USOO890 1 133B2

(12) United States Patent (10) Patent No.: US 8,901,133 B2 Ren et al. (45) Date of Patent: Dec. 2, 2014

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Kwok et al., “The anti-inflammatory natural product parthenolide Oppermann et al., “Forms and functions of human SDR enzymes.” from the medicinal herb feverfew directly binds to and inhibits IkB Chem. Biol. Interact. 130-132(1-3):699-705 (2001). kinase”, Chem. Biol., 2001, vol. 8, pp. 759-766. PubChem publication, "3-Phenylisoquinoline Compound Sum Ledbetter et al., “Crosslinking of Surface antigens cause mobilization mary (CID 6096.14).” (create date: Mar. 28, 2005), http://pubchem. of intracellular ionized calcium in T lymphocytes'. Proc. Natl. Acad. incbi.nlm.nih.gov/summary/summary.cgi?cid=609614), retrieved Sci., USA, Mar. 1987, vol. 84, pp. 1384-1388. from the Internet May 23, 2014. US 8,901,133 B2 1. 2 HETEROCYCLIC COMPOUNDS AND USES PI3Ks play a key role in intracellular trafficking through the THEREOF synthesis of PI(3)P and PI(3,4)P2. The PI3Ks are protein kinases that control cell growth (mTORC1) or monitor This application claims the benefit of U.S. Provisional genomic integrity (ATM, ATR, DNA-PK, and hSmg-1). Application Ser. No. 61/509,454, filed on Jul. 19, 2011, and The delta (ö) isoform of class I PI3K has been implicated, U.S. Provisional Application Ser. No. 61/412.384, filed on in particular, in a number of diseases and biological pro Nov. 10, 2010, each of which is incorporated herein by ref cesses. PI3K 8 is expressed primarily in hematopoietic cells erence in its entirety. including leukocytes such as T-cells, dendritic cells, neutro phils, mast cells, B-cells, and macrophages. PI3K 8 is inte BACKGROUND 10 grally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, den The activity of cells can be regulated by external signals dritic cell function, and neutrophil activity. Due to its integral that stimulate or inhibit intracellular events. The process by role in immune system function, PI3K 8 is also involved in a which stimulatory or inhibitory signals are transmitted into number of diseases related to undesirable immune response and within a cell to elicit an intracellular response is referred 15 Such as allergic reactions, inflammatory diseases, inflamma to as signal transduction. Over the past decades, cascades of tion mediated angiogenesis, rheumatoid arthritis, and auto signal transduction events have been elucidated and found to immune diseases such as lupus, asthma, emphysema and play a central role in a variety of biological responses. Defects other respiratory diseases. Other class I PI3K involved in in various components of signal transduction pathways have immune system function includes PI3KY, which plays a role been found to account for a vast number of diseases, including in leukocyte signaling and has been implicated in inflamma numerous forms of cancer, inflammatory disorders, meta tion, rheumatoid arthritis, and autoimmune diseases such as bolic disorders, vascular and neuronal diseases (Gaestel et al. lupus. Current Medicinal Chemistry (2007) 14:2214-2234). Unlike PI3K 6, the beta (B) isoform of class I PI3Kappears Kinases represent a class of important signaling molecules. to be ubiquitously expressed. PI3K B has been implicated Kinases can generally be classified into protein kinases and 25 primarily in various types of cancer including PTEN-negative lipid kinases, and certain kinases exhibit dual specificities. cancer (Edgar et al. Cancer Research (2010) 70(3): 1164 Protein kinases are enzymes that phosphorylate other pro 1172), and HER2-overexpressing cancer Such as breast can teins and/or themselves (i.e., autophosphorylation). Protein cer and ovarian cancer. kinases can be generally classified into three major groups based upon their substrate utilization: tyrosine kinases which 30 SUMMARY predominantly phosphorylate Substrates on tyrosine residues Described herein are compounds capable of selectively (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, inhibiting certain isoform(s) of class I PI3K without substan Src, abl), serine/threonine kinases which predominantly phos tially affecting the activity of the remaining isoforms of the phorylate Substrates on serine and/or threonine residues (e.g., same class. For example, non-limiting examples of inhibitors mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and dual 35 capable of selectively inhibiting PI3K-8 and/or PI3K-Y, but specificity kinases which phosphorylate Substrates on without substantially affecting the activity of PI3K-B are tyrosine, serine and/or threonine residues. disclosed. Such inhibitors can be effective in ameliorating Lipid kinases are enzymes that catalyze the phosphoryla disease conditions associated with PI3K-ö?y activity. tion of lipids. These enzymes, and the resulting phosphory In one aspect, described herein are compounds of Formula lated lipids and lipid-derived biologically active organic mol 40 (I): ecules, play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differ entiation. Certain lipid kinases are membrane associated and Formula (I) they catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of Such enzymes 45 include phosphoinositide(s) kinases (e.g., PI3 kinases, PI4 Kinases), diacylglycerol kinases, and sphingosine kinases. The phosphoinositide 3-kinases (PI3Ks) signaling path way is one of the most highly mutated systems in human cancers. PI3K signaling is also a key factor in many other 50 diseases and disorders. PI3K signaling is involved in many disease states including allergic contact dermatitis, rheuma toid arthritis, osteoarthritis, inflammatory bowel diseases, or its pharmaceutically acceptable forms thereof, wherein chronic obstructive pulmonary disorder, psoriasis, multiple WS is N, CHR or CR; Sclerosis, asthma, disorders related to diabetic complications, 55 R" is hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alky and inflammatory complications of the cardiovascular system nyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, Such as acute coronary syndrome. heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, PI3Ks are members of a unique and conserved family of acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, intracellular lipid kinases that phosphorylate the 3'-OH group Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbon on phosphatidylinositols or phosphoinositides. The PI3K 60 ate, or NR'R'" wherein R' and R" are taken together with family comprises 15 kinases with distinct Substrate specifici nitrogen to form a cyclic moiety; ties, expression patterns, and modes of regulation. The class I Cy is aryl or heteroaryl substituted by 0-4 occurrences of PI3Ks (p110C, p110B, p1106, and p110y) are typically acti R; vated by tyrosine kinases or G-protein coupled receptors to R" is -(L)-R'; generate PIP3, which engages downstream effectors such as 65 each L is independently a bond, alkylene, heteroalkylene, those in the Akt/PDK1 pathway, mTOR, the Tec family N(R) , S(O) , S(O) , S: , —C(=O) , kinases, and the Rho family GTPases. The class II and III - P(=O)R’ or —O : US 8,901,133 B2 3 4 R" is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het Formula (II) eroarylalkyl, alkoxy, heterocyclyloxy, heterocycloalkyloxy, RI amino, amido, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, y’s NN (C—O) NR'R' or NR'R''. R'' and R' are each independently hydrogen, alkyl, het eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, W&2S4 i arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, 10 R4 Yw, Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or R'' and R* are taken or its pharmaceutically acceptable forms thereof, wherein n, together with nitrogen to form a cyclic moiety; Z, Ral, R2, L. R", R'', R°, R, X,Y, R, Rio, R, R l, R12, R13 R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, het and W are as defined for Formula (I); eroalkyl, aryl, or heteroaryl; 15 W is Nor CR, W is N or CR, W is Nor CR7, and W. each R is independently alkyl, heteroalkyl, haloalkyl, alk is N or CR, wherein no more than two Natoms are adjacent; enyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, R. R. R and R'' are independently hydrogen, alkyl, amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, nitro, phos cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phate, urea, carbonate, or NR'R'" wherein R' and R" are taken alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, together with nitrogen to form a cyclic moiety; alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, X is absent or is —(CH(R')) ; cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'" wherein R' and R" are taken together with nitrogen to form a 25 cyclic moiety. In some embodiments, the compound of Formula (II) has (=O)NH , N(R)C(R') , C(=O) (CHR') , the structure of Formula (IIa): C(=O) N(R)-(CHR) or - P(=O)R : each Z is an integer of 1, 2, 3, or 4: n is an integer of 0, 1, 2, 3, or 4: 30 each R is independently hydrogen, alkyl, cycloalkyl, het Formula (IIa) erocycloalkyl, heterocycloalkylalkyl, heteroalkyl, aryl, or heteroaryl; W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, wherein W is optionally substituted with one or more R', 35 Rl', R12, and R13; each R is independently hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl; and each R', R'', R', and R' is independently hydrogen, 40 alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or its pharmaceutically acceptable forms thereof, wherein heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo W is Nor CR, W is N or CR, W is Nor CR7, and W. nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, is N or CR, wherein no more than two Natoms are adjacent; 45 R" is -(L)-R'; phosphate, urea, carbonate, or NR'R'" wherein R' and R" are each L is independently alkylene, heteroalkylene, taken together with nitrogen to form a cyclic moiety. S(O), ... —S , —N(R)—, or —O—; In some embodiments, the compound of Formula (I) has n is an integer of 0, 1, 2, 3 or 4: the structure of Formula (Ia): R" is alkyl, Substituted alkyl, a heterocyclic group com 50 prising at least two heteroatoms chosen from O, N and S. wherein R' is optionally substituted by R'; or R' is Formula (Ia) NRail R2, R'' and R' are each independently hydrogen, alkyl, het eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, 55 arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or R'' and R' are taken together with nitrogen to form a cyclic moiety; 60 R. R. R. R7 and Rare each independently hydrogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, or its pharmaceutically acceptable forms thereof, wherein n, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Z, Ral, R2, L. R", R", R2, R, R, X, Y, R, R10, R, R11, R12, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, R" and W are as defined for Formula (I); and alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, W is N or CR. 65 cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R''. In some embodiments, the compound of Formula (I) is a wherein R' and R" are taken together with nitrogen to form a compound of Formula (II): cyclic moiety; US 8,901,133 B2 6 Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or R'' and R' are taken together with nitrogen to form a cyclic moiety; R. R. R. R7 and Rare independently hydrogen, alkyl, C(R') , or -C(=O)–(CHR') : heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero each Z is an integer of 1, 2, 3, or 4: cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each R and R is independently hydrogen, C-Clo alkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, C-C,cycloalkyl, heterocycloalkyl, C-Coheteroalkyl, aryl, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, or heteroaryl; cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R''. each R" is independently hydrogen, alkyl, cycloalkyl, het 10 wherein R' and R" are taken together with nitrogen to form a eroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halo: cyclic moiety; W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, X is absent or is —(CH(R')) ; wherein W is substituted with one or more R. R'', R', or R'; and each R', R', R', and R' is independently hydrogen, 15 alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy C(R') , or C(=O)–(CHR') : cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, each Z is an integer of 1, 2, 3, or 4: heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo each R and R is independently hydrogen, C-Coalkyl, nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, C-C cycloalkyl, heterocycloalkyl, C-Coheteroalkyl, aryl, phosphate, urea, carbonate, or NR'R", wherein R' and R" are or heteroaryl; taken together with nitrogen to form a cyclic moiety; and each R" is independently hydrogen, alkyl, cycloalkyl, het at least one of R. R. R. and R7 is halo. eroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halo: In some embodiments, the compound of Formula (II) has and the structure of Formula (IIb): 25 W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, wherein Wis substituted with one or more R. R'', R', and Formula (IIb) R; and R8 R1 each R', R', R', and R' is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy NN 30 cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, 2 i phosphate, urea, carbonate, or NR'R", wherein R' and R" are 4 R Yn 35 taken together with nitrogen to form a cyclic moiety. In some embodiments, the compound of Formula (III) has the structure of Formula (IIIa): or its pharmaceutically acceptable forms thereof, wherein R. Ra Rs. X, Y, and W are as defined for Formula (II). In some embodiments, the compound of Formula (I) has 40 Formula (IIIa) the structure of Formula (III): Ral / (YNL Formula (III) 4 pi Ra2 O W. Ral 45 w31"S1SN / L W2 2 (YNpi Ra2 Y wi 2 i W w81'N1SN R4 Y 50 YW, W2 2 els2 Y wi W5 i or its pharmaceutically acceptable forms thereof, wherein L. Y n, z, R, R2, X,Y, R,R,R,R,R,R,R,R, and W. YW, 55 are as defined for Formula (III); W is Nor CR, Wis N or CR, W is Nor CR7, and W. or its pharmaceutically acceptable forms thereof, wherein is N or CR, wherein no more than two Natoms are adjacent; W' is Nor CR', W is Nor CR, Wis N or CR7, W is N and or CR, and W is N or CR, wherein no more than two N R. R. R. and R'' are independently hydrogen, alkyl, atoms are adjacent; 60 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each L is alkylene, heteroalkylene. —S-, -N(R)—, or aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy —O—; cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, n is 0 or 1; Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, R'' and R' are each independently hydrogen, alkyl, het nitro, phosphate, urea, carbonate, or NRR", wherein R' and eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, 65 R" are taken together with nitrogen to form a cyclic moiety. arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy In some embodiments, the compound of Formula (IIIa) has cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, the structure of Formula (IIIb): US 8,901,133 B2 8 In some embodiments, the compound of Formula (IVa) has Formula (IIIb) the structure of Formula (IVb): O Formula (IVb) 10 R8 R NN or its pharmaceutically acceptable forms thereof, wherein L. Il Z, Rail, R2, R, X, Y, R, R8, R2, R, R10, Rl l, R12, R13 and 15 W are as defined for Formula (III). In some embodiments, the compound of Formula (I) has r the structure of Formula (IV): R4 Yn W.

Formula (IV) or its pharmaceutically acceptable forms thereof, wherein Z. X, Y, R, R7, R. R. R. R., R, R2, R', and W are as defined for Formula (IV). In some embodiments, the compound of Formula (I) has 25 the structure of Formula (V):

Formula (V) R3 R1 30 NN or its pharmaceutically acceptable forms thereof, wherein Z. n, L,R,R, X,Y, R,R,R,R,R,R,R,R, and W. 21 i are as defined for Formula (I); 35 W' is Nor CR', W is Nor CR, Wis N or CR7, W is N Yn or CR, and W is N or CR, wherein no more than two N atoms are adjacent; and R. R. R and R'' are independently hydrogen, alkyl, or its pharmaceutically acceptable form thereof, wherein n, Z. heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, 40 L., X, Y, R", R'', Ral, R2, R°, R, R, R10, R, R l, R12, R13 alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, and W areas defined for Formula (I). alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, In another aspect, provided herein are compositions (e.g., a cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'" pharmaceutical composition) comprising one or more phar wherein R' and R" are taken together with nitrogen to form a maceutically acceptable excipients and a compound as cyclic moiety. 45 described herein (e.g., a compound of Formula I, II, III, IV or In some embodiments, the compound of Formula (IV) has V). For example, the composition is a liquid, Solid, semi the structure of Formula (IVa): Solid, gel, or an aerosol form. In another aspect, provided herein is a method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase), comprising: Formula (IVa) 50 contacting the PI3 kinase with an effective amount of a com pound described herein. In some embodiments, the PI3 kinase is PI3 kinase delta or PI3 kinase gamma. The step of contacting can further com CN prise contacting a cell that expresses said PI3 kinase. In some 55 embodiments, the method further comprises administering a second therapeutic agent to the cell. In another aspect, provided herein is a method for treating W a condition associated with PI3 kinase, comprising adminis y n n N tering to a subject in need thereof an effective amount of the W& 2 60 compound described herein, such as a compound of Formula Y wi 21N (I), (II), (III). (IV) or (V). In some embodiments, the condi tion associated with PI3 kinase is selected from asthma, R4 ls emphysema, bronchitis, psoriasis, allergy, anaphylaxis, rheu Wd matoid arthritis, graft versus host disease, lupus erythemato or its pharmaceutically acceptable forms thereof, wherein Z. 65 Sus, psoriasis, restenosis, benign prostatic hypertrophy, dia X, Y, Wil, W2, W3, W4, R*, R, R7, R8, R14, R, R10, R, R11, betes, pancreatitis, proliferative glomerulonephritis, R'', R', and W are as defined for Formula (IV). diabetes—induced renal disease, inflammatory bowel dis US 8,901,133 B2 10 ease, atherosclerosis, eczema, Scleroderma, diabetes, diabetic In certain embodiments, provided herein is a reaction mix retinopathy, retinopathy of prematurity, age-related macular ture comprising a compound as described herein. degeneration, hemangioma, glioma, melanoma, Kaposi's In certain embodiments, provided herein is a kit compris sarcoma and ovarian, breast, lung, pancreatic, prostate, colon ing a compound as described herein. and epidermoid cancer. In some embodiments, a method is provided for treating a In certain embodiments, a compound as disclosed herein disease or disorder described herein, the method comprising selectively modulates phosphatidyl inositol-3 kinase (PI3 administering a therapeutically effective amount of a com kinase) delta isoform. In certain embodiments, the compound pound or pharmaceutical composition described herein to a selectively inhibits the delta isoform over the beta isoform. Subject. By way of non-limiting example, the ratio of selectivity can 10 In some embodiments, provided herein is a method for be greater than a factor of about 10, greater than a factor of treating a PI3K mediated disorder in a subject, the method about 50, greater than a factor of about 100, greater than a comprising administering a therapeutically effective amount factor of about 200, greater than a factor of about 400, greater of a compound or pharmaceutical composition described than a factor of about 600, greater than a factor of about 800, herein. greater than a factor of about 1000, greater than a factor of 15 In certain embodiments, provided herein is the use of a about 1500, greater than a factor of about 2000, greater than compound of a pharmaceutical composition described herein a factor of about 5000, greater than a factor of about 10,000, in the manufacture of a medicament for the treatment of a or greater than a factor of about 20,000, where selectivity can disease or disorder described herein in a subject. be measured by ICso, among other means. In certain embodi In certain embodiments, provided herein is use of a com ments, the PI3 kinase delta isoform ICso activity of a com pound or a pharmaceutical composition described herein in pound as disclosed herein can be less than about 1000 nM, the manufacture of a medicament for the treatment of a PI3K less than about 100 nM, less than about 10 nM, or less than mediated disorder in a Subject. about 1 nM. In certain embodiments, provided herein is a composition INCORPORATION BY REFERENCE (e.g., a pharmaceutical composition) comprising a compound 25 as described hereinandone or more pharmaceutically accept All publications, patents, and patent applications men able excipients. In some embodiments, provided herein is a tioned in this specification are herein incorporated by refer method of inhibiting a phosphatidyl inositol-3 kinase (PI3 ence to the same extent as if each individual publication, kinase), comprising contacting the PI3 kinase with an effec patent, or patent application was specifically and individually tive amount of a compound orpharmaceutical composition as 30 indicated to be incorporated by reference. described herein. In certain embodiments, a method is pro vided for inhibiting a phosphatidyl inositol-3 kinase (PI3 DETAILED DESCRIPTION kinase) wherein said PI3 kinase is present in a cell. The inhibition can take place in a Subject Suffering from a disorder While specific embodiments of the present disclosure have selected from cancer, bone disorder, inflammatory disease, 35 been discussed, the specification is illustrative and not restric immune disease, nervous system disease (e.g., a neuropsy tive. Many variations of this disclosure will become apparent chiatric disorder), metabolic disease, respiratory disease, to those skilled in the art upon review of this specification. thrombosis, and cardiac disease. In certain embodiments, a The full scope of the disclosure should be determined by second therapeutic agent is administered to the Subject. reference to the claims, along with their full scope of equiva In certain embodiments, a method is provided of selec 40 lents, and the specification, along with Such variations. tively inhibiting a phosphatidylinositol-3 kinase (PI3 kinase) In one embodiment, provided are heterocyclyl compounds, delta isoform over PI3 kinase beta isoform wherein the inhi and pharmaceutically acceptable forms, including, but not bition takes place in a cell. Non-limiting examples of the limited to, salts, hydrates, Solvates, isomers, prodrugs, and methods disclosed herein can comprise contacting PI3 kinase isotopically labeled derivatives thereof. delta isoform with an effective amount of a compound or 45 In another embodiment, provided are methods of treating pharmaceutical composition as disclosed herein. In an and/or managing various diseases and disorders, which com embodiment, such contact can occur in a cell. In certain prises administering to a patient a therapeutically effective embodiments, a method is provided of selectively inhibiting a amount of a compound provided herein, or a pharmaceuti phosphatidyl inositol-3 kinase (PI3 kinase) delta isoform cally acceptable form (e.g., salts, hydrates, Solvates, isomers, over PI3 kinase beta isoform wherein the inhibition takes 50 prodrugs, and isotopically labeled derivatives) thereof. place in a subject Suffering from a disorder selected from Examples of diseases and disorders are described herein. cancer, bone disorder, inflammatory disease, immune dis In another embodiment, provided are methods of prevent ease, nervous system disease (e.g., a neuropsychiatric disor ing various diseases and disorders, which comprises admin der), metabolic disease, respiratory disease, thrombosis, and istering to a patient in need of Such prevention a prophylac cardiac disease, said method comprising administering an 55 tically effective amount of a compound provided herein, or a effective amount of a compound or pharmaceutical compo pharmaceutically acceptable form (e.g., salts, hydrates, Sol sition to said subject. In certain embodiments, provided Vates, isomers, prodrugs, and isotopically labeled derivatives) herein is a method of treating a Subject Suffering from a thereof. Examples of diseases and disorders are described disorder associated with phosphatidyl inositol-3 kinase (PI3 herein. kinase), said method comprising selectively modulating the 60 In other embodiments, a compound provided herein, or a phosphatidyl inositol-3 kinase (PI3 kinase) delta isoform pharmaceutically acceptable form (e.g., salts, hydrates, Sol over PI3 kinase beta isoform by administering an amount of a Vates, isomers, prodrugs, and isotopically labeled derivatives) compound or pharmaceutical composition to said subject, thereof, is administered in combination with another drug wherein said amount is sufficient for selective modulation of ("second active agent”) or treatment. Second active agents PI3 kinase delta isoform over PI3 kinase beta isoform. 65 include Small molecules and large molecules (e.g., proteins In some embodiments, provided herein is a method of and antibodies), examples of which are provided herein, as making a compound as described herein. well as stem cells. Other methods ortherapies that can be used US 8,901,133 B2 11 12 in combination with the administration of compounds pro the administration of one or more chemotherapeutic drugs vided herein include, but are not limited to, surgery, blood and/or other agents to a cancer patient by various methods, transfusions, immunotherapy, biological therapy, radiation including intravenous, oral, intramuscular, intraperitoneal, therapy, and other non-drug based therapies presently used to intravesical, Subcutaneous, transdermal, buccal, or inhalation treat, prevent or manage various disorders described herein. or in the form of a Suppository. Also provided are pharmaceutical compositions (e.g., The term “cell proliferation” refers to a phenomenon by single unit dosage forms) that can be used in the methods which the cell number has changed as a result of division. provided herein. In one embodiment, pharmaceutical compo This term also encompasses cell growth by which the cell sitions comprise a compound provided herein, or a pharma morphology has changed (e.g., increased in size) consistent ceutically acceptable form (e.g., salts, hydrates, Solvates, iso 10 with a proliferative signal. mers, prodrugs, and isotopically labeled derivatives) thereof, The term “co-administration,” “administered in combina and optionally one or more second active agents. tion with and their grammatical equivalents, as used herein, Unless defined otherwise, all technical and scientific terms encompasses administration of two or more agents to subject used herein have the same meaning as is commonly under so that both agents and/or their metabolites are present in the stood by one of skill in the art to which this specification 15 Subject at the same time. Co-administration includes simul pertains. taneous administration in separate compositions, administra As used in the specification and claims, the singular form tion at different times in separate compositions, or adminis “a”, “an and “the includes plural references unless the tration in a composition in which both agents are present. context clearly dictates otherwise. The term “effective amount’ or “therapeutically effective As used herein, “agent” or “biologically active agent” amount refers to that amount of a compound or pharmaceu refers to a biological, pharmaceutical, or chemical compound tical composition described herein that is sufficient to effect or other moiety. Non-limiting examples include simple or the intended application including, but not limited to, disease complex organic or inorganic molecules, a peptide, a protein, treatment, as illustrated below. The therapeutically effective an oligonucleotide, an antibody, an antibody derivative, an amount can vary depending upon the intended application (in antibody fragment, a vitamin, a vitamin derivative, a carbo 25 vitro or in vivo), or the Subject and disease condition being hydrate, a toxin, or a chemotherapeutic compound, and treated, e.g., the weight and age of the Subject, the severity of metabolites thereof. Various compounds can be synthesized, the disease condition, the manner of administration and the for example, Small molecules and oligomers (e.g., oligopep like, which can readily be determined by one of ordinary skill tides and oligonucleotides), and synthetic organic com in the art. The term also applies to a dose that will induce a pounds based on various core structures. In addition, various 30 particular response in target cells, e.g., reduction of platelet natural sources can provide compounds for screening, Such as adhesion and/or cell migration. The specific dose will vary plant or animal extracts, and the like. A skilled artisan can depending on the particular compounds chosen, the dosing readily recognize that there is no limit as to the structural regimen to be followed, whether it is administered in combi nature of the agents of this disclosure. nation with other agents, timing of administration, the tissue The term “agonist’ as used herein refers to a compound or 35 to which it is administered, and the physical delivery system agent having the ability to initiate or enhance a biological in which it is carried. function of a target protein or polypeptide, such as increasing As used herein, the terms “treatment”, “treating”, “palliat the activity or expression of the target protein or polypeptide. ing” and “ameliorating are used interchangeably herein. Accordingly, the term “agonist' is defined in the context of These terms refer to an approach for obtaining beneficial or the biological role of the target protein or polypeptide. While 40 desired results including, but not limited to, therapeutic ben Some agonists herein specifically interact with (e.g., bind to) efit and/or a prophylactic benefit. By therapeutic benefit is the target, compounds and/or agents that initiate or enhance a meant eradication or amelioration of the underlying disorder biological activity of the target protein or polypeptide by being treated. Also, a therapeutic benefit is achieved with the interacting with other members of the signal transduction eradication or amelioration of one or more of the physiologi pathway of which the target polypeptide is a member are also 45 cal symptoms associated with the underlying disorder Such specifically included within this definition. that an improvement is observed in the patient, notwithstand The terms “antagonist' and “inhibitor are used inter ing that the patient can still be afflicted with the underlying changeably, and they refer to a compound or agent having the disorder. For prophylactic benefit, the pharmaceutical com ability to inhibit a biological function of a target protein or positions can be administered to a patient at risk of develop polypeptide. Such as by inhibiting the activity or expression of 50 ing a particular disease, or to a patient reporting one or more the target protein or polypeptide. Accordingly, the terms of the physiological symptoms of a disease, even though a “antagonist' and “inhibitors' are defined in the context of the diagnosis of this disease may not have been made. biological role of the target protein or polypeptide. While A “therapeutic effect,” as that term is used herein, encom Some antagonists herein specifically interact with (e.g., bind passes a therapeutic benefit and/or a prophylactic benefit as to) the target, compounds that inhibit a biological activity of 55 described above. A prophylactic effect includes delaying or the target protein or polypeptide by interacting with other eliminating the appearance of a disease or condition, delaying members of the signal transduction pathway of which the or eliminating the onset of symptoms of a disease or condi target protein or polypeptide is a member are also specifically tion, slowing, halting, or reversing the progression of a dis included within this definition. Non-limiting examples of ease or condition, or any combination thereof. biological activity inhibited by an antagonist include those 60 As used herein, a “pharmaceutically acceptable form of a associated with the development, growth, or spread of a disclosed compound includes, but is not limited to, pharma tumor, or an undesired immune response as manifested in ceutically acceptable salts, hydrates, Solvates, isomers, pro autoimmune disease. drugs, and isotopically labeled derivatives of disclosed com An “anti-cancer agent”, “anti-tumor agent' or “chemo pounds. therapeutic agent” refers to any agent useful in the treatment 65 In certain embodiments, the pharmaceutically acceptable of a neoplastic condition. One class of anti-cancer agents form thereof is a pharmaceutically acceptable salt. As used comprises chemotherapeutic agents. "Chemotherapy means herein, the term “pharmaceutically acceptable salt” refers to US 8,901,133 B2 13 14 those salts which are, within the scope of Sound medical In certain embodiments, the pharmaceutically acceptable judgment, Suitable for use in contact with the tissues of Sub form thereof is a prodrug. As used herein, the term “prodrug jects without undue toxicity, irritation, allergic response and refers to compounds that are transformed in vivo to yield a the like, and are commensurate with a reasonable benefit/risk disclosed compound or a pharmaceutically acceptable form ratio. Pharmaceutically acceptable salts are well known in the 5 of the compound. In some embodiments, a prodrug is a com art. For example, Berge et al. describes pharmaceutically pound that may be converted under physiological conditions acceptable salts in detail in J. Pharmaceutical Sciences or by Solvolysis to a biologically active compound described (1977) 66:1-19. Pharmaceutically acceptable salts of the herein. Thus, the term “prodrug” refers to a precursor of a compounds provided herein include those derived from suit biologically active compound that is pharmaceutically able inorganic and organic acids and bases. Examples of 10 acceptable. A prodrug can be inactive when administered to a pharmaceutically acceptable, nontoxic acid addition salts are Subject, but is converted in vivo to an active compound, for salts of an amino group formed with inorganic acids such as example, by hydrolysis (e.g., hydrolysis in blood). In certain hydrochloric acid, hydrobromic acid, phosphoric acid, Sulfu cases, a prodrug has improved physical and/or delivery prop ric acid and perchloric acid or with organic acids such as erties over the parent compound. Prodrugs are typically acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, 15 designed to enhance pharmaceutically and/or pharmacoki Succinic acid or malonic acid or by using other methods used netically based properties associated with the parent com in the art such as ion exchange. Other pharmaceutically pound. The prodrug compound often offers advantages of acceptable salts include adipate, alginate, ascorbate, aspar solubility, tissue compatibility or delayed release in a mam tate, benzenesulfonate, besylate, benzoate, bisulfate, borate, malian organism (see, e.g., Bundgard, H., Design of Prodrugs butyrate, camphorate, camphorsulfonate, citrate, cyclopen (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of tanepropionate, digluconate, dodecylsulfate, ethane prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Sulfonate, formate, fumarate, glucoheptonate, glycerophos Novel Delivery Systems.” A.C.S. Symposium Series, Vol. 14, phate, gluconate, hemisulfate, heptanoate, hexanoate, and in Bioreversible Carriers in Drug Design, ed. Edward B. hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lac Roche, American Pharmaceutical Association and Pergamon tate, laurate, lauryl Sulfate, malate, maleate, malonate, meth 25 Press, 1987, both of which are incorporated in full by refer anesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, ence herein. Exemplary advantages of a prodrug can include, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, but are not limited to, its physical properties, such as 3-phenylpropionate, phosphate, picrate, pivalate, propionate, enhanced water solubility for parenteral administration at Stearate. Succinate, Sulfate, tartrate, thiocyanate, p-toluene physiological pH compared to the parent compound, or it Sulfonate, undecanoate, Valerate salts, and the like. In some 30 enhances absorption from the digestive tract, or it can embodiments, organic acids from which salts can be derived enhance drug stability for long-term storage. include, for example, acetic acid, propionic acid, glycolic The term "prodrug is also meant to include any covalently acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, bonded carriers, which release the active compound in vivo Succinic acid, fumaric acid, tartaric acid, citric acid, benzoic when such prodrug is administered to a Subject. Prodrugs of acid, cinnamic acid, mandelic acid, methanesulfonic acid, 35 an active compound, as described herein, can be prepared by ethanesulfonic acid, p-toluenesulfonic acid, Salicylic acid, modifying functional groups present in the active compound and the like. Salts derived from appropriate bases include in Such a way that the modifications are cleaved, either in alkali metal, alkaline earth metal, ammonium and N+(Ca routine manipulation or in Vivo, to the parent active com alkyl)-salts. Representative alkali or alkaline earth metal pound. Prodrugs include compounds wherein a hydroxy, salts include Sodium, lithium, potassium, calcium, magne 40 amino or mercapto group is bonded to any group that, when sium, iron, Zinc, copper, manganese, aluminum, and the like. the prodrug of the active compound is administered to a Further pharmaceutically acceptable salts include, when subject, cleaves to form a free hydroxy, free amino or free appropriate, nontoxic ammonium, quaternary ammonium, mercapto group, respectively. Examples of prodrugs include, and amine cations formed using counterions such as halide, but are not limited to, acetate, formate and benzoate deriva hydroxide, carboxylate, Sulfate, phosphate, nitrate, lower 45 tives of an alcohol or acetamide, formamide and benzamide alkylsulfonate and arylsulfonate. Organic bases from which derivatives of an amine functional group in the active com salts can be derived include, for example, primary, secondary, pound and the like. and tertiary amines, Substituted amines including naturally For example, if a disclosed compound or a pharmaceuti occurring Substituted amines, cyclic amines, basic ion cally acceptable form of the compound contains a carboxylic exchange resins, and the like. Such as isopropylamine, trim 50 acid functional group, a prodrug can comprise an ester ethylamine, diethylamine, triethylamine, tripropylamine, and formed by the replacement of the hydrogenatom of the acid ethanolamine. In some embodiments, the pharmaceutically group with a group Such as (C-Cs)alkyl, (C-C)alkanoy acceptable base addition salt is chosen from ammonium, loxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon potassium, Sodium, calcium, and magnesium salts. atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 In certain embodiments, the pharmaceutically acceptable 55 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 form is a “solvate” (e.g., a hydrate). As used herein, the term carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to “solvate” refers to compounds that further include a stoichio 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl hav metric or non-stoichiometric amount of solvent bound by ing from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminom non-covalent intermolecular forces. The solvate can be of a ethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbo disclosed compound or a pharmaceutically acceptable salt 60 nyl)amino)ethyl having from 4 to 10 carbon atoms, thereof. Where the solvent is water, the solvate is a “hydrate'. 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, Pharmaceutically acceptable Solvates and hydrates are com di-N,N-(C-C)alkylamino(C-C)alkyl (such as B-dim plexes that, for example, can include 1 to about 100, or 1 to ethylaminoethyl), carbamoyl-(C-C)alkyl, N,N-di(C-C) about 10, or one to about 2, 3 or 4, solventor water molecules. alkylcarbamoyl-(C-C)alkyl and piperidino-, pyrrolidino It will be understood that the term “compound” as used herein 65 or morpholino(C-C)alkyl. encompasses the compound and Solvates of the compound, as Similarly, if a disclosed compound or a pharmaceutically well as mixtures thereof. acceptable form of the compound contains an alcohol func US 8,901,133 B2 15 16 tional group, a prodrug can be formed by the replacement of Prelog R-S system. When a compound is a pure enantiomer, the hydrogen atom of the alcohol group with a group Such as the stereochemistry at each chiral carbon can be specified by (C-C)alkanoyloxymethyl, 1-((C-C)alkanoyloxy)ethyl, either R or S. Resolved compounds whose absolute configu 1-methyl-1-((C-C)alkanoyloxy)ethyl (C-C)alkoxycarbo ration is unknown can be designated (+) or (-) depending on nyloxymethyl, N-(C-C)alkoxycarbonylaminomethyl, the direction (dextro- or levorotatory) which they rotate plane Succinoyl, (C-C)alkanoyl, C.-amino(C-C)alkanoyl, aryla polarized light at the wavelength of the sodium D line. Certain cyl and C-aminoacyl, or C.-aminoacyl-C-aminoacyl, where of the compounds described herein contain one or more each -aminoacyl group is independently selected from the asymmetric centers and can thus give rise to enantiomers, naturally occurring L-amino acids, P(O)(OH), —P(O)(O diastereomers, and other stereoisomeric forms that can be (C-C)alkyl) or glycosyl (the radical resulting from the 10 defined, in terms of absolute stereochemistry, as (R)- or (S)-. removal of a hydroxyl group of the hemiacetal form of a The present chemical entities, pharmaceutical compositions carbohydrate). and methods are meant to include all Such possible isomers, If a disclosed compound or a pharmaceutically acceptable including racemic mixtures, optically pure forms and inter form of the compound incorporates an amine functional mediate mixtures. Optically active (R)- and (S)-isomers can group, a prodrug can be formed by the replacement of a 15 be prepared, for example, using chiral synthons or chiral hydrogen atom in the amine group with a group Such as reagents, or resolved using conventional techniques. The R-carbonyl, RO-carbonyl, NRR'-carbonyl where RandR'are optical activity of a compound can be analyzed via any Suit each independently (C-Co.)alkyl, (C-C)cycloalkyl, ben able method, including but not limited to chiral chromatog Zyl, or R-carbonyl is a natural O-aminoacyl or natural C-ami raphy and polarimetry, and the degree of predominance of noacyl-natural O-aminoacyl, -C(OH)C(O)CY' wherein Y' one stereoisomer over the other isomer can be determined. is H., (C-C)alkyl or benzyl, -C(OY)Y wherein Y is Isolation and purification of the chemical entities and inter (C-C) alkyl and Y is (C-C)alkyl, carboxy(C-C)alkyl, mediates described herein can be effected, if desired, by any amino(C-C)alkyl or mono-N- or di-N,N-(C-C)alky Suitable separation or purification procedure Such as, for laminoalkyl, -C(Y)Y wherein Y is Hor methyl and Y is example, filtration, extraction, crystallization, column chro mono-N- or di-N,N-(C-C)alkylamino, morpholino, pip 25 matography, thin-layer chromatography or thick-layer chro eridin-1-yl or pyrrolidin-1-yl. matography, or a combination of these procedures. Specific Geometric isomers can be represented by the symbol illustrations of Suitable separation and isolation procedures which denotes a bond that can be a single, double or can be had by reference to the examples hereinbelow. How triple bond as described herein. Provided herein are various ever, other equivalent separation or isolation procedures can geometric isomers and mixtures thereof resulting from the 30 also be used. arrangement of Substituents around a carbon-carbon double When desired, the (R)- and (S)-isomers of the compounds bond or arrangement of substituents around a carbocyclic of the present invention, if present, may be resolved by meth ring. Substituents around a carbon-carbon double bond are ods known to those skilled in the art, for example by forma designated as being in the “Z” or “E” configuration wherein tion of diastereoisomeric salts or complexes which may be the terms “Z and “E” are used in accordance with IUPAC 35 separated, for example, by crystallization; via formation of standards. Unless otherwise specified, structures depicting diastereoisomeric derivatives which may be separated, for double bonds encompass both the “E” and “Z” isomers. example, by crystallization, gas-liquid or liquid chromatog Substituents around a carbon-carbon double bond alterna raphy; selective reaction of one enantiomer with an enanti tively can be referred to as “cis' or “trans,” where “cis' omer-specific reagent, for example enzymatic oxidation or represents substituents on the same side of the double bond 40 reduction, followed by separation of the modified and and “trans' represents substituents on opposite sides of the unmodified enantiomers; or gas-liquid or liquid chromatog double bond. The arrangement of Substituents around a car raphy in a chiral environment, for example on a chiral Sup bocyclic ring can also be designated as “cis' or “trans.” The port, such as silica with a bound chiral ligand or in the pres term “cis' represents substituents on the same side of the ence of a chiral solvent. Alternatively, a specific enantiomer plane of the ring, and the term “trans' represents Substituents 45 may be synthesized by asymmetric synthesis using optically on opposite sides of the plane of the ring. Mixtures of com active reagents, Substrates, catalysts or solvents, or by con pounds wherein the substituents are disposed on both the Verting one enantiomer to the other by asymmetric transfor same and opposite sides of plane of the ring are designated mation. “cis/trans.” The “enantiomeric excess' or “96 enantiomeric excess' of In certain embodiments, the pharmaceutically acceptable 50 a composition can be calculated using the equation shown form thereof is an isomer. “Isomers' are different compounds below. In the example shown below, a composition contains that have the same molecular formula. “Stereoisomers' are 90% of one enantiomer, e.g., the Senantiomer, and 10% of the isomers that differ only in the way the atoms are arranged in other enantiomer, e.g., the Renantiomer. space. As used herein, the term "isomer' includes any and all geometric isomers and Stereoisomers. For example, "iso 55 ee=(90–10)/100=80%. mers' include cis- and trans-isomers, E- and Z-isomers, R Thus, a composition containing 90% of one enantiomer and and S-enantiomers, diastereomers, (d)-isomers, (1)-isomers, 10% of the other enantiomer is said to have an enantiomeric racemic mixtures thereof, and other mixtures thereof, as fall excess of 80%. Some of the compositions described herein ing within the scope of this disclosure. contain an enantiomeric excess of at least about 50%, 75%, "Enantiomers' are a pair of stereoisomers that are non 60 90%. 95%, or 99% of the S-enantiomer. In other words, the Superimposable mirror images of each other. A mixture of a compositions contain an enantiomeric excess of the Senan pair of enantiomers in any proportion can be known as a tiomer over the Renantiomer. In other embodiments, some “racemic mixture. The term “(t)' is used to designate a compositions described herein contain an enantiomeric racemic mixture where appropriate. “Diastereoisomers' are excess of at least about 50%, 75%, 90%, 95%, or 99% of the Stereoisomers that have at least two asymmetric atoms, but 65 Renantiomer. In other words, the compositions contain an which are not mirror-images of each other. The absolute enantiomeric excess of the Renantiomer over the Senanti Stereochemistry is specified according to the Cahn-Ingold O. US 8,901,133 B2 17 18 For instance, an isomer?enantiomer can, in some embodi entities is a racemic mixture of (S)- and (R)-isomers. In ments, be provided substantially free of the corresponding another embodiment, the mixture of the identical chemical enantiomer, and can also be referred to as "optically entities (except for their stereochemical orientations), contain enriched,” “enantiomerically enriched.” “enantiomerically predominately (S)-isomers or predominately (R)-isomers. pure' and “non-racemic, as used interchangeably herein. For example, the (S)-isomers in the mixture of identical These terms refer to compositions in which the percent by chemical entities are present at about 55%, about 60%, about weight of one enantiomer is greater than the amount of that 65%, about 70%, about 75%, about 80%, about 85%, about one enantiomer in a control mixture of the racemic composi 90%, about 95%, about 96%, about 97%, about 98%, about tion (e.g., greater than 1:1 by weight). For example, an enan 99%, about 99.5%, or more, relative to the (R)-isomers. In tiomerically enriched preparation of the Senantiomer, means 10 some embodiments, the (S)-isomers in the mixture of identi a preparation of the compound having greater than about 50% cal chemical entities are present at an (S)-enantiomeric by weight of the Senantiomer relative to the Renantiomer, excess of greater than about 55% to about 99.5%, greater than such as at least about 75% by weight, further such as at least about 60% to about 99.5%, greater than about 65% to about about 80% by weight. In some embodiments, the enrichment 99.5%, greater than about 70% to about 99.5%, greater than can be much greater than about 80% by weight, providing a 15 about 75% to about 99.5%, greater than about 80% to about “substantially enantiomerically enriched,” “substantially 99.5%, greater than about 85% to about 99.5%, greater than enantiomerically pure' or a “substantially non-racemic' about 90% to about 99.5%, greater than about 95% to about preparation, which refers to preparations of compositions 99.5%, greater than about 96% to about 99.5%, greater than which have at least about 85% by weight of one enantiomer about 97% to about 99.5%, greater than about 98% to greater relative to other enantiomer, such as at least about 90% by than about 99.5%, greater than about 99% to about 99.5% or weight, and further such as at least 95% by weight. In certain O. embodiments, the compound provided herein is made up of at In another embodiment, the (R)-isomers in the mixture of least about 90% by weight of one enantiomer. In other identical chemical entities (except for their stereochemical embodiments, the compound is made up of at least about orientations), are present at about 55%, about 60%, about 95%, 98%, or 99% by weight of one enantiomer. 25 65%, about 70%, about 75%, about 80%, about 85%, about In some embodiments, the compound is a racemic mixture 90%, about 95%, about 96%, about 97%, about 98%, about of (S)- and (R)-isomers. In other embodiments, provided 99%, about 99.5%, or more, relative to the (S)-isomers. In herein is a mixture of compounds wherein individual com some embodiments, the (R)-isomers in the mixture of iden pounds of the mixture exist predominately in an (S)- or (R)- tical chemical entities (except for their stereochemical orien isomeric configuration. For example, the compound mixture 30 tations), are presentata (R)-enantiomeric excess greater than has an (S)-enantiomeric excess of greater than about 55%, about 55% to about 99.5%, greater than about 60% to about about 60%, about 65%, about 70%, about 75%, about 80%, 99.5%, greater than about 65% to about 99.5%, greater than about 85%, about 90%, about 95%, about 96%, about 97%, about 70% to about 99.5%, greater than about 75% to about about 98%, about 99%, about 99.5%, or more. In other 99.5%, greater than about 80% to about 99.5%, greater than embodiments, the compound mixture has an (S)-enantio 35 about 85% to about 99.5%, greater than about 90% to about meric excess of greater than about 55% to about 99.5%, 99.5%, greater than about 95% to about 99.5%, greater than greater than about 60% to about 99.5%, greater than about about 96% to about 99.5%, greater than about 97% to about 65% to about 99.5%, greater than about 70% to about 99.5%, 99.5%, greater than about 98% to greater than about 99.5%, greater than about 75% to about 99.5%, greater than about greater than about 99% to about 99.5%, or more. 80% to about 99.5%, greater than about 85% to about 99.5%, 40 Enantiomers can be isolated from racemic mixtures by any greater than about 90% to about 99.5%, greater than about method known to those skilled in the art, including chiral high 95% to about 99.5%, greater than about 96% to about 99.5%, pressure liquid chromatography (HPLC), the formation and greater than about 97% to about 99.5%, greater than about crystallization of chiral salts, or prepared by asymmetric Syn 98% to greater than about 99.5%, greater than about 99% to theses. See, for example, Enantiomers, Racemates and Reso about 99.5%, or more. 45 lutions (Jacques, Ed., Wiley Interscience, New York, 1981); In other embodiments, the compound mixture has an (R)- Wilenet al., Tetrahedron 33:2725 (1977); Stereochemistry of enantiomeric purity of greater than about 55%, about 60%, Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, N.Y., about 65%, about 70%, about 75%, about 80%, about 85%, 1962); and Tables of Resolving Agents and Optical Resolu about 90%, about 95%, about 96%, about 97%, about 98%, tions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, about 99%, about 99.5% or more. In some other embodi 50 Notre Dame, Ind. 1972). ments, the compound mixture has an(R)-enantiomeric excess In certain embodiments, the pharmaceutically acceptable of greater than about 55% to about 99.5%, greater than about form thereof is a tautomer. As used herein, the term “tau 60% to about 99.5%, greater than about 65% to about 99.5%, tomer' includes two or more interconvertable compounds greater than about 70% to about 99.5%, greater than about resulting from at least one formal migration of a hydrogen 75% to about 99.5%, greater than about 80% to about 99.5%, 55 atom and at least one change in Valency (e.g., a single bond to greater than about 85% to about 99.5%, greater than about a double bond, a triple bond to a single bond, or vice versa). 90% to about 99.5%, greater than about 95% to about 99.5%, “Tautomerization' includes prototropic or proton-shift tau greater than about 96% to about 99.5%, greater than about tomerization, which is considered a Subset of acid-base chem 97% to about 99.5%, greater than about 98% to greater than istry. “Prototropic tautomerization' or “proton-shift tau about 99.5%, greater than about 99% to about 99.5% or more. 60 tomerization' involves the migration of a proton In other embodiments, the compound mixture contains accompanied by changes in bond order. The exact ratio of the identical chemical entities except for their stereochemical tautomers depends on several factors, including temperature, orientations, namely (S)- or (R)-isomers. For example, if a Solvent, and pH. Where tautomerization is possible (e.g., in compound disclosed herein has —CH(R)— unit, and R is not Solution), a chemical equilibrium of tautomers can be hydrogen, then the —CH(R)— is in an (S)- or (R)-stere 65 reached. Tautomerizations (i.e., the reaction providing a tau ochemical orientation for each of the identical chemical enti tomeric pair) can be catalyzed by acid or base, or can occur ties. In some embodiments, the mixture of identical chemical without the action or presence of an external agent. Exem US 8,901,133 B2 19 20 plary tautomerizations include, but are not limited to, keto The compounds provided herein may also contain unnatu to-enol; amide-to-imide; lactam-to-lactim; enamine-to ral proportions of atomic isotopes at one or more of atoms that imine; and enamine-to-(a different) enamine constitute Such compounds. For example, the compounds tautomerizations. A specific example of keto-enol tautomer may be radiolabeled with radioactive isotopes, such as for ization is the interconversion of pentane-2,4-dione and 4-hy example tritium (H), iodine-125 ('I) or carbon-14 (''C). droxypent-3-en-2-one tautomers. Another example of tau Unless otherwise stated, structures depicted herein are also tomerization is phenol-keto tautomerization. A specific meant to include compounds which differ only in the pres example of phenol-keto tautomerization is the interconver ence of one or more isotopically enriched atoms. For sion of pyridin-4-ol and pyridin-4(1H)-one tautomers. example, compounds having the present structures except for 10 the replacement of a hydrogen by a deuterium or tritium, or “Pharmaceutically acceptable carrier' or “pharmaceuti the replacement of a carbon by 'C- or 'C-enriched carbon cally acceptable excipient' includes any and all solvents, are within the scope of this disclosure. dispersion media, coatings, antibacterial and antifungal The disclosure also embraces isotopically labeled com agents, isotonic and absorption delaying agents and the like. pounds which are identical to those recited herein, except that The use of such media and agents for pharmaceutically active 15 one or more atoms are replaced by an atom having an atomic Substances is well known in the art. Except insofar as any mass or mass number different from the atomic mass or mass conventional media or agent is incompatible with the active number usually found in nature. Examples of isotopes that ingredient, its use in the therapeutic compositions as dis can be incorporated into disclosed compounds include iso closed herein is contemplated. Supplementary active ingre topes of hydrogen, carbon, nitrogen, oxygen, phosphorus, dients can also be incorporated into the pharmaceutical com fluorine and chlorine, such as H, H, C, C, N, O, O, positions. ''PP, S, F, and Cl, respectively. Certain isotopically “Signal transduction' is a process during which stimula labeled disclosed compounds (e.g., those labeled with Hand tory or inhibitory signals are transmitted into and within a cell '''C) are useful in compound and/or substrate tissue distribu to elicit an intracellular response. A modulator of a signal tion assays. Tritiated (i.e., H) and carbon-14 (i.e., ''C) iso transduction pathway refers to a compound which modulates 25 topes can allow for ease of preparation and detectability. the activity of one or more cellular proteins mapped to the Further, substitution with heavier isotopes such as deuterium same specific signal transduction pathway. A modulator can (i.e., H) can afford certain therapeutic advantages resulting augment (agonist) or Suppress (antagonist) the activity of a from greater metabolic stability (e.g., increased in vivo half signaling molecule. life or reduced dosage requirements). Isotopically labeled The term “selective inhibition” or “selectively inhibit” as 30 disclosed compounds can generally be prepared by Substitut applied to a biologically active agent refers to the agents ing an isotopically labeled reagent for a non-isotopically ability to selectively reduce the target signaling activity as labeled reagent. In some embodiments, provided herein are compared to off-target signaling activity, via director interact compounds that can also contain unnatural proportions of interaction with the target. For example, a compound that atomic isotopes at one or more of atoms that constitute Such selectively inhibits one isoform of PI3K over another isoform 35 compounds. All isotopic variations of the compounds as dis of PI3K has an activity of at least 2x against a first isoform closed herein, whether radioactive or not, are encompassed relative to the compounds activity against the second iso within the scope of the present disclosure. form (e.g., at least 3x, 5x, 10x, 20x, 50x, or 100x). The following abbreviations and terms have the indicated The term “B-ALL as used herein refers to B-cell Acute meanings throughout: PI3K=Phosphoinositide 3-kinase; Lymphoblastic Leukemia. 40 PI-phosphatidylinositol; PDK=Phosphoinositide Dependent “Subject to which administration is contemplated Kinase; DNA-PK=Deoxyribose Nucleic Acid Dependent includes, but is not limited to, humans (i.e., a male or female Protein Kinase; PTEN=Phosphatase and Tensin homolog of any age group, e.g., a pediatric Subject (e.g., infant, child, deleted on chromosome Ten; PIKK=Phosphoinositide adolescent) or adult Subject (e.g., young adult, middle-aged Kinase Like Kinase: AIDS-Acquired Immuno Deficiency adult or senior adult)) and/or other primates (e.g., cynomol 45 Syndrome; HIV-Human Immunodeficiency Virus; gus monkeys, rhesus monkeys); mammals, including com Mel-Methyl Iodide; POC1-Phosphorous Oxychloride: mercially relevant mammals such as cattle, pigs, horses, KCNS=Potassium Isothiocyanate; TLC-Thin Layer Chro sheep, goats, cats, and/or dogs; and/or birds, including com matography; MeOH=Methanol; and CHC1-Chloroform. mercially relevant birds such as chickens, ducks, geese, and/ Alkyl refers to a straight or branched hydrocarbon chain or turkeys. 50 radical consisting solely of carbon and hydrogenatoms, con "Radiation therapy means exposing a patient, using rou taining no unsaturation, having from one to ten carbon atoms tine methods and compositions known to the practitioner, to (e.g., C-C alkyl). Whenever it appears herein, a numerical radiation emitters such as, but not limited to, alpha-particle range such as “1 to 10” refers to each integer in the given emitting radionuclides (e.g., actinium and thorium radionu range; e.g., “1 to 10 carbonatoms” means that the alkyl group clides), low linear energy transfer (LET) radiation emitters 55 can consist of 1 carbonatom, 2 carbonatoms, 3 carbonatoms, (i.e., beta emitters), conversion electron emitters (e.g., stron etc., up to and including 10 carbon atoms, although the tium-89 and samarium-153-EDTMP, or high-energy radia present definition also covers the occurrence of the term tion, including without limitation X-rays, gamma rays, and “alkyl where no numerical range is designated. In some neutrons. embodiments, it is a C-C alkyl group. Typical alkyl groups The term “in vivo” refers to an event that takes place in a 60 include, but are in no way limited to, methyl, ethyl, propyl. subjects body. isopropyl. n-butyl, iso-butyl, sec-butyl isobutyl, tertiary The term “in vitro' refers to an event that takes places butyl, pentyl, isopentyl, neopentyl, hexyl, Septyl, octyl, outside of a subject's body. For example, an in vitro assay nonyl, decyl, and the like. The alkyl is attached to the rest of encompasses any assay conducted outside of a Subject. In the molecule by a single bond, for example, methyl (Me), vitro assays encompass cell-based assays in which cells, alive 65 ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, or dead, are employed. In vitro assays also encompass a n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-me cell-free assay in which no intact cells are employed. thylhexyl, and the like. Unless stated otherwise specifically in US 8,901,133 B2 21 22 the specification, an alkyl group is optionally Substituted by heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each one or more of substituents which independently include: of these moieties can be optionally substituted as defined alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy herein. cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimeth radical where alkenyl and cycloalkyl are as disclosed herein ylsilanyl, -OR. - SR", OC(O) R', N(R), C(O) and which are optionally substituted by one or more of the R", C(O)CR, OC(O)N(R), C(O)N(R), N(R) substituents described as suitable substituents for alkenyl and C(O)CR, N(R)C(O)R’, N(R)C(O)N(R), N(R)C cycloalkyl respectively. The “alkenyl-cycloalkyl is bonded (NR)N(R) - N(R)S(O).R" (where t is 1 or 2), to the parent molecular structure through the alkenyl group. 10 Alkynyl refers to a straight or branched hydrocarbon —S(O),OR" (wheret is 1 or 2), S(O)N(R) (wheret is 1 or chain radical group consisting solely of carbon and hydrogen 2), or PO,(R), wherein each R" is independently hydrogen, atoms, containing at least one triple bond, having from two to alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, ten carbon atoms (i.e., C-C alkynyl). Whenever it appears aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl herein, a numerical range such as “2 to 10” refers to each or heteroarylalkyl, and each of these moieties can be option 15 integer in the given range; e.g., “2 to 10 carbonatoms” means ally substituted as defined herein. that the alkynyl group can consist of 2 carbonatoms, 3 carbon Alkyl-cycloalkyl refers to an -(alkyl)cycloalkyl radical atoms, etc., up to and including 10 carbon atoms. In certain where alkyl and cycloalkyl areas disclosed herein and which embodiments, an alkynyl comprises two to eight carbon are optionally substituted by one or more of the substituents atoms. In other embodiments, an alkynyl has two to five described as suitable substituents for alkyl and cycloalkyl carbonatoms (e.g., C-C alkynyl). The alkynyl is attached to respectively. The “alkyl-cycloalkyl is bonded to the parent the parent molecular structure by a single bond, for example, molecular structure through the alkyl group. ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkylaryl' refers to an -(alkyl)aryl radical where aryland Unless Stated otherwise specifically in the specification, an alkyl are as disclosed herein and which are optionally Substi alkynyl group is optionally substituted by one or more Sub tuted by one or more of the substituents described as suitable 25 stituents which independently include: alkyl, heteroalkyl, substituents for aryland alkyl respectively. The “alkylaryl' is alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, bonded to the parent molecular structure through the alkyl heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluorom group. ethyl, trifluoromethoxy, nitro, trimethylsilanyl. —OR, Alkylheteroaryl refers to an -(alkyl)heteroaryl radical where heteroaryland alkyl are as disclosed herein and which 30 are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respec (R), N(R)S(O).R" (where t is 1 or 2), S(O),OR tively. The “alkylheteroaryl' is bonded to the parent molecu (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or lar structure through the alkyl group. PO.(R), where each R" is independently hydrogen, alkyl, Alkyl-heterocyclyl refers to an -(alkyl)heterocyclyl radi 35 fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het cal where alkyl and heterocyclyl are as disclosed herein and erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het which are optionally substituted by one or more of the sub eroarylalkyl and each of these moieties can be optionally stituents described as suitable substituents for heterocyclyl substituted as defined herein. and alkyl respectively. The “alkyl-heterocyclyl is bonded to Alkynyl-cycloalkyl refers to refers to an -(alkynyl)cy the parent molecular structure through the alkyl group. 40 cloalkyl radical where alkynyl and cycloalkyl areas disclosed Alkenyl refers to a straight or branched hydrocarbon herein and which are optionally substituted by one or more of chain radical group consisting solely of carbon and hydrogen the substituents described as suitable substituents for alkynyl atoms, containing at least one double bond, and having from and cycloalkyl respectively. The “alkynyl-cycloalkyl is two to ten carbon atoms (i.e., C.-Coalkenyl). Whenever it bonded to the parent molecular structure through the alkenyl appears herein, a numerical range Such as “2 to 10” refers to 45 group. each integer in the given range; e.g., “2 to 10 carbon atoms” “Carbonate” refers to a O C(=O) O R' wherein means that the alkenyl group can consist of 2 carbon atoms, 3 each R" is independently hydrogen, alkyl, fluoroalkyl, car carbon atoms, etc., up to and including 10 carbon atoms. In bocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, certain embodiments, an alkenyl comprises two to eight car heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. In some bonatoms. In other embodiments, an alkenyl comprises two 50 embodiments, when R is hydrogen and depending on the pH, to five carbon atoms (e.g., C-C alkenyl). The alkenyl is the hydrogen can be replaced by an appropriately charged attached to the parent molecular structure by a single bond, counter ion. for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), “Carboxaldehyde' refers to a —(C=O)H radical. but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. “Carboxyl refers to a —(C=O)OH radical. Unless Stated otherwise specifically in the specification, an 55 “Carboxylic acid” refers to a C(=O)CH radical. alkenyl group is optionally substituted by one or more Sub “Cyano” refers to a CN radical. stituents which independently include: alkyl, heteroalkyl, “Cycloalkyl refers to a monocyclic or polycyclic radical alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, that contains only carbon and hydrogen, and can be saturated, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluorom or partially unsaturated. Cycloalkyl groups include groups ethyl, trifluoromethoxy, nitro, trimethylsilanyl. —OR, 60 having from 3 to 10 ring atoms (i.e., C.-Co cycloalkyl). SR, OC(O) R, N(R), C(O)R, C(O)OR, Whenever it appears herein, a numerical range Such as “3 to OC(O)N(R), C(O)N(R), N(R)C(O)OR, 10 refers to each integer in the given range; e.g., “3 to 10 N(R)C(O)R, N(R)-(O)N(R)?, N(R) (NR)^(R)?, carbonatoms” means that the cycloalkyl group can consist of - N(R)S(O).R., (where t is 1 or 2), S(O).O." (where t is 1 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to or 2), S(O)N(R) (where t is 1 or 2), or PO.(R), where 65 and including 10 carbon atoms. In some embodiments, it is a each R" is independently hydrogen, alkyl, fluoroalkyl, car C-Cs cycloalkyl radical. In some embodiments, it is a C-Cs bocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, cycloalkyl radical. Illustrative examples of cycloalkyl groups US 8,901,133 B2 23 24 include, but are not limited to the following moieties: cyclo fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het propyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het cyclohexenyl, cycloSeptyl, cyclooctyl, cyclononyl, cyclode eroarylalkyl and each of these moieties can be optionally cyl, norbornyl, and the like. The term “cycloalkyl also substituted as defined herein. includes bridged and spiro-fused cyclic structures containing The term “alkoxycarbonyl refers to a group of the formula no heteroatoms. The term also includes monocyclic or fused (alkoxy)(C=O)—attached to the parent molecular structure ring polycyclic (i.e., rings which share adjacent pairs of ring through the carbonyl carbon wherein the alkoxy group has the atoms) groups. Unless stated otherwise specifically in the indicated number of carbonatoms, such as from 1-10 carbon specification, a cycloalkyl group is optionally substituted by atoms. Thus a C-C alkoxycarbonyl group is an alkoxy one or more substituents which independently include: alkyl, 10 group having from 1 to 6 carbon atoms attached through its heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, oxygen to a carbonyl linker. The C-C designation does not aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, include the carbonyl carbon in the atom count. “Lower cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsi alkoxycarbonyl refers to an alkoxycarbonyl group wherein lanyl, -OR. - SR", —OC(O) R, N(R), C(O)R’, the alkylportion of the alkoxy group is a lower alkyl group. In C(O)CR, OC(O)N(R), C(O)N(R), N(R)C 15 Some embodiments, C-C alkoxy is an alkoxy group which (OOR, N(RC(O)R, N(R)C(O)N(R), N(R)C(N- encompasses both straight and branched chain alkoxy groups R")N(R) - N(R)S(O).R" (where t is 1 or 2), S(O),OR of from 1 to 4 carbon atoms. (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or The term “substituted alkoxycarbonyl refers to the group PO.(R), where each R" is independently hydrogen, alkyl, (substituted alkyl)-O C(O)— wherein the group is attached fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het to the parent molecular structure through the carbonyl func erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het tionality. Unless stated otherwise specifically in the specifi eroarylalkyl and each of these moieties can be optionally cation, the alkyl moiety of analkoxycarbonyl group is option substituted as defined herein. ally substituted by one or more substituents which “Cycloalkyl-alkyl refers to a -(cycloalkyl)alkyl radical independently include: alkyl, heteroalkyl, alkenyl, alkynyl, where cycloalkyl and alkyl areas disclosed herein and which 25 cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het are optionally substituted by one or more of the substituents eroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluo described as suitable substituents for cycloalkyl and alkyl romethoxy, nitro, trimethylsilanyl. —OR', SR', OC(O)— respectively. The “cycloalkyl-alkyl is bonded to the parent R", N(R), C(O)R", C(O)OR", OC(O)N(R), molecular structure through the cycloalkyl group. C(O)N(R) - N(R)C(O)OR, N(R)C(O)R", “Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl) 30 N(R)C(O)N(R), N(R)C(NR)N(R), N(R)S heterocycyl radical where cycloalkyl and heterocycloalkyl (O).R" (where t is 1 or 2), S(O),OR" (where t is 1 or 2), are as disclosed herein and which are optionally substituted —S(O)N(R') (wheretis 1 or 2), or PO.(R), where each R" by one or more of the substituents described as suitable sub is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, stituents for heterocycloalkyl and cycloalkyl respectively. carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocy The “cycloalkyl-heterocycloalkyl is bonded to the parent 35 cloalkylalkyl, heteroaryl or heteroarylalkyl and each of these molecular structure through the cycloalkyl group. moieties can be optionally substituted as defined herein. “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl) het Acyl' refers to R C(O)— groups such as (alkyl)-C eroaryl radical where cycloalkyl and heteroaryl are as dis (O) , (aryl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C closed herein and which are optionally substituted by one or (O)—, and (heterocycloalkyl)-C(O)—, wherein the group is more of the substituents described as suitable substituents for 40 attached to the parent molecular structure through the carbo heteroaryl and cycloalkyl respectively. The “cycloalkyl-het nyl functionality. In some embodiments, it is a C-Coacyl eroaryl' is bonded to the parent molecular structure through radical which refers to the total number of chain or ring atoms the cycloalkyl group. of the alkyl, aryl, heteroaryl or heterocycloalkylportion of the The term “alkoxy' refers to the group —O-alkyl, including alkyl group plus the carbonyl carbon of acyl, i.e., a C-acyl from 1 to 10 carbon atoms of a straight, branched, cyclic 45 has three other ring or chain atoms plus carbonyl. If the R configuration and combinations thereof, attached to the par radical is heteroaryl or heterocycloalkyl, the hetero ring or ent molecular structure through an oxygen. Examples include chain atoms contribute to the total number of chain or ring methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, atoms. Unless stated otherwise specifically in the specifica cyclohexyloxy and the like. “Lower alkoxy' refers to alkoxy tion, the “R” of an acyloxy group is optionally substituted by groups containing one to six carbons. In some embodiments, 50 one or more substituents which independently include: alkyl, C-C alkyl is an alkyl group which encompasses both heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, straight and branched chain alkyls of from 1 to 4 carbon aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, atOmS. cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsi The term “substituted alkoxy” refers to alkoxy wherein the lanyl, -OR', SR, —OC(O) R, N(R), C(O)R’, alkyl constituent is substituted (i.e., —O-(substituted alkyl)). 55 C(O)CR, OC(O)N(R), C(O)N(R), N(R)C Unless stated otherwise specifically in the specification, the (O)OR, N(R)C(O)R, N(R)C(O)N(R), N(R)C(N- alkyl moiety of an alkoxy group is optionally Substituted by R")N(R) - N(R)S(O).R" (where t is 1 or 2), S(O),OR one or more substituents which independently include: alkyl, (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, PO.(R), where each R" is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, 60 fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsi erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het lanyl, -OR', SR, OC(O) R', N(R), C(O)R", eroarylalkyl and each of these moieties can be optionally -C(O)OR", OC(O)N(R), C(O)N(R), N(R)C substituted as defined herein. (O)OR, N(R)C(O)R, N(R)C(O)N(R), N(R)C(N- “Acyloxy” refers to a R(C=O)C) radical wherein “R” is R")N(R) - N(R')S(O).R" (where t is 1 or 2), S(O).R. 65 alkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or which are as described herein. The acyloxy group is attached PO.(R), where each R" is independently hydrogen, alkyl, to the parent molecular structure through the oxygen func US 8,901,133 B2 25 26 tionality. In some embodiments, it is a C-C acyloxy radical Unless Stated otherwise specifically in the specification, an which refers to the total number of chain or ring atoms of the amido group is optionally substituted independently by one alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acy or more of the substituents as described herein for alkyl, loxy group plus the carbonyl carbon of acyl, i.e., a C-acyloxy cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide has three other ring or chain atoms plus carbonyl. If the R 5 can be an amino acid or a peptide molecule attached to a radical is heteroaryl or heterocycloalkyl, the hetero ring or compound of Formula (I), thereby forming a prodrug. Any chain atoms contribute to the total number of chain or ring amine, hydroxy, or carboxyl side chain on the compounds atoms. Unless stated otherwise specifically in the specifica described herein can be transformed into an amide group. The tion, the “R” of an acyloxy group is optionally substituted by procedures and specific groups to make such amides are one or more substituents which independently include: alkyl, 10 known to those of skill in the art and can readily be found in heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, reference sources such as Greene and Wuts, Protective aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsi New York, N.Y., 1999, which is incorporated herein by ref lanyl, -OR. - SR", —OC(O) R, N(R), C(O)R’, erence in its entirety. C(O)CR, OC(O)N(R), C(O)N(R), N(R)C 15 “Aromatic' or “aryl' refers to a radical with six to ten ring (OOR, N(R)C(O)R, N(R)C(O)N(R), N(R)C(N- atoms (e.g., C-C aromatic or C-C aryl) which has at R")N(R) - N(R)S(O).R" (where t is 1 or 2), S(O),OR least one ring having a conjugated pi electron system which is (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent PO.(R), where each R" is independently hydrogen, alkyl, radicals formed from substituted benzene derivatives and fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het having the free Valences at ring atoms are named as Substi erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het tuted phenylene radicals. Bivalent radicals derived from uni eroarylalkyl and each of these moieties can be optionally Valent polycyclic hydrocarbon radicals whose names end in substituted as defined herein. “-yl” by removal of one hydrogenatom from the carbonatom Amino” or "amine” refers to a N(R') radical group, with the free valence are named by adding “-idene' to the where each R" is independently hydrogen, alkyl, haloalkyl, 25 name of the corresponding univalent radical, e.g., a naphthyl carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl group with two points of attachment is termed naphthylidene. (bonded through a chain carbon), heterocycloalkylalkyl, het Whenever it appears herein, a numerical range Such as “6 to eroaryl (bonded through a chain carbon), or heteroarylalkyl, 10' refers to each integer in the given range; e.g., “6 to 10 ring unless stated otherwise specifically in the specification. When atoms” means that the aryl group can consist of 6 ring atoms, a—N(R) group has two Rother than hydrogen, they can be 30 7 ring atoms, etc., up to and including 10 ring atoms. The term combined with the nitrogen atom to form a 4-, 5-, 6-, or includes monocyclic or fused-ring polycyclic (i.e., rings 7-membered ring. For example, N(R') is meant to include, which share adjacent pairs of ring atoms) groups. Unless but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. stated otherwise specifically in the specification, an aryl moi Unless Stated otherwise specifically in the specification, an ety can be optionally substituted by one or more substituents amino group is optionally Substituted by one or more Sub 35 which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, stituents which independently include: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, eroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluo heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluorom romethoxy, nitro, trimethylsilanyl. —OR', SR', —OC ethyl, trifluoromethoxy, nitro, trimethylsilanyl. —OR, (O) R, N(R), C(O)R, C(O)OR, OC(O)N 40 (R), C(O)N(R), N(R)C(O)OR, N(R)C(O)R’, N(R)C(O)N(R), N(R)C(NR)N(R), N(R)S(O), R (where t is 1 or 2), —S(O), OR (where t is 1 or 2), (R) - N(R')S(O).R" (where t is 1 or 2), S(O),OR —S(O)N(R) (where t is 1 or 2), or PO(R'), where each (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or R" is independently hydrogen, alkyl, fluoroalkyl, carbocy PO.(R), where each R" is independently hydrogen, alkyl, 45 clyl carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, hetero fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het cycloalkylalkyl, heteroaryl or heteroarylalkyl and each of erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het these moieties can be optionally substituted as defined herein. eroarylalkyl and each of these moieties can be optionally Aralkyl or “arylalkyl refers to an (aryl)alkyl-radical substituted as defined herein. where aryl and alkyl are as disclosed herein and which are The term "substituted amino” also refers to N-oxides of the 50 optionally substituted by one or more of the substituents groups - N'-(H)(R')O, and - N*(R)(R)O, R as described as suitable substituents for aryl and alkyl respec described above, where the N-oxide is bonded to the parent tively. The “aralkyl/arylalkyl is bonded to the parent molecular structure through the N atom. N-oxides can be molecular structure through the alkyl group. prepared by treatment of the corresponding amino group As used herein, a “covalent bond' or “direct bond' refers to with, for example, hydrogen peroxide or m-chloroperoxy 55 a single bond joining two groups. benzoic acid. The person skilled in the art is familiar with "Ester” refers to a chemical radical of formula—COOR, reaction conditions for carrying out the N-oxidation. where R is selected from alkyl, cycloalkyl, aryl, heteroaryl Amide' or "amido” refers to a chemical moiety with (bonded through a ring carbon) and heteroalicyclic (bonded formula - C(O)N(R), or - NRC(O)R, where R is selected through a ring carbon). Any amine, hydroxy, or carboxyl side from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded 60 chain on the compounds described herein can be esterified. through a ring carbon) and heteroalicyclic (bonded through a The procedures and specific groups to make Such esters are ring carbon), each of which moiety can itself be optionally known to those of skill in the art and can readily be found in Substituted. In some embodiments it is a C-C amido or reference sources such as Greene and Wuts, Protective amide radical, which includes the amide carbonyl in the total Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, number of carbons in the radical. The R of —N(R) of the 65 New York, N.Y., 1999, which is incorporated herein by ref amide can optionally be taken together with the nitrogen to erence in its entirety. Unless stated otherwise specifically in which it is attached to form a 4-, 5-, 6-, or 7-membered ring. the specification, an ester group can be optionally substituted US 8,901,133 B2 27 28 by one or more substituents which independently are: alkyl, cloalkyl are as disclosed herein and which are optionally heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, substituted by one or more of the substituents described as aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, suitable substituents for heteroalkyl and heterocycloalkyl cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsi respectively. The "heteroalkyl-heterocycloalkyl is bonded to lanyl, -OR. - SR", OC(O) R', N(R), C(O)R’, the parent molecular structure through a carbon atom of the C(O)CR, OC(O)N(R), C(O)N(R), N(R)C heteroalkyl group. (OOR, N(R)C(O)R, N(R)C(O)N(R), N(R)C(N- “Heteroalkylcycloalkyl refers to an -(heteroalkyl)cy R")N(R) - N(R)S(O).R" (where t is 1 or 2), S(O),OR cloalkyl radical where heteroalkyl and cycloalkyl are as dis (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or closed herein and which are optionally substituted by one or PO.(R), where each R" is independently hydrogen, alkyl, 10 more of the substituents described as suitable substituents for fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het heteroalkyl and cycloalkyl respectively. The "heteroalkylcy erocycloalkyl, heterocycloalkylalkyl, heteroaryl or het cloalkyl is bonded to the parent molecular structure through eroarylalkyl and each of these moieties can be optionally a carbon atom of the heteroalkyl group. substituted as defined herein. “Heteroaryl' or, alternatively, "heteroaromatic' refers to a “Fluoroalkyl refers to an alkyl radical, as defined above, 15 5- to 18-membered aromatic radical (e.g., C5-C1s heteroaryl) that is substituted by one or more fluoro radicals, as defined that includes one or more ring heteroatoms selected from above, for example, trifluoromethyl, difluoromethyl, 2.2.2- nitrogen, oxygen and Sulfur, and which can be a monocyclic, trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. bicyclic, tricyclic or tetracyclic ring system. In some embodi The alkyl part of the fluoroalkyl radical can be optionally ments, aromatic ring systems can have 6, 10 or 14 telectrons Substituted as defined above for an alkyl group. shared in a cyclic array, having ring carbonatoms and 1-6 ring "Halo', “halide', or, alternatively, “halogen' means fluoro, heteroatoms provided in the aromatic ring system. Whenever chloro, bromo or iodo. The terms “haloalkyl.” “haloalkenyl.” it appears herein, a numerical range such as “5 to 18” refers to “haloalkynyl and “haloalkoxy” include alkyl, alkenyl, alky each integer in the given range; e.g., “5 to 18 ring atoms” nyland alkoxy structures that are substituted with one or more means that the heteroaryl group can consist of 5 ring atoms, 6 halo groups or with combinations thereof. For example, the 25 ring atoms, etc., up to and including 18 ring atoms. Bivalent terms “fluoroalkyl and “fluoroalkoxy” include haloalkyland radicals derived from univalent heteroaryl radicals whose haloalkoxy groups, respectively, in which the halo is fluorine. names end in “-yl by removal of one hydrogenatom from the “Heteroalkyl” “heteroalkenyl and “heteroalkynyl atom with the free valence are named by adding “-idene' to include optionally Substituted alkyl, alkenyl and alkynyl radi the name of the corresponding univalent radical, e.g., a cals and which have one or more skeletal chain atoms selected 30 pyridyl group with two points of attachment is a pyridylidene. from anatom other than carbon, e.g., oxygen, nitrogen, Sulfur, Heteroaryl polycyclic ring systems can include one or more phosphorus or combinations thereof. A numerical range can heteroatoms in one or both rings. An N-containing "het be given, e.g., C-C heteroalkyl which refers to the chain eroaromatic' or "heteroaryl moiety refers to an aromatic length in total, which in this example is 4 atoms long. For group in which at least one of the skeletal atoms of the ring is example, a —CHOCHCH radical is referred to as a “C” 35 a nitrogenatom. The polycyclic heteroaryl group can be fused heteroalkyl, which includes the heteroatom center in the atom or non-fused. The heteroatom(s) in the heteroaryl radical is chain length description. Connection to the rest of the parent optionally oxidized. One or more nitrogen atoms, if present, molecular structure can be through either a heteroatom or a are optionally quaternized. The heteroaryl is attached to the carbon in the heteroalkyl chain. A heteroalkyl group can be parent molecular structure through any atom of the ring(s). substituted with one or more substituents which indepen 40 “Heteroaryl also includes ring systems wherein the het dently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, eroaryl ring, as defined above, is fused with one or more aryl heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, groups wherein the point of attachment to the parent molecu hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl. lar structure is either on the aryl or on the heteroaryl ring, or OR, OC(O) R, N(R), C(O)R", C(O)CR, wherein the heteroaryl ring, as defined above, is fused with C(O)N(R) - N(R)C(O)OR, N(R)C(O)R’, 45 one or more cycloalkyl or heterocycyl groups wherein the - N(R)S(O).R" (wheret is 1 or 2), S(O).R" (wheretis 1 or point of attachment to the parent molecular structure is on the 2), —S(O)N(R) (wheret is 1 or 2), or PO.(R), where each heteroaryl ring. For polycyclic heteroaryl groups wherein one R" is independently hydrogen, alkyl, fluoroalkyl, carbocy ring does not contain a heteroatom (e.g., indolyl, quinolinyl, clyl carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, hetero carbazolyl and the like), the point of attachment to the parent cycloalkylalkyl, heteroaryl or heteroarylalkyl and each of 50 molecular structure can be on either ring, i.e., either the ring these moieties can be optionally substituted as defined herein. bearing a heteroatom (e.g., 2-indolyl) or the ring that does not “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical contain a heteroatom (e.g., 5-indolyl). In some embodiments, where heteroalkyl and aryl are as disclosed herein and which a heteroaryl group is a 5-10 membered aromatic ring system are optionally substituted by one or more of the substituents having ring carbon atoms and 1-4 ring heteroatoms provided described as suitable substituents for heteroalkyl and aryl 55 in the aromatic ring system, wherein each heteroatom is inde respectively. The "heteroalkylaryl is bonded to the parent pendently selected from nitrogen, oxygen, and Sulfur ("5-10 molecular structure through a carbon atom of the heteroalkyl membered heteroaryl). In some embodiments, a heteroaryl group. group is a 5-8 membered aromatic ring system having ring “Heteroalkylheteroaryl” refers to an -(heteroalkyl)het carbon atoms and 1-4 ring heteroatoms provided in the aro eroaryl radical where heteroalkyl and heteroaryl are as dis 60 matic ring system, wherein each heteroatomis independently closed herein and which are optionally substituted by one or selected from nitrogen, oxygen, and sulfur (“5-8 membered more of the substituents described as suitable substituents for heteroaryl'). In some embodiments, a heteroaryl group is a heteroalkyl and heteroaryl respectively. The "heteroalkylhet 5-6 membered aromatic ring system having ring carbon eroaryl' is bonded to the parent molecular structure through a atoms and 1-4 ring heteroatoms provided in the aromatic ring carbon atom of the heteroalkyl group. 65 system, wherein each heteroatom is independently selected “Heteroalkyl-heterocycloalkyl refers to an -(heteroalkyl) from nitrogen, oxygen, and Sulfur ("5-6 membered het heterocycloalkyl radical where heteroalkyl and heterocy eroaryl'). In some embodiments, the 5-6 membered het US 8,901,133 B2 29 30 eroaryl has 1-3 ring heteroatoms selected from nitrogen, oxy cloalkyl are as disclosed herein and which are optionally gen, and Sulfur. In some embodiments, the 5-6 membered substituted by one or more of the substituents described as heteroaryl has 1-2 ring heteroatoms selected from nitrogen, suitable substituents for heteroaryl and heterocycloalkyl oxygen, and Sulfur. In some embodiments, the 5-6 membered respectively. The "heteroaryl-heterocycloalkyl is bonded to heteroaryl has 1 ring heteroatom selected from nitrogen, oxy 5 the parent molecular structure through an atom of the het gen, and Sulfur. eroaryl group. Examples of heteroaryls include, but are not limited to, “Heteroaryl-cycloalkyl refers to an -(heteroaryl)cy azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzo cloalkyl radical where heteroaryl and cycloalkyl are as dis dioxolyl, benzofuranyl, benzooxazolyl, benzodthiazolyl, closed herein and which are optionally substituted by one or benzothiadiazolyl, benzob 1,4-dioxepinyl, benzob.14 10 more of the substituents described as suitable substituents for oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzox heteroaryl and cycloalkyl respectively. The "heteroaryl-cy azolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, ben cloalkyl is bonded to the parent molecular structure through Zopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, a carbon atom of the heteroaryl group. benzofurazanyl, benzothiazolyl, benzothienyl (ben “Heterocyclyl, "heterocycloalkyl or "heterocarbocy Zothiophenyl), benzothieno 3.2-dpyrimidinyl, benzotriaz 15 clyl each refer refers to any 3- to 18-membered aromatic olylbenzo 4,6imidazol-2-alpyridinyl, carbazolyl, cinnoli radical monocyclic or polycyclic moiety comprising at least nyl, cyclopentadpyrimidinyl, 6,7-dihydro-5H-cyclopenta one heteroatom selected from nitrogen, oxygen and Sulfur. In 4,5thieno 2,3-dipyrimidinyl, 5,6-dihydrobenzoh Some embodiments, a heterocyclyl group comprises two to quinazolinyl, 5,6-dihydrobenzohcinnolinyl, 6,7-dihydro twelve carbonatoms and from one to six heteroatoms selected 5H-benzo 6,7cyclohepta 1.2-cpyridazinyl, from nitrogen, oxygen and Sulfur. As used herein, heterocy dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, fura clyl moieties can be aromatic or nonaromatic. A heterocyclyl nonyl, furo3.2-cpyridinyl, 5,6,7,8,9,10-hexahydrocy group can be a monocyclic, bicyclic, tricyclic or tetracyclic clooctadpyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctad ring system. Whenever it appears herein, a numerical range pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctadpyridinyl, Such as “3 to 18” refers to each integer in the given range; e.g., isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoin 25 “5 to 18 ring atoms” means that the heterocyclyl group can dolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isox consist of 5 ring atoms, 6 ring atoms, etc., up to and including azolyl, 5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naph 18 ring atoms. In some embodiments, it is a Cs-Co hetero thyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, cycloalkyl. In some embodiments, it is a 2-oxoazepinyl, oxazolyl, oxiranyl, 5.6,6a,7,8,9,10,10a-oc Ca-Coheterocycloalkyl. In some embodiments, it is a tahydrobenzohlquinazolinyl, 1-phenyl-1H-pyrrolyl, phena 30 C-Coheterocycloalkyl. Bivalent radicals derived from uni Zinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, valent heterocyclyl radicals whose names end in “-y1' by purinyl, pyranyl, pyrrolyl pyrazolyl pyrazolo 3,4-dipyrim removal of one hydrogen atom from the atom with the free idinyl, pyridinyl, pyrido3.2-dpyrimidinyl, pyrido3,4-dpy valence are named by adding “-idene' to the name of the rimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, corresponding univalent radical, e.g., a piperidine group with quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tet 35 two points of attachment is a piperidylidene. An N-containing rahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8- heterocyclyl moiety refers to an non-aromatic group in which tetrahydrobenzo 4,5thieno 2,3-dipyrimidinyl, 6,7,8,9-tet at least one of the skeletal atoms of the ring is a nitrogenatom. rahydro-5H-cyclohepta4,5thieno2,3-dipyrimidinyl, 5.6.7. Unless stated otherwise specifically in the specification, the 8-tetrahydropyrido4.5-cpyridazinyl, thiazolyl, heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, 40 tetracyclic ring system, which may include fused or bridged thieno2,3-dipyrimidinyl, thieno3,2-dpyrimidinyl, thieno ring systems. The heteroatom(s) in the heterocyclyl radical is 2,3-cpridinyl, and thiophenyl (i.e., thienyl). Unless stated optionally oxidized. One or more nitrogen atoms, if present, otherwise specifically in the specification, a heteroaryl moi are optionally quaternized. The heteroaryl is attached to the ety is optionally substituted by one or more substituents parent molecular structure through any atom of the ring(s). which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, 45 “Heterocyclyl also includes ring systems wherein the het cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het erocycyl ring, as defined above, is fused with one or more eroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trim carbocyclyl groups wherein the point of attachment is either ethylsilanyl, OR, SR, OC(O) R, N(R), on the carbocycyl or heterocyclyl ring, or ring systems -C(O)R", C(O)OR, C(O) (R), N(R)C(O)OR", wherein the heterocyclyl ring, as defined above, is fused with - N(R)C(O)R", N(R)S(O).R" (where t is 1 or 2), 50 one or more aryl or heteroaryl groups, wherein the point of —S(O),OR" (wheret is 1 or 2), S(O)N(R) (wheret is 1 or attachment to the parent molecular structure is on the hetero 2), or PO(R), where each R" is independently hydrogen, cyclyl ring. In some embodiments, a heterocyclyl group is a alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, 3-10 membered non-aromatic ring system having ring carbon aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl atoms and 1-4 ring heteroatoms, wherein each heteroatom is or heteroarylalkyl and each of these moieties can be option 55 independently selected from nitrogen, oxygen, and Sulfur ally substituted as defined herein. (“3-10 membered heterocyclyl). In some embodiments, a Substituted heteroaryl also includes ring systems Substi heterocyclyl group is a 5-8 membered non-aromatic ring tuted with one or more oxide (-O ) Substituents, such as system having ring carbon atoms and 1-4 ring heteroatoms, pyridinyl N-oxides. wherein each heteroatom is independently selected from “Heteroaryl-alkyl refers to an -(heteroaryl)alkyl radical 60 nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl). where heteroaryland alkyl are as disclosed herein and which In some embodiments, a heterocyclyl group is a 5-6 mem are optionally substituted by one or more of the substituents bered non-aromatic ring system having ring carbon atoms described as suitable substituents for heteroaryl and alkyl and 1-4 ring heteroatoms, wherein each heteroatom is inde respectively. The "heteroaryl-alkyl is bonded to the parent pendently selected from nitrogen, oxygen, and Sulfur ("5-6 molecular structure through any atom of the heteroaryl group. 65 membered heterocyclyl). In some embodiments, the 5-6 “Heteroaryl-heterocycloalkyl refers to an -(heteroaryl) membered heterocyclyl has 1-3 ring heteroatoms selected heterocycloalkyl radical where heteroaryl and heterocy from nitrogen, oxygen, and Sulfur. In some embodiments, the US 8,901,133 B2 31 32 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected C(O)CR, C(O)N(R), N(R)C(O)CR, N(R)C from nitrogen, oxygen, and Sulfur. In some embodiments, the (O)R", N(R)S(O).R" (where t is 1 or 2), —S(O),OR 5-6 membered heterocyclyl has 1 ring heteroatom selected (where t is 1 or 2), —S(O)N(R) (where t is 1 or 2), or from nitrogen, oxygen, and Sulfur. In some embodiments, a PO.(R), where each R" is independently hydrogen, alkyl, heterocyclyl group is a 3-7 membered non-aromatic bicyclic fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl, het ring system having at least 2 carbon atoms in addition to 1-3 erocycloalkyl, heteroaryl or heteroarylalkyl and each of these heteroatoms independently selected from nitrogen, oxygen, moieties can be optionally substituted as defined herein. and Sulfur, as well as combinations comprising at least one of "Moiety' refers to a specific segment or functional group the foregoing heteroatoms; and the other ring, usually having of a molecule. Chemical moieties are often recognized 3 to 7 ring atoms, optionally contains 1-3 heteroatoms inde 10 pendently selected from nitrogen, oxygen, and Sulfur and is chemical entities embedded in or appended to a molecule. not aromatic. “Nitro” refers to the NO, radical. Exemplary 3-membered heterocyclyls containing 1 het “Oxa' refers to the —O— radical. eroatom include, without limitation, azirdinyl, oxiranyl. “Oxo’ refers to the –O radical. thiorenyl. Exemplary 4-membered heterocyclyls containing 15 “Phosphate” refers to a P=O(OR), radical wherein 1 heteroatom include, without limitation, aZetidinyl, oxetanyl each R is independently hydrogen, alkyl, fluoroalkyl, car and thietanyl. Exemplary 5-membered heterocyclyls contain bocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl ing 1 heteroatom include, without limitation, tetrahydrofura (bonded through a ring carbon), heterocycloalkylalkyl, het nyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophe eroaryl (bonded through a ring carbon) or heteroarylalkyl. In nyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Some embodiments, when R is hydrogen and depending on Exemplary 5-membered heterocyclyls containing 2 heteroa the pH, the hydrogen can be replaced by an appropriately toms include, without limitation, dioxolanyl, Oxathiolanyl charged counter ion. and dithiolanyl. Exemplary 5-membered heterocyclyls con A "leaving group or atom' is any group or atom that will, taining 3 heteroatoms include, without limitation, triazolinyl, under the reaction conditions, cleave from the starting mate oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered 25 rial, thus promoting reaction at a specified site. Suitable non heterocyclyl groups containing 1 heteroatom include, with limiting examples of Such groups unless otherwise specified out limitation, piperidinyl, tetrahydropyranyl, dihydropyridi include halogen atoms, mesyloxy, p-nitrobenzensulphony nyl, and thianyl. Exemplary 6-membered heterocyclyl groups loxy and tosyloxy groups. containing 2 heteroatoms include, without limitation, piper “Protecting group” has the meaning conventionally asso azinyl, morpholinyl, dithianyl, dioxanyl, and triaZinanyl. 30 ciated with it in organic synthesis, i.e., a group that selectively Exemplary 7-membered heterocyclyl groups containing 1 blocks one or more reactive sites in a multifunctional com heteroatom include, without limitation, azepanyl, oxepanyl pound such that a chemical reaction can be carried out selec and thiepanyl. Exemplary 8-membered heterocyclyl groups tively on another unprotected reactive site and such that the containing 1 heteroatom include, without limitation, azoca group can readily be removed after the selective reaction is nyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl 35 complete. A variety of protecting groups are disclosed, for groups include, without limitation, indolinyl, isoindolinyl, example, in T. H. Greene and P. G. M. Wuts, Protective dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydroben Groups in Organic Synthesis, Third Edition, John Wiley & Zothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tet Sons, New York (1999). For example, a hydroxy protected rahydroquinolinyl, tetrahydroisoquinolinyl, decahydro form is where at least one of the hydroxy groups present in a quinolinyl, decahydroisoquinolinyl, octahydrochromenyl, 40 compound is protected with a hydroxy protecting group. octahydroisochromenyl, decahydronaphthyridinyl, decahy Likewise, amines and other reactive groups can similarly be dro-1,8-naphthyridinyl, octahydropyrrolo3.2-bipyrrole, protected. indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chrome “Substituted” means that the referenced group can be sub nyl, 1H-benzoe 1.4 diazepinyl, 1,4,5,7-tetrahydropyrano stituted with one or more additional group(s) individually and 3,4-bipyrrolyl, 5,6-dihydro-4H-furo3,2-bipyrrolyl. 6,7-di 45 independently selected from acyl, alkyl, alkylaryl, hydro-5H-furo3,2-bipyranyl, 5,7-dihydro-4H-thieno2.3-c. cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, pyranyl, 2,3-dihydro-1H-pyrrolo2,3-bipyridinyl, 2.3- heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alky dihydrofuro2,3-bipyridinyl. 4,5,6,7-tetrahydro-1H-pyrrolo lthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, iso 2,3-bipyridinyl, 4,5,6,7-tetrahydrofuro3.2-cpyridinyl, 4.5, cyanato, thiocyanato, isothiocyanato, nitro, Oxo, perha 6,7-tetrahydrothieno 3.2-bipyridinyl, 1,2,3,4-tetrahydro-1, 50 loalkyl, perfluoroalkyl, phosphate, silyl, Sulfinyl, Sulfonyl, 6-naphthyridinyl, and the like. Sulfonamidyl, Sulfonyl, Sulfonate, urea, and amino, including In some embodiments, heterocycloalkyl radicals include, mono- and di-substituted amino groups, and the protected but are not limited to, dioxolanyl, thienyl 1.3dithianyl, derivatives thereof. Di-substituted amino groups encompass decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothia those which form a ring together with the nitrogen of the Zolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, 55 amino group. Such as for instance, morpholino. The Substitu octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, ents themselves can be substituted, for example, a cycloalkyl 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, Substituent can have a halide Substituted at one or more ring 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, carbons, and the like. The protecting groups that can form the thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, protective derivatives of the above substituents are known to thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 60 those of skill in the art and can be found in references such as and 1,1-dioxo-thiomorpholinyl. Greene and Wuts, above. Unless stated otherwise, heterocyclyl moieties are option "Sulfanyl refers to the groups: —S-(optionally substi ally substituted by one or more substituents which indepen tuted alkyl). —S-(optionally substituted aryl), —S-(option dently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, ally substituted heteroaryl), and —S-(optionally substituted heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, 65 heterocycloalkyl). hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl. “sulfinyl refers to the groups: —S(O)—H. —S(O)-(op OR, SR, OC(O) R', N(R), C(O)R", tionally substituted alkyl). —S(O)-(optionally substituted US 8,901,133 B2 33 34 amino). —S(O)-(optionally substituted aryl), —S(O)-(op R" is -(L)-R'; tionally substituted heteroaryl), and —S(O)-(optionally sub each L is independently a bond, alkylene, heteroalkylene, stituted heterocycloalkyl). N(R) s S(O) s S(O), s S—, C(=O) s "Sulfonyl refers to the groups: —S(O)—H. —S(O)- - P(=O)R’ , or - O -: (optionally substituted alkyl). —S(O)-(optionally substi R" is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, tuted amino), —S(O)-(optionally substituted aryl), cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het —S(O)-(optionally substituted heteroaryl), and —S(O)- eroarylalkyl, alkoxy, heterocyclyloxy, amino, amido, acyl, (optionally substituted heterocycloalkyl). acyloxy, alkoxycarbonyl, Sulfonamido, halo, cyano, hydroxy, "Sulfonamidyll” or "sulfonamido” refers to a S(=O) nitro, phosphate, urea, carbonate. —(C=O) NR'R'', or NRR or N(R)—S(=O)— radical, where each R is 10 NRR2, selected independently from hydrogen, alkyl, cycloalkyl, R'' and R' are each independently hydrogen, alkyl, het aryl, heteroaryl (bonded through a ring carbon) and hetero eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, cycloalkyl (bonded through a ring carbon). The R groups in arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy —NRR of the —S(=O) NRR radical can be taken cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. In some embodiments, it is a 15 Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, C-C sulfonamido, wherein each Rin Sulfonamido contains nitro, phosphate, urea, carbonate, or R'' and R' are taken 1 carbon, 2 carbons, 3 carbons, or 4 carbons total. A Sulfona together with nitrogen to form a cyclic moiety; mido group is optionally Substituted by one or more of the R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, het substituents described for alkyl, cycloalkyl, aryl, and het eroalkyl, aryl, or heteroaryl; eroaryl respectively each R is independently alkyl, heteroalkyl, haloalkyl, alk “Sulfoxyl refers to a S(=O).OH radical. enyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, "Sulfonate” refers to a S(=O) OR radical, where Ris heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, through a ring carbon) and heteroalicyclic (bonded through a thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, nitro, phos ring carbon). A Sulfonate group is optionally Substituted on R 25 phate, urea, carbonate, or NR'R", wherein RandR" are taken by one or more of the substituents described for alkyl, together with nitrogen to form a cyclic moiety; cycloalkyl, aryl, and heteroaryl respectively. X is absent or is —(CH(R')) ; “Thio’ or “thiol refers to a S radical. “Thioxo’ refers to a -S radical. “Urea” refers to a N(R) C(=O) N(R) radical 30 wherein each R" is independently hydrogen, alkyl, fluoro (R') , —C(=O)–(CHR') -, -C(=O) N(R)- alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocy (CHR') , or - P(=O)R ; cloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryla each Z is an integer of 1, 2, 3, or 4: lkyl. n is an integer of 0, 1, 2, 3, or 4: Where substituent groups are specified by their conven each R is independently hydrogen, alkyl, cycloalkyl, het tional chemical formulae, written from left to right, they 35 erocycloalkyl, heterocycloalkylalkyl, heteroalkyl, aryl, or equally encompass the chemically identical Substituents that heteroaryl; would result from writing the structure from right to left, e.g., W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, —CH2O— is equivalent to —OCH2—. wherein W is optionally substituted with one or more R', Compounds R'', R'', and R'; and As noted above, provided herein are various compounds 40 each R, R', R'', R', and R' is independently hydrogen, that are useful as antagonists for one or more lipid kinases alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy and/or protein kinases. cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, In one aspect, described herein are compounds of Formula heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo (I): nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, 45 phosphate, urea, carbonate, or NR'R", wherein R' and R" are taken together with nitrogen to form a cyclic moiety.

Formula (I) In some embodiments, the compound of Formula (I) has the structure of Formula (Ia):

50 Formula (Ia)

55 or its pharmaceutically acceptable forms thereof, wherein WS is N, CHR or CR; R" is hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alky nyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, 60 heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, or its pharmaceutically acceptable forms thereof, wherein n, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Z, Ral, R2, L. R", R", R°, R, R, X,Y, R, Rio, R, Ril, R12, Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbon R" and W are as defined for Formula (I); and ate, or NR'R", wherein R' and R" are taken together with W is N or CR. nitrogen to form a cyclic moiety. 65 In some embodiments, each L is independently a bond, Cy is aryl or heteroaryl substituted by 0-4 occurrences of alkylene, N(R) , S(O) , S(O) , S , R; —C(=O)—, or —O—. US 8,901,133 B2 35 36 In Some embodiments, L is —O—, —C(=O)— —S— or haloalkyl, cyano, hydroxyl. nitro, phosphate, urea, carbonate, a bond. In some embodiments, L is a bond. In some embodi or NR'R", wherein RandR" are taken together with nitrogen ments, L is —O—. In some embodiments, L is —S—. In to form a heterocyclic moiety. Some embodiments, L is —C(=O)—. In some embodiments, In some embodiments of the compound of Formula (I), Cy L is alkylene (e.g., methylene, ethylene or propylene). In is aryl substituted with 0-4 occurrences of R. In some Some embodiments, n is 1. embodiments, Cy is phenyl substituted with 0-4 occurrences In Some embodiments, n is 2. In some embodiments, one L. of R. In some embodiments, Cy is phenyl substituted with 0 is alkylene (e.g., methylene) and one L is —C(=O)—. In occurrences of R. In some embodiments, Cy is phenyl sub Some embodiments, one L is —O— and one L is alkylene stituted with 1 occurrence of R. In some embodiments, R is (e.g., methylene or ethylene). In some embodiments, one L is 10 halo (e.g., fluoro or chloro). In some embodiments, R is alkyl —S - and one L is alkylene (e.g., ethylene). In some embodi (e.g., methyl). In some embodiments, R is haloalkyl (e.g., ments, one L is —S(O)—and one L is alkylene (e.g., ethyl trifluoromethyl). In some embodiments, R is heteroaryl ene). In some embodiments, one L is —S(O) and one L is (e.g., 1-methyl-4-pyrazolyl or 3-pyridyl). In some embodi alkylene (e.g., ethylene). ments, R is acyl (e.g., —C(=O)-N-morphonlinyl, In Some embodiments, n is 3. In some embodiments, one L. 15 —C(=O) N-methyl-N-piperizinyl, or N-((1R,5S)-3-oxa is —O—, one L is alkylene (e.g., methylene) and one L is 8-azabicyclo[3.2.1]octanyl)). —C(O)—. In some embodiments, R' is NR'R''. In some embodi In some embodiments, Cy is phenyl substituted with 2 ments, R'' is —(C=O) NR'R''. In some embodiments, occurrences of R. In some embodiments, each R is halo R'' and R' are taken together with nitrogen to form a cyclic (e.g., chloro or fluoro). moiety (e.g., a heterocyclic moiety), such as N-pyrollyl, N-(3. In some embodiments, W is heteroaryl optionally substi 3-difluoro)pyrolyl N-azetidinyl, N-(2,2-difluoro)azetidinyl, tuted with one or more R. R'', R', R', or R' (e.g., a N-morpholinyl, 2-methyl-N-morpholinyl, N-methyl-N-pip monocyclic heteroaryl). erazinyl, N-(2-methyl)-piperazinyl, N-(2,2-difluoro)pyrol In some embodiments, W is: lyl, N-(2-hydroxy)azetidinyl, 4-hydroxy-N-piperidinyl,

N-isopropyl-4-piperidinyl, 4-tetrahydropyran, 4-isopropyl 25 N-piperazinyl, 4-ethyl-N-piperazinyl, N-methyl-4-piperidi nyl, N-(methylsulfonyl)-4-piperidinyl, 4-piperidinyl, N-me thyl-4-piperidinyl, 3-tetrahydrofuranyl, N-piperazinyl-2- one, 3-methyl-N-morpholinyl, N-(1,4)-oxazepanyl, N-((1R, 5S)-3-oxa-8-azabicyclo[3.2.1]octanyl), N-((1R,5S)-8-oxa 30 3-azabicyclo[3.2.1]octanyl) or 44-difluoro-N-piperidinyl). In some embodiments, R' is hydrogen. In some embodi ments, R' is alkyl (e.g., methyl). In some embodiments, R' is alkyl (e.g., methyl). In some embodiments, R is cycloalkyl (e.g., cyclopentyl, cyclo wherein A is N or CR'. hexyl or 4-hydroxycyclohexyl). In some embodiments, R' is 35 In some embodiments, W is aryl (e.g., phenyl). In some embodiments, R is aralkyl (e.g., benzyl). In some embodiments, R' is heterocycloalkyl (e.g., 2-tetrahydrofuranyl, 4-piperidyl, N-methyl-4-piperidyl or tetrahydropyranyl). In some embodiments, R' is heterocy cloalkylalkyl (e.g., methyl-4-tetrahydropyranyl). In some embodiments, R' is acyl (e.g., —C(O)CH). In some embodiments, R" is heteroaryl (e.g., 5-methyl-2- (1,2,4-oxadiazolyl) or 5-hydroxymethyl-3-isoxazolyl). In some embodiments, R' is alkyl (e.g., methyl, isopropyl or hydroxyisopropyl). In some embodiments, R' is hydroxy. In some embodiments, Wis N. In some embodiments, W is CR. In some embodiments, Wis CHR. In some embodi ments, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy or NR'R''. In some embodiments, R is hydrogen. In some embodiments, X is absent or is —(CH(R')) . In some embodiments, Z is 1. In some embodiments, R' is methyl or hydrogen. In some instances, X is —CH2—, or —CH(CH)—. In some embodiments, the —CH(CH)— moiety has a (S) stereochemical configuration. Alternatively, the carbon of the —CH(CH)— moiety has a (R) stere ochemical configuration. In some embodiments, Y is absent, O-, - N(R)-, or—S(=O), . In some embodiments, X Y is —CH N(CH)—. Alternatively, X Y is (S)-

CH(CH) NH- or (R)-CH(CH) NH-. In some embodiments, each R is alkyl, alkenyl, alkynyl, 60 cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, Sulfonamido, halo, cyano, het eroaryl, aryl, hydroxyl, or nitro. In some embodiments, each R is alkyl, heteroalkyl, alk enyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, 65 heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, halo, US 8,901,133 B2 37 38 In some embodiments, W is -continued

N 5

r N. R12 2

R13 10 In some embodiments, W is aryl optionally substituted with one or more R, R'', R', or R'. In some embodiments, W, is heteroaryl optionally substituted with one or more R', R'', R', or R' (e.g., a bicyclic heteroaryl). In some embodi 15 ments, W is selected from:

US 8,901,133 B2 39 40 -continued In some embodiments, W is

In some embodiments, W is

2O 7NN N N le 2

25

N1\ 2 ls -N/ N X-r 30 N

35 In other embodiments, W is

40 N N N S N 2 21 X O 21SN1 N / N 45 21Ne. N NH2 N 1N -N / In yet other embodiments, W is R N N R12 2 50

7 N O \ and syS, 55 Ol N N

In some embodiments, W is wherein each W is optionally further substituted with one or 60 more R, R'', R', and R'. In some embodiments, R is hydrogen, halo, alkyl, cycloalkyl or heterocycloalkyl. N21 N In some embodiments, each R'' and R'' is independently 65 ls y hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, het- s S eroaryl, alkoxy, amino, cyano, halo or hydroxyl. US 8,901,133 B2 41 42 In some embodiments, W is In some embodiments, W is

10 In some embodiments, R'' is hydrogen. In some embodiments, R' is hydrogen. In some embodi ments, R' is halo (e.g., fluoro or chloro). In some embodi ments, R' is haloalkyl (e.g., trifluoromethyl). In some 15 embodiments, R' is cyano. In some embodiments, R' is amido (e.g., —C(O)NH2). In some embodiments, R' is amino (e.g., -NH2). In some embodiments, Rishydrogen, alkyl, alkenyl, alky nyl, cycloalkyl, heteroalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, Sulfonamido, halo, cyano, hydroxyl or nitro. In some embodiments, the compound of Formula (I) has In some embodiments, W is the structure of Formula (Ia):

25 Formula (Ia) C 30

In some embodiments, W is 35 or its pharmaceutically acceptable forms thereof, wherein n, Z, Ral, R2, L. R", R", R2, R, R, X,Y, R, R10, R, R11, R12, R" and W are as defined for Formula (I); and N W is N or CR. 40 In some embodiments, the compound of Formula (I) has n the structure of Formula (II): R12 \ NH Formula (II) 45 In some embodiments, W is

50 O

or its pharmaceutically acceptable forms thereof, wherein n, C NH2. 55 N Z, Ral, R2, L. R", R'', R°, R, X,Y, R, Rio, R, R l, R12, R13 R12 2 and W are as defined for Formula (I); W is Nor CR, W is N or CR, W is Nor CR7, and W. is N or CR, wherein no more than two Natoms are adjacent; In some embodiments, W is and 60 R. R. R and R'' are independently hydrogen, alkyl,

haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, 65 cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'" wherein R' and R" are taken together with nitrogen to form a cyclic moiety. US 8,901,133 B2 43 44 In yet other embodiments, the compound of Formula (II) In some embodiments, the compound of Formula (II) has has the structure of Formula (IIa): the structure of Formula (IIb):

Formula (IIa) 5 Formula (IIb) R8 R1

W. NN w81"S1SN | 10 2 X W&Y wi 2 2 i R4 n R4 YYW, 15 or its pharmaceutically acceptable forms thereof, wherein R. or its pharmaceutically acceptable forms thereof, wherein R. Rs. X, Y, and W are as defined for Formula (II). W is Nor CR'', W is Nor CR, W is Nor CR7, and W. In some embodiments, L is a bond and R' is an optionally is N or CR, wherein no more than two Natoms are adjacent; Substituted 5-membered heterocyclic group comprising at R" is -(L)-R'; least two heteroatoms chosen from O and N. each L is independently alkylene, heteroalkylene, In some embodiments, X is absentoris —(CH(R') and S(O), , -S-, -N(R)—, or —O—; Z is an integer of 1, 2, 3, or 4. n is an integer of 0, 1, 2, 3 or 4: In some embodiments, each R is independently hydrogen, R" is alkyl, Substituted alkyl, a heterocyclic group com C-Coalkyl, C-C-7 cycloalkyl, heterocycloalkyl, C-Cohet prising at least two heteroatoms chosen from O, N and S. 25 eroalkyl, aryl, or heteroaryl. wherein R' is optionally substituted by R'; or R' is In some embodiments, each R' is independently hydro NRR2, gen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, arylalkyl, R'' and R' are each independently hydrogen, alkyl, het heteroarylalkyl or halo. eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, In some embodiments, W' is CR'', W is CR, Wis CR", arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy 30 and Wis CR. In some embodiments, W' is N, Wis CR, W cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, is CR, and Wis CR. In some embodiments, W' is CR''. W’ Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, is N, Wis CR, and W is CR. In some embodiments, W' is nitro, phosphate, urea, carbonate, or R'' and R' are taken CR'', W is CR, W is N, and W is CR. In some embodi together with nitrogen to form a cyclic moiety; 35 ments, W' is CR'', W is CR, W is CR, and W is N. In R. R. R. R7 and Rare each independently hydrogen, some embodiments, W' is N, W is CR, W is N, and W is alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, CR. In some embodiments, W' is N, W’’ is CR, Wis N, and heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, W is CR. In some embodiments, W' is N, Wis CR, W is alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, CR', and W is N. In some embodiments, W' is CR'', W is alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, 40 N, W is N, and W is CR. In some embodiments, W' is cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R''. CR'', W is N, W is CR 7, and W is N. In some embodi wherein R' and R" are taken together with nitrogen to form a ments, W is CR'', Wis CR, W is N, and W is N. cyclic moiety; In other embodiments of compounds of Formula (II), R' is X is absent or is —(CH(R')) ; hydrogen, alkoxy, alkyl, heterocycloalkyl, aryl, or NR'R''. 45 wherein R' and R" are taken together with nitrogen to form a cyclic moiety. In some embodiments, R' is amino, alkoxy, alkyl, or NR'R", wherein R' and R" are taken together with nitrogen to form a cyclic moiety. C(R') , or -C(=O)–(CHR') : In some embodiments, R is hydrogen, alkyl, haloalkyl, each Z is an integer of 1, 2, 3, or 4: 50 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each R and R is independently hydrogen, C-Clo alkyl, alkoxy, Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, C-C cycloalkyl, heterocycloalkyl, C-Coheteroalkyl, aryl, hydroxy, amino or NR'R", wherein R and R" taken together or heteroaryl; with nitrogen to form a cyclic moiety. For example, R is each R" is independently hydrogen, alkyl, cycloalkyl, het hydrogen or alkyl. In other embodiments, R is haloalkyl eroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halo: 55 (e.g., trifluoromethyl). In some embodiments, R is halo (e.g., W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, chloro). In still other embodiments, X is —CH2—, —CH(CH)—, wherein W is substituted with one or more R, R', R', or —CH(CHs)— or —CH(CHCH)—. In some embodi R; and ments, —CH(CH)—or —CH(CHCH)—has a predomi each R', R'', R', and R' is independently hydrogen, 60 nately (S) stereochemical configuration. alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy In some embodiments, Y is absent, —O , N(R) , cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, - N(R)C(R') , or—S(=O) , where each R is inde heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo pendently hydrogen, methyl or ethyl. nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, Alternatively, X is CH(R')) , Z is 1,Y is N(R) , phosphate, urea, carbonate, or NR'R", wherein R' and R" are 65 and R is hydrogen; or Y is N(CH2CH)CH or taken together with nitrogen to form a cyclic moiety; and —N(CH)CH . In some embodiments, X Y is —CH2— at least one of R. R. R. and R7 is halo. N(CH)—, or —CH N(CH2CH)—. US 8,901,133 B2 45 46 Also contemplated herein are compounds wherein W is a In other embodiments, W is Formula (XVI): monocyclic or polycyclic heteroaryl which is unsubstituted or substituted with one or more substituents selected from alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocy Formula (XVI) N =\ cloalkyl, cycloalkyl, cyano, amino, hydroxy, alkoxy, acyloxy, NH alkoxycarbonyl, and amido. N For example, W is a bicyclic heteroaryl. In some embodi ments, W is a pyrazolopyrimidine, thiazolo.5,4-dipyrimi dine, pyrido3.2-dpyrimidine, pyrazolo 1.5-alpyrimidine, 10 l quinazoline, imidazol-2-bipyridazine, or a purine. R12 In some embodiments, W is purine, and X Y is —(CH wherein R' is H. alkyl, alkynyl, alkenyl, halo, aryl, het (R'))N(R)-. Ris, for example, hydrogen. eroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, acyloxy, 15 alkoxycarbonyl, or amido. In other embodiments, W is one of the following formu In some embodiments, R'' is amino. In other embodi lae: ments, R' is a monocyclic heteroaryl, a bicyclic heteroaryl, or a heterocycloalkyl. In still other embodiments, R' is

hydrogen. In some embodiments of the compounds of Formula II, R' and R" are taken together with nitrogen to form a cyclic moiety. For example, the cyclic moiety is 5- or 6-membered. In some embodiments of the compounds of Formula II, n is 1 and L is alkylene (e.g., methylene or ethylene). In other 25 embodiments, L is alkyl substituted by R', wherein R' is aryl, heteroaryl or halo. In one aspect, the compound of Formula (I) has the struc ture of Formula (III):

30 Formula (III)

35

wherein each R is independently hydrogen or alkyl: 40 R'' is hydrogen, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R" is hydrogen, alkyl, haloalkyl, cyano, alkynyl, alkenyl, or its pharmaceutically acceptable forms thereof, wherein halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, 45 W is Nor CR, W is Nor CR, W is Nor CR7, Wis N alkoxycarbonyl, or amido. or CR, and W is N or CR, wherein no more than two N atoms are adjacent; In some embodiments, W is Formula (X): each L is alkylene, heteroalkylene, -S-, - N(R)-, or —O—; 50 n is 0 or 1; Formula (X) R'' and R' are each independently hydrogen, alkyl, het eroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy %. cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, N Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, 55 nitro, phosphate, urea, carbonate, or R'' and R' are taken together with nitrogen to form a cyclic moiety; R12 7, R. R. R. R7 and Rare independently hydrogen, alkyl, N heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero R cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, 60 alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, wherein R'' is H, alkyl, halo, amino, amido, hydroxy, or cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R''. alkoxy, and wherein R' and R" are taken together with nitrogen to form a cyclic moiety; R’ is H. alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, 65 X is absent or is —(CH(R')) ; heterocycloalkyl, cycloalkyl, cyano, amino, acyloxy, alkoxy Y is absent, —O— —S —S(=O)—, carbonyl, or amido. - N(R)-, -C(=O)–(CHR') , US 8,901,133 B2 47 48 N(R) C(=O) , or N(R), C(=O)NH N(R) In some embodiments, n is 0 or 1. C(R') , or -C(-O)–(CHR') : In some embodiments, X is absent or is —(CH(R'))— each Z is an integer of 1, 2, 3, or 4: each R and Ris independently hydrogen, C-Coalkyl, and Z is an integer of 1, 2, 3, or 4. C-C,cycloalkyl, heterocycloalkyl, C-Coheteroalkyl, aryl, In some embodiments, L is alkylene (e.g., methylene or or heteroaryl; ethylene), heteroalkylene. —S , N(R)—, or —O—. each R' is independently hydrogen, alkyl, cycloalkyl, het In some embodiments, R" is hydrogen, alkyl, cycloalkyl, eroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halo: heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or and halo. W is heterocycloalkyl, aryl, cycloalkyl, or heteroaryl, In some embodiments, W' is CR'', W is CR, Wis CR", wherein W is substituted with one or more R, R'', R', and 10 and W is CR. In some embodiments, R'' is hydrogen. In R'; and some embodiments, R is hydrogen. In some embodiments, each R', R'', R', and R' is independently hydrogen, R’ is hydrogen. In some embodiments, R. R. and R7 are alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocy hydrogen. cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, In some embodiments, R is halo (e.g., chloro). In some heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbo 15 embodiments, R is alkyl (e.g., methyl). In some embodi nyl, Sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, ments, R is heteroaryl (e.g., 1-methyl-4-pyrazolyl). phosphate, urea, carbonate, or NR'R", wherein R' and R" are In some embodiments, the compound of Formula (I) has taken together with nitrogen to form a cyclic moiety. the structure of Formula (IV): In some embodiments, the compound of Formula (III) has the structure of Formula (IIIa): Formula (IV)

Formula (IIIa) O Ral / N 25

4 ( \Ra2 w81"S1SNW. W&Y wia 21 i 30 or its pharmaceutically acceptable forms thereof, wherein Z. R4 YYw, n, L, Ral, R2, R°, R, X,Y, R, Rio, R, Ril, R12, R13, and W. are as defined for Formula (I); 35 W is Nor CR', W is Nor CR, Wis Nor CR7, Wis N or its pharmaceutically acceptable forms thereof, wherein L. or CR, and W is N or CR, wherein no more than two N n, Z, R1, R, X,Y, R,R,R,R,R,R,R,R, and W. atoms are adjacent; and are as defined for Formula (III); R. R. R. and R'' are independently hydrogen, alkyl, W' is Nor CR'', W is N or CR, W is Nor CR7, and W. heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero is N or CR, wherein no more than two Natoms are adjacent; cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and 40 alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, R. R. R and R'' are independently hydrogen, alkyl, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, Sulfone, halo, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'" aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocy wherein R' and R" are taken together with nitrogen to form a cloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, cyclic moiety. Sulfonamido, thio. Sulfoxide, Sulfone, halo, cyano, hydroxy, 45 In some embodiments, the compound of Formula (IV) has nitro, phosphate, urea, carbonate, or NR'R", wherein R' and the structure of Formula (IVa): R" are taken together with nitrogen to form a cyclic moiety. In some embodiments, the compound of Formula (IIIa) has the structure of Formula (IIIb): Formula (IVa) 50

Formula (IIIb)

55

60

or its pharmaceutically acceptable forms thereof, wherein L. 65 or its pharmaceutically acceptable forms thereof, wherein Z. nz, R, R2, R, X,Y, R,R,R,R,R,R, R2, R1, and X, Y, Wil, W2, W3, W4, R*, R, R7, R8, R14, R, R10, R, R11, W are as defined for Formula (III). R', R', and W are as defined for Formula (IV). US 8,901,133 B2 49 50 In some embodiments, the compound of Formula (IVa) has In some embodiments, X is absent or is —(CH(R')) . In the structure of Formula (IVb): some embodiments, R' is methyl or hydrogen. In some embodiments, Z is 1. In some instances, X is —CH2—, or —CH(CH)—. In some embodiments, the —CH(CH)— Formula (IVb) 5 moiety has a (S) stereochemical configuration. Alternatively, the CH carbon of the —CH(CH)— moiety has a (R) stere ochemical configuration. In some embodiments, Y is absent, O-, -N(R)—, or—S(=O)2 -. In some embodiments, O X-Y is —CH N(CH). Alternatively, X-Y is (S)-CH 10 (CH) NH or (R)-CH(CH) NH-. R8 In some embodiments, R" is selected from hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, amido, amino, R acyl, acyloxy, alkoxycarbonyl, Sulfonamido, halo, cyano, and NN hydroxyl. For example, R' is selected from hydrogen, 15 2 X amino, and chloro. In one instance, R' is selected from amino and chloro. R4 ls In Some embodiments of compounds described herein, L is W. a bond and R' is a heteroaryl group. In some embodiments, the compound is a compound of or its pharmaceutically acceptable forms thereof, wherein Z. Formula (V), wherein: X, Y, R. R. R. R. R. R. R'', R', R', and W are as each L is O—, C(=O)—, S(=O) , S defined for Formula (IV). (=O) , —S—, or alkylene (e.g. —O— or alkylene); In some embodiments, X is —(CH(R')) and Z is an R" is alkyl, hydroxy, aryl, heteroaryl, aralkyl, —(C=O)— integer of 1, 2, 3, or 4. In some embodiments, each Risindependently hydrogen, 25 NR'R'', or NR'R''. C-Coalkyl, C-C-7 cycloalkyl, heterocycloalkyl, C-Cohet W is: eroalkyl, aryl, or heteroaryl. In some embodiments, each R' is independently hydro gen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halo. 30 In some embodiments, at least one of R. R. R. R. and N NNN1S R is halo (e.g., chloro or fluoro). 7 N N N le 2 In some embodiments, the compound of Formula (I) has N the structure of Formula (V): 35

Formula (V) R3 R1 NN 40 2 i

Yn 45 or its pharmaceutically acceptable forms thereof, wherein n, Z, L. X,Y, R", R", Ral, R2, R2, R, R, Rio R, Rl l, R12, R13 and W areas defined for Formula (I). 50 In some embodiments, R is halo, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or hetero cycloalkyl. In some embodiments, R is halo, alkyl, haloalkyl, acyl, or heteroaryl. In some embodiments, R is alkyl (e.g., methyl) or halo (e.g., chloro or fluoro). 55 In other embodiments, each L is —O—, —C(=O)—, S(=O)— —S(=O) , —S , alkylene, or a bond. In Some embodiments, L is —(C(=O))— or —O—. In some embodiments, R'' is alkyl, hydroxy, aryl, het eroaryl, aralkyl, -(C=O) NR'R'', or NR'R''. In some 60 embodiments, R' is substituted alkyl, -(C=O) NR'R'', NR'R'', a it wherein R'' and R' are taken together with nitrogen to form a cyclic moiety. For instance, the cyclic moiety is a heterocyclic or heteroaryl group Such as a mor pholino group. In other instances, R' is substituted alkyl, 65 including alkyl which is substituted with a heterocycloalkyl group. US 8,901,133 B2 51 52 -continued or R' is unsubstituted or substituted heterocycloalkyl which R12 includes, but is not limited to, pyrrolidinyl, tetrahydrofuranyl, NH, or s piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments, R' or R' is unsubstituted or substituted alkoxy including, but lsN1 N not limited to, C-C alkoxy such as methoxy, ethoxy, pro poxy or butoxy. In some embodiments, R' can also be unsub R" it is hydrogen; stituted or Substituted heterocycloalkyloxy, including, but not R" is hydrogen, halo, haloalkyl, cyano, amino, or amido; 10 limited to, 4-NHpiperidin-1-yl-oxy, 4-methylpiperidin-1-yl and oxy, 4-ethylpiperidin-1-yl-oxy, 4-isopropylpiperidin-1-yl n is 0, 1, 2, 3, or 4 (e.g. 0, 1, or 2). oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R' is In some embodiments, the compounds described herein unsubstituted or substituted amino, wherein the substituted can exist as a tautomer, and Such tautomers are contemplated amino includes, but is not limited to, dimethylamino, diethy herein. 15 lamino, di-isopropyl amino, N-methyl N-ethyl amino, and In some embodiments of the compounds described herein, dibutylamino. In some embodiments, R' or R' is unsubsti W is CR, W2 is CR, W is CR7, Wis CR; W is N, W2 is CR, W is CR 7, Wis CR; W is CR, W2 is N, Wis CR7, tuted or substituted acyl, unsubstituted or substituted acyloxy, W is CR; W is CR; W2 is CR, W is N, Wis CR; W is unsubstituted or Substituted C-C acyloxy, unsubstituted or CR'', Wis CR, Wis CR7, Wis N; W is N, Wis CR, W substituted alkoxycarbonyl, unsubstituted or substituted is N, Wis CR; W is N, W2 is CR, W is N, Wis CR; W amido, or unsubstituted or substituted sulfonamido. In other is N, W2 is CR, Wis CR7, Wis N; W is CR, W2 is N, W embodiments, R' or R' is halo, selected from I, F, is N, Wis CR; W is CR; W is N, W is CR7, Wis N; or —Cl, or —Br. In some embodiments, R' or R' is selected W is CR, W2 is CR, W is N, W is N. from cyano, hydroxy, nitro, phosphate, urea, or carbonate. In some embodiments of the compounds of Formulas (I) 25 Also contemplated are R' or R' being —CH, —CH2CHs. and (III), R' or R' can be hydrogen, or unsubstituted or n-propyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, Substituted alkyl (including, but not limited to. —CH, hexyl, heptyl, —OCH —OCHCH, or —CF. —CH2CH., n-propyl, isopropyl. n-butyl, tert-butyl, Sec-bu In some embodiments of the compounds of Formulas (I) tyl, pentyl, hexyl, and heptyl). In other embodiments, R' or and (V), R'' and R* are taken together with the nitrogen to R’ is unsubstituted or substituted alkenyl (including, but not 30 form a cyclic moiety having from 3 to 8 ring atoms. In some limited to, unsubstituted or substituted C-C alkenyl such as, embodiments, the cyclic moiety so formed can further vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or include one or more heteroatoms which are selected from S, O, or N. In other embodiments, the cyclic moiety so formed is unsubstituted or Substituted alkynyl (including, but not lim unsubstituted or substituted, including, but not limited to, ited to, unsubstituted or Substituted C-C alkynyl such as 35 morpholinyl, aZetidinyl, pyrrolidinyl, piperidinyl, piperazi acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, nyl, isothiazolidinyl-1,1-dioxide, and thiomorpholinyl. Fur R' or R' is unsubstituted or substituted aryl (including, but ther non-limiting exemplary cyclic moieties include the fol not limited to, monocyclic or bicyclic aryl) or unsubstituted lowing: or Substituted arylalkyl (including, but not limited to, mono cyclic or bicyclic aryl linked to alkyl wherein alkyl includes, 40 but is not limited to. —CH, -CH2CH., n-propyl, isopropyl. n-butyl, Sec-butyl, and pentyl). In some other embodiments, R' or R' is unsubstituted or substituted heteroaryl, includ ing, but not limited to, monocyclic and bicyclic heteroaryl. 45 Monocyclic heteroaryl R' or R' includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl. Bicyclic heteroaryl R' or R' includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiaz olyl, quinazolinyl, azaindolyl pyrazolopyrimidinyl, purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazol-2-alpyridinyl, and pyrrolo1, 55 2-f 1.2.4 triazinyl. In some embodiments, R' or R' is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes, but is not limited to. —CH, —CHCH. n-propyl. isopropyl. n-butyl, sec-butyl, and pentyl. In some embodi ments, R' or R' is unsubstituted or substituted cycloalkyl (including, but not limited to, cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non 65 limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R' US 8,901,133 B2 53 54 -continued In some embodiments of the compounds of Formula (I) and O (V), L is N(R)—, wherein R is hydrogen, unsubstituted or substituted C-C alkyl (which includes, but is not limited to. —CH, —CH2CHs, n-propyl, isopropyl. n-butyl, tert butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted > CSu O 5 or substituted C-C, cycloalkyl (which includes, but is not O limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclo O hexyl). In other embodiments, R is unsubstituted or substi tuted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl. r and 10 piperidinyl, and piperazinyl), or unsubstituted or Substituted C-Co heteroalkyl (which includes, but is not limited to, methoxyethoxy, methoxymethyl, and diethylaminoethyl). > Alternatively, R is unsubstituted or substituted monocyclic 15 heteroaryl (which includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, -v ch pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl) O or unsubstituted or Substituted monocyclic aryl. Nu In some embodiments of the compounds of Formulas (I) 2O and (V), L is alkylene (e.g., —C(R'). ). In some embodi ments of the compounds of Formulas (I) and (V), L is —C(R') , wherein R' is hydrogen, unsubstituted or sub In some embodiments of compounds of Formulas (I) and stituted C-C alkyl (including, but not limited to. —CH, (V), wherein when R' or R' is alkyl, alkenyl, alkynyl, —CH2CHs, n-propyl, isopropyl. n-butyl, tert-butyl, Sec-bu cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalky- 25 tyl, pentyl, hexyl, and heptyl), or halo selected from —I, —F. loxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, —Cl, or —Br. In further embodiments, R' is unsubstituted amido, amino, Sulfonamido, acyloxy, oralkoxycarbonyl, then or Substituted monocyclic heteroaryl (including, but not lim R' or R' is optionally substituted with one or more of the ited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidi following Substituents: alkyl, alkenyl, alkynyl, cycloalkyl, nyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, ary 30 and oxazolyl) or unsubstituted or Substituted monocyclic lalkyl, heteroaryl, heteroarylalkyl, acyl, heterocycloalkyloxy, aryl. In some embodiments of the compounds of Formula (I) and alkoxy, amido, amino, Sulfonamido, acyloxy, alkoxycarbo (V), L is heteroalkylene (e.g., —C(R') ). In some nyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, embodiments of the compound of Formulas (I) and (V), L is or NR'R", wherein R' and R" are taken together with nitrogen 35 —O C(R') , wherein R' is hydrogen, unsubstituted or to form a cyclic moiety. Each of the above substituents can be Substituted C-Co alkyl (including, but not limited to, further substituted with one or more substituents chosen from —CH, —CH2CHs, n-propyl, isopropyl. n-butyl, tert-butyl, alkyl, alkoxy, amido, amino, Sulfonamido, acyloxy, alkoxy sec-butyl, pentyl, hexyl, and heptyl), or halo selected from carbonyl, halo, cyano, hydroxy, nitro, Oxo, phosphate, urea, —I, F, —Cl, or —Br. In further embodiments, R' is and carbonate. 40 unsubstituted or substituted monocyclic heteroaryl (includ For example, in Some embodiments are compounds of ing, but not limited to, pyrrolyl, thienyl, furyl, pyridinyl, Formulas (I) and (V), wherein when R' or R' is alkyl, the pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, alkyl is substituted with NR'R", wherein R' and R" are taken thiazolyl pyrazolyl, and oxazolyl) or unsubstituted or Substi together with the nitrogen to form a cyclic moiety. In some tuted monocyclic aryl. embodiments, the cyclic moiety so formed can be unsubsti- 45 In some embodiments of the compound of Formulas (III) tuted or Substituted. Non-limiting exemplary cyclic moieties and (IV), L is a bond and R' is an optionally substituted include, but are not limited to, morpholinyl, aZetidinyl, pyr 5-membered heterocyclic group comprising at least two het rolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In eroatoms chosen from O and N. For example, R' can be other examples, when R' is alkyl, the alkyl is substituted with oxazole. In other embodiments, R'' is isoxazole. heterocycloalkyl, which includes oxetanyl azetidinyl, tet- 50 In some embodiments of compounds of Formulas (I) and rahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, (III), R is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, morpholinyl, and piperazinyl. All of the above listed hetero cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, het cycloalkyl substituents can be unsubstituted or substituted. eroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, In yet other examples of the compounds of Formula (I) and acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, (V), when R' or R' is alkyl, the alkyl is substituted with a 5, 55 Sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbon 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, ate, (C–O) NR'R'', or NR'R'', wherein R or R' which is unsubstituted or substituted. In some embodiments, are taken together with nitrogen to form a cyclic moiety. the monocyclic heteroaryl includes, but is not limited to, In some embodiments of the compounds of Formulas (I), pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, (II) and (III), R' can be hydrogen, or unsubstituted or substi pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and 60 tuted alkyl (including, but not limited to. —CH-CHCH oxazolyl. In other embodiments, the bicyclic heteroaryl n-propyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, includes, but is not limited to, benzothiophenyl, benzofuryl, hexyl, and heptyl). In other embodiments, R' is unsubstituted indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzox or Substituted alkenyl (including, but not limited to, unsub azolyl, benzothiazolyl, quinazolinyl, azaindolyl pyrazolopy stituted or substituted C-C alkenyl such as, vinyl, allyl, rimidinyl, purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrim- 65 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted idinyl, indazolyl pyrazolylpyridinyl, imidazol-2-a or Substituted alkynyl (including, but not limited to, unsub pyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. stituted or Substituted C-C alkynyl such as acetylenyl, pro US 8,901,133 B2 55 pargyl, butynyl, or pentynyl). Alternatively, R' is unsubsti tuted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic orbicyclic aryl linked to alkyl wherein alkyl includes, but is not limited to. —CH, —CH2CH., n-propyl, isopropyl. n-butyl, Sec-bu tyl, and pentyl). In some other embodiments, R' is unsubsti tuted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. In some embodiments, monocyclic heteroaryl R' includes, but is not limited to, 10 pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl. In some embodiments, bicyclic heteroaryl R' includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzox 15 azolyl, benzothiazolyl, quinazolinyl, azaindolyl pyrazolopy rimidinyl, purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrim idinyl, indazolyl pyrazolylpyridinyl, imidazol-2-a pyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. Also provided herein are compounds which are unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes, but is not limited to. —CH, —CH2CH., n-propyl, isopropyl. n-butyl, sec-butyl, and pen 25 tyl. In some embodiments, R' is unsubstituted or substituted cycloalkyl (including, but not limited to, cyclopropyl. cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further 30 embodiments, R' is unsubstituted or substituted heterocy cloalkyl which includes, but is not limited to, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidi nyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds described herein, R' is 35 unsubstituted or substituted alkoxy including, but not limited to, C-C alkoxy Such as methoxy, ethoxy, propoxy or butoxy. R" can also be unsubstituted or substituted heterocycloalky loxy, including, but not limited to, 4-NH piperidin-1-yl-oxy, 40 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R' is unsubstituted or substitutedamino, wherein the substituted amino includes, but is not limited to, dimethylamino, diethylamino, di-isopropylamino, N-methyl 45 N-ethylamino, and dibutylamino. In some embodiments, R' is unsubstituted or substituted acyl, unsubstituted or substi tuted acyloxy, unsubstituted or substituted C-C acyloxy, Also provided are compounds of Formulas (I), (II) or (III), unsubstituted or substituted alkoxycarbonyl, unsubstituted or wherein when R' is alkyl, alkenyl, alkynyl, cycloalkyl, het substituted amido, or unsubstituted or substituted sulfona 50 eroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, aryla mido. In other embodiments, R' is halo, selected from I. lkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, —F. —Cl, or —Br. In some embodiments, R' is selected Sulfonamido, acyloxy, or alkoxycarbonyl, then R' is option from cyano, hydroxy, nitro, phosphate, urea, or carbonate. ally substituted with one or more of the following substitu Also contemplated are R' being —CH, -CH2CHs, n-pro 55 ents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, hetero pyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, cycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heptyl, —OCH, —OCHCH, or —CF. heteroarylalkyl, acyl, heterocycloalkyloxy, alkoxy, amido, In some embodiments of the compounds of Formulas (I), amino, Sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, (II) or (III), R is NR'R'', where R' or R are taken hydroxy, nitro, phosphate, urea, carbonate, or NR'R". together with the nitrogen to form a cyclic moiety having 60 wherein R' and R" are taken together with nitrogen to form a from 3 to 8 ring atoms. The cyclic moiety so formed can cyclic moiety. Each of the above substituents can be further further include one or more heteroatoms which are selected substituted with one or more substituents chosen from alkyl, from S. O. and N. The cyclic moiety so formed is unsubsti alkoxy, amido, amino, Sulfonamido, acyloxy, alkoxycarbo tuted or substituted, including but not limited to morpholinyl, nyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and aZetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazo 65 carbonate. lidinyl-1,1-dioxide, and thiomorpholinyl. Further non-limit For example, provided herein are compounds of Formulas ing exemplary cyclic moieties are the following: (I), (II) or (III), wherein when R' is alkyl, the alkyl is substi US 8,901,133 B2 57 58 tuted with NR'R", wherein R' and R" are taken together with includes, but is not limited to, pyrrolidinyl, tetrahydrofuranyl, the nitrogen to form a cyclic moiety. The cyclic moiety so piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, formed can be unsubstituted or substituted. Non-limiting morpholinyl, and piperazinyl. In yet other embodiments of exemplary cyclic moieties include, but are not limited to, the compounds described herein, R is unsubstituted or sub morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazi stituted alkoxy including, but not limited to, C-C alkoxy nyl, and thiomorpholinyl. In other examples of the com Such as methoxy, ethoxy, propoxy or butoxy. In some embodi pounds disclosed herein, when R'' is alkyl, the alkyl is sub ments, R' can also be unsubstituted or substituted heterocy stituted with heterocycloalkyl, which includes, but is not cloalkyloxy, including, but not limited to, 4-NH piperidin-1- limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl, yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. 10 oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl All of the above listed heterocycloaklyl substituents can be unsubstituted or substituted. oxy. In some embodiments, R is unsubstituted or substituted In yet other examples of the compounds of Formulas (I), acyl, unsubstituted or Substituted acyloxy, unsubstituted or (II) or (III), when R'' is alkyl, the alkyl is substituted with a 5. substituted C-C acyloxy, unsubstituted or substituted 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, 15 alkoxycarbonyl, unsubstituted or Substituted amido, or which is unsubstituted or substituted. In some embodiments, unsubstituted or substituted sulfonamido. In some embodi the monocyclic heteroaryl includes, but is not limited to, ments, R is selected from cyano, hydroxy, nitro, phosphate, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, urea, or carbonate. Also contemplated is R' being —CHs. pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and —CH2CHs, n-propyl, isopropyl. n-butyl, tert-butyl, Sec-bu oxazolyl. In other embodiments, the bicyclic heteroaryl tyl, pentyl, hexyl, heptyl, OCH —OCHCH, or—CF. includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzox In some embodiments, R' can also be NR'R", wherein R' azolyl, benzothiazolyl, quinazolinyl, azaindolyl pyrazolopy and R" are taken together with the nitrogen to form a cyclic rimidinyl, purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrim moiety having from 3 to 8 ring atoms. The cyclic moiety so idinyl, indazolyl pyrazolylpyridinyl, imidazol-2-a 25 formed can further include one or more heteroatoms which pyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. are selected from S. O. and N. The cyclic moiety so formed is In some embodiments of the compound disclosed herein, unsubstituted or substituted, including, but not limited to, R" can be hydrogen, or unsubstituted or substituted alkyl morpholinyl, aZetidinyl, pyrrolidinyl, piperidinyl, piperazi (including, but not limited to, —CH, —CH2CH., n-propyl. nyl, isothiazolidinyl-1,1, -dioxide, and thiomorpholinyl. Fur isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and 30 heptyl). In other embodiments, R is unsubstituted or substi ther non-limiting exemplary cyclic moieties include the fol tuted alkenyl (including, but not limited to, unsubstituted or lowing: Substituted C-C alkenyl such as, vinyl, allyl, 1-methyl pro pen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including, but not limited to, unsubstituted or Sub 35 stituted C-C alkynyl Such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, monocyclic or bicyclic aryl linked to alkyl 40 wherein alkyl includes, but is not limited to, —CH, —CHCH. n-propyl, isopropyl. n-butyl, sec-butyl, and pen tyl). In some other embodiments, R is unsubstituted or sub stituted heteroaryl, including but not limited to, monocyclic and bicyclic heteroaryl. In other embodiments, monocyclic 45 heteroaryl R' includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl. In some embodiments, bicyclic heteroaryl R' includes, but is not lim ited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, iso 50 quinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyr rolo 1.2-bipyridazinyl, pyrrolopyrimidinyl, indazolyl pyra Zolylpyridinyl, imidazol-2-alpyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. 55 In some embodiments, provided herein are compounds wherein R is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic het eroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to. —CH, —CH2CHs, n-pro 60 pyl, isopropyl. n-butyl, sec-butyl, and pentyl. In some embodiments, R is unsubstituted or substituted cycloalkyl (including, but not limited to, cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non limiting examples include ethoxymethyl, methoxymethyl, 65 and diethylaminomethyl). In some further embodiments, R' is unsubstituted or substituted heterocycloalkyl which US 8,901,133 B2 59 60 -continued other embodiments, each of R'', R', and R' independently is O unsubstituted or substituted alkenyl (including, but not lim ited to, unsubstituted or Substituted C-C alkenyl such as, ls vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or r 2 and unsubstituted or Substituted alkynyl (including, but not lim ited to, unsubstituted or Substituted C-C alkynyl Such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, each of R'', R. R', and Rindependently is unsubstituted or x - Substituted aryl (including, but not limited to, monocyclic or 10 bicyclic aryl) or unsubstituted or substituted arylalkyl (in r 1v CH3. cluding, but not limited to, monocyclic orbicyclic aryl linked O to alkyl wherein alkyl includes, but is not limited to, —CH, —CH2CHs, n-propyl, isopropyl. n-butyl, sec-butyl, and pen >, Nu tyl). In some other embodiments, each of R. R. and R' 15 independently is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic het In some embodiments, provided herein are compounds eroaryl. In some embodiments, monocyclic heteroaryl for wherein when R is alkyl, alkenyl, alkynyl, cycloalkyl, het each of R'', R. R', and R includes, but is not limited to, eroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, aryla pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, lkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and sulfonamido, or NR'R'" (wherein RandR" are taken together oxazolyl. In other embodiments, bicyclic heteroaryl for each with nitrogen to form a cyclic moiety), then R is optionally of R. R. R', and R includes, but is not limited to, ben substituted with one or more of the following substituents: Zothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocy benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, cloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, het 25 aZaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo 1.2-bpy eroarylalkyl, acyl, alkoxy, amido, amino, Sulfonamido, acy ridazinyl, pyrrolopyrimidinyl, indazolyl pyrazolylpyridinyl, loxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, imidazol-2-alpyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. urea, carbonate, or NR'R", wherein R and R" are taken In some embodiments, provided herein are compounds of together with nitrogen to form a cyclic moiety. Each of the Formulas (II), (III), and (IV), wherein each of R'',R,R, and above substituents can be further substituted with one or more 30 Rindependently is unsubstituted or substituted heteroaryla Substituents chosen from alkyl, alkoxy, amido, amino, Sul lkyl, including but not limited to, monocyclic and bicyclic fonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, heteroarylas described above, that are linked to alkyl, which nitro, oxo, phosphate, urea, and carbonate. in turn includes, but is not limited to. —CH, —CHCH For example, provided herein are compounds wherein n-propyl, isopropyl. n-butyl, sec-butyl, and pentyl. In some when R is alkyl, the alkyl is substituted with NR'R", wherein 35 embodiments, each of R. R. R. and R independently is RandR" are taken together with the nitrogen to form a cyclic unsubstituted or substituted cycloalkyl (including, but not moiety. The cyclic moiety so formed can be unsubstituted or limited to, cyclopropyl, cyclobutyl, and cyclopentyl) or Substituted. Non-limiting exemplary cyclic moieties include, unsubstituted or substituted heteroalkyl (non-limiting but are not limited to, morpholinyl, aZetidinyl, pyrrolidinyl, examples include ethoxymethyl, methoxymethyl, and diethy piperidinyl, piperazinyl, isothiazolidinyl-1,1-dioxide, and 40 laminomethyl). In some further embodiments, each of R'', thiomorpholinyl. In other examples of the compounds R. R. and Rindependently is unsubstituted or substituted described herein, when R is alkyl, the alkyl is substituted heterocycloalkyl which includes, but is not limited to, pyrro with heterocycloalkyl, which includes, but is not limited to, lidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl. oxetanyl, aZetidinyl, tetrahydrofuranyl, pyrrolyl, tetrahydro thiazolidinyl, imidazolidinyl, morpholinyl, isothiazolidinyl pyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the 45 1,1-dioxide, and piperazinyl. In yet other embodiments of the above listed heterocycloaklyl substituents can be unsubsti compounds disclosed herein, each of R'', R. R. and R' tuted or substituted. independently is unsubstituted or substituted alkoxy includ In yet other examples of the compounds described herein, ing, but not limited to, C-C alkoxy such as methoxy, ethoxy, when R is alkyl, the alkyl is substituted with a 5,6,7,8,9, or propoxy or butoxy. In some embodiments, each of R'', R. 10 membered monocyclic or bicyclic heteroaryl, which is 50 R", and R can also independently be unsubstituted or substi unsubstituted or substituted. In some embodiments, the tuted heterocycloalkyloxy, including, but not limited to, monocyclic heteroaryl includes, but is not limited to, pyrro 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, lyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl. In and pyrrolidin-3-yl-oxy. In other embodiments, each of R'', other embodiments, the bicyclic heteroaryl includes, but is 55 R. R. and Rindependently is unsubstituted or substituted not limited to, benzothiophenyl, benzofuryl, indolyl, quino amino, wherein the Substituted amino includes, but is not linyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, ben limited to, dimethylamino, diethylamino, di-isopropyl Zothiazolyl, quinazolinyl, azaindolyl pyrazolopyrimidinyl, amino, N-methyl N-ethylamino, and dibutylamino. In some purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrimidinyl, inda embodiments, each of R. R. R. and R independently is Zolyl pyrazolylpyridinyl, imidazol-2-alpyridinyl, and pyr 60 unsubstituted or substituted acyl, unsubstituted or substituted rolo 1.2-f 1.2.4 triazinyl. acyloxy, unsubstituted or substituted C-C acyloxy, unsub In some of the embodiments of the compounds of Formulas stituted or substituted alkoxycarbonyl, unsubstituted or sub (II), (III), and (IV), W is CR, Wis CR, Wis CR7, and W. stituted amido, or unsubstituted or substituted sulfonamido. is CR. Each of R. R. R', and R can independently be In some embodiments, each of R'', R. R', and Rindepen hydrogen, or unsubstituted or Substituted alkyl (including, 65 dently is halo, selected from —I. —F. —Cl, or—Br. In some but not limited to, —CH, —CH2CH., n-propyl, isopropyl. embodiments, each of R. R. R. and R independently is n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In selected from cyano, hydroxy, nitro, phosphate, urea, or car US 8,901,133 B2 61 62 bonate. Also contemplated are each of R'', R, and R' inde eroarylalkyl, acyl, alkoxy, amido, amino, Sulfonamido, acy pendently being —CH, —CHCH. n-propyl, isopropyl. loxy, alkoxycarbonyl, or NR'R' (wherein R' and R" are taken n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH, together with nitrogen to form a cyclic moiety), then each of —OCHCH, or—CF. R'', R. R', and R independently is optionally substituted In some embodiments, each of R. R. R. and Rican also with one or more of the following substituents: alkyl, alkenyl, independently be NRR", wherein R' and R" are taken alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocy together with the nitrogen to form a cyclic moiety having cloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, from 3 to 8 ring atoms. The cyclic moiety so formed can alkoxy, amido, amino, Sulfonamido, acyloxy, alkoxycarbo further include one or more heteroatoms which are selected nyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, 10 or NR'R", wherein RandR" are taken together with nitrogen from S. O. and N. The cyclic moiety so formed is unsubsti to form a cyclic moiety. Each of the above substituents can be tuted or Substituted, including, but not limited to, morpholi further substituted with one or more substituents chosen from nyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothia alkyl, alkoxy, amido, amino, Sulfonamido, acyloxy, alkoxy Zolidinyl-1,1-dioxide, and thiomorpholinyl. Further non carbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, limiting exemplary cyclic moieties include the following: 15 and carbonate. For example, provided herein are compounds wherein when each of R. R. R', and Rindependently is alkyl, the alkyl is substituted with NR'R", wherein R' and R" are taken together with the nitrogen to form a cyclic moiety. The cyclic moiety so formed can be unsubstituted or substituted. Non limiting exemplary cyclic moieties include, but are not lim ited to, morpholinyl, aZetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl-1,1-dioxide, and thiomorpholi nyl. In other examples of the compounds disclosed herein, 25 when each of R. R. R', and Rindependently is alkyl, the alkyl is substituted with heterocycloalkyl, which includes, but is not limited to, oxetanyl, aZetidinyl, tetrahydrofuranyl, pyr rolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and pip erazinyl. All of the above listed heterocycloaklyl substituents 30 can be unsubstituted or substituted. In yet other examples of the compounds disclosed herein, when each of R. R. R', and Rindependently is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, which is unsubstituted or 35 Substituted. In some embodiments, the monocyclic heteroaryl for each of R'', R. R', and R includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl. In other embodiments, the bicyclic heteroaryl for 40 each of R. R. R', and R includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinoli nyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyr rolo 1.2-bipyridazinyl, pyrrolopyrimidinyl, indazolyl pyra 45 Zolylpyridinyl, imidazol-2-alpyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. In some embodiments of the compounds disclosed herein, W is CR, Wis CR, Wis CR 7, Wis CR and R,R,R, and Rare hydrogen. 50 In some embodiments of the compounds disclosed herein, at least one X or Y is present. In some embodiments, provided here are compounds wherein Y is N(R)-, - N(R)(C=O)— —N(R) (C=O)NH-, - N(R)C(R) , or C(=O)-(CH 55 R") — and Z is an integer of 1, 2, 3, or 4. In some embodi ments, R is hydrogen, unsubstituted or substituted C-Co alkyl (including, but not limited to, —CH, -CH2CH, n-propyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C-C, 60 cycloalkyl (non-limiting examples include cyclopropyl. cyclobutyl, cyclopentyl, and cyclohexyl). In other embodi ments, R is unsubstituted or substituted heterocycloalkyl (including, but not limited to, oxetanyl, tetrahydrofuranyl. In some embodiments, provided herein are compounds pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazi wherein when each of R'', R. R', and R independently is 65 nyl), or unsubstituted or Substituted C-Coheteroalkyl (C- alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocy Coheteroalkyl includes, but is not limited to, methoxy cloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, het ethoxy, methoxymethyl, and diethylaminoethyl). US 8,901,133 B2 63 64 Alternatively, R is unsubstituted or substituted monocyclic benzothiazolyl pyrazolopyridinyl, pyrazolopyrimidinyl, or heteroaryl (non-limiting examples include pyrrolyl, thienyl, isoquinolinyl. Additionally, the W bicyclic heteroaryl can furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, have at least two nitrogen ring atoms, such as indazole, pyr imidazolyl, thiazolyl pyrazolyl, and oxazolyl) or unsubsti rolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, ben tuted or substituted monocyclic aryl. For example, Y is Zimidazolyl, benzothiazolyl azaindolyl, quinazolinyl, ben - N(CH)CH-, - N(CH(CH))CH , N(CHCH.) ZOxazolyl, or pyrazolopyrimidinyl. In yet other CH , N(CH) , N(CHCH) , or N(CH embodiments, Wis a bicyclic heteroaryl having at least three (CH))—. In some embodiments, Y is —NH-. nitrogen ring atoms, such as pyrazolopyridinyl, pyrrolopyri In other embodiments, X is —(CH(R')), and Z is an midinyl, thiazolylpyrimidinyl, pyrrolo 1.2-bipyridazinyl, or integer of 1 or 2. In some embodiments, provided herein are 10 compounds wherein R' is hydrogen or unsubstituted or sub imidazo[1,2-alpyridinyl. Alternatively, W is a bicyclic het stituted C-Co alkyl (non-limiting exemplary alkyl Substitu eroaryl having at least four nitrogen ring atoms, including, but ents include, but are not limited to. —CH, —CH2CH, not limited to, pyrazolopyrimidinyl, purinyl, or pyrrolo 1.2- n-propyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, f1.2.4 triazinyl. In some embodiments, W is a bicyclic hexyl, and heptyl), or halo (Such as —I, —F. —Cl, or —Br). 15 heteroaryl having two heteroatoms in the ring which is con In further embodiments, R' is unsubstituted or substituted nected to XY. monocyclic heteroaryl (including, but not limited to, pyrrolyl, In some embodiments, W is one of the following: thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl pyrazolyl, and oxazolyl) or unsubstituted or Substituted monocyclic aryl. For example, H CN X is —CH2—, —CHCH , —CH2CH2CH2—, —CH (CH)— —CH(CHCH), —CH(CH) , —CH (CHCH)— or —CH(CH)— or —CH(CH)—. In some Yi Y embodiments, when X is —CH(CH)— —CH(CH2CH)— N N or —CH(CH)—, the asymmetric carbon center is predomi 25 nately in the (S)- or predominately in the (R)-stereochemical configuration. In some embodiments, an asymmetric carbon center is predominately (S)- or predominately (R)- when the predominate stereoisomer is present in greater than about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 95%, or 30 99% of the total proportion of the two possible stereoisomers at that asymmetric center. In some embodiments, X-Y is —CH2—, —CH2— NH-, -CH N(CH) , —CH(CH) NH-, -CH (CHCH) NH , —CH(CH) NH , (S)-CH 35 (CH) NH , (R)-CH(CH) NH-, (S)-CH (CHCH) NH , (R)-CH(CHCH) NH-, (S)-CH (C.H.) NH , or (R)-CH(CH)—NH-. In some embodiments, X Y is —N(CH) CH N(CH2CH) CH. , N(CH(CH))CH , or - NHCH . 40 In some embodiments of the compounds disclosed herein, W is unsubstituted or substituted heterocycloalkyl, wherein the heterocycloalkyl includes, but is not limited to, morpholi nyl, piperidinyl, piperazinyl, tetrahydro-2H-pyranyl, and pyr rolidinyl. In some embodiments, also provided herein are 45 In some embodiments of W R is selected from hydrogen, compounds wherein W is unsubstituted or substituted halo, phosphate, urea, carbonate, unsubstituted or Substituted cycloalkyl wherein the cycloalkyl includes, but is not limited alkyl, unsubstituted or substituted alkenyl, unsubstituted or to, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, W substituted alkynyl, unsubstituted or substituted cycloalkyl, is monocyclic aryl (for example, phenyl) or bicyclic aryl (for unsubstituted or substituted heteroalkyl, and unsubstituted or example, naphthyl), wherein the monocyclic aryl or bicyclic 50 substituted heterocycloalkyl. aryl is unsubstituted or substituted. In some embodiments, W is unsubstituted or substituted monocyclic heteroaryl. In some embodiments of W, when R is alkyl, alkynyl, Non-limiting exemplary monocyclic heteroaryls include pyr cycloalkyl, heteroalkyl, or heterocycloalkyl, it is substituted rolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazi by phosphate, urea, carbonate, or combinations thereof. nyl, pyridazinyl, imidazolyl, isothiazolyl, isoxazolyl, thiaz 55 In the compounds disclosed herein, W. can be substituted olyl, triazinyl, pyrazolyl, and oxazolyl. In some by R' wherein R'' is hydrogen, unsubstituted or substituted embodiments, also provided herein are compounds wherein alkyl, and halo (Such as —I, —F. —Cl, and —Br). In some W is unsubstituted or substituted bicyclic heteroaryl, includ embodiments, R'' is unsubstituted or substituted amino, ing, but not limited to, benzothiophenyl, benzofuryl, indolyl, unsubstituted or substituted amido, hydroxy, or unsubstituted quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, 60 or substituted alkoxy. In some embodiments, R' can also be benzothiazolyl, quinazolinyl, azaindolyl pyrazolopyrimidi phosphate, unsubstituted or Substituted urea, or carbonate. nyl, purinyl, pyrrolo 1.2-bipyridazinyl, pyrrolopyrimidinyl, Additionally, when R'' is alkyl, amino, amido, hydroxy, or indazolyl pyrazolylpyridinyl, imidazol-2-alpyridinyl, and alkoxy, R' can be substituted by phosphate, urea, or carbon pyrrolo 1.2-f 1.2.4 triazinyl. In some embodiments, the ate. quinolinyl W bicyclic heteroaryl is 4-quinolinyl. In some 65 In some embodiments of the compound disclosed herein, embodiments, the W bicyclic heteroaryl has at least one when W is purinyl, X is —(CH(R')) , Z is 1, and Y is heteroatom, including, but not limited to, indolyl, quinolinyl, - N(R)-, then R is NH-. US 8,901,133 B2 65 66 In some embodiments of the compound disclosed herein, -continued —X Y W is one of the following moieties: aCH3

5 N X, CH3 N\ / / NY-ch N eN NN N N N1 N 10 R12 \NR Y-H \ / Y-H HN2 eN 2 eN R HN HN 15 CH3 N

\ / y- \ / Y- 2O R12 HN eN

HN HN 25 O CH3 N N N N N / N Y N 30 N

35 CH3 CH3 - N N N -N N 40 \ W y-4

R12 eN R12 eN HN HN HN 45 aCH3 Et

N N N 50 / N N1 N N1 N \ / N N eN eN R12 e R12 R12 55 HN HN HN

y O CH

N N 60 N N N N1 N / N CH CH N VNF \ \ | N eN R12 -e-N R12 eN 65 US 8,901,133 B2 67 68 -continued continued A. wCH3 N N / N N \ / Nu 2 e

HN

N N / N N \ Nu 2 HN

25

30

35

40

45

50

55

60

65 US 8,901,133 B2 69 70 -continued -continued A. aCH3 5 N AllHN N H s HN H K / y- CH3 7.K / Y-ch l 2 eN 10 HN HN

A - Et N R12 N R12 DCn ls \ NH

A -l 25 N R12 n C 30 \ NH

35 y N - Et

N H N DC 40 \ NH

45

N Sry 50 ry eN

HN

SryN eN 65 HN US 8,901,133 B2 71 72 -continued -continued

N N N H N N H N le Me1 N E1 N \N y \,-a 2N 2N eN N N 10 \-h \ NH HN x CH3 his N 15 W/ N N-"s 2Nn

In some embodiments of the compounds disclosed herein, W. can be substituted by R' wherein R' is hydrogen, cyano, 6s halo, unsubstituted or substituted alkenyl (including, but not limited to, unsubstituted or Substituted C-C alkenyl Such as, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or US 8,901,133 B2 73 74 unsubstituted or Substituted alkynyl (including, but not lim ited to, unsubstituted or Substituted C-C alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). In other embodi

ments, R' is unsubstituted or substituted alkyl (including, but not limited to, —CH, —CH2CH., n-propyl, isopropyl. n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). Additionally, R' can be unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl). In some embodiments, R' is unsubstituted or substituted het 10 eroaryl, wherein the heteroaryl has a 5 membered ring (in cluding, but not limited to, imidazolyl, furyl, thienyl, pyrro lyl pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, and thiazolyl). In some embodiments, the R' heteroaryl can be heteroaryl having a six membered ring, including, but not 15 limited to, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In other embodiments, the R' het eroaryl can also be heteroaryl with at least one nitrogen ring atom, including, but not limited to, pyrrolyl, thiazolyl pyra Zolyl, imidazolyl pyrimidinyl, pyridinyl, indolyl, benzox azolyl, or pyrazinyl. Alternatively, the R' heteroaryl is het eroaryl with two nitrogen ring atoms, where non-limiting exemplary heteroaryls include pyrazolyl, indazolyl, benzimi dazolyl, and imidazolyl. In some embodiments, the R' het 25 Additionally, R' can be unsubstituted or substituted eroaryl can be monocylic heteroaryl, including, but not lim cycloalkyl (including, but not limited to, cyclopropyl. ited to, imidazolyl, pyrrolyl, and thiazolyl. In further cyclobutyl, cyclopentyl, or cyclohexyl). In other embodi embodiments, the R' heteroaryl is bicylic heteroaryl, ments, R' is cycloalkyl substituted by one oxo (including but wherein non-limiting exemplary bicyclic heteroaryls include, not limited to, 2-oxo-cyclobutyl, 3-oxo-cyclopentyl, and 30 4-oxo-cyclohexyl). In yet other embodiments, R' is unsub but are not limited to, benzoxazolyl, benzoisoxazolyl ben stituted or substituted amido, unsubstituted or substituted Zothiazolyl, benzimidazolyl, benzothiophenyl, benzofuryl, acyloxy, or unsubstituted or substituted alkoxycarbonyl. indolyl, quinolinyl, isoquinolinyl, quinazolinyl, azaindolyl, In some embodiments, when R' is alkyl, alkynyl, alkenyl, pyrazolopyrimidinyl, purinyl, pyrrolo 1.2-bipyridazinyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, the R' moi pyrrolopyrimidinyl, indazolyl pyrazolylpyridinyl, imidazo 35 ety is Substituted with phosphate. In some embodiments, 1,2-alpyridinyl, and pyrrolo 1.2-f 1.2.4 triazinyl. In some when R' is alkyl, alkynyl, alkenyl, aryl, heteroaryl, hetero embodiments, R' can also be unsubstituted or substituted cycloalkyl, or cycloalkyl, the R' moiety is substituted with heterocycloalkyl, wherein the R' heterocycloalkyl is a het urea. In some embodiments, when R' is alkyl, alkynyl, alk erocycloalkyl with one nitrogen ring atom (including, but not 40 enyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, the R' limited to, pyrrolidinyl, piperidinyl, morpholinyl, isothiazo moiety is substituted with carbonate. lidinyl-1,1-dioxide, or caprolactam). In other embodiments, In other embodiments, when R' is alkyl, alkynyl, alkenyl, the R' heterocyloalkyl is heterocycloalkyl with one oxygen aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkoxycarbo ring atom, including, but not limited to, tetrahydrofuranyl. nyl, amido, or acyloxy, the R' moiety is substituted with one tetrahydropyranyl, morpholinyl, or oxetanyl. Alternatively, 45 or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, the R' heterocycloalkyl is heterocycloalkyl with one sulfur heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, ring atom, including, but not limited to, thiomorpholinyl and acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sulfoxide, isothiazolidinyl-1,1-dioxide. In yet other embodiments, the Sulfone, halo, cyano, hydroxy or nitro. Each of the Substitu R" heterocyloalkyl is a 5 membered heterocycloalkyl, ents selected from alkyl, heteroalkyl, alkenyl, alkynyl, including, but not limited to, tetrahydrofuranyl, imidazolidi 50 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, nyl, isothiazolidinyl-1,1-dioxide, or pyrrolidinyl. In some amino, acyl, acyloxy, aloxycarbonyl, and Sulfonamido, can embodiments, the R' heterocycloalkyl is a 6 membered het be further substituted by one or more of alkyl, alkoxy, amido, erocycloalkyl (non-limiting exemplary 6 membered hetero amino, acyl, acyloxy, alkoxycarbonyl, Sulfonamido, thio. Sul cycloalkyls include tetrahydropyranyl, piperidinyl, piperazi 55 foxide, Sulfone, halo, cyano, hydroxy or nitro Substituents. nyl, morpholinyl, or thiomorpholinyl). In some In some embodiments, R' of W is one of the following embodiments, the R' heterocyloalkyl is saturated heterocy moieties: cloalkyl, including, but not limited to, tetrahydrofuranyl, tet rahydropyranyl, morpholinyl, oxetanyl, pyrrolidinyl, pip eridinyl, morpholinyl, piperazinyl, or azetidinyl. In other 60 embodiments, the R' heterocyloalkyl is heterocycloalkyl having an unsaturated moiety connected to the heterocy cloalkyl ring, including, but not limited to, cyano, imidazolyl, OH or pyrazolyl moieties. Alternatively, the R'' heterocycloalkyl 65 is heterocycloalkyl Substituted by oxo, including, but not OH limited to, one of the following: US 8,901,133 B2 75 76 -continued -continued OH CH

5 CH3

OH 10 o (

F

15 OH Et F /cN 2

c. F /orOH /o NH2 NH2

F 35 2N 21 /cC F NH NH2 ser N 40 OCH N 2 OCH N(Et) / / 45 NH-N NH-N OCH

N OCH 50 F OCH

F 55

HN HN

6065 /o COOH NH2

US 8,901,133 B2 79 -continued -continued Formula (IIIb) O Ral N^ R8 ( L W pi Ra2 In some embodiments, W is a pyrazolopyrimidine of For NN mula XIII: 10 2 X R4 ls Formula (XIII) W Formula (IVb) N-N 15 N -N/ \ N SN R11 NN wherein R'' is hydrogen, alkyl, halo, amino, amido, hydroxy, or alkoxy; and 2 R" is hydrogen, alkyl, alkynyl, alkenyl, halo, aryl, het 25 eroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, acyloxy, YN alkoxycarbonyl, or amido. W. In some embodiments, R'' is amino and R' is hydrogen, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocy 30 In some embodiments of compounds of Formulas (IIb). cloalkyl, or cycloalkyl. In some embodiments, R' is amino (IIIb) or (IVb), R is methyl or halo. For example, R is halo. and R' is alkyl, halo, aryl, heteroaryl, heterocycloalkyl, or In some embodiments of compounds of Formulas (IIb), (IIIb) cycloalkyl. In some embodiments, R'' is amino and R'' is or (IVb), R is C1. monocyclic heteroaryl. In some embodiments, R' is amino In some embodiments, provided herein are compounds of and R' is bicyclic heteroaryl. In some embodiments, R' is 35 Formula (IVb), wherein R is halo. For example, R7 is Clor F. amino and R' is cyano, amino, acyloxy, alkoxycarbonyl or In some embodiments of compounds of Formula (IIb), R' amido. is NR'R''. In other embodiments of compounds of Formula In some embodiments, W is a purine of the following (IIb), n is 0 or 1. Formula XIV: Some illustrative compounds include those in which R is 40 —H, —CH, —CH2CH, or—CF in combination with any R' or R' moiety described in Table 1, and any R'' as N Formula XIV described in Table 2. A compound disclosed herein includes -\ any combination of R. R', R* and R'. Additional exem N plary compounds are illustrated in Table 3. 45 N TABLE 1 NY R' moieties of the compounds disclosed herein, include but are R12 not limited to the following:

50 Sub wherein R' is H, alkyl, alkynyl, alkenyl, halo, aryl, het class if Rail or Ra2 eroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, Ra 1-1 acyloxy, alkoxycarbonyl, or amido. In some embodiments, provided herein are compounds of Formula (IIb), (IIIb) and (IVb): 55

Formula (IIb) R8 R1 -- 60 Ra 1-2 CH3 NN 2 X O R4 ls 65 -- US 8,901,133 B2 81 82 TABLE 1-continued TABLE 1-continued R' moieties of the compounds disclosed herein, include but are R' moieties of the compounds disclosed herein, include but are not limited to the following: not limited to the following: Sub 5 Sub class if Rail O Ra2 class if Rail O Ra2 Rol-3 CH Ra 1-13

1 CH O YCH, 10

15 -- R-14 R-4

-- Ra 1-15 Rol-5 -- 25 Ral-6 R-16 O 30

Ral-7 CH r 35 Nu Rel-17

40

45 R-18

Ral-9

Rol-10 50 +. Rel-19 R-11 55

Ra 1-20

R-12 60

Ra 1-21

65 US 8,901,133 B2 83 84 TABLE 1-continued TABLE 1-continued

R' moieties of the compounds disclosed herein, include but are R' moieties of the compounds disclosed herein, include but are not limited to the following: not limited to the following: 5 Sub Sub- class if R or R-2 class if R or R-2 Ra 1-29 1S-1 CN Ra1-22 N 10 N IOCN -- 15 Ra -30 1n-CN Ra1-23 M N

2O O sO

25 R1-31 O R-24 S ls /X- N N 30

Rol-25 O

1s 35 Ra 1-32 O

O

40 O

N Y Rol-26 H3C JCC/ NN 45 R-33 N 1n-OH

50 Ra1-27 N OH R-34 MN 55 o R-28 CHCH r 2-113 60 Rol-35 1N-SO:Me Nu N O

65 US 8,901,133 B2 85 86 TABLE 1-continued TABLE 1-continued R' moieties of the compounds disclosed herein, include but are not limited to the following: R' moieties of the compounds disclosed herein, include but are not limited to the following: Sub- 5 class if Ral or Ra2 Sub Ro-36 SOMe class if Rail or Ra2 1S-1 2 al 10 R-46 Nurrn Ral-37 N 15 2 Rol-47 SOMe O N N

O 2O R-38 N

2 N R -48 25 O

O

R-39al S 30

N R-49 O

R-40 H 35

Ro-41 S ) c." X- N 40 N R-50 Ac

R-42al S /s N MX-N M 45

N Ro-43 N 50 R-51 -C -SOMe

O al 55 R-44

N

O 60 Ra 1-52 () Ro-45 X O 65 O US 8,901,133 B2

TABLE 1-continued TABLE 1-continued R' moieties of the compounds disclosed herein, include but are not limited to the following: R' moieties of the compounds disclosed herein, include but are 5 not limited to the following: Sub class if Rail or Ra2 Sub Rol-53 -CH3 class if Rail or Ra2 N 10 Rel-58 SOMe M N O ( ) 15 N

R-54 Ac O M ( N 2O Raa 1-1-59 AeA N O 25 ()

Rol-55 O ( R-60 - Ac N N 35

HN O

40

R-61 N1 CH3 Ral-56 y H. N 45 HN

50 Ral-62 O O

HN 55 -- Ra1-57 SOMe

N R-63 Ac ) 60 N1

65 US 8,901,133 B2

TABLE 1-continued TABLE 1-continued R' moieties of the compounds disclosed herein, include but are R' moieties of the compounds disclosed herein, include but are not limited to the following: not limited to the following: class if R or R-2 Sub class if R or R-2 Ra-64 CH N1 Ra 1-71

10 HN

Ra 1-72 O. O Ral-65 CH 15 V/

NH-O 20 Ral-73

Ro-66 -CH3 ON as R'-74al

rol. 30 Ral-75 H R-67 O v. C 35 Ral-76

40 R-68 r - Ral-77 H 45 ". / \, HN rol. Ra 1-78 Rol-69 O Ac 50 Ra 1-79 ol. 55

Raal 1-70 O 60 Ra 1-80 CN

ol. 65 US 8,901,133 B2 91 92 TABLE 1-continued TABLE 2-continued

R' moieties of the compounds disclosed herein, include but are Illustrative R' of compounds of Formula I, include but are not limited to the following: 5 not limited to the following:

Sub Sub classif class if Rail or Ra2

10 12-14 Ral-81

N Os/n N / \ O2v N O 15 CH3 \ / CONH2

12-15

TABLE 2 2O Illustrative R' of compounds of Formula I, include but are not limited to the following:

Sub classif R12 25 12-16

12-1 - CN 12-2 —Br 12-3 —Cl 12-4 —CH2CH 12-5 —CH 30 12-6 —CH(CH3)2

12-7

35 12-17

12-8

40

12-9 N 12-18

2 45 N

12-10 OH

50 12-19 12-11

OH 55

12-12

60 12-2O 12-13

N N 65 H US 8,901,133 B2

TABLE 2-continued TABLE 2-continued Illustrative R2 of compounds of Formula I, include but are Illustrative R' of compounds of Formula I, include but are not limited to the following: not limited to the following: 5 Sub Sub- classif R12 classif R12 12-29 12-21 F N 10

N N 12-30 Et N NH2 15 N 2 12-22

n N 12-31 OCH 2 2O NH /or 12-23 12-32 OH

/c, 25 7. C NH-N 30 12-33

12-24 F F 35 12-34 / F NH-N

12-25 40 OH

N 12-3S —H 2N 12-36 \ 45 NH

12-26 OH

50 12-37

OCH F

12-27 55 12-38 F F

rs2N \ 60 OH NH 12-39

12-28 OH

65 OH US 8,901,133 B2 95 96 TABLE 2-continued TABLE 2-continued Illustrative R' of compounds of Formula I, include but are not limited to the following: Illustrative R' of compounds of Formula I, include but are not limited to the following: 5 Sub classif R12 Sub classif R12 12-40 /c 10 12-48 C 15 12–41 COOH

12-49 OCH 2O

F

12-42 F OCH 25 12-SO

OCH

12-43 30 NY OCH HN 35 12-44 12-51 F

40 O S HN ul-Is 12-45 n^^ss 45 12-52

HN 50 /

12-46 RN HN 55 12-53 OCH

12-47 60

\ N/ 65 NH H N US 8,901,133 B2 97 98 TABLE 2-continued TABLE 2-continued

Illustrative R' of compounds of Formula I, include but are Illustrative R' of compounds of Formula I, include but are not limited to the following: not limited to the following: 5 Sub Sub- classif R12 classif R12 12-60

12-54 10 O 21 HN

15 O 12-61 —I 2N 12-62 NH2 OH 2O 12-55

12-63 25 OH NY NH2 F 30 12-64 12-56 OH

HN 35 W F N 12-65 CH3 \=N o

40 CH 12-57 12-66 N e n N M 45 He1 s N 2

12-58 N(Et(Et)

50 12-67

e

N NN/ 55 N OH y 12-59 HN

60 12-68

N y-O 65 NN US 8,901,133 B2 99 100 TABLE 2-continued TABLE 2-continued Illustrative R' of compounds of Formula I, include but are Illustrative R' of compounds of Formula I, include but are not limited to the following: not limited to the following: 5 Sub- Sub class H R12 class H R12

12-69 12-77 10

NC

12-78 15 12-70

HN

M 2O 12-79 N H 12-71 y

25 \ 12-80 N F Y 30 12-72 O NHMe

N 12-81 Y.M 35 N H

O 40 e NH 12-82

45 12-74 H3C O

12-83

50

12-75 N NY NH

55 12-84 e O

O HN^ HN I O 12-76 60 HO

12-85 H e N N/ 65 H2 N-{ N H US 8,901,133 B2

TABLE 2-continued TABLE 2-continued Illustrative R' of compounds of Formula I, include but are Illustrative R' of compounds of Formula I, include but are not limited to the following: not limited to the following: 5 Sub classif R12 Sub- 12-93 classif R12

10 12-86 H O N HN -{ N

-( N 15 O O 12-94 12-87

2O | O F NH2 F 12-95 25 12-88 \ | MN N1 N N N NN N 30 H 12-8.9 N 12-96 N1 NM | MN N N N H 35 CH3 12-97 12-90 NX 40 F

O 12-98 NH2 45 FHC 12-91 12-99 %

FC 50 12-100 N N-() N HN nAc 55 12-101 HO 12-92 N 60 O 12-102 K) "N / US 8,901,133 B2 103 104 In some embodiments, one or more Subject compounds to the rest of the type I PI3 kinases, or selectively inhibit PI3 bind specifically to a PI3 kinase. kinase Y and PI3 kinase B as compared to the rest of the type In some embodiments, the ICso of a Subject compound for I PI3 kinases. p110C., p110B, p110y, or p1108 is less than about 1 uM, less In yet another aspect, an inhibitor that selectively inhibits than about 100 nM, less than about 50 nM, less than about 10 one or more members of type IPI3 kinases, oran inhibitor that nM, less than about 1 nM, less than about 0.5 nM, less than selectively inhibits one or more type I PI3 kinase mediated about 100 pM, or less than about 50 pM. In some embodi signaling pathways, alternatively can be understood to refer ments, the ICs of a subject compound for mTor is less than to a compound that exhibits a 50% inhibitory concentration about 1 uM, less than about 100 nM, less than about 50 nM, (IC50) with respect to a given type I PI3 kinase, that is at least 10 at least 10-fold, at least 20-fold, at least 50-fold, at least less than about 10 nM, less than 1 nM or even less than about 100-fold, at least 1000-fold, at least 10,000-fold, or lower, 0.5 nM. In some other embodiments, one or more subject than the inhibitor's IC50 with respect to the rest of the other compounds exhibit dual binding specificity and are capable type I PI3 kinases. In one embodiment, an inhibitor selec of inhibiting a PI3 kinase (e.g., a class I PI3 kinase) as well as tively inhibits PI3 kinase 8 as compared to PI3 kinase B with a protein kinase (e.g. mTor) with an ICs value less than 15 at least about 10-fold lower ICs for PI3 kinase 6. In certain about 1 uM, less than about 100 nM, less than about 50 nM, embodiments, the ICs for PI3 kinase 8 is below about 100 less than about 10 nM, less than 1 nM or even less than about nM, while the ICs for PI3 kinase B is above about 1000 nM. 0.5 nM. One or more subject compounds are capable of In certain embodiments, the ICs for PI3 kinase 8 is below inhibiting tyrosine kinases including, for example, DNA about 50 nM, while the ICs for PI3 kinase f3 is above about dependent protein kinase DNA-dependent protein kinase 5000 nM. In certain embodiments, the ICs for PI3 kinase 8 is (Pubmed protein accession number (PPAN)AAA79184), Abl below about 10 nM, while the ICs for PI3 kinase B is above tyrosine kinase (CAA52387), Bcr-Abl, hemopoietic cell about 1000 nM, above about 5,000 nM, or above about 10,000 kinase (PPANCAI19695), Src (PPANCAA24495), vascular nM. endothelial growth factor receptor 2 (PPANABB82619), vas Pharmaceutical Compositions cular endothelial growth factor receptor-2 (PPAN 25 In some embodiments, provided herein are compositions ABB82619), epidermal growth factor receptor (PPAN (e.g., pharmaceutical compositions) comprising one or more AG43241), EPH receptor B4 (PPAN EAL23820), stem cell compounds as disclosed herein. In some embodiments, the factor receptor (PPAN AAF22141), Tyrosine-protein kinase one or more compounds can each independently be a phar receptor TIE-2 (PPAN Q02858), fms-related tyrosine kinase maceutically acceptable form thereof (e.g., pharmaceutically 3 (PPANNP 004.110), platelet-derived growth factor recep 30 acceptable salts, hydrates, Solvates, isomers, prodrugs, and tor alpha (PPAN NP 990080), RET (PPAN CAA73131), isotopically labeled derivatives). In other embodiments, pro and functional mutants thereof. In some embodiments, the vided herein are pharmaceutical compositions comprising tyrosine kinase is Abl, Bcr-Abl, EGFR, or Flt-3, and any other one or more compounds as disclosed herein, or a pharmaceu kinases listed in the Tables herein. tically acceptable form thereof (e.g., pharmaceutically In some embodiments, non-limiting exemplary com 35 acceptable salts, hydrates, Solvates, isomers, prodrugs, and pounds exhibit one or more functional characteristics dis isotopically labeled derivatives), and one or more pharmaceu closed herein. For example, one or more Subject compounds tically acceptable excipients carriers, including inert Solid bind specifically to a PI3 kinase. In some embodiments, the diluents and fillers, diluents, including sterile aqueous solu ICs of a subject compound for p110C., p110B, p110y, or tion and various organic solvents, permeation enhancers, p1108 is less than about 1 uM, less than about 100 nM, less 40 solubilizers and adjuvants. In some embodiments, a pharma than about 50 nM, less than about 10 nM, less than about 1 ceutical composition described herein includes an second nM, less than about 0.5 nM, less than about 100 pM, or less active agent such as an additional therapeutic agent, (e.g., a than about 50 pM. chemotherapeutic). In some embodiments, one or more of the Subject com In some embodiments, provided herein are pharmaceutical pound can selectively inhibit one or more members of type I 45 compositions for the treatment of disorders such as hyperpro or class I phosphatidylinositol 3-kinases (PI3 kinase) with an liferative disorder including but not limited to cancer such as IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM, acute myeloid leukemia, thymus, brain, lung, squamous cell, 10pM or 1 pM, or less as measured in an in vitro kinase assay. skin, eye, retinoblastoma, intraocular melanoma, oral cavity In some embodiments, one or more of the Subject com and oropharyngeal, bladder, gastric, stomach, pancreatic, pound can selectively inhibit one or two members of type I or 50 bladder, breast, cervical, head, neck, renal, kidney, liver, ova class I phosphatidylinositol 3-kinases (PI3 kinase) consisting rian, prostate, colorectal, esophageal, testicular, gynecologi of PI3 kinase C. PI3 kinase f3, PI3 kinase Y, and PI3 kinase 6. cal, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g. In some aspects, some of the Subject compounds selectively Lymphoma and Kaposi's Sarcoma) or Viral-Induced cancer. inhibit PI3 kinase 8 as compared to all other type I PI3 In some embodiments, said pharmaceutical composition is kinases. In other aspects, some of the Subject compounds 55 for the treatment of a non-cancerous hyperproliferative dis selectively inhibit PI3 kinase 8 and PI3 kinasey as compared order Such as benign hyperplasia of the skin (e.g., psoriasis), to the rest of the type I PI3 kinases. In yet other aspects, some restenosis, or prostate (e.g., benign prostatic hypertrophy of the subject compounds selectively inhibit PI3 kinase C. and (BPH)). PI3 kinase B as compared to the rest of the type I PI3 kinases. In some embodiments, provided herein are pharmaceutical In still yet some other aspects, some of the Subject compounds 60 compositions for treating diseases or conditions related to an selectively inhibit PI3 kinase 8 and PI3 kinase C. as compared undesirable, over-active, harmful or deleterious immune to the rest of the type I PI3 kinases. In still yet some other response in a Subject. Such undesirable immune response can aspects, some of the Subject compounds selectively inhibit be associated with or result in, e.g., asthma, emphysema, PI3 kinase 8 and PI3 kinase f3 as compared to the rest of the bronchitis, psoriasis, allergy, anaphylaxsis, auto-immune dis type I PI3 kinases, or selectively inhibit PI3 kinase 6 and PI3 65 eases, rhuematoid arthritis, graft versus host disease, and kinase C. as compared to the rest of the type I PI3 kinases, or lupus erythematosus. The pharmaceutical compositions dis selectively inhibit PI3 kinase C. and PI3 kinasey as compared closed herein can be used to treat other respiratory diseases US 8,901,133 B2 105 106 including but not limited to diseases affecting the lobes of ceutical compositions. Where desired, the subject com lung, pleural cavity, bronchial tubes, trachea, upper respira pounds and other agent(s) can be mixed into a preparation or tory tract, or the nerves and muscle for breathing. both components can be formulated into separate prepara In some embodiments, provided herein are pharmaceutical tions to use them in combination separately or at the same compositions for the treatment of multiorgan failure. Also time. provided herein are pharmaceutical compositions for the The Subject pharmaceutical composition can, for example, treatment of liver diseases (including diabetes), gallbladder be in a form Suitable for oral administration as a tablet, cap disease (including gallstones), pancreatitis or kidney disease Sule, pill, powder, Sustained release formulations, Solution, (including proliferative glomerulonephritis and diabetes— Suspension, for parenteral injection as a sterile solution, Sus induced renal disease) or pain in a Subject. 10 pension or emulsion, for topical administration as an oint In some embodiments, provided herein are pharmaceutical ment or cream or for rectal administration as a Suppository. compositions for the prevention of blastocyte implantation in The pharmaceutical composition can be in unit dosage forms a subject. Suitable for single administration of precise dosages. The In some embodiments, provided herein are pharmaceutical pharmaceutical composition will include a conventional compositions for treating a disease related to vasculogenesis 15 pharmaceutical carrier or excipient and a compound as dis or angiogenesis in a Subject which can manifest as tumor closed herein as an active ingredient. In addition, it can angiogenesis, chronic inflammatory disease such as rheuma include other medicinal or pharmaceutical agents, carriers, toid arthritis, inflammatory bowel disease, atherosclerosis, adjuvants, etc. skin diseases such as psoriasis, eczema, and Scleroderma, Pharmaceutical compositions can be specially formulated diabetes, diabetic retinopathy, retinopathy of prematurity, for administration in Solid or liquid form, including those age-related macular degeneration, hemangioma, glioma, adapted for the following: oral administration, for example, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pan drenches (aqueous or non-aqueous Solutions or Suspensions), creatic, prostate, colon and epidermoid cancer. tablets (e.g., those targeted for buccal, Sublingual, and sys In some embodiments, provided herein are pharmaceutical temic absorption), capsules, boluses, powders, granules, compositions for the treatment of disorders involving platelet 25 pastes for application to the tongue, and intraduodenal routes; aggregation or platelet adhesion, including but not limited to parenteral administration, including intravenous, intraarte Idiopathic thrombocytopenic purpura, Bernard-Soulier Syn rial, Subcutaneous, intramuscular, intravascular, intraperito drome, Glanzmann's thrombasthenia, Scott's syndrome, Von neal or infusion as, for example, a sterile solution or Suspen Willebrand disease, Hermansky-Pudlak Syndrome, and Gray Sion, or Sustained-release formulation; topical application, platelet syndrome. 30 for example, as a cream, ointment, or a controlled-release In some embodiments, pharmaceutical compositions are patch or spray applied to the skin; intravaginally or intrarec provided for treating a disease which is skeletal muscle atro tally, for example, as a pessary, cream, stent or foam; sublin phy, skeletal or muscle hypertrophy. In some embodiments, gually: ocularly; pulmonarily; local delivery by catheter or provided herein are pharmaceutical compositions for the stent; intrathecally, or nasally. treatment of disorders that include, but are not limited to, 35 Examples of Suitable aqueous and nonaqueous carriers cancers as discussed herein, transplantation-related disorders which can be employed in pharmaceutical compositions (e.g., lowering rejection rates, graft-Versus-host disease, etc.), include water, ethanol, polyols (such as glycerol, propylene muscular Sclerosis (MS), allergic disorders (e.g., arthritis, glycol, polyethylene glycol, and the like), and Suitable mix allergic encephalomyelitis) and other immunosuppressive tures thereof, vegetable oils, such as olive oil, and injectable related disorders, metabolic disorders (e.g., diabetes), reduc 40 organic esters, such as ethyl oleate. Proper fluidity can be ing intimal thickening following vascular injury, and mis maintained, for example, by the use of coating materials, such folded protein disorders (e.g., Alzheimer's Disease, as lecithin, by the maintenance of the required particle size in Gaucher's Disease, Parkinson's Disease, Huntington's Dis the case of dispersions, and by the use of Surfactants. ease, cystic fibrosis, macular degeneration, retinitis pigmen These compositions can also contain adjuvants such as tosa, and prion disorders) (as mTOR inhibition can alleviate 45 preservatives, wetting agents, emulsifying agents, dispersing the effects of misfolded protein aggregates). The disorders agents, lubricants, and/or antioxidants. Prevention of the also include hamartoma syndromes, such as tuberous Sclero action of microorganisms upon the compounds described sis and Cowden Disease (also termed Cowden syndrome and herein can be ensured by the inclusion of various antibacterial multiple hamartoma syndrome). and antifungal agents, for example, paraben, chlorobutanol, 1. Formulations 50 phenol sorbic acid, and the like. It can also be desirable to The Subject pharmaceutical compositions are typically for include isotonic agents. Such as Sugars, sodium chloride, and mulated to provide a therapeutically effective amount of a the like into the compositions. In addition, prolonged absorp compound described herein as the active ingredient, or a tion of the injectable pharmaceutical form can be brought pharmaceutically acceptable form thereof (e.g., pharmaceu about by the inclusion of agents which delay absorption Such tically acceptable salts, hydrates, Solvates, isomers, prodrugs, 55 as aluminum monostearate and gelatin. and isotopically labeled derivatives). Where desired, the Methods of preparing these formulations or compositions pharmaceutical compositions can contain one or more dis include the step of bringing into association a compound closed compounds or its pharmaceutically acceptable form described herein and/or the chemotherapeutic with the carrier thereof (e.g., pharmaceutically acceptable salts, hydrates, and, optionally, one or more accessory ingredients. In gen Solvates, isomers, prodrugs, and isotopically labeled deriva 60 eral, the formulations are prepared by uniformly and inti tives), and one or more pharmaceutically acceptable excipi mately bringing into association a compound as disclosed ents, carriers, including inert Solid diluents and fillers, dilu herein with liquid carriers, or finely divided solid carriers, or ents, including sterile aqueous Solution and various organic both, and then, if necessary, shaping the product. Solvents, permeation enhancers, Solubilizers and adjuvants. Preparations for Such pharmaceutical compositions are The Subject pharmaceutical compositions can be adminis 65 well-known in the art. See, e.g., Anderson, Philip O. Knoben, tered alone or in combination with one or more other agents, James E.; Troutman, William G., eds., Handbook of Clinical which are also typically administered in the form of pharma Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and US 8,901,133 B2 107 108 Taylor, eds. Principles of Drug Action. Third Edition, approximately 4.5%, approximately 0.03% to approximately Churchill Livingston, New York, 1990; Katzung, ed., Basic 4%, approximately 0.04% to approximately 3.5%, approxi and Clinical Pharmacology, Ninth Edition, McGraw Hill, mately 0.05% to approximately 3%, approximately 0.06% to 20037ybg; Goodman and Gilman, eds. The Pharmacologi approximately 2.5%, approximately 0.07% to approximately cal Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001, 2%, approximately 0.08% to approximately 1.5%, approxi Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott mately 0.09% to approximately 1%, approximately 0.1% to Williams & Wilkins., 2000; Martindale, The Extra Pharma approximately 0.9% w/w, wif v or V/v. copoeia. Thirty-Second Edition (The Pharmaceutical Press, In some embodiments, the amount of one or more of the London, 1999); all of which are incorporated by reference compounds as disclosed herein is equal to or less than 10 g, herein in their entirety. Except insofar as any conventional 10 excipient medium is incompatible with the compounds pro 9.5g, 9.0 g, 8.5g, 8.0 g, 7.5g, 7.0 g. 6.5 g. 6.0 g, 5.5g, 5.0 g, vided herein, such as by producing any undesirable biological 4.5 g. 4.0 g, 3.5g, 3.0g, 2.5g, 2.0 g, 1.5g, 1.0 g, 0.95 g, 0.9 effect or otherwise interacting in a deleterious manner with g, 0.85g. 0.8 g. 0.75 g, 0.7g, 0.65 g, 0.6 g. 0.55g, 0.5g, 0.45 any other component(s) of the pharmaceutically acceptable g, 0.4g, 0.35g, 0.3 g, 0.25 g, 0.2g, 0.15g, 0.1 g, 0.09 g, 0.08 composition, the excipients use is contemplated to be within 15 g, 0.07 g., 0.06g, 0.05 g, 0.04g, 0.03 g, 0.02g, 0.01 g, 0.009 the scope of this disclosure. g, 0.008 g., 0.007 g., 0.006 g., 0.005 g, 0.004g, 0.003 g, 0.002 In some embodiments, the concentration of one or more of g, 0.001 g, 0.0009 g, 0.0008g, 0.0007 g., 0.0006g, 0.0005g, the compounds provided in the pharmaceutical compositions 0.0004g, 0.0003 g, 0.0002 g, or 0.0001 g. is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, In some embodiments, the amount of one or more of the 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, compounds as disclosed herein is more than 0.0001 g, 0.0002 10%, 9%, 8%, 7%, 6%. 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, g, 0.0003g, 0.0004.g., 0.0005 g, 0.0006g, 0.0007 g., 0.0008g, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.0035 g, 0.004 g., 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0065 g, 0.007 g., 0.0075 g, 0.008 g., 0.0085 g, 0.009 g, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 25 0.0095g, 0.01 g, 0.015g, 0.02g, 0.025 g, 0.03g, 0.035g, 0.04 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v. g, 0.045 g, 0.05 g, 0.055 g, 0.06 g., 0.065 g, 0.07 g., 0.075 g, In some embodiments, the concentration of one or more of 0.08g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15g, 0.2g, 0.25 g, 0.3 the compounds as disclosed herein is greater than 90%. 80%, g, 0.35 g, 0.4g, 0.45 g, 0.5g, 0.55g, 0.6 g. 0.65 g, 0.7g, 0.75 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% g, 0.8 g., 0.85g. 0.9 g, 0.95 g, 1 g, 1.5g, 2g, 2.5, 3 g, 3.5, 4 g. 19%. 18.75%, 18.50%, 18.25%. 18%, 17.75%, 17.50%, 30 4.5g, 5 g, 5.5 g. 6 g. 6.5g, 7 g, 7.5 g., 8 g, 8.5g, 9 g, 9.5g, or 17.25%. 17%, 16.75%, 16.50%, 16.25%. 16%, 15.75%, 10 g. 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25%. 14%, In some embodiments, the amount of one or more of the 13.75%, 13.50%, 13.25%. 13%, 12.75%, 12.50%, 12.25% compounds as disclosed herein is in the range of 0.0001-10g, 12%, 11.75%, 11.50%, 11.25%. 11%, 10.75%, 10.50%, 0.0005-9 g, 0.001-8g., 0.005-7 g., 0.01-6g, 0.05-5g, 0.1-4g, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 35 0.5-4g, or 1-3g. 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% The compounds as disclosed herein are effective over a 6%, 5.75%, 5.50%, 5.25%. 5%, 4.75%, 4.50%, 4.25%, 4%, wide dosage range. For example, in the treatment of adult 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg. 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, from 1 to 50 mg per day, and from 5 to 40 mg per day are 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 40 examples of dosages that can be used. An exemplary dosage 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, is 10 to 30 mg per day. The exact dosage will depend upon the 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, route of administration, the form in which the compound is 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or administered, the subject to be treated, the body weight of the 0.0001% w/w, w/v, or V/v. subject to be treated, and the preference and experience of the In some embodiments, the concentration of one or more of 45 attending physician. the compounds as disclosed herein is in the range from A pharmaceutical composition disclosed herein typically approximately 0.0001% to approximately 50%, approxi contains an active ingredient (e.g., a compound disclosed mately 0.001% to approximately 40%, approximately 0.01% herein or a pharmaceutically acceptable form and/or coordi to approximately 30%, approximately 0.02% to approxi nation complex thereof, and one or more pharmaceutically mately 29%, approximately 0.03% to approximately 28%, 50 acceptable excipients, carriers, including but not limited to approximately 0.04% to approximately 27%, approximately inert Solid diluents and fillers, diluents, sterile aqueous solu 0.05% to approximately 26%, approximately 0.06% to tion and various organic solvents, permeation enhancers, approximately 25%, approximately 0.07% to approximately solubilizers and adjuvants). 24%, approximately 0.08% to approximately 23%, approxi Described below are non-limiting exemplary pharmaceu mately 0.09% to approximately 22%, approximately 0.1% to 55 tical compositions and methods for preparing the same. approximately 21%, approximately 0.2% to approximately 1A. Formulations for Oral Administration 20%, approximately 0.3% to approximately 19%, approxi In some embodiments, provided herein are pharmaceutical mately 0.4% to approximately 18%, approximately 0.5% to compositions for oral administration containing a compound approximately 17%, approximately 0.6% to approximately as disclosed herein, and a pharmaceutical excipient Suitable 16%, approximately 0.7% to approximately 15%, approxi 60 for oral administration. mately 0.8% to approximately 14%, approximately 0.9% to In some embodiments, provided herein are solid pharma approximately 12%, approximately 1% to approximately ceutical compositions for oral administration containing: (i) 10% w/w, w/v or V/v. V/v. an effective amount of a compound disclosed herein; option In some embodiments, the concentration of one or more of ally (ii) an effective amount of a second agent, and (iii) a the compounds as disclosed herein is in the range from 65 pharmaceutical excipient Suitable for oral administration. In approximately 0.001% to approximately 10%, approxi Some embodiments, the composition further contains: (iv) an mately 0.01% to approximately 5%, approximately 0.02% to effective amount of a third agent. US 8,901,133 B2 109 110 In some embodiments, the pharmaceutical composition Binders Suitable for use in pharmaceutical compositions can be a liquid pharmaceutical composition Suitable for oral and dosage forms include, but are not limited to, corn starch, consumption. Pharmaceutical compositions as disclosed potato starch, or other starches, gelatin, natural and synthetic herein Suitable for oral administration can be presented as gums such as acacia, Sodium alginate, alginic acid, other discrete dosage forms, such as capsules, cachets, or tablets, or alginates, powdered tragacanth, guar gum, cellulose and its liquids or aerosol sprays each containing a predetermined derivatives (e.g., ethylcellulose, cellulose acetate, carboxym amount of an active ingredient as a powder or in granules, a ethyl cellulose calcium, Sodium carboxymethyl cellulose), Solution, or a suspension in an aqueous or non-aqueous liq polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized uid, an oil-in-water emulsion, or a water-in-oil liquid emul starch, hydroxypropyl methyl cellulose, microcrystalline cel Sion. Such dosage forms can be prepared by any of the meth 10 lulose, and mixtures thereof. ods of pharmacy, but all methods include the step of bringing Examples of suitable fillers for use in the pharmaceutical the active ingredient into association with the carrier, which compositions and dosage forms disclosed herein include, but constitutes one or more necessary ingredients. In general, the are not limited to, talc, calcium carbonate (e.g., granules or compositions are prepared by uniformly and intimately powder), microcrystalline cellulose, powdered cellulose, 15 dextrates, kaolin, mannitol, silicic acid, Sorbitol, starch, pre admixing the active ingredient with liquid carriers or finely gelatinized starch, and mixtures thereof. divided Solid carriers or both, and then, if necessary, shaping Disintegrants can be used in the pharmaceutical composi the product into the desired presentation. For example, a tions as provided herein to provide tablets that disintegrate tablet can be prepared by compression or molding, optionally when exposed to an aqueous environment. Too much of a with one or more accessory ingredients. Compressed tablets disintegrant can produce tablets which can disintegrate in the can be prepared by compressing in a suitable machine the bottle. Too little can be insufficient for disintegration to occur active ingredient in a free-flowing form such as powder or and can thus alter the rate and extent of release of the active granules, optionally mixed with an excipient such as, but not ingredient(s) from the dosage form. Thus, a Sufficient amount limited to, a binder, a lubricant, an inert diluent, and/or a of disintegrant that is neither too little nor too much to detri Surface active or dispersing agent. Molded tablets can be 25 mentally alter the release of the active ingredient(s) can be made by molding in a suitable machine a mixture of the used to form the dosage forms of the compounds disclosed powdered compound moistened with an inert liquid diluent. herein. The amount of disintegrant used can vary based upon This present disclosure further encompasses anhydrous the type of formulation and mode of administration, and can pharmaceutical compositions and dosage forms comprising be readily discernible to those of ordinary skill in the art. an active ingredient, since water can facilitate the degradation 30 About 0.5 to about 15 weight percent of disintegrant, or about of Some compounds. For example, water can be added (e.g., 1 to about 5 weight percent of disintegrant, can be used in the about 5%) in the pharmaceutical arts as a means of simulating pharmaceutical composition. Disintegrants that can be used long-term storage in order to determine characteristics Such to form pharmaceutical compositions and dosage forms as shelf-life or the stability of formulations over time. Anhy include, but are not limited to, agar-agar, alginic acid, calcium drous pharmaceutical compositions and dosage forms can be 35 carbonate, microcrystalline cellulose, croScarmellose prepared using anhydrous or low moisture containing ingre Sodium, crospovidone, polacrilin potassium, Sodium starch dients and low moisture or low humidity conditions. Pharma glycolate, potato or tapioca Starch, other starches, pre-gelati ceutical compositions and dosage forms which contain lac nized starch, other starches, clays, other algins, other cellu tose can be made anhydrous if Substantial contact with loses, gums or mixtures thereof. moisture and/or humidity during manufacturing, packaging, 40 Lubricants which can be used to form pharmaceutical com and/or storage is expected. An anhydrous pharmaceutical positions and dosage forms include, but are not limited to, composition can be prepared and stored such that its anhy calcium Stearate, magnesium Stearate, mineral oil, light min drous nature is maintained. Accordingly, anhydrous pharma eral oil, glycerin, Sorbitol, mannitol, polyethylene glycol, ceutical compositions can be packaged using materials other glycols, Stearic acid, sodium lauryl Sulfate, talc, hydro known to prevent exposure to water Such that they can be 45 genated vegetable oil (e.g., peanut oil, cottonseed oil, Sun included in suitable formulary kits. Examples of suitable flower oil, Sesame oil, olive oil, corn oil, and soybean oil), packaging include, but are not limited to, hermetically sealed Zinc Stearate, ethyl oleate, ethylaureate, agar, or mixtures foils, plastic or the like, unit dose containers, blister packs, thereof. Additional lubricants include, for example, a syloid and strip packs. silica gel, a coagulated aerosol of synthetic silica, or mixtures An active ingredient can be combined in an intimate 50 thereof. A lubricant can optionally be added, in an amount of admixture with a pharmaceutical carrier according to conven less than about 1 weight percent of the pharmaceutical com tional pharmaceutical compounding techniques. The carrier position. can take a wide variety of forms depending on the form of When aqueous Suspensions and/or elixirs are desired for preparation desired for administration. In preparing the phar oral administration, the essential active ingredient thereincan maceutical compositions for an oral dosage form, any of the 55 be combined with various Sweetening or flavoring agents, usual pharmaceutical media can be employed as carriers, coloring matter or dyes and, if so desired, emulsifying and/or Such as, for example, water, glycols, oils, alcohols, flavoring Suspending agents, together with Such diluents as water, etha agents, preservatives, coloring agents, and the like in the case nol, propylene glycol, glycerin and various combinations of oral liquid preparations (such as Suspensions, Solutions, thereof. and elixirs) or aerosols; or carriers such as starches, Sugars, 60 The tablets can be uncoated or coated by known techniques micro-crystalline cellulose, diluents, granulating agents, to delay disintegration and absorption in the gastrointestinal lubricants, binders, and disintegrating agents can be used in tract and thereby provide a Sustained action over a longer the case of oral Solid preparations, in some embodiments period. For example, a time delay material Such as glyceryl without employing the use of lactose. For example, Suitable monostearate or glyceryl distearate can be employed. Formu carriers include powders, capsules, and tablets, with the Solid 65 lations for oral use can also be presented as hard gelatin oral preparations. If desired, tablets can be coated by standard capsules wherein the active ingredient is mixed with an inert aqueous or nonaqueous techniques. Solid diluent, for example, calcium carbonate, calcium phos US 8,901,133 B2 111 112 phate or kaolin, or as Soft gelatin capsules wherein the active sides; lauryl macrogolglycerides; polyoxyalkylene alkyl ingredient is mixed with water oran oil medium, for example, ethers such as polyethylene glycol alkyl ethers; polyoxyalky peanut oil, liquid paraffin or olive oil. lene alkylphenols such as polyethylene glycol alkyl phenols; Surfactant which can be used to form pharmaceutical com polyoxyalkylene alkyl phenol fatty acid esters such as poly positions and dosage forms include, but are not limited to, ethylene glycol fatty acids monoesters and polyethylene gly hydrophilic Surfactants, lipophilic Surfactants, and mixtures col fatty acids diesters; polyethylene glycol glycerol fatty thereof. That is, a mixture of hydrophilic surfactants can be acid esters; polyglycerol fatty acid esters; polyoxyalkylene employed, a mixture of lipophilic Surfactants can be Sorbitan fatty acid esters such as polyethylene glycol Sorbitan employed, or a mixture of at least one hydrophilic Surfactant fatty acid esters; hydrophilic transesterification products of a and at least one lipophilic Surfactant can be employed. 10 polyol with at least one member of the group consisting of A Suitable hydrophilic Surfactant can generally have an glycerides, vegetable oils, hydrogenated vegetable oils, fatty HLB value of at least 10, while suitable lipophilic surfactants acids, and sterols; polyoxyethylene sterols, derivatives, and can generally have an HLB value of or less than about 10. An analogues thereof; polyoxyethylated vitamins and derivatives empirical parameter used to characterize the relative hydro thereof; polyoxyethylene-polyoxypropylene block copoly philicity and hydrophobicity of non-ionic amphiphilic com 15 mers; and mixtures thereof; polyethylene glycol Sorbitan pounds is the hydrophilic-lipophilic balance (“HLB' value). fatty acid esters and hydrophilic transesterification products Surfactants with lower HLB values are more lipophilic or of a polyol with at least one member of the group consisting hydrophobic, and have greater solubility in oils, while sur of triglycerides, vegetable oils, and hydrogenated vegetable factants with higher HLB values are more hydrophilic, and oils. The polyol can be glycerol, ethylene glycol, polyethyl have greater solubility in aqueous Solutions. Hydrophilic Sur ene glycol, Sorbitol, propylene glycol, pentaerythritol, or a factants are generally considered to be those compounds hav saccharide. ing an HLB value greater than about 10, as well as anionic, Other hydrophilic-non-ionic surfactants include, without cationic, or Zwitterionic compounds for which the HLB scale limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, is not generally applicable. Similarly, lipophilic (i.e., hydro PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 phobic) surfactants are compounds having an HLB value 25 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, equal to or less than about 10. However, HLB value of a PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 Surfactant is merely a rough guide generally used to enable distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 formulation of industrial, pharmaceutical and cosmetic emul dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG sions. 20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyc Hydrophilic Surfactants can be either ionic or non-ionic. 30 eryl Stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl ole Suitable ionic surfactants include, but are not limited to, ate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG alkylammonium salts; fusidic acid salts; fatty acid derivatives 40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 of amino acids, oligopeptides, and polypeptides; glyceride castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 derivatives of amino acids, oligopeptides, and polypeptides; hydrogenated castor oil, PEG-60 hydrogenated castor oil, lecithins and hydrogenatedlecithins; lysolecithins and hydro 35 PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 genated lysolecithins; phospholipids and derivatives thereof; caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG lysophospholipids and derivatives thereof; carnitine fatty 30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, acid ester salts; salts of alkylsulfates; fatty acid salts; sodium PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan docusate; acylactylates; mono- and di-acetylated tartaric acid laurate, polysorbate 20, polysorbate 80. POE-9 lauryl ether, esters of mono- and di-glycerides; Succinylated mono- and 40 POE-23 lauryl ether, POE-10 oleylether, POE-20 oleylether, di-glycerides; citric acid esters of mono- and di-glycerides; POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG and mixtures thereof. 24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, Within the aforementioned group, ionic Surfactants Sucrose monostearate. Sucrose monolaurate. Sucrose mono include, by way of example: lecithins, lysolecithin, phospho palmitate, PEG 10-100 nonyl phenol series, PEG 15-100 lipids, lysophospholipids and derivatives thereof, carnitine 45 octyl phenol series, and poloxamers. fatty acid ester salts; salts of alkylsulfates; fatty acid salts; Suitable lipophilic surfactants include, by way of example Sodium docusate; acylactylates; mono- and di-acetylated tar only: fatty alcohols; glycerol fatty acid esters; acetylated taric acid esters of mono- and di-glycerides; Succinylated glycerol fatty acid esters; lower alcohol fatty acids esters; mono- and di-glycerides; citric acid esters of mono- and propylene glycol fatty acid esters; Sorbitan fatty acid esters; di-glycerides; and mixtures thereof. 50 polyethylene glycol Sorbitan fatty acid esters; sterols and Ionic surfactants can be the ionized forms of lecithin, lyso sterol derivatives; polyoxyethylated sterols and sterol deriva lecithin, phosphatidylcholine, phosphatidylethanolamine, tives; polyethylene glycol alkyl ethers; Sugar esters; Sugar phosphatidylglycerol, phosphatidic acid, phosphatidylserine, ethers; lactic acid derivatives of mono- and di-glycerides; lysophosphatidylcholine, lysophosphatidylethanolamine, hydrophobic transesterification products of a polyol with at lysophosphatidylglycerol, lysophosphatidic acid, lysophos 55 least one member of the group consisting of glycerides, Veg phatidylserine, PEG-phosphatidylethanolamine, PVP-phos etable oils, hydrogenated vegetable oils, fatty acids and Ste phatidylethanolamine, lactylic esters of fatty acids, Stearoyl rols; oil-soluble vitamins/vitamin derivatives; and mixtures 2-lactylate, Stearoyl lactylate. Succinylated monoglycerides, thereof. Within this group, preferred lipophilic surfactants mono/diacetylated tartaric acid esters of mono/diglycerides, include glycerol fatty acid esters, propylene glycol fatty acid citric acid esters of mono/diglycerides, cholylsarcosine, 60 esters, and mixtures thereof, or are hydrophobic transesteri caproate, caprylate, caprate, laurate, myristate, palmitate, fication products of a polyol with at least one member of the oleate, ricinoleate, linoleate, linolenate, Stearate, lauryl Sul group consisting of vegetable oils, hydrogenated vegetable fate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl oils, and triglycerides. carnitines, myristoyl carnitines, and salts and mixtures In one embodiment, the pharmaceutical composition can thereof. 65 include a solubilizer to ensure good solubilization and/or Hydrophilic non-ionic Surfactants can include, but not lim dissolution of the compound disclosed herein and to mini ited to, alkylglucosides; alkylmaltosides; alkylthiogluco mize precipitation of the compound. This can be especially US 8,901,133 B2 113 114 important for pharmaceutical compositions for non-oral use, preservatives. Exemplary antioxidants include, but are not e.g., compositions for injection. A solubilizer can also be limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, added to increase the solubility of the hydrophilic drug and/or butylated hydroxyanisole, butylated hydroxytoluene, mono other components, such as Surfactants, or to maintain the thioglycerol, potassium metabisulfite, propionic acid, propyl pharmaceutical composition as a stable or homogeneous gallate, sodium ascorbate, sodium bisulfite, sodium met Solution or dispersion. abisulfite, and Sodium Sulfite. Exemplary chelating agents Examples of suitable solubilizers include, but are not lim include ethylenediaminetetraacetic acid (EDTA), citric acid ited to, the following: alcohols and polyols, such as ethanol, monohydrate, disodium edetate, dipotassium edetate, edetic isopropanol, butanol, benzyl alcohol, ethylene glycol, propy acid, fumaric acid, malic acid, phosphoric acid, Sodium ede lene glycol, butanediols and isomers thereof glycerol, pen 10 tate, tartaric acid, and trisodium edetate. Exemplary antimi taerythritol, Sorbitol, mannitol, transcutol, dimethyl isosor crobial preservatives include, but are not limited to, benza bide, polyethylene glycol, polypropylene glycol, lkonium chloride, benzethonium chloride, benzyl alcohol, polyvinylalcohol, hydroxypropyl methylcellulose and other bronopol, cetrimide, cetylpyridinium chloride, chlorhexi cellulose derivatives, cyclodextrins and cyclodextrin deriva dine, chlorobutanol, chlorocresol, chloroxylenol, cresol, tives; ethers of polyethylene glycols having an average 15 ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phe molecular weight of about 200 to about 6000, such as tetrahy noxyethanol, phenylethyl alcohol, phenylmercuric nitrate, drofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG: propylene glycol, and thimerosal. Exemplary antifungal pre amides and other nitrogen-containing compounds such as servatives include, but are not limited to, butyl paraben, 2-pyrrolidone, 2-piperidone, e-caprolactam, N-alkylpyrroli methyl paraben, ethyl paraben, propyl paraben, benzoic acid, done, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, hydroxybenzoic acid, potassium benzoate, potassium Sor N-alkylcaprolactam, dimethylacetamide and polyvinylpyr bate, Sodium benzoate, Sodium propionate, and Sorbic acid. rolidone; esters such as ethyl propionate, tributylcitrate, Exemplary alcohol preservatives include, but are not limited acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, to, ethanol, polyethylene glycol, phenol, phenolic com ethyl oleate, ethyl caprylate, ethylbutyrate, triacetin, propy pounds, bisphenol, chlorobutanol, hydroxybenzoate, and lene glycol monoacetate, propylene glycol diacetate, e-capro 25 phenylethyl alcohol. Exemplary acidic preservatives include, lactone and isomers thereof, Ö-Valerolactone and isomers but are not limited to, vitamin A, vitamin C, vitamin E, beta thereof, B-butyrolactone and isomers thereof; and other solu carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic bilizers known in the art, Such as dimethyl acetamide, dim acid, Sorbic acid, and phytic acid. Other preservatives ethyl isosorbide, N-methylpyrrolidones, monooctanoin, include, but are not limited to, tocopherol, tocopherol acetate, diethylene glycol monoethyl ether, and water. 30 deteroxime mesylate, cetrimide, butylated hydroxyanisol Mixtures of solubilizers can also be used. Examples (BHA), butylated hydroxytoluened (BHT), ethylenediamine, include, but not limited to, triacetin, triethylcitrate, ethyl ole sodium lauryl sulfate (SLS), sodium lauryl ether sulfate ate, ethyl caprylate, dimethylacetamide, N-methylpyrroli (SLES), sodium bisulfite, sodium metabisulfite, potassium done, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, sulfite, potassium metabisulfite, Glydant Plus, Phenonip, hydroxypropyl methylcellulose, hydroxypropyl cyclodex 35 methylparaben, Germall 115, Germaben II, Neolone, trins, ethanol, polyethylene glycol 200-100, glycofurol, tran Kathon, and Euxyl. In certain embodiments, the preservative Scutol, propylene glycol, and dimethyl isosorbide. In some is an anti-oxidant. In other embodiments, the preservative is a embodiments, solubilizers include Sorbitol, glycerol, triace chelating agent. tin, ethyl alcohol, PEG-400, glycofuroland propylene glycol. Exemplary oils include, but are not limited to, almond, The amount of solubilizer that can be included is not par 40 apricot kernel, avocado, babassu, bergamot, black current ticularly limited. The amount of a given solubilizer can be Seed, borage, cade, camomile, canola, caraway, carnauba, limited to a bioacceptable amount, which can be readily castor, cinnamon, cocoa butter, coconut, cod liver, coffee, determined by one of skill in the art. In some circumstances, corn, cotton seed, emu, eucalyptus, evening primrose, fish, it can be advantageous to include amounts of solubilizers far flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, iso in excess of bioacceptable amounts, for example to maximize 45 propyl myristate, jojoba, kukui nut, lavandin, lavender, the concentration of the drug, with excess solubilizer lemon, litsea cubeba, macademia nut, mallow, mango seed, removed prior to providing the pharmaceutical composition meadowfoam seed, mink, nutmeg, olive, orange, orange to a subject (e.g., a patient) using conventional techniques, roughy, palm, palm kernel, peach kernel, peanut, poppy seed, Such as distillation or evaporation. Thus, if present, the solu pumpkin seed, rapeseed, rice bran, rosemary, Safflower, San bilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or 50 dalwood, Sasquana, savoury, sea buckthorn, Sesame, shea up to about 200% by weight, based on the combined weight of butter, silicone, soybean, Sunflower, tea tree, thistle, tsubaki, the drug, and other excipients. If desired, very small amounts Vetiver, walnut, and wheat germ oils. Exemplary oils include, of solubilizer can also be used, such as 5%, 2%, 1% or even but are not limited to, butyl Stearate, caprylic triglyceride, less. Typically, the Solubilizer can be present in an amount of capric triglyceride, cyclomethicone, diethyl sebacate, dime about 1% to about 100%, more typically about 5% to about 55 thicone 360, isopropyl myristate, mineral oil, octyldode 25% by weight. canol, oleyl alcohol, silicone oil, and combinations thereof. The pharmaceutical composition can further include one or In addition, an acid or a base can be incorporated into the more pharmaceutically acceptable additives and excipients. pharmaceutical composition to facilitate processing, to Such additives and excipients include, without limitation, enhance stability, or for other reasons. Examples of pharma detackifiers, anti-foaming agents, buffering agents, poly 60 ceutically acceptable bases include amino acids, amino acid mers, antioxidants, preservatives, chelating agents, visco esters, ammonium hydroxide, potassium hydroxide, Sodium modulators, tonicifiers, flavorants, colorants, odorants, hydroxide, sodium hydrogen carbonate, aluminum hydrox opacifiers, Suspending agents, binders, fillers, plasticizers, ide, calcium carbonate, magnesium hydroxide, magnesium lubricants, and mixtures thereof. aluminum silicate, synthetic aluminum silicate, synthetic Exemplary preservatives can include antioxidants, chelat 65 hydrocalcite, magnesium aluminum hydroxide, diisopropyl ing agents, antimicrobial preservatives, antifungal preserva ethylamine, ethanolamine, ethylenediamine, triethanola tives, alcohol preservatives, acidic preservatives, and other mine, triethylamine, triisopropanolamine, trimethylamine, US 8,901,133 B2 115 116 tris(hydroxymethyl)aminomethane (TRIS) and the like. Also Sterile injectable solutions are prepared by incorporating Suitable are bases that are salts of a pharmaceutically accept the compound as disclosed herein in the required amount in able acid, Such as acetic acid, acrylic acid, adipic acid, alginic the appropriate solvent with various other ingredients as enu acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic merated above, as appropriate, followed by filtered steriliza acid, boric acid, butyric acid, carbonic acid, citric acid, fatty tion. Generally, dispersions are prepared by incorporating the acids, formic acid, fumaric acid, gluconic acid, hydroquino various sterilized active ingredients into a sterile vehicle Sulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic which contains the basic dispersion medium and the appro acid, para-bromophenylsulfonic acid, propionic acid, p-tolu priate other ingredients from those enumerated above. In the enesulfonic acid, salicylic acid, Stearic acid, Succinic acid, case of sterile powders for the preparation of sterile injectable tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic 10 Solutions, certain methods of preparation are vacuum-drying acid, uric acid, and the like. Salts of polyprotic acids, such as and freeze-drying techniques which yield a powder of the Sodium phosphate, disodium hydrogen phosphate, and active ingredient plus any additional ingredient from a previ Sodium dihydrogen phosphate can also be used. When the ously sterile-filtered solution thereof. base is a salt, the cation can be any convenient and pharma The injectable formulations can be sterilized, for example, ceutically acceptable cation, such as ammonium, alkali met 15 by filtration through a bacterial-retaining filter, or by incor als, alkaline earth metals, and the like. Example can include, porating sterilizing agents in the form of sterile solid compo but not limited to, Sodium, potassium, lithium, magnesium, sitions which can be dissolved or dispersed in sterile water or calcium and ammonium. other sterile injectable medium prior to use. Injectable com Suitable acids are pharmaceutically acceptable organic or positions can contain from about 0.1 to about 5% w/w of a inorganic acids. Examples of suitable inorganic acids include compound as disclosed herein. hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric The pharmaceutical compositions provided herein can also acid, nitric acid, boric acid, phosphoric acid, and the like. be delivered via an impregnated or coated device Such as a Examples of Suitable organic acids include acetic acid, stent, for example, or an artery-inserted cylindrical polymer. acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, Such a method of administration can, for example, aid in the amino acids, ascorbic acid, benzoic acid, boric acid, butyric 25 prevention or amelioration of restenosis following proce acid, carbonic acid, citric acid, fatty acids, formic acid, dures such as balloon angioplasty. Without being bound by fumaric acid, gluconic acid, hydroquinosulfonic acid, theory, compounds disclosed herein can slow or inhibit the isoascorbic acid, lactic acid, maleic acid, methanesulfonic migration and proliferation of Smooth muscle cells in the acid, oxalic acid, para-bromophenylsulfonic acid, propionic arterial wall which contribute to restenosis. A compound as acid, p-toluenesulfonic acid, salicylic acid, Stearic acid, suc 30 disclosed herein can be administered, for example, by local cinic acid, tannic acid, tartaric acid, thioglycolic acid, tolu delivery from the struts of a stent, from a stent graft, from enesulfonic acid, uric acid and the like. grafts, or from the cover or sheath of a stent. In some embodi 1B. Formulations for Parenteral Administration ments, a compound as disclosed herein is admixed with a In some embodiments, provided herein are pharmaceutical matrix. Such a matrix can be a polymeric matrix, and can compositions for parenteral administration containing a com 35 serve to bond the compound to the stent. Polymeric matrices pound as disclosed herein and a pharmaceutical excipient Suitable for Such use, include, for example, lactone-based Suitable for parenteral administration. Components and polyesters or copolyesters such as polylactide, polycaprolac amounts of agents in the pharmaceutical compositions are as tonglycolide, polyorthoesters, polyanhydrides, polyami described herein. In some embodiments, provided herein are noacids, polysaccharides, polyphosphaZenes, poly(ether-es pharmaceutical compositions for parenteral administration 40 ter) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, containing: (i) an effective amount of a disclosed compound; poly(ethylene-vinylacetate), acrylate-based polymers or optionally (ii) an effective amount of one or more second copolymers (e.g. polyhydroxyethyl methylmethacrylate, agents; and (iii) one or more pharmaceutical excipients Suit polyvinyl pyrrolidinone), fluorinated polymers such as poly able for parenteral administration. In some embodiments, the tetrafluoroethylene and cellulose esters. Suitable matrices pharmaceutical composition further contains: (iv) an effec 45 can be nondegrading or can degrade with time, releasing the tive amount of a third agent. compound or compounds. Compounds described herein can The forms in which the disclosed pharmaceutical compo be applied to the surface of the stent by various methods such sitions disclosed herein can be incorporated for administra as dip/spin coating, spray coating, dip-coating, and/or brush tion by injection include aqueous or oil suspensions, or emul coating. The compounds can be applied in a solvent and the sions, with Sesame oil, corn oil, cottonseed oil, or peanut oil, 50 Solvent can be allowed to evaporate, thus forming a layer of as well as elixirs, mannitol, dextrose, or a sterile aqueous compound onto the Stent. Alternatively, the compound can be Solution, and similar pharmaceutical vehicles. Exemplary located in the body of the stent or graft, for example in parenteral administration forms include Solutions or Suspen microchannels or micropores. When implanted, the com sions of active compound in Sterile aqueous solutions, for pound diffuses out of the body of the stent to contact the example, aqueous propylene glycol or dextrose Solutions. 55 arterial wall. Such stents can be prepared by dipping a stent Such dosage forms can be suitably buffered, if desired. manufactured to contain such micropores or microchannels Aqueous solutions in Saline are also conventionally used into a solution of the compound as disclosed herein in a for injection. Ethanol, glycerol, propylene glycol, liquid suitable solvent, followed by evaporation of the solvent. polyethylene glycol, and the like (and Suitable mixtures Excess drug on the Surface of the stent can be removed via an thereof), cyclodextrin derivatives, and vegetable oils can also 60 additional brief solvent wash. In yet other embodiments, be employed. The proper fluidity can be maintained, for compounds described herein can be covalently linked to a example, by the use of a coating, such as lecithin, for the stent or graft. A covalent linker can be used which degrades in maintenance of the required particle size in the case of dis vivo, leading to the release of the compound. Any bio-labile persion and by the use of surfactants. The prevention of the linkage can be used for Such a purpose, such as ester, amide or action of microorganisms can be brought about by various 65 anhydride linkages Compounds described herein can addi antibacterial and antifungal agents, for example, parabens, tionally be administered intravascularly from a balloon used chlorobutanol, phenol, Sorbic acid, thimerosal, and the like. during angioplasty. Extravascular administration of the com US 8,901,133 B2 117 118 pounds via the pericard or via advential application of formu equivalents thereof. Jet injection devices which deliver liquid lations can also be performed to decrease restenosis. vaccines to the dermis via a liquid jet injector and/or via a A variety of stent devices which can be used as described needle which pierces the stratum corneum and produces a jet are disclosed, for example, in the following references, all of which reaches the dermis are suitable. Jet injection devices which are hereby incorporated by reference: U.S. Pat. No. 5 are described, for example, in U.S. Pat. Nos. 5,480,381: 5,451,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273: 5,599,302; 5,334,144; 5,993,412: 5,649,912; 5,569,189: U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,292,331; U.S. Pat. 5,704,911; 5,383,851; 5,893,397; 5,466.220; 5,339,163; No. 5,674,278; U.S. Pat. No. 3,657,744: U.S. Pat. No. 4,739, 5,312,335; 5,503,627; 5,064.413: 5,520,639; 4,596,556; 762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. 4,790,824; 4.941,880; 4.940,460; and PCT publications WO Pat. No. 5,674,278; U.S. Pat. No. 5,879,382: U.S. Pat. No. 10 97/37705 and WO 97/13537. Ballistic powder/particle deliv 6,344,053. ery devices which use compressed gas to accelerate vaccine 1C. Formulations for Topical Administration in powder form through the outer layers of the skin to the In some embodiments, provided herein are pharmaceutical dermis are suitable. Alternatively or additionally, conven compositions for transdermal delivery containing a com tional Syringes can be used in the classical mantoux method of pound as disclosed herein and a pharmaceutical excipient 15 intradermal administration. suitable for transdermal delivery. In some embodiments, pro Topically-administrable formulations can, for example, vided herein are pharmaceutical compositions for topical comprise from about 1% to about 10% (w/w) compound of administration containing: (i) an effective amount of a dis formula (I), although the concentration of the compound of closed compound; optionally (ii) an effective amount of one formula (I) can be as high as the solubility limit of the com or more second agents; and (iii) one or more pharmaceutical pound of formula (I) in the solvent. In some embodiments, excipients suitable for topical administration. In some topically-administrable formulations can, for example, com embodiments, the pharmaceutical composition further con prise from about 1% to about 9% (w/w) compound of formula tains: (iv) an effective amount of a third agent. (I), such as from about 1% to about 8% (w/w), further such as Pharmaceutical compositions provided herein can be for from about 1% to about 7% (w/w), further such as from about mulated into preparations in Solid, semi-solid, or liquid forms 25 1% to about 6% (w/w), further such as from about 1% to about Suitable for local or topical administration, such as gels, water 5% (w/w), further such as from about 1% to about 4% (w/w), soluble jellies, creams, lotions, Suspensions, foams, powders, further such as from about 1% to about 3% (w/w), and further slurries, ointments, solutions, oils, pastes, Suppositories, such as from about 1% to about 2% (w/w) compound of sprays, emulsions, saline Solutions, dimethylsulfoxide formula (I). Formulations for topical administration can fur (DMSO)-based solutions. In general, carriers with higher 30 ther comprise one or more of the additional pharmaceutically densities are capable of providing an area with a prolonged acceptable excipients described herein. exposure to the active ingredients. In contrast, a solution 1D. Formulations for Inhalation Administration formulation can provide more immediate exposure of the In some embodiments, provided herein are pharmaceutical active ingredient to the chosen area. compositions for inhalation administration containing a com The pharmaceutical compositions also can comprise Suit 35 pound as disclosed herein, and a pharmaceutical excipient able Solid or gel phase carriers or excipients, which are com Suitable for topical administration. In some embodiments, pounds that allow increased penetration of or assist in the provided herein are pharmaceutical compositions for inhala delivery of therapeutic molecules across the stratum cor tion administration containing: (i) an effective amount of a neum permeability barrier of the skin. There are many of disclosed compound; optionally (ii) an effective amount of these penetration-enhancing molecules known to those 40 one or more second agents; and (iii) one or more pharmaceu trained in the art of topical formulation. Examples of such tical excipients suitable for inhalation administration. In carriers and excipients include, but are not limited to, humec Some embodiments, the pharmaceutical composition further tants (e.g., urea), glycols (e.g., propylene glycol), alcohols contains: (iv) an effective amount of a third agent. (e.g., ethanol), fatty acids (e.g., oleic acid). Surfactants (e.g., Pharmaceutical compositions for inhalation or insufflation isopropyl myristate and sodium lauryl Sulfate), pyrrolidones, 45 include Solutions and Suspensions in pharmaceutically glycerol monolaurate, Sulfoxides, terpenes (e.g., menthol), acceptable, aqueous or organic solvents, or mixtures thereof, amines, amides, alkanes, alkanols, water, calcium carbonate, and powders. The liquid or Solid compositions can contain calcium phosphate, various Sugars, starches, cellulose deriva Suitable pharmaceutically acceptable excipients as described tives, gelatin, and polymers such as polyethylene glycols. Supra. In some embodiments, the compositions are adminis Another exemplary formulation for use in the disclosed 50 tered by the oral or nasal respiratory route for local or sys methods employs transdermal delivery devices (“patches”). temic effect. Pharmaceutical compositions in pharmaceuti Such transdermal patches can be used to provide continuous cally acceptable solvents can be nebulized by use of inert or discontinuous infusion of a compound as disclosed herein gases. Nebulized solutions can be inhaled directly from the in controlled amounts, either with or without another agent. nebulizing device or the nebulizing device can be attached to The construction and use of transdermal patches for the 55 a face mask tent, or intermittent positive pressure breathing delivery of pharmaceutical agents is well known in the art. machine. Solution, Suspension, or powder compositions can See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. be administered, e.g., orally or nasally, from devices that Such patches can be constructed for continuous, pulsatile, or deliver the formulation in an appropriate manner on demand delivery of pharmaceutical agents. 1E. Formulations for Ocular Administration Suitable devices for use in delivering intradermal pharma 60 In some embodiments, the disclosure provides a pharma ceutically acceptable compositions described herein include ceutical composition for treating ophthalmic disorders. The short needle devices such as those described in U.S. Pat. Nos. pharmaceutical composition can contain an effective amount 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; of a compound as disclosed herein and a pharmaceutical 5,015,235; 5,141.496; and 5,417,662. Intradermal composi excipient suitable for ocular administration. Pharmaceutical tions can be administered by devices which limit the effective 65 compositions suitable for ocular administration can be pre penetration length of a needle into the skin, such as those sented as discrete dosage forms, such as drops or sprays each described in PCT publication WO99/34850 and functional containing a predetermined amount of an active ingredient a US 8,901,133 B2 119 120 Solution, or a suspension in an aqueous or non-aqueous liq nium halide or a mixture of two or more thereof. In some uid, an oil-in-water emulsion, or a water-in-oil liquid emul cases, cationic agent is a benzalkonium chloride, lauralko Sion. Other administration forms include intraocular injec nium chloride, benzododecinium bromide, benzethenium tion, intravitreal injection, topically, or through the use of a chloride, hexadecyltrimethylammonium bromide, tetrade drug eluting device, microcapsule, implant, or microfluidic cyltrimethylammonium bromide, dodecyltrimethylammo device. In some cases, the compounds as disclosed herein are nium bromide or a mixture of two or more thereof. In some administered with a carrier or excipient that increases the cases, the oil phase is mineral oil and light mineral oil, intraocular penetrance of the compound Such as an oil and medium chain triglycerides (MCT), coconut oil; hydroge water emulsion with colloid particles having an oily core nated oils comprising hydrogenated cottonseed oil, hydroge surrounded by an interfacial film. It is contemplated that all 10 nated palm oil, hydrogenate castor oil or hydrogenated Soy local routes to the eye can be used including topical, Subcon bean oil; polyoxyethylene hydrogenated castor oil derivatives junctival, periocular, retrobulbar, Subtenon, intracameral, comprising polyoxyl-40 hydrogenated castor oil, polyoxyl intravitreal, intraocular, Subretinal, juxtascleral and Supra 60 hydrogenated castor oil or polyoxyl-100 hydrogenated choroidal administration. Systemic or parenteral administra castor oil. tion can be feasible including but not limited to intravenous, 15 1F. Formulations for Controlled Release Administration Subcutaneous, and oral delivery. An exemplary method of In some embodiments, provided herein are pharmaceutical administration will be intravitreal or subtenon injection of compositions for controlled release administration contain Solutions or Suspensions, or intravitreal or Subtenon place ing a compound as disclosed herein, and a pharmaceutical ment of bioerodible or non-bioerodible devices, or by topical excipient suitable for controlled release administration. In ocular administration of Solutions or Suspensions, or poste Some embodiments, provided herein are pharmaceutical rior juxtascleral administration of agel or cream formulation. compositions for controlled release administration contain Eye drops can be prepared by dissolving the active ingre ing: (i) an effective amount of a disclosed compound; option dient in a sterile aqueous solution Such as physiological ally (ii) an effective amount of one or more secondagents; and saline, buffering solution, etc., or by combining powder com (iii) one or more pharmaceutical excipients suitable for con positions to be dissolved before use. Other vehicles can be 25 trolled release administration. In some embodiments, the chosen, as is known in the art, including, but not limited to: pharmaceutical composition further contains: (iv) an effec balance salt solution, Saline solution, water Soluble poly tive amount of a third agent. ethers such as polyethyene glycol, polyvinyls, such as poly Active agents such as the compounds provided herein can vinyl alcohol and povidone, cellulose derivatives such as be administered by controlled release means or by delivery methylcellulose and hydroxypropyl methylcellulose, petro 30 devices that are well known to those of ordinary skill in the leum derivatives Such as mineral oil and white petrolatum, art. Examples include, but are not limited to, those described animal fats such as lanolin, polymers of acrylic acid such as in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598, carboxypolymethylene gel, vegetable fats such as peanut oil 123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120, and polysaccharides Such as dextrans, and glycosaminogly 548; 5,073,543:5,639,476; 5,354,556; 5,639,480; 5,733,566; cans such as Sodium hyaluronate. In some embodiments, 35 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; additives ordinarily used in the eye drops can be added. Such 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; additives include isotonizing agents (e.g., Sodium chloride, 6,248,363; 6,264,970; 6,267,981; 6,376.461; 6,419,961: etc.), buffer agent (e.g., boric acid, Sodium monohydrogen 6,589,548; 6,613.358; 6,699,500 each of which is incorpo phosphate, Sodium dihydrogen phosphate, etc.), preserva rated herein by reference. Such dosage forms can be used to tives (e.g., benzalkonium chloride, benzethonium chloride, 40 provide slow or controlled release of one or more active chlorobutanol, etc.), thickeners (e.g., saccharide such as lac agents using, for example, hydropropylmethyl cellulose, tose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salt other polymer matrices, gels, permeable membranes, osmotic Such as Sodium hyaluronate, potassium hyaluronate, etc.; systems, multilayer coatings, microparticles, liposomes, e.g., mucopolysaccharide Such as chondroitin Sulfate, etc.; microspheres, or a combination thereof to provide the desired e.g., Sodium polyacrylate, carboxyvinyl polymer, crosslinked 45 release profile in varying proportions. Suitable controlled polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, release formulations known to those of ordinary skill in the methyl cellulose, hydroxy propyl methylcellulose, hydroxy art, including those described herein, can be readily selected ethyl cellulose, carboxymethyl cellulose, hydroxy propyl cel for use with the active agents provided herein. Thus, the lulose or other agents known to those skilled in the art). pharmaceutical compositions provided encompass single In some cases, the colloid particles include at least one 50 unit dosage forms suitable for oral administration Such as, but cationic agent and at least one non-ionic Surfactant such as a not limited to, tablets, capsules, gelcaps, and caplets that are poloxamer, tyloxapol, a polysorbate, a polyoxyethylene cas adapted for controlled release. tor oil derivative, a Sorbitan ester, or a polyoxyl Stearate. In All controlled release pharmaceutical products have a Some cases, the cationic agent is an alkylamine, a tertiary common goal of improving drug therapy over that achieved alkyl amine, a quarternary ammonium compound, a cationic 55 by their non controlled counterparts. In some embodiments, lipid, an amino alcohol, a biguanidine salt, a cationic com the use of a controlled release preparation in medical treat pound or a mixture thereof. In some cases, the cationic agent ment is characterized by a minimum of drug Substance being is a biguanidine salt such as chlorhexidine, polyaminopropyl employed to cure or control the disease, disorder, or condition biguanidine, phenformin, alkylbiguanidine, or a mixture in a minimum amount of time. Advantages of controlled thereof. In some cases, the quaternary ammonium compound 60 release formulations include extended activity of the drug, is a benzalkonium halide, lauralkonium halide, cetrimide, reduced dosage frequency, and increased subject compliance. hexadecyltrimethylammonium halide, tetradecyltrimethy In addition, controlled release formulations can be used to lammonium halide, dodecyltrimethylammonium halide, cet affect the time of onset of action or other characteristics, such rimonium halide, benzethonium halide, behenalkonium as blood levels of the drug, and can thus affect the occurrence halide, cetalkonium halide, cetethyldimonium halide, 65 of side (e.g., adverse) effects. cetylpyridinium halide, benzododecinium halide, chlorallyl In some embodiments, controlled release formulations are methenamine halide, rnyristylalkonium halide, Stearalko designed to initially release an amount of a compound as US 8,901,133 B2 121 122 disclosed herein that promptly produces the desired therapeu still other instances, the compound described herein and the tic effect, and gradually and continually release other additional therapeutic agent can be administered in the same amounts of the compound to maintain this level of therapeutic pharmaceutical composition. or prophylactic effect over an extended period of time. In The selected dosage level will depend upon a variety of order to maintain this constant level of the compound in the factors including, for example, the activity of the particular body, the compound should be released from the dosage form compound employed, the route of administration, the time of at a rate that will replace the amount of drug being metabo administration, the rate of excretion or metabolism of the lized and excreted from the body. Controlled release of an particular compound being employed, the rate and extent of active agent can be stimulated by various conditions includ absorption, the duration of the treatment, other drugs, com 10 pounds and/or materials used in combination with the par ing, but not limited to, pH, temperature, enzymes, water, or ticular compound employed, the age, sex, weight, condition, other physiological conditions or compounds. general health and prior medical history of the patient being In certain embodiments, the pharmaceutical composition treated, and like factors well known in the medical arts. can be administered using intravenous infusion, an implant In general, a Suitable daily dose of a compound described able osmotic pump, a transdermal patch, liposomes, or other 15 herein and/or a chemotherapeutic will be that amount of the modes of administration. In one embodiment, a pump can be compound which, in Some embodiments, can be the lowest used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 dose effective to produce a therapeutic effect. Such an effec (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et tive dose will generally depend upon the factors described al., N. Engl.J. Med. 321:574 (1989)). In another embodiment, above. Generally, doses of the compounds described herein polymeric materials can be used. In yet another embodiment, for a patient, when used for the indicated effects, will range a controlled release system can be placed in a Subject at an from about 0.0001 mg to about 100 mg per day, or about 0.001 appropriate site determined by a practitioner of skill, i.e., thus mg to about 100 mg per day, or about 0.01 mg to about 100 mg requiring only a fraction of the systemic dose (see, e.g., Good per day, or about 0.1 mg to about 100 mg per day, or about son, Medical Applications of Controlled Release, 115-138 0.0001 mg to about 500 mg per day, or about 0.001 mg to (vol. 2, 1984). Other controlled release systems are discussed 25 about 500 mg per day, or about 0.01 mg to 1000 mg. or about in the review by Langer, Science 249:1527-1533 (1990). The 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 one or more active agents can be dispersed in a solid inner mg per day, or about 1 mg to 50 mg per day, or about 5 mg to matrix, e.g., polymethylmethacrylate, polybutylmethacry 40 mg. late, plasticized or unplasticized polyvinylchloride, plasti The amount of the compound administered will be depen cized nylon, plasticized polyethyleneterephthalate, natural 30 dent on the subject being treated, the severity of the disorder rubber, polyisoprene, polyisobutylene, polybutadiene, poly or condition, the rate of administration, the disposition of the ethylene, ethylene-vinylacetate copolymers, silicone rub compound and the discretion of the prescribing physician. bers, polydimethylsiloxanes, silicone carbonate copolymers, However, an effective dosage can be in the range of about hydrophilic polymers such as hydrogels of esters of acrylic 0.001 to about 100 mg per kg body weight per day, such as and methacrylic acid, collagen, cross-linked polyvinylalco 35 from about 1 to about 35 mg/kg/day, in single or divided hol and cross-linked partially hydrolyzed polyvinyl acetate, doses. For a 70kg human, this would amount to about 0.05 to that is Surrounded by an outer polymeric membrane, e.g., about 7 g/day, such as about 0.05 to about 2.5 g/day. In some polyethylene, polypropylene, ethylene/propylene copoly instances, dosage levels below the lower limit of the aforesaid mers, ethylene/ethyl acrylate copolymers, ethylene/vinylac range can be more than adequate, while in other cases still etate copolymers, silicone rubbers, polydimethyl siloxanes, 40 larger doses can be employed without causing any harmful neoprene rubber, chlorinated polyethylene, polyvinylchlo side effect, e.g. by dividing Such larger doses into several ride, vinylchloride copolymers with vinyl acetate, vinylidene Small doses for administration throughout the day. chloride, ethylene and propylene, ionomer polyethylene In some embodiments, a compound as disclosed herein is terephthalate, butyl rubber epichlorohydrin rubbers, ethyl administered in a single dose. Typically, Such administration ene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl 45 will be by injection, e.g., intravenous injection, in order to alcohol terpolymer, and ethylene/vinyloxyethanol copoly introduce the agent quickly. However, other routes can be mer, that is insoluble in body fluids. The one or more active used as appropriate. A single dose of a compound as provided agents then diffuse through the outer polymeric membrane in herein can also be used for treatment of an acute condition. a release rate controlling step. The percentage of active agent In some embodiments, the compounds can be administered in Such parenteral compositions is highly dependent on the 50 daily, every other day, three times a week, twice a week, specific nature thereof, as well as the needs of the subject. weekly, or bi-weekly. The dosing schedule can include a 2. Dosage “drug holiday, i.e., the drug can be administered for two A compound described herein can be delivered in the form weeks on, one week off, or three weeks on, one week off, or of pharmaceutically acceptable compositions which com four weeks on, one week off, etc., or continuously, without a prise a therapeutically effective amount of one or more com 55 drug holiday. The compounds can be administered orally, pounds described herein and/or one or more additional thera intravenously, intraperitoneally, topically, transdermally, peutic agents such as a chemotherapeutic, formulated intramuscularly, Subcutaneously, intranasally, Sublingually, together with one or more pharmaceutically acceptable or by any other route. excipients. In some instances, the compound described herein In some embodiments, a compound as provided herein is and the additional therapeutic agent are administered in sepa 60 administered in multiple doses. Dosing can be about once, rate pharmaceutical compositions and can (e.g., because of twice, three times, four times, five times, six times, or more different physical and/or chemical characteristics) be admin than six times per day. Dosing can be about once a month, istered by different routes (e.g., one therapeutic is adminis once every two weeks, once a week, or once every other day. tered orally, while the other is administered intravenously). In In another embodiment a compound as disclosed herein and other instances, the compound described herein and the addi 65 another agent are administered together about once per day to tional therapeutic agent can be administered separately, but about 6 times per day. In another embodiment the adminis via the same route (e.g., both orally or both intravenously). In tration of a compound as disclosed herein and an agent con US 8,901,133 B2 123 124 tinues for less than about 7 days. In yet another embodiment or promoted to health providers, including physicians, nurses, the administration continues for more than about 6, 10, 14, 28 pharmacists, formulary officials, and the like. Kits can also, in days, two months, six months, or one year. In some cases, Some embodiments, be marketed directly to the consumer. continuous dosing is achieved and maintained as long as In some embodiments, a memory aid is provided with the necessary. kit, e.g., in the form of numbers next to the tablets or capsules Administration of the agents as disclosed herein can con whereby the numbers correspond with the days of the regi tinue as long as necessary. In some embodiments, an agent as men which the tablets or capsules so specified should be disclosed herein is administered for more than 1, 2, 3, 4, 5, 6, ingested. Another example of Such a memory aid is a calendar 7, 14, or 28 days. In some embodiments, an agent as disclosed printed on the card, e.g., as follows “First Week, Monday, herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 10 Tuesday,...etc....Second Week, Monday,Tuesday,...etc. 1 day. In some embodiments, an agent as disclosed herein is Other variations of memory aids will be readily apparent. A administered chronically on an ongoing basis, e.g., for the "daily dose” can be a single tablet or capsule or several tablets treatment of chronic effects. or capsules to be taken on a given day. An effective amount of a compound as disclosed hereincan An example of such a kit is a so-called blister pack. Blister be administered in either single or multiple doses by any of 15 packs are well known in the packaging industry and are being the accepted modes of administration of agents having simi widely used for the packaging of pharmaceutical unit dosage lar utilities, including rectal, buccal, intranasal and transder forms (tablets, capsules, and the like). Blister packs generally mal routes, by intra-arterial injection, intravenously, intrap consist of a sheet of relatively stiff material covered with a foil eritoneally, parenterally, intramuscularly, Subcutaneously, of a preferably transparent plastic material. During the pack orally, topically, or as an inhalant. aging process, recesses are formed in the plastic foil. The Since the compounds described herein can be administered recesses have the size and shape of the tablets or capsules to in combination with other treatments (such as additional che be packed. Next, the tablets or capsules are placed in the motherapeutics, radiation or Surgery), the doses of each agent recesses and the sheet of relatively stiff material is sealed or therapy can be lower than the corresponding dose for against the plastic foil at the face of the foil which is opposite single-agent therapy. The dose for single-agent therapy can 25 from the direction in which the recesses were formed. As a range from, for example, about 0.0001 to about 200 mg. or result, the tablets or capsules are sealed in the recesses about 0.001 to about 100 mg. or about 0.01 to about 100 mg. between the plastic foil and the sheet. The strength of the or about 0.1 to about 100 mg. or about 1 to about 50 mg per sheet is such that the tablets or capsules can be removed from kilogram of body weight per day. the blister pack by manually applying pressure on the When a compound provided herein, is administered in a 30 recesses whereby an opening is formed in the sheet at the pharmaceutical composition that comprises one or more place of the recess. The tablet or capsule can then be removed agents, and the agent has a shorter half-life than the com via said opening. pound provided herein unit dose forms of the agent and the Kits can further comprise pharmaceutically acceptable compound provided herein can be adjusted accordingly. vehicles that can be used to administer one or more active The compounds provided herein can be administered in 35 agents. For example, if an active agent is provided in a solid dosages. It is known in the art that due to intersubject vari form that must be reconstituted for parenteral administration, ability in compound pharmacokinetics, individualization of the kit can comprise a sealed container of a Suitable vehicle in dosing regimen is necessary for optimal therapy. Dosing for a which the active agent can be dissolved to form a particulate compound as disclosed hereincan be found by routine experi free sterile solution that is suitable for parenteral administra mentation in light of the instant disclosure. 40 tion. Examples of pharmaceutically acceptable vehicles 3. Kits include, but are not limited to: Water for Injection USP; In some embodiments, provided herein are kits. The kits aqueous vehicles such as, but not limited to, Sodium Chloride can include a compound or compounds as described herein, in Injection, Ringer's Injection, Dextrose Injection, Dextrose Suitable packaging, and written material that can include and Sodium Chloride Injection, and Lactated Ringer's Injec instructions for use, discussion of clinical studies, listing of 45 tion; water-miscible vehicles such as, but not limited to, ethyl side effects, and the like. In some embodiments, the kits can alcohol, polyethylene glycol, and polypropylene glycol, and contain one or more pharmaceutical compositions as non-aqueous vehicles such as, but not limited to, corn oil, described herein. Such kits can also include information, Such cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl as Scientific literature references, package insert materials, myristate, and benzyl benzoate. clinical trial results, and/or Summaries of these and the like, 50 The present disclosure further encompasses anhydrous which indicate or establish the activities and/or advantages of pharmaceutical compositions and dosage forms comprising the pharmaceutical composition, and/or which describe dos an active ingredient, since water can facilitate the degradation ing, administration, side effects, drug interactions, or other of some compounds. For example, water can be added (e.g., information useful to the health care provider. Such informa about 5%) in the pharmaceutical arts as a means of simulating tion can be based on the results of various studies, for 55 long-term storage in order to determine characteristics Such example, studies using experimental animals involving in as shelf-life or the stability of formulations over time. Anhy vivo models and studies based on human clinical trials. The drous pharmaceutical compositions and dosage forms can be kit can further contain another agent. In some embodiments, prepared using anhydrous or low moisture containing ingre the compound as disclosed herein and the agent are provided dients and low moisture or low humidity conditions. For as separate pharmaceutical compositions in separate contain 60 example, pharmaceutical compositions and dosage forms ers within the kit. In some embodiments, the compound which contain lactose can be made anhydrous if Substantial described herein and the agent are provided as a single phar contact with moisture and/or humidity during manufacturing, maceutical composition within a container in the kit. Suitable packaging, and/or storage is expected. An anhydrous phar packaging and additional articles for use (e.g., measuring cup maceutical composition can be prepared and stored Such that for liquid preparations, foil wrapping to minimize exposure to 65 its anhydrous nature is maintained. Accordingly, anhydrous air, and the like) are known in the art and can be included in pharmaceutical compositions can be packaged using materi the kit. Kits described herein can be provided, marketed and/ als known to prevent exposure to water Such that they can be US 8,901,133 B2 125 126 included in suitable formulary kits. Examples of suitable Numerous publications support roles of PI3K-8, PI3K-Y, packaging include, but are not limited to, hermetically sealed and PI3K-B in the differentiation, maintenance, and activa foils, plastic or the like, unit dose containers, blister packs, tion of immune and malignant cells, as described in more and strip packs. detail below. 4. Therapeutic Methods The importance of PI3K-8 in the development and function Phosphoinositide 3-kinases (PI3Ks) are members of a con of B-cells is supported from inhibitor studies and genetic served family of lipid kinases that regulate numerous cell models. PI3K-8 is an important mediator of B-cell receptor functions, including proliferation, differentiation, cell Sur (BCR) signaling, and is upstream of AKT, calcium flux, vival and metabolism. Several classes of PI3Ks exist in cells PLCY, MAP kinase, P70S6k, and FOXO3a activation. 10 PI3K-6 is also important in IL4R, S1P and CXCR5 signaling, (e.g., mammalian cells), including Class IA subgroup (e.g., and has been shown to modulate responses to toll-like recep PI3K-C. B., 8), which are generally activated by receptor tors 4 and 9 Inhibitors of PI3K-8 have shown the importance tyrosine kinases (RTKs); Class IB (e.g., PI3K-Y), which is of PI3K-8 in B-cell development (Marginal Zone and B1 activated by G-protein coupled receptors, among others. cells), B-cell activation, chemotaxis, migration and homing PI3Ks exert their biological activities via a “PI3K-mediated 15 to lymphoid tissue, and in the control of immunoglobulin signaling pathway' that includes several components that class Switching leading to the production of IgE. Clayton E et directly and/or indirectly transduce a signal triggered by a al. (2002).J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) PI3K, including the generation of secondary messenger pho Blood 107(2):642-50; Okkenhaug K. et al. (2002) Science photidylinositol, 3,4,5-triphosphate (PIP3) at the plasma 297(5583):1031-4; Al-Alwan M M et al. (2007).J Immunol. membrane, activation of heterotrimeric G protein signaling, 178(4):2328-35; ZhangTT, et al. (2008).JAllergy Clin Immu and generation of further second messengers such as cAMP mol. 2008: 122(4):811-819.e2: Srinivasan L, et al. (2009) Cell DAG, and IP3, all of which leads to an extensive cascade of 139(3):573-86) protein kinase activation (reviewed in Vanhaesebroeck, B. et In T-cells, PI3K-8 has been demonstrated to have a role in al. (2001) Annu Rev Biochem. 70:535-602). For example, T-cell receptor and cytokine signaling, and is upstream of PI3K-8 is activated by cellular receptors through interaction 25 AKT, PLCY, and GSK3b. In PI3K-8 deletion or kinase-dead between the PI3K regulatory subunit (p85) SH2 domains, or knock-in mice, or in inhibitor studies, T-cell defects including through direct interaction with RAS. PIP3 produced by PI3K proliferation, activation, and differentiation have been activates effector pathways downstream through interaction observed, leading to reduced T helper cell 2 (TH2) response, with plextrin homology (PH) domain containing enzymes memory T-cell specific defects (DTH reduction), defects in (e.g., PDK-1 and AKT PKB). (Fung-Leung W P. (2011) 30 antigen dependent cellular trafficking, and defects in chemo Cell Signal. 23(4):603-8). Unlike PI3K-8, PI3K-Y is not a taxis/migration to chemokines (e.g., S1P, CCR7, CD62L). Class 1API3K, and is not associated with a regulatory subunit (Garcon F. etal. (2008) Blood 111(3):1464-71; Okkenhaug K of the P85 family, but rather with a regulatory subunit in the et al. (2006). J Immunol. 177(8):51 22-8; Soond D R, et al. p101 family. PI3K-Y is associated with G-protein coupled (2010) Blood 115(11):2203-13; Reif K, (2004). J Immunol. receptors (GPCRs), and is responsible for the very rapid 35 2004; 173(4):2236-40; Ji H. etal. (2007) Blood 110(8):2940 induction of PIP3, and can be also activated by RAS. 7; Webb LM, et al. (2005).J Immunol. 175(5):2783-7; Liu D, As used herein, a “PI3K-mediated disorder” refers to a etal. (2010).J Immunol. 184(6):3098-105: Haylock-Jacobs S, disease or condition involving aberrant PI3K-mediated sig et al. (2011).JAutoimmun. 2011:36(3–4):278-87; Jarmin SJ, naling pathway. In one embodiment, provided herein is a et al. (2008).J Clin Invest. 118(3): 1154–64). method of treating a PI3K mediated disorder in a subject, the 40 In neutrophils, PI3K-8 along with PI3K-Y, and PI3K-B, method comprising administering a therapeutically effective contribute to the responses to immune complexes, FCgRII amount of a compound or a pharmaceutical composition as signaling, including migration and neutrophil respiratory disclosed herein. In some embodiments, provided herein is a burst. Human neutrophils undergo rapid induction of PIP3 in method of treating a PI3K-8 or PI3K-Y mediated disorder in a response to formyl peptide receptor (FMLP) or complement Subject, the method comprising administering a therapeuti 45 component C5a (C5a) in a PI3K-Y dependent manner, fol cally effective amount of a compound or a pharmaceutical lowed by a longer PIP3 production period that is PI3K-8 composition as disclosed herein. In some embodiments, pro dependent, and is essential for respiratory burst. The response vided herein is a method for inhibiting at least one of PI3K-8 to immune complexes is contributed by PI3K-8, PI3K-Y, and or PI3K-Y, the method comprising contacting a cell express PI3K-B, and is an important mediator of tissue damage in ing PI3K in vitro or in vivo with an effective amount of the 50 models of autoimmune disease (Randis T Metal. (2008) Eur compound or composition disclosed herein PI3Ks have been J Immunol. 38(5):1215-24; Pinho V. (2007).J Immunol. 179 associated with a wide range of conditions, including immu (11):7891-8: Sadhu C. et al. (2003).J Immunol. 170(5):2647 nity, cancer and thrombosis (reviewed in Vanhaesebroeck, B. 54; Condliffe A Metal. (2005) Blood 106(4): 1432-40). et al. (2010) Current Topics in Microbiology and Immunol In macrophages collected from patients with chronic ogy, DOI 10.1007/82 2010 65). For example, Class I 55 obstructive pulmonary disease (COPD), glucocorticoid PI3Ks, particularly PI3KY and PI3Kö isoforms, are highly responsiveness can be restored by treatment of the cells with expressed in leukocytes and have been associated with adap inhibitors of PI3K-8. Macrophages also rely on PI3K-8 and tive and innate immunity; thus, these PI3Ks are believed to be PI3K-Y for responses to immune complexes through the important mediators in inflammatory disorders and hemato arthus reaction (FCgR and C5a signaling) (RandisTM, et al. logic malignancies (reviewed in Harris, S J et al. (2009) Curr 60 (2008) EurJ Immunol. 38(5):1215-24; Marwick J A et al. Opin Investig Drugs 10(11): 1151-62); Rommel C. et al. (2009) Am J Respir Crit Care Med. 179(7):542-8: Konrad S. (2007) Nat Rev Immunol 7(3):191-201: Durand C A et al. et al. (2008).J. Biol Chem. 283 (48):33296-303). (2009) J Immunol. 183(9):5673-84: Dil N, Marshall A. J. In mast cells, stem cell factor-(SCF) and IL3-dependent (2009) Mol Immunol. 46(10): 1970-8: Al-Alwan M M et al. proliferation, differentiation and function are PI3K-8 depen (2007).J Immunol. 178(4):2328-35; Zhang TT, et al. (2008).J 65 dent, as is chemotaxis. The allergen/IgE crosslinking of Allergy Clin Immunol. 2008: 122(4):811-819.e2: Srinivasan FCgR1 resulting in cytokine release and degranulation of the L., et al. (2009) Cell 139(3):573-86). mast cells is severely inhibited by treatment with PI3K-8 US 8,901,133 B2 127 128 inhibitors, suggesting a role for PI3K-6 in allergic disease activation in a passive cutaneous anaphalaxis assay (Ali Ket (Ali Ketal. (2004) Nature 431 (7011):1007-11; Lee KS, et al. al. (2008).J Immunol. 180(4):2538-44; Ali K, (2004) Nature (2006) FASEB.J. 20(3):455-65; Kim MS, et al. (2008) Trends 431 (7011):1007-11). In a pulmonary measure of response to Immunol. 29(10):493-501). immune complexes (Arthus reaction) a PI3K-8 knockout is Natural killer (NK) cells are dependent on both PI3K-8 and resistant, showing a defect in macrophage activation and C5a PI3K-Y for efficient migration towards chemokines including production. Knockout studies and studies with inhibitors for CXCL10, CCL3, S1P and CXCL12, or in response to LPS in both PI3K-8 and PI3K-y support a role for both of these the peritoneum (Guo H, et al. (2008) J Exp Med. 205(10): enzymes in the ovalbumin induced allergic airway inflamma 2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27; Sau tion and hyper-responsiveness model (Lee K S et al. (2006) demont A, (2009) Proc Natl AcadSci USA. 106(14):5795 10 FASEB.J. 2003):455-65). Reductions of infiltration of eosino 800; Kim N, et al. (2007) Blood 110(9):3202-8). phils, neutrophils, and lymphocytes as well as TH2 cytokines The roles of PI3K-8, PI3K-Y, and PI3K-B in the differen tiation, maintenance, and activation of immune cells Support (IL4, IL5, and IL13) were seen with both PI3K-8 specific and a role for these enzymes in inflammatory disorders ranging dual PI3K-8 and PI3K-Y inhibitors in the Ova induced asthma from autoimmune diseases (e.g., rheumatoid arthritis, mul 15 model (Lee KS et al. (2006) J Allergy Clin Immunol 118(2): tiple Sclerosis) to allergic inflammatory disorders, such as 403-9). asthma and COPD. Extensive evidence is available in experi PI3K-8 and PI3K-Y inhibition can be used in treating mental animal models, or can be evaluated using art-recog COPD. In the smoked mouse model of COPD, the PI3K-8 nized animal models. In an embodiment, described herein is knockoutdoes not develop Smoke induced glucocorticoid a method of treating inflammatory disorders ranging from resistance, while wild-type and PI3K-y knockout mice do. An autoimmune diseases (e.g., rheumatoid arthritis, multiple inhaled formulation of dual PI3K-8 and PI3K-Y inhibitor Sclerosis) to allergic inflammatory disorders, such as asthma blocked inflammation in a LPS or smoke COPD models as and COPD using a compound described herein. measured by neutrophilia and glucocorticoid resistance For example, inhibitors of PI3Kö and/ory have been shown (Doukas J, et al. (2009).JPharmacol Exp. Ther: 328(3):758 to have anti-inflammatory activity in several autoimmune 25 65). animal models for rheumatoid arthritis (Williams, O. et al. Class I PI3Ks, particularly PI3Kö and PI3KY isoforms, are (2010) Chem Biol, 17(2): 123-34; WO 2009/088986: also associated with cancers (reviewed, e.g., in Vogt, P Ketal. WO2009/088880; WO 2011/008302). PI3Kö is expressed in (2010) Curr Top Microbiol Immunol. 347:79-104; Fresno the RA Synovial tissue (especially in the synovial lining Vara, J A et al. (2004) Cancer Treat Rev. 30(2):193-204; which contains fibroblast-like synoviocytes (FLS), and selec 30 Zhao, L and Vogt, P K. (2008). Oncogene 27(41):5486-96). tive PI3Kd inhibitors have been shown to be effective in Inhibitors of PI3K, e.g., PI3Kö and/or Y, have been shown to inhibiting synoviocyte growth and survival (Bartok et al. have anti-cancer activity (e.g., Courtney, KD et al. (2010).J (2010) Arthritis Rheum 62.Suppl 10:362). Several PI3Kö and Clin Oncol. 28(6):1075-1083); Markman, Betal. (2010) Ann Y inhibitors have been shown to ameliorate arthritic symp Oncol. 21(4):683-91: Kong, D and Yamori, T (2009) Curr toms (e.g., Swelling of joints, reduction of serum-induced 35 Med. Chem. 16(22):2839-54; Jimeno, A et al. (2009) J Clin collagen levels, reduction of joint pathology and/or inflam Oncol. 27:156s (suppl; abstr3542); Flinn, IW et al. (2009).J mation), in art-recognized models for RA. Such as collagen Clin Oncol. 27:156s (suppl; abstr 3543); Shapiro, G. et al. induced arthritis and adjuvant induced arthritis (WO 2009/ (2009).J. Clin Oncol. 27:146s (suppl; abstr3500); Wagner, A 088986: WO2009/088880, WO 2011/008302). T et al. (2009) J Clin Oncol. 27:146s (suppl; abstr 3501); The role of PI3K-8 has also been shown in models of T-cell 40 Vogt, P Ketal. (2006) Virology 344(1): 131-8: Ward, Set al. dependent response, including the DTH model. In the murine (2003) Chem. Biol. 10(3):207-13; WO 2011/041399; US experimental autoimmune encephalomyelitis (EAE) model 2010/0029693; US 2010/0305096; US 2010/0305084). In an of multiple sclerosis, the PI3K-g/d-double mutant mice are embodiment, described herein is a method of treating cancer. resistant. PI3K-6 inhibitors have also been shown to block Types of cancer that can be treated with an inhibitor of EAE disease induction and development of TH-17 cells both 45 PI3K (particularly, PI3Kö and/or Y) include, e.g., leukemia, in vitro and in vivo (Haylock-Jacobs, S. et al. (2011) J. chronic lymphocytic leukemia, acute myeloid leukemia, Autoimmunity 36(3–4):278-87). chronic myeloid leukemia (e.g., Salmena, Letal. (2008) Cell Systemic lupus erythematosus (SLE) is a complex disease 133:403-414; Chapuis, N et al. (2010) Clin Cancer Res. that at different stages requires memory T-cells, B-cell poly 16(22):5424-35; Khwaja, A (2010) Curr Top Microbiol clonal expansion and differentiation into plasma cells, and the 50 Immunol. 347: 169-88); lymphoma, e.g., non-Hodgkin’s lym innate immune response to endogenous damage associated phoma (e.g., Salmena, Letal. (2008) Cell 133:403-414); lung molecular pattern molecules (DAMPS), and the inflamma cancer, e.g., non-Small cell lung cancer, Small cell lung cancer tory responses to immune complexes through the comple (e.g., Herrera, VA et al. (2011) Anticancer Res. 31(3):849 ment system as well as the F receptors. The role of PI3K-8 54); melanoma (e.g., Halluska, F et al. (2007) Semin Oncol. and PI3K-Y together in these pathways and cell types suggest 55 34(6):546-54); prostate cancer (e.g., Sarker, D et al. (2009) that blockade with an inhibitor would be effective in these Clin Cancer Res. 15(15):4799-805); glioblastoma (e.g., diseases. A role for PI3K in lupus is also predicted by two Chen, JS et al. (2008) Mol Cancer Ther. 7:841-850); endome genetic models of lupus. The deletion of phosphatase and trial cancer (e.g., Bansal, N et al. (2009) Cancer Control. tensin homolog (PTEN) leads to a lupus-like phenotype, as 16(1):8-13); pancreatic cancer (e.g., Furukawa, T (2008) J does a transgenic activation of Class 1A PI3Ks, which 60 Gastroenterol. 43 (12):905-11); renal cell carcinoma (e.g., includes PI3K-8. The deletion of PI3K-Y in the transgenically Porta, C and Figlin, RA (2009) J Urol. 182(6):2569-77); activated class 1A lupus model is protective, and treatment colorectal cancer (e.g., Saif. MW and Chu, E (2010) Cancer with a PI3K-y selective inhibitor in the murine MLR/lpr J. 16(3):196-201); breast cancer (e.g., Torbett, N E et al. model of lupus improves symptoms (Barber, D F et al. (2006) (2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brze J. Immunol. 176(1): 589-93). 65 Zianska, E and Pastuszak-Lewandoska, D (2011) Front Bio In allergic disease, PI3K-8 has been shown by genetic sci. 16:422-39); and ovarian cancer (e.g., Mazzoletti, Mand models and by inhibitor treatment to be essential for mast-cell Broggini, M. (2010) Curr Med Chem. 17(36):4433-47). US 8,901,133 B2 129 130 Numerous publications support a role of PI3K-8 and PI3K-8 is also expressed in endothelial cells. It has been PI3K-Y in treating hematological cancers. PI3K-6 and PI3K-y shown that tumors in mice treated with PI3K-6 selective are highly expressed in the heme compartment, and some inhibitors are killed more readily by radiation therapy. In this Solid tumors, including prostate, breast and glioblastomas same study, capillary network formation is impaired by the (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50; Ikeda PI3K inhibitor, and it is postulated that this defect contributes H. et al. (2010) Blood 116(9): 1460-8). In hematological can to the greater killing with radiation. PI3K-6 inhibitors can cers including acute myeloid leukemia (AML), multiple affect the way in which tumors interact with their microenvi myeloma (MM), and chronic lymphocytic leukemia (CLL), ronment, including stromal cells, immune cells, and endot overexpression and constitutive activation of PI3K-8 Sup helial cells and be therapeutic either on its own or in conjunc 10 tion with another therapy (Meadows, S A. et al. Paper ports the model that PI3K-8 inhibition would be therapeutic presented at: 52" Annual ASH Meeting and Exposition; Billottet C, et al. (2006) Oncogene 25(50):6648-59; Billottet 2010 Dec. 4-7: Orlando, Fla.: Geng L, et al. (2004) Cancer C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, SA, Res. 64(14):4893-9). 52" Annual ASH Meeting and Exposition; 2010 Dec. 4-7; In other embodiments, inhibition of PI3K (such as PI3K-8 Orlando, Fla.: Ikeda H, et al. (2010) Blood 116(9): 1460-8: 15 and/or -y) can be used to treat a neuropsychiatric disorder, Herman S E et al. (2010) Blood 116(12):2078-88: Herman S e.g., an autoimmune brain disorder. Infectious and immune E et al. (2011). Blood 117(16):4323-7. In an embodiment, factors have been implicated in the pathogenesis of several described herein is a method of treating hematological can neuropsychiatric disorders, including, but not limited to, cers including, but not limited to acute myeloid leukemia Sydenham's chorea (SC) (Garvey, M.A. etal. (2005).J. Child (AML), multiple myeloma (MM), and chronic lymphocytic Neurol. 20:424-429), Tourette's syndrome (TS), obsessive leukemia (CLL). compulsive disorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. A PI3K-8 inhibitor (CAL-101) has been evaluated in a Psychiatry 155:1122-1124), attention deficit/hyperactivity phase 1 trial in patients with haematological malignancies, disorder (AD/HD) (Hirschtritt, M. E. etal. (2008) Child Neu and showed activity in CLL in patients with poor prognostic ropsychol. 1:1-16: Peterson, B. S. et al. (2000) Arch. Gen. characteristics. In CLL, inhibition of PI3K-8 not only affects 25 Psychiatry 57:364-372), anorexia nervosa (Sokol, M. S. tumor cells directly, but it also affects the ability of the tumor (2000) J. Child Adolesc. Psychopharmacol. 10:133-145: cells to interact with their microenvironment. This microen Sokol, M.S. et al. (2002) Am. J. Psychiatry 159:1430-1432), Vironment includes contact with and factors from Stromal depression (Leslie, D. L. et al. (2008) J. Am. Acad. Child cells, T-cells, nurse like cells, as well as other tumor cells. Adolesc. Psychiatry 47:1166-1172), and autism spectrum CAL-101 suppresses the expression of stromal and T-cell 30 disorders (ASD) (Hollander, E. etal. (1999) Am. J. Psychiatry derived factors including CCL3, CCL4, and CXCL13, as well 156:317-320; Margutti, P. et al. (2006) Curr. Neurovasc. Res. as the CLL tumor cells’ ability to respond to these factors. 3:149-157). A subset of childhood obsessive compulsive dis CAL-101 treatment in CLL patients induces rapid lymph orders and tic disorders has been grouped as Pediatric node reduction and redistribution of lymphocytes into the Autoimmune Neuropsychiatric Disorders Associated with circulation, and affects tonic Survival signals through the 35 Streptococci (PANDAS). PANDAS disorders provide an BCR, leading to reduced cell viability, and an increase in example of disorders where the onset and exacerbation of apoptosis. Single agent CAL-101 treatment was also active in neuropsychiatric symptoms is preceded by a streptococcal mantle cell lymphoma and refractory non Hodgkin’s lym infection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113: phoma (Furman, R R, et al. 52" Annual ASH Meeting and 883-886; Garvey, M. A. etal. (1998).J. Clin. Neurol. 13:413 Exposition: 2010 Dec. 4-7: Orlando, Fla.; Hoellenriegel, J, et 40 423). Many of the PANDAS disorders share a common al. 52" Annual ASHMeeting and Exposition: 2010 Dec. 4-7; mechanism of action resulting from antibody responses Orlando, Fla.; Webb, H K, et al. 52' Annual ASH Meeting against Streptococcal associated epitopes. Such as GlcNAc, and Exposition; 2010 Dec. 4-7: Orlando, Fla.; Meadows, et which produces neurological effects (Kirvan. C. A. et al. al. 52" Annual ASHMeeting and Exposition: 2010 Dec. 4-7; (2006).J. Neuroimmunol. 179:173-179). Autoantibodies rec Orlando, Fla.: Kahl, B, et al. 52" Annual ASH Meeting and 45 ognizing central nervous system (CNS) epitopes are also Exposition: 2010 Dec. 4-7: Orlando, Fla.; Lannutti BJ, et al. found in sera of most PANDAS subjects (Yaddanapudi, K. et (2011) Blood 117(2):591-4). al. (2010) Mol. Psychiatry. 15:712-726). Thus, several neu PI3K-8 inhibitors have shown activity against PI3K-8 posi ropsychiatric disorders have been associated with immune tive gliomas in vitro (Kashishian A, et al. Poster presented at: and autoimmune components, making them Suitable for The American Association of Cancer Research 102". Annual 50 therapies that include PI3K-6 and/or -y inhibition. Meeting: 2011 Apr. 2-6: Orlando, Fla.). PI3K-B is the PI3K In certain embodiments, a method of treating (e.g., reduc isoform that is most commonly activated in tumors where the ing or ameliorating one or more symptoms of) a neuropsy PTEN tumor suppressor is mutated (Ward S, et al. (2003) chiatric disorder, (e.g., an autoimmune brain disorder), using Chem. Biol. 10(3):207-13). In this subset of tumors, treatment a PI3K-8 and/or -y inhibitor is described, alone or in combi with the PI3K-6 inhibitor either alone or in combination with 55 nation therapy. For example, one or more PI3K-8 and/or -y a cytotoxic agent can be effective. inhibitors described herein can be used alone or in combina Another mechanism for PI3K-6 inhibitors to have an affect tion with any suitable therapeutic agent and/or modalities, in solid tumors involves the tumor cells interaction with their e.g., dietary Supplement, for treatment of neuropsychiatric micro-environment. PI3K-8, PI3K-Y, and PI3K-B are disorders. Exemplary neuropsychiatric disorders that can be expressed in the immune cells that infiltrate tumors, including 60 treated with the PI3K-8 and/or -y inhibitors described herein tumor infiltrating lymphocytes, macrophages, and neutro include, but are not limited to, PANDAS disorders, Syden phils. PI3K-8 inhibitors can modify the function of these ham's chorea, Tourette's syndrome, obsessive compulsive tumor-associated immune cells and how they respond to sig disorder, attention deficit/hyperactivity disorder, anorexia nals from the stroma, the tumor, and each other, and in this nervosa, depression, and autism spectrum disorders. Perva way affect tumor cells and metastasis (Hoellenriegel, J, et al. 65 sive Developmental Disorder (PDD) is an exemplary class of 52" Annual ASH Meeting and Exposition: 2010 Dec. 4-7: autism spectrum disorders that includes Autistic Disorder, Orlando, Fla.). Asperger's Disorder, Childhood Disintegrative Disorder US 8,901,133 B2 131 132 (CDD), Rett's Disorder and PDD-Not Otherwise Specified improved side effects profile or lessened reduction in the (PDD-NOS). Animal models for evaluating the activity of the ability to reduce a bacterial, viral, and/or fungal infection. PI3K-8 and/or -y inhibitor are known in the art. For example, In some embodiments, the method of treating inflamma a mouse model of PANDAS disorders is described in, e.g., tory or autoimmune diseases includes administering to a Sub Yaddanapudi, K. et al. (2010) supra; and Hoffman, K.I. et al. 5 ject (e.g. a mammal) atherapeutically effective amount of one (2004).J. Neurosci. 24:1780-1791. or more compounds of that selectively inhibit PI3K-8 and/or In some embodiments, provided herein are methods of PI3K-Y as compared to all other type I PI3 kinases. Such using the compounds orpharmaceutical compositions as dis- selective inhibition of PI3K-8 and/or PI3K-Y can be advanta closed herein to treat disease conditions, including, but not geous for treating any of the diseases or conditions described limited to, diseases associated with malfunctioning of one or " herein. For example, selective inhibition of PI3K-8 can more types of PI3 kinase and/or mTOR. A detailed descrip- inhibit inflammatory responses associated with inflammatory tion of conditions and disorders mediated by p1108 kinase diseases, autoimmune disease, or diseases related to an unde activity is set forth in Sadu et al., WO 01/81346, which is sirable immune response including but not limited to asthma, incorporated herein by reference in its entirety for all pur- emphysema, allergy, dermatitis, rhuematoid arthritis, psoria poses. 15 sis, lupus erythematosus, or graft versus host disease. Selec The treatment methods provided herein comprise admin- tive inhibition of PI3K-8 can further provide for a reduction in istering to the Subject a therapeutically effective amount of a the inflammatory or undesirable immune response without a compound as disclosed herein. concomitant reduction in the ability to reduce a bacterial, In some embodiments, the disclosure relates to a method of 20 viral, and/or fungal infection. Selective inhibition of both treating a hyperproliferative disorder in a Subject that com- PI3K-8 and PI3K-Y can be advantageous for inhibiting the prises administering to said Subject atherapeutically effective inflammatory response in the Subject to a greater degree than amount of a compound as disclosed herein, or a pharmaceu- that would be provided for by inhibitors that selectively tically acceptable salt, ester, prodrug or derivative thereof. In inhibit PI3K-8 or PI3K-Y alone. In one aspect, one or more of Some embodiments, said method relates to the treatment of 25 the Subject methods are effective in reducing antigen specific cancer Such as acute myeloid leukemia, thymus, brain, lung, antibody production in vivo by about 2-fold, 3-fold, 4-fold, squamous cell, skin, eye, retinoblastoma, intraocular mela- 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250 noma, oral cavity and oropharyngeal, bladder, gastric, stom- fold, 500-fold, 750-fold, or about 1000-fold or more. In ach, pancreatic, bladder, breast, cervical, head, neck, renal, another aspect, one or more of the Subject methods are effec kidney, liver, ovarian, prostate, colorectal, esophageal, tes- 30 tive in reducing antigen specific IgG3 and/or IgGM produc ticular, gynecological, thyroid, CNS, PNS, AIDS-related tion in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, (e.g. Lymphoma and Kaposi’s Sarcoma) or viral-induced 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, 750 cancer. In some embodiments, said method relates to the fold, or about 1000-fold or more. treatment of a non-cancerous hyperproliferative disorder In one aspect, one of more of the Subject methods are Such as benign hyperplasia of the skin (e.g., psoriasis), rest- 35 effective in ameliorating symptoms associated with rhuema enosis, or prostate (e.g., benign prostatic hypertrophy toid arthritis including but not limited to a reduction in the (BPH)). Swelling of joints, a reduction in serum anti-collagen levels, In one embodiment, provided herein is a method of treating and/or a reduction in joint pathology Such as bone resorption, an inflammation disorder, including autoimmune diseases in cartilage damage, pannus, and/or inflammation. In another a subject. The method comprises administering to said Sub- 40 aspect, the Subject methods are effective in reducing ankle ject a therapeutically effective amount of a compound as inflammation by at least about 2%. 5%, 10%, 15%, 20%, disclosed herein, or a pharmaceutically acceptable salt, ester, 25%, 30%, 50%, 60%, or about 75% to 90%. In another prodrug or derivative thereof. Examples of autoimmune dis- aspect, the Subject methods are effective in reducing knee eases includes but is not limited to acute disseminated inflammation by at least about 2%. 5%, 10%, 15%, 20%, encephalomyelitis (ADEM), Addison's disease, antiphos- 45 25%, 30%, 50%, 60%, or about 75% to 90% or more. In still pholipid antibody syndrome (APS), aplastic anemia, autoim- another aspect, the Subject methods are effective in reducing mune hepatitis, coeliac disease, Crohn's disease, Diabetes serum anti-type II collagen levels by at least about 10%, 12%, mellitus (type 1), Goodpasture’s syndrome, Graves disease, 15%, 20%, 24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus 86%, 87%, or about 90% or more. In another aspect, the erythematosus, multiple Sclerosis, myasthenia gravis, opso- 50 subject methods are effective in reducing ankle histopathol clonus myoclonus syndrome (OMS), optic neuritis, Ord’s ogy scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, thyroiditis, oemphigus, polyarthritis, primary biliary cirrho- 50%. 60%, 75%, 80%, 90% or more. In still another aspect, sis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Taka- the Subject methods are effective in reducing knee histopa yasu's arteritis, temporal arteritis (also known as "giant cell thology scores by about 5%, 10%, 15%, 20%, 25%, 30%, arteritis'), warm autoimmune hemolytic anemia, Wegener's 55 40%, 50%, 60%, 75%, 80%, 90% or more. granulomatosis, alopecia universalis, Chagas disease, In other embodiments, provided herein are methods of chronic fatigue syndrome, dysautonomia, endometriosis, using the compounds orpharmaceutical compositions to treat hidradenitis Suppurativa, interstitial cystitis, neuromyotonia, respiratory diseases including but not limited to diseases sarcoidosis, Scleroderma, ulcerative colitis, vitiligo, and Vul- affecting the lobes of lung, pleural cavity, bronchial tubes, Vodynia. Other disorders include bone-resorption disorders 60 trachea, upper respiratory tract, or the nerves and muscle for and thromobsis. breathing. For example, methods are provided to treat In some embodiments, provided herein are methods for obstructive pulmonary disease. Chronic obstructive pulmo treating disorders or conditions in which the 8 isoform of nary disease (COPD) is an umbrella term for a group of PI3K is implicated to a greater extent than other PI3K iso- respiratory tract diseases that are characterized by airflow forms such as PI3K.C. and/or B. Selective inhibition of PI3K-ö 65 obstruction or limitation. Conditions included in this and/or PI3K-Y can provide advantages over using less selec- umbrella term include, but are not limited to: chronic bron tive compounds which inhibit PI3K C. and/or B, such as an chitis, emphysema, and bronchiectasis. US 8,901,133 B2 133 134 In another embodiment, the compounds described herein is a skin condition that sometimes develops into squamous are used for the treatment of asthma. Also, the compounds or cell carcinoma, eye retinoblastoma; cutaneous or intraocular pharmaceutical compositions described herein can be used (eye) melanoma; primary liver cancer (cancer that begins in for the treatment of endotoxemia and sepsis. In one embodi the liver); kidney cancer, thyroid cancer Such as papillary, ment, the compounds or pharmaceutical compositions follicular, medullary and anaplastic: AIDS-related lym described herein are used to for the treatment of rheumatoid phoma Such as diffuse large B-cell lymphoma, B-cell immu arthritis (RA). In yet another embodiment, the compounds or noblastic lymphoma and Small non-cleaved cell lymphoma; pharmaceutical compositions described herein is used for the Kaposi's Sarcoma; viral-induced cancers including hepatitis treatment of contact or atopic dermatitis. Contact dermatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular includes irritant dermatitis, phototoxic dermatitis, allergic 10 carcinoma; human lymphotropic virus-type 1 (HTLV-1) and dermatitis, photoallergic dermatitis, contact urticaria, sys adult T-cell leukemia/lymphoma; and human papillomavirus temic contact-type dermatitis and the like. Irritant dermatitis (HPV) and cervical cancer; central nervous system cancers can occur when too much of a substance is used on the skin of (CNS) Such as primary brain tumor, which includes gliomas when the skin is sensitive to certain Substance. Atopic derma (astrocytoma, anaplastic astrocytoma, or glioblastoma multi titis, sometimes called eczema, is a kind of dermatitis, an 15 forme), Oligodendroglioma, Ependymoma, Meningioma, atopic skin disease. Lymphoma, Schwannoma, and Medulloblastoma; peripheral In some embodiments, the disclosure provides a method of nervous system (PNS) cancers such as acoustic neuromas and treating diseases related to vasculogenesis orangiogenesis in malignant peripheral nerve sheath tumor (MPNST) including a Subject that comprises administering to said Subject athera neurofibromas and Schwannomas, malignant fibrous cytoma, peutically effective amount of a compound as disclosed malignant fibrous histiocytoma, malignant meningioma, herein, or a pharmaceutically acceptable form (e.g., pharma malignant mesothelioma, and malignant mixed Millerian ceutically acceptable salts, hydrates, Solvates, isomers, pro tumor, oral cavity and oropharyngeal cancer Such as, drugs, and isotopically labeled derivatives) thereof. In some hypopharyngeal cancer, laryngeal cancer, nasopharyngeal embodiments, said method is for treating a disease selected cancer, and oropharyngeal cancer, stomach cancer Such as tumor angiogenesis, chronic inflammatory disease Such as 25 lymphomas, gastric stromal tumors, and carcinoid tumors; rheumatoid arthritis, atherosclerosis, inflammatory bowel testicular cancer Such as germ cell tumors (GCTs), which disease, skin diseases such as psoriasis, eczema, and Sclero include seminomas and nonseminomas, and gonadal stromal derma, diabetes, diabetic retinopathy, retinopathy of prema tumors, which include Leydig cell tumors and Sertoli cell turity, age-related macular degeneration, hemangioma, tumors; thymus cancer Such as to thymomas, thymic carci glioma, melanoma, Kaposi's sarcoma and ovarian, breast, 30 nomas, Hodgkin disease, non-Hodgkin lymphomas carcino lung, pancreatic, prostate, colon and epidermoid cancer. ids or carcinoid tumors; rectal cancer; and colon cancer. Subjects (e.g., patients) that can be treated with compounds Patients that can be treated with compounds disclosed as disclosed herein, or a pharmaceutically acceptable form herein, or pharmaceutically acceptable form (e.g., pharma (e.g., pharmaceutically acceptable salts, hydrates, Solvates, ceutically acceptable salts, hydrates, Solvates, isomers, pro isomers, prodrugs, and isotopically labeled derivatives) 35 drugs, and isotopically labeled derivatives) thereof of said thereof of said compounds, according to the methods as dis compounds, according to the methods disclosed herein closed herein include, for example, patients that have been include, for example, patients that have been diagnosed as diagnosed as having psoriasis; restenosis; atherosclerosis: having conditions including, but not limited to, acoustic neu BPH; breast cancer Such as a ductal carcinoma induct tissue roma, adenocarcinoma, adrenal gland cancer, anal cancer, in a mammary gland, medullary carcinomas, colloid carcino 40 angiosarcoma (e.g., lymphangiosarcoma, lymphangioendot mas, tubular carcinomas, and inflammatory breast cancer, heliosarcoma, hemangiosarcoma), benign monoclonal gam ovarian cancer, including epithelial ovarian tumors such as mopathy, biliary cancer (e.g., cholangiocarcinoma), bladder adenocarcinoma in the ovary and an adenocarcinoma that has cancer, breast cancer (e.g., adenocarcinoma of the breast, migrated from the ovary into the abdominal cavity; uterine papillary carcinoma of the breast, mammary cancer, medul cancer, cervical cancer Such as adenocarcinoma in the cervix 45 lary carcinoma of the breast), brain cancer (e.g., meningioma; epithelial including squamous cell carcinoma and adenocar glioma, e.g., astrocytoma, oligodendroglioma; medulloblas cinomas; prostate cancer, Such as a prostate cancer selected toma), bronchus cancer, cervical cancer (e.g., cervical adeno from the following: an adenocarcinoma oran adenocarinoma carcinoma), choriocarcinoma, chordoma, craniopharyn that has migrated to the bone; pancreatic cancer Such as gioma, colorectal cancer (e.g., colon cancer, rectal cancer, epitheliod carcinoma in the pancreatic duct tissue and an 50 colorectal adenocarcinoma), epithelial carcinoma, ependy adenocarcinoma in a pancreatic duct; bladder cancer Such as moma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple a transitional cell carcinoma in urinary bladder, urothelial idiopathic hemorrhagic sarcoma), endometrial cancer, esoph carcinomas (transitional cell carcinomas), tumors in the ageal cancer (e.g., adenocarcinoma of the esophagus, Bar urothelial cells that line the bladder, squamous cell carcino rett's adenocarinoma), Ewing sarcoma, familiar hypereosi mas, adenocarcinomas, and Small cell cancers; leukemia Such 55 nophilia, gastric cancer (e.g., stomach adenocarcinoma). as acute myeloid leukemia (AML), acute lymphocytic leuke gastrointestinal Stromal tumor (GIST), head and neck cancer mia, chronic lymphocytic leukemia, chronic myeloid leuke (e.g., head and neck squamous cell carcinoma, oral cancer mia, hairy cell leukemia, myelodysplasia, myeloproliferative (e.g., oral squamous cell carcinoma (OSCC)), heavy chain disorders, acute myelogenous leukemia (AML), chronic disease (e.g., alpha chain disease, gamma chain disease, mu myelogenous leukemia (CML), mastocytosis, chronic lym 60 chain disease), hemangioblastoma, inflammatory myofibro phocytic leukemia (CLL), multiple myeloma (MM), and blastic tumors, immunocytic amyloidosis, kidney cancer myelodysplastic syndrome (MDS); bone cancer, lung cancer (e.g., nephroblastoma a.k.a. Wilms tumor, renal cell carci such as non-small cell lung cancer (NSCLC), which is noma), liver cancer (e.g., hepatocellular cancer (HCC), divided into squamous cell carcinomas, adenocarcinomas, malignant hepatoma), lung cancer (e.g., bronchogenic carci and large cell undifferentiated carcinomas, and Small cell 65 noma, Small cell lung cancer (SCLC), non-small cell lung lung cancer, skin cancer Such as basal cell carcinoma, mela cancer (NSCLC), adenocarcinoma of the lung), leukemia noma, squamous cell carcinoma and actinic keratosis, which (e.g., acute lymphocytic leukemia (ALL), which includes US 8,901,133 B2 135 136 B-lineage ALL and T-lineage ALL, chronic lymphocytic leu mune hepatitis, coeliac disease, crohn's disease, diabetes kemia (CLL), prolymphocytic leukemia (PLL), hairy cell mellitus (type 1), goodpasture's syndrome, graves' disease, leukemia (HLL) and Waldenstrom's macroglobulinemia guillain-barré syndrome (GBS), hashimoto's disease, inflam (WM); peripheral T cell lymphomas (PTCL), adult T cell matory bowel disease, lupus erythematosus, myasthenia leukemia/lymphoma (ATL), cutaneous T-cell lymphoma 5 gravis, opSoclonus myoclonus syndrome (OMS), optic neu (CTCL), large granular lymphocytic leukemia (LGF), ritis, ords thyroiditis, ostheoarthritis, uveoretinitis, pemphi Hodgkin’s disease and Reed-Stemberg disease; acute myelo gus, polyarthritis, primary biliary cirrhosis, reiter's Syn cytic leukemia (AML), chronic myelocytic leukemia (CML), drome, takayasu's arteritis, temporal arteritis, warm chronic lymphocytic leukemia (CLL)), lymphoma (e.g., autoimmune hemolytic anemia, wegener's granulomatosis, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), 10 alopecia universalis, chagas disease, chronic fatigue Syn follicular lymphoma, diffuse large B-cell lymphoma (DL drome, dysautonomia, endometriosis, hidradenitis Suppura BCL), mantle cell lymphoma (MCL)), leiomyosarcoma tiva, interstitial cystitis, neuromyotonia, sarcoidosis, Sclero (LMS), mastocytosis (e.g., systemic mastocytosis), multiple derma, ulcerative colitis, vitiligo, Vulvodynia, appendicitis, myeloma (MM), myelodysplastic syndrome (MDS), arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervi mesothelioma, myeloproliferative disorder (MPD) (e.g., 15 citis, cholangitis, cholecystitis, chorioamnionitis, colitis, polycythemia Vera (PV), essential thrombocytosis (ET), conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis endocarditis, endometritis, enteritis, enterocolitis, epi (MF), chronic idiopathic myelofibrosis, chronic myelocytic condylitis, epididymitis, fasciitis, fibrositis, gastritis, gastro leukemia (CML), chronic neutrophilic leukemia (CNL), enteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, lar hypereosinophilic syndrome (HES)), neuroblastoma, neu- 20 yngitis, mastitis, meningitis, myelitis, myocarditis, myositis, rofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pan Schwannomatosis), neuroendocrine cancer (e.g., gastroen creatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleu teropancreatic neuroendoctrine tumor (GEP-NET), carcinoid ritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelone tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarci phritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, noma, ovarian embryonal carcinoma, ovarian adenocarci- 25 tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or Vulvitis. noma), Paget’s disease of the Vulva, Paget’s disease of the Further, the compounds disclosed herein can be used for penis, papillary adenocarcinoma, pancreatic cancer (e.g., the treatment of Perennial allergic rhinitis, Mesenteritis, Peri pancreatic andenocarcinoma, intraductal papillary mucinous tonitis, Acrodermatitis, Angiodermatitis, Atopic dermatitis, neoplasm (IPMN)), pinealoma, primitive neuroectodermal Contact dermatitis, Eczema, Erythema multiforme, Inter tumor (PNT), prostate cancer (e.g., prostate adenocarci- 30 trigo, Stevens Johnson syndrome, Toxic epidermal necroly noma), rhabdomyosarcoma, retinoblastoma, salivary gland sis, Skin allergy, Severe allergic reaction/anaphylaxis, Aller cancer, skin cancer (e.g., squamous cell carcinoma (SCC), gic granulomatosis, Wegener granulomatosis, Allergic keratoacanthoma (KA), melanoma, basal cell carcinoma conjunctivitis, Chorioretinitis, Conjunctivitis, Infectious (BCC)). Small bowel cancer (e.g., appendix cancer), Soft tis keratoconjunctivitis, Keratoconjunctivitis, Ophthalmia neo Sue Sarcoma (e.g., malignant fibrous histiocytoma (MFH), 35 natorum, Trachoma, Uveitis, Ocular inflammation, Ble liposarcoma, malignant peripheral nerve sheath tumor (MP pharoconjunctivitis, Mastitis, Gingivitis, Pericoronitis, Phar NST), chondrosarcoma, fibrosarcoma, myxosarcoma), Seba yngitis, Rhinopharyngitis, Sialadenitis, Musculoskeletal ceous gland carcinoma, Sweat gland carcinoma, Synovioma, system inflammation, Adult onset Stills disease, Behcets dis testicular cancer (e.g., seminoma, testicular embryonal car ease, Bursitis, Chondrocalcinosis, Dactylitis, Felty syn cinoma), thyroid cancer (e.g., papillary carcinoma of the thy- 40 drome, Gout, Infectious arthritis, Lyme disease, Inflamma roid, papillary thyroid carcinoma (PTC), medullary thyroid tory osteoarthritis, Periarthritis, Reiter syndrome, Ross River cancer), and Waldenström's macroglobulinemia. virus infection, Acute Respiratory, Distress Syndrome, Acute In some embodiments, the disclosure relates to a method of bronchitis, Acute sinusitis, Allergic rhinitis, Asthma, Severe treating diabetes in a Subject that comprises administering to refractory asthma, Pharyngitis, Pleurisy, Rhinopharyngitis, said subject atherapeutically effective amount of a compound 45 Seasonal allergic rhinitis, Sinusitis, Status asthmaticus, Tra disclosed herein, or a pharmaceutically acceptable form (e.g., cheobronchitis, Rhinitis, Serositis, Meningitis, Neuromyeli pharmaceutically acceptable salts, hydrates, Solvates, iso tis optica, Poliovirus infection, Alport syndrome, Balanitis, mers, prodrugs, and isotopically labeled derivatives) thereof. Epididymitis, Epididymo orchitis, Focal segmental, Glom In addition, the compounds described herein can be used to erulosclerosis, Glomerulonephritis, IgA Nephropathy (Berg treat acne. 50 er's Disease), Orchitis, Parametritis, Pelvic inflammatory In addition, the compounds described herein can be used disease, Prostatitis, Pyelitis, Pyelocystitis, Pyelonephritis, for the treatment of arteriosclerosis, including atherosclero Wegener granulomatosis, Hyperuricemia, Aortitis, Arteritis, sis. Arteriosclerosis is a general term describing any harden Chylopericarditis, Dressler syndrome, Endarteritis, ing of medium or large arteries. Atherosclerosis is a harden Endocarditis, Extracranial temporal arteritis, HIV associated ing of an artery specifically due to an atheromatous plaque. 55 arteritis, Intracranial temporal arteritis, Kawasaki disease, Further the compounds described herein can be used for Lymphangiophlebitis, Mondor disease, Periarteritis, or Peri the treatment of glomerulonephritis. Glomerulonephritis is a carditis. primary or secondary autoimmune renal disease character In other aspects, the compounds disclosed herein are used ized by inflammation of the glomeruli. It can be asymptom for the treatment of Autoimmune hepatitis, Jeunitis, Mesen atic, or present with hematuria and/or proteinuria. There are 60 teritis, Mucositis, Non alcoholic steatohepatitis, Non viral many recognized types, divided in acute, Subacute or chronic hepatitis, Autoimmune pancreatitis, Perihepatitis, Peritonitis, glomerulonephritis. Causes are infectious (bacterial, viral or Pouchitis, Proctitis, Pseudomembranous colitis, Rectosig parasitic pathogens), autoimmune or paraneoplastic. moiditis, Salpingoperitonitis, Sigmoiditis, Steatohepatitis, Additionally, the compounds described herein can be used Ulcerative colitis, Churg Strauss syndrome, Ulcerative proc for the treatment of bursitis, lupus, acute disseminated 65 titis, Irritable bowel syndrome, Gastrointestinal inflamma encephalomyelitis (ADEM), addison's disease, antiphospho tion, Acute enterocolitis, Anusitis, Balser necrosis, Cholecys lipid antibody syndrome (APS), aplastic anemia, autoim titis, Colitis, Crohns disease, Diverticulitis, Enteritis, US 8,901,133 B2 137 138 Enterocolitis, Enterohepatitis, Eosinophilic esophagitis, activity by contacting a PI3 kinase with an amount of a Esophagitis, Gastritis, Hemorrhagic enteritis, Hepatitis, compound as disclosed herein coefficient to inhibit the activ Hepatitis virus infection, Hepatocholangitis, Hypertrophic ity of the PI3 kinase. In some embodiments, provided herein gastritis, Ileitis, Ileocecitis, Sarcoidosis, Inflammatory bowel are methods of inhibiting PI3 kinase activity. Such inhibition disease, Ankylosing spondylitis, Rheumatoid arthritis, Juve can take place in Solution, in a cell expressing one or more PI3 nile rheumatoid arthritis, Psoriasis, Psoriatic arthritis, Lupus kinases, in a tissue comprising a cell expressing one or more (cutaneous/systemic/nephritis), AIDS, Agammaglobuline PI3 kinases, or in an organism expressing one or more PI3 mia, AIDS related complex, Bretons disease, Chediak kinases. In some embodiments, provided herein are methods Higashi syndrome, Common variable immunodeficiency, of inhibiting PI3 kinase activity in a Subject (including mam DiGeorge syndrome, Dysgammaglobulinemia, Immunoglo 10 mals such as humans) by contacting said Subject with an bulindeficiency, Job syndrome, Nezelof syndrome, Phago amount of a compound as disclosed herein Sufficient to inhibit cyte bactericidal disorder, Wiskott Aldrich syndrome, Asple the activity of the PI3 kinase in said subject. nia, Elephantiasis, Hypersplenism, Kawasaki disease, 5. Combination Therapy Lymphadenopathy, Lymphedema, Lymphocele, Norme Mil In some embodiments, provided herein are methods for roy Meige syndrome, Spleen disease, Splenomegaly, Thy 15 combination therapies in which an agent known to modulate moma, Thymus disease, Perivasculitis, Phlebitis, Pleuroperi other pathways, or other components of the same pathway, or carditis, Polyarteritis nodosa, Vasculitis, Takayasus arteritis, even overlapping sets of target enzymes are used in combi Temporal arteritis, Thromboangiitis, Thromboangiitis oblit nation with a compound as disclosed herein, or a pharmaceu erans, Thromboendocarditis, Thrombophlebitis, or COPD. tically acceptable salt, ester, prodrug or derivative thereof. In In some embodiments, provided herein is a method of one aspect, Such therapy includes but is not limited to the treating a cardiovascular disease in a Subject that comprises combination of the Subject compound with chemotherapeutic administering to said subject a therapeutically effective agents, therapeutic antibodies, and radiation treatment, to amount of a compound as disclosed herein, or a pharmaceu provide a synergistic or additive therapeutic effect. tically acceptable form (e.g., pharmaceutically acceptable In one aspect, the compounds or pharmaceutical composi salts, hydrates, Solvates, isomers, prodrugs, and isotopically 25 tions as disclosed herein can present synergistic or additive labeled derivatives) thereof. Examples of cardiovascular con efficacy when administered in combination with agents that ditions include, but are not limited to, atherosclerosis, rest inhibit IgE production or activity. Such combination can enosis, vascular occlusion and carotid obstructive disease. reduce the undesired effect of high level of IgE associated In another aspect, provided herein are methods of disrupt with the use of one or more PI3Kö inhibitors, if such effect ing the function of a leukocyte or disrupting a function of an 30 occurs. This can be particularly useful in treatment of autoim osteoclast. The method includes contacting the leukocyte or mune and inflammatory disorders (AIID) Such as rheumatoid the osteoclast with a function disrupting amount of a com arthritis. Additionally, the administration of PI3Kö or PI3Ky pound as described herein. inhibitors as disclosed herein in combination with inhibitors In another aspect, methods are provided for treating oph of mTOR can also exhibit synergy through enhanced inhibi thalmic disease by administering one or more of the Subject 35 tion of the PI3K pathway. compounds or pharmaceutical compositions to the eye of a In a separate but related aspect, provided herein is a com Subject. bination treatment of a disease associated with PI3Kö com In some embodiments, provided herein are methods of prising administering to a PI3Kö inhibitor and an agent that modulating a PI3K and/or mTorkinase activity by contacting inhibits IgE production or activity. Other exemplary PI3Kö the kinase with an amount of an effective amount of com 40 inhibitors are applicable and they are described, e.g., U.S. Pat. pound as disclosed herein. Modulate can be inhibiting or No. 6,800,620. Such combination treatment is particularly activating kinase activity. In some embodiments, provided useful for treating autoimmune and inflammatory diseases herein are methods of inhibiting kinase activity by contacting (AIID) including but not limited to rheumatoid arthritis. the kinase with an amount of an effective amount of a com Agents that inhibit IgE production are known in the art and pound disclosed herein in Solution. In some embodiments, 45 they include but are not limited to one or more of TEI-9874, provided herein are methods of inhibiting the kinase activity 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)ben by contacting a cell, tissue, organ that express the kinase of Zoic acid, rapamycin, rapamycin analogs (i.e. rapalogs). interest. In some embodiments, provided herein are methods TORC1 inhibitors, TORC2 inhibitors, and any other com of inhibiting kinase activity in a Subject (e.g., a human) by pounds that inhibit mTORC1 and mTORC2. Agents that administering into the Subject an effective amount of a com 50 inhibit IgE activity include, for example, anti-IgE antibodies pound as disclosed herein. In some embodiments, the per such as for example Omalizumab and TNX-901. centage of inhibiting exceeds 50%, 60%, 70%, 80%, or 90%. For treatment of autoimmune diseases, the Subject com In some embodiments, the kinase is a lipid kinase or a pounds or pharmaceutical compositions can be used in com protein kinase. In some embodiments, the kinase is selected bination with commonly prescribed drugs including but not from a PI3 kinase including different isorforms such as PI3 55 limited to Enbrel R., RemicadeR), Humira R, AvoneXOR, and kinase C. PI3 kinase B, PI3 kinasey, PI3 kinase 8: DNA-PK: RebifR). For treatment of respiratory diseases, the subject mTor; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK compounds or pharmaceutical compositions can be adminis receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase tered in combination with commonly prescribed drugs 3 (FLT-3); Platelet derived growth factor receptor (PDGFR): including but not limited to Xolair R, Advair R, Singulair R, RET; ATM; ATR; hSmg-1; Hok: Src.: Epidermal growth fac 60 and SpirivaR). tor receptor (EGFR); KIT: Inulsin Receptor (1R) and IGFR. The compounds as disclosed herein can be formulated or In some embodiments, disclosed herein are methods of administered in conjunction with other agents that act to modulating PI3 kinase activity by contacting a PI3 kinase relieve the symptoms of inflammatory conditions such as with an amount of a compound as disclosed herein Sufficient encephalomyelitis, asthma, and the other diseases described to modulate the activity of the PI3 kinase. Modulate can be 65 herein. These agents include non-steroidal anti-inflammatory inhibiting or activating PI3 kinase activity. In some embodi drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen; ments, provided herein are methods of inhibiting PI3 kinase naproxen; indomethacin: nabumetone; tolmetin, etc. Corti US 8,901,133 B2 139 140 costeroids are used to reduce inflammation and Suppress tone; anti-adrenals such as aminoglutethimide, mitotane, activity of the immune system. A commonly prescribed drug triloStane; folic acid replenisher such as frolinic acid; acegla of this type is Prednisone. Chloroquine (Aralen) or hydroxy tone; aldophosphamide glycoside; aminolevulinic acid; chloroquine (Plaquenil) can also be very useful in some indi amsacrine; bestrabucil; bisantrene; ediatraxate; defofamine; viduals with lupus. They can be prescribed for skin and joint demecolcine; diaziquone; elfomithine; elliptinium acetate; symptoms of lupus. AZathioprine (Imuran) and cyclophos etoglucid, gallium nitrate; hydroxyurea; lentinan; phamide (Cytoxan) Suppress inflammation and tend to Sup lonidamine; mitoguaZone; mitoxantrone; mopidamol; nitra press the immune system. Other agents, e.g. methotrexate and crine; pentostatin: phenamet, pirarubicin; podophyllinic cyclosporin are used to control the symptoms of lupus. Anti acid; 2-ethylhydrazide; procarbazine: PSKR); razoxane: sizo coagulants are employed to prevent blood from clotting rap 10 furan; spirogermanium; tenuaZonic acid; triaziquone; 2.2.2"- idly. They range from aspirin at very low dose which prevents trichlorotriethyla-mine; urethan; vindesine; dacarbazine; platelets from Sticking, to heparin/coumadin. Other com mannomustine, mitobronitol; mitolactol; pipobroman, gacy pounds used in the treatment of lupus include belimumab tosine; arabinoside ("Ara-C); cyclophosphamide; thiotepa; (BenlystaR). taxanes, e.g., paclitaxel (TAXOLTM, Bristol-Myers Squibb In another aspect, provided herein are pharmaceutical 15 Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, compositions for inhibiting abnormal cell growth in a subject Rhone-Poulenc Rorer, Antony, France) and ABRAXANER) which comprises an amount of a compound as disclosed (paclitaxel protein-bound particles); retinoic acid; esperam herein, or a pharmaceutically acceptable form (e.g., pharma icins; capecitabine; and pharmaceutically acceptable forms, ceutically acceptable salts, hydrates, Solvates, isomers, pro salts, acids orderivatives of any of the above. Also included as drugs, and isotopically labeled derivatives) thereof, in com Suitable chemotherapeutic cell conditioners are anti-hor bination with an amount of an anti-cancer agent (e.g. a monal agents that act to regulate or inhibit hormone action on biotherapeutic chemotherapeutic agent). Many chemothera tumors such as anti-estrogens including for example tamox peutics are presently known in the art and can be used in ifen (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imi combination with the compounds described herein. Other dazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY cancer therapies can also be used in combination with the 25 117018, onapristone, and toremifene (Fareston); and anti compounds described herein and include, but are not limited androgens such as flutamide, nilutamide, bicalutamide, leu to, Surgery and Surgical treatments, and radiation therapy. prolide, and goserelin; chlorambucil; gemcitabine; In some embodiments, the chemotherapeutic is selected 6-thioguanine; mercaptopurine; methotrexate; platinum ana from mitotic inhibitors, alkylating agents, anti-metabolites, logs such as cisplatin and carboplatin: vinblastine; platinum; intercalating antibiotics, growth factor inhibitors, cell cycle 30 etoposide (VP-16); ifosfamide: mitomycin C; mitoxantrone: inhibitors, enzymes, topoisomerase inhibitors, biological Vincristine; Vinorelbine; navelbine; novantrone; teniposide; response modifiers, anti-hormones, angiogenesis inhibitors, daunomycin; aminopterin: Xeloda; ibandronate; camptoth and anti-androgens. Non-limiting examples are chemothera ecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluo peutic agents, cytotoxic agents, and non-peptide Small mol romethylornithine (DMFO). Where desired, the compounds ecules such as Gleevec R (Imatinib Mesylate), Velcade(R) 35 or pharmaceutical composition as disclosed herein can be (bortezomib), Casodex (bicalutamide), Iressa R, and Adria used in combination with commonly prescribed anti-cancer mycin as well as a host of chemotherapeutic agents. Non drugs such as HerceptinR), Avastin R, Erbitux(R), Rituxan.R., limiting examples of chemotherapeutic agents include alky Taxol R, Arimidex(R, TaxotereR, ABVD, AVICINE, Abago lating agents such as thiotepa and cyclosphosphamide vomab, Acridine carboxamide, Adecatumumab, 17-N-Ally (CYTOXANTM); alkylsulfonates such as busulfan, improsul 40 lamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, fan and piposulfan; aziridines such as benzodopa, carbo 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, quone, meturedopa, and uredopa; ethylenimines and methy Amonafide, Anthracenedione, Anti-CD22 immunotoxins, lamelamines including altretamine, triethylenemelamine, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atipri trietylenephosphoramide, triethylenethiophosphaoramide mod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, and trimethylolomelamine; nitrogen mustards such as 45 Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, chlorambucil, chlornaphazine, cholophosphamide, estra CBV (chemotherapy), Calyculin, cell-cycle nonspecific anti mustine, ifosfamide, mechlorethamine, mechlorethamine neoplastic agents, Dichloroacetic acid, Discodermolide, oxide hydrochloride, melphalan, novembichin, phenesterine, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, prednimustine, trofosfamide, uracil mustard; nitroSureas Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE Such as carmustine, chlorozotocin, fotemustine, lomustine, 50 chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolo nimustine, ranimustine; antibiotics such as aclacinomysins, carbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, actinomycin, authramycin, azaserine, bleomycins, cactino Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, mycin, calicheamicin, carabicin, caminomycin, carZinophi Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Paw lin, CasodexTM, chromomycins, dactinomycin, daunorubicin, paw, Pixantrone, Proteasome inhibitor, Rebeccamycin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epi 55 Residuimod, Rubitecan, SN-38, Salinosporamide A, Sapac rubicin, esorubicin, idarubicin, marcellomycin, mitomycins, itabine, Stanford V. Swainsonine, Talaporfin, Tariquidar, mycophenolic acid, nogalamycin, olivomycins, peplomycin, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris potfiromycin, puromycin, quelamycin, rodorubicin, Strep (2-chloroethyl)amine, Troxacitabine, Uramustine, Vadime tonigrin, Streptozocin, tubercidin, ubenimex, Zinostatin, Zan, Vinflunine, ZD6126, and Zosuduidar. Zorubicin; anti-metabolites such as methotrexate and 5-fluo 60 In some embodiments, the chemotherapeutic is selected rouracil (5-FU); folic acid analogues such as denopterin, from hedgehog inhibitors including, but not limited to IPI methotrexate, pteropterin, trimetrexate; purine analogs such 926 (See U.S. Pat. No. 7,812,164). Other suitable hedgehog as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; inhibitors include, for example, those described and disclosed pyrimidine analogs such as ancitabine, azacitidine, 6-azauri in U.S. Pat. No. 7,230,004, U.S. Patent Application Publica dine, carmofur, cytarabine, dideoxyuridine, doxifluridine, 65 tion No. 2008/0293754, U.S. Patent Application Publication enocitabine, floXuridine, androgens Such as calusterone, dro No. 2008/0287.420, and U.S. Patent Application Publication mostanolone propionate, epitiostanol, mepitioStane, testolac No. 2008/0293755, the entire disclosures of which are incor US 8,901,133 B2 141 142 porated by reference herein. Examples of other suitable dine, ratitrexed, tegafur-uracil, capecitabine), cytosine ana hedgehog inhibitors include those described in U.S. Patent logs (e.g. cytarabine (ara C), cytosine arabinoside, and flu Application Publication Nos. US 2002/0006931, US 2007/ darabine), purine analogs (e.g. mercaptopurine and 0021493 and US 2007/0060546, and International Applica Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, tion Publication Nos. WO 2001/19800, WO 2001/26644, WO and KH 1060), isoprenylation inhibitors (e.g. lovastatin), 2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/ dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyri 011219, WO 2003/088970, WO 2004/020599, WO 2005/ dinium ion), cell cycle inhibitors (e.g. staurosporine), actino 0.13800, WO 2005/033288, WO 2005/032343, WO 2005/ mycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. 042700, WO 2006/028958, WO 2006/050351, WO 2006/ bleomycin A2, bleomycin B2, peplomycin), anthracycline 078283, WO 2007/054623, WO 2007/059157, WO 2007/ 10 120827, WO 2007/131201, WO 2008/070357, WO 2008/ (e.g. daunorubicin, doxorubicin, pegylated liposomal doxo 110611, WO 2008/112913, and WO 2008/131354. rubicin, idarubicin, epirubicin, pirarubicin, Zorubicin, mitox Additional examples of hedgehog inhibitors include, but are antrone), MDR inhibitors (e.g. Verapamil), Ca2+ ATPase not limited to, GDC-0449 (also known as RG3616 or vismo inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenali degib) described in, e.g., Von Hoff D. et al., N. Engl. J. Med. 15 domide, tyrosine kinase inhibitors (e.g., axitinib 2009: 361 (12): 1164-72; Robarge K. D. et al., Bioorg Med (AG013736), bosutinib (SKI-606), cediranib (RECEN Chem Lett. 2009; 19(19):5576-81; Yauch, R. L. et al. (2009) TINTM, AZD2171), dasatinib (SPRYCELR, BMS-354825), Science 326:572-574: Sciencexpress: 1-3 (10.1126/science. erlotinib (TARCEVAR), gefitinib (IRESSAR), imatinib 11793.86); Rudin, C. etal. (2009) New England Jof Medicine (Gleevec(R), CGP57148B, STI-571), lapatinib (TYKERB(R), 361-366 (10.1056/nema0902903); BMS-833923 (also TY VERB(R), lestaurtinib (CEP-701), neratinib (HKI-272), known as XL 139) described in, e.g., in Siu L. et al., J. Clin. nilotinib (TASIGNAR), semaxanib (semaxinib, SU5416), Oncol. 2010; 28:15s (suppl; abstr 2501); and National Insti sunitinib (SUTENTR), SU11248), toceranib (PALLADIAR), tute of Health Clinical Trial Identifier No. NCT006701891; vandetanib (ZACTIMAR, ZD6474), Vatalanib (PTK787, LDE-225 described, e.g., in Pan S. et al., ACS Med. Chem. PTK/ZK), trastuzumab (HERCEPTINR), bevacizumab Lett., 2010; 1(3): 130-134; LEQ-506 described, e.g., in 25 (AVASTINR), rituximab (RITUXANR), cetuximab (ER National Institute of Health Clinical Trial Identifier No. BITUX(R), panitumumab (VECTIBIX(R), ranibizumab (Lu NCT01106508; PF-04449913 described, e.g., in National centis(R), nilotinib (TASIGNAR), Sorafenib (NEXAVARR), Institute of Health Clinical Trial Identifier No. everolimus (AFINITORR), alemtuzumab (CAMPATHR), NCT00953758; Hedgehog pathway antagonists disclosed in gemtuzumab ozogamicin (MYLOTARG(R), temsirolimus U.S. Patent Application Publication No. 2010/0286114; 30 (TORISEL(R), ENMD-2076, PCI-32765, AC220, dovitinib SMOi2-17 described, e.g., U.S. Patent Application Publica lactate (TKI258, CHIR-258), BIBW 2.992 (TOVOKTM), tion No. 2010/0093.625; SANT-1 and SANT-2 described, SGX523, PF-04217903, PF-02341066, PF-299804, BMS e.g., in Rominger C. M. et al., J. Pharmacol. Exp. Ther: 2009: 777607, ABT-869, MP470, BIBF 1120 (VARGATEF(R), 329(3):995-1005: 1-piperazinyl-4-arylphthalazines or ana AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS logues thereof, described in Lucas B. S. et al., Bioorg. Med. 35 690154, CEP-11981, tivozanib (AV-951), OSI-930, Chem. Lett. 2010; 20(12):3618-22. MM-121, XL-184, XL-647, and/or XL228), proteasome Other chemotherapeutic agents include, but are not limited inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), (e.g., rapamycin, temsirolimus (CCI-779), everolimus LHRH agonists (e.g. goScrclin and leuprolide), anti-andro (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (As gens (e.g. flutamide and bicalutamide), photodynamic thera 40 traZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 pies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosen (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 sitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, tro oblimersen, gemcitabine, caminomycin, leucovorin, pemetr fosfamide, chlorambucil, estramustine, and melphalan), exed, cyclophosphamide, dacarbazine, procarbizine, pred nitrosoureas (e.g. carmustine (BCNU) and lomustine 45 nisolone, dexamethasone, campathecin, plicamycin, aspara (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), ginase, aminopterin, methopterin, porfiromycin, melphalan, triaZenes (e.g. dacarbazine, temozolomide), platinum con leurosidine, leurosine, chlorambucil, trabectedin, procarba taining compounds (e.g. cisplatin, carboplatin, oxaliplatin), Zine, discodermolide, caminomycin, aminopterin, and hex Vinca alkaloids (e.g. Vincristine, vinblastine, Vindesine, and amethyl melamine. Vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent 50 Exemplary biotherapeutic agents include, but are not lim Such as nanoparticle albumin-bound paclitaxel (Abraxane), ited to, interferons, cytokines (e.g., tumor necrosis factor, docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, interferon C, interferon Y), vaccines, hematopoietic growth Taxoprexin), polyglutamate bound-paclitaxel (PG-pacli factors, monoclonal serotherapy, immunostimulants and/or taxel, paclitaxel poliglumex, CT-2103, XYOTAX), the immunodulatory agents (e.g., IL-1,2,4,6, or 12), immune cell tumor-activated prodrug (TAP) ANG 1005 (Angiopep-2 55 growth factors (e.g., GM-CSF) and antibodies (e.g. Herceptin bound to three molecules of paclitaxel), paclitaxel-EC-1 (pa (trastuzumab), T-DM1, AVASTIN (bevacizumab), clitaxel bound to the erbB2-recognizing peptide EC-1), and ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl (rituximab), Bexxar (to situmomab)). 2-glucopyranosyl Succinate; docetaxel, taxol), epipodophyl In some embodiments, the chemotherapeutic is selected lins (e.g. etoposide, etoposide phosphate, teniposide, topote 60 from HSP90 inhibitors. The HSP90 inhibitor can be a can, 9-aminocamptothecin, camptoirinotecan, irinotecan, geldanamycin derivative, e.g., a benzoquinone or hygro crisinatol, mytomycin C), anti-metabolites, DHFR inhibitors quinone ansamycin HSP90 inhibitor (e.g., IPI-493 and/or (e.g. methotrexate, dichloromethotrexate, trimetrexate, ediatr IPI-504). Non-limiting examples of HSP90 inhibitors include exate), IMP dehydrogenase inhibitors (e.g. mycophenolic IPI-493, IPI-504, 17-AAG (also known as tanespimycin or acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reduc 65 CNF-1010), BIIB-021 (CNF-2024), BIIB-028, AUY-922 tase inhibitors (e.g. hydroxyurea and deferoxamine), uracil (also known as VER-49009), SNX-5422, STA-9090, analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluri AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG, CNF US 8,901,133 B2 143 144 1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT acceptable form in this method can be determined according 018159, CCT-129397, PU-H71, or PF-04928473 (SNX to the means for ascertaining effective amounts of Such com 2112). pounds described herein. In some embodiments, the chemotherapeutic is selected The compounds or pharmaceutical compositions as dis from PI3K inhibitors (e.g., including those PI3K inhibitors 5 closed herein can be used in combination with an amount of disclosed herein and those PI3K inhibitors not disclosed one or more Substances selected from anti-angiogenesis herein). In some embodiment, the PI3K inhibitor is an inhibi agents, signal transduction inhibitors, and antiproliferative tor of delta and gamma isoforms of PI3K. In some embodi agents, glycolysis inhibitors, or autophagy inhibitors. ments, the PI3K inhibitor is an inhibitor of alpha isoforms of Anti-angiogenesis agents, such as MMP-2 (matrix-metal PI3K. In other embodiments, the PI3K inhibitor is an inhibi 10 loproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase tor of one or more alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can be used in combi 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, nation are described in, WO 09/088,990, WO 09/088,086, can be used in conjunction with a compound as disclosed WO 2011/008302, WO 2010/036380, WO 2010/006086, herein and pharmaceutical compositions described herein. WO 09/114,870, WO 05/113556; US 2009/0312310, and US 15 Anti-angiogenesis agents include, for example, rapamycin, 2011/0046165. Additional PI3K inhibitors that can be used in temsirolimus (CCI-779), everolimus (RAD001), Sorafenib, combination with the pharmaceutical compositions, include Sunitinib, and bevacizumab. Examples of useful COX-II but are not limited to, GSK2126458, GDC-0980, GDC-0941, inhibitors include CELEBREXTM (alecoxib), Valdecoxib, Sanofi XL 147, XL756, XL 147, PF-469 15032, BKM 120, and rofecoxib. Examples of useful matrix metalloproteinase CAL-101, CAL 263, SF1126, PX-886, and a dual PI3K inhibitors are described in WO 96/33172 (published Oct. 24, inhibitor (e.g., Novartis BEZ235). In one embodiment, the 1996), WO 96/27583 (published Mar. 7, 1996), European PI3K inhibitor is an isoquinolinone. Patent Application No. 97304971.1 (filed Jul. 8, 1997), Euro In some embodiments, provided herein is a method for pean Patent Application No. 99308617.2 (filed Oct. 29, using the compounds orpharmaceutical composition in com 1999), WO 98/07697 (published Feb. 26, 1998), WO bination with radiation therapy in inhibiting abnormal cell 25 98/03516 (published Jan. 29, 1998), WO 98/34918 (pub growth or treating the hyperproliferative disorder in the sub lished Aug. 13, 1998), WO 98/34915 (published Aug. 13, ject. Techniques for administering radiation therapy are 1998), WO 98/33768 (published Aug. 6, 1998), WO known in the art, and these techniques can be used in the 98/30566 (published Jul. 16, 1998), European Patent Publi combination therapy described herein. The administration of cation 606,046 (published Jul. 13, 1994), European Patent the compound as disclosed herein in this combination therapy 30 Publication 931,788 (publishedJul. 28, 1999), WO 90/05719 can be determined as described herein. (published Can 31, 1990), WO 99/52910 (published Oct. 21, Radiation therapy can be administered through one of sev 1999), WO 99/52889 (published Oct. 21, 1999), WO eral methods, or a combination of methods, including without 99/29667 (published Jun. 17, 1999), PCT International limitation external-beam therapy, internal radiation therapy, Application No. PCT/IB98/011 13 (filed Jul. 21, 1998), Euro implant radiation, Stereotactic radioSurgery, systemic radia 35 pean Patent Application No. 99302232.1 (filed Mar. 25, tion therapy, radiotherapy and permanent or temporary inter 1999), Great Britain Patent Application No. 9912961.1 (filed stitial brachytherapy. The term “brachytherapy,” as used Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 herein, refers to radiation therapy delivered by a spatially (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, confined radioactive material inserted into the body at or near 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and a tumor or other proliferative tissue disease site. The term is 40 European Patent Publication 780,386 (published Jun. 25, intended without limitation to include exposure to radioactive 1997), all of which are incorporated herein in their entireties isotopes (e.g. At-211, I-131, I-125, Y-90, Re-186, Re-188, by reference. In some embodiments, MMP-2 and MMP-9 Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suit inhibitors are those that have little or no activity inhibiting able radiation sources for use as a cell conditioner include MMP-1. In other embodiments, are those that selectively both Solids and liquids. By way of non-limiting example, the 45 inhibit MMP-2 and/or AMP-9 relative to the other matrix radiation Source can be a radionuclide, Such as I-125, I-131, metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, other radionuclides that emit photons, beta particles, gamma and MMP-13). Some specific examples of MMP inhibitors radiation, or other therapeutic rays. The radioactive material are AG-3340, RO32-3555, and RS 13-0830. can also be a fluid made from any Solution of radionuclide(s), 50 Autophagy inhibitors include, but are not limited to, chlo e.g., a solution of I-125 or I-131, or a radioactive fluid can be roquine, 3-methyladenine, hydroxychloroquine (Plaque produced using a slurry of a suitable fluid containing Small nil TM), bafilomycin A1, 5-amino-4-imidazole carboxamide particles of solid radionuclides, such as Au-198, Y-90. More riboside (AICAR), okadaic acid, autophagy-suppressive over, the radionuclide(s) can be embodied in a gel or radio algal toxins which inhibit protein phosphatases of type 2A or active micro spheres. 55 type 1, analogues of cAMP, and drugs which elevate cAMP Without being limited by any theory, the compounds as levels such as adenosine, LY204002, N-mercaptopurine disclosed herein can render abnormal cells more sensitive to riboside, and vinblastine. In addition, antisense or siRNA that treatment with radiation for purposes of killing and/or inhib inhibits expression of proteins including but not limited to iting the growth of such cells. Accordingly, provided herein is ATG5 (which are implicated in autophagy), can also be used. a method for sensitizing abnormal cells in a subject to treat 60 In some embodiments, disclosed herein is a method of ment with radiation which comprises administering to the and/or a pharmaceutical composition for treating a cardiovas Subject an amount of a compound as disclosed herein or cular disease in a Subject which comprises an amount of a pharmaceutically acceptable forms (e.g., pharmaceutically compound as disclosed herein, or a pharmaceutically accept acceptable salts, hydrates, Solvates, isomers, prodrugs, and able forms (e.g., pharmaceutically acceptable salts, hydrates, isotopically labeled derivatives) thereof, which amount is 65 Solvates, isomers, prodrugs, and isotopically labeled deriva effective is sensitizing abnormal cells to treatment with radia tives) thereof, and an amount of one or more therapeutic tion. The amount of the compound or pharmaceutically agents use for the treatment of cardiovascular diseases. US 8,901,133 B2 145 146 Exemplary agents for use in cardiovascular disease appli echolamines, sympathomimetic drugs, and adrenergic recep cations are anti-thrombotic agents, e.g., prostacyclin and sali toragonists or antagonists; and 5-hydroxytryptamine (5-HT, cylates, thrombolytic agents, e.g., Streptokinase, urokinase, serotonin) receptor agonists and antagonists. tissue plasminogen activator (TPA) and anisoylated plasmi Therapeutic agents can also include agents for pain and nogen-streptokinase activator complex (APSAC), anti-plate inflammation such as histamine and histamine antagonists, lets agents, e.g., acetyl-Salicylic acid (ASA) and clopidrogel, bradykinin and bradykininantagonists, 5-hydroxytryptamine vasodilating agents, e.g., nitrates, calcium channel blocking (serotonin), lipid Substances that are generated by biotrans drugs, anti-proliferative agents, e.g., colchicine and alkylat formation of the products of the selective hydrolysis of mem ing agents, intercalating agents, growth modulating factors brane phospholipids, eicosanoids, prostaglandins, thrombox Such as interleukins, transformation growth factor-beta and 10 anes, leukotrienes, aspirin, nonsteroidal anti-inflammatory congeners of platelet derived growth factor, monoclonal anti agents, analgesic-antipyretic agents, agents that inhibit the bodies directed against growth factors, anti-inflammatory synthesis of prostaglandins and thromboxanes, selective agents, both steroidal and non-steroidal, and other agents that inhibitors of the inducible cyclooxygenase, selective inhibi can modulate vessel tone, function, arteriosclerosis, and the tors of the inducible cyclooxygenase-2, autacoids, paracrine healing response to vessel or organ injury post intervention. 15 hormones, Somatostatin, gastrin, cytokines that mediate inter Antibiotics can also be included in combinations or coatings. actions involved in humoral and cellular immune responses, Moreover, a coating can be used to effect therapeutic delivery lipid-derived autacoids, eicosanoids, B-adrenergic agonists, focally within the vessel wall. By incorporation of the active ipratropium, glucocorticoids, methylxanthines, sodium agent in a Swellable polymer, the active agent will be released channel blockers, opioid receptor agonists, calcium channel upon Swelling of the polymer. blockers, membrane stabilizers and leukotriene inhibitors. The compounds described herein can be formulated or Additional therapeutic agents contemplated herein include administered in conjunction with liquid or solid tissue barri diuretics, vasopressin, agents affecting the renal conservation ers also known as lubricants. Examples of tissue barriers of water, rennin, angiotensin, agents useful in the treatment of include, but are not limited to, polysaccharides, polyglycans, myocardial ischemia, anti-hypertensive agents, angiotensin seprafilm, interceed and hyaluronic acid. 25 converting enzyme inhibitors, B-adrenergic receptor antago Medicaments which can be administered in conjunction nists, agents for the treatment of hypercholesterolemia, and with the compounds described herein include any suitable agents for the treatment of dyslipidemia. drugs usefully delivered by inhalation for example, analge Other therapeutic agents contemplated include drugs used sics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or for control of gastric acidity, agents for the treatment of peptic morphine; anginal preparations, e.g. diltiazem; antiallergics, 30 ulcers, agents for the treatment of gastroesophageal reflux e.g. cromoglycate, ketotifen or nedocromil, anti-infectives, disease, prokinetic agents, antiemetics, agents used in irri e.g. cephalosporins, penicillins, streptomycin, Sulphona table bowel syndrome, agents used for diarrhea, agents used mides, tetracyclines or pentamidine; antihistamines, e.g. for constipation, agents used for inflammatory bowel disease, methapyrilene; anti-inflammatories, e.g. beclomethasone, agents used for biliary disease, agents used for pancreatic flunisolide, budesonide, tipredane, triamcinolone acetonide 35 disease. Therapeutic agents used to treat protozoan infec or fluticasone; antitussives, e.g. noscapine; bronchodilators, tions, drugs used to treat malaria, amebiasis, giardiasis, tri e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprena chomoniasis, trypanosomiasis, and/or leishmaniasis, and/or line, metaproterenol, phenylephrine, phenylpropanolamine, drugs used in the chemotherapy of helminthiasis. Other thera pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terb peutic agents include antimicrobial agents, Sulfonamides, tri utalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino 40 methoprim-Sulfamethoxazole quinolones, and agents for uri 3,5-dichloro-O-(6-2-(2-pyridinyl)ethoxyhexyl-amino nary tract infections, penicillins, cephalosporins, and other, methylbenzenemethanol: diuretics, e.g. amiloride; B-lactamantibiotics, an agent containing an aminoglycoside, anticholinergics e.g. ipratropium, atropine or oxitropium; protein synthesis inhibitors, drugs used in the chemotherapy hormones, e.g. cortisone, hydrocortisone or prednisolone; of tuberculosis, mycobacterium avium complex disease, and Xanthines e.g. aminophylline, choline theophyllinate, lysine 45 leprosy, antifungal agents, antiviral agents including nonret theophyllinate or theophylline; and therapeutic proteins and roviral agents and antiretroviral agents. peptides, e.g. insulin or glucagon. It will be clear to a person Examples of therapeutic antibodies that can be combined skilled in the art that, where appropriate, the medicaments can with a subject compound include but are not limited to anti be used in the form of salts (e.g. as alkali metal or amine salts receptor tyrosine kinase antibodies (cetuximab, panitu or as acid addition salts) or as esters (e.g. lower alkyl esters) 50 mumab, trastuzumab), anti CD20 antibodies (rituximab, tosi to optimize the activity and/or stability of the medicament. tumomab), and other antibodies Such as alemtuzumab, Other exemplary therapeutic agents useful for a combina bevacizumab, and gemtuzumab. tion therapy include but are not limited to agents as described Moreover, therapeutic agents used for immunomodula above, radiation therapy, hormone antagonists, hormones and tion, such as immunomodulators, immunosuppressive their releasing factors, thyroid and antithyroid drugs, estro 55 agents, tolerogens, and immunostimulants are contemplated gens and progestins, androgens, adrenocorticotropic hor by the methods herein. In addition, therapeutic agents acting mone; adrenocortical steroids and their synthetic analogs; on the blood and the blood-forming organs, hematopoietic inhibitors of the synthesis and actions of adrenocortical hor agents, growth factors, minerals, and vitamins, anticoagulant, mones, insulin, oral hypoglycemic agents, and the pharma thrombolytic, and antiplatelet drugs. cology of the endocrine pancreas, agents affecting calcifica 60 For treating renal carcinoma, one can combinea compound tion and bone turnover: calcium, phosphate, parathyroid as disclosed herein with Sorafenib and/oravastin. For treating hormone, Vitamin D, calcitonin, vitamins such as water an endometrial disorder, one can combine a compound as soluble vitamins, vitamin B complex, ascorbic acid, fat disclosed herein with doxorubincin, taxotere (taxol), and/or soluble vitamins, vitamins A, K, and E. growth factors, cytok cisplatin (carboplatin). For treating ovarian cancer, one can ines, chemokines, muscarinic receptor agonists and 65 combine a compound as disclosed herein with cisplatin (car antagonists; anticholinesterase agents; agents acting at the boplatin), taxotere, doxorubincin, topotecan, and/or tamox neuromuscular junction and/or autonomic ganglia; cat ifen. For treating breast cancer, one can combine a compound US 8,901,133 B2 147 148 as disclosed herein with taxotere (taxol), gemcitabine Unless specified to the contrary, the reactions described (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, herein take place at atmospheric pressure, generally within a PD0325901, avastin, herceptin, OSI-906, and/or OSI-930. temperature range from -10°C. to 200° C. Further, except as For treating lung cancer, one can combine a compound as otherwise specified, reaction times and conditions are disclosed herein with taxotere (taxol), gemcitabine, cisplatin, intended to be approximate, e.g., taking place at about atmo pemetrexed, Tarceva, PD0325901, and/or avastin. spheric pressure within a temperature range of about -10°C. Further therapeutic agents that can be combined with a to about 110° C. over a period of about 1 to about 24 hours: Subject compound can be found in Goodman and Gilman’s reactions left to run overnight average a period of about 16 “The Pharmacological Basis of Therapeutics' Tenth Edition hours. edited by Hardman, Limbird and Gilman or the Physicians The terms “solvent.” “organic solvent,” or “inert solvent' Desk Reference, both of which are incorporated herein by 10 each mean a solventinert under the conditions of the reaction reference in their entirety. being described in conjunction therewith including, for The compounds described herein can be used in combina example, benzene, toluene, acetonitrile, tetrahydrofuran tion with the agents disclosed herein or other Suitable agents, (“THF), dimethylformamide (“DMF'), chloroform, meth depending on the condition being treated. Hence, in some ylene chloride (or dichloromethane), diethyl ether, methanol, embodiments the compounds described herein will be co 15 N-methylpyrrolidone (NMP), pyridine and the like. Unless administered with other agents as described above. When specified to the contrary, the solvents used in the reactions used in combination therapy, the compounds described herein described herein are inert organic solvents. Unless specified can be administered with the second agent simultaneously or to the contrary, for each gram of the limiting reagent, one cc separately. This administration in combination can include (or mL) of solvent constitutes a Volume equivalent. simultaneous administration of the two agents in the same Isolation and purification of the chemical entities and inter dosage form, simultaneous administration in separate dosage mediates described herein can be effected, if desired, by any forms, and separate administration. That is, a compound Suitable separation or purification procedure Such as, for described herein and any of the agents described above can be example, filtration, extraction, crystallization, column chro formulated together in the same dosage form and adminis matography, thin-layer chromatography or thick-layer chro tered simultaneously. Alternatively, a compound as disclosed 25 matography, or a combination of these procedures. Specific herein and any of the agents described above can be simulta illustrations of Suitable separation and isolation procedures neously administered, wherein both the agents are present in are given by reference to the examples hereinbelow. However, separate formulations. In another alternative, a compound as other equivalent separation or isolation procedures can also disclosed herein can be administered just followed by and any be used. of the agents described above, or vice versa. In the separate When desired, the (R)- and (S)-isomers of the non-limiting administration protocol, a compound as disclosed herein and 30 exemplary compounds, if present, can be resolved by meth any of the agents described above can be administered a few ods known to those skilled in the art, for example by forma minutes apart, or a few hours apart, or a few days apart. tion of diastereoisomeric salts or complexes which can be Administration of the compounds as disclosed herein can separated, for example, by crystallization; via formation of be effected by any method that enables delivery of the com diastereoisomeric derivatives which can be separated, for pounds to the site of action. An effective amount of a com 35 example, by crystallization, gas-liquid or liquid chromatog pound disclosed herein can be administered in either single or raphy; selective reaction of one enantiomer with an enanti multiple doses by any of the accepted modes of administra omer-specific reagent, for example enzymatic oxidation or tion of agents having similar utilities, including rectal, buccal, reduction, followed by separation of the modified and intranasal and transdermal routes, by intra-arterial injection, unmodified enantiomers; or gas-liquid or liquid chromatog intravenously, intraperitoneally, parenterally, intramuscu 40 raphy in a chiral environment, for example on a chiral Sup larly, Subcutaneously, orally, topically, as an inhalant, or via port, such as silica with a bound chiral ligand or in the pres an impregnated or coated device such as a stent, for example, ence of a chiral solvent. Alternatively, a specific enantiomer or an artery-inserted cylindrical polymer. can be synthesized by asymmetric synthesis using optically When a compound as disclosed herein is administered in a active reagents, Substrates, catalysts or solvents, or by con pharmaceutical composition that comprises one or more 45 Verting one enantiomer to the other by asymmetric transfor agents, and the agent has a shorter half-life than the com mation. pound unit dose forms of the agent and the compound can be The compounds described herein can be optionally con adjusted accordingly. tacted with a pharmaceutically acceptable acid to form the The examples and preparations provided below further corresponding acid addition salts. Also, the compounds illustrate and exemplify the compounds as disclosed herein 50 described herein can be optionally contacted with a pharma and methods of preparing Such compounds. It is to be under ceutically acceptable base to form the corresponding basic stood that the scope of the present disclosure is not limited in addition salts. any way by the scope of the following examples and prepa In Some embodiments, disclosed compounds can generally rations. In the following examples molecules with a single be synthesized by an appropriate combination of generally chiral center, unless otherwise noted, exist as a racemic mix 55 well known synthetic methods. Techniques useful in synthe ture. Those molecules with two or more chiral centers, unless sizing these chemical entities are both readily apparent and otherwise noted, exist as a racemic mixture of diastereomers. accessible to those of skill in the relevant art, based on the Single enantiomers/diastereomers can be obtained by meth instant disclosure. Many of the optionally substituted Starting ods known to those skilled in the art. compounds and other reactants are commercially available, 60 e.g., from Aldrich Chemical Company (Milwaukee, Wis.) or EXAMPLES can be readily prepared by those skilled in the art using commonly employed synthetic methodology. Chemical Examples The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed The chemical entities described herein can be synthesized 65 compounds and is not intended to limit the scope of reactions according to one or more illustrative schemes herein and/or or reaction sequences that can be used in preparing the com techniques known in the art. pounds provided herein. US 8,901,133 B2 149 150 General Synthetic Methods General conditions for the preparation of The compounds now being generally described, it will be 4-chloropyrido3.2-dpyrimidine more readily understood by reference to the following examples, which are included merely for purposes of illus 3-Aminopicolinic acid (B-1) (30 g. 217 mmol. 1.0 eq) is tration of certain aspects and embodiments of the embodi suspended in formamide (75 mL, 1.88 mol, 8.66 eq). The ments disclosed herein, and are not intended to limit these resulting mixture is stirred at 140°C. for 1 hand at 170° C. for embodiments. 1 h and then at 180° C. for an additional 1 h. The mixture is cooled to RT and filtered. The filter cake is washed with water, and dried in vacuo to afford the product, pyrido3.2-dpyri (i) General Methods for the Synthesis of C1 W, and 10 midin-4-ol (B-2). TsO W. Heterocycles To a stirred solution pyrido3.2-dpyrimidin-4-ol (B-2) (16 g, 109 mmol, 1.0 eq) in DCM (200 mL) and DMF (0.4 mL) at RT, oxalyl chloride (23.2 mL. 272 mmol. 2.5 eq) is added dropwise (over 5 min) and the resulting mixture is stirred at Method A: 15 reflux overnight. The mixture is allowed to cool to RT and C concentrated in vacuo. The residue is diluted with water (200 mL), neutralized with saturated aqueous NaHCO, solution N below 10°C. to adjust the pH to 8-9 and then extracted with C N21 N ethyl acetate (4x100 mL). The combined organic layers are washed with brine, dried over NaSO and filtered. The fil N 2 N ls R12 N N trate is concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (16-50% ethyl acetate petroleum ether) to afford the product, 4-chloropyrido 3.2-d pyrimidine (B-3). 25

A-2 Method C: NH2 30 General conditions for the preparation of 6-chloro-9- HN (tetrahydro-2H-pyran-2-yl)-9H-purines O N Ethyl formate NS 1N HeEtona toluene BioH.Renus To a solution of 6-chloro-9H-purine (A-1) (1.29 mol, 1 eq) R T and anhydrous TsOH (0.02 mol, 0.015 eq) in ethyl acetate 35 (1000 mL), 3,4-dihydro-2H-pyran (1.94 mol, 1.5 eq) is added OH C and the resulting mixture is stirred at reflux for 2 h. The -N -N reaction mixture is allowed to cool to RT, aqueous NaCO, 21 N N POCl3 21 N N solution (3%, 500 mL) is added and the resulting mixture is N S. N,N-Dimethylaniline N S. stirred for 10 min. The organic layer is separated, washed with 40 N Reflux overnight N water (2x500 mL) and brine (500 mL), dried over anhydrous C-1 C-2 NaSO, and filtered. The filtrate is concentrated in vacuo. The product is dissolved in ethyl acetate (50 mL), and then n-heptane (500 mL) is added. The resulting mixture is stirred at RT for 1 h. The precipitate is collected by filtration, rinsed 45 General conditions for the preparation of with heptane (100 mL) and dried in vacuo to afford the prod 7-chloropyrazolo 1.5-alpyrimidine uct, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (A-2). To a mixture of ethyl acetate (88 g, 1.0 mol, 1.0 eq) and ethyl formate (74 g, 1.0 mol, 1.0 eq) in toluene (100 mL), 50 sodium ethoxide (68 g, 1.0 mol, 1.0 eq) is added and the Method B: resulting mixture is stirred at RT overnight. The reaction mixture is concentrated in vacuo to remove the solvent. The O resulting residue is suspended in EtOH (100 mL) and then N 1H-pyrazol-5-amine (41.5 g., 0.5 mol, 0.5 eq) is added in n HCONH2 55 portions to the mixture. The resulting mixture is stirred at 130-180° C. reflux for 5 h and concentrated in vacuo. The residue is suspended in ice-water (200 mL) and neutralized with conc. 21 NH2 HCl to adjust pH to 1. The resulting solid is collected by B-1 filtration and dried in vacuo to afford the product, pyrazolo OH C 60 1.5-alpyrimidin-7-ol (C-1). To a solution of pyrazolo 1.5-alpyrimidin-7-ol (C-1) (19.0 Nn n N Oxalyl chloride Nn n N g, 14.1 mmol. 1.0 eq) in phosphoroxychloride (100 mL, 1.06 mol. 76 eq) at RT, N.N-dimethylaniline (7.0g, 58.0 mmol. 4.1 4\ 2 4N 2 eq) is added dropwise and the resulting mixture is stirred at 65 reflux overnight. The mixture is allowed to cool to RT and B-2 B-3 concentrated in vacuo to remove the phosphoroxychloride. The residue is poured into ice water (200 mL), neutralized US 8,901,133 B2 151 152 with saturated aqueous NaHCO solution to adjust the pH to purified by flash column chromatography on silica gel 8-9 while keeping the temperature below 5°C. The mixture is (0-50% ethyl acetate-petroleum ether) to afford the product, stirred at RT for 30 min and then extracted with ethyl acetate 4-bromo-6-chloropyridazin-3-amine (D-2). (4x200 mL). The combined organic layers are washed with To a stirred solution of 4-bromo-6-chloropyridazin-3- brine, dried over NaSO and filtered. The filtrate is concen amine (D-2) (16 g, 77.3 mmol. 1.0 eq) in EtOH (200 mL), trated in vacuo and the residue is purified by flash column 2-chloroacetaldehyde (45% in water, 67.4g,386.6 mmol. 5.0 chromatography on silica gel (1-3% ethyl acetate-petroleum eq) is added and the resulting mixture is stirred at reflux ether) to afford the product, 7-chloropyrazolo 1.5-alpyrimi overnight. The mixture is allowed to cool to RT and concen dine (C-2). trated in vacuo to remove EtOH. The residue is slurried in 10 acetone. The solid is collected by filtration and washed with acetone. The solid is suspended in water, neutralized with Method D: aqueous ammonia to adjust the pH to 8 at 0-5° C. and then C C H extracted with ethyl acetate (2x150 mL). The combined lay 15 ers are washed with brine, dried over NaSO and filtered. The filtrate is concentrated in vacuo to afford the product, SN Br, NaCO, NN er O 8-bromo-6-chloroimidazo[1,2-bipyridazine (D-3). -- -- To a stirred solution of phenylmethanol (3.35 g, 31 mmol. 2 l MeOH, RT l EtOH, reflux 12h Br 1.2 eq) in THF (80 mL), NaH (60% dispersion in mineral oil, 1.34g, 33.5 mmol. 1.3 eq) is added in portions. The resulting NH2 NH2 mixture is stirred at RT for 30 min and then 8-bromo-6- D-1 D-2 chloroimidazo 1,2-bipyridazine (D-3) (6 g. 25.8 mmol. 1.0 Br eq) is added. The resulting mixture is stirred at RT for an additional 2 h and then poured into water (30 mL). The 21 2N 25 mixture is extracted with ethyl acetate (2x100 mL). The com N y bined organic layers are washed with brine, dried over C N1 NaSO and filtered. The filtrate is concentrated in vacuo to afford the product, 8-(benzyloxy)-6-chloroimidazo 1,2-b D-3 Br pyridazine (D-4). 30 To a stirred solution of 8-(benzyloxy)-6-chloroimidazo1, N 2-bipyridazine (D-4) (6.2 g, 23.8 mmol. 1.0 eq) in MeCH 21 N2 BOH (100 mL), Pd/C (10%. 620 mg) is added. The resulting mix -- N-N / NaH, THF ture is degassed and back-filled with hydrogen three times C N and then stirred at 50° C. under hydrogen for 24 h. The 35 D-3 resulting mixture is filtered and concentrated in vacuo to Bn afford the product, imidazo 1,2-bipyridazin-8-ol hydrochlo O1 OH ride (D-5). To a stirred solution of imidazo[1,2-bipyridazin-8-ol N N hydrochloride (D-5) (4 g. 23.3 mmol. 1.0 eq) and triethy 21 Ne. Pd/C (10%) 21 Ne. TSC 40 -as- -- lamine (7.1 g, 70.0 mmol. 3.0 eq) in DCM (50 mL), 4-tolu N-N / H/MeOH N-N / EtN, enesulfonyl chloride (5.3.g. 28.0 mmol. 1.2 eq) is added in C N N DCM portions and the resulting mixture is stirred at RT for 1 h. The D-4 D-5 mixture is washed with brine, dried over NaSO and filtered. OTs The filtrate is concentrated in vacuo and the residue is purified 45 by flash column chromatography on silica gel (10-50% ethyl 21 2N acetate-petro ether) to afford the product, imidazo 1.2-bpy N y ridazin-8-yl-4-methylbenzenesulfonate (D-6). N1 D-6 50 Method E: C C NO. SnCl2·2H2O/ NH2 NaHS/ General conditions for the preparation of 6,8-dichlor N1 N EtOH N1N MeOH oimidazol-2-bipyridazine and imidazo 1.2-bpy 55 - - || -e- ridazin-8-yl-4-methylbenzenesulfonate 2 reflux 2h 2 reflux 3h N C N C To a stirred mixture of 6-chloropyridazin-3-amine (D-1) E-1 E-2 (52.0 g, 0.4 mol, 1.0 eq) and sodium carbonate (84.8 g. 0.8 C C mol, 2.0 eq) in MeOH (500 mL) at RT, bromine (70.6 g., 0.44 60 mol. 1.1 eq) is added dropwise and the resulting mixture is N1N NH2 CH(OCH), N1 S Ny stirred overnight. The reaction mixture is filtered and the filter He cake is washed with ethyl acetate. The filtrate is concentrated l 2 reflux 3h l 2 in vacuo and the residue is poured into water (300 mL). The N C N S resulting mixture is extracted with ethyl acetate (2x300 mL). 65 E-3 E-4 The combined organic layers are dried over NaSO and filtered. The filtrate is concentrated in vacuo and the residue is US 8,901,133 B2 153 154 General conditions for the preparation of 7-chlorothiazolo 5,4-dipyrimidine Method G: C C Br A mixture of 4,6-dichloro-5-nitroprimidine (E-1) (20.0 g, 5 n-BuLi, 104 mmol) and stannous chloride dihydrate (117.7 g. 520 N NBS, DCM N N DMF mmol) in EtOH (300 mL) is stirred at reflux for 2 h. The He- Hs resulting mixture is allowed to cool to RT and then concen l N 2NNH RT3 l N 2NNH -78°PCM C. trated in vacuo. The residue is poured into ice water (300 mL) to RT 10 F-1 G-1 and neutralized with saturated NaHCO aqueous solution to C adjust the pH value to 5-6. The resulting mixture is stirred at CHO RT for 30 min and then extracted with ethyl acetate (3x200 N N NH2OHHCI mL). The combined organic layers are washed with brine, He dried over NaSO and filtered. The filtrate is concentrated in 15 l 2NN EtOHNNaOH vacuo to afford the product, 4,6-dichloropyrimidine-5-amine N H (E-2). G-2 C N C 2- N CN A mixture of 4,6-dichloropyrimidine-5-amine (E-2) (16.0 OH g, 98.2 mmol) and sodium hydrosulphide (7.15g, 128 mmol) N1 N N1 N in MeOH (320 mL) is stirred at reflux for 3 h. The resulting l N SOCl N mixture is allowed to cool to RT and then concentrated in 2 DCM 2 vacuo. The residue is poured into aqueous NaOH solution N N N N G-3 G-4 (200 mL, 1 M) and then neutralized with acetic acid to adjust 25 the pH value to 5-6. The resulting mixture is stirred at RT for 30 min. The solid is collected by filtration, rinsed with water (2x50 mL) and dried in vacuo to afford the product, 5-amino General conditions for the preparation of 4-chloro 6-chloropyrimidine-4-thiol (E-3). 7H-pyrrolo2,3-dipyrimidine-5-carbonitrile 30 5-Amino-6-chloropyrimidine-4-thiol (E-3) (14.0 g, 86.9 To a suspension of 4-chloro-7H-pyrrolo2,3-dipyrimidine mmol) is dissolved in triethoxy methane (180 mL) and the (F-1) (3.99 g, 26.0 mmol, 1.0 eq) in anhydrous DCM (150 resulting mixture is stirred at reflux for 3 h. The mixture is mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol. allowed to cool to RT and then concentrated in vacuo. The 1.3 eq) is added and the resulting mixture is stirred at RT for residue is purified by flash column chromatography on silica 35 3 h. The reaction mixture is diluted with MeOH (30 mL) and gel (5-10% ethyl acetate-petro ether) to afford the product, then concentrated in vacuo. The residue is triturated with HO (150 mL). This is collected by filtration and then re-crystal 7-chlorothiazolo 5,4-dipyrimidine (E-4). lized in MeOH to afford the product, 5-bromo-4-chloro-7H pyrrolo2,3-dipyrimidine (G-1). 40 To a solution of 5-bromo-4-chloro-7H-pyrrolo2,3-dipyri Method F: midine (G-1) (2.33 g, 10.0 mmol. 1.0 eq) in anhydrous THF C C (100 mL) at -78°C. under argon, n-Bulli solution (2.5M in F THF, 8.8 mL, 22.0 mmol. 2.2 eq) is added dropwise (over 10 min). The resulting mixture is stirred at -78°C. for 1 h and N N selectfluor N N 45 then DMF (2.0 g, 11.0 mmol. 1.1 eq) is added dropwise (over l 2 N CHCN, AcOH, 70° C. l 2 N 10 min). The mixture is stirred at -78°C. for an additional 30 N H N H min and then stirred at RT overnight. The reaction mixture is quenched with HO (50 mL) and then concentrated in vacuo. F-1 F-2 The residue is triturated with saturated aqueous NHCl solu 50 tion. The solid is collected by filtration, rinsed with ethyl acetate, and dried in vacuo to afford the product, 4-chloro 7H-pyrrolo2,3-dipyrimidine-5-carbaldehyde (G-2). General conditions for the preparation of To a suspension of 4-chloro-7H-pyrrolo2,3-dipyrimidine 4-chloro-5-fluoro-7H-pyrrolo2,3-dipyrimidine 5-carbaldehyde (G-2) (1.17 g. 6.47 mmol. 1.0 eq) and 55 hydroxylamine hydrochloride (0.54g, 7.77 mmol. 1.2 eq) in 4-Chloro-7H-pyrrolo2,3-dipyrimidine (F-1) (5.01 g, 32.6 EtOH (25 mL), aqueous NaOH solution (0.31 g, 7.77 mmol. mmol. 1 eq) and selectfluor (17.32 g, 48.9 mmol. 1.5 eq) are 1.2 eq) in HO (4 mL) is added dropwise. The resulting dissolved in a mixture of anhydrous acetonitrile (250 mL) and mixture is stirred at RT for 30 min and then is diluted with a AcOH (50 mL). The resulting mixture is stirred at 70° C. sufficient amount of EtOH to allow stirring for additional 30 60 min. The solid is collected by filtration, rinsed with HO and under argon for 16 h. The mixture is concentrated in vacuo. dried in vacuo to afford the product, 4-chloro-7H-pyrrolo2, The residue is dissolved in a mixture of DCM-ethyl acetate 3-dipyrimidine-5-carbaldehyde oxime (G-3) as a mixture of (v/v=1/1, 50 mL) and filtered through celite. The filtrate is isomers. concentrated in vacuo and the residue is purified by flash To a suspension of 4-chloro-7H-pyrrolo2,3-dipyrimidine chromatography on silica gel (0-0.7% MeOH-DCM) to 65 5-carbaldehyde oxime (G-3) (865 mg, 4.40 mmol. 1.0 eq) in afford the product, 4-chloro-5-fluoro-7H-pyrrolo2,3-dipyri DCM (20 mL), thionyl chloride (3.1 mL, 43.7 mmol. 10.0 eq) midine (F-2). is added and the resulting mixture is stirred at RT overnight. US 8,901,133 B2 155 156 The reaction mixture is concentrated in vacuo. The residue is The filter cake is rinsed with HO (30 mLx2). The filtrate is suspended in water (60 mL) and saturated aqueous NaHCO acidified with conc. HCl to adjust the pH to 4-5. The solid is is added to adjust the pH to 4. The solid is collected by collected by filtration, rinsed with water and dried in vacuo to filtration, rinsed with water and followed by ethyl acetate to afford the product, 4-chloro-7H-pyrrolo2,3-dipyrimidine-5- afford the first batch of product. The filtrate is extracted with 5 carboxamide (H-2). ethyl acetate (3x50 mL). The combined organic layers are washed with brine, dried over NaSO and filtered. The fil trate is concentrated in vacuo and the residue is combined (ii) General Method for the Synthesis of with the above-obtained solid. The product is re-crystallized Isoquinolinyl Amine Core Precursors in ethyl acetate/hexanes (v/v=1/1) and dried in vacuo to 10 afford the product, 4-chloro-7H-pyrrolo2,3-dipyrimidine-5- carbonitrile (G-4). Method I:

Method H: 15 R O (COC), H2N 3 DMF 1. C Br r N OH (Cat.) O RT, DCM NEt3, RT n-BuLif 21 Hs N Dry ice He I-1 2 THF, -78° C. N H to RT O COC. R O Y HCI s G-1 la Y - 5, O Ol BocN OMe reflux C OH 25 27 O1 BuLi, I-2, PrMgCl -50° C.--20° C., THF N1 N N Oxalyl chloride NH3H2O I-2 l 2 DMF, DCM -e-DCM o1 N N H 30 H-1 C CONH2 O FmocCl, R3 NaHCO Ny 35 t N N - N N H 2n 21 H-2 40 NH, General method for the synthesis of I-3 4-chloro-7H-pyrrolo2,3-dipyrimidine-5-carboxamide o1

To a mixture of 5-bromo-4-chloro-7H-pyrrolo2,3-dipyri 45 midine (G-1) (6.24g, 26.8 mmol. 1.0 eq) in anhydrous THF (100 mL) at -78°C. under argon, n-Bulli solution (2.5 M in O THF, 23.6 mL, 59.0 mmol. 2.2 eq) is added dropwise over 30 TFA min. The reaction mixture is stirred at -78°C. for 1 hand then R3 Hs dry ice (300 g) is added in portions under an argon atmo 50 N N sphere. The resulting mixture is allowed to warm to RT and then stirred at RT overnight. The reaction mixture is diluted 21N 2 with HO (200 mL) and extracted with ethyl acetate (50 mLx4). The aqueous layer is acidified with conc. HCl to HS adjust the pH to 3-4. The precipitate is collected by filtration, 55 n Fmoc rinsed with HO (30 mL) and dried in vacuo to afford the I-4 product, 4-chloro-7H-pyrrolo2,3-dipyrimidine-5-carboxy O lic acid (H-1). To a stirred suspension of 4-chloro-7H-pyrrolo2,3-dpy R3 rimidine-5-carboxylic acid (H-1) (3.11 g, 15.7 mmol. 1.0 eq) 60 X N NH and a catalytic amount of DMF in a mixture of DCM (40 mL) SOCl. and THF (40 mL) at RT, oxalyl chloride (2.0 mL, 23.5 mmol. 2N2 He 1.5 eq) is added dropwise. The resulting mixture is stirred for HN 2 hand then concentrated in vacuo. The residue is dissolved SFmoc in DCM (50 mL) and the resulting solution is added dropwise 65 to saturated aqueous ammonium hydroxide (200 mL) at RT. I-5 The resulting mixture is stirred for 30 min and then filtered. US 8,901,133 B2 157 158 -continued 140 mmol. 0.8 eq) is added in one portion at RT. After stirring C at RT for 30 min, solid precipitates and the mixture is slurried R3 at RT for 10 h. The solid is collected by filtration and rinsed * N1 NN with MeOH (3x50 mL). The collected solid is suspended in water (500 mL) and then neutralized with concentrated 21N 2 ammonium hydroxide solution at RT to adjust the pH value to 9-10. The mixture is extracted with DCM (3x200 mL). The combined organic layers are washed with brine, dried over n Fmoc MgSO and filtered. The filtrate is concentrated in vacuo to I-6 10 afford the product (I-3). To a stirred mixture of (I-3) (10.0 mmol. 1.0 eq) in DCM (20 mL), saturated aqueous NaHCO solution (2.8 mL) is General conditions for the preparation of (S)-(9H added. The mixture is cooled to 0°C. and 9-fluorenylmethyl fluoren-9-yl)methyl 1-(1-chloroisoquinolin-3-yl) chloroformate (10.5 mmol. 1.05 eq) is added in one portion. ethylcarbamates 15 The resulting mixture is allowed to warm to RT and stirred at RT for 1 h. The organic layers are separated, washed with To a stirred mixture of methylbenzoic acid (I-1) (0.41 mol, water (2x50 mL), dried over anhydrous MgSO and filtered. 1 eq) and DMF (0.5 mL) in DCM (500 mL) at RT, oxalyl The filtrate is concentrated in vacuo to afford the product chloride (0.45 mol, 1.1 eq) is added slowly over 5 min. The (I-4). resulting mixture is stirred at RT for 2 hand then concentrated Compound (I-4) (10.0 mmol. 1.0 eq) is dissolved in TFA in vacuo to afford the product, methylbenzoyl chloride. The (25 mL) and the resulting mixture is stirred at reflux for 1 h. product is used directly in the next step. The mixture is allowed to cool to RT and concentrated in To a stirred mixture of 4-methoxybenzylamine (0.45 mol, vacuo to remove TFA. The resulting residue is partitioned 1.1 eq) and triethylamine (0.86 mol, 2.1 eq) in DCM (600 between DCM (50 mL) and saturated aqueous NaHCO (50 mL), a solution of methylbenzoyl chloride in DCM (50 mL) 25 mL) solution. The organic layer is washed with water (2x20 is added dropwise while keeping the reaction temperature mL), dried over anhydrous MgSO and filtered. The filtrate is between 25°C. and 40°C. (controlling by an ice-water bath). concentrated in vacuo to afford the product (I-5). The resulting mixture is stirred at RT for 2 h and then water A mixture of compound (I-5) (45.0 mmol) and DMF (0.3 (200 mL) is added. The organic layer is separated, washed mL) in SOCl (100 mL) is stirred at reflux for 2 h. The mixture with water (2x200 mL), dried over anhydrous NaSO and 30 is allowed to cool to RT and concentrated in vacuo. The filtered. The filtrate is concentrated in vacuo and the residue is residue is purified by flash column chromatography on silica suspended in n-heptane (200 mL) and stirred at RT for 30 min. gel to afford the product (I-6). The precipitate is collected by filtration, rinsed with heptane (100 mL) and further dried in vacuo to afford the product (iii) General Conditions for Attachment of W. amide (I-2). 35 Substituents To a stirred mixture of amide (I-2) (173 mmol. 1 eq) in anhydrous THF (250 mL) at -30°C. under an argon atmo sphere, a solution of n-butyllithium in hexanes (2.5 M, 173 Method J: mL, 432 mol, 2.5 eq) is added dropwise over 30 min while R keeping inner temperature between -30°C. and -10°C. The 40 R3 resulting mixture A is stirred at -30°C. for 30 min To a stirred mixture of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxo X N1 NN propan-2-ylcarbamate (60.3 g, 260 mmol. 1.5 eq) in anhy drous THF (250 mL) at -30°C. under an argon atmosphere, 2N2 a solution of isopropylmagnesium chloride in THF (2 M. 143 45 mL, 286 mmol. 1.65 eq) is added dropwise over 30 min while HS keeping the inner temperature between -30°C. and -10°C. n Fmoc The resulting mixture is stirred at -30°C. for 30 min. This J-1 R solution is then slowly added to above reaction mixture A R3 while keeping the inner temperature between -30° C. and 50 -10°C. The resulting mixture is stirred at -15°C. for 1 h. The Xs-1s W-Cl reaction mixture is then quenched with water (50 mL) and Hos then acidified with conc. HCl (80 mL) at -10-0° C. to adjust 2 21 O the pH to 1-3. The mixture is allowed to warm to RT and : W-OTs concentrated in vacuo to afford the product. 55 NH, This solid is dissolved in MeOH (480 mL), and then conc. J-2 HCl (240 mL) is added quickly at RT. The resulting mixture R is stirred at reflux for 1 h. The reaction mixture is concentrated R3 in vacuo to reduce the volume to ca. 450 mL. The residue is extracted with a mixture of heptanes and ethyl acetate (v/v=2/ 60 * N1 NN 1, 2x500 mL). The aqueous layer is basified with concen trated ammonium hydroxide to adjust the pH value to 9-10 21N 2 while keeping the inner temperature between -10°C. and 0° C. The mixture is then extracted with DCM (3x300 mL), HS yw. washed with brine, dried over MgSO and filtered. The filtrate 65 is concentrated in vacuo and the residue is dissolved in MeOH J-3 (1200 mL) at RT. To this solution, D-(-)-tartaric acid (21 g, US 8,901,133 B2 159 160 A mixture of compound (J-1) (0.961 mmol. 1.0 eq) in -continued morpholine (45.68 mmol, 47.5 eq) is stirred at RT for 30 min. O The reaction mixture is diluted with 1,4-dioxane (10 mL) and R3 then evaporated in vacuo. The residue is purified by flash column chromatography on silica gel (eluting with a mixture N NH solvent of MeOH and DCM) to give the product (J-2). A mixture of compound (J-2) (1.0 mmol. 1.0 eq), Wa-C1 or 21N 21 POCl3, reflux Wd-OTs (1.50 mmol. 1.5 eq) and triethylamine (3.0 mmol. E He 3.0 eq) in n-BuOH (5 mL) is stirred at reflux for 1-5 h. The NH reaction mixture is allowed to cool to RT and then concen 10 trated in vacuo. The residue is purified by flash column chro N 21 N matography on silica gel (eluting with a mixture solvent of lyN MeOH and DCM) to afford the product (J-3). N1 N (iv) General method for the synthesis of (S)-1-(1- K-4 chloroisoquinolin-3-yl)ethanamine cores 15 C Method K: R3

C * N1 NN C PMBC1, K2CO 2 N 21N 2° DMF, RT N E He N21 NN Method A ls N NH N N N N 2 N N H N O 25 lyN N1 N K-5 K-1 K-2 C 30 R3 o1 PS NN (K-2) 21N 2° NEt3, 35 O n-BuOH SH R3 reflux X N N N 21 N lyN 21N 2 N 40 N V NH, PMB K-6 I-3 o1 45 General conditions for the preparation of (S) N-(1- (1-chloroisoquinolin-3-yl)ethyl)-9-(4-methoxyben Zyl)-9H-purin-6-amines O R3 50 Compound (K-2) is prepared from (K-1) in analogous X^n N FCCOOH, fashion to (A-2) using Method A. reflux Compound (K-3) is prepared from (I-3) in analogous fash Her ion to (J-3) using Method J. 2n.2 Compound (K-3) (91 mmol) is dissolved in TFA (300 mL) 55 and the resulting mixture is stirred at reflux for 2 h. The NH mixture is cooled to RT and concentrated in vacuo to remove TFA. The resulting suspension is diluted with water (300 mL) 21 N N and then neutralized with concentrated ammonium hydroxide to adjust the pH value to 7-8 while keeping the temperature N y 60 N N below 0°C. The resulting mixture is stirred at RT for 30 min. The solid is collected by filtration, rinsed with water (2x50 O mL) and dried in vacuo to afford the product (K-4). Compound (K-4) (58.8 mmol) is dissolved in POCl. (200 mL) and the resulting mixture is stirred at reflux for 1 h. The 65 mixture is cooled to RT and concentrated in vacuo to remove K-3 POCl. The residue is poured into ice water (300 mL) and neutralized with Saturated aqueous NaCO Solution to adjust US 8,901,133 B2 161 the pH value to 7-8 while keeping the temperature below 0°C. The resulting mixture is stirred at RT for 30 min and then Method M: extracted with a mixture of DCM and MeOH (v/v=10/1, 3x200 mL). The combined organic layers are washed with O R brine, dried over NaSO and filtered. The filtrate is concen SOC1/DMF trated in vacuo and the residue is purified by flash column * N OH (cat) R-NH2 chromatography on silica gel (2-10% MeOH-DCM) to afford -ie- -e- the product (K-5). Toluene EtN, RT To a stirred solution of (K-5) (22 mmol. 1.0 eq) and KCO 21 NO Reflux (9.1 g, 66 mmol. 3 eq) in DMF (100 mL) at RT 1-(chlorom 10 M-1 ethyl)-4-methoxybenzene (4g, 25.6 mmol. 1.1 eq) is slowly O added, and the resulting mixture is stirred at RT overnight. O The reaction mixture is poured into water (200 mL) and R BocN X R., SOCI2, DMF OH extracted with DCM (3x100 mL). The combined organic N N1 (cat) layers are washed with brine, dried over NaSO and filtered. 15 -> --> The filtrate is concentrated in vacuo and the residue is purified Toluene DCM, DIPEA by flash column chromatography on silica gel (1-5% MeOH 21 NO Reflux

DCM) to afford the product (K-6). (v) PMB Deprotection Procedure

Zn, AcOH -e- Method A: R 25 R3

N NN HCJMeOH (2N) 4N4N 30 Hs SH -- N21 y 35 M-4 O R ls-- R2 PMB N N1 L-1 R R3 40 21 N 1 N NN NH, 4N-4N M-5 45 SH To a stirred mixture of nitrobenzoic acid (M-1) (1.0 mol, 1.0 eq) and DMF (2.0 mL) in toluene (800 mL), thionyl chloride (292 mL, 1.0 mol. 4.0 eq) is added dropwise (over 15 N21 y min) and the resulting mixture is stirred at reflux for 1.5h. The 50 mixture is allowed to cool to RT and then concentrated in ls-- vacuo. The residue is dissolved in DCM (100 mL) to form L-2 solution A, which is used directly in the next step. To a stirred mixture of a given amine R. NH (102.4g, 1.1 mol, 1.1 eq) and triethylamine (280 mL, 2.0 mol. 2.0 eq) General conditions for the PMB deprotection of 55 in DCM (700 mL), solution A is added dropwise while keep (S)-N-(1-(isoquinolin-3-yl)ethyl)-9-(4-methoxy ing the reaction temperature below 10°C. The resulting mix benzyl)-9H-purin-6-amines ture is allowed to warm to RT and then stirred at RT overnight. The reaction mixture is diluted with ice-water (1.0 L) and Compound (L-1) (0.27 mmol) is dissolved in TFA (30 mL) stirred for 15 min. The precipitate is collected by filtration, and the resulting mixture is stirred at reflux for 30 min. The 60 rinsed with isopropyl ether (3x100 mL) and petroleum ether mixture is allowed to cool to RT and then concentrated in (3x100 mL), and then dried in vacuo to afford product amide vacuo to remove TFA. The residue is diluted with water (50 (M-2). mL), neutralized with concentrated ammonium hydroxide to A mixture of nitro-benzamide (M-2) (20.0 mmol. 1.0 eq) adjust the pH to 7-8 and then stirred at RT for 30 min. The and DMF (cat.) in toluene (60 mL) at RT, thionyl chloride (12 solid is collected by filtration and further purified by flash 65 mL, 164 mmol, 8.2 eq) is added dropwise (over 5 min) and the column chromatography on silica gel to afford the product resulting mixture is stirred at reflux for 2 h. The mixture is (L-2). allowed to cool to RT and then concentrated in vacuo. The US 8,901,133 B2 163 164 residue is dissolved in DCM (10 mL) to form solution B. -continued which is used directly in the next step. C 21 To a stirred mixture of N-(tert-butoxycarbonyl)-L-alanine (16.0 mmol. 0.8 eq) and N,N-diisopropylethylamine (4.0 g, NN 31.0 mol, 1.5 eq) in DCM (20 mL), solution B is added dropwise while keeping the reaction temperature between 2 0-10°C. The resulting mixture is stirred at this temperature HS. N for 1 h and then stirred at RT overnight. The reaction mixture n is quenched with ice-water (100 mL). The organic layer is 10 separated and the aqueous layer is extracted with DCM (2x80 2N mL). The combined organic layers are washed with brine, N dried over NaSO and filtered. The filtrate is concentrated in \- vacuo and the residue is slurried in isopropyl ether (100 mL) 15 PMB for 15 min. The solid is collected by filtration and dried in 2 vacuo to afford product (M-3). To a suspension of zinc dust (7.2g, 110 mmol, 10.0 eq) in glacial acetic acid (40 mL) at 15°C., a solution of M-3 (11.0 ON mmol. 1.0 eq) in glacial acetic acid (40 mL) is added and the resulting mixture is stirred at RT for 4 h. The mixture is C poured into ice-water (200 mL) and neutralized with satu rated aqueous NaHCO solution to adjust the pH to 8. The NN resulting mixture is extracted with DCM (3x150 mL). The 25 combined organic layers are washed with brine, dried over 2 -e- NaSO and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel NH (7% ethyl acetate-petroleum ether) to afford product (M-4). 30 Compound (M-4) (0.5 mmol. 1.0 eq) is dissolved in hydro N21 y chloric methanol solution (2N, 20 mL) and the resulting mixture is stirred at RT for 2h. The mixture is concentrated in ls, N vacuo. The residue is diluted with water (30 mL) and then 35 PMB neutralized with saturated aqueous NaHCO to adjust the pH 3 to 8 while keeping the temperature below 5°C. The resulting mixture is extracted with DCM (3x30 mL). The combined organic layers are washed with brine, dried over NaSO and CN filtered. The filtrate is concentrated in vacuo and the residue is 40 slurried in petroleum ether (10 mL). The solid is collected by filtration and dried in vacuo to afford product (M-5). C The quinazolinone (M-5) can be used to synthesize com pounds described herein using, for example, Method J to 45 NN couple the amine to W groups. 2 Example 1 NH 50 Na y C C ls-- NN 55 4 21 Compound 1 was prepared according to Method Kand was then converted to compound 2 by the following method: Hš N To a stirred mixture of (S)-N-(1-(1,8-dichloroisoquino 60 lin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 l (2.58 g. 5.4 mmol. 1 eq), Pd(OAc), (363 mg, 1.62 mmol, 0.3 N eq) and PPhs (846 mg, 3.24 mol, 0.6 eq) in THF (50 mL) at \- RT, tributyl (vinyl)tin (1.97g, 5.94 mmol. 1.1 eq) was added N and the resulting mixture was stirred at reflux overnight. The PMB 65 mixture was allowed to cool to RT and filtered through silica gel (10 g). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on US 8,901,133 B2 165 166 silica gel (1-5% MeOH-DCM) to afford the product (S)-N- -continued (1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxy benzyl)-9H-purin-6-amine 2. Compound 2 was then converted to compound 4 in two r steps: To a stirred mixture of (S) N-(1-(8-chloro-1-vinyl C su isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6- amine 2 (200 mg, 0.42 mmol. 1 eq) in EtOH (50 mL) at RT, morpholine (183 mg, 2.1 mmol. 5 eq) and triethylamine (213 NN mg, 2.1 mmol. 5 eq) were added sequentially. The resulting mixture was stirred at reflux for 4 h. The mixture was allowed 2 to cool to RT and then concentrated in vacuo and the residue 10 was purified by flash column chromatography on silica gel NH (1-5% MeOH-DCM) to afford the product (S)-N-(1-(8- chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9-(4- methoxybenzyl)-9H-purin-6-amine 3. The PMB group was Na N then subsequently deprotected using Method L to provide compound 4. ESI-MS m/z: 438.8 M+H". 15 Example 2

C 21 Compound 7 was prepared from compound 2 in 3 steps according to the following procedures: To a stirred mixture of (S) N-(1-(8-chloro-1-vinyliso NN quinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6- amine 2 (3.6 g., 7.6 mmol. 1 eq) in a mixture of 1,4-dioxane 21 (40 mL) and H2O (40 mL) at RT, osmium tetraoxide (5 mg) i b 25 was added and the resulting mixture was stirred at RT for 30 NH min. To this mixture, sodium periodate (3.3 g, 15.2 mmol. 2 eq) was added and the resulting mixture was stirred at RT overnight. The reaction mixture was filtered through silica gel Na y (10 g). The filtrate was extracted with DCM (3x60 mL), washed with brine, dried over NaSO and filtered. The fil 30 trate was concentrated in vacuo and the residue was purified su by flash column chromatography on silica gel (1-5% MeOH PMB DCM) to afford the product, (S)-8-chloro-3-(1-((9-(4-meth 2 oxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-car O baldehyde 5. C 21 To a stirred solution of (S)-8-chloro-3-(1-(4-methoxyben 35 Zyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbalde hyde 5 (150 mg. 0.317 mmol. 1 eq), H2O (1 mL) and AcOH NN (a drop) in DCM (30 mL), NaB(OAc)H (134 mg. 0.634 mmol. 2 eq) was added and the resulting mixture was stirred 21 at RT for 2 h. The mixture was concentrated in vacuo and the i -- 40 residue was purified by flash column chromatography on NH silica gel (1-5% MeOH-DCM) to afford the product, (S)- N-(1-(8-chloro-1-(morpholinomethyl)isoquinolin-3-yl) ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 6. Com N 21 N pound 6 was then deprotected using Method L to provide ly 45 compound 7. ESI-MS m/z: 424.8 M+H". N N Example 3 PMB 5 r 50 C Nu C SN 55 2 i Method L. -- NH

60 N 21 N lys N PMB 65 Compound 8 was prepared in analogous fashion to com pound 7 in Example 2 except that 3.3-difluoropyrrolidine was used in place of morpholine. ESI-MS m/z. 458.0 M+H". US 8,901,133 B2 167 168 Example 4 -continued O) r C C O Nu NN NN

21 21 Method L. 10 5 H NH N21 y N21 y ls 15 N1 N ls-- Compound 9 was prepared in analogous fashion to com PMB pound 7 in Example 2 except that aZetidine was used in place 12 of morpholine. ESI-MS m/z: 394.0 M+H". Example 5 O r C 21 C O Nu NN 25 NN 2 Oxone 21 i DMF -as NH SH 30 N21 y N ls N NCy N V N N PMB 35 5 O OH C Amide 13 was prepared in 4 steps from aldehyde 5 accord ing to the following procedures: NN 40 To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)- CCOCOC 21 DCM 9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5 E RT (1.67 g, 3.53 mmol. 1 eq) in DMF (40 mL) at RT, oxone (6.5 NH -e- g, 10.59 mmol. 3 eq) was slowly added and the resulting 45 mixture was stirred at RT overnight. The reaction was com 2 N plete based on TLC analysis. The reaction mixture was N poured into water (50 mL) and neutralized with concentrated lyN ammonium hydroxide to adjust the pH value to 7-8. The N N V mixture was stirred at RT for 30 min and then extracted with PMB 50 ethyl acetate (3x50 mL). The combined organic layers were 10 washed with brine, dried over NaSO and filtered. The fil O C trate was concentrated in vacuo and the residue was purified C by flash column chromatography on silica gel (1-5% MeOH DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-meth NN 55 oxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-car DCM boxylic acid 10. 2 EtN RT To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)- -e- 9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid O 60 10 (160 mg, 0.327 mol, 1 eq) and DMF (0.1 mL) in DCM (10 NH ~ mL), oxalyl chloride (83.1 mg, 0.654 mmol. 2 eq) was added N 21 N Null and the resulting mixture was stirred at RT for 1 h. The lyN mixture was concentrated in vacuo to afford the product (S)- N N V 8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino) PMB 65 ethyl) isoquinoline-1-carbonyl chloride 11. The product obtained was used directly in the next step without purifica tion. US 8,901,133 B2 169 170 To a solution of morpholine (34 mg. 0.392 mmol. 1.3 eq) Example 8 and triethylamine (100 mg. 0.981 mol, 3 eq) in DCM (20 mL), 16 (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl) amino)ethyl) isoquinoline-1-carbonyl chloride 11 was added at RT. The resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3x50 mL). The combined organic layers were washed with brine, dried over NaSO and filtered. The fil trate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH 10 DCM) to afford the product (S)-(8-chloro-3-(1-((9-(4-meth oxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl) (morpholino)methanone 12. Compound 12 was then deprotected using Method L to provide compound 13. ESI-MS m/z: 438.0 M+H". 15 Example 6 Compound 16 was prepared in analogous fashion to com pound 13 in Example 5 except that 3-oxa-8-azabicyclo3.2.1 octane was used in place of morpholine. ESI-MS m/z: 464.0 14 M+H". Example 9 ... O 17 C 25 NN 2 sh 30 N21ls-- y Compound 14 was prepared in analogous fashion to com pound 13 in Example 5 except that pyrollidine was used in 40 place of morpholine. ESI-MS m/z. 422.0M+H". Compound 17 was prepared in analogous fashion to com pound 13 in Example 5 except that (R)-2-methylpiperazine Example 7 was used in place of morpholine. ESI-MS m/z: 451.0 M+H". 45 Example 10 18 15

O N 50 C C NN 2 55 sh

N N21 y 60 y N ls, NH ls N N Compound 18 was prepared in analogous fashion to com Compound 15 was prepared in analogous fashion to com- 65 pound 13 in Example 5 except that (S)-2-methylpiperazine pound 13 in Example 5 except that N-methylpiperidine was was used in place of morpholine. ESI-MS m/z: 451.0 used in place of morpholine. ESI-MS m/z.: 451.2 M+H". M+H". US 8,901,133 B2 171 172 Example 11 Example 14 19 22 O

O C

10 21

N N I 15 N1 N) Compound 19 was prepared in analogous fashion to com Compound 22 was prepared in analogous fashion to com pound 13 in Example 5 except that 8-oxa-3-azabicyclo[3.2.1 20 pound 13 in Example 5 except that 2-hydroxyazetidine was octane was used in place of morpholine. ESI-MS m/z: 464.0 used in place of morpholine. ESI-MS m/z: 424.0 M+H". M+H". Example 12 Example 15 25 23

C O NH 30 C NN 21 s H 35 : NH N

N 21 N S.Cy N1 N 40 ly Compound 20 was prepared in analogous fashion to com N1 N pound 13 in Example 5 except that 3.3-difluoropyrrolidine Compound 23 was prepared in analogous fashion to com was used in place of morpholine. ESI-MS m/z. 458.0 pound 13 in Example 5 except that cyclobutylamine was used M+H". 45 in place of morpholine. ESI-MS m/z: 422.0 M+H". Example 13 21 Example 16 F 24 50 F O N O N C C NN 55 21

s H NH

60 N N 21 N lyN N N1 N N1 N Compound 21 was prepared in analogous fashion to com 65 Compound 24 was prepared in analogous fashion to com pound 13 in Example 5 except that 2,2-difluoroazetidine was pound 13 in Example 5 except that aZetidine was used in place used in place of morpholine. ESI-MS m/z. 444.0M+H". of morpholine. ESI-MS m/z. 408.2 M+H". US 8,901,133 B2 173 174 Example 17 Compound 27 was prepared in analogous fashion to com 25 pound 13 in Example 5 except that N-methylaniline was used in place of morpholine. ESI-MS m/z. 458.0M+H". Example 20

O NH C 28 NN 10 OH

2 O N i C NH 15 N n N N 21 y 2

N1 N 2O NH Compound 25 was prepared in analogous fashion to com pound 13 in Example 5 except that aniline was used in place N21 N of morpholine. ESI-MS m/z. 444.2 M+H". ls y Example 18 N N p 26, 25 N H Compound 28 was prepared in analogous fashion to com pound 13 in Example 5 except that 4-hydroxypiperidine was used in place of morpholine. ESI-MS m/z. 452.2 M+H". O NH-O C Example 21 NN 35 21 C C NH NN

N 21 N 40 2 S. y N N NH He Compound 26 was prepared in analogous fashion to com- N21 N pound 13 in Example 5 except that benzylamine was used in 5 y place of morpholine. ESI-MS m/z. 458.0M+H". N N Example 19 YMB 27 1 50

C CN O N C N 55 NN NN 4\ 21 SH Hip i 60 NH N21 N

N N

ll 65 29 US 8,901,133 B2 175 176 -continued was purified by flash column chromatography on silica gel pi (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3- N NH (1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)iso C Sa 2 quinoline-1-carbonitrile 29. A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)- NN 9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonitrile 29 (600 mg, 1.28 mmol. 1.0 eq), hydroxylamine hydrochloride 2 Ho (269 mg, 3.84 mmol. 3 eq) and NaOH (154 mg. 3.84 mmol. 3 10 eq) in EtOH (15 mL) was stirred at reflux 4h. The mixture was SH cooled to RT, poured into water (100 mL) and then extracted with DCM (3x100 mL). The combined organic layers were N washed with brine, dried over NaSO and filtered. The fil trate was concentrated in vacuo and the residue was purified S.Cy 15 by flash column chromatography on silica gel (1-10% N N MeOH-DCM) to afford the product (S.Z)-8-chloro-N'-hy PMB droxy-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino) 30 ethyl)isoquinoline-1-carboximidamide 30. (S.Z)-8-chloro-N'-hydroxy-3-(1-((9-(4-methoxybenzyl)- O 9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboximida { mide 30 (502 mg, 1 mmol. 1.0 eq) was dissolved in acetic C N anhydride (10 mL) and the resulting mixture was stirred at reflux overnight. The mixture was cooled to RT and concen NN trated in vacuo to remove acetic anhydride. The resulting 25 suspension was diluted with water (50 mL) and neutralized 2 Method L. with concentrated ammonium hydroxide to adjust the pH value to 7-8. The mixture was extracted with DCM (3x100 NH mL). The combined organic layers were washed with brine, 30 dried over NaSO and filtered. The filtrate was concentrated N in vacuo and the residue was purified by flash column chro matography on silica gel (1-10% MeOH-DCM) to afford the NCy product (S)-N-(1-(8-chloro-1-(5-methyl-1,2,4-oxadiazol N N 3-yl)isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-pu PMB rin-6-amine 31. 35 31 Oxadiazole 31 was then deprotected to using Method L to provide compound 32. ESI-MS m/z. 407.0 M+H". O { Example 22 C N 40

NN O O

21 45 C r Compound 1 SH -- -- O OEt O OEt Null N 33 O NC) N1 N 32 C n O Compound 32 was prepared in 4 steps from compound 1 55 ls, N according to the following procedures: 2 To a stirred solution of ((S) N-(1-(1,8-dichloroisoquino i Method L. lin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 NH e (1.5 g., 3.1 mmol. 1.0 eq) and tetrakis(triphenylphosphine) 60 palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at N21 N RT, dicyanozinc (476 mg, 4.06 mmol. 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3x100 mL). The combined organic 65 layers were washed with brine, dried over NaSO and fil 34 tered. The filtrate was concentrated in vacuo and the residue US 8,901,133 B2 177 178 -continued Compound 36 was prepared in analogous fashion to com pound 35 in Example 22 except that pyrollidine was used in place of morpholine in step 1. ESI-MS m/z. 436.0M+H". C 5 Example 24

21

10 37 sh O N21 NN C r N I? 15 NN N 35 2 Amide 35 was prepared in 3 steps from ethyl 3-chloro-3- Oxopropanate according to the following procedures: s H To a stirred solution of morpholine (479 mg, 5.5 mmol. 1.1 eq) and triethylamine (1.01 g, 10 mmol. 10 eq) in DCM (20 mL) at 0°C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 Na N mmol. 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 25 I? mL) and extracted with ethyl acetate (3x50 mL). The com bined organic layers were washed with brine, dried over Compound 37 was prepared in analogous fashion to com NaSO and filtered. The filtrate was concentrated in vacuo pound 35 in Example 22 except that N-methylpiperazine was and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the prod 30 used in place of morpholine in step 1. ESI-MS m/z: 465.2 uct ethyl 3-morpholino-3-oxopropanoate 33. M+H". To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol. 1.0 eq) and NaH (144 mg., 3 mmol. 1.5 eq) Example 25 in THF (3 mL) at RT, (S)-N-(1-(1,8-dichloroisoquinolin-3- yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 35 mg, 1.6 mmol. 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was C C poured into water (50 mL) and extracted with DCM (3x50 mL). The combined organic layers were washed with brine, 40 NN BocO, EtN/ dried over NaSO and filtered. The filtrate was concentrated DMAP in vacuo and the residue was purified by flash column chro 2 DCM matography on silica gel (1-5% MeOH-DCM) to afford the -- product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H NH purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoet 45 hanone 34. N Amide 34 was then deprotected to provide the compound N21 y 35 using Method L. ESI-MS m/z. 452.2 M+H". ls N N H Example 23 50 38 36 C C

C 55 n N HO1N1 1 2 O i NaH, THF NH -e-

60 N21 Ny lsN N 65 Boc 39 US 8,901,133 B2 179 180 -continued H -continued C C c o1N1 N NN NN O 21 2

sh 10 N21 N

15 41 40

Compound 38 was prepared from compound 1 using Method Jand then converted to compound 40 according to the following procedures: To a stirred mixture of (S) N-(1-(1,8-dichloroisoquino lin-3-yl)ethyl)-9H-purin-6-amine 38 (4.7 g, 13.1 mmol. 1.0 eq) in THF (20 mL) at 0° C., triethylamine (1.8 mL, 13.0 mmol. 0.99 eq), N,N-dimethylpyridin-4-amine (0.16g, 1.31 25 mmol, 0.1 eq) and di-tert-butyl dicarbonate (3.0 g, 13.75 mmol. 1.05 eq) were added sequentially. The resulting mix ture was stirred at 0-5° C. for 10 min and then at RT for an additional 2h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on 30 silica gel (3% MeOH-DCM) to afford the product (S)-tert 42 butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethylamino)-9H 2-Hydroxy-1-(4-methyl piperazin-1-yl)ethanone was pre purine-9-carboxylate 39. pared according to the following procedure: Ethyl 2-hy To a stirred mixture of N-(2-hydroxyethyl)acetamide (110 35 droxyacetate (6.85 g, 65.8 mmol. 1.0 eq) and 1-methylpip erazine (5.26 g, 52.6 mmol. 0.8 eq) were dissolved in 1,4- mg, 1.07 mmol, 2.43 eq) in THF (20 mL) at 0°C., NaH (60% dioxane (10 mL) in a sealed tube and the mixture was stirred in mineral oil, 110 mg, 2.75 mmol. 6.25 eq) was added and the at 120° C. overnight. The mixture was allowed to cool to RT resulting mixture was stirred for 15 min. To this mixture, and then concentrated in vacuo. The residue was purified by (S)-tert-butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethy flash column chromatography on silica gel (2% MeOH lamino)-9H-purine-9-carboxylate 39 (200 mg, 0.44 mmol. 40 DCM) to afford the product 2-hydroxy-1-(4-methyl piper 1.0 eq) was added. The resulting mixture was stirred at reflux azin-1-yl)ethanone. for 2 h, cooled to RT and then poured into water (30 mL). The Compound 42 was prepared in analogous fashion to com mixture was extracted with DCM (3x30 mL). The combined pound 40 in Example 25 except that 2-hydroxy-1-(4-meth organic layers were washed with brine, dried over NaSO ylpiperazin-1-yl)ethanone was used in place of N-(2-hy and filtered. The filtrate was concentrated in vacuo and the 45 droxyethyl)acetamide in step 2. ESI-MS m/z: 481.0M+H". residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)-N- Example 27 (2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1- 43 yloxy)ethyl)acetamide 40. ESI-MS m/z: 426.0 M+H". 50 Example 26 s 55

N 2

O -e- HO N-1 1,4-dioxane sh Sealed tube, 60 O 120° C. r y N ls-- r 65 Compound 43 was prepared in analogous fashion to com O pound 42 in Example 26 except that morpholine was used in place of N-methylpiperidine. ESI-MS m/z: 468.0 M+H". US 8,901,133 B2 181 182 Example 28 -continued

C C O NN 10 2 SH

15 N NCC) N Compound 44 was prepared in analogous fashion to com 46 pound 42 in Example 26 except that methylamine was used in Compound 46 was prepared from compound 38 according place of N-methylpiperidine. ESI-MS m/z. 412.0 M+H". to the following procedure: To a mixture of (S)- N-(1-(1,8-dichloroisoquinolin-3-yl) Example 29 ethyl)-9H-purin-6-amine 38 (300 mg, 0.84 mmol. 1 eq) in 1,4-dioxane (10 mL) at RT 1-methylpiperazine (167 mg, 1.68 25 mmol. 2 eq) was added and the resulting mixture was stirred at reflux for 8 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by flash 45 column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)- N-(1-(8-chloro-1-(4-methylpiper 30 azin-1-yl)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 46. ESI-MS m/z: 423.2 M+H". Example 31 C C 35 n N N 1s 2 i HO 40 NH NaH, THF N21 y ls Compound 45 was prepared in analogous fashion to com 45 N1 N pound 42 in Example 26 except that pyrrolidine was used in 38 place of N-methylpiperidine. ESI-MS m/z. 452.2 M+H". Example 30 1. 50

C O C C NN 55 NN 21 4N -e- SH

sh 60 N 2 N lyN N21 y N1 N 47 65 38 Compound 47 was prepared from 38 according to the fol lowing procedure: