WO2014151147A1 - Combination of kinase inhibitors and uses thereof - Google Patents

Combination of kinase inhibitors and uses thereof Download PDF

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Publication number
WO2014151147A1
WO2014151147A1 PCT/US2014/025090 US2014025090W WO2014151147A1 WO 2014151147 A1 WO2014151147 A1 WO 2014151147A1 US 2014025090 W US2014025090 W US 2014025090W WO 2014151147 A1 WO2014151147 A1 WO 2014151147A1
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kinase
aryl
inhibitor
ioalkyl
alkyl
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PCT/US2014/025090
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English (en)
French (fr)
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Yi Liu
Pingda Ren
Katayoun JESSEN
Xin Guo
Christian Rommel
Troy Edward Wilson
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Intellikine, Llc
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Priority to JP2016501741A priority Critical patent/JP2016512835A/ja
Priority to HK16107451.9A priority patent/HK1219421A1/zh
Priority to US14/776,133 priority patent/US20160089371A1/en
Priority to EP14771022.2A priority patent/EP2968340A4/en
Priority to CA2906542A priority patent/CA2906542A1/en
Priority to CN201480026545.8A priority patent/CN105246482A/zh
Publication of WO2014151147A1 publication Critical patent/WO2014151147A1/en

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • kinases signaling pathways play a central role in numerous biological processes. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al, Current Medicinal Chemistry (2007) 14:2214-2234). In recent years, kinases that are associated with oncogenic signaling pathways have emerged as important drug targets in the treatment of various diseases including many types of cancers.
  • mTOR The mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin, is a serine/threonine protein kinase that regulates cell growth, translational control, angiogenesis and/or cell survival.
  • mTOR is encoded by the FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) gene.
  • FRAP1 12-rapamycin associated protein 1
  • mTOR is the catalytic subunit of two complexes, mTORCl and mTORC2.
  • mTORCl is composed of mTOR, regulatory associated protein of mTOR (Raptor), mammalian LST8/G-protein ⁇ -subunit like protein
  • mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GPL, and mammalian stress- activated protein kinase interacting protein 1 (mSINl).
  • mTORCl and mTORC2 are distinguished by their differential sensitivities to rapamycin and its analogs (also known as rapalogs). Rapamycin binds to and allosterically inhibits mTORCl, but mTORC2 is generally rapamycin- insensitive. As a result of this rapamycin-insensitive mTOR signaling mediated by mTORC2, cancer cells treated with rapamycin analogs usually display only partial inhibition of mTOR signaling, which can lead to enhanced survival and resistance to rapamycin treatment.
  • PI 3-kinases Phosphatidylinositol-3 -kinases
  • PI3Ks Phosphatidylinositol-3 -kinases
  • These lipid kinases phosphorylate the 3-position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns), activating signaling cascades associated with such processes as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking.
  • Disruption of these processes involving PI3K leads to many diseases including cancer, allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.
  • the PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation.
  • the class I PI3Ks (pi 10a, pi 10 ⁇ , pi 10 ⁇ , and pi 10 ⁇ ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate
  • PIP 3 phosphatidylinositol-3,4,5-trisphosphate
  • the alpha (a) isoform of type I PI3K has been implicated in a variety of human cancers.
  • Angiogenesis has been shown to selectively require the a isoform of PI3K in the control of endothelial cell migration. (Graupera et al., Nature 2008;453;662-6).
  • Mutations in the gene coding for PI3K a or mutations which lead to upregulation of PI3K a are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain and skin cancers.
  • mutations in the gene coding for PI3K a are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of- function mutations. While other PI3K isoforms such as PI3K ⁇ or PI3K ⁇ are expressed primarily in hematopoietic cells, PI3K a, along with PI3K ⁇ , is expressed constitutively.
  • PI3K ⁇ The delta ( ⁇ ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes.
  • PI3K ⁇ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages.
  • PI3K ⁇ is integrally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity.
  • PI3K ⁇ Due to its integral role in immune system function, PI3K ⁇ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus, asthma, emphysema and other respiratory diseases.
  • Other class I PI3K involved in immune system function includes PI3K ⁇ , which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
  • PI3K ⁇ has been implicated primarily in various types of cancer including PTEN- negative cancer (Edgar et al. Cancer Research (2010) 70(3): 1164-1172), and HER2- overexpressing cancer such as breast cancer and ovarian cancer.
  • PI3K ⁇ due to the diverse essential functions of mTOR and PI3Ks, drugs that bind to and inhibit a broad range of kinase iso forms and complexes with low specificity can lead to deleterious side effects. For example, excessive inhibition of PI3K ⁇ may lead to undesirable effects on metabolic pathways and disruption of insulin signaling. Alternatively, excessive inhibition of PI3K ⁇ and/or PI3K ⁇ may disrupt or reduce immune function.
  • the present disclosure provides an alternative approach that effectively targets disease-related pathways, while limiting undesirable side effects.
  • the invention provides a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a therapeutically effective amount of a combination of a PI3 -kinase a inhibitor and an mTOR inhibitor, wherein the PI3 -kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3- kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • PI3 -kinase type I phosphatidylinositol-3- kinases
  • the combination comprises a therapeutic effective amount of a PI3 -kinase a inhibitor and a therapeutic effective amount of an mTOR inhibitor.
  • the combination comprises a synergistically effective therapeutic amount of PI3 -kinase a inhibitor and an mTOR inhibitor, wherein the PI3 -kinase a inhibitor and/or the mTOR inhibitor is present in a sub-therapeutic amount.
  • the invention also provides a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, comprising administering to said subject
  • PI3 -kinase a inhibitor exhibits selective inhibition of PI3-kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase ⁇ , PI3- kinase ⁇ , and PI3 -kinase ⁇ , wherein each dosing regimen independently comprising repeating cycles of a treatment period followed by a rest period, wherein at least one dosing regimen has one rest period of more than 0 day.
  • each dosing regimen independently comprising repeating cycles of a treatment period followed by a rest period, wherein at least one dosing regimen has one rest period of more than 0 day.
  • the first dosing regimen and the second dosing regimen are the same and are administered simultaneously. In some methods, the first dosing regimen and the second dosing regimen are different. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of at least 1 day followed by a rest period of at least 1 day. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 1 day. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 3, 4, or 5 consecutive days.
  • the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of at least 1 day followed by a rest period of 6 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 3 consecutive days followed by a rest period of 4 consecutive days, optionally the first dosing regimen and the second dosing regimen are the same and are administered simultaneously. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days.
  • the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 1 consecutive days followed by a rest period of 6 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle comprising at least 3 treatment periods on alternate days within the 7 days.
  • the second dosing regimen has a rest period of 0 day.
  • the first dosing regimen has a rest period of 0 day.
  • the first dosing regimen has a rest period of 0 day, and the second dosing regimen comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days.
  • the first dosing regimen has a rest period of 0 day, the second dosing regimen comprises at least one 7-day cycle of a treatment period of 1 consecutive days followed by a rest period of 6 consecutive days.
  • the invention also provides a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, comprising administering to said subject
  • PI3 -kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3- kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ , wherein the clinical and therapeutic effects of the treatment of the disease condition continue for a durability of effect period of at least as long as the administration period.
  • PI3 -kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or
  • the combination comprises a synergistically effective therapeutic amount of PI3 -kinase a inhibitor and an mTOR inhibitor, wherein the PI3-kinase a inhibitor and/or the mTOR inhibitor is present in a sub-therapeutic amount.
  • the clinical and therapeutic effects are selected from the group consisting of sustained tumor regression, inhibited tumor re-growth, reduction of proliferation, increased apoptosis, or downregulation of activity of a target protein.
  • the clinical and therapeutic effects are sustained tumor regression and inhibited tumor re-growth.
  • the durability of effect period is at least 30 days. In some methods, the durability of effect period is at least 5 days.
  • the PI3 -kinase a inhibitor is administered according to a first intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period.
  • the mTOR inhibitor is administered according to a second intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period.
  • the invention also provides a method of treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, comprising administering to the subject
  • PI3-kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase ⁇ ,
  • the disease condition associated with PI3-kinase a and/or mTOR can include but are not limited to a neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease and kidney disease.
  • the neoplastic condition can be NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers, renal cell carcinoma, prostate cancer, neuroendocrine cancer, endometrial cancers, and other forms of cancer.
  • the invention further provides a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell, comprising contacting a cell with an effective amount of a PI3 -kinase a inhibitor and an mTOR inhibitor that selectively inhibits both mTORCl and mTORC2 activity relative to one or more type I phosphatidylinositol-3 -kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the PI3 -kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-
  • the PI3-kinase a inhibitor selectively inhibits PI3 -kinase a relative to all other type I phosphatidylinositol-3 -kinases (P 13 -kinase) consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • P 13 -kinase all other type I phosphatidylinositol-3 -kinases
  • the PI3 -kinase a inhibitor utilized in the subject methods inhibits PI3- kinase a with an IC50 value of about 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 10 nM or less, InM or less as ascertained in an in vitro kinase assay.
  • the PI3-kinase a inhibitor selectively inhibits PI3-kinase a with an IC50 value that is at least 2, 5, 10, 50, 100, 1000 times less than its IC50 value against one, two, three or all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3- kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor selectively inhibits PI3-kinase a with an IC50 value that is less than about 200 nM, and said IC50 value is at least 2, 5 or 10 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor selectively inhibits PI3-kinase a and/or PI3-kinase ⁇ with an IC50 value that is at least 5 times less than its IC50 value against PI3-kinase ⁇ or PI3-kinase ⁇ . In yet other embodiments, the PI3-kinase a inhibitor selectively inhibits PI3-kinase a and/or PI3-kinase ⁇ with an IC50 value that is at least 50 times less than its IC50 value against PI3-kinase ⁇ or PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor selectively inhibits PI3-kinase a with an IC50 value that is at least 50 times less than its IC50 value against PI3 -kinase ⁇ or PI3 -kinase ⁇ .
  • the mTOR inhibitor binds to and directly inhibits both mTORCl and mTORC2.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, or InM or less, as ascertained in an in vitro kinase assay.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTOR inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and the IC50 value is at least 2, 5 or 10 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase a, PI3- kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the mTor inhibitor inhibits mTORCl selectively.
  • the mTor inhibitor inhibits mTORCl with an IC50 value of about 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, as ascertained in an in vitro kinase.
  • the mTor inhibitor is rapamycin or an analogue of rapamycin.
  • the mTor inhibitor is sirolimus (rapamycin), deforolimus (AP23573, MK- 8669), everolimus (RAD-001), temsirolimus (CCI-779), zotarolimus (ABT-578), or biolimus A9 (umirolimus).
  • the mTOR inhibitor is a compound of Formula I:
  • Xi is N or C-E 1
  • X 2 is N or C
  • X 3 is N or C
  • X 4 is C-R 9 or N
  • X 5 is N or C-E 1
  • X 6 is C or N
  • X 7 is C or N; and wherein no more than two nitrogen ring atoms are adjacent;
  • Ri is H, -L-Ci_ioalkyl, -L-C 3 _scycloalkyl, -L-Ci_ioalkyl -C 3 _scycloalkyl, -L- aryl, -L- heteroaryl, -L-Ci_ioalkylaryl, -L- Ci_ioalkylhetaryl, -L- Ci_ioalkylheterocylyl, -L-C 2 _ioalkenyl, -L-C 2 _ioalkynyl, -L-C 2 _ioalkenyl-C 3 _ 8 cycloalkyl, -L-C 2 _ioalkynyl-C 3 _ 8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalky
  • E 1 and E 2 are independently -(W 1 ) ] -R 4 ;
  • Mi is a 5, 6, 7, 8, 9, or-10 membered ring system, wherein the ring system is monocyclic or bicyclic, substituted with R 5 and additionally optionally substituted with one or more -(W ) k
  • each k is 0 or 1 ;
  • j in E 1 or j in E 2 is independently 0 or 1;
  • W 1 is -0-, -NR 7 -, -S(0)o- 2 -,-C(0)-,-C(0)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )S(0)-,- N(R 7 )S(0) 2 - -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or - CH(R 7 )N(R 8 )S(0) 2 -;
  • W 2 is -0-, -NR 7 -, -S(0)o- 2 -,-C(0)-,-C(0)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )C(0)N(R 8 )-,- N(R 7 )S(0)-, -N(R 7 )S(0) 2 -,-C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, - CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, - CH(R 7 )N(R 8 )S(0)-, or -CH(R 7 )N(R 8 )S(0) 2 -;
  • Ci_ioalkyl C 3 _scycloalkyl, Ci_ioalkyl-C 3 _ 8 cycloalkyl, C 3 _scycloalkyl -Ci_ioalkyl, C 3 _scycloalkyl -C 2 _ioalkenyl, C 3 _scycloalkyl- C 2 _ioalkynyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkynyl, Ci_ioalkylaryl (e.g.
  • each of R , R , and R is independently H or Ci_ioalkyl , wherein the Ci_ioalkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more halo, -OH, - Ci_ioalkyl, -CF , -O-aryl, -OCF , -OCi_ l oalkyl, -NH 2 , - N(Ci_i 0 alkyl)(Ci_i 0 alkyl), - NH(Ci_i 0 alkyl), - NH( aryl), -NR 34 R 35 , - C(O)(Ci_i 0 alkyl), -C(O)(Ci_i 0 al
  • NR 31 R 32 hydroxyl, halogen, oxo, aryl, hetaryl, Ci_ 6 alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;
  • each of R 7 and R 8 is independently hydrogen, Ci_ioalkyl, C 2 _ioalkenyl, aryl, heteroaryl, heterocyclyl or C 3 _iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R 6 ;
  • R 6 is halo, -OR 31 , -SH, -NH? -NR 34 R 35 .
  • the mTOR inhibitor is a compound of
  • the PI3 -kinase a inhibitor is a compound of formula
  • W 1' is N, NR 3' , or CR 3' ;
  • W 3' is N, NR 5' or CR 5' ;
  • W 4' is
  • W 6' is N or CR 8' ;
  • W a' and W b' are independently N or CR 9 ;
  • W c' and W d' are N, and the other is O, NR 10' , or S;
  • R and R" are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety;
  • R 3' and R 4' are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety;
  • R 5 , R 6' , R 7' and R 8' are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety;
  • R 9 is alkyl or halo
  • R 10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety.
  • the PI3-kinase a inhibitor is a compound of formula:
  • X is O or S or N;
  • W 1' is S, N, NR 3' or CR 3' ,
  • W 2' is N or CR 4' ,
  • W 3' is S, N or CR 5' ,
  • W 4' is N or C, and
  • W 5' is N or CR 7' ;
  • W 6' is N or CR 8' ;
  • R and R" are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety;
  • R 3' and R 4' are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety;
  • R 5' , R 7' and R 8' are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,
  • heterocycloalkyloxy amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" wherein R' and R" are taken together with nitrogen to form a cyclic moiety.
  • the PI3-kinase a inhibitor and/or the mTOR inhibitor can be administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally.
  • the PI3-kinase a inhibitor and/or the mTOR inhibitor are co-administered to the subject in the same formulation.
  • the PI3-kinase a inhibitor and/or the mTOR inhibitor are co-administered to the subject in different formulations.
  • the invention also provides a pharmaceutical composition comprising a combination of an amount of PI3 -kinase a inhibitor and an amount of mTOR inhibitor, wherein said combination provides a synergistic therapeutic effect in a subject in need thereof.
  • the pharmaceutical composition is formulated in an oral dosage.
  • the pharmaceutical composition is formulated a tablet or a capsule.
  • the PI3-kinase a inhibitor and the mTOR inhibitor are packaged as separate tablets.
  • the PI3 -kinase a inhibitor and the mTOR inhibitor are formulated as a single oral dosage form.
  • the invention also provides a pharmaceutical kit comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise (a) a therapeutically effective amount of a PI3-kinase a inhibitor and/or (b) a therapeutically effective amount of an mTOR inhibitor; wherein the daily dosage units comprising the PI3- kinase a inhibitor and/or mTOR inhibitor are effective for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, and (ii) a number of daily dosage units containing no active agent placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day.
  • the number of daily dosage units comprising the PI3-kinase a inhibitor and/or mTOR inhibitor is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units containing no active agent is at least 1. In some kits, the number of daily dosage units comprising the PI3- kinase a inhibitor and/or mTOR inhibitor is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units containing no active agent is at least 3, 4, or 5 or multiple of 3, 4, or 5.
  • the number of daily dosage units comprising the PI3- kinase a inhibitor and/or mTOR inhibitor is at least 1, and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6. In some kits, the number of daily dosage units comprising the PI3-kinase a inhibitor and/or mTOR inhibitor is 3, or multiple of 3, and wherein the number of daily dosage units containing no active agent is 4 or multiple of 4. In some kits, the number of daily dosage units comprising the PI3-kinase a inhibitor and/or mTOR inhibitor is 5, or multiple of 5, and wherein the number of daily dosage units containing no active agent is 2 or multiple of 2. In some kits, the number of daily dosage units comprising the PI3-kinase a inhibitor and/or mTOR inhibitor is 1, or multiple of 1, and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6.
  • the invention further provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a combination of (a) a therapeutically effective amount of a PI3 -kinase a inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor; and (ii) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a therapeutically effective amount of a PI3 -kinase a inhibitor.
  • the number of daily dosage units comprising the combination is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units comprising PI3 -kinase a inhibitor only is at least 1. In some kits, the number of daily dosage units comprising the combination is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units comprising PI3- kinase a inhibitor only is at least 3, 4, or 5 or multiple of 3, 4, or 5. In some kits, the number of daily dosage units comprising the combination is at least 1 , and wherein the number of daily dosage units comprising PI3 -kinase a inhibitor only is 6 or multiple of 6.
  • the number of daily dosage units comprising the combination is 3, or multiple of 3, and wherein the number of daily dosage units comprising PI3 -kinase a inhibitor only is 4 or multiple of 4. In some kits, the number of daily dosage units comprising the combination is 5, or multiple of 5, and wherein the number of daily dosage units containing no active agent is 2 or multiple of 2. In some kits, the number of daily dosage units comprising the combination is 1 , or multiple of 1 , and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6.
  • the invention further provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a combination of (a) a therapeutically effective amount of a PI3 -kinase a inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor; and (ii) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a therapeutically effective amount of an mTOR inhibitor.
  • the invention also provides a method comprising: (a) determining the presence in a subject of a mutation in PI3 -kinase a that is associated with a disease condition mediated by PI3 -kinase a; and (b) administering to said subject a pharmaceutical composition of the invention.
  • the mutation is in the nucleotide sequence coding for PI3 -kinase a.
  • Exemplary mutations can include without limitation, deletion, insertion, translation, which can result in point mutations, frame shifts, and/or translation of the nucleic acid sequence coding for PI3 -kinase a.
  • the mutation is in the amino acid sequence of PI3 -kinase a.
  • the subject or cell comprises a mutation in PI3 -kinase a which is associated with a disease condition mediated by PI3 -kinase a.
  • Figure 1 is a schematic illustration of multiple and distinct signaling pathways that are activated in human cancer.
  • Figure 2 is a graph showing the synergistic effect of combined treatment with a PI3- kinase a inhibitor (Compound A) and an mTor inhibitor (Compound B) on tumor weight in a preclinical breast cancer model.
  • Figure 3 is a western blot depicting the synergistic effect of combined treatment with Compound A and Compound B in terms of downregulating Akt and S6 phosphorylation.
  • Figure 4 is a graph showing the synergistic effect of combined treatment with Compound A and rapamycin in terms of reducing tumor volume of a preclinical breast cancer model.
  • Figure 5 shows A) an illustration of the distinct signaling pathways mediated by mTORCl and mTORC2 and B) a western blot depicting sensitivity of mTORCl -dependent NRDG1 phosphorylation to Compound B, but not rapamycin.
  • Figure 6 shows A) a graph depicting the selectivity of Compound B over Compound A in a PTEN-mutant negative control tumor model, B) a western blot depicting selective inhibition of Akt, S6, and 4EBP phosphorylation by Compound B and not Compound A in PTEN mutant cells, and C) a chart depicting the specificity of Compound A in inhibiting PI3K a over mTOR and other PI3K isoforms, and the specificity of Compound B in inhibiting mTOR over PI3K isoforms.
  • Figure 7 is a western blot depicting differential inhibition of Akt phosphorylation at serine 473 over threonine 308 by Compound B (top panel). Also shown is the comparison of Akt phosphorylation inhibition for Pan-PI3K inhibitor versus Compound B.
  • Figure 8 is a graph showing that Pan-PI3K inhibitor, but not Compound A, blocks B cell function in vivo. Mice were immunized with TNP-Ficoll and treated with 1) vehicle; 2) 70 mg/kg GDC0941; 3) 30 mg/kg Compound A; 4) 60mg/kg Compound A; or 5) 120mg/kg Compound A for 7 days. Antibody production was measured as a percentage of control group that were treated with vehicle.
  • Figure 9 shows, left panel, a graph showing reduction in tumor weight of a breast cancer model using 70 mg/kg Pan-PI3K inhibitor and 60 mg/kg compound A and, right panel, reduced presence of MZB cells in mouse spleen for 70 mg/kg Pan-PI3K inhibitor compared to 60 mg/kg Compound A.
  • Figure 10 illustrates the frequency of PI3K a mutation in various human cancers.
  • Figure 11 is a western blot depicting inhibition of the PI3K pathway by Compound A in cell lines with elevated PI3K a activity.
  • the left column shows data from MDA-MB-361 breast cancer cells harboring PIK3CA mutation.
  • the middle column shows data from MDA- MB-453 breast cancer cells harboring PIK3CA mutation.
  • the right column shows data from SKBr3breast cancer cells harboring HER2 mutation.
  • Figure 12 shows A) a western blot showing inhibition of Akt phosphorylation at serine 473 by Compound A; and B) reduced inhibition of Akt phosphorylation at serine 473 by Compound A in a PTEN-mutant cell line.
  • Figure 13 is a chart showing that Compound A preferentially inhibits proliferation of tumor cells harboring PI3K a mutations.
  • Figure 14 is an isobologram depicting the additive or synergistic anticancer activity achieved by a combination of Compound A and Compound B.
  • the in vitro combination analysis demonstrated the additive or synergistic effects of the combination across tumor types or genetic types.
  • Figure 15 is a western blot depicting induction of cell apoptosis by Compound A, Compound B, or combination thereof in breast cell cancer cells.
  • Cleaved PARP is a biomarker for apoptosis.
  • the result show that a greater degree of apoptosis and pathway regulation (TORC 1 and 2 substrates) can be induced by a combination of compound A and compound B as compared to single agents.
  • the left column shows data from MDA-MB-361 breast cancer cells harboring PIK3CA and HER2 mutations.
  • the right column shows data from HCC-1419 breast cancer cells harboring HER2 mutation.
  • Figure 16 shows that an intermittent dosing regimen of the combination of
  • Compound A and Compound B leads to tumor growth inhibition similar to that observed on the QD schedule in vivo.
  • Figure 17 shows that the combination of Compound A and Compound B leads to increased durability of tumor control in vivo, and sustained tumor regression whereas the single agent control arms demonstrate re-growth.
  • Figure 18 shows that the combination of Compound A and Compound B leads to increased tumor growth inhibition in a PTEN null model, suggesting utility of this combination in diverse genotypes.
  • Figure 19 shows that the combination of Compound A and Compound B
  • the term can mean within an order of magnitude, preferably within 5 -fold, and more preferably within 2-fold, of a value.
  • Treatment refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the term "neoplastic condition” refers to the presence of cells possessing abnormal growth characteristics, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, perturbed oncogenic signaling, and certain characteristic morphological features. This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or
  • a receptor tyrosine kinase overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.
  • the term "effective amount” or “therapeutically effective amount” refers to that amount of an inhibitor described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • a "sub-therapeutic amount" of an agent or therapy is an amount less than the effective amount for that agent or therapy, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.
  • a "synergistically effective therapeutic amount" of an agent or therapy is an amount which, when combined with an effective or sub-therapeutic amount of another agent or therapy, produces a greater effect than when either of the two agents are therapies are used alone.
  • a synergistically effective therapeutic amount of an agent or therapy produces a greater effect when used in combination than the additive effects of each of the two agents or therapies when used alone.
  • agent refers to a biological, pharmaceutical, or chemical compound or other moiety.
  • Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound.
  • Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
  • various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present invention.
  • agonist refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.
  • a preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
  • mTOR inhibitor that binds to and directly inhibits both mTORC 1 and mTORC2 kinases refers to an mTOR inhibitor that interacts with and reduces the kinase activity of both mTORC 1 and mTORC2 complexes.
  • an "anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition.
  • One class of anti-cancer agents comprises chemotherapeutic agents.
  • “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
  • cell proliferation refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
  • co-administration encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time.
  • Coadministration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • Co-administered agents may be in the same formulation.
  • Coadministered agents may also be in different formulations.
  • a "therapeutic effect,” as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • salts refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Signal transduction is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
  • a modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway.
  • a modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
  • selective inhibition or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.
  • Subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics, pre-clinical, and veterinary applications.
  • the subject is a mammal, and in some embodiments, the subject is human.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • an in vitro assay encompasses any assay run outside of a subject assay.
  • in vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • PI3K Phosphoinositide-3 -kinase
  • PI phosphatidylinositol
  • connection of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any linking moieties, and ends with the linking moiety.
  • heteroarylthio Ci_ 4 alkyl has a heteroaryl group connected through a thio sulfur to a Ci_ 4 alkyl radical that connects to the chemical species bearing the substituent. This condition does not apply where a formula such as, for example "-L-C 1-10 alkyl - C 3 _ 8 cycloalkyl" is represented.
  • the terminal group is a C 3 -scycloalkyl group attached to a linking C 1-10 alkyl moiety which is attached to an element L, which is itself connected to the chemical species bearing the substituent.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-Cio alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated. In some embodiments, it is a C 1 -C4 alkyl group.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like.
  • the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (z ' so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl,
  • Acyl refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-,
  • it is a C 1 -C 10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e. three other ring or chain atoms plus carbonyl.
  • the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a ,
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e., C 2 -Cio cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10" refers to each integer in the given range; e.g., "3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C 3 -Cs cycloalkyl radical.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,
  • Ci-ioalkyl - C 3 - 8 cycloalkyl is used to describe an alkyl group, branched or straight chain and containing 1 to 10 carbon atoms, attached to a linking cycloalkyl group which contains 3 to 8 carbons, such as for example, 2-methyl cyclopropyl, and the like.
  • bicycloalkyl refers to a structure consisting of two cycloalkyl moieties, unsubstituted or substituted, that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be “fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be "bridged”. Examples include, but are not limited to, bicyclo[2.2.1]heptyl ("norbornyl”), bicyclo[2.2.2]octyl, and the like.
  • heteroatom or "ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • Heteroalkyl “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given, e.g., C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a "C 4 " heteroalkyl, which includes the heteroatom center in the atom chain length description.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • heteroalkylaryl refers to a heteroalkyl group as defined above which is attached to an aryl group, and may be attached at a terminal point or through a branched portion of the heteroalkyl, for example, an benzyloxymethyl moiety. Either portion of the moiety is unsubstituted or substituted.
  • heteroalkylheteroaryl refers likewise to a heteroalkyl group which is attached to a heteroaryl moiety, for example, an ethoxymethylpyridyl group. Either portion of the moiety is unsubstituted or substituted.
  • heteroalkyl-heterocyclyl refers to a heteroalkyl group as defined above, which is attached to a heterocyclic group, for example, 4(3-aminopropyl)-N-piperazinyl. Either portion of the moiety is unsubstituted or substituted.
  • heteroalkyl-C 3 _ 8 cycloalkyl refers to a heteroalkyl group as defined above, which is attached to a cyclic alkyl containing 3 to 8 carbons, for example, l-aminobutyl-4- cyclohexyl. Either portion of the moiety is unsubstituted or substituted.
  • heterocycloalkyl refers to a bicycloalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • heterospiroalkyl refers to a spiroalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an "alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C 2 -Cio alkenyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkenyl comprises two to eight carbon atoms.
  • an alkenyl comprises two to five carbon atoms (e.g., C 2 -Cs alkenyl).
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , - SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)OR a , -N(R a )C(0)R a ,
  • C 2 _io alkenyl-heteroalkyl refers to a group having an alkenyl moiety, containing 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroalkyl group, such as, for example, allyloxy, and the like. Either portion of the moiety is unsubstituted or substituted.
  • C 2-10 alkynyl-heteroalkyl refers to a group having an alkynyl moiety, which is unsubstituted or substituted, containing 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroalkyl group, such as, for example, 4-but-l- ynoxy, and the like. Either portion of the moiety is unsubstituted or substituted.
  • haloalkenyl refers to an alkenyl group substituted with one or more halo groups.
  • cycloalkenyl refers to a cyclic aliphatic 3 to 8 membered ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1 ,4-cyclohexadienyl, and the like.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., C 2 -Cio alkynyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl has two to five carbon atoms (e.g., C2-C5 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a ,
  • C 2 _io alkynyl- C 3 _8 cycloalkyl refers to a group containing an alkynyl group, containing 2 to 10 carbons and branched or straight chain, which is attached to a linking cycloalkyl group containing 3 to 8 carbons, such as, for example 3-prop-3-ynyl- cyclopent-lyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • haloalkenyl refers to an alkynyl group substituted with one or more independent halo groups.
  • Amino or "amine” refers to a -N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • a -N(R a ) 2 group When a -N(R a ) 2 group has two R a other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -N(R a ) 2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , - SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)OR a , -N(R a )C(0)R a
  • Amide or “amido” refers to a chemical moiety with formula -C(0)N(R) 2 or - NHC(0)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. In some embodiments it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical.
  • the R of - N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified.
  • Aromatic or "aryl” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -Cio aromatic or C 6 -Cio aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as “6 to 10” refers to each integer in the given range; e.g., "6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,
  • Heteroaryl or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., Cs-Ci 3 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as “5 to 18” refers to each integer in the given range; e.g., "5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • An N-containing "heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[3 ⁇ 4][l,4]dioxepinyl,
  • a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • aryl-alkyl arylalkyl
  • arylalkyl arylalkyl
  • aralkyl a group wherein the alkyl chain can be branched or straight chain forming a linking portion with the terminal aryl, as defined above, of the aryl-alkyl moiety.
  • aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3- fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2- methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5- dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2- methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4-(trifluoromethyl)phenyl)propy
  • Ci_ioalkylaryl refers to an alkyl group, as defined above, containing 1 to 10 carbon atoms, branched or unbranched, wherein the aryl group replaces one hydrogen on the alkyl group, for example, 3-phenylpropyl. Either portion of the moiety is unsubstituted or substituted.
  • C2-10 alkyl monocycloaryl refers to a group containing a terminal alkyl group, branched or straight chain and containing 2 to 10 atoms attached to a linking aryl group which has only one ring, such as for example, 2-phenyl ethyl. Either portion of the moiety is unsubstituted or substituted.
  • Ci_io alkyl bicycloaryl refers to a group containing a terminal alkyl group, branched or straight chain and containing 2 to 10 atoms attached to a linking aryl group which is bicyclic, such as for example, 2-(l-naphthyl)- ethyl. Either portion of the moiety is unsubstituted or substituted.
  • aryl-cycloalkyl and "arylcycloalkyl” are used to describe a group wherein the terminal aryl group is attached to a cycloalkyl group, for example
  • heteroaryl-C 3 _ 8 cycloalkyl and “heteroaryl- C 3 _scycloalkyl " are used to describe a group wherein the terminal heteroaryl group is attached to a cycloalkyl group, which contains 3 to 8 carbons, for example pyrid-2-yl-cyclopentyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl- heteroalkyl refers to a group wherein the terminal heteroaryl group is attached to a linking heteroalkyl group, such as for example, pyrid-2-yl
  • aryl-alkenyl arylalkenyl
  • arylalkenyl arylalkenyl
  • aralkenyl a group wherein the alkenyl chain can be branched or straight chain forming a linking portion of the aralkenyl moiety with the terminal aryl portion, as defined above, for example styryl (2-phenylvinyl), phenpropenyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • aryl -C2-ioalkenyl means an arylalkenyl as described above wherein the alkenyl moiety contains 2 to 10 carbon atoms such as for example, styryl (2-phenylvinyl), and the like. Either portion of the moiety is unsubstituted or substituted.
  • C2-ioalkenyl-aryl is used to describe a group wherein the terminal alkenyl group, which contains 2 to 10 carbon atoms and can be branched or straight chain, is attached to the aryl moiety which forms the linking portion of the alkenyl-aryl moiety, such as for example, 3-propenyl- naphth-l-yl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • aryl-alkynyl arylalkynyl
  • arylalkynyl arylalkynyl
  • aralkynyl a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the aryl-alkynyl moiety with the terminal aryl portion, as defined above, for example 3- phenyl-l-propynyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • aryl- C2-ioalkynyl means an arylalkynyl as described above wherein the alkynyl moiety contains two to ten carbons, such as, for example 3-phenyl-l-propynyl, and the like . Either portion of the moiety is unsubstituted or substituted.
  • C2-ioalkynyl- aryl means a group containing an alkynyl moiety attached to an aryl linking group, both as defined above, wherein the alkynyl moiety contains two to ten carbons, such as, for example 3-propynyl-naphth-l-yl. Either portion of the moiety is unsubstituted or substituted.
  • aryl-oxy aryloxy
  • aryloxy aryloxy
  • aroxy a terminal aryl group attached to a linking oxygen atom.
  • Typical aryl-oxy groups include phenoxy, 3,4- dichlorophenoxy, and the like. Either portion of the moiety is unsubstituted or substituted.
  • aryl-oxyalkyl aryloxyalkyl
  • aryloxyalkyl aryloxyalkyl
  • aroxyalkyl a group wherein an alkyl group is substituted with a terminal aryl-oxy group, for example pentafluorophenoxymethyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • Ci_ioalkoxy-Ci_ioalkyl refers to a group wherein an alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example methoxypropyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • Ci_ioalkoxy-C2_ioalkenyl refers to a group wherein an alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkenyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example 3-methoxybut-2-en-l-yl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • Ci_ioalkoxy-C2-ioalkynyl refers to a group wherein an alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkynyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example 3-methoxybut-2-in-l-yl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocycloalkenyl refers to a cycloalkenyl structure, which is unsubstituted or substituted in which at least one carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.
  • heteroaryl-oxy used to describe a terminal heteroaryl group, which is unsubstituted or substituted, attached to a linking oxygen atom.
  • Typical heteroaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.
  • heteroarylalkyl used to describe a group wherein the alkyl chain can be branched or straight chain forming a linking portion of the heteroaralkyl moiety with the terminal heteroaryl portion, as defined above, for example 3-furylmethyl, thenyl, furfuryl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl-Ci_ioalkyl is used to describe a heteroaryl alkyl group as described above where the alkyl group contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • Ci_ioalkyl-heteroaryl is used to describe a alkyl attached to a hetaryl group as described above where the alkyl group contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • heteroarylalkenyl is used to describe a alkyl attached to a hetaryl group as described above where the alkyl group contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl-alkenyl "heteroaryl-alkenyl”
  • taralkenyl and “heteroaralkenyl” are used to describe a
  • heteroarylalkenyl group wherein the alkenyl chain can be branched or straight chain forming a linking portion of the heteroaralkenyl moiety with the terminal heteroaryl portion, as defined above, for example 3-(4-pyridyl)-l-propenyl. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl- C2-ioalkenyl group is used to describe a group as described above wherein the alkenyl group contains 2 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • C2-ioalkenyl- heteroaryl is used to describe a group containing an alkenyl group, which is branched or straight chain and contains 2 to 10 carbon atoms, and is attached to a linking heteroaryl group, such as, for example 2-styryl-4-pyridyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heteroarylalkynyl heteroarylalkynyl
  • heteroarylalkynyl heteroaryl-alkynyl
  • heteroaryl-alkynyl “hetaralkynyl” and “heteroaralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the heteroaralkynyl moiety with the heteroaryl portion, as defined above, for example 4-(2- thienyl)-l-butynyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl- C2-ioalkynyl is used to describe a heteroarylalkynyl group as described above wherein the alkynyl group contains 2 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • C2-ioalkynyl- heteroaryl is used to describe a group containing an alkynyl group which contains 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroaryl group such as, for example, 4(but-l-ynyl) thien-2-yl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclyl refers to a four-, five-, six-, or seven-membered ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the four-membered ring has zero double bonds
  • the five-membered ring has zero to two double bonds
  • the six- and seven-membered rings have zero to three double bonds.
  • heterocyclyl also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclyl group, or a four- to seven-membered aromatic or nonaromatic carbocyclic ring.
  • heterocyclyl group can be attached to the parent molecular moiety through any carbon atom or nitrogen atom in the group.
  • Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., "3 to 18 ring atoms" means that the
  • heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl. In some embodiments, it is a C3-C10 heterocycloalkyl.
  • the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-piperidony
  • a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a ,
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as
  • heterocyclylalkyl heterocyclyl-alkyl
  • heterocyclylalkyl hetcyclylalkyl
  • heterocyclyl-alkyl are used to describe a group wherein the alkyl chain can be branched or straight chain forming a linking portion of the heterocyclylalkyl moiety with the terminal heterocyclyl portion, as defined above, for example 3-piperidinylmethyl and the like.
  • heterocycloalkylene refers to the divalent derivative of heterocycloalkyl.
  • Ci_ioalkyl-heterocycyl refers to a group as defined above where the alkyl moiety contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclyl- Ci_ioalkyl refers to a group containing a terminal heterocyclic group attached to a linking alkyl group which contains 1 to 10 carbons and is branched or straight chain, such as, for example, 4-morpholinyl ethyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclylalkenyl refers to the divalent derivative of
  • heterocyclylalkenyl Either portion of the moiety is unsubstituted or substituted.
  • heterocycyl- C 2-10 alkenyl refers to a group as defined above where the alkenyl group contains 2 to 10 carbon atoms and is branched or straight chain, such as, for example, 4-(N-piperazinyl)-but-2-en-l-yl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclylalkynyl refers to a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the heterocyclylalkynyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-pyrrolidinyl-l-butynyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocycyl- C 2-10 alkynyl refers to a group as defined above where the alkynyl group contains 2 to 10 carbon atoms and is branched or straight chain, such as, for example, 4-(N-piperazinyl)-but-2-yn-l-yl, and the like.
  • aryl- heterocycyl refers to a group containing a terminal aryl group attached to a linking heterocyclic group, such as for example, N4-(4-phenyl)- piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heteroaryl- heterocycyl refers to a group containing a terminal heteroaryl group attached to a linking heterocyclic group, such as for example, N4-(4- pyridyl)- piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • carboxylalkyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkyl groups as defined above.
  • carboxylalkenyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkenyl groups as defined above.
  • carboxylalkynyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkynyl groups as defined above.
  • carboxylcycloalkyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined above.
  • carboxylcycloalkenyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having ethylenic bonds as defined above.
  • cycloalkylalkyl and “cycloalkyl-alkyl” refer to a terminal cycloalkyl group as defined above attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • cycloalkylalkenyl and “cycloalkyl-alkenyl” refer to a terminal cycloalkyl group as defined above attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • cycloalkylalkynyl and “cycloalkyl-alkynyl” refer to a terminal cycloalkyl group as defined above attached to an alkynyl group, for example
  • cyclopropylpropargyl 4-cyclopentyl-2-butynyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • cycloalkenylalkyl and “cycloalkenyl-alkyl” refer to a terminal cycloalkenyl group as defined above attached to an alkyl group, for example 2-(cyclopenten- l-yl)ethyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • cycloalkenylalkenyl and “cycloalkenyl-alkenyl” refer to terminal a cycloalkenyl group as defined above attached to an alkenyl group, for example 1- (cyclohexen-3-yl)allyl and the like.
  • cycloalkenylalkynyl and “cycloalkenyl-alkynyl” refer to terminal a cycloalkenyl group as defined above attached to an alkynyl group, for example 1- (cyclohexen-3-yl)propargyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • alkoxy refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen.
  • “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • C 1 -C 4 alkyl is an alkyl group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.
  • haloalkoxy refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the like.
  • alkoxyalkoxyalkyl refers to an alkyl group substituted with an alkoxy moiety which is in turn is substituted with a second alkoxy moiety, for example
  • alkylthio includes both branched and straight chain alkyl groups attached to a linking sulfur atom, for example methylthio and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • alkoxyalkenyl refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • alkoxyalkynyl refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • C 2 -ioalkenylC 3 _ 8 cycloalkyl refers to an alkenyl group as defined above substituted with a three to eight membered cycloalkyl group, for example, 4-(cyclopropyl) -2- butenyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • C 2 -ioalkynylC 3 _ 8 cycloalkyl refers to an alkynyl group as defined above substituted with a three to eight membered cycloalkyl group, for example, 4-(cyclopropyl) -2- butynyl and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclyl-Ci_ioalkyl refers to a heterocyclic group as defined above substituted with an alkyl group as defined above having 1 to 10 carbons, for example, 4-(N- methyl)-piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclyl-C 2 -ioalkenyl refers to a heterocyclic group as defined above, substituted with an alkenyl group as defined above, having 2to 10 carbons, for example, 4-(N-allyl) piperazinyl, and the like. Moieties wherein the heterocyclic group is substituted on a carbon atom with an alkenyl group are also included. Either portion of the moiety is unsubstituted or substituted.
  • heterocyclyl-C2-ioalkynyl refers to a heterocyclic group as defined above, substituted with an alkynyl group as defined above, having 2 to 10 carbons, for example, 4-(N-propargyl) piperazinyl, and the like. Moieties wherein the heterocyclic group is substituted on a carbon atom with an alkenyl group are also included. Either portion of the moiety is unsubstituted or substituted.
  • oxo refers to an oxygen that is double bonded to a carbon atom.
  • an "oxo” requires a second bond from the atom to which the oxo is attached. Accordingly, it is understood that oxo cannot be substituted onto an aryl or heteroaryl ring, unless it forms part of the aromatic system as a tautomer.
  • oligomer refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
  • R * is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl
  • Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Compounds may be shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of the disclosed compounds and
  • the present invention includes all manner of rotamers and conformationally restricted states of an inhibitor of the invention.
  • R, R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" or R" and R'" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl, 4 piperazinyl, and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF ) and acyl (e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • exemplary substituents for aryl and heteroaryl groups are varied and are selected from, for example: halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR', -NR'R", -SR, -halogen, - SiR'R"R"', -OC(0)R*, -C(0)R*, -C0 2 R, -C(0)NR*R", - OC(0)NR*R", -NR"C(0)R, -NR-C(0)NR"R”*, -NR"C(0)OR*, -NR-
  • 0-2 in the context of -S(O) (0-2) - are integers of 0, 1, and 2.
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR) q -U-, wherein T and U are independently -NR- , -0-, -CRR- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR-, -O- , -NR-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR) s -X'-(C"R"') d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR-.
  • R, R, R" and R' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • treatment period as used herein is defined as the time period in which a subject is administered the daily doses of the pharmaceutical composition according to a dosing regimen.
  • rest period refers to a period of time during which a subject is not administered a pharmaceutical composition according to a dosing regimen. For example, if the pharmaceutical composition has been given on a daily basis, there would be rest period if the daily administration is discontinued, e.g., for some number of days or weeks. If a dose is administered on a different schedule a rest period would occur where that dosing is discontinued for some time. In some dosing regimens, a rest period occurs where the concentration of the pharmaceutical composition is maintained at a sub-therapeutic level. Preferably, during the rest period, the plasma concentration of the pharmaceutical
  • a combination therapy can have different dosing regimens for different compounds, e.g., one dosing regimen for a first compound and another dosing regimen for a second compound. Under such a combination therapy, a subject can undergo a rest period with respect to the first compound, at the same time undergoes a treatment period with respect to the second compound.
  • a rest period refers to a period of time during which a subject is not administered any
  • intermittent dosing regimen refers to a dosing regimen that comprises administering a pharmaceutical composition, followed by a rest period.
  • the term "durability of effect” refers to the continuation of at least one of the clinical and/or therapeutic effects of the PI3 -kinase a inhibitor and/or mTOR inhibitor after discontinuing the administration thereof. Such continuation of the clinical and therapeutic effects can last for a period of time at least as long as the administration period of the PI3- kinase a inhibitor and/or mTOR inhibitor.
  • the term “durability of effect period” refers to the period beginning immediately following the administration period. This period occurring after the administration period relates is characterized by no PI3 -kinase a inhibitor or mTOR inhibitor being administered, but where the therapeutic and clinical effects of the inhibitor administration still continue. Depending on the dosage as well as the length of the
  • the durability of effect period lasts at least as long as the administration period, but can last up to about 5 or more times the length of the administration period. In some regimens, the durability of effect period is at least 5, 10, 20, 30 days. In some regimens, the durability of effect period is at least a month, three months, six months, or a year.
  • the present invention provides methods for treating treating a disease condition associated with PI3-kinase a and/or mTOR, in particular neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease and kidney disease, which provide for durability of effect periods which are at least as long as the administration period of PI3- kinase a inhibitor or mTOR inhibitor.
  • the clinical and therapeutic effects which are extended from the administration period into the durability of effect period can include sustained tumor regression, inhibited tumor re-growth, reduction of proliferation, increased apoptosis, or downregulation of activity of a target protein, or combinations thereof.
  • An administration period refers to the period of time in which a dosing regimen (e.g., an intermittent dosing regimen) is administered to a subject.
  • the administration period can be from about 1 to about 52 weeks, or from about 4 to about 24 weeks, or from about 6 to about 12 weeks, or about 8 weeks, or about 4 weeks.
  • the administration period can include one or more treatment periods and one or more rest periods. With each administration period there is a corresponding durability of effect period which lasts at least as long as the administration period.
  • the present invention provides a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject.
  • the method typically comprises administering to a subject simultaneously or sequentially a therapeutically effective amount of a combination of a PI3 -kinase a inhibitor and an mTOR inhibitor.
  • a therapeutically effective amount of a combination of a PI3 -kinase a inhibitor and an mTOR inhibitor refers to a combination of a PI3 -kinase a inhibitor and an mTOR inhibitor, wherein the combination is sufficient to effect the intended application including but not limited to disease treatment, as defined herein.
  • a therapeutically effective amount of a PI3-kinase a inhibitor and an mTOR inhibitor in combination to effect such treatment.
  • Also contemplated in the subject methods is the use of a sub-therapeutic amount of a PI3-kinase a inhibitor and/or an mTOR inhibitor in the combination for treating an intended disease condition.
  • the present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject, comprising administering to the subject simultaneously or sequentially a
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • the PI3 -kinase a inhibitor utilized in the subject methods typically exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3- kinases (PI3-kinase) including, e.g., PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • PI3-kinase type I phosphatidylinositol-3- kinases
  • PI3-kinase a can be ascertained by an in vitro or an in vivo method. Any assay known in the art may be used, including without limitation,
  • immunoassays immunoprecipitation, fluorescence or cell-based assays.
  • fluorescence or cell-based assays In some embodiments
  • an in vitro assay is used to determine selective inhibition of PI3 -kinase a by an assay which measures the activity of the PI3Ka protein relative to the activity of another PI3- kinase such as PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • a time resolved FRET assay that indirectly measures PIP3 product formed by the activity of a PI3-K may be used to determine an IC50 value for a test compound for PI3-kinase a and/or any of the other PI3 -kinases.
  • IC50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50).
  • IC50 refers to the plasma concentration required for obtaining 50% of a maximum effect in vivo.
  • an in vitro kinase assay includes the use of labeled ATP as a phosphate donor, and following the kinase reaction the substrate peptide is captured on an appropriate filter. Unreacted labeled ATP and metabolites are resolved from the radioactive peptide substrate by various techniques, involving trichloroacetic acid precipitation and extensive washing.
  • a cell-based assay is used to ascertain selective inhibition of PI3 -kinase a.
  • an inhibitor can be shown to be selective for PI3 -kinase a if it selectively downregulates PI3 -kinase signal transduction in cells that express PI3 -kinase a, preferably in cells that exhibit abnormally high level or activity of PI3 -kinase a.
  • a variety of cells having PI3 -kinase a mutations and hence exhibiting such PI3 -kinase a abnormalities are known in the art.
  • Non-limiting examples of cell lines harboring such mutations include those that carry point mutations, deletions, substitutions, or translation of nucleic acid sequence of the PI3-kinase a gene.
  • Examples of such cell lines include but are not limited to BT20 (H1047R mutation), MCF-7 (E545K mutation), MDA-MB-361 (E545K mutation), MDA- MB-453 (H1047R mutation), T47D (H1047R mutation), Hec-IA (G1049R mutation) and HCT-116 (H1047R mutation).
  • Other cell lines having mutations in the PDKa protein may be used, such as cells harboring mutations in the p85, C2, helical or kinase domains.
  • inhibition of PI3 -kinase a activity can be determined by a reduction in signal transduction of the PI3-kinase a pathway.
  • a wide variety of readouts can be utilized to establish a reduction of the output of such signaling pathway.
  • Some non-limiting exemplary readouts include (1) a decrease in phosphorylation of Akt at residues, including but not limited to S473 and T308; (2) a decrease in activation of Akt as evidenced by a reduction of phosphorylation of Akt substrates including but not limited to Fox01/03a T24/32, GSIQa/ ⁇ S21/9, and TSC2 T1462; (3) a decrease in phosphorylation of signaling molecules downstream of PI3-kinase a, including but not limited to ribosomal S6 S240/244, 70S6K T389, and 4EBP1 T37/46; (4) inhibition of proliferation of cells including but not limited to normal or neoplastic cells, mouse embryonic fibroblasts, leukemic blast cells, cancer stem cells, and cells that mediate autoimmune reactions; (5) induction of apoptosis of cells or cell cycle arrest; (6) reduction of cell chemotaxis; and (7) an increase in binding of 4EBP1 to
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a relative to one, two or three other type I phosphatidylinositol-3 -kinases (PI3 -kinases) consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • PI3 -kinases type I phosphatidylinositol-3 -kinases
  • some of the subject inhibitors selectively inhibit PI3 -kinase a and PI3 -kinase ⁇ as compared to the rest of the type I PI3 -kinases.
  • some of the subject inhibitors selectively inhibit PI3-kinase a and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases. In still yet other embodiments, some of the subject inhibitors selectively inhibit PI3 -kinase a and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases.
  • the subject methods utilizes a PI3 -kinase a inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro kinase assay.
  • the PI3-kinase a inhibitor inhibits PI3-kinase a with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less,
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less than its IC50 value against one, two, or three other type I PD-kinase(s) selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a with an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM,
  • the PI3-kinase a inhibitor inhibits PI3-kinase a with an IC50 value of about 200 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor selectively inhibits PI3-kinase a with an IC50 value that is less than about 100 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor inhibits PI3-kinase a with an IC50 value of about 50 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a with an IC50 value that is less than about 20 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a with an IC50 value that is less than about 20 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor inhibits PI3-kinase a with an IC50 value of about 20 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 100 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3-kinase a inhibitor inhibits PI3-kinase a with an EC50 value of about 10 ⁇ or less, 5 ⁇ or less, 2.5 ⁇ or ⁇ , ⁇ or less, 500nM or less, 100 nM or less, 75 nM or less, 50 nM or less, 25 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 500 pM or less, or 100 pM or less as ascertained in an in vitro kinase assay.
  • the PI3 -kinase a inhibitor selectively inhibits PI3 -kinase a with an EC50 value that is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its EC50 value against one, two or three other type I PI3 -kinases selected from the group consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the PI3 -kinase a inhibitor inhibits PI3 -kinase a with an EC50 value of about 10 ⁇ or less, 5 ⁇ or less, 2.5 ⁇ or ⁇ , ⁇ or less, 500nM or less, 100 nM or less, 75 nM or less, 50 nM or less, 25 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 500 pM or less, or 100 pM or less as ascertained in an in vitro kinase assay, and such EC50 value is at least 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its EC50 value against one, two or three other type I PI3 -kinases selected from the group consisting of PI3- kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the mTOR inhibitor utilized in the subject methods is typically highly selective for the target molecule.
  • the mTOR inhibitor binds to and directly inhibits both mTORCl and mTORC2.
  • Such ability can be ascertained using any method known in the art or described herein.
  • inhibition of mTorCl and/or mTorC2 activity can be determined by a reduction in signal transduction of the PI3K/Akt/mTor pathway.
  • a wide variety of readouts can be utilized to establish a reduction of the output of such signaling pathway.
  • Some non-limiting exemplary readouts include (1) a decrease in phosphorylation of Akt at residues, including but not limited to S473 and T308; (2) a decrease in activation of Akt as evidenced by a reduction of phosphorylation of Akt substrates including but not limited to Fox01/03a T24/32, GSIQa/ ⁇ S21/9, and TSC2 T1462; (3) a decrease in phosphorylation of signaling molecules downstream of mTor, including but not limited to ribosomal S6 S240/244, 70S6K T389, and 4EBP1 T37/46; (4) inhibition of proliferation of cells including but not limited to normal or neoplastic cells, mouse embryonic fibroblasts, leukemic blast cells, cancer stem cells, and cells that mediate autoimmune reactions; (5) induction of apoptosis of cells or cell cycle arrest; (6) reduction of cell chemotaxis; and (7) an increase in binding of 4EBP1 to eIF4E.
  • mTor exists in two types of complexes, mTorCl containing the raptor subunit and mTorC2 containing rictor.
  • rictor refers to a cell growth regulatory protein having human gene locus 5pl3.1. These complexes are regulated differently and have a different spectrum of substrates. For instance, mTorCl phosphorylates S6 kinase (S6K) and 4EBP1, promoting increased translation and ribosome biogenesis to facilitate cell growth and cell cycle progression. S6K also acts in a feedback pathway to attenuate
  • PI3K/Akt activation results in inhibition of mTorCl (e.g. by a biologically active agent as discussed herein) results in activation of 4EBP1, resulting in inhibition of (e.g. a decrease in) RNA translation.
  • mTorC2 is generally insensitive to rapamycin and selective inhibitors and is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt.
  • Akt AGC kinases
  • mTorC2 is required for phosphorylation of the S473 site of Akt.
  • mTorCl activity is partly controlled by Akt whereas Akt itself is partly controlled by mTorC2.
  • Akt Growth factor stimulation of PI3K causes activation of Akt by phosphorylation at the two key sites, S473 and T308. It has been reported that full activation of Akt requires phosphorylation of both S473 and T308Active. Akt promotes cell survival and proliferation in many ways including suppressing apoptosis, promoting glucose uptake, and modifying cellular metabolism. Of the two phosphorylation sites on Akt, activation loop
  • phosphorylation at T308, mediated by PDK1 is believed to be indispensable for kinase activity, while hydrophobic motif phosphorylation at S473 enhances Akt kinase activity.
  • Selective mTor inhibition may also be determined by expression levels of the mTor genes, its downstream signaling genes (for example by RT-PCR), or expression levels of the proteins (for example by immunocytochemistry, immunohistochemistry, Western blots) as compared to other PI3-kinases or protein kinases.
  • Cell-based assays for establishing selective inhibition of mTorCl and/or mTorC2 can take a variety of formats. This generally will depend on the biological activity and/or the signal transduction readout that is under investigation. For example, the ability of the agent to inhibit mTorCl and/or mTorC2 to phosphorylate the downstream substrate(s) can be determined by various types of kinase assays known in the art. Representative assays include but are not limited to immunoblotting and immunoprecipitation with antibodies such as anti- phosphotyrosine, anti-phosphoserine or anti-phosphothreonine antibodies that recognize phosphorylated proteins.
  • kinase activity can be detected by high throughput chemiluminescent assays such as AlphaScreenTM (available from Perkin Elmer) and eTagTM assay (Chan-Hui, et al. (2003) Clinical Immunology 111 : 162-174).
  • single cell assays such as flow cytometry as described in the Phosflow experiment can be used to measure phosphorylation of multiple downstream mTOR substrates in mixed cell
  • phosphorylation of multiple kinase substrates can be measured simultaneously. This provides the advantage that efficacy and selectivity can be measured at the same time.
  • cells may be contacted with an mTOR inhibitor at various concentrations and the
  • phosphorylation levels of substrates of both mTOR and other kinases can be measured.
  • a large number of kinase substrates are assayed in what is termed a
  • Selective mTOR inhibitors are expected to inhibit phosphorylation of mTOR substrates without inhibiting phosphorylation of the substrates of other kinases.
  • selective mTOR inhibitors may inhibit phosphorylation of substrates of other kinases through anticipated or unanticipated mechanisms such as feedback loops or redundancy.
  • Non- limiting examples of cell proliferation assays include testing for tritiated thymidine uptake assays, BrdU (5'-bromo-2'-deoxyuridine) uptake (kit marketed by Calbiochem), MTS uptake (kit marketed by Promega), MTT uptake (kit marketed by Cayman Chemical), CyQUANT® dye uptake (marketed by Invitrogen).
  • Apoptosis and cell cycle arrest analysis can be performed with any methods exemplified herein as well other methods known in the art. Many different methods have been devised to detect apoptosis. Exemplary assays include but are not limited to the
  • TUNEL TdT -mediated dUTP Nick-End Labeling
  • ISEL in situ end labeling
  • DNA laddering analysis for the detection of fragmentation of DNA in populations of cells or in individual cells
  • Annexin-V analysis that measures alterations in plasma membranes, detection of apoptosis related proteins such p53 and Fas.
  • a cell-based assay typically proceeds with exposing the target cells (e.g., in a culture medium) to a test compound which is a potential mTorCl and/or mTorC2 selective inhibitor, or a PI3 -kinase a inhibitor and then assaying for readout under investigation.
  • a test compound which is a potential mTorCl and/or mTorC2 selective inhibitor, or a PI3 -kinase a inhibitor
  • the candidate mTor inhibitors or PI3-kinase a inhibitors can directly be added to the cells or in conjunction with carriers.
  • the agent when it is nucleic acid, it can be added to the cell culture by methods well known in the art, which include without limitation calcium phosphate precipitation, microinjection or electroporation.
  • the nucleic acid can be incorporated into an expression or insertion vector for incorporation into the cells.
  • Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operatively linked are well known in the art.
  • Such vectors are capable of transcribing RNA in vitro or in vitro, and are commercially available from sources such as Stratagene (La Jolla, CA) and Promega Biotech (Madison, WI).
  • Stratagene La Jolla, CA
  • Promega Biotech Promega Biotech
  • consensus ribosome binding sites can be inserted immediately 5' of the start codon to enhance expression.
  • vectors are viruses, such as baculovirus and retrovirus, bacteriophage, adenovirus, adeno- associated virus, cosmid, plasmid, fungal vectors and other recombination vehicles typically used in the art which have been described for expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple protein expression.
  • viruses such as baculovirus and retrovirus, bacteriophage, adenovirus, adeno- associated virus, cosmid, plasmid, fungal vectors and other recombination vehicles typically used in the art which have been described for expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple protein expression.
  • non-viral vectors including DNA/liposome complexes, and targeted viral protein DNA complexes.
  • the nucleic acid or proteins of this invention can be conjugated to antibodies or binding fragments thereof which bind cell surface anti
  • Liposomes that also comprise a targeting antibody or fragment thereof can be used in the methods of this invention.
  • Other biologically acceptable carriers can be utilized, including those described in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 19th Ed. (2000), in conjunction with the subject compounds.
  • the subject agents can also be utilized to inhibit phosphorylation of both Akt (S473) and Akt (T308) in a cell.
  • the present invention provides a method comprises the step of contacting a cell with an effective amount of such biologically active agent such that Akt phosphorylation at residues S473 and T308 is simultaneously inhibited.
  • the biologically active agent inhibits phosphorylation of S473 of Akt more effectively than phosphorylation of T308 of Akt when tested at a comparable molar concentration, preferably at an identical molar concentration.
  • Inhibition of Akt phosphorylation can be determined using any methods known in the art or described herein. Representative assays include but are not limited to
  • any cells that express PI3-kinase a, mTorC 1 , mTorC2 and/or Akt can be utilized.
  • specific cell types whose proliferation can be inhibited include fibroblast, cells of skeletal tissue (bone and cartilage), cells of epithelial tissues (e.g. liver, lung, breast, skin, bladder and kidney), cardiac and smooth muscle cells, neural cells (glia and neurones), endocrine cells (adrenal, pituitary, pancreatic islet cells), melanocytes, and many different types of haemopoietic cells (e.g., cells of B-cell or T-cell lineage, and their corresponding stem cells, lymphoblasts).
  • haemopoietic cells e.g., cells of B-cell or T-cell lineage, and their corresponding stem cells, lymphoblasts.
  • cells exhibiting a neoplastic propensity or phenotype are also of interest.
  • diseases involving abnormal functioning of genes include but are not limited to autoimmune diseases, cancer, obesity, hypertension, diabetes, neuronal and/or muscular degenerative diseases, cardiac diseases, endocrine disorders, and any combinations thereof.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 200, 100, 75, 50, 25, 10, 5, 1 or 0.5 nM or less as ascertained in an in vitro kinase assay. In one instance, the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about ⁇ or less as ascertained in an in vitro kinase assay.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay.
  • the present invention provides the use of an mTOR inhibitor, wherein the mTOR inhibitor directly binds to and inhibits both mTORC 1 and mTORC2 with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro kinase assay.
  • the mTOR inhibitor inhibits both mTORC 1 and mTORC2 with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 425
  • the mTOR inhibitor inhibits both mTORC 1 and mTORC2 with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425
  • the mTOR inhibitor inhibits both mTORC 1 and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTOR inhibitor is substantially inactive against one or more types I PI3 -kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • substantially inactive refers to an inhibitor that inhibits the activity of its target by less than approximately 1%, 5%, 10%, 15% or 20% of its maximal activity in the absence of the inhibitor, as determined by an in vitro enzymatic assay (e.g. in vitro kinase assay).
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 2, 5, 10, 15, 20, 50, 100 or 100 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 5 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 5 times less than its IC50 value against all other type I PI3 -kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3- kinase ⁇ .
  • the mTOR inhibitor utilized in the subject methods inhibits one of mTORCl and mTORC2 selectively with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase.
  • the mTOR inhibitor utilized in the subject methods inhibits mTORCl selectively with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase.
  • rapamycin and rapamycin derivatives or analogues have been shown to primarily inhibit mTORCl and not mTORC2.
  • Suitable mTORCl inhibitors compounds include, for example, sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), zotarolimus (ABT-578), and biolimus A9 (umirolimus).
  • PI3 -kinase a inhibitors or mTOR inhibitors suitable for use in the subject methods can be selected from a variety types of molecules.
  • an inhibitor can be biological or chemical compound such as a simple or complex organic or inorganic molecule, peptide, peptide mimetic, protein (e.g. antibody), liposome, or a polynucleotide (e.g. small interfering RNA, microRNA, anti-sense, aptamer, ribozyme, or triple helix).
  • a polynucleotide e.g. small interfering RNA, microRNA, anti-sense, aptamer, ribozyme, or triple helix.
  • cancer cells may depend on overactive signaling for their survival (known as the oncogene addiction hypothesis). In this way, cancer cells are frequently observed to adapt to drug inhibition of an aberrant signaling component by selecting for mutations in the same pathway that overcome the effect of the drug. Therefore, cancer therapies may be more successful in overcoming the problem of drug resistance if they target a signaling pathway as a whole, or target more than one component within a signaling pathway.
  • selective inhibition of PI3-kinase a provides a more targeted treatment to a disease condition mediated by PI3 -kinase without disrupting one or more pathways that are implicated by one or more other type I phosphatidylinositol-3- kinases, namely PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
  • Akt serine/threonine kinase Akt serine/threonine kinase Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, which binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either PIP3 (phosphatidylinositol (3,4,5)-trisphosphate, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate, PtdIns(3,4)P2).
  • PIP3 phosphatidylinositol (3,4,5)-trisphosphate
  • PtdIns(3,4,5)P3 PtdIns(3,4,5)P3
  • PIP2 phosphatidylinositol (3,4)-bisphosphate
  • PI3K phosphorylates PIP2 in response to signals from chemical messengers, such as ligand binding to G protein-coupled receptors or receptor tyrosine kinases. Phosphorylation by PI3K converts PIP2 to PIP3, recruiting Akt to the cell membrane where it is phosphorylated at serine 473 (S473) by mTORC2. Phosphorylation of Akt at another site, threonine 308 (T308), is not directly dependent on mTORC2, but requires PI3K activity. Therefore, PI3K activity towards Akt can be isolated from mTOR activity by examining Akt threonine 308 phosphorylation status in cells lacking mTORC2 activity.
  • the subject methods are useful for treating a disease condition associated with PI3- kinase a and/or mTOR.
  • Any disease condition that results directly or indirectly from an abnormal activity or expression level of PI3-kinase a and/or mTOR can be an intended disease condition.
  • PI3-kinase a has been implicated, for example, in a variety of human cancers.
  • Angiogenesis has been shown to selectively require the a isoform of PI3K in the control of endothelial cell migration. (Graupera et al, Nature 2008;453;662-6). Mutations in the gene coding for PI3K a or mutations which lead to upregulation of PI3K a are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain and skin cancers.
  • mutations in the gene coding for PI3K a are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of- function mutations. Because of the high rate of PI3K a mutations, targeting of this pathway provides valuable therapeutic opportunities. While other PI3K isoforms such as PI3K ⁇ or PI3K ⁇ are expressed primarily in hematopoietic cells, PI3K a, along with PI3K ⁇ , is expressed constitutively.
  • Disease conditions associated with PI3-kinase a and/or mTOR can also be characterized by abnormally high level of activity and/or expression of downstream messengers of PI3 -kinase a.
  • proteins or messengers such as PIP2, PIP3, PDK, Akt, PTEN, PRAS40, GSK-3P, p21, p27 may be present in abnormal amounts which can be identified by any assays known in the art.
  • Deregulation of the mTOR pathway is emerging as a common theme in diverse human diseases and as a consequence drugs that target mTOR have therapeutic value.
  • the diseases associated with deregulation of mTORCl include, but are not limited to, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), both of which are caused by mutations in TSC1 or TSC2 tumor suppressors.
  • TSC tuberous sclerosis complex
  • LAM lymphangioleiomyomatosis
  • Patients with TSC develop benign tumors that when present in brain, however, can cause seizures, mental retardation and death.
  • LAM is a serious lung disease.
  • Inhibition of mTORCl may help patients with Peutz-Jeghers cancer-prone syndrome caused by the LKB 1 mutation.
  • mTORC 1 may also have role in the genesis of sporadic cancers.
  • Akt PI3K/Akt pathway is activated in many cancers. Activated Akt regulates cell survival, cell proliferation and metabolism by phosphorylating proteins such as BAD, FOXO, NF- KB, p21Cipl, p27Kipl, GSK3P and others. Akt might also promote cell growth by phosphorylating proteins such as BAD, FOXO, NF- KB, p21Cipl, p27Kipl, GSK3P and others. Akt might also promote cell growth by
  • Akt activation probably promotes cellular transformation and resistance to apoptosis by collectively promoting growth, proliferation and survival, while inhibiting apoptotic pathways.
  • the combination of an inhibitor of mTORCl and mTORC2 and a PI3 -kinase a inhibitor is beneficial for treatment of tumors with elevated Akt phosphorylation, and should down-regulate cell growth, cell survival and cell proliferation.
  • the subject to be treated is tested prior to treatment using a diagnostic assay to determine the sensitivity of tumor cells to a PI3Ka kinase inhibitor.
  • a diagnostic assay to determine the sensitivity of tumor cells to a PI3Ka kinase inhibitor. Any method known in the art that can determine the sensitivity of the tumor cells of a subject to a PI3Ka kinase inhibitor can be employed.
  • the subject is tested prior to treatment using a diagnostic assay to determine the sensitivity of tumor cells to an PI3Ka kinase inhibitor
  • a diagnostic assay to determine the sensitivity of tumor cells to an PI3Ka kinase inhibitor when the subject is identified as one whose tumor cells are predicted to have low sensitivity to an PI3Ka kinase inhibitor as a single agent, are likely to display enhanced sensitivity in the presence of an mTOR inhibitor, or vice versa, when the subject is administered, simultaneously or sequentially, a therapeutically effective amount of a combination of an PI3Ka kinase inhibitor and an mTOR inhibitor.
  • the subject when the subject is identified as one whose tumor cells are predicted to have high sensitivity to an PI3Ka kinase inhibitor as a single agent, but may also display enhanced sensitivity in the presence of an mTOR inhibitor based on the results described herein, the subject is administered, simultaneously or sequentially, a therapeutically effective amount of a combination of an PI3Ka kinase inhibitor and an mTOR inhibitor.
  • one or more additional anti-cancer agents or treatments can be co-administered simultaneously or sequentially with the PI3Ka kinase inhibitor and mTOR inhibitor, as judged to be appropriate by the administering physician given the prediction of the likely responsiveness of the subject to the combination of PI3Ka kinase inhibitor and mTOR inhibitor, in combination with any additional circumstances pertaining to the individual subject.
  • the present invention provides for a method comprising: (a) determining the presence in a subject of a mutation in PI3 -kinase a that is associated with a disease condition mediated by PI3 -kinase a; and (b) administering to said subject a pharmaceutical composition of the invention.
  • the present invention provides for a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell, comprising contacting a cell with an effective amount of a PI3 -kinase a inhibitor and an mTOR inhibitor, biologically active agent that selectively inhibits both mTORC 1 and mTORC2 activity relative to one or more type I phosphatidylinositol-3 -kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the PI3 -kinase a inhibitor exhibits selective inhibition of PI3 -kinase a relative to one or more type I phosphatidylinositol-3 -kinases (PI3 -kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase
  • megakaryoblastic leukemia Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma,
  • Angiomyolipoma, Angiosarcoma, Appendix cancer Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcom
  • Desmoplastic small round cell tumor Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,
  • Gallbladder cancer Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymp
  • Lymphangiosarcoma Lymphoepithelioma
  • Lymphoid leukemia Lymphoma
  • Macro globulinemia Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple myeloma, Mycosis Fungoides
  • Polyembryoma Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma,
  • the methods of using a PBKa inhibitor and an mTOR inhibitor described herein are applied to the treatment of heart conditions including atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstriction.
  • the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a PBKa inhibitor and an mTOR inhibitor of the present invention, or any pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity
  • age-related macular degeneration hemangio
  • the invention provides for the use of a PBKa inhibitor and an mTOR inhibitor for treating a disease condition associated with PB-kinase a and/or mTOR, including, but not limited to, conditions related to an undesirable, over-active, harmful or deleterious immune response in a mammal, collectively termed "autoimmune disease.”
  • Autoimmune disorders include, but are not limited to, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, juvenile arthritis and ankylosing spondilitis.
  • Other non- limiting examples of autoimmune disorders include autoimmune diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), rheumatoid spondylitis, gouty arthritis, allergy, autoimmune uveitis, nephrotic syndrome, multisystem autoimmune diseases, autoimmune hearing loss, adult respiratory distress syndrome, shock lung, chronic pulmonary disease.
  • inflammatory disease pulmonary sarcoidosis, pulmonary fibrosis, silicosis, idiopathic interstitial lung disease, chronic obstructive pulmonary disease, asthma, restenosis, spondyloarthropathies, Reiter's syndrome, autoimmune hepatitis, inflammatory skin disorders, vasculitis oflarge vessels, medium vessels or small vessels, endometriosis, prostatitis and Sjogren's syndrome.
  • Undesirable immune response can also be associated with or result in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis, autoimmune diseases, rheumatoid arthritis, graft versus host disease, transplantation rejection, lung injuries, and lupus erythematosus.
  • the pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.
  • the compositions of the invention can be further used to treat multiorgan failure.
  • the invention also provides methods of using a PBKa inhibitor and an mTOR inhibitor for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or pain in a mammal.
  • liver diseases including diabetes
  • pancreatitis or kidney disease including proliferative glomerulonephritis and diabetes- induced renal disease
  • pain in a mammal.
  • the invention also provides a method of using a PBKa inhibitor and an mTOR inhibitor for the treatment of sperm motility.
  • the invention further provides a method of using a PBKa inhibitor and an mTOR inhibitor for the treatment of neurological or neurodegenerative diseases including, but not limited to, Alzheimer's disease, Huntington's disease, CNS trauma, and stroke.
  • the invention further provides a method of using a PBKa inhibitor and an mTOR inhibitor for the prevention of blastocyte implantation in a mammal.
  • the invention also relates to a method of using a PBKa inhibitor and an mTOR inhibitor for treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age- related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, reti
  • the invention further provides a method of using a PBKa inhibitor and an mTOR inhibitor for the treatment of disorders involving platelet aggregation or platelet adhesion, including but not limited to Bernard-Soulier syndrome, Glanzmann's thrombasthenia, Scott's syndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, and Gray platelet syndrome.
  • methods of using a PBKa inhibitor and an mTOR inhibitor are provided for treating a disease which is skeletal muscle atrophy, skeletal muscle hypertrophy, leukocyte recruitment in cancer tissue, invasion metastasis, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, glomerulo sclerosis, glomerulo, nephritis, or progressive renal fibrosis.
  • Certain embodiments contemplate a human subject such as a subject that has been diagnosed as having or being at risk for developing or acquiring a disease condition associated with PI3-kinase a and/or mTOR.
  • a non-human subject for example a non-human primate such as a macaque, chimpanzee, gorilla, vervet, orangutan, baboon or other non-human primate, including such non-human subjects that can be known to the art as preclinical models, including preclinical models for inflammatory disorders.
  • a non-human subject that is a mammal, for example, a mouse, rat, rabbit, pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or other mammal.
  • the subject or biological source can be a non-mammalian vertebrate, for example, another higher vertebrate, or an avian, amphibian or reptilian species, or another subject or biological source.
  • a transgenic animal is utilized.
  • a transgenic animal is a non-human animal in which one or more of the cells of the animal includes a nucleic acid that is non-endogenous (i.e., heterologous) and is present as an
  • extrachromosomal element in a portion of its cell or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells).
  • the invention provides a compound which is an inhibitor of mTor of the Formula I:
  • Xi is N or C-E 1
  • X 2 is N or C
  • X 3 is N or C
  • X 4 is C-R 9 or N
  • X 5 is N or C-E 1
  • X 6 is C or N
  • X 7 is C or N; and wherein no more than two nitrogen ring atoms are adjacent;
  • Ri is H, -L-Ci_ioalkyl, -L-C 3 _scycloalkyl, -L-Ci_ioalkyl -C 3 _scycloalkyl, -L- aryl, -L- heteroaryl, -L-Ci_ioalkylaryl, -L- Ci_ioalkylhetaryl, -L- Ci_ioalkylheterocylyl, -L-C 2 _ioalkenyl, -L-C 2 _ioalkynyl, -L-C 2 _ioalkenyl-C 3 _ 8 cycloalkyl, -L-C 2 _ioalkynyl-C 3 _ 8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalky
  • E 1 and E 2 are independently -(W 1 ) ] -R 4 ;
  • Mi is a 5, 6, 7, 8, 9, or-10 membered ring system, wherein the ring system is monocyclic or bicyclic, substituted with R 5 and additionally optionally substituted with one or more -(W ) k
  • each k is 0 or 1 ;
  • j in E 1 or j in E 2 is independently 0 or 1;
  • W 1 is -0-, -NR 7 -, -S(0)o_ 2 -,-C(0)-,-C(0)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )S(0)-,- N(R 7 )S(0) 2 - -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or - CH(R 7 )N(R 8 )S(0) 2 -;
  • W 2 is -0-, -NR 7 -, -S(0)o_ 2 -,-C(0)-,-C(0)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )C(0)N(R 8 )-,- N(R 7 )S(0)-, -N(R 7 )S(0) 2 -,-C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, - CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, - CH(R 7 )N(R 8 )S(0)-, or -CH(R 7 )N(R 8 )S(0) 2 -;
  • Ci_ioalkyl C 3 _scycloalkyl, Ci_ioalkyl-C 3 _ 8 cycloalkyl, C 3 _scycloalkyl -Ci_ioalkyl, C 3 _scycloalkyl -C 2 _ioalkenyl, C 3 _scycloalkyl- C 2 _ioalkynyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkynyl, Ci_ioalkylaryl (e.g.
  • each of R , R , and R is independently H or Ci_ioalkyl , wherein the Ci_ioalkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more halo, -OH, - Ci_ioalkyl, -CF 3 , -O-aryl, -OCF 3 , -OCi_ l oalkyl, -NH 2 , - N(Ci_i 0 alkyl)(Ci_i 0 alkyl), - NH(Ci_i 0 alkyl), - NH( aryl), -NR 34 R 35 , - C(O)(Ci_i 0 alkyl), -C(O)(Ci_i
  • NR 31 R 32 hydroxyl, halogen, oxo, aryl, hetaryl, Ci_ 6 alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;
  • each of R 7 and R 8 is independently hydrogen, Ci_ioalkyl, C 2 _ioalkenyl, aryl, heteroaryl, heterocyclyl or C 3 _iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R 6 ;
  • Mi is a 5, 6, 7, 8, 9, or-10 membered ring system, wherein the ring system is monocyclic or bicyclic.
  • the monocyclic Mi ring is unsubstituted or substituted with one or more R 5 substituents (including 0, 1, 2, 3, 4, or 5 R 5 substituents).
  • the monocyclic Mi ring is aromatic (including phenyl) or heteroaromatic (including but not limited to pyridinyl, pyrrolyl, imidazolyl, thiazolyl, or pyrimidinyl) .
  • the monocyclic Mi ring may be a 5 or 6 membered ring (including but not limited to pyridinyl, pyrrolyl, imidazolyl, thiazolyl, or pyrimidinyl).
  • M 2 is a five membered heteroaromatic group with one heteroatom, wherein the heteroatom is N, S, or O.
  • M 2 is a five membered heteroaromatic group with two heteroatoms, wherein the heteroatoms are nitrogen and oxygen or nitrogen and sulfur.
  • the bicyclic Mi ring is unsubstituted or substituted with one or more R 5 substituents (including 0, 1, 2, 3, 4, 5, 6 or 7 R 5 substituents).
  • Bicyclic Mi ring is a 7, 8, 9, or 10 membered aromatic or heteroaromatic. Examples of an aromatic bicyclic Mi ring include naphthyl.
  • the bicyclic Mi ring is heteroaromatic and includes but is not limited to benzothiazolyl, quinolinyl, quinazolinyl, benzoxazolyl, and benzimidazolyl.
  • the invention also provides compounds wherein Mi is a moiety having a structure of Formula Ml -A or Formula Ml-B:
  • W 6 and Ws are independently N or C-R ;
  • W 5 and Wg are independently N or C-R ;
  • W 3 is C or N, provided no more than two N and/or N-R 5 are adjacent and no two O or S are adjacent.
  • the Mi moiety of Formula Ml -A is a moiety of Formula Ml-Al , Formula M1-A2, Formula M1-A3, or Formula M1-A4:
  • R 5 is -(W 1 ⁇ -R 53 or R 55 ; each k is independently 0 or 1 , n is 0, 1 , 2, or 3, and - (W l ) k -R 53 and R 55 are as defined above.
  • the Mi moiety of Formula Ml-B is a moiety of Formula Ml-Bl , Formula M1-B2, Formula M1-B3, or Formula M1-B4:
  • Formula Ml-Bl Formula M 1 -B2 Formula M1-B3 Formula Ml -B4 wherein W i0 is N-R 5 , O, or S, W 8 is N or C-R 5 , and W 5 is N or C-R 2 .
  • Some nonlimiting examples of the Mi moiety of Formula Ml-B include:
  • R 55 are as defined above.
  • the invention also provides compounds wherein Mi is a moiety having a structure of Formula Ml-C or Formula Ml-D:
  • W 12 , W 13 , W 14 , and W 15 are independently N or C-R 5 ; Wn and Wis are
  • N-R 5 independently N-R 5 , O, or S; W 16 and Wn are independently N or C-R 5 ; provided no more than two N are adjacent.
  • the Mi moiety of Formula Ml-C or Formula Ml-D is a moiety of Formula Ml -CI or Formula Ml-Dl :
  • Formula Ml-Dl Formula M 1 -C 1 wherein Wn and Wis are N-R 5 , O, or S; and W 16 and Wn are N or C-R 5 .
  • Mi moiety of Formula Ml-C and Formula Ml-D include:
  • R' 5 is -(W l ) -R 53 or R 55 ; k is 0 or 1 , and -(W l ) -R 53 and R 55 are as defined above .
  • the invention also provides compounds wherein Mi is a moiety having a structure of Formula Ml-E:
  • Xn, Xi 2 , X13, X14 , X15, Xi6, and X 17 are independently N, or C-R 5 ; provided that no more than two N are adjacent.
  • the Mi moiety having a structure of Formula Ml-E is a moiety having a structure of Formula Ml -El , M1-E2, M1-E3, M1-E4, M1-E5, M1-E6, M1-E7, or Ml-E8:
  • the Mi moiety having a structure of Formula Ml-E is a moiety having a gagture:
  • Mi moiety of Formula Ml-E include :
  • R' 5 is - W l ⁇ -R 53 or R 55 ; k is 0 or 1, n i sO, 1, 2, or 3, and -(W l ) k -R 53 or R 55 are as
  • k is 0, and R is R .
  • R is hydrogen, unsubstituted or substituted Ci-Cioalkyl (which includes but is not limited to -CH 3 , -CH 2 CH , n-propyl, isopropyl, n- butyl, tert- butyl, sec -butyl, pentyl, hexyl, and heptyl),or unsubstituted or substituted C 3 -Cscycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).
  • Ci-Cioalkyl which includes but is not limited to -CH 3 , -CH 2 CH , n-propyl, isopropyl, n- butyl, tert- butyl, sec -butyl, pentyl, hexyl, and heptyl
  • C 3 -Cscycloalkyl which includes but is not
  • R is monocyclic or bicyclic aryl, wherein the R aryl is unsubstituted or substituted.
  • aryl include but are not limited to phenyl, naphthyl or
  • R is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl.
  • Monocyclic heteroaryl
  • R includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, imidazolyl,
  • Bicyclic heteroaryl R includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
  • benzoxazolyl benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, and purinyl.
  • R 53 may be alkylcycloalkyl (including but not limited to cyclopropylethyl, cyclopentylethyl, and cyclobutylpropyl), -alkylaryl (including but not limited to benzyl, phenylethyl, and phenylnaphthyl), - alkylhetaryl (including but not limited to
  • alkylcycloalkyl pyridinylmethyl, pyrrolylethyl, and imidazolylpropyl
  • -alkylheterocyclyl non-limiting examples are morpholinylmethyl, 1-piperazinylmethyl, and azetidinylpropyl.
  • alkylcycloalkyl, alkylaryl , alkylhetaryl, or -alkylheterocyclyl the moiety is connected to Mi
  • R is unsubstituted or substituted C 2 -Cioalkenyl (including but not limited to alkenyl such as, for example, vinyl, allyl, 1 -methyl propen-l-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-Cioalkynyl such as acetylenyl, propargyl, butynyl, or pentynyl).
  • C 2 -Cioalkenyl including but not limited to alkenyl such as, for example, vinyl, allyl, 1 -methyl propen-l-yl, butenyl, or pentenyl
  • alkynyl including but not limited to unsubstituted or substituted C2-Cioalkynyl such as acetylenyl, propargyl, butynyl, or pentynyl
  • R is alkenylaryl, alkenylheteroaryl, alkenylheteroalkyl, or alkenylheterocyclyl, wherein each of alkenyl, aryl, heteroaryl, heteroalkyl, and heterocyclyl is as described herein and wherein the alkenylaryl,
  • alkenylhetaryl, alkenylheteroalkyl, or alkenylheterocyclcyl moiety is attached to Mi through the alkenyl.
  • Some nonlimiting examples in include styryl, 3-pyridinylallyl, 2-
  • R is -alkynylaryl, - alkynylhetaryl, -alkynylheteroalkyl, -alkynylheterocylyl, -alkynylcycloalkyl, or -alkynylC 3 _ 8 cycloalkenyl, wherein each of alkynyl, aryl, heteroaryl, heteroalkyl, and heterocyclyl is as described herein and wherein the alkynylaryl, alkynylhetaryl, alkynylheteroalkyl, or
  • R is - alkoxyalkyl, -alkoxyalkenyl, or -alkoxyalkynyl, wherein each of alkoxy, alkyl, alkenyl, and alkynyl is as described herein and wherein the -alkoxyalkyl, -alkoxyalkenyl, or -
  • R is -heterocyclylalkyl, -heterocyclylalkenyl, or -heterocyclylalkynyl, wherein the heterocyclyl, alkyl, alkenyl, or alkynyl is as described herein and wherein the -heterocyclylalkyl,- heterocyclyl alkenyl, or -heterocyclylalkynyl is attached to Mi through the heterocyclyl
  • R may be aryl-alkenyl, aryl-alkynyl, or aryl-heterocyclyl, wherein the aryl, alkenyl, alkynyl, or heterocyclyl is as described herein and wherein the aryl-alkenyl, aryl-alkynyl, or aryl-heterocyclyl moiety is attached to Mi through the aryl
  • R is heteroaryl - alkyl, heteroaryl - alkenyl, heteroaryl -alkynyl, heteroaryl -cycloalkyl, heteroaryl -heteroalkyl, or heteroaryl - heterocyclyl, wherein each of heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, and heterocyclyl is as described herein and wherein the heteroaryl - alkyl, heteroaryl -alkenyl, heteroaryl -alkynyl, heteroaryl -cycloalkyl, heteroaryl -heteroalkyl, or heteroaryl - heterocyclyl moiety is attached to Mi through the heteroaryl portion of the moiety.
  • R 5 is -W 1 -R 53 .
  • R 5 is -OR 53 , including but not limited to -O-alkyl (including but not limited to methoxy or ethoxy), -O- aryl (including but not limited to phenoxy), -O-heteroaryl (including but not limited to pyridinoxy) and -0-heterocycloxy( including but not limited to 4-N-piperidinoxy).
  • R 5 is -NR 6 R 53 including but not limited to anilinyl, diethylamino, and 4-N-
  • R is -S(0)o_ 2 R , including but not limited to phenylsulfonyl and pyridinylsulfonyl.
  • the invention also provides compounds wherein R 5
  • R 53 is-C(O) (including but not limited to acetyl, benzoyl, and pyridinoyl) or -C(0)0 R (including but not limited to carboxyethyl, and carboxybenzyl).
  • R 5 is - C(0)N(R 6 )R 53 (including but not limited to C(0)NH(cyclopropyl) and C(0)N(Me)(phenyl)) or -CH(R 6 )N(R 7 )R 53 (including but not limited to -CH 2 -NH-pyrrolidinyl, CH 2 - NHcyclopropyl, and CH 2 -anilinyl).
  • R 5 is -N(R 6 )C(0)R 53 (including but not limited to -NHC(0)phenyl, -NHC(0)cyclopentyl, and to -NHC(O)piperidinyl) or - N(R 6 )S(0) 2 R 53 (including but not limited to -NHS(0) 2 phenyl, -NHS(0) 2 piperazinyl, and - NHS(0) 2 methyl.
  • R 5 is-N(R 6 )S(0) R 53 , -CH(R 6 )N(C(0)OR 7 ) R 53 , - CH(R 7 )N(C(0)R 7 ) R 53 ,-CH(R 6 )N(S0 2 R 7 ) R 53 , -CH(R 6 )N(R 7 ) R 53 , -CH(R 6 )C(0)N(R 7 ) R 53 , - CH(R 6 )N(R 7 )C(0) R 53 , -CH(R 6 )N(R 7 )S(0) R 53 , or -CH(R 6 )N(R 7 )S(0) 2 R 53 .
  • R 5 is R 55 .
  • R 55 is halo, -OH, -N0 2 , -CF 3 , -OCF 3 , or -CN.
  • R is -R , -OR (including but not limited to methoxy, ethoxy, and
  • R 55 is-NR 34 R 35 or -S0 2 NR 34 R 35 , wherein R 34 R 35 are taken together with the nitrogen to which R 34 R 35 are attached to form a cyclic moiety.
  • the cyclic moiety so formed may be unsubstituted or substituted, wherein the substituents are selected from the group consisting of alkyl, -C(0)alkyl, -S(0) 2 alkyl, and -S(0) 2 aryl .
  • substituents include but are not limited to morpholinyl, piperazinyl, or -S0 2 -(4-N-methyl-piperazin-l-yl.
  • R 55 is -O- aryl, including but not limited to phenoxy, and naphthyloxy.
  • the invention further provides a compound which is an mTor inhibitor, wherein the compound has the Formula I- A:
  • Xi is N or C-E 1 , X 2 is N, X 3 is C, and X 4 is C-R 9 or N; or Xi is N or C-E 1 , X 2 is C, X 3 is N, and X 4 is C-R 9 or N;
  • Ri is -H, -L-Ci_ioalkyl, -L-C 3 _scycloalkyl, -L-Ci_ioalkyl -C 3 _scycloalkyl, -L- aryl, - L-heteroaryl, -L-Ci_ioalkylaryl, -L- Ci_ioalkylheteroaryl, -L- Ci_ioalkylheterocyclyl, -L-C 2 _ l oalkenyl, -L-C 2 _ioalkynyl, -L-C 2 _ioalkenyl-C 3 _ 8 cycloalkyl, -L-C 2 _ioalkynyl-C 3 _ 8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl
  • Mi is a moiety having the structure of Formula M 1 -F 1 or M 1 -F2 :
  • k is O or l
  • E 1 and E 2 are independently -(W ⁇ j -R 4 ; [00281] j, in each instance (i.e., in E 1 or j in E 2 ), is independently 0 or 1
  • W 1 is -0-, -NR 7 -, -S(O) 0 - 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )S(0)-, -
  • W 2 is -0-, -NR 7 -, -S(O) 0 _ 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, - N(R 7 )C(0)N(R 8 )-,-N(R 7 )S(0)-, -N(R 7 )S(0) 2 -,-C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, - CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, - CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or -CH(R 7 )N(R 8 )S(0)
  • Ci_ioalkyl bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci_ioalkyl, C 3 _scyc loalkyl, Ci_ioalkyl-C 3 _ 8 cycloalkyl, C 3 _ scycloalkyl -Ci_ioalkyl, C 3 _scycloalkyl -C 2 _ioalkenyl, C 3 _scycloalkyl- C 2 _ioalkynyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkynyl, Ci_ioalkylaryl (e.g.
  • R , R , and R are independently H or Ci_ioalkyl , wherein the Ci_ioalkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, -OH, - Ci_ioalkyl, -CF 3 , -O-aryl, - OCF 3 , -OCi_i 0 alkyl, -NH 2 , - N(Ci_i 0 alkyl)(Ci_i 0 alkyl), - NH(Ci_i 0 alkyl), - NH( aryl), - NR 34 R 35 , -C(O)(Ci_i 0 alkyl), -C(O)(Ci_i 0 alkyl),
  • R 7 and R 8 are each independently hydrogen, Ci_ioalkyl, C 2 _ioalkenyl, aryl, heteroaryl, heterocyclyl or C 3 _iocycloalkyl, each of which except for hydrogen is
  • X 4 is C-R 9 .
  • the invention also provides an inhibitor as defined above, wherein the compound is of Formula I:
  • the compound of Formula I-B or its pharmaceutically acceptable salt thereof is a com ound having the structure of Formula I-Bl or Formula I-B2:
  • X 1 is N and X 2 is N.
  • Xi is C-E 1 and X 2 is N.
  • Xi is NH and X 2 is C.
  • Xi is CH-E 1 and X 2 is C.
  • Xi is N and X 2 is C. In further embodiments, Xi is C-E 1 and X 2 is C.
  • Xi is C ⁇ W 1 ) ] -R 4 , where j is 0.
  • Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.
  • X l s it is C -(W 1 ) ] -R 4 .
  • X l s j is
  • W is -0-.
  • X l s j is 1
  • W is— NR -.
  • W 1 is— NH-.
  • W 1 is — S(0)o- 2 -
  • W 1 is— C(O)-.
  • X l s j is 1 , and W is— C(0)N(R )-. In various embodiments of X l s j is 1 , and W 1 is -N(R 7 )C(0)-. In various embodiments of X u j is 1 , and W 1 is -N(R 7 )S(0)-. In
  • Xi, j is 1
  • W is— N(R )S(0) 2 -
  • W 1 is -C(0)0-.
  • W 1 is 1
  • X l s j is 1
  • W is -CH(R )N(S0 2 R )-.
  • X l s j 1 7 8 1 of X l s j is 1 , and W is -CH(R )N(R )-.
  • W is - CH(R 7 )C(0)N(R 8 )-.
  • W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • X l s j is 1
  • W is— CH(R )N(R )S(0)-.
  • X u j is 1
  • W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Xi is CH 2 .
  • Xi is CH-halogen, where halogen is CI, F, Br, or I.
  • Xi is N.
  • X 2 is N. In other embodiments, X 2 is C.
  • E is -(W ) j -R , where j is 0.
  • E is CH. In yet another embodiment, E is C-halogen, where halogen is CI, F, Br, or I.
  • E it is -(W ) j -R . In various embodiments of E , j is 1 ,
  • W is -0-. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is—
  • E , j is 1, and W is— NH-.
  • W is
  • E , j is 1, and W is— C(0)N(R )-.
  • W 1 is -N(R 7 )C(0)-.
  • W 1 is -N(R 7 )S(0)-.
  • E , j is 1, and W is— N(R )S(0) 2 -.
  • W is— N(R )S(0) 2 -.
  • E j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments of E , j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments
  • E 1 7 8 2 1 of E
  • j is 1, and W is -CH(R )N(R )-.
  • W is - CH(R 7 )C(0)N(R 8 )-.
  • W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • E j is 1, and W is— CH(R )N(R )S(0)-.
  • E 2 , j is 1, and W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Mi is a moiety of Formula Ml-Fl
  • Mi is a benzoxazolyl
  • Mi is either a 5- benzoxazolyl or a 6- benzoxazolyl moiety, optionally substituted at the 2-position with -(W ) j -R .
  • Exemplary Formula Ml-Fl Mi moieties include but are not limited to the following:
  • Formula M1-F2 is an aza-substituted benzoxazolyl moiety having a structure of one of the following formulae:
  • Exemplary Formula M1-F2 Mi moieties include but are not limited to the f llowing: 2
  • k is 0. In other embodiments of Mi, k is 1, and W is selected from one of the following: -0-, -NR 7 -, -S(O) 0-2 -, -C(O)-, -C(0)N(R 7 )-, - N(R 7 )C(0)-, or -N(R 7 )C(0)N(R 8 )-.
  • M u k is 1
  • W 2 is - N(R 7 )S(0)-, -N(R 7 )S(0) 2 -, -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, or - CH(R 7 )N(S0 2 R 8 )-.
  • M u k In a further embodiment of M u k is 1 , and W 2 is -CH(R 7 )N(R 8 )-, - CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, or -CH(R 7 )N(R 8 )S(0)-. In yet another embodiment of M u k is 1 , and W 2 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • the invention provides an inhibitor of mTor which is a compound of Formula I-C or Formula I-D: 2
  • Formula I-C Formula I-D or a pharmaceutically acceptable salt thereof, wherein Xi is N or C-E 1 , X 2 is N, and X 3 is C; or Xi is N or C-E 1 , X 2 is C, and X 3 is N;
  • Ri is -H, -L-Ci_ioalkyl, -L-C 3 _scycloalkyl, -L- Ci_ioalkyl -C 3 _scycloalkyl, -L- aryl, - L-heteroaryl, -L-Ci_ioalkylaryl, -L- Ci_ioalkylheteroaryl, -L- Ci_ioalkylheterocyclyl, -L-C 2 _ l oalkenyl, -L-C 2 _ioalkynyl, -L-C 2 _ioalkenyl-C 3 _ 8 cycloalkyl, -L-C 2 _ioalkynyl-C 3 _ 8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,
  • E 1 and E 2 are independently -(W 1 ) ] -R 4 ;
  • j in E or j in E is independently 0 or 1 ;
  • W 1 is -0-, -NR 7 -, -S(O) 0 _ 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )S(0)-, - N(R 7 )S(0) 2 -, -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or - CH(R 7 )N(R 8 )S(0) 2 -;
  • W 2 is -0-, -NR 7 -, -S(O) 0 - 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, - N(R 7 )C(0)N(R 8 )-, -N(R 7 )S(0)-, -N(R 7 )S(0) 2 - -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, - CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, - CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or -CH(R 7 )N(R 8 )S(0)
  • k is O or l
  • Ci_ioalkyl bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci_ioalkyl, C 3 _scyc loalkyl, Ci_ioalkyl-C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkyl -Ci_ioalkyl, C 3 _scycloalkyl -C 2 _ioalkenyl, C 3 _scycloalkyl- C 2 _ioalkynyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkynyl, Ci_ioalkylaryl (e.g.
  • R , R , and R are independently H or Ci_ioalkyl , wherein the Ci_ioalkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, -OH, - Ci_ioalkyl, -CF , -O-aryl, - OCF 3 , -OCi_ioalkyl, -NH 2 , - N(Ci_i 0 alkyl)(Ci_i 0 alkyl), - NH(Ci_i 0 alkyl), - NH( aryl), - NR 34 R 35 , -C(O)(Ci_i 0 alkyl), -C(O)(Ci__i_)(Ci__
  • R 7 and R 8 are each independently hydrogen, Ci_ioalkyl, C 2 _ioalkenyl, aryl, heteroaryl, heterocyclyl or C 3 _iocycloalkyl, each of which except for hydrogen is
  • the compound of Formula I-C has a structure of Formula I-Cl or Formula I-C2:
  • Xi is N and X 2 is N. In other embodiments, Xi is C-E 1 and X 2 is N. In yet other embodiments, Xi is NH and X 2 is C. In further embodiments, Xi is CH-E 1 and X 2 is C.
  • Xi is N and X 2 is C. In yet other embodiments, Xi is NH and X 2 is C. In further embodiments, Xi is CH-E 1 and X 2 is C.
  • the compound of Formula I-D has a structure of Formula I-Dl or Formula I-D2:
  • Xi is N and X 2 is N. In other embodiments, Xi is C-E 1 and X 2 is N. In yet other embodiments, Xi is NH and X 2 is C. In further embodiments, Xi is CH-E 1 and X 2 is C.
  • Xi is N and X 2 is C. In further embodiments, Xi is C-E 1 and X 2 is C.
  • Xi is C ⁇ W 1 ) ] -R 4 , where j is 0.
  • Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I. [00332] In various embodiments of X ls it is C -(W 1 ) ] -R 4 . In various embodiments of X ls j is
  • W is -0-.
  • X ls j is 1, and W is— NR -.
  • W 1 is— NH-.
  • W 1 is — S(0)o-2-
  • W 1 is— C(O)-.
  • X ls j is 1, and W is— C(0)N(R )-. In various embodiments of X ls j is 1, and W 1 is -N(R 7 )C(0)-. In various embodiments ofX u j is 1, and W 1 is -N(R 7 )S(0)-. In
  • Xi, j is 1, and W is— N(R )S(0) 2 -. In various embodiments of Xi, j is 1, and W 1 is -C(0)0-. In various embodiments of Xi, j is 1, and W 1 is
  • X ls j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments,
  • X ls j 1 7 8 1 of X ls j is 1, and W is -CH(R )N(R )-.
  • W is - CH(R 7 )C(0)N(R 8 )-.
  • W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • X ls j is 1, and W is— CH(R )N(R )S(0)-.
  • Xi is CH ⁇ W 1 ) ] -R 4 , where j is 0.
  • Xi is CH 2 .
  • Xi is CH-halogen, where halogen is CI, F, Br, or I.
  • Xi, j is 1, and W is -0-.
  • W is— NR -.
  • W 1 is— NH-.
  • W 1 is — S(0)o_ 2 -.
  • W 1 is— C(O)-.
  • X ls j is 1, and W is— C(0)N(R )-. In various embodiments of X ls j is 1, and W 1 is -N(R 7 )C(0)-. In various embodiments of Xi, j is 1, and W 1 is -N(R 7 )S(0)-. In various embodiments of X ls j is 1, and W is— C(0)N(R )-. In various embodiments of X ls j is 1, and W 1 is -N(R 7 )C(0)-. In various embodiments of Xi, j is 1, and W 1 is -N(R 7 )S(0)-. In
  • Xi, j is 1, and W is— N(R )S(0) 2 -. In various embodiments of Xi, j is 1, and W 1 is -C(0)0-. In various embodiments of X ls j is 1, and W 1 is
  • Xi, j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments of Xi, j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments
  • X ls j 1 7 8 1 of X ls j is 1, and W is -CH(R )N(R )-.
  • W is - CH(R 7 )C(0)N(R 8 )-.
  • W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • X ls j is 1, and W is— CH(R )N(R )S(0)-.
  • Xi, j is 1, and W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Xi is N.
  • X 2 is N. In other embodiments, X 2 is C.
  • E is -(W ) j -R , where j is 0.
  • E 2 is CH.
  • E 2 is C-halogen, where halogen is CI, F, Br, or I.
  • E it is -(W )j -R . In various embodiments of E , j is 1,
  • W is -0-.
  • E , j is 1, and W is— NR -.
  • E , j is 1, and W is— NH-. In various embodiments of E , j is 1, and W is
  • E j is 1, and W is— C(0)N(R )-.
  • W 1 is -N(R 7 )C(0)-.
  • W 1 is -N(R 7 )S(0)-.
  • E , j is 1, and W is— N(R )S(0) 2 -.
  • W is— N(R )S(0) 2 -.
  • E j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments of E , j is 1, and W is -CH(R )N(S0 2 R )-. In various embodiments
  • E 1 7 8 2 1 of E
  • j is 1, and W is -CH(R )N(R )-.
  • W is - CH(R 7 )C(0)N(R 8 )-.
  • W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • E j is 1, and W is— CH(R )N(R )S(0)-.
  • E 2 , j is 1, and W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • k is 0. In other embodiments, k is 1 and W is -0-. In another embodiment, k is 1 and W 2 is -NR 7 -. In yet another embodiment of, k is 1 , and W 2 is -S(0)o- 2 -. In another embodiment of, k is 1 and W is -C(O)-. In a further embodiment, k is 1 and W 2 is -C(0)N(R 7 )-. In another embodiment, k is 1, and W 2 is -N(R 7 )C(0)-. In another embodiment, k is 1 and W 2 is -N(R 7 )C(0)-. In another embodiment, k is 1 and W 2 is -N(R 7 )C(0)N(R 8 )-.
  • k is 1 and W 2 is -N(R 7 )S(0)-. In still yet another embodiment, k is 1 and W 2 is -N(R 7 )S(0) 2 -. In a further embodiment, k is 1 and W 2 is -C(0)0-. In another embodiment, k is 1 and W 2 is - CH(R 7 )N(C(0)OR 8 )-. In another embodiment, k is 1 and W 2 is -CH(R 7 )N(C(0)R 8 )-. In
  • k is 1 and W is -CH(R )N(S0 2 R )-. In a further embodiment, k is 1 and W 2 is -CH(R 7 )N(R 8 )-. In another embodiment, k is 1 and W 2 is -CH(R 7 )C(0)N(R 8 )-. In yet another embodiment, k is 1 and W 2 is -CH(R 7 )N(R 8 )C(0)-. In another embodiment, k is 1 and W 2 is -CH(R 7 )N(R 8 )S(0)-. In yet another embodiment, k is 1 and W 2 is - CH(R 7 )N(R 8 )S(0) 2 -. [00342] The invention also provides a compound which is an mTor inhibitor of Formula I-E:
  • X 1 is N or C-E 1 , X 2 is N, and X 3 is C; or Xi is N or C-E 1 , X 2 is C, and X 3 is N;
  • Ri is -H, -L-Ci_ioalkyl, -L-C 3 _scycloalkyl, -L-Ci_ioalkyl -C 3 _scycloalkyl, -L- aryl, - L-heteroaryl, -L-Ci_ioalkylaryl, -L- Ci_ioalkylheteroaryl, -L- Ci_ioalkylheterocyclyl, -L-C 2- l oalkenyl, -L-C 2 -ioalkynyl, -L-C 2 -ioalkenyl-C 3 _ 8 cycloalkyl, -L-C 2 -ioalkynyl-C 3 _ 8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,
  • Mi is a moiety having the structure of Formula Ml-Fl or Formula M1-F2:
  • k is O or l
  • E 1 and E 2 are independently -(W 1 ) ] -R 4 ;
  • j in E 1 or j in E 2 is independently 0 or 1;
  • W 1 is -0-, -NR 7 -, -S(O) 0 _ 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, -N(R 7 )S(0)-,- N(R 7 )S(0) 2 -, -C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, -CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, -CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or - CH(R 7 )N(R 8 )S(0) 2 -;
  • W 2 is -0-, -NR 7 -, -S(O) 0 _ 2 -,-C(O)-,-C(O)N(R 7 )-, -N(R 7 )C(0)-, - N(R 7 )C(0)N(R 8 )-,-N(R 7 )S(0)-, -N(R 7 )S(0) 2 -,-C(0)0-, -CH(R 7 )N(C(0)OR 8 )-, - CH(R 7 )N(C(0)R 8 )-, -CH(R 7 )N(S0 2 R 8 )-, -CH(R 7 )N(R 8 )-, -CH(R 7 )C(0)N(R 8 )-, - CH(R 7 )N(R 8 )C(0)-, -CH(R 7 )N(R 8 )S(0)-, or -CH(R 7 )N(R 8 )S(0)
  • Ci_ioalkyl bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci_ioalkyl, C 3 _scyc loalkyl, Ci_ioalkyl-C 3 _ 8 cycloalkyl, C 3 _ scycloalkyl -Ci_ioalkyl, C 3 _scycloalkyl -C 2 _ioalkenyl, C 3 _scycloalkyl- C 2 _ioalkynyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkenyl, Ci_ioalkyl- C 2 _ioalkynyl, Ci_ioalkylaryl (e.g.
  • R , R , and R are independently H or Ci_ioalkyl , wherein the Ci_ioalkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, -OH, - Ci_ioalkyl, -CF 3 , -O-aryl, - OCF 3 , -OCi-ioalkyl, -NH 2 , - N(Ci_i 0 alkyl)(Ci_i 0 alkyl), - NH(Ci_i 0 alkyl), - NH( aryl), - NR 34 R 35 , -C(O)(Ci_i 0 alkyl), -C(O)(Ci__i__)(Ci_)
  • R 7 and R 8 are each independently hydrogen, Ci_ioalkyl, C 2 _ioalkenyl, aryl, heteroaryl, heterocyclyl or C 3 _iocycloalkyl, each of which except for hydrogen is
  • the compound of Formula I-E has a structure of Formula I-El or Formula I-E2:
  • Xi is N and X 2 is N. In other embodiments, Xi is C-E 1 and X 2 is N. In yet other embodiments, Xi is NH and X 2 is C. In further embodiments, Xi is CH-E 1 and X 2 is C.
  • Xi is N and X 2 is C. In further embodiments, Xi is C-E 1 and X 2 is C.
  • Xi is C ⁇ W 1 ) ] -R 4 , where j is 0.
  • Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.
  • Xi it is C -(W 1 ) ] -R 4 .
  • j is
  • W is -0-.
  • Xi, j is 1, and W is— NR -.
  • W 1 is— NH-.
  • W 1 is — S(0)o- 2 -
  • W 1 is— C(O)-.
  • Xi, j is 1, and W is— C(0)N(R )-. In various embodiments of Xi, j is 1, and W 1 is -N(R 7 )C(0)-. In various embodiments of Xi, j is 1, and W 1 is -N(R 7 )S(0)-. In various embodiments of Xi, j is 1, and W 1 is -N(R 7 )S(0)-. In
  • X ls j is 1, and W is— N(R )S(0) 2 ⁇ . In various embodiments of X ls j is 1, and W 1 is -C(0)0-. In various embodiments of X ls j is 1, and W 1 is
  • X l s j is 1 , and W is -CH(R )N(S0 2 R )-. In various embodiments of Xi, j is 1 , and W 1 is -CH(R 7 )N(R 8 )-. In various embodiments of X l s j is 1 , and W 1 is - CH(R 7 )C(0)N(R 8 )-. In various embodiments of X h j is 1 , and W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • Xi, j is 1
  • W is— CH(R )N(R )S(0)-.
  • X u j is 1
  • W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Xi is N.
  • X 2 is N. In other embodiments, X 2 is C.
  • E is -(W ) j -R , where j is 0.
  • E is CH. In yet another embodiment, E is C-halogen, where halogen is CI, F, Br, or I.
  • E it is -(W ) j -R . In various embodiments of E , j is 1 ,
  • W is -0-. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is— NR -. In various embodiments of E , j is 1 , and W is—
  • E , j is 1, and W is— NH-.
  • W is
  • E j is 1
  • W is— C(O)-.
  • E , j is 1, and W is— C(0)N(R )-.
  • W 1 is -N(R 7 )C(0)-.
  • W 1 is -N(R 7 )S(0)-.
  • E , j is 1
  • W is— N(R )S(0) 2 -.
  • E In various embodiments of E , j is 1 , and W is -CH(R )N(S0 2 R )-. In various embodiments of E 2 , j is 1 , and W 1 is -CH(R 7 )N(R 8 )-. In various embodiments of E 2 , j is 1 , and W 1 is - CH(R 7 )C(0)N(R 8 )-. In various embodiments of E 2 , j is 1 , and W 1 is -CH(R 7 )N(R 8 )C(0)-.
  • E In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-. In various embodiments of E , j is 1 , and W is— CH(R )N(R )S(0)-.
  • E 2 , j is 1, and W 1 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Mi is benzoxazolyl substituted with -(W 2 ) k -R 2 .
  • Mi is a benzoxazolyl moiety, substituted at the 2-position with -(W 2 ) k -R 2 .
  • Mi is either a 5- benzoxazolyl or a 6- benzoxazolyl moiety, optionally substituted with -(W 2 ) k -R 2 .
  • Exemplary Formula I-El Mi moieties include but are not limited to the following:
  • Formula I-E2 is an aza- substituted benzoxazolyl moiety having a structure of one of the following formulae:
  • Exemplary Formula I-E2 Mi moieties include but are not limited to the following:
  • k is 0. In other embodiments of Mi, k is 1 and W is
  • Mi k is 1 and W is -S(O) 0-2 - In another embodiment of Mi, k is 1 and W is -C(O)-. In a further embodiment of Mi, k is 1 and W 2 is -C(0)N(R 7 )-. In another embodiment of Mi, k is 1 and W 2 is -N(R 7 )C(0)-. In another embodiment, k is 1 and W 2 is -N(R 7 )C(0)N(R 8 )-. In yet another embodiment of Mi, k is 1 and W 2 is -N(R 7 )S(0)-. In still yet another
  • Mi is 1 and W is -N(R )S(0) 2 -. In a further embodiment of Mi, k is 1 and W 2 is -C(0)0-. In another embodiment of M u k is 1 and W 2 is -CH(R 7 )N(C(0)OR 8 )-.
  • k is 1 and W 2 is -CH(R 7')N(C(0)R 8°)-. In another embodiment of Mi, k is 1 and W 2 is -CH(R 7 )N(S0 2 R 8 )-. In a further embodiment of M u k is 1 and W 2 is -CH(R 7 )N(R 8 )-. In another embodiment of M k is 1 and W 2 is -CH(R 7 )C(0)N(R 8 )-. In yet
  • Mi is 1 and W is -CH(R')N(R°)C(0)-. In another embodiment of Mi, k is 1 and W 2 is -CH(R 7 )N(R 8 )S(0)-. In yet another embodiment of M k is 1 and W 2 is -CH(R 7 )N(R 8 )S(0) 2 -.
  • Ri is -L-Ci_ioalkyl, which is unsubstituted.
  • Ri is -L-Ci_ioalkyl, which is substituted by one or more independent R .
  • Ri is -L- unsubstituted Ci_ioalkyl, where L is absent.
  • Ri is -L-Ci_ioalkyl, which is substituted by one or more independent R , and L is absent.
  • Ri is -L-C 3 -scycloalkyl, which is unsubstituted.
  • Ri is L-C 3 _scycloalkyl, which is substituted by one or more independent R .
  • Ri is -L-C 3 _scycloalkyl, which is unsubstituted, and L is absent.
  • Ri is -L-C 3 -scycloalkyl which is substituted by one or more independent R , and L is absent.
  • Ri is H.
  • Ri is -L- aryl, which is unsubstituted.
  • Ri is -L- aryl, which is substituted by one or more independent R .
  • Ri is -L- aryl which is unsubstituted, and L is absent.
  • Ri is -L- aryl, which is substituted by one or more independent R , and L is absent.
  • Ri is -L-heteroaryl, which is unsubstituted.
  • Ri is -L-heteroaryl, which is substituted by one or more independent R .
  • Ri is -L-heteroaryl which is unsubstituted and L is absent.
  • Ri is -L- heteroaryl, which is substituted by one or more independent R , and L is absent.
  • Ri is - L- Ci_ioalkyl -C 3- scycloalkyl, which is unsubstituted.
  • Ri is - L- Ci_ioalkyl -C 3 _ scycloalkyl, which is substituted by one or more independent R .
  • Ri is - L- Ci_ioalkyl -C 3 _ 8 cycloalkyl which is unsubstituted and L is absent.
  • Ri is - L- Ci_ioalkyl -C 3 -scycloalkyl, which is substituted by one or more independent R , and L is absent.
  • Ri is - L-Ci_ioalkylaryl, which is unsubstituted. In another embodiment, Ri is - L-Ci_ioalkylaryl, which is substituted by one or more independent R . In a further embodiment, Ri is - L-Ci_ioalkylaryl which is unsubstituted and L is absent. In yet another embodiment, Ri is - L-C 1-10 alkylaryl, which is substituted by one or more independent R , where L is absent. [00384] In various embodiments of compounds of Formula I, Ri is -L- Ci_ioalkylheteroaryl, which is unsubstituted.
  • Ri is -L- Ci_ioalkylheteroaryl, which is substituted by one or more independent R .
  • Ri is -L- Ci_ l oalkylheteroaryl which is unsubstituted and L is absent.
  • Ri is -L- Ci_ioalkylheteroaryl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L- Ci_
  • Ri is -L- Ci_
  • Ri is -L- C l oalkylheterocyclyl which is unsubstituted and L is absent.
  • Ri is -L- Ci_ioalkylheterocyclyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-C 2 -ioalkenyl, which is unsubstituted.
  • Ri is -L-C 2 _ioalkenyl which is substituted by one or more independent R .
  • Ri is -L-C 2 _ioalkenyl which is unsubstituted and L is absent.
  • Ri is -L-C 2-10 alkenyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-C 2-10 alkynyl, which is unsubstituted.
  • Ri is -L-C 2 -ioalkynyl which is substituted by one or more independent R .
  • Ri is -L-C 2 -ioalkynyl which is unsubstituted and L is absent.
  • Ri is -L-C 2-10 alkynyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-C 2 -ioalkenyl-C 3 _ 8 cycloalkyl, which is unsubstituted.
  • Ri is -L-C 2 -ioalkenyl-C 3 _ 8 cycloalkyl which is substituted by one or more independent R .
  • Ri is -L-C 2 -ioalkenyl-C3_ 8 cycloalkyl which is unsubstituted and L is absent.
  • Ri is -L-C 2-10 alkenyl-C 3-8 cycloalkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-C 2 -ioalkynyl-C 3 - scycloalkyl, which is unsubstituted.
  • Ri is -L-C 2 -ioalkynyl-C 3 _ 8 cycloalkyl which is substituted by one or more independent R .
  • Ri is -L-C 2 -ioalkynyl-C 3 - 8 cycloalkyl which is unsubstituted and L is absent.
  • Ri is -L-C 2-10 alkynyl-C 3-8 cycloalkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-C 2 -ioalkynyl-C 3 _ scycloalkyl, which is unsubstituted.
  • Ri is -L-C 2 -ioalkynyl-C 3 _ scycloalkyl which is substituted by one or more independent R .
  • Ri is -L-C 2 -ioalkynyl-C3- 8 cycloalkyl which is unsubstituted and L is absent.
  • Ri is -L-C 2 -ioalkynyl-C 3 _scycloalkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroalkyl, which is unsubstituted.
  • Ri is -L-heteroalkyl which is substituted by one or more independent R .
  • Ri is -L-heteroalkyl which is unsubstituted and L is absent.
  • Ri is -L-heteroalkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroalkylaryl, which is unsubstituted.
  • Ri is -L-heteroalkylaryl which is substituted by one or more independent R .
  • Ri is -L-heteroalkylaryl which is unsubstituted and L is absent.
  • Ri is -L-heteroalkylaryl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroalkylheteroaryl, which is unsubstituted.
  • Ri is -L-heteroalkylheteroaryl, which is substituted by one or more independent R .
  • Ri is -L- heteroalkylheteroaryl which is unsubstituted and L is absent.
  • Ri is -L-heteroalkylheteroaryl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroalkyl- heterocyclyl, which is unsubstituted.
  • Ri is -L-heteroalkyl- heterocyclyl, which is substituted by one or more independent R .
  • Ri is -L-heteroalkyl-heterocyclyl which is unsubstituted, and L is absent.
  • Ri is -L-heteroalkyl-heterocyclyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroalkyl-C 3 _ scycloalkyl, which is unsubstituted.
  • Ri is -L-heteroalkyl-C 3 _ scycloalkyl, which is substituted by one or more independent R .
  • Ri is -L-heteroalkyl-C 3 _ 8 cycloalkyl which is unsubstituted and L is absent.
  • Ri is -L-heteroalkyl-C 3 _scycloalkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-aralkyl, which is unsubstituted. In another embodiment, Ri is -L-aralkyl, which is substituted by one or more independent R . In a further embodiment, Ri is -L-aralkyl which is unsubstituted. In yet another embodiment, Ri is -L-aralkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heteroaralkyl, which is unsubstituted.
  • Ri is -L-heteroaralkyl, which is substituted by one or more independent R .
  • Ri is -L-heteroaralkyl which is unsubstituted and L is absent.
  • Ri is -L-heteroaralkyl, which is substituted by one or more independent R , where L is absent.
  • Ri is -L-heterocyclyl, which is unsubstituted.
  • Ri is -L-heterocyclyl, which is substituted by one or more independent R .
  • Ri is -L-heterocyclyl which is unsubstituted and L is absent.
  • Ri is -L- heterocyclyl, which is substituted by one or more independent R , where L is absent.
  • Ri is a substituent as shown below:
  • R is hydrogen.
  • R 2 is halogen.
  • R 2 is -OH.
  • R 2 is -R 31.
  • R 2 is -CF 3 .
  • R 2 is -OCF 3 .
  • R 2 is -OR 31.
  • R 2 is -NR 31 R 32.
  • R 2 is -NR 34 R 35.
  • R 2 is -C(0)R 31.
  • R 2 is monocyclic aryl. In another embodiment, R 2 is bicyclic aryl.
  • R 2 is substituted monocyclic aryl. In another embodiment, R 2 is heteroaryl. In another embodiment, R 2 is Ci_ 4 alkyl. In another embodiment, R 2 is Ci_ioalkyl.
  • R 2 is C 3 _ 8 cycloalkyl. In another embodiment, R 2 is C 3 _ 8 cycloalkyl- Ci_ioalkyl. In another embodiment, R is Ci_ioalkyl -C 3 _ 8 cycloalkyl. In another embodiment,
  • R 2 is Ci_ioalkyl-monocyclic aryl. In another embodiment, R 2 is C 2 -ioalkyl -monocyclic aryl.
  • R 2 is monocyclic aryl- C 2 -ioalkyl. In another embodiment, R 2 is Ci_ l oalkyl-bicyclic aryl. In another embodiment, R is bicyclic aryl- Ci_ioalkyl. In another embodiment, R 2 is - Ci_ioalkylheteroaryl. In another embodiment, R 2 is - Ci_
  • R 2 is -C 2 -ioalkenyl. In another embodiment, R 2 is -C 2 -ioalkynyl. In another embodiment, R 2 is C 2 -ioalkenylaryl. In another embodiment, R 2 is C 2 -ioalkenylheteroaryl. In another embodiment, R is C 2 -ioalkenylheteroalkyl. In another embodiment, R 2 is C 2 -ioalkenylheterocyclcyl. In another embodiment, R 2 is -C 2 -ioalkynylaryl.
  • R 2 is -C 2 -ioalkynylheteroaryl. In another embodiment, R 2 is -C 2- l oalkynylheteroalkyl. In another embodiment, R is -C 2 -ioalkynylheterocyclyl. In another embodiment, R 2 is -C 2 -ioalkynylC 3 _ 8 cycloalkyl. In another embodiment, R 2 is -C 2-
  • R is - Ci_ioalkoxy-Ci_ioalkyl.
  • R 2 is - Ci_ioalkoxy-C 2 _ioalkenyl.
  • R 2 is - Ci_ioalkoxy- C 2 -ioalkynyl.
  • R is -heterocyclyl Ci_ioalkyl.
  • R 2 is heterocyclylC 2 -ioalkenyl. In another embodiment, R 2 is heterocyclylC 2 -ioalkynyl. In another embodiment, R 2 is aryl-C 2 -ioalkyl. In another embodiment, R 2 is aryl-Ci_ioalkyl. In another embodiment, R 2 is aryl-C 2 _ioalkenyl. In another embodiment, R 2 is aryl-C 2 -ioalkynyl.
  • R 2 is aryl-heterocyclyl. In another embodiment, R 2 is heteroaryl- Ci_ l oalkyl. In another embodiment, R 2 is heteroaryl-C 2 -ioalkenyl. In another embodiment, R 2 is heteroaryl-C 2 -ioalkynyl. . In another embodiment, R is heteroaryl- C 3 _ 8 cycloalkyl. In another embodiment, R 2 is heteroaryl- heteroalkyl. In another embodiment, R 2 is heteroaryl- heterocyclyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2- l oalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- 2
  • Ci_ioalkyl it is unsubstituted.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ l oalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent halo.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -OH.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl
  • C 3 _scycloalkyl- Ci_ioalkyl it is substituted wi .
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _ 8 cycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -CF 3 .
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -OCF.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ l oalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl-
  • Ci_ioalkyl it is substituted with one or more independent -OR 31.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or l, it is substituted with one or more independent -NR 3 J 1 1 R 32
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -NR 34 R 35 .
  • R 4 when R 4 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -C(0)R 31.
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or oalkyl- Ci_ioalkyl, it is substituted with one or more independent -C0 2 R 31
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -N0 2 .
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -CN.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -S0 2 NR 31 R 32.
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -S0 2 NR 34 R 35 .
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 _ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, it is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is bicyclic aryl, mono
  • C3_ 8 cycloalkyl- Ci_ioalkyl it is su .
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent , -
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or
  • 3_ 8 cycloalkyl- Ci_ioalkyl it is sub .
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2- l oalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl-
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -P(0)OR 31 OR 32.
  • R 2 is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2- l oalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl-
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent alkyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent heteroalkyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent alkenyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent alkynyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent cycloalkyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ l oalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl- C 2-10 alkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent heterocycloalkyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2- l oalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent aryl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _ 8 cycloalkyl- Ci_ioalkyl, it is substituted with one or more independent arylalkyl.
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, heterocyclyl, heteroalkyl, C 2 _ioalkenyl, C 2 -ioalkynyl, monocyclic aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent 2
  • R is bicyclic aryl, monocyclic aryl, heteroaryl, Ci_ l oalkyl, C 3 _ 8 cycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, monocyclic aryl- C 2-10 alkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent heteroarylalkyl.
  • R is hydrogen.
  • R 3 is halogen.
  • R 3 is -OH.
  • R 3 is -R 31.
  • R 3 is -CF 3 .
  • R 3 is -OCF 3 .
  • R 3 is -OR 31.
  • R 3 is -NR 31 R 32.
  • R 3 is -NR 34 R 35.
  • R 3 is -C(0)R 31.
  • R 3 is -NR 31 S(O) 0 - 2 R 32 .
  • R 3 is aryl. In another embodiment, R 2 is heteroaryl. In another embodiment, R 3 is Ci_ 4 alkyl. In another embodiment, R 3 is Ci_ioalkyl. In another
  • R 3 is C 3 _ 8 cycloalkyl. In another embodiment, R 3 is C 3 _ 8 cycloalkyl- Ci_ioalkyl.
  • R 3 is - Ci_ioalkyl -C 3 _ 8 cycloalkyl. In another embodiment, R 3 is C 2- l oalkyl-monocyclic aryl. In another embodiment, R is monocyclic aryl- C 2-10 alkyl. In another
  • R is C 1-10 alkyl-bicyclicaryl. In another embodiment, R is bicyclic aryl- Ci_ l oalkyl. In another embodiment, R 3 is C 1-10 alkylheteroaryl. In another embodiment, R 3 is Ci_ l oalkylheterocyclyl. In another embodiment, R 3 is C 2 -ioalkenyl. In another embodiment, R 3 is
  • R 3 is C 2 -ioalkynyl.
  • R 3 is C 2 -ioalkenylaryl.
  • R 3 is C 2- l oalkenylheteroaryl.
  • R is C 2-10 alkenylheteroalkyl.
  • R is C 2-10 alkenylheterocyclcyl. In another embodiment, R is -C 2-10 alkynylaryl.
  • R 3 is -C 2-10 alkynylheteroaryl. In another embodiment, R 3 is -C 2- l oalkynylheteroalkyl. In another embodiment, R is C 2-10 alkynylheterocyclyl. In another 3 3
  • R is -C 2 -ioalkynylC 3 _ 8 cycloalkyl. In another embodiment, R is C 2- ioalkynylC 3 _ 8 cycloalkenyl. In another embodiment, R is - Ci_ioalkoxy-Ci_ioalkyl. In another
  • R is Ci_ioalkoxy-C 2 -ioalkenyl. In another embodiment, R is - Ci_ioalkoxy-C 2 _
  • R is heterocyclyl- Ci_ioalkyl.
  • R is -heterocyclylC 2 -ioalkenyl.
  • R is heterocyclyl-C 2 -ioalkynyl.
  • R is aryl-Ci_ioalkyl. In another embodiment, R is aryl-C 2 _ioalkenyl.
  • R is aryl-C 2 -ioalkynyl. In another embodiment, R is aryl- heterocyclyl. In another embodiment, R is heteroaryl- C 1-10 alkyl. In another embodiment,
  • R is heteroaryl-C 2-10 alkenyl. In another embodiment, R is heteroaryl-C 2-10 alkynyl. . In
  • R is heteroaryl- C 3-8 cycloalkyl. In another embodiment, R is heteroaryl- heteroalkyl. In another embodiment, R is heteroaryl- heterocyclyl.
  • R when R is aryl, heteroaryl, Ci_ l oalkyl, C 3-8 cycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is unsubstituted.
  • R when R is aryl, heteroaryl, Ci_ l oalkyl, C 3-8 cycloalkyl, C 3 -scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent halo.
  • R when R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl,
  • heterocyclyl when R is aryl, heteroaryl, C 1-10 alkyl, C 3 _ 8 cycloalkyl, C 3 -scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent -OH.
  • R when R is aryl, heteroaryl, C 1-10 alkyl, C 3 _ 8 cycloalkyl, C 3 -scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it
  • 31 3 is substituted with one or more independent -R .
  • R when R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent -CF 3 .
  • R when R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 -scycloalkyl- Ci_ l oalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent -OCF.
  • R is aryl, heteroaryl, C 1-10 alkyl, C 3 _ 8 cycloalkyl, C 3 -scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it
  • R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl
  • C 1-10 alkyl, or heteroalkyl it is substituted with one or more independent -NR R .
  • R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 -scycloalkyl- Ci_ l oalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more
  • R is aryl, heteroaryl, C 1-10 alkyl, C 3- scycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • it is substituted with one or more independent -
  • R 3 when R 3 is aryl, heteroaryl, Ci_ l oalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -N0 2 .
  • R when R is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl,
  • heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl it is substituted with one or more independent -CN.
  • R is aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -CN.
  • R is aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R 31 3 is substituted with one or more independent -S(0)o- 2 R .
  • R is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 _scycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent -
  • R 3 is aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 3 _ 8 cycloalkyl- C 1-10 alkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, or heteroalkyl, it is substituted with one or more independent -S0 2 NR 34 R 35.
  • R 3 when R 3 is aryl, heteroaryl, C 1-10 alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl-C 2-10 alkyl, heterocyclyl C 1-10 alkyl, or C 3 _scycloalkyl- C 1-10 alkyl, it is substituted with one
  • R 3 when R 3 is aryl, heteroaryl, Ci_ l oalkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl-C 2-10 alkyl, heterocyclyl C 1-10 alkyl, or C 3 _scycloalkyl- C 1-10 alkyl, it is substituted with one or more
  • R is aryl, heteroaryl, Ci_ l oalkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl-C 2-10 alkyl, heterocyclyl C 1-10 alkyl, or C 3 _scycloalkyl- C 1-10 alkyl, it is substituted with one or more
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R is aryl, heteroaryl, Ci_ioalkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2- l oalkynyl, aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 _scycloalkyl- Ci_ioalkyl, it is
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, cycloalkyl, heterocyclyl, heteroalkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, aryl-C 2 -ioalkyl, heterocyclyl Ci_ioalkyl, or C 3 -scycloalkyl- Ci_ioalkyl, it is substituted with one or more independent -
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R 3 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl
  • R 4 is -N0 2 .
  • R 4 is -CN.
  • R 4 is -S(0)o 2 R 3
  • R 4 is -S0 2 NR 31 R 32 .
  • R 4 is -S0 2 NR 34 R 35 .
  • R 4 is -NR 31 S(O) 0 2 R 32 .
  • R 4 is C 3 _ 8 cycloalkyl. In another embodiment, R 4 is Ci_ioalkyl -C 3 _ 8 cycloalkyl. In another embodiment, R 4 is Ci_ioalkylaryl. In another embodiment, R 4 is Ci_
  • R 4 is Ci_ioalkylheterocyclyl.
  • R 4 is C 2 _ioalkenyl. In another embodiment, R 4 is C 2 _ioalkynyl. In another embodiment, R 4 is C 2 _ioalkynyl- C 3 _ 8 cycloalkyl. R 4 is C 2 _ioalkenyl- C 3 _ 8 cycloalkyl. In another embodiment, R 4 is C 2 _ioalkenylaryl. In another embodiment, R 4 is C 2 _ioalkenyl-heteroaryl. In another embodiment, R 4 is C 2 _ioalkenylheteroalkyl. In another embodiment, R 4 is C 2 _ l oalkenylheterocyclcyl. In another embodiment, R 4 is -C 2 _ioalkynylaryl. In another embodiment, R 4 is C 2 _ioalkynylheteroaryl. In another embodiment, R 4 is C 2 _ioalkynylaryl. In another embodiment,
  • R 4 is C 2 _ioalkynylheterocyclyl. In another embodiment, R 4 is C 2 _ioalkynylC 3 _ 8 cycloalkyl. In another embodiment, R 4 is heterocyclyl Ci_ l oalkyl. In another embodiment, R 4 is heterocyclylC 2 _ioalkenyl. In another embodiment, R 4 is heterocyclyl-C 2 _ioalkynyl. In another embodiment, R 4 is aryl- Ci_ioalkyl. In another embodiment, R 4 is aryl-C 2 _ioalkenyl.
  • R 4 is aryl-C 2 _ioalkynyl. In another embodiment, R 4 is aryl-heterocyclyl. In another embodiment, R 4 is heteroaryl- Ci_ l oalkyl. In another embodiment, R 4 is heteroaryl-C 2 _ioalkenyl. In another embodiment, R 4 is heteroaryl-C 2 _ioalkynyl. In another embodiment, R 4 is C 3 _ 8 cycloalkyl- Ci_ioalkyl. In another embodiment, R 4 is C 3 _scycloalkyl- C 2 _ioalkenyl. In another embodiment, R 4 is C 3 _scycloalkyl- C 2-10 alkynyl.
  • R 4 when R 4 is aryl, heteroaryl, Ci_ l oalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is unsubstituted.
  • R 4 when R 4 is aryl, heteroaryl, Ci_ l oalkyl, C 3 -scycloalkyl, C 3 -scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent halo.
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl,
  • heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl it is substituted with one or more independent -OH.
  • R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -R 31 .
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, C 3 -scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -CF 3 .
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ l oalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -OCF.
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, C 3 -scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -OR 31 .
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl
  • Ci_ioalkyl, or heteroalkyl it is substituted with one or more independent -NR 31 R 32.
  • R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 -scycloalkyl, C 3 -scycloalkyl- Ci_ l oalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -NR 34 R 35 .
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _ scycloalkyl, C 3 -scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent -C(0)R 31 .
  • R 4 when R 4 is aryl, heteroaryl, Ci_ioalkyl, C 3 _scycloalkyl, C 3 _scycloalkyl- Ci_ioalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, or heteroalkyl, it is substituted with one or more independent - C0 2 R 31 .

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