WO2018231604A1 - Bicyclic compounds and methods of use - Google Patents
Bicyclic compounds and methods of use Download PDFInfo
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- WO2018231604A1 WO2018231604A1 PCT/US2018/036276 US2018036276W WO2018231604A1 WO 2018231604 A1 WO2018231604 A1 WO 2018231604A1 US 2018036276 W US2018036276 W US 2018036276W WO 2018231604 A1 WO2018231604 A1 WO 2018231604A1
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- Prior art keywords
- optionally substituted
- alkyl
- compound
- membered heterocyclyl
- cycloalkyl
- Prior art date
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- GALKLDFYLMAFCH-LBPRGKRZSA-N CC(Nc1c[s]c(C(N2[C@@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc1c[s]c(C(N2[C@@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O GALKLDFYLMAFCH-LBPRGKRZSA-N 0.000 description 2
- GALKLDFYLMAFCH-GFCCVEGCSA-N CC(Nc1c[s]c(C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc1c[s]c(C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O GALKLDFYLMAFCH-GFCCVEGCSA-N 0.000 description 2
- SJTDIXDNWIVTOY-LBPRGKRZSA-N CC(Nc([s]cc1C(N2[C@@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc([s]cc1C(N2[C@@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O SJTDIXDNWIVTOY-LBPRGKRZSA-N 0.000 description 1
- OMCHPHZSSNPMGR-CYBMUJFWSA-N CC(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c3ccc4OCCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c3ccc4OCCOc4c3)=O)c1C2=O)=O OMCHPHZSSNPMGR-CYBMUJFWSA-N 0.000 description 1
- SJTDIXDNWIVTOY-GFCCVEGCSA-N CC(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O SJTDIXDNWIVTOY-GFCCVEGCSA-N 0.000 description 1
- YXFSGJIOUGWTRV-CYBMUJFWSA-N CC(Nc([s]cc1C(N2[C@H](CS(N(C)C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound CC(Nc([s]cc1C(N2[C@H](CS(N(C)C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O YXFSGJIOUGWTRV-CYBMUJFWSA-N 0.000 description 1
- KQCXUTOOOSVYHJ-CYBMUJFWSA-N CC(Nc([s]cc1C(N2[C@H](Cc3ccc4OCCOc4c3)CS(C)(=O)=O)=O)c1C2=O)=O Chemical compound CC(Nc([s]cc1C(N2[C@H](Cc3ccc4OCCOc4c3)CS(C)(=O)=O)=O)c1C2=O)=O KQCXUTOOOSVYHJ-CYBMUJFWSA-N 0.000 description 1
- SWQMTIXSTAALLF-QGZVFWFLSA-N CCC(CC)C(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c(cc3OCC)ccc3OC)=O)c1C2=O)=O Chemical compound CCC(CC)C(Nc([s]cc1C(N2[C@H](CS(C)(=O)=O)c(cc3OCC)ccc3OC)=O)c1C2=O)=O SWQMTIXSTAALLF-QGZVFWFLSA-N 0.000 description 1
- XMKWKHUIJRQWRL-CQSZACIVSA-N CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c2[s]cc1NC(COC)=O)=O)C2=O)cc1)c1OC Chemical compound CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c2[s]cc1NC(COC)=O)=O)C2=O)cc1)c1OC XMKWKHUIJRQWRL-CQSZACIVSA-N 0.000 description 1
- WDEVITWWKZQQQF-OAHLLOKOSA-N CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c2[s]cc1NCCOC)=O)C2=O)cc1)c1OC Chemical compound CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c2[s]cc1NCCOC)=O)C2=O)cc1)c1OC WDEVITWWKZQQQF-OAHLLOKOSA-N 0.000 description 1
- LCVPDLONNRWBPU-GFCCVEGCSA-N CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)cc1)c1OC Chemical compound CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)cc1)c1OC LCVPDLONNRWBPU-GFCCVEGCSA-N 0.000 description 1
- IMDHESZOGSHYMP-OAHLLOKOSA-N CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)cc1)c1OC Chemical compound CCOc(cc([C@@H](CS(C)(=O)=O)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)cc1)c1OC IMDHESZOGSHYMP-OAHLLOKOSA-N 0.000 description 1
- TXGHQBHHUZGPJF-GFCCVEGCSA-N CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c3[s]cc2NC(C(F)(F)F)=O)=O)C3=O)ccc1OC Chemical compound CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c3[s]cc2NC(C(F)(F)F)=O)=O)C3=O)ccc1OC TXGHQBHHUZGPJF-GFCCVEGCSA-N 0.000 description 1
- HVXYMEIFISZOQT-OAHLLOKOSA-N CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c3[s]cc2NC(C2CC2)=O)=O)C3=O)ccc1OC Chemical compound CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c3[s]cc2NC(C2CC2)=O)=O)C3=O)ccc1OC HVXYMEIFISZOQT-OAHLLOKOSA-N 0.000 description 1
- JKHHTJAHVBTZBW-GOSISDBHSA-N CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c[s]c(N(C(C3CC3)=O)C(C3CC3)=O)c22)=O)C2=O)ccc1OC Chemical compound CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c[s]c(N(C(C3CC3)=O)C(C3CC3)=O)c22)=O)C2=O)ccc1OC JKHHTJAHVBTZBW-GOSISDBHSA-N 0.000 description 1
- GSGFDNNHMWKXQA-SBXXRYSUSA-N CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c[s]c(NC(C(C)C(F)(F)F)=O)c22)=O)C2=O)ccc1OC Chemical compound CCOc1cc([C@@H](CS(C)(=O)=O)N(C(c2c[s]c(NC(C(C)C(F)(F)F)=O)c22)=O)C2=O)ccc1OC GSGFDNNHMWKXQA-SBXXRYSUSA-N 0.000 description 1
- HVXKIHQUPBEPJC-OAHLLOKOSA-N CCOc1cc([C@@H](CS(N(C)C)(=O)=O)N(C(c2c[s]c(NC(C)=O)c22)=O)C2=O)ccc1OC Chemical compound CCOc1cc([C@@H](CS(N(C)C)(=O)=O)N(C(c2c[s]c(NC(C)=O)c22)=O)C2=O)ccc1OC HVXKIHQUPBEPJC-OAHLLOKOSA-N 0.000 description 1
- VOTXSXHEECEZMH-LBPRGKRZSA-N COCC(Nc1c[s]c(C(N2[C@@H](CS(C)(=O)=O)c(cc3)cc4c3OCO4)=O)c1C2=O)=O Chemical compound COCC(Nc1c[s]c(C(N2[C@@H](CS(C)(=O)=O)c(cc3)cc4c3OCO4)=O)c1C2=O)=O VOTXSXHEECEZMH-LBPRGKRZSA-N 0.000 description 1
- VOTXSXHEECEZMH-GFCCVEGCSA-N COCC(Nc1c[s]c(C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O Chemical compound COCC(Nc1c[s]c(C(N2[C@H](CS(C)(=O)=O)c3ccc4OCOc4c3)=O)c1C2=O)=O VOTXSXHEECEZMH-GFCCVEGCSA-N 0.000 description 1
- FGJPLVLLUTVKGH-JTQLQIEISA-N CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c2[s]cc1NC(C(F)(F)F)=O)=O)C2=O)(=O)=O Chemical compound CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c2[s]cc1NC(C(F)(F)F)=O)=O)C2=O)(=O)=O FGJPLVLLUTVKGH-JTQLQIEISA-N 0.000 description 1
- VLPVQZPPVKOUMW-JTQLQIEISA-N CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)(=O)=O Chemical compound CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)(=O)=O VLPVQZPPVKOUMW-JTQLQIEISA-N 0.000 description 1
- GFSIGLOHQGVQFD-ZDUSSCGKSA-N CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)(=O)=O Chemical compound CS(C[C@@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)(=O)=O GFSIGLOHQGVQFD-ZDUSSCGKSA-N 0.000 description 1
- FGJPLVLLUTVKGH-SNVBAGLBSA-N CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c2[s]cc1NC(C(F)(F)F)=O)=O)C2=O)(=O)=O Chemical compound CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c2[s]cc1NC(C(F)(F)F)=O)=O)C2=O)(=O)=O FGJPLVLLUTVKGH-SNVBAGLBSA-N 0.000 description 1
- VLPVQZPPVKOUMW-SNVBAGLBSA-N CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)(=O)=O Chemical compound CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C(F)(F)F)=O)c11)=O)C1=O)(=O)=O VLPVQZPPVKOUMW-SNVBAGLBSA-N 0.000 description 1
- GFSIGLOHQGVQFD-CYBMUJFWSA-N CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)(=O)=O Chemical compound CS(C[C@H](c1ccc2OCOc2c1)N(C(c1c[s]c(NC(C2CC2)=O)c11)=O)C1=O)(=O)=O GFSIGLOHQGVQFD-CYBMUJFWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- cytokines Aberrant protein function, and/or protein imbalance is a hallmark of many disease states.
- the functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines.
- Some cytokines promote inflammation (pro-inflammatory cytokines), whereas other cytokines suppress the activity of the pro-inflammatory cytokines (anti-inflammatory cytokines).
- IL-4, IL-10, and IL-13 are potent activators of B lymphocytes, and also act as anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro-inflammatory cytokines such as IL-1, TNF, and chemokines.
- lymphocytes erythematos
- macrophages erythematos
- a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers.
- lymphocytes recognize an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction.
- Genetic predisposition has also been postulated to be responsible for autoimmune disorders.
- PDE4 phosphodiesterase 4
- cAMP cyclic adenosine monophosphate
- inhibitors of PDE4 may block the synthesis of several pro-inflammatory cytokines and chemokines, such as tumor necrosis factor alpha, interleukin 23, CXCL9, and CXCLIO in multiple cell types, and may interfere with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinases.
- This interference reduces certain inflammatory processes, such as dendritic cell infiltration, epidermal skin thickening, and joint destruction, for example in psoriasis and other inflammatory and/or autoimmune diseases such as arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, and contact dermatitis.
- psoriasis and other inflammatory and/or autoimmune diseases such as arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, and contact dermatitis.
- Psoriasis is an autoimmune skin disease caused by pro-inflammatory cytokines, interferon gamma (IFN- ⁇ ) and TNF-a.
- IFN- ⁇ interferon gamma
- TNF-a TNF-a.
- the psoriatic immune response involves monocytes, dendritic cells, neutrophils and T cells, which all contribute to aberrant keratinocyte proliferation.
- PDE4 inhibition may reduce production of multiple mediators including TNF-a, IFN- ⁇ , CXCL9 (monokine induced by IFN- ⁇ , or MIG), CXCLIO (IFN-y-induced protein of 10 kDa, or IP- 10), IL-2, IL-12, IL-23, macrophage inflammatory protein- 1 -alpha ( ⁇ - ⁇ ), monocyte chemoattractant protein- 1 and granulocyte macrophage-colony stimulating factor (GM-CSF) from PBMCs.
- mediators including TNF-a, IFN- ⁇ , CXCL9 (monokine induced by IFN- ⁇ , or MIG), CXCLIO (IFN-y-induced protein of 10 kDa, or IP- 10), IL-2, IL-12, IL-23, macrophage inflammatory protein- 1 -alpha ( ⁇ - ⁇ ), monocyte chemoattractant protein- 1 and granulocyte macrophage-colony stimulating factor (GM-CSF) from
- the compounds disclosed in the present application have been discovered to exert surprising and unexpected biological effects.
- the compounds disclosed in the present application may reduce inflammation, cellular cAMP levels, and inhibit PDE4.
- Some embodiments provide a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing,
- Y is H, deuterium, halogen, or an optionally substituted Ci-C 6 alkyl.
- Ri is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted Ci-Ce alkoxy, - H2, - HRIA, - RIARIB, - HC(0)RIC, - RIAC(0)RIC, - HSO2R1C, - R1ASO2R1C, -N[C(0)RIA] [C(0)RIC], an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- RIA, RIB, and Ric are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2 is hydroxy, - H2, -NHRIA, -NRIARIB, an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R3, R 6 , and R7 are independently selected from a hydrogen, a deuterium, a halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R 4 and Rs are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R 4 and R5 together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- Rs is hydrogen or deuterium. In some embodiments, Rs is hydrogen. In other embodiments, Rs is deuterium.
- R2 when R2 is an optionally substituted Ci-Ce alkyl, at least one of R 4 and R5 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, an optionally substituted 5 to 10 membered heteroaryl, or R 4 and R5, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- R2 when R2 is an optionally substituted Ci-C 4 alkyl or H(Ci-C6 alkyl), at least one of R 4 and R5 is an optionally substituted cyclopropyl.
- R 4 and R5 are each independently an optionally substituted Ci-C 6 alkyl
- R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2, R 4 , and R5 are not all an optionally substituted Ci-C 6 alkyl.
- R2 is hydroxy, - H2, - HRIA, or -NRIARIB
- R 4 and R5 are each independently an optionally substituted Ci-C 6 alkyl, or R 4 and R5, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- the substituted substituents are independently selected from a deuterium, an oxo, a halogen, cyano, a nitro, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C6-C10 aryl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted 5 to 10 membered heteroaryl, -C(0)RA, -C(0)ORA, -C(0) RBRC, -ORA, -OC(0)
- each RA, RB, and Rc are independently selected from a hydrogen, an unsubstituted Ci-C 6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C 6 -Cio aryl, and an unsubstituted 5 to 10 membered heteroaryl.
- RB and Rc together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 10 membered heterocyclyl.
- Y is H. In some embodiments, Y is deuterium. In some embodiments, Y is halogen. In some embodiments, Y is an optionally substituted Ci-C 6 alkyl.
- Ri is - HRIA, - RIARIB, - HC(0)RIC or - RIAC(0)RIC. In some embodiments, Ri is -N[C(0)RIA][C(0)RIC]. In some embodiments, Ri is - HC(0)Ric. In some embodiments, RIA, RIB, and Ric are independently an optionally substituted Ci-C 6 alkyl or an optionally substituted C3-C6 cycloalkyl. In some embodiments, Ric is an optionally substituted Ci-C 6 alkyl. In some embodiments, Ric is an unsubstituted Ci-C 6 alkyl.
- R3, R 6 , and R7 are independently selected from a hydrogen, a halogen, and an optionally substituted Ci-C 6 alkyl. In some embodiments, R3, R 6 , and R7 are each hydrogen.
- R 2 is an optionally substituted Ci-C 6 alkyl and one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
- R2 is an unsubstituted Ci-C 6 alkyl and one of R 4 and R5 is an unsubstituted Ci-C 6 alkyl and the other is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
- R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R 4 and R5 are independently an optionally substituted Ci-C 6 alkyl.
- R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R 4 and R5 are independently unsubstituted Ci-C 6 alkyl.
- R2 is hydroxy, - H2, - HRIA, or - RIARIB, and RiA and RIB are each independently an optionally substituted Ci-C 6 alkyl or an optionally substituted C6-C10 aryl.
- R 4 and R5 together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 5 or 6 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 5 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 6 membered heterocyclyl.
- the compound Formula (I) or the compound of Formula (II) is selected from:
- the compound is a pharmaceutically acceptable salt.
- Some embodiments provide a pharmaceutical composition comprising a compound of any of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier.
- the composition is formulated for oral, parenteral, topical, ophthalmic, inhalation, nasal, or intravenous administration.
- the composition is formulated as a tablet or capsule.
- the pharmaceutical composition further comprises a second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of anti -inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents.
- the second therapeutic agent is anti-inflammatory agent or an immunosuppressive agent.
- Some embodiments provide a method of treating, ameliorating, or preventing a disease, disorder, or condition associated with T F-a, INF- ⁇ , IL-2, IL-17, IL-23, or a combination thereof, comprising administering a therapeutically effective amount of a compound of any one of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, or a composition comprising any one of Formula (I) or Formula (II) to a subject in need thereof.
- the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and combinations thereof.
- Some embodiments provide a method of treating, ameliorating, or preventing a disease, disorder, or condition associated with PDE4, comprising administering a therapeutically effective amount of a compound of any one of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, or a composition comprising any one of Formula (I) or Formula (II) to a subject in need thereof.
- the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and combinations thereof.
- the compound or composition is administered in combination with a second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of anti-inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents. In some embodiments, the second therapeutic agent is an anti-inflammatory agent or an immunosuppressive agent.
- Some embodiments provide a method of decreasing expression of a protein selected from TNF-a, INF- ⁇ , IL-2, IL-17, IL-23, or a combination thereof, comprising contacting a cell with a compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.
- the protein is TNF-a.
- Some embodiments provide a method of inhibiting PDE4 activitiy, comprising contacting a cell with a compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.
- Some embodiments provide a method of treating psoriasis, comprising topically administering a therapeutically effective amount of a composition comprising any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, to a subject in need thereof.
- the subject is known to possess wild-type PDE4. In some embodiments, the subject is known to possess wild-type TNF-a. In some embodiments, the subject is known to possess wild-type INF- ⁇ , IL-2, IL-17, or IL-23. In some embodiments, the subject is known to possess aberrant PDE4. In some embodiments, the subject is known to possess aberrant TNF-a. In some embodiments, the subject is known to possess aberrant INF- ⁇ , IL-2, IL-17, or IL-23.
- the cell is known to possess wild-type PDE4. In some embodiments, the cell is known to possess wild-type TNF-a. In some embodiments, the cell is known to possess wild-type INF- ⁇ , IL-2, IL-17, or IL-23. In some embodiments, the cell is known to possess aberrant PDE4. In some embodiments, the cell is known to possess aberrant TNF-a. In some embodiments, the cell is known to possess aberrant INF- ⁇ , IL-2, IL-17, or IL-23.
- any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment. DETAILED DESCRIPTION
- protein malfunction refers to a protein or proteins not properly performing its intended biological function. For example, overexpression or underexpression and mutations in structure/function constitute a protein malfunction. Likewise, a protein or proteins that are expressed normally, and function normally, but are unable to perform their intended biological function (i.e., suppress tumor growth) are also malfunctioning proteins.
- co-administration and similar terms as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
- an "effective amount” and “therapeutically effective amount” are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
- an "effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
- an appropriate "effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
- a drug has been approved by the U.S. Food and Drug Administration (FDA) or a counterpart foreign medicines agency
- a "therapeutically effective amount” an optionally refers to the dosage approved by the FDA or its counterpart foreign agency for treatment of the identified disease or condition.
- pharmaceutical combination is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- fixed combination means that the active ingredients, e.g., a compound of a preferred embodiment and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- non-fixed combination means that the active ingredients, e.g., a compound of a preferred embodiment and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
- active ingredients e.g., a compound of a preferred embodiment and a co-agent
- cocktail therapy e.g., the administration of three or more active ingredients.
- any "R” group(s) such as, without limitation, R 2 , R 3 , R4, R5, R 6 , R9, and Rio represent substituents that can be attached to the indicated atom.
- An R group may be substituted or an unsubstituted. If two "R” groups are described as being “taken together" the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl, or heterocycle.
- R 2 and R 3 , or R 2 , R 3 , or R 4 , and the atom to which it is attached are indicated to be “taken together” or “joined together” it means that they are covalently bonded to one another to form a ring:
- an optionally substituted” or “substituted” group may be individually and independently substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-car
- C a to Cb in which "a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
- alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to "b", inclusive, carbon atoms.
- a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH3CH2CH2CH2-, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
- alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
- the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
- the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
- the alkyl group of the compounds may be designated as "C1-C4 alkyl” or similar designations.
- C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyls.
- the alkyl group may be substituted or an unsubstituted.
- Substituted alkyl groups include, but are not limited to benzyl, substituted benzyl, aminoalkyl, substituted aminoalkyl, carboxyalkyl, alkoxyalkyl, and the like.
- alkenyl refers to an alkyl group, as defined herein, that contains in the straight or branched hydrocarbon chain one or more double bonds.
- An alkenyl group may be an unsubstituted or substituted.
- Typical alkyl groups include, but are in no way limited to, vinyl, allyl, 1-propenyl, and 2-propenyl.
- alkynyl refers to an alkyl group as defined herein, that contains in the straight or branched hydrocarbon chain one or more triple bonds.
- An alkynyl group may be an unsubstituted or substituted.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be an unsubstituted or substituted.
- Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged, or spiro fashion. A cycloalkenyl group may be an unsubstituted or substituted.
- cycloalkynyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. A cycloalkynyl group may be an unsubstituted or substituted.
- Carbocyclyl or “cyclic hydrocarbyl” refers to all carbon ring systems. Such systems can be unsaturated, can include some unsaturation, or can contain some aromatic portion, or be all aromatic. Carbocyclyl group can contain from 3 to 30 carbon atoms. A carbocyclyl group may be an unsubstituted or substituted.
- aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including, e.g., fused, bridged, or spiro ring systems where two carbocyclic rings share a chemical bond, e.g., one or more aryl rings with one or more aryl or non-aryl rings) that has a fully delocalized pi-electron system throughout at least one of the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group can be a C 6 -Ci4 aryl group, a C 6 -Cio aryl group, or a C 6 aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene.
- An aryl group may be substituted or an unsubstituted.
- heterocyclyl refers to mono- or polycyclic ring systems including at least one heteroatom (e.g., O, N, S), and up to five heteroatoms, for example, 1, 2, 3, 4, or 5 heteroatoms. Such systems can be unsaturated, can include some unsaturation, or can contain some aromatic portion, or be all aromatic.
- a heterocyclyl group can contain from 3 to 30 atoms.
- a heterocyclyl group may be an unsubstituted or substituted.
- heterocycles include, but are not limited to oxirane, aziridine, thiirane, diazidiridine, oxaziridine, azetidine, oxetane, thietane, oxazetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, tetrahydropyran, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, azepine, diazepine, oxepane, dioxapane, oxazepane, thiazepane, thiepane, azocane, diazocane, oxocane, diox
- heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system having a least one ring with a fully delocalized pi-electron system) that contain(s) at least heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen, and sulfur, and at least one aromatic ring and up to five heteroatoms, for example, 1, 2, 3, 4, or 5 heteroatoms. .
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine.
- a heteroaryl group may be substituted
- heteroalicyclic or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may an optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
- the heteroatoms are independently selected from oxygen, sulfur, and nitrogen.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heteroalicyclyl or heteroalicyclic groups may be an unsubstituted or substituted. Examples of such "heteroalicyclic" or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin,
- Lower alkylene groups are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms.
- Lower alkylene groups contain from 1 to 6 carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-).
- a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of "substituted.”
- aralkyl and aryl(alkyl) refer to an aryl group, as defined above, connected, as a substituent, via a lower alkylene group, as described above.
- the lower alkylene and aryl group of an aralkyl may be substituted or an unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
- heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group , as defined above, connected, as a substituent, via a lower alkylene group, as defined above.
- the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or an unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.
- a "(heteroalicyclyl)alkyl” is a heterocyclic or a heteroalicyclylic group, as defined above, connected, as a substituent, via a lower alkylene group, as defined above.
- the lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or an unsubstituted. Examples include but are not limited to tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl,
- alkoxy refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl, as defined above.
- R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl, as defined above.
- a non-limiting list of alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
- An alkoxy may be substituted or an unsubstituted.
- acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl, as defined above, connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or an unsubstituted.
- hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
- exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxy ethyl.
- a hydroxyalkyl may be substituted or an unsubstituted.
- haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl).
- a halogen e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl.
- groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2-fluorom ethyl, 2-fluoroisobutyl.
- a haloalkyl may be substituted or an unsubstituted.
- haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy).
- a halogen e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy.
- groups include but are not limited to, chloromethoxy, fluorom ethoxy, difluorom ethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2-fluoroisobutoxy.
- a haloalkoxy may be substituted or an unsubstituted.
- aryloxy and arylthio refers to RO- and RS-, in which R is an aryl, as defined above, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or an unsubstituted.
- a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- a sulfenyl may be substituted or an unsubstituted.
- a sulfinyl may be substituted or an unsubstituted.
- a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
- a sulfonyl may be substituted or an unsubstituted.
- R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
- An O-carboxy may be substituted or an unsubstituted.
- An ester and C-carboxy may be substituted or an unsubstituted.
- a thiocarbonyl may be substituted or an unsubstituted.
- a "trihalomethanesulfonyl” group refers to an "X3CSO2-" group wherein X is a halogen.
- a "trihalomethanesulfonamido” group refers to an "X 3 CS(0) 2 N(RA)-" group wherein X is a halogen and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.
- amino refers to a - H2 group.
- hydroxy refers to a -OH group.
- a "cyano" group refers to a "-CN” group.
- a "thiocyanato" group refers to a "-CNS” group.
- a “mercapto” group refers to an "-SH” group.
- S-sulfonamido refers to a "-S0 2 N(RARB)" group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- An S-sulfonamido may be substituted or an unsubstituted.
- N-sulfonamido refers to a "RS0 2 N(RA)-" group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- An N-sulfonamido may be substituted or an unsubstituted.
- An O-carbamyl may be substituted or an unsubstituted.
- R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- An N-carbamyl may be substituted or an unsubstituted.
- An O-thiocarbamyl may be substituted or an unsubstituted.
- R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- An N-thiocarbamyl may be substituted or an unsubstituted.
- a "C-amido" group refers to a group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- a C-amido may be substituted or an unsubstituted.
- R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.
- An N-amido may be substituted or an unsubstituted.
- a urea group may be substituted or an unsubstituted.
- a thiourea group may be substituted or an unsubstituted.
- halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine, and iodine.
- substituents there may be one or more substituents present.
- haloalkyl may include one or more of the same or different halogens.
- C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two, or three atoms.
- protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W.
- protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art.
- a non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls ⁇ e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls ⁇ e.g., benzyloxycarbonyl or benzoyl); substituted methyl ether ⁇ e.g., methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyl ethers ⁇ e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl); esters ⁇ e.g., benzoate ester); carbonates ⁇ e.g., methoxymethylcarbonate); sulfonates ⁇ e.g.,
- leaving group refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens.
- Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry, 5 th ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.
- salt is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- the salt is an acid addition salt of the compound.
- Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid.
- Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesul
- Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.
- a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl
- solvate as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to mean that the solvent is complexed with a compound in a reproducible molar ratio, including, but not limited to, 0.5 : 1, 1 : 1, or 2: 1.
- pharmaceutically acceptable solvate refers to a solvate wherein the solvent is one that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- prodrug as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a compound or a pharmaceutical composition that can be administered to a patient in a less active or inactive form, which can then be metabolized in vivo into a more active metabolite.
- a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
- a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.
- each center may independently be of R-configuration or S-configuration or a mixture thereof.
- the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or may be stereoisomeric mixtures, and include all diastereomeric, and enantiomeric forms.
- each double bond may independently be E or Z a mixture thereof.
- Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
- the compounds described herein for example, compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts of any of the foregoing
- the compounds described herein for example, compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts of any of the foregoing
- the compounds described herein for example, compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts of any of the foregoing
- a substituent is depicted as a di-radical ⁇ i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
- a substituent depicted as -AE- or 3 ⁇ 4 E includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
- the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
- Each chemical element as represented in a compound structure may include any isotope of said element.
- a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
- the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium).
- hydrogen- 1 protium
- hydrogen-2 deuterium
- tritium tritium
- the methods and formulations described herein include the use of crystalline forms, amorphous phases, and/or pharmaceutically acceptable salts, solvates, hydrates, and conformers of compounds of preferred embodiments, as well as metabolites and active metabolites of these compounds having the same type of activity.
- a conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond.
- the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- Other forms in which the compounds of preferred embodiments can be provided include amorphous forms, milled forms and nano-particulate forms.
- the compounds described herein include the compound in any of the forms described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous form, solvated forms, enantiomeric forms, tautomeric forms, and the like).
- Some embodiments provide a compound of Formula (I), Formula (II), or a pharmaceuticall acceptable salt of any of the foregoing,
- Y is H. In some embodiments, Y is deuterium. In some embodiments, Y is halogen, for example, fluoro, chloro, or bromo. In some embodiments, Y is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. [0128] In some embodiments, Ri is - H 2 , -NHRIA, -NRIARIB, -NHC(0)RIC, -NRIAC(0)RIC, -NHSO2R1C, or -NHRIAS0 2 RIC. In some embodiments, Ri is -N[C(0)RIA] [C(0)RIC] .
- RIA, RIB, and Ric are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted Ci-C 6 alkyl or an optionally substituted C3-C6 cycloalkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
- Ri is -NRIAC(0)RIC
- RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, phenyl, naphthyl, furan, pyrrole, imidazole, thiophene, pyridine, or pyrimidine.
- Ri is -N[C(0)RIA] [C(0)RIC]
- RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, phenyl, naphthyl, furan, pyrrole, imidazole, thiophene, pyridine, or pyrimidine.
- Ri is hydroxy. In some embodiments, Ri is halogen, for example, fluoro, chloro, or bromo. In some embodiments, Ri is nitro. In some embodiments, Ri is cyano. In some embodiments, Ri is optionally substituted Ci-C 6 alkoxy. In some embodiments, Ri is -NH 2 . In some embodiments, Ri is -NHRIA, -NRIARIB, -NHC(0)RIC, -NRIAC(0)RIC, -NHSO2R1C, or -NRIAS0 2 RIC. In some embodiments, Ri is -N[C(0)RIA] [C(0)RIC].
- Ri is an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- Ri is an optionally substituted Ci-C 6 alkyl.
- Ri is an optionally substituted C3-C6 cycloalkyl.
- Ri is an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is an optionally substituted C6-C10 aryl.
- Ri is an optionally substituted 5 to 10 membered heteroaryl.
- R2 is an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2 is an unsubstituted Ci-C 6 alkyl, an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, or an unsubstituted 5 to 10 membered heteroaryl.
- R2 is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.
- R2 is an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
- R3, R 6 , and R7 are independently selected from a hydrogen, a deuterium, a halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R3, R 6 , and R7 are each hydrogen. In some embodiments, one of R3, R 6 , and R7 is halogen, and the other two are hydrogen. In some embodiments, one of R3, R 6 , and R7 is an optionally substituted Ci-C 6 alkyl, and the other two are hydrogen. In some embodiments, two of R3, R 6 , and R7 are halogen, and the other one is hydrogen. In some embodiments, two of R3, R 6 , and R7 are an optionally substituted Ci-C 6 alkyl, and the other one is hydrogen.
- R 4 and Rs are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R 4 and R5 are independently selected from an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.
- R 4 and R5 are independently an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
- one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other is an optionally substituted C3-C6 cycloalkyl.
- R 4 and R5, together with the atoms to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl, for example, an optionally substituted dioxolane or an optionally substituted 1,4-dioxane.
- R 4 and R5, together with the atoms to which they are attached form an unsubstituted dioxolane or an unsubstituted 1,4-dioxane.
- R2 when R2 is an optionally substituted Ci-C 6 alkyl, at least one of R 4 and R5 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, an optionally substituted 5 to 10 membered heteroaryl, or R 4 and R5, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- R2 when R2 is an optionally substituted Ci-C 4 alkyl or H(Ci-C6 alkyl), at least one of R 4 and R5 is an optionally substituted cyclopropyl.
- R 4 and R5 are independently selected from an optionally substituted C3-C6 cycloalkyl. In some embodiments, when R2 is an optionally substituted Ci-C 6 alkyl, R 4 is an optionally substituted C3-C6 cycloalkyl and R5 is an optionally substituted Ci-C 6 alkyl. In some embodiments, when R2 is an optionally substituted Ci-C 6 alkyl, R5 is an optionally substituted C3-C6 cycloalkyl and R 4 is an optionally substituted Ci-C 6 alkyl.
- R2 when R2 is an optionally substituted Ci-C 6 alkyl, R 4 and R5, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl, for example, an optionally substituted dioxolane or an optionally substituted 1,4-dioxane.
- the substituted substituents are independently selected from a deuterium, an oxo, a halogen, cyano, a nitro, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C6-C10 aryl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted 5 to 10 membered heteroaryl, -C(0)RA, -C(0)ORA, -C(0) RBRC, -ORA, -OC(0)
- each RA, RB, and Rc are independently selected from a hydrogen, an unsubstituted Ci-C 6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, and an unsubstituted 5 to 10 membered heteroaryl.
- RB and Rc together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is - HRIA, - HC(0)RIC or - RIAC(0)RIC. In some embodiments, Ri is - HC(0)Ric. In some embodiments, Ri is -N[C(0)RIA] [C(0)RIC]. In some embodiments, RIA, RIB, and Ric are independently an optionally substituted Ci-C 6 alkyl or an optionally substituted C3-C6 cycloalkyl. In some embodiments, Ric is an optionally substituted Ci-C 6 alkyl. In some embodiments, Ric is an unsubstituted Ci-C 6 alkyl.
- R 3 , R 6 , and R7 are independently selected from a hydrogen, a halogen, and an optionally substituted Ci-C 6 alkyl. In some embodiments, R3, R 6 , and R7 are each hydrogen.
- Rs is hydrogen or deuterium. In some embodiments, Rs is hydrogen. In other embodiments, Rs is deuterium.
- R2 is an optionally substituted Ci-Ce alkyl and one ofR 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
- R2 is an unsubstituted Ci-C 6 alkyl and one of R 4 and R5 is an unsubstituted Ci-C 6 alkyl and the other is an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
- R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R 4 and R5 are independently an optionally substituted Ci-C 6 alkyl.
- R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R 4 and R5 are independently unsubstituted Ci-C 6 alkyl.
- R 4 and R5 together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 5 or 6 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 5 membered heterocyclyl.
- R 4 and R5 together with the atoms to which they are attached, form an unsubstituted 6 membered heterocyclyl.
- the compound of Formula (I) is selected from:
- R2 is hydroxy, - H2, - HRIA, - RIARIB, an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2 is hydroxy.
- R2 is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, -CF3, -CH2F, -CF2H, -CD3, -C(CH3)2CF3, benzyl, or substituted benzyl
- R2 is an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R2 is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R2 is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R2 is optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- RIA and RIB are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R 2 is - HRIA
- RIA is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- R 2 is -NHRIA
- RIA is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R 2 is -NHRIA
- RIA is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R 2 is -NHRIA
- RIA is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R 2 is -NHRIA
- RIA is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- R 2 is -NRIARIB
- RIA and RIB are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- R 2 is -NRIARIB
- RIA and RIB are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R 2 is -NRIARIB
- RIA and RIB are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R 2 is -NRIARIB
- RIA and RIB are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R 2 is -NRIARIB
- RIA and RIB are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- R2 is - RIARIB
- one of RIA and RIB is an optionally substituted Ci-C 6 alkyl
- the other of RIA and RIB is an optionally substituted C 6 -Cio aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- R 4 and R5 are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R 4 and R5 together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- R 4 and R5 are independently selected from an optionally substituted Ci-C 6 alkyl.
- R 4 and R5 are independently selected from an optionally substituted C3-C6 cycloalkyl.
- R 4 and R5 are independently selected from, an optionally substituted 3 to 10 membered heterocyclyl.
- R 4 and R5 are independently selected from an optionally substituted C6-C10 aryl.
- R 4 and R5 are independently selected from and an optionally substituted 5 to 10 membered heteroaryl.
- one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other of R 4 and R5 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other of R 4 and R5 is an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, or an unsubstituted 5 to 10 membered heteroaryl.
- one of R 4 and R5 is an unsubstituted Ci-C 6 alkyl and the other of R 4 and R5 is an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, or an unsubstituted 5 to 10 membered heteroaryl.
- R2 is an optionally substituted Ci-C 4 alkyl or H(Ci-C6 alkyl)
- at least one of R.4 and Rs is an optionally substituted cyclopropyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, an optionally-substituted 5 to 10 membered heteroaryl, or R 4 and Rs, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- the compound of Formula (II) is selected from:
- R2 is hydroxy, - H2, - HRIA, - RIARIB, an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2 is hydroxy.
- R2 is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, -CF3, -CH2F, -CF2H, -CD3, -C(CH3)2CF3, benzyl, or substituted benzyl
- R2 is an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R2 is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R2 is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R2 is optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- RIA and RIB are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- R2 is - HRIA
- RIA is an optionally substituted Ci-Ce alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- R2 is -NHRIA
- RIA is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R2 is -NHRIA
- RIA is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R2 is -NHRIA
- RIA is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R2 is -NHRIA
- RIA is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- R2 is -NRIARIB
- RIA and RIB are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- R2 is -NRIARIB
- RIA and RIB are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- R2 is -NRIARIB
- RIA and RIB are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- R2 is - RIARIB
- RIA and RIB are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- R2 is -NRIARIB
- RIA and RIB are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- R2 is -NRIARIB
- one of RIA and RIB is an optionally substituted Ci-C 6 alkyl and the other of RIA and RIB is an optionally substituted C6-C10 aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- R 4 and R5 are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, and an optionally substituted 5 to 10 membered heteroaryl.
- R 4 and R5 are independently selected from an optionally substituted Ci-C 6 alkyl.
- R 4 and R5 are independently selected from an optionally substituted C3-C6 cycloalkyl.
- R 4 and R5 are independently selected from , an optionally substituted 3 to 10 membered heterocyclyl.
- R 4 and R5 are independently selected from an optionally substituted C 6 -Cio aryl.
- R 4 and R5 are independently selected from and an optionally substituted 5 to 10 membered heteroaryl.
- one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other of R 4 and R5 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- one of R 4 and R5 is an optionally substituted Ci-C 6 alkyl and the other of R 4 and R5 is an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, or an unsubstituted 5 to 10 membered heteroaryl.
- one of R.4 and Rs is an unsubstituted Ci-Ce alkyl and the other of R 4 and Rs is an unsubstituted C3-C6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C6-C10 aryl, or an unsubstituted 5 to 10 membered heteroaryl.
- R2 is an optionally substituted C1-C4 alkyl or H(Ci-C6 alkyl)
- at least one of R 4 and R5 is an optionally substituted cyclopropyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, an optionally-substituted 5 to 10 membered heteroaryl, or R4 and R5, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
- the compound of Formula (I) is selected from:
- Ri is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted Ci-C 6 alkoxy, - H2, - HRIA, - RIARIB, - HC(0)RIC, - RIAC(0)RIC, - HSO2R1C, - R1ASO2R1C, -N[C(0)RIA] [C(0)RIC].
- RIA, RIB, and Ric are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- Ri is H.
- Ri is hydroxy. In some embodiments of this paragraph, Ri is nitro. In some embodiments of this paragraph, Ri is cyano. In some embodiments of this paragraph, Ri is halogen, for example, fluoro, chloro, or bromo. In some embodiments of this paragraph, Ri is optionally substituted Ci-Ce alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, t-butoxy, -OCF3, or -OCD3.
- Ri is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, -CF3, -CH2F, - CF2H, -CD3, -C(CH3)2CF3, benzyl, or substituted benzyl In some embodiments of this paragraph, Ri is - H2.
- Ri is an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - HRIA
- RIA is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is -NHRIA
- RIA is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - HRIA
- RIA is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is -NHRIA
- RIA is an optionally substituted C 6 -Cio aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is -NHRIA
- RIA is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is -NRIARIB, one of RIA and RIB is an optionally substituted Ci-C 6 alkyl and the other of RIA and RIB is an optionally substituted C 6 -Cio aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is - HC(0)Ric, and Ric is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - HC(0)Ric
- Ric is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - HC(0)Ric
- Ric is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - HC(0)Ric
- Ric is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - HC(0)Ric
- Ric is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - HSO2R1C
- Ric is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is -N[C(0)RIA][C(0)RIC], and RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - HSO2R1C
- Ric is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - RIAC(0)RIC, and RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - RIAC(0)RIC, and RIA and Ric are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - RIAC(0)RIC, one of RIA and Ric is an optionally substituted Ci-C 6 alkyl and the other of RIA and Ric is an optionally substituted C6-C10 aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is - R1ASO2R1C, and RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - R1ASO2R1C
- one of RIA and Ric is an optionally substituted Ci-C 6 alkyl and the other of RIA and Ric is an optionally substituted C6-C10 aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- the compound of Formula (II) is selected from:
- Ri is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted Ci-C 6 alkoxy, - H 2 , - HRIA, - RIARIB, - HC(0)RIC, - RIAC(0)RIC, - HSO2R1C, - R1ASO2R1C, -N[C(0)RIA] [C(0)RIC], an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -Cio aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- RIA, RIB, and Ric are independently selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted 5 to 10 membered heteroaryl.
- Ri is H.
- Ri is hydroxy.
- Ri is nitro.
- Ri is cyano.
- Ri is halogen, for example, fluoro, chloro, or bromo.
- Ri is optionally substituted Ci-Ce alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, t-butoxy, -OCF3, or -OCD3.
- Ri is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, -CF 3 , -CH2F, -CF2H, -CD3, -C(CH3)2CF3, benzyl, or substituted benzyl
- Ri is - H2.
- Ri is an optionally substituted C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is an optionally substituted C 6 -Cio aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - HRIA
- RIA is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is -NHRIA
- RIA is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is -NHRIA
- RIA is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is -NHRIA
- RIA is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is -NHRIA
- RIA is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - RIARIB
- RIA and RIB are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is -NRIARIB
- RIA and RIB are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is -NRIARIB, one of RIA and RIB is an optionally substituted Ci-C 6 alkyl and the other of RIA and RIB is an optionally substituted C6-C10 aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is -NHC(0)Ric, and Ric is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is -NHC(0)Ric
- Ric is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is -NHC(0)Ric
- Ric is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is -NHC(0)Ric
- Ric is an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - HC(0)Ric
- Ric is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is -N[C(0)RIA] [C(0)RIC], and RiA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - HSO2R1C, and Ric is an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - HSO2R1C
- Ric is an optionally substituted C 6 -Cio aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - HSO2R1C
- Ric is an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - RIAC(0)RIC, and RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - RIAC(0)RIC, and RIA and Ric are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted C 6 -Cio aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - RIAC(0)RIC
- RIA and Ric are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - RIAC(0)RIC, one of RIA and Ric is an optionally substituted Ci-C 6 alkyl and the other of RIA and Ric is an optionally substituted C 6 -Cio aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- Ri is - R1ASO2R1C, and RIA and Ric are independently an optionally substituted Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted C3-C6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted 3 to 10 membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine, morpholine, dioxane.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted C6-C10 aryl, for example, substituted phenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl.
- Ri is - R1ASO2R1C
- RIA and Ric are independently an optionally substituted 5 to 10 membered heteroaryl, for example, substituted or unsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine.
- Ri is - R1ASO2R1C
- one of RiA and Ric is an optionally substituted Ci-Ce alkyl and the other of RIA and Ric is an optionally substituted C 6 -Cio aryl or an optionally substituted 3 to 10 membered heterocyclyl.
- the compound is a pharmaceutically acceptable salt.
- One or more of the compounds of preferred embodiments can be provided in the form of pharmaceutically acceptable salts, solvates, active metabolites, tautomers, or prodrugs thereof. Some embodiments can be provided in pharmaceutical compositions comprising a therapeutically effective amount of the compound. In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient.
- the pharmaceutical composition can be formulated for intravenous injection, subcutaneous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, transdermal administration, ophthalmic administration, or otic administration.
- the pharmaceutical composition can be in the form of a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
- the pharmaceutical composition is formulated as a gel, salve, ointment, cream, emulsion, or paste for topical application to the skin.
- compositions of preferred embodiments can further comprise one or more additional therapeutically active agents other than a compound of the preferred embodiments.
- additional therapeutically active agents can include, but are not limited to, anti-inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents.
- Some embodiments provide a method of treating, ameliorating, or preventing a disease, disorder, or condition associated with PDE4, comprising administering a therapeutically effective amount of a compound of any one of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, or a composition comprising any one of Formula (I) or Formula (II) to a subject in need thereof.
- the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and combinations thereof.
- the disease, disorder, or condition is arthritis.
- the disease, disorder, or condition is ankylosing spondylitis.
- the disease, disorder, or condition is osteoarthritis.
- the disease, disorder, or condition is rheumatoid arthritis.
- the disease, disorder, or condition is Behcet's disease. In some embodiments, the disease, disorder, or condition is Crohn's disease. In some embodiments, the disease, disorder, or condition is ulcerative colitis. In some embodiments, the disease, disorder, or condition is psoriasis. In some embodiments, the disease, disorder, or condition is psoriatic arthritis. In some embodiments, the disease, disorder, or condition is atopic dermatitis. In some embodiments, the disease, disorder, or condition is contact dermatitis.
- the disease, disorder, or condition is selected from two of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis, and contact dermatitis.
- arthritis ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis, and contact dermatitis.
- the compound or composition is administered in combination with a second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of anti-inflammatory agents, anti-cancer agents, immunostimulatory agents, and immunosuppressive agents.
- the second therapeutic agent is an anti-inflammatory agent or an immunosuppressive agent.
- Some embodiments provide a method of decreasing expression of a protein selected from T F-a, INF- ⁇ , IL-2, IL-17, IL-23, or a combination thereof, comprising contacting a cell with a compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.
- the protein is TNF-a.
- Some embodiments provide a method of decreasing expression of TNF-a.
- Some embodiments provide a method of decreasing expression of INF- ⁇ .
- Some embodiments provide a method of decreasing expression of IL-2.
- Some embodiments provide a method of decreasing expression of IL-17.
- Some embodiments provide a method of decreasing expression of IL-23.
- Some embodiments provide a method of decreasing expression of two proteins selected from T F-a, INF- ⁇ , IL-2, IL-17, and IL-23. Some embodiments provide a method of decreasing expression of three proteins selected from TNF-a, INF- ⁇ , IL-2, IL-17, and IL-23. Some embodiments provide a method of decreasing expression of four proteins selected from TNF-a, INF- ⁇ , IL-2, IL-17, and IL-23. Some embodiments provide a method of decreasing expression of TNF-a, INF- ⁇ , IL-2, IL-17, and IL-23.
- protein expression is decreased by about 10% to about 90%, about 5% to about 25%, about 20% to about 40%, about 35% to about 55%, about 50%) to about 75%>, about 70%> to about 90%>, or any value in between.
- protein expression is decreased by about 5%>, 6%>, 7%>, 8%>, 9%>, 10%>, 11%>, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,
- Some embodiments provide a method of inhibiting PDE4 activity, comprising contacting a cell with a compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing.
- PDE4 activity is decreased by about 10%> to about 90%>, about 5%> to about 25%>, about 20%> to about 40%, about 35% to about 55%, about 50% to about 75%, about 70% to about 90%, or any value in between.
- protein expression is decreased by about 5%>, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,
- Some embodiments provide a method of treating psoriasis, comprising topically administering a therapeutically effective amount of a composition comprising any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of any of the foregoing, to a subject in need thereof.
- the subject is known to possess wild-type PDE4. In some embodiments, the subject is known to possess wild-type TNF-a. In some embodiments, the subject is known to possess wild-type INF- ⁇ , IL-2, IL-17, or IL-23. In some embodiments, the subject is known to possess aberrant PDE4. In some embodiments, the subject is known to possess aberrant TNF-a. In some embodiments, the subject is known to possess aberrant INF- ⁇ , IL-2, IL-17, or IL-23.
- the cell is known to possess wild-type PDE4. In some embodiments, the cell is known to possess wild-type TNF-a. In some embodiments, the cell is known to possess wild-type INF- ⁇ , IL-2, IL-17, or IL-23. In some embodiments, the cell is known to possess aberrant PDE4. In some embodiments, the cell is known to possess aberrant TNF-a. In some embodiments, the cell is known to possess aberrant INF- ⁇ , IL-2, IL-17, or IL-23.
- compositions comprising a compound of Formula (I) or Formula (II), and a pharmaceutically acceptable carrier.
- Some embodiments provide pharmaceutical compositions comprising of Formula (I) or Formula (II)a pharmaceutically acceptable carrier, and a second therapeutic agent.
- the second therapeutic agent is anti-inflammatory agent. In some embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory agent. In some embodiments, the second therapeutic agent is anti-cancer agent. In some embodiments, the second therapeutic agent is an immunostimulatory agent. In some embodiments, the second therapeutic agent is an immunosuppressive agent. In some embodiments, the second therapeutic agent is antibody.
- the second therapeutic agent is selected from aspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam; meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides; clonixin; licofelone; dexamethasone; and prednisone.
- the second therapeutic agent is selected from mechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine; mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ); cisplatin; carboplatin; and oxaliplatin.
- the second therapeutic agent is selected from vincristine; vinblastine; vinorelbine; vindesine; vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; and teniposide.
- the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; and procarbazine.
- the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine; cytarabine liposomal; pralatrexate; floxuridine; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine.
- the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin; pirarubicin; valrubicin; zorubicin; mitoxantrone; pixantrone; mechlorethamine; chlorambucil; prednimustine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thioTEPA; triaziquone; and triethylenemelamine.
- the second therapeutic agent is selected from nedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral; talaporfin; temoporfin; verteporfin; alvocidib; seliciclib; palbociclib; bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecol
- the second therapeutic agent is selected from azathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab; visili
- the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab; siplizumab; talizumab; tel
- about 1 mg to about 5 grams; 2 mg to 2 gram; 5 mg to about 1 gram; 10 mg to about 800 mg; 20 mg to 600 mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg of a compound of Formula (I), Formula (II), or any amount in between, is administered each day.
- about 1 mg to about 5 grams; 2 mg to 2 gram; 5 mg to about 1 gram; 10 mg to about 800 mg; 20 mg to 600 mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg of a compound of Formula (I), Formula (II), or any amount in between is administered each week.
- a compound of Formula (I) or Formula (II) is administered at least once per day, at least twice per day, at least three times per day, or at least four times per day. In some embodiments, a compound of Formula (I) or Formula (II) is administered at least once per day, at least twice per day, at least three times per day, or at least four times per week. In some embodiments, each cycle of treatment lasts 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or any value in between. In some embodiments, each cycle of treatment has at least 1, 2, 3, 4, 5, 6, or 7 days between administrations of a compound of Formula (I), Formula (II), or any value in between.
- a compound of Formula (I) or Formula (II) is provided intravenously over about 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, or 240 minutes, or any value in between.
- Example 1 Compound 1 : (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl) -4,6-dioxo-5,6-dihydro-4H-thien -clpyrrol-l-yl)acetamide
- Example 2j Compound 2j (S)-N-(5 -( 1 -(3 -ethoxy-4-methoxyphenyl)-2-
- Example 4 Compound 4: (S)-N-(cvclopropanecarbonyl)-N-(5-(l-(3-ethoxy-4-hydroxy phenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thienor3,4-c1pyrrol-l-yl)cvclopr opanecarboxamide
- Example 5 Compound 5: N-(5-((S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl) -4,6-dioxo-5,6-dihydro-4H-thienor3,4-c1pyrrol-l-yl)-3,3,3-trifluoro-2-methylpropanamide
- Example 6 Compound 6: S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)- 4,6-dioxo-5,6-dihvdro-4H-thienor3,4-c1pyrrol-l-yl)-2-ethylbutanamide
- Example 7 Compound 7: (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl) -4,6-dioxo-5,6-dihydro-4H-thieno[3,4-clpyrrol-l-yl)-2,2,2-trifluoroacetamide
- Example 9 Compound 9: (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl) -4,6-dioxo-5,6-dihydro-4H-thieno[2,3-clpyrrol-3-yl)-2,2,2-trifluoroacetamide
- Example 10 Compound 10: (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-clpyrrol-3-yl)-2-methoxyacetamide
- Example 11 Compound 11 : (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-4,6-dioxo-5,6-dihvdro-4H-thienor2,3-c1pyrrol-3-yl)cyclopropanecarboxamide
- Example 12 Compound 12 (S) and Compound 18 (R): N-(5-(l-(benzordiri.31dioxol-5-ylV 2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihvdro-4H-thienor3,4-c1pyrrol-l-yl)acetamide
- Example 13 Compound 13 (S) and Compound 19 (R): N-(5-(l-(benzordirL31dioxol-5-vn-2-
- Example 14 Compound 14 (S) and Compound 20 (R): N-(5-(l-(2.3-dihydrobenzorbiri.41 dioxin-6-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thienor3,4-c1pyrrol-l-yl) acetamide
- Example 15 Compound 15 : (S)-N-(5-(2-(N.N-dimethylsulfamovn-l-(3-ethoxy-4- methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-clpyrrol-l-yl)acetamide
- Example 17 Compound 21 (S) and Compound 22 (R): N-(5-(l- benzordiri.31dioxol-5-yl)-2-
- Example 18 Compound 23 (S) and Compound 24 (R): N-(5-(l-(benzordirL31dioxol-5-vn-2- (methylsulfonyl)ethyl)-4,6-dioxo-5,6- dihvdro-4H-thienor2,3-c1pyrrol-3-yl)acetamide
- Example 20 Compound 27 (S) and Compound 28 (R): N-(5-(l- benzordiri.31dioxol-5-yl)-2- dimethylsulfamoyl)ethyl)-4,6-dioxo-5,6-dihvdro-4H-thienor3,4-c1pyrrol-l-yl)acetamide
- Example 21 Compound 29: (R)-N-(5-(2-(N.N-dimethylsulfamovn-l-(3-ethoxy-4- methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thienor3,4-c1pyrrol-l-yl)acetamide
- Example 22 Compound 30: (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-6-oxo-5,6-dihvdro-4H-thienor2,3-c1pyrrol-3-yl)-2,2,2-trifluoroacetamide
- Example 23 Compound 31 : (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-6-oxo-5,6-dihvdro-4H-thie -c1pyrrol-3-yl)-2-methoxyacetamide
- Example 24 Compound 32: (S)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-6-oxo-5.6-dihydro-4H-thieno[2.3-clpyrrol-3-yl)cyclopropanecarboxamide
- PBMCs induced with LPS lipopoly saccharide: Frozen primary blood mononuclear cells (PBMCs) are purchased from AllCells. Cells are quick thawed, washed once with Roswell Park Memorial Institute medium (RPMI)- 1640/10% FBS/1% Penicillin/1%) Streptomycin and plated in 96 well plates at 200,000 cells per well. Cells are pretreated with DMSO only or the indicated compounds for 1 hr and then induced with lOOng/mL for 18-24 hrs. The supernatant is analyzed for TNF-a using Meso Scale assay according to manufacturer's protocol. The negative control wells are treated with DMSO. Compound activity is measured as a percentage of the DMSO control.
- RPMI Roswell Park Memorial Institute medium
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EP4101848A4 (en) * | 2020-02-24 | 2023-07-26 | Suzhou Longbotai Pharmaceuticals Co., Ltd. | Pde4 inhibitor compound and medical use thereof |
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WO2019210869A1 (en) * | 2018-05-02 | 2019-11-07 | 天津合美医药科技有限公司 | Thiophene derivative crystal form |
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AU2019262286B2 (en) * | 2018-05-02 | 2022-08-11 | Tianjin Hemay Pharmaceutical Sci-Tech Co., Ltd | Thiophene derivative crystal form |
EP4101848A4 (en) * | 2020-02-24 | 2023-07-26 | Suzhou Longbotai Pharmaceuticals Co., Ltd. | Pde4 inhibitor compound and medical use thereof |
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