Dohme Corp. | Substituted indazole compounds as RORgammaT inhibitors and uses thereof |
US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
US10344000B2 (en) | 2015-10-27 | 2019-07-09 | Merck Sharp & Dohme Corp. | Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof |
US10532088B2 (en) | 2014-02-27 | 2020-01-14 | Lycera Corporation | Adoptive cellular therapy using an agonist of retinoic acid receptor-related orphan receptor gamma and related therapeutic methods |
US10584121B2 (en) | 2015-10-27 | 2020-03-10 | Merck Sharp & Dohme Corp. | Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof |
US10611740B2 (en) | 2015-06-11 | 2020-04-07 | Lycera Corporation | Aryl dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US10829481B2 (en) | 2016-01-29 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Benzimidazole derivatives as modulators of ROR-gamma |
US10913739B2 (en) | 2017-07-24 | 2021-02-09 | Vitae Pharmaceuticals, LLC (121374) | Inhibitors of RORγ |
US11008340B2 (en) | 2015-11-20 | 2021-05-18 | Vitae Pharmaceuticals, Llc | Modulators of ROR-gamma |
US11186573B2 (en) | 2017-07-24 | 2021-11-30 | Vitae Pharmaceuticals, Llc | Inhibitors of ROR gamma |
WO2022106550A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Crystalline polymorphic form of a ror gamma inhibitor |
WO2022106549A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Crystalline salts of a ror gamma inhibitor |
WO2022106548A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Solid forms of a ror gamma inhibitor |
WO2022106551A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Co-crystals of a ror gamma inhibitor |
US11571423B2 (en) | 2017-06-22 | 2023-02-07 | Curadev Pharma Limited | Small molecule modulators of human sting |
AU2020390377B2 (en) * | 2019-11-29 | 2023-12-21 | Wuhan Ll Science And Technology Development Co., Ltd. | Compound containing benzene ring and application thereof |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR122019007990B1 (en) | 2013-11-18 | 2021-05-04 | Forma Therapeutics, Inc | COMPOUND, AND, PHARMACEUTICAL COMPOSITION |
US9422281B2 (en) | 2013-11-18 | 2016-08-23 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
JO3638B1 (en) * | 2015-09-09 | 2020-08-27 | Lilly Co Eli | Compounds useful for inhibiting ror-gamma-t |
WO2018052903A1 (en) * | 2016-09-13 | 2018-03-22 | The Scripps Research Intitute | RORγ MODULATORS |
CN106854177B (en) * | 2017-01-04 | 2019-10-11 | 苏州健雄职业技术学院 | A kind of preparation method of 6- chloro-4-hydroxyl pyridine -3- formaldehyde |
CN108689942B (en) * | 2017-04-11 | 2023-06-09 | 广东东阳光药业有限公司 | Nitrogen-containing bicyclic compound, and preparation method and application thereof |
WO2020108538A1 (en) * | 2018-11-27 | 2020-06-04 | 正大天晴药业集团股份有限公司 | RORγ INHIBITOR HAVING SULFONYL STRUCTURE |
WO2021047406A1 (en) * | 2019-09-10 | 2021-03-18 | 四川科伦博泰生物医药股份有限公司 | Tricyclic compound, pharmaceutical composition containing same, preparation method therefor and use thereof |
CN111658651B (en) * | 2020-06-08 | 2021-08-03 | 重庆医科大学附属第一医院 | Application of CQMU151 in preparing medicament for treating Th17 cell-mediated autoimmune disease |
CA3186628A1 (en) * | 2020-06-30 | 2022-01-06 | Dermira, Inc. | Ror.gamma.t inhibitors and topical uses thereof |
CN114149427A (en) * | 2021-12-18 | 2022-03-08 | 上海鼎雅药物化学科技有限公司 | Synthesis method of non-neferitone and intermediate thereof |
Family Cites Families (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8607294D0 (en) | 1985-04-17 | 1986-04-30 | Ici America Inc | Heterocyclic amide derivatives |
TW263508B (en) | 1991-02-12 | 1995-11-21 | Pfizer | |
JP3414433B2 (en) | 1993-03-01 | 2003-06-09 | 日本化薬株式会社 | Electrophotographic toner |
DE19523446A1 (en) | 1995-06-28 | 1997-01-02 | Bayer Ag | Benzotriazoles |
WO1997003945A1 (en) | 1995-07-14 | 1997-02-06 | Smithkline Beecham Corporation | Substituted-pent-4-ynoic acids |
JPH11514969A (en) | 1995-08-10 | 1999-12-21 | バイエル・アクチエンゲゼルシヤフト | Halobenzimidazoles and their use as microbicides |
AU722514B2 (en) | 1995-12-28 | 2000-08-03 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
EP0934307B1 (en) | 1996-06-19 | 2011-04-27 | Aventis Pharma Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
WO1998022457A1 (en) | 1996-11-19 | 1998-05-28 | Amgen Inc. | Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents |
BR9810508A (en) * | 1997-07-03 | 2000-09-05 | Du Pont Pharm Co | Compound, pharmaceutical composition and method of treating a disorder |
US6828344B1 (en) | 1998-02-25 | 2004-12-07 | Genetics Institute, Llc | Inhibitors of phospholipase enzymes |
SK3852001A3 (en) | 1998-09-18 | 2003-03-04 | Basf Ag | 4-Aminopyrrolopyrimidines as kinase inhibitors |
US6348032B1 (en) | 1998-11-23 | 2002-02-19 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with benzimidazole derivatives |
WO2001012600A1 (en) | 1999-08-12 | 2001-02-22 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
EP1218336A2 (en) | 1999-09-20 | 2002-07-03 | Takeda Chemical Industries, Ltd. | Melanin concentrating hormone antagonist |
TWI239942B (en) | 2001-06-11 | 2005-09-21 | Dainippon Pharmaceutical Co | N-arylphenylacetamide derivative and pharmaceutical composition containing the same |
AR034390A1 (en) | 2001-08-03 | 2004-02-25 | Schering Corp | DERIVATIVES OF 1-SULFONIL-TETRAHIDRO REPLACED KINOLINES, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE PREPARATION OF MEDICINES AS INHIBITORS OF THE SECRET RANGE |
DE10229777A1 (en) * | 2002-07-03 | 2004-01-29 | Bayer Ag | Indoline-phenylsulfonamide derivatives |
FR2845382A1 (en) | 2002-10-02 | 2004-04-09 | Sanofi Synthelabo | INDAZOLECARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS |
UA80171C2 (en) | 2002-12-19 | 2007-08-27 | Pfizer Prod Inc | Pyrrolopyrimidine derivatives |
JP4601038B2 (en) | 2003-03-26 | 2010-12-22 | 第一三共株式会社 | Indolylmaleimides |
CN101906106A (en) | 2003-09-18 | 2010-12-08 | 康福玛医药公司 | New heterogeneous ring compound as the HSP90-inhibitor |
SE0302760D0 (en) | 2003-10-20 | 2003-10-20 | Biovitrum Ab | New compounds |
US7420059B2 (en) | 2003-11-20 | 2008-09-02 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
ES2339670T3 (en) | 2003-12-23 | 2010-05-24 | Novartis Ag | BICYCLE HYPERCYCLIC INHIBITORS OF QUINASA P-38. |
EP1771204A4 (en) | 2004-07-01 | 2008-08-13 | Univ New York | Compositions and methods for modulation of ror gamma t |
US20070010537A1 (en) | 2004-08-20 | 2007-01-11 | Kazumasa Hamamura | Fused pyramidine derivative and use thereof |
AR051780A1 (en) | 2004-11-29 | 2007-02-07 | Japan Tobacco Inc | FUSIONED RING COMPOUNDS CONTAINING NITROGEN AND USING THEMSELVES |
US8003624B2 (en) | 2005-08-25 | 2011-08-23 | Schering Corporation | Functionally selective ALPHA2C adrenoreceptor agonists |
US7803828B2 (en) | 2005-08-25 | 2010-09-28 | Schering-Plough Corporation | Functionally selective alpha2C adrenoreceptor agonists |
DK1937669T3 (en) | 2005-09-01 | 2012-05-07 | Janssen Pharmaceutica Nv | New benzopyran derivatives such as potassium channel openers |
BRPI0616246A2 (en) | 2005-09-15 | 2011-06-14 | Hoffmann La Roche | compounds, process for their manufacture, pharmaceutical compositions comprising them, method for the therapeutic and / or prophylactic treatment of diseases that are modulated by l-cpt1 inhibitors and use of the compounds |
AU2007214594B2 (en) | 2006-02-13 | 2010-11-11 | F. Hoffmann-La Roche Ag | Heterobicyclic sulfonamide derivatives for the treatment of diabetes |
CA2642211C (en) | 2006-02-17 | 2012-01-24 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds for treating or preventing autoimmune diseases |
US7998978B2 (en) | 2006-05-01 | 2011-08-16 | Pfizer Inc. | Substituted 2-amino-fused heterocyclic compounds |
US20080305169A1 (en) | 2006-05-26 | 2008-12-11 | Japan Tobacco Inc. | Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds |
BRPI0712730A2 (en) | 2006-06-01 | 2013-12-17 | Wyeth Corp | Compound of Formula I; METHOD FOR TREATMENT OF A CENTRAL NERVOUS SYSTEM DISORDER RELATED TO OR AFFECTED BY THE 5-HT6 RECEIVER IN A PATIENT NEEDING THIS; PHARMACEUTICAL COMPOSITION; PROCESS FOR PREPARING A COMPOUND OF FORMULA IA; AND USE OF A COMPOUND FORMULA I |
JP5324437B2 (en) | 2006-07-03 | 2013-10-23 | プロキシマゲン・リミテッド | Indole as a 5-HT6 modulator |
TWI315304B (en) * | 2006-08-31 | 2009-10-01 | Univ Taipei Medical | Indoline-sulfonamides compounds |
US20090275586A1 (en) | 2006-10-06 | 2009-11-05 | Kalypsys, Inc. | Heterocyclic inhibitors of pde4 |
WO2008062740A1 (en) | 2006-11-20 | 2008-05-29 | Japan Tobacco Inc. | Nitrogenated fused ring compound and use thereof |
US7799933B2 (en) | 2006-12-21 | 2010-09-21 | Hoffman-La Roche Inc. | Sulfonamide derivatives |
US20080186971A1 (en) | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
JP2010529031A (en) | 2007-05-29 | 2010-08-26 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | Naphthyridine derivatives as PI3 kinase inhibitors |
US7776877B2 (en) * | 2007-06-22 | 2010-08-17 | Chemocentryx, Inc. | N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides |
US20110190280A1 (en) | 2007-08-29 | 2011-08-04 | George Adjabeng | Thiazole And Oxazole Kinase Inhibitors |
WO2009035997A2 (en) | 2007-09-14 | 2009-03-19 | Cara Therapeutics, Inc. | Benzo-fused heterocycles |
RU2364597C1 (en) | 2007-12-14 | 2009-08-20 | Андрей Александрович Иващенко | HETEROCYCLIC INHIBITORS OF Hh-SYGNAL CASCADE, BASED ON THEM MEDICINAL COMPOSITIONS AND METHOD OF TREATING DISEASES INDUCED BY ABBARANT ACTIVITY OF Hh-SIGNAL SYSTEM |
US7960377B2 (en) * | 2008-03-28 | 2011-06-14 | Cara Therapeutics, Inc. | Substituted pyridoxazines |
US8765743B2 (en) | 2008-06-05 | 2014-07-01 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
JP5502858B2 (en) | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | 4-Carboxamide indazole derivatives useful as inhibitors of PI3 kinase |
ES2445199T3 (en) | 2008-06-05 | 2014-02-28 | Glaxo Group Limited | Benzpyrazole derivatives as PI3-kinase inhibitors |
EP2288605B1 (en) | 2008-06-09 | 2014-06-25 | Sanofi | Annelated pyrrolidin sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals |
NZ589694A (en) | 2008-06-09 | 2012-05-25 | Sanofi Aventis | Annelated n-heterocyclic sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals |
US9334242B2 (en) | 2008-06-16 | 2016-05-10 | Gtx, Inc. | Compounds for treatment of cancer |
WO2009157196A1 (en) | 2008-06-25 | 2009-12-30 | 武田薬品工業株式会社 | Amide compound |
WO2010017827A1 (en) | 2008-08-14 | 2010-02-18 | European Molecular Biology Laboratory | 6-substituted 1-sulfonyl-2, 3-dihydro-indole derivatives for the treatment of proliferative diseases |
BRPI0925343A2 (en) | 2008-10-02 | 2015-07-28 | Taisho Pharmaceutical Co Ltd | Compound, pharmaceutical composition, and prophylactic or therapeutic drug |
EP2181710A1 (en) | 2008-10-28 | 2010-05-05 | Phenex Pharmaceuticals AG | Ligands for modulation of orphan receptor-gamma (NR1F3) activity |
WO2010057101A2 (en) | 2008-11-17 | 2010-05-20 | Schering Corporation | Compounds useful as hiv blockers |
CA2743609A1 (en) | 2008-11-19 | 2010-05-27 | Schering Corporation | Inhibitors of diacylglycerol acyltransferase |
CN102388054B (en) | 2008-12-19 | 2015-03-04 | 西特里斯药业公司 | Thiazolopyridine sirtuin modulating compounds |
TW201030007A (en) | 2009-02-06 | 2010-08-16 | Gruenenthal Gmbh | Substituted spiro-amides as b1r modulators |
EP2406255B1 (en) | 2009-03-09 | 2015-04-29 | Glaxo Group Limited | 4-oxadiazol-2-yl-indazoles as inhibitors of pi3 kinases |
WO2010117425A1 (en) | 2009-03-31 | 2010-10-14 | Biogen Idec Ma Inc. | Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use |
WO2010123139A1 (en) | 2009-04-24 | 2010-10-28 | 持田製薬株式会社 | Arylcarboxamide derivative having sulfamoyl group |
ES2876933T3 (en) | 2009-04-30 | 2021-11-15 | Glaxo Group Ltd | Oxazole-substituted indazoles as PI3-kinase inhibitors |
US8119683B2 (en) | 2009-08-10 | 2012-02-21 | Taipei Medical University | Aryl substituted sulfonamide compounds and their use as anticancer agents |
US9556201B2 (en) | 2009-10-29 | 2017-01-31 | Glaxosmithkline Llc | Bicyclic pyridines and analogs as sirtuin modulators |
US20120238571A1 (en) | 2009-12-03 | 2012-09-20 | Glaxo Group Limited | Indazole derivatives as pi 3-kinase |
EP2507223A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Benzpyrazole derivatives as inhibitors of p13 kinases |
EP2507226A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Novel compounds |
WO2011073276A1 (en) * | 2009-12-16 | 2011-06-23 | Evotec Ag | Benzoxazine aryl sulfonamide derivatives as kv1.3 modulators |
ES2445917T3 (en) * | 2010-02-03 | 2014-03-06 | Takeda Pharmaceutical Company Limited | Inhibitors of apoptosis signal regulatory kinase 1 |
WO2012032067A1 (en) | 2010-09-08 | 2012-03-15 | Glaxo Group Limited | Polymorphs and salts of n- [5- [4- (5- { [(2r,6s) -2, 6 - dimethyl - 4 -morpholinyl] methyl} - 1, 3 - oxazol - 2 - yl) - 1h- inda zol-6-yl] -2- (methyloxy) - 3 - pyridinyl] methanesulfonamide |
US9326987B2 (en) | 2010-09-08 | 2016-05-03 | Glaxo Group Limited | Indazole derivatives for use in the treatment of influenza virus infection |
WO2012037108A1 (en) | 2010-09-13 | 2012-03-22 | Glaxosmithkline Llc | Aminoquinoline derivatives as antiviral agents |
AU2011326071A1 (en) | 2010-11-08 | 2013-05-23 | Lycera Corporation | N- sulfonylated tetrahydroquinolines and related bicyclic compounds inhibition of RORy activity and the treatment of diseases |
EP2487159A1 (en) * | 2011-02-11 | 2012-08-15 | MSD Oss B.V. | RorgammaT inhibitors |
EP2511263A1 (en) | 2011-04-14 | 2012-10-17 | Phenex Pharmaceuticals AG | Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORgamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
KR20150007300A (en) | 2012-05-08 | 2015-01-20 | 머크 샤프 앤드 돔 코포레이션 | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
JP6236067B2 (en) | 2012-05-08 | 2017-11-22 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Bicyclic sulfone compounds for inhibiting RORγ activity and treating diseases |
US9783511B2 (en) | 2013-12-20 | 2017-10-10 | Lycera Corporation | Carbamate benzoxazine propionic acids and acid derivatives for modulation of RORgamma activity and the treatment of disease |
WO2015095788A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | 2-ACYLAMIDOMETHYL AND SULFONYLAMIDOMETHYL BENZOXAZINE CARBAMATES FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
US9809561B2 (en) | 2013-12-20 | 2017-11-07 | Merck Sharp & Dohme Corp. | Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
-
2013
- 2013-05-07 KR KR20147031132A patent/KR20150007300A/en active IP Right Grant
- 2013-05-07 MX MX2014013549A patent/MX367341B/en active IP Right Grant
- 2013-05-07 AU AU2013259737A patent/AU2013259737A1/en not_active Abandoned
- 2013-05-07 RU RU2014149136A patent/RU2014149136A/en unknown
- 2013-05-07 JP JP2015511594A patent/JP6236068B2/en not_active Expired - Fee Related
- 2013-05-07 EP EP13788167.8A patent/EP2846804B1/en active Active
- 2013-05-07 WO PCT/US2013/039839 patent/WO2013169704A2/en active Application Filing
- 2013-05-07 BR BR112014028017A patent/BR112014028017A2/en not_active IP Right Cessation
- 2013-05-07 CA CA2871514A patent/CA2871514C/en not_active Expired - Fee Related
- 2013-05-07 US US14/398,061 patent/US9657033B2/en active Active
- 2013-05-07 CN CN201380024191.9A patent/CN104812393A/en active Pending
-
2015
- 2015-09-08 HK HK15108736.5A patent/HK1207990A1/en not_active IP Right Cessation
-
2017
- 2017-05-05 US US15/587,934 patent/US10377768B2/en active Active
Non-Patent Citations (18)
Title |
---|
"Comprehensive Organic Synthesis", 1991 |
"Current protocols in immunology", 1991 |
"Current protocols in molecular biology", 1987 |
"Handbook of experimental immunology" |
ANDRE ET AL., EMBO J., vol. 17, 1998, pages 3867 - 3877 |
BECKER-ANDRE ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 194, 1993, pages 1371 - 1379 |
CARLBERG ET AL., MOL. ENDOCRINOL., vol. 8, 1994, pages 757 - 770 |
DUSSAULT ET AL., MECH. DEV., vol. 70, 1998, pages 147 - 153 |
GIGUERE ET AL., GENES. DEV., vol. 8, 1994, pages 538 - 553 |
HE ET AL., IMMUNITY, vol. 9, 1998, pages 797 - 806 |
HIROSE ET AL., BIOCHEM. BIOPHYS. RES. COMMUN, vol. 205, 1994, pages 1976 - 1983 |
HIROSE ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 205, 1994, pages 1976 - 1983 |
MARTIN: "Remington's Pharmaceutical Sciences", 1975, MACK PUBL. CO. |
MEDVEDEV ET AL., GENE, vol. 181, 1996, pages 199 - 206 |
ORTIZ ET AL., MOL. ENDOCRINOL., vol. 9, 1995, pages 1679 - 1691 |
See also references of EP2846804A4 |
VILLEY ET AL., EUR. J. IMMUNOL., vol. 29, 1999, pages 4072 - 4080 |
WIESENBERG ET AL., NUCLEIC ACIDS RES., vol. 23, 1995, pages 327 - 333 |
Cited By (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9512111B2 (en) | 2010-11-08 | 2016-12-06 | Lycera Corporation | N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
US9802958B2 (en) | 2012-05-08 | 2017-10-31 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORy and the treatment of disease |
US10377768B2 (en) | 2012-05-08 | 2019-08-13 | Lycera Corporation | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
US9394315B2 (en) | 2012-05-08 | 2016-07-19 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US9657033B2 (en) | 2012-05-08 | 2017-05-23 | Lycera Corporation | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
US10208061B2 (en) | 2012-05-08 | 2019-02-19 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US9988381B2 (en) | 2013-06-19 | 2018-06-05 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Five-member-heterocycle fused pyridine compounds, method of producing the same, and use thereof |
WO2014201857A1 (en) * | 2013-06-19 | 2014-12-24 | 中国科学院上海药物研究所 | Five-membered heterocyclic pyridine compounds and preparation method and use thereof |
JP2016521757A (en) * | 2013-06-19 | 2016-07-25 | 中国科学院上海薬物研究所 | Five-membered heterocyclic condensed pyridine-based compound, and preparation method and use thereof |
US9663502B2 (en) | 2013-12-20 | 2017-05-30 | Lycera Corporation | 2-Acylamidomethyl and sulfonylamidomethyl benzoxazine carbamates for inhibition of RORgamma activity and the treatment of disease |
US10221146B2 (en) | 2013-12-20 | 2019-03-05 | Lycera Corporation | Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
US20190292159A1 (en) * | 2013-12-20 | 2019-09-26 | Merck Sharp & Dohme Corp. | TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
WO2015095795A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE, AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
US9809561B2 (en) | 2013-12-20 | 2017-11-07 | Merck Sharp & Dohme Corp. | Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
US10745364B2 (en) | 2013-12-20 | 2020-08-18 | Lycera Corporation | Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
US9783511B2 (en) | 2013-12-20 | 2017-10-10 | Lycera Corporation | Carbamate benzoxazine propionic acids and acid derivatives for modulation of RORgamma activity and the treatment of disease |
WO2015095788A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | 2-ACYLAMIDOMETHYL AND SULFONYLAMIDOMETHYL BENZOXAZINE CARBAMATES FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
WO2015095792A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Carbamate benzoxaxine propionic acids and acid derivatives for modulation of rorgamma activity and the treatment of disease |
CN106132931A (en) * | 2014-01-06 | 2016-11-16 | 百时美施贵宝公司 | Carbocyclic ring sulfone ROR gamma modulators |
CN106061947A (en) * | 2014-01-06 | 2016-10-26 | 百时美施贵宝公司 | Cyclohexyl sulfone ror [gamma] modulators |
US11535614B2 (en) | 2014-02-03 | 2022-12-27 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10047085B2 (en) | 2014-02-03 | 2018-08-14 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US9624217B2 (en) | 2014-02-03 | 2017-04-18 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10807980B2 (en) | 2014-02-03 | 2020-10-20 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10399976B2 (en) | 2014-02-03 | 2019-09-03 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US9266886B2 (en) | 2014-02-03 | 2016-02-23 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10532088B2 (en) | 2014-02-27 | 2020-01-14 | Lycera Corporation | Adoptive cellular therapy using an agonist of retinoic acid receptor-related orphan receptor gamma and related therapeutic methods |
US9896441B2 (en) | 2014-05-05 | 2018-02-20 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US10442798B2 (en) | 2014-05-05 | 2019-10-15 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US10189777B2 (en) | 2014-05-05 | 2019-01-29 | Lycera Corporation | Benzenesulfonamido and related compounds for use as agonists of RORγ and the treatment of disease |
US10364237B2 (en) | 2014-05-05 | 2019-07-30 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US9796710B2 (en) | 2014-10-14 | 2017-10-24 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10087184B2 (en) | 2014-10-14 | 2018-10-02 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of RORγ |
US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
US11001583B2 (en) | 2014-11-05 | 2021-05-11 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
US10221142B2 (en) | 2015-02-11 | 2019-03-05 | Merck Sharp & Dohme Corp. | Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof |
WO2016179343A1 (en) * | 2015-05-05 | 2016-11-10 | Lycera Corporation | DIHYDRO-2H-BENZO[b][1,4]OXAZINE SULFONAMIDE AND RELATED COMPOUNDS FOR USE AS AGONISTS OF RORy AND THE TREATMENT OF DISEASE |
US10421751B2 (en) | 2015-05-05 | 2019-09-24 | Lycera Corporation | Dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US10611740B2 (en) | 2015-06-11 | 2020-04-07 | Lycera Corporation | Aryl dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US11059796B2 (en) | 2015-06-11 | 2021-07-13 | The Regents Of The University Of Michigan | Aryl dihydro-2H benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
US10829448B2 (en) | 2015-08-05 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Substituted benzoimidazoles as modulators of ROR-γ |
US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
US10584121B2 (en) | 2015-10-27 | 2020-03-10 | Merck Sharp & Dohme Corp. | Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof |
US10689369B2 (en) | 2015-10-27 | 2020-06-23 | Merck Sharp & Dohme Corp. | Substituted indazole compounds as RORgammaT inhibitors and uses thereof |
US10287272B2 (en) | 2015-10-27 | 2019-05-14 | Merck Sharp & Dohme Corp. | Substituted indazole compounds as RORgammaT inhibitors and uses thereof |
US10344000B2 (en) | 2015-10-27 | 2019-07-09 | Merck Sharp & Dohme Corp. | Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof |
US11008340B2 (en) | 2015-11-20 | 2021-05-18 | Vitae Pharmaceuticals, Llc | Modulators of ROR-gamma |
US11358967B2 (en) | 2016-01-20 | 2022-06-14 | Boehringer Ingelheim International Gmbh | Substituted pyrazino[2,3-b]pyrazines and pyrazino[2,3-c]pyridazines as modulators of ROR gamma |
WO2017127375A1 (en) * | 2016-01-20 | 2017-07-27 | Boehringer Ingelheim International Gmbh | Pyrazinedihydropyrimidinone or pyridazinedihydropyrimidinone compounds as modulators of ror gamma |
US10829481B2 (en) | 2016-01-29 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Benzimidazole derivatives as modulators of ROR-gamma |
US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
WO2018234805A1 (en) * | 2017-06-22 | 2018-12-27 | Curadev Pharma Limited | Small molecule modulators of human sting |
US11571423B2 (en) | 2017-06-22 | 2023-02-07 | Curadev Pharma Limited | Small molecule modulators of human sting |
US10913739B2 (en) | 2017-07-24 | 2021-02-09 | Vitae Pharmaceuticals, LLC (121374) | Inhibitors of RORγ |
US11186573B2 (en) | 2017-07-24 | 2021-11-30 | Vitae Pharmaceuticals, Llc | Inhibitors of ROR gamma |
AU2020390377B2 (en) * | 2019-11-29 | 2023-12-21 | Wuhan Ll Science And Technology Development Co., Ltd. | Compound containing benzene ring and application thereof |
WO2022106550A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Crystalline polymorphic form of a ror gamma inhibitor |
WO2022106549A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Crystalline salts of a ror gamma inhibitor |
WO2022106548A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Solid forms of a ror gamma inhibitor |
WO2022106551A1 (en) | 2020-11-19 | 2022-05-27 | Boehringer Ingelheim International Gmbh | Co-crystals of a ror gamma inhibitor |
Also Published As
Publication number | Publication date |
---|---|
RU2014149136A (en) | 2016-07-10 |
EP2846804A4 (en) | 2016-07-13 |
US20150111877A1 (en) | 2015-04-23 |
JP2015523329A (en) | 2015-08-13 |
JP6236068B2 (en) | 2017-11-22 |
WO2013169704A3 (en) | 2015-05-28 |
KR20150007300A (en) | 2015-01-20 |
BR112014028017A2 (en) | 2017-06-27 |
US20170313722A1 (en) | 2017-11-02 |
CA2871514A1 (en) | 2013-11-14 |
AU2013259737A1 (en) | 2014-10-02 |
MX2014013549A (en) | 2015-06-23 |
HK1207990A1 (en) | 2016-02-19 |
CA2871514C (en) | 2020-08-25 |
EP2846804A2 (en) | 2015-03-18 |
US9657033B2 (en) | 2017-05-23 |
CN104812393A (en) | 2015-07-29 |
US10377768B2 (en) | 2019-08-13 |
MX367341B (en) | 2019-08-14 |
EP2846804B1 (en) | 2017-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2013169704A2 (en) | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE | |
US10640503B2 (en) | Imidazopyridines and imidazopyrazines as LSD1 inhibitors | |
EP2846794B1 (en) | BICYCLIC SULFONE COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE | |
JP6063870B2 (en) | Treatment of N-sulfonylated tetrahydroquinolines and related bicyclic compounds and diseases for inhibition of RORγ activity | |
TWI478920B (en) | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof | |
AU2016320297B2 (en) | Pyrazolyl-substituted heteroaryls and their use as medicaments | |
WO2016007736A1 (en) | Imidazopyrazines as lsd1 inhibitors | |
EP2855476A2 (en) | Tetrahydropyrazolopyrimidine compounds | |
CA3091486A1 (en) | Oxadiazole transient receptor potential channel inhibitors | |
WO2007011810A1 (en) | Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease | |
US8877742B2 (en) | Compounds | |
WO2011012622A1 (en) | Benzoxazinone derivatives for the treatment of glytl mediated disorders | |
US10016439B2 (en) | Fused imidazole compounds | |
JP6893516B2 (en) | 3-((Hetero-) aryl) -8-amino-2-oxo-1,3-diaza-spiro- [4.5] -decane derivative | |
AU2008316895A1 (en) | (1,4-diaza-bicyclo[3.2.2]non-6-en-4-yl)-heterocyclyl-methanone ligands for nicotinic acetylcholine receptors, useful for the treatment of disease | |
AU2023202293A1 (en) | Novel salts | |
WO2006051413A1 (en) | Azabenoxazoles for the treatment of cns disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13788167 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 2013259737 Country of ref document: AU Date of ref document: 20130507 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2871514 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14398061 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 20147031132 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2015511594 Country of ref document: JP Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2013788167 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/013549 Country of ref document: MX Ref document number: 2013788167 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2014149136 Country of ref document: RU Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014028017 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112014028017 Country of ref document: BR Kind code of ref document: A2 Effective date: 20141110 |