US008263610B2

(12) United States Patent (10) Patent No.: US 8.263,610 B2 Ali et al. (45) Date of Patent: Sep. 11, 2012

(54) SUBSTITUTED (56) References Cited IMIDAZOLYL-5,6-DIHYDROBENZONISO QUINOLINE COMPOUNDS U.S. PATENT DOCUMENTS 4,522,811 A 6/1985 Eppstein et al. (75) Inventors: Syed M. Ali, North Andoyer, MA (US); 2005/01434424,612,318 AA1 * 9/19866/2005 WintersHudkins et...... al. 514,293 Mark A. Ashwell, Carlisle, MA (US); 2008.0160028 A1 7/2008 Reicheltet al. Chris Brassard, Somerville, MA (US); Audra Dalton, Revere, MA (US); Anton FOREIGN PATENT DOCUMENTS Filikov, Stoneham, MA (US); Jason EP 104522 A2 4, 1984 Hill, Auburndale, MA (US); Nivedita EP 1238979 A1 9, 2002 Namdev, Westford, MA (US); Rocio E. A. is: Palma, North Andover, MA (US); SU 1626648 A1 9, 1995 Manish Tandon, Framingham, MA WO WO-O 144244 A1 6, 2001 (US); David Vensel, Boston, MA (US); WO WO-2005OO9389 A2 2/2005 JianqiangWang, Acton, MA (US); Neil WO WO-2006010567 A1 2/2006 Westlund, Groton, MA (US) WO WO-2007095628 A1 8, 2007 s s OTHER PUBLICATIONS

(73) Assignee: ArCule, Inc., Woburn, MA (US) Diaz-ortizDaz-Ortiz etet al.,al., “Synthesis Tetrahedron, of Pyrazolo56(2000), 3,4-bipyridines pp. 1569-1577. by Cycload (*) b discl h f thi dition Reactions under Microwave Irradiation', Tetrahedron, Notice: Subject to any disclaimer, the term of this 56(11): 1569-1577 (2000). patent is extended or adjusted under 35 International Search Report and Written Opinion for PCT/US2009/ U.S.C. 154(b) by 165 days. 069821, mailed on Apr. 27, 2010. Paronikyan et al. “Synthesis and Anticonvulsant Activity of Pyrazolo 3,4-bipyrano (thiopyrano04,3-dipyridine and (21) Appl. No.: 12/649,762 pyrazolo 3,4-c isoquinoline Derivatives.” Pharm. Chem. J. 35.1(2001):8-10. Paronikyan et al. “Synthesis and Some Conversions of Partially (22) Filed: Dec. 30, 2009 Hydrogenated 1-Aminopyrano(thiopyrano)4,3-dipyrazolo 3,4- bipyridines and pyrazolo 3,4-c isoquinolines.” Chemistry of H ereocycticlic CUompounas. ds. 39.3(2003):374-378: (65) Prior Publication Data Sharlow et al. “Development and Implementation of a Miniaturized US 2010/O239526A1 Sep. 23, 2010 High-Throughput Time-Resolved Fluorescence Energy Transfer Assay to Identify Small Molecule Inhibitors of Polo-Like Kinase 1.” O O ASSAY and Drug Development Technologies. 5.6(2007):723-726. Related U.S. Application Data Winters et al. “Easy Synthesis of New Ring-Fused Pyridones from (60) Provisional application No. 61/141,371, filed on Dec. Heteroaromatic B-vinylamines.” Synthesis. 12(1984): 1052-1054. 30, 2008. * cited by examiner Primary Examiner — Niloofar Rahmani (51) Int. Cl. (74) Attorney, Agent, or Firm — Mintz Levin Cohn Ferris AOIN 43/42 (2006.01) Glovsky and Popeo, P.C.: Ivor R. Elrifi; Matthew Pavao, J.D. A6 IK3I/44 (2006.01) (57) ABSTRACT CO7D 47L/00 (2006.01) The present invention relates to substituted imidazolyl-5,6- CO7D 49/00 (2006.01) dihydrobenzonisoquinoline compounds and methods of CO7D 49.8/00 (2006.01) synthesizing these compounds. The present invention also CO7D 53/00 (2006.01) relates to pharmaceutical compositions containing Substi C07D 515/00 (2006.01) tuted imidazolyl-5,6-dihydrobenzonisoquinoline com (52) U.S. Cl...... 514/293; 546/82 pounds and methods of treating cell proliferative disorders, (58) Field of Classification Search 546/82 Such as cancer, by administering these compounds and phar ------5141293 maceutical compositions to Subjects in need thereof. See application file for complete search history. 21 Claims, No Drawings US 8,263,610 B2 1. 2 SUBSTITUTED is abnormally active (overexpressed) in certain types of stom IMIDAZOLYL-5,6-DIHYDROBENZONISO ach cancers, and this amplification is associated with a poorer QUINOLINE COMPOUNDS prognosis and response to standard clinical methods. Abnor mal expression of FGFR2 is also found in patients with pros CROSS-REFERENCE TO RELATED tate cancer. More than 60 percent of women with breast APPLICATIONS cancer in the United States carry at least a single mutation in this gene as well. The present application claims priority to, and the benefit of, U.S. Provisional Application No. 61/141,371, filed Dec. Accordingly, new compounds and methods for modulating 30, 2008. The contents of this application is herein incorpo 10 FGFR2 and treating proliferation disorders, including cancer, rated by reference in its entirety. are needed. The present invention addresses these needs.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION Cancer is the second leading cause of death in the United 15 States, exceeded only by heart disease. (Cancer Facts and The present invention provides, in part, Substituted imida Figures 2004, American Cancer Society, Inc.). Despite recent Zolyl-5,6-dihydrobenzonisoquinoline compounds of For advances in cancer diagnosis and treatment, Surgery and mula I, II, III or IV and methods of preparing the compounds radiotherapy may be curative if a cancer is found early, but of Formula I, II, III or IV: current drug therapies for metastatic disease are mostly pal liative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for (I) new drugs effective in monotherapy or in combination with Rc2 existing agents as first line therapy, and as second and third N-N^ line therapies in treatment of resistant tumors. 25 W Cancer cells are by definition heterogeneous. For example, Rel a NN within a single tissue or cell type, multiple mutational "mechanisms' may lead to the development of cancer. As Rc4 S Such, heterogeneity frequently exists between cancer cells taken from tumors of the same tissue and same type that have 30 X originated in different individuals. Frequently observed R1 Nx1 mutational "mechanisms' associated with some cancers may (II) differ between one tissue type and another (e.g., frequently observed mutational "mechanisms' leading to colon cancer may differ from frequently observed “mechanisms' leading 35 to leukemias). It is therefore often difficult to predict whether a particular cancer will respond to a particular chemothera peutic agent (Cancer Medicine, 5' edition, Bast et al., B.C. Decker Inc., Hamilton, Ontario). Components of cellular signal transduction pathways that 40 regulate the growth and differentiation of normal cells can, when dysregulated, lead to the development of cellular pro (III) liferative disorders and cancer. Mutations in cellular signal Rc2 ing proteins may cause Such proteins to become expressed or N-N? activated at inappropriate levels or at inappropriate times 45 W during the cell cycle, which in turn may lead to uncontrolled Rel 21 NN cellular growth or changes in cell-cell attachment properties. For example, dysregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification, and over N expression of both receptor and ligand has been implicated in 50 the development and progression of human cancers. Rc6, FGFR2 is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved Rc5 between members and throughout evolution. FGFR family members differ from one another in their ligandaffinities and 55 tissue distribution. A full-length representative protein con (IV) sists of an extracellular region, composed of three immuno Rc2 globulin-like domains, a single hydrophobic membrane N-N? spanning segment and a cytoplasmic tyrosine kinase domain. W The extracellular portion of the protein interacts with fibro 60 Rel 21 NN blast growth factors, setting downstream signals, ultimately influencing mitogenesis and differentiation. Rc4 N Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers. The altered gene expres sion may enhance several cancer-related events such as cell 65 R Y Rc6, proliferation, cell movement, and the development of new blood vessels that nourish a growing tumor. The FGFR2 gene US 8,263,610 B2 3 4 or a salt, Solvate, hydrate or prodrug thereof, wherein: the atom they attach to, form a 5-, 6- or 7-member ring which comprises 1-4 heteroatoms selected from N, O and S and is optionally substituted; R, is H, unsubstituted or substituted Co-Co aryl, unsub stituted or substituted heteroaryl comprising one or two 5- or O 6-member ring and 1-4 heteroatoms selected from N, O and S. unsubstituted or Substituted C-Cs carbocycle, unsubstituted is a 5- or 6-member ring which optionally comprises 1-4 or Substituted heterocycle comprising one or two 5- or heteroatoms selected from N, O and S, and is optionally 6-member ring and 1-4 heteroatoms selected from N, O and S. substituted; 10 - NRR', NR"C(O)NR'R'', NR"C(O)R - NR"C R is H. halogen, unsubstituted or Substituted C-C alkyl, (O)OR - NR"S(O).R., or—C(O)NR'R'; unsubstituted or substituted phenyl, or unsubstituted or sub Rs and Rs' are each independently H, or-T'-Q,"; stituted heteroaryl comprising one or two 5- or 6-member ring R" is H, or unsubstituted or substituted C-C alkyl; and 1-4 heteroatoms selected from N, O and S; 15 T.T., and Ts are each independently a bond, or unsub R is H, or unsubstituted or substituted C-C alkyl: stituted or substituted C-C alkyl linker; R. and Ra are each independently H, unsubstituted or Q, is H, unsubstituted or substituted Co-Co aryl, unsub Substituted C-C alkyl, or R and Ra, together with the stituted or substituted heteroaryl comprising one or two 5- or atoms they attach to, form a 5-, 6- or 7-member ring which 6-member ring and 1-4 heteroatoms selected from N, O and S. optionally comprises 1-4 heteroatoms selected from N, O and unsubstituted or Substituted C-Cs carbocycle, unsubstituted Sand is optionally substituted; or Substituted heterocycle comprising one or two 5- or Rs and R are each independently H, unsubstituted or 6-member ring and 1-4 heteroatoms selected from N, O and S. substituted C-C alkyl, or unsubstituted or substituted —C(O)CR, —C(O)R. —C(O)NRR', or—NRR"; Co-Co aryl; Q," is H, unsubstituted or substituted Co-Cls aryl, unsub each R, is independently halogen, hydroxyl, cyano, nitro, 25 stituted or substituted heteroaryl comprising one or two 5- or amino, unsubstituted or Substituted C-C alkoxy, unsubsti 6-member ring and 1-4 heteroatoms selected from N, O and S. tuted or Substituted C-C alkyl, —C(O)R. unsubstituted or Substituted C-Cs carbocycle, unsubstituted C(O)OR, —NHC(O)R —NHC(O)OR; or Substituted heterocycle comprising one or two 5- or n is 0, 1, 2, 3, or 4: 6-member ring and 1-4 heteroatoms selected from N, O and S. X-X, is CH, CHR, CH, NR, CR.R.' O, CH, 30 —C(O)CR, —C(O)R. —C(O)NRR', or—NRR"; CH NR, or X'-X.'; Q, is H, unsubstituted or substituted Co-Co aryl, unsub X-X" is CHR-CHR CHR, O, O CHR, stituted or substituted heteroaryl comprising one or two 5- or CHR CHR-CHR-CHR, CHR-CHR. O. 6-member ring and 1-4 heteroatoms selected from N, O and S. O—CHR-CHR2, CHR-O-CHR2, CHR, S, unsubstituted or Substituted C-Cs carbocycle, unsubstituted S CHR CHR-CHR, NR, CR.R.' O, CHR, 35 or Substituted heterocycle comprising one or two 5- or NR, CHR, or NR CHR-CHR: 6-member ring and 1-4 heteroatoms selected from N, O and S. Ryal, Rya2. Rt. Re. Rya, Ryaz, Rya. Rye. Re2, O Rare —C(O)CR, —C(O)R. —C(O)NR'R'', or — each independently H, unsubstituted or substituted C-C, NRR'; and alkyl, or unsubstituted or substituted phenyl: R. R. R. and R' are each independently H, unsub R and R. are each independently unsubstituted or Sub 40 stituted or substituted C-C alkyl, unsubstituted or substi stituted C-C aryl, unsubstituted or substituted heteroaryl tuted C-C aryl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member ring and 1-4 heteroa comprising one or two 5- or 6-member ring and 1-4 heteroa toms selected from N, O and S, unsubstituted or substituted toms selected from N, O and S. C-Cs carbocycle, unsubstituted or Substituted heterocycle The present invention also provides pharmaceutical com comprising one or two 5- or 6-member ring and 1-4 heteroa 45 positions comprising one or more compounds of Formula I, toms selected from N, O and S, or R and R', together with II, III or IV and one or more pharmaceutically acceptable the atom they attach to, form a 5-, 6- or 7-member ring which carriers. comprises 0-4 heteroatoms selected from N, O and S and is The present invention also provides methods of treating a optionally substituted; cell proliferative disorder by administering to a subject in Riis H. unsubstituted or Substituted C-C alkyl, unsub 50 need thereof, a therapeutically effective amount of a com stituted or Substituted Co-Co aryl, or unsubstituted or Substi pound of Formula I, II, III or IV, or a pharmaceutically accept tuted heteroaryl comprising one or two 5- or 6-member ring able salt, prodrug, metabolite, analog or derivative thereof, in and 1-4 heteroatoms selected from N, O and S; combination with a pharmaceutically acceptable carrier, Such Y is NR, or CHR.'; that the disorder is treated. R is H, unsubstituted or substituted Co-Co aryl, unsubsti 55 The present invention also provides methods of treating tuted or substituted heteroaryl comprising one or two 5- or cancer by administering to a Subject in need thereof, a thera 6-member ring and 1-4 heteroatoms selected from N, O and S. peutically effective amount of a compound of Formula I, II, unsubstituted or Substituted C-Cs carbocycle, unsubstituted III or IV, or a pharmaceutically acceptable salt, prodrug, or Substituted heterocycle comprising one or two 5- or metabolite, analog or derivative thereof, in combination with 6-member ring and 1-4 heteroatoms selected from N, O and S. 60 a pharmaceutically acceptable carrier, such that the cancer is —S(O).R. —C(O)R. —C(O)CR, —(CH).R. treated. —C(=NH)NRR', —C(O)NRR', or - C(S)NRR'; The present invention also provides methods of selectively o is 0, 1, 2, 3, or 4: inducing cell death in precancerous or cancerous cells by R is H. unsubstituted or substituted C-C alkyl, or-T- contacting a cell with an effective amount of a compound of Q.: 65 Formula I, II, III or IV, or a pharmaceutically acceptable salt, R. and R are each independently H, unsubstituted or prodrug, metabolite, analog or derivative thereof, in combi substituted C-C alkyl, -Ts-Qs, or R2 and R2', together with nation with a pharmaceutically acceptable carrier, Such that US 8,263,610 B2 5 6 contacting the cell results in selective induction of cell death Ris RY2s Rt. R e Rya, Ryaz, Rya. R rel, RSre2. Of Rare in the precancerous or cancer cells. each independently H, unsubstituted or substituted C-C, Unless otherwise defined, all technical and scientific terms alkyl, or unsubstituted or substituted phenyl: used herein have the same meaning as commonly understood R and R are each independently unsubstituted or Sub by one of ordinary skill in the art to which this invention stituted C-C aryl, unsubstituted or substituted heteroaryl belongs. In the specification, the singular forms also include comprising one or two 5- or 6-member ring and 1-4 heteroa the plural unless the context clearly dictates otherwise. toms selected from N, O and S, unsubstituted or substituted Although methods and materials similar or equivalent to C-C carbocycle, unsubstituted or substituted heterocycle those described herein can be used in the practice or testing of comprising one or two 5- or 6-member ring and 1-4 heteroa the present invention, Suitable methods and materials are 10 toms selected from N, O and S, or R and R', together with described below. All publications, patent applications, pat the atom they attach to, form a 5-, 6- or 7-member ring which ents, and other references mentioned herein are incorporated comprises 0-4 heteroatoms selected from N, O and S and is by reference. The references cited herein are not admitted to optionally substituted; be prior art to the claimed invention. In the case of conflict, the 15 R is H. unsubstituted or substituted Co-Co aryl, unsubsti present specification, including definitions, will control. In tuted or substituted heteroaryl comprising one or two 5- or addition, the materials, methods, and examples are illustra 6-member ring and 1-4 heteroatoms selected from N, O and S. tive only and are not intended to be limiting. unsubstituted or substituted C-C carbocycle, unsubstituted Other features and advantages of the invention will be or Substituted heterocycle comprising one or two 5- or apparent from the following detailed description and claims. 6-member ring and 1-4 heteroatoms selected from N, O and S. —S(O).R. —C(O)R. —C(O)CR, —(CH).R. DETAILED DESCRIPTION OF THE INVENTION - C(-NH)NRR', —C(O)NRR', or - C(S)NRR'; o is 0, 1, 2, 3, or 4: 1. The Substituted R is H, unsubstituted or substituted C-C alkyl, or-T- Imidazolyl-5,6-Dihydrobenzon Isoquinoline 25 Q,1: Compounds R. and R are each independently H, unsubstituted or substituted C-C alkyl, -Ts-Qs, or R2 and R2', together with The present invention provides novel substituted imida the atom they attach to, form a 5-, 6- or 7-member ring which Zolyl-5,6-dihydrobenzonisoquinoline compounds, Syn comprises 1-4 heteroatoms selected from N, O and S and is thetic methods for making the compounds, pharmaceutical 30 optionally substituted; compositions containing them and the use of the disclosed R, is H, unsubstituted or substituted Co-Co aryl, unsub compounds. stituted or substituted heteroaryl comprising one or two 5- or The compounds of the present invention include substi 6-member ring and 1-4 heteroatoms selected from N, O and S. tuted imidazolyl-5,6-dihydrobenzonisoquinoline com unsubstituted or Substituted C-Cs carbocycle, unsubstituted pounds of Formula I: 35 or Substituted heterocycle comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S. - NRR', NR"C(O)NR'R'', NR"C(O)R - NR"C R (I) (O)OR - NR"S(O).R., or –C(O)NR'R'; 2 Rs and Rs' are each independently H, or-T'-Q.: N-y 40 R" is H, or unsubstituted or substituted C-C alkyl: W T.T., and Ts are each independently a bond, or unsub stituted or substituted C-C alkyl linker; Rel 21 N, Q, is H, unsubstituted or substituted Co-Co aryl, unsub Rc4 N stituted or substituted heteroaryl comprising one or two 5- or 45 6-member ring and 1-4 heteroatoms selected from N, O and S. unsubstituted or Substituted C-Cs carbocycle, unsubstituted X or Substituted heterocycle comprising one or two 5- or R1 Nx1 6-member ring and 1-4 heteroatoms selected from N, O and S. —C(O)CR, —C(O)R. —C(O)NRR', or—NRR"; or a salt, Solvate, hydrate or prodrug thereof, wherein: 50 Q," is H, unsubstituted or substituted Co-Cls aryl, unsub R is H. halogen, unsubstituted or Substituted C-C alkyl, stituted or substituted heteroaryl comprising one or two 5- or unsubstituted or substituted phenyl, or unsubstituted or sub 6-member ring and 1-4 heteroatoms selected from N, O and S. stituted heteroaryl comprising one or two 5- or 6-member ring unsubstituted or Substituted C-Cs carbocycle, unsubstituted and 1-4 heteroatoms selected from N, O and S; or Substituted heterocycle comprising one or two 5- or R is H, or unsubstituted or substituted C-C alkyl: 55 6-member ring and 1-4 heteroatoms selected from N, O and S. R. and Ra are each independently H, unsubstituted or —C(O)CR, —C(O)R. —C(O)NRR', or—NRR"; Substituted C-C alkyl, or R and Ra, together with the Q, is H, unsubstituted or substituted Co-Co aryl, unsub atoms they attach to, form a 5-, 6- or 7-member ring which stituted or substituted heteroaryl comprising one or two 5- or optionally comprises 1-4 heteroatoms selected from N, O and 6-member ring and 1-4 heteroatoms selected from N, O and S. Sand is optionally substituted; 60 unsubstituted or Substituted C-Cs carbocycle, unsubstituted X-X, is CH, CHR, CH, NR, CR.R.' O, CH, or Substituted heterocycle comprising one or two 5- or CH NR, or X'-X.'; 6-member ring and 1-4 heteroatoms selected from N, O and S. X-X," is CHR-CHR CHR, O, O CHR, OOR, , —C(O)R. —C(O)NR'R'', or—NRR'; CHR, CHR-CHR-CHRs, CHR-CHR. O. al O—CHR-CHR2, CHR-O-CHR2, CHR, S, 65 R. R. R. and R' are each independently H, unsub S CHR CHR-CHR, NRCR.R.' O, CHR, stituted or substituted C-C alkyl, unsubstituted or substi NR, CHR, or NR CHR CHR; tuted C-C aryl, or unsubstituted or substituted heteroaryl US 8,263,610 B2 7 8 comprising one or two 5- or 6-member ring and 1-4 heteroa S-butyl, t-butyl, n-pentyl, S-pentyl and n-hexyl, each of which toms selected from N, O and S. is optionally substituted with halogen (e.g., fluorine, chlorine, For example, R is H. bromine and iodine)), Co-Co aryl (e.g., phenyl, which is For example, R is fluorine, chlorine, bromine, or iodine. optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. For example, R is unsubstituted or Substituted, straight thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet chain or branched C-C alkyl, including but not limited to, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, pyridazinyl, and pyrimidinyl, and the like, and is optionally n-pentyl, S-pentyl, and n-hexyl. Substituted), C-C carbocycle (e.g., cyclopropyl, cyclobutyl, For example, R is methyl. cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally For example, R is unsubstituted phenyl. 10 Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi For example, R is phenyl substituted with one or more nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. and the like, and is optionally Substituted). n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 15 For example, R is heteroaryl selected from furanyl, pyra of which is optionally substituted with halogen (e.g., fluorine, Zolyl, purinyl, indolyl, tetrahydropyridinyl, and pyrrolopyri chlorine, bromine, and iodine)), unsubstituted or substituted midinyl, and is optionally Substituted with one or more C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, groups, each of which can be the same of different, selected butoxy, i-butoxy, and t-butoxy, each of which is optionally from methyl, ethyl, t-butyl, amino, and heterocycle (e.g., Substituted with halogen (e.g., fluorine, chlorine, bromine, piperidinyl, which is optionally substituted). and iodine)), and -T-Q, wherein: For example, R is H. T is a bond, or unsubstituted or Substituted C-C alkyl For example, R is unsubstituted or Substituted, straight linker; chain or branched C-C alkyl, including but not limited to, Q is H. —NRR', methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, R. —NHC(O)OR, 25 n-pentyl, S-pentyl, and n-hexyl. —S(O).R., and For example, R is methyl substituted with unsubstituted R, and Rare each independently H, or unsubstituted phenyl. or substituted C-C alkyl. For example, R is methyl substituted with phenyl substi For example, R is phenyl substituted with one or more tuted with one or more groups, each of which can be the same groups, each of which can be the same or different, selected 30 or different, selected from hydroxyl, halogen, nitro, cyano, from -T-Q. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, T is a bond. n-propyl, i-propyl. n-butyl, s-butyl, t-butyl, n-pentyl, s-pen For example, T is unsubstituted or substituted C-C, tyl, and n-hexyl, each of which is optionally substituted with alkyl linker, including but not limited to, methyl, ethyl, n-pro halogen (e.g., fluorine, chlorine, bromine, and iodine)), and pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and 35 unsubstituted or substituted C-C alkoxy (e.g., methoxy, n-hexyl linker. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, T is a methyl linker. toxy, each of which is optionally substituted with halogen For example, Q is H. (e.g., fluorine, chlorine, bromine, and iodine)). For example, both R and Rare H. For example, R is methyl substituted with phenyl substi For example, at least one of R and R is unsubstituted 40 tuted with one or more groups, each of which can be the same or Substituted, straight-chain or branched C-C alkyl, includ or different, selected from methyl, ethyl, t-butyl, and trifluo ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu romethyl. tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is methyl substituted with phenyl substi For example, at least one of R and R' is methyl, ethyl tuted with one or more groups, each of which can be the same or t-butyl. 45 or different, selected from methoxy, ethoxy, i-propyloxy, and For example, R is phenyl substituted with one or more t-butoxy. groups, each of which can be the same or different, selected For example, R is H. from methyl, ethyl, t-butyl and trifluoromethyl. For example, R is unsubstituted or Substituted, straight For example, R is phenyl substituted with one or more chain or branched C-C alkyl, including but not limited to, groups, each of which can be the same or different, selected 50 methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, from methoxy, t-butoxy and trifluoromethoxy. n-pentyl, S-pentyl, and n-hexyl. For example, R is phenyl substituted with two or more For example, R is H. groups, each of which can be the same or different, selected For example, R is unsubstituted or Substituted, straight from hydroxyl, cyano, methyl, ethyl, t-butyl, trifluoromethyl, chain or branched C-C alkyl, including but not limited to, methoxy, t-butoxy, trifluoromethoxy, and halogen. 55 methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, For example, R is heteroaryl selected from pyrrolyl, fura n-pentyl, S-pentyl, and n-hexyl. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, both of R and R are H. razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, R. and Ra, together with the atoms they pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, attach to, form a 5- or 6-member ring selected from: benzothiazolyl, benzoimidazolyl, benzothienyl, methylene 60 1) phenyl, which is optionally substituted with one or more dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, groups, each of which can be the same or different, selected indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and imidazothiazolyl, quinoxalinyl, tetrahydropyridinyl, pyrrol iodine), cyano, nitro, unsubstituted or Substituted amino, opyrimidinyl, and the like, and is optionally substituted with unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub 65 n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen stituted or substituted amino, unsubstituted or substituted tyl, and n-hexyl), unsubstituted or Substituted C-C alkoxy C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu US 8,263,610 B2 9 10 toxy, and t-butoxy), —C(O)R. —C(O)CR —NHC including but not limited to, methyl, ethyl, n-propyl, i-propyl. (O)R —NHC(O)OR, and —C(O)NRR): n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. 2) heteroaryl (e.g., pyrrolyl pyrazolyl, imidazolyl, For example, R is H. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxa For example, Riis unsubstituted or Substituted, straight diazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, chain or branched C-C alkyl, including but not limited to, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thienyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, and pyridinone, and the like, and is optionally Substituted n-pentyl, S-pentyl, and n-hexyl. with one or more groups, each of which can be the same or For example, R is methyl. different, selected from hydroxyl, halogen (e.g., fluorine, For example, both of R and R are H. 10 For example, at least one of Rs 1 and R2 is -T-Qs. chlorine, bromine, and iodine), unsubstituted or substituted For example, T is a bond. C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, For example, T is unsubstituted or Substituted C-C, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl), unsubsti alkyl linker, including but not limited to, methyl, ethyl, n-pro tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy), unsub 15 n-hexyl linker. stituted or Substituted phenyl, -NRR, and —SR); For example, T is a methyl, ethyl, or propyl linker. 3) carbocycle (e.g., cyclopropyl, cyclobutyl, cyclopentyl, For example, Q is H. cyclohexyl, or cycloheptyl, and is optionally Substituted); or For example, Q is unsubstituted phenyl. 4) heterocycle (e.g., pyrrolidinyl, imidazolidinyl, pyrazo For example, Q is phenyl Substituted with one or more lidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahy groups, each of which can be the same or different, selected drofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and like, and is optionally substituted), iodine), cyano, nitro, unsubstituted or Substituted amino, wherein: unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, Rand Rare each independently H, unsubstituted or n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen substituted C-C alkyl, unsubstituted or substituted 25 tyl, and n-hexyl, each of which is optionally substituted with Co-Co aryl, or unsubstituted or Substituted heteroaryl halogen (e.g., fluorine, chlorine, bromine, and iodine)), comprising one or two 5- or 6-member ring and 1-4 unsubstituted or Substituted C-C alkoxy (e.g., methoxy, heteroatoms selected from N, O and S; ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu Rs 1 and R2 are each independently H, -T-Qs, or Rs toxy, each of which is optionally substituted with halogen and R, together with the atom they attach to, form a 5 30 (e.g., fluorine, chlorine, bromine, and iodine)). or 6-member ring which optionally comprises 1-4 het For example, Q is phenyl Substituted with one or more eroatoms selected from N, O and S and is optionally groups, each of which can be the same or different, selected Substituted; from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, T is a bond, or unsubstituted or Substituted C-C alkyl t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and linker; 35 iodine). Q is H, unsubstituted or substituted phenyl, unsubstituted For example, Q is phenyl substituted with two or more or Substituted heteroaryl comprising one or two 5- or groups, each of which can be the same or different, selected 6-member ring and 1-4 heteroatoms selected from N.O from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, and S, unsubstituted or Substitute C-C carbocycle, t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and unsubstituted or Substituted heterocycle comprising one 40 iodine). or two 5- or 6-member ring and 1-4 heteroatoms selected For example, Q is heteroaryl selected from pyrrolyl, fura from N, O and S, or —OR; and nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet R is H. unsubstituted or Substituted C-C alkyl, or razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, unsubstituted or substituted phenyl. pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, For example, R. and Ra, together with the atoms they 45 benzothiazolyl, benzoimidazolyl, benzothienyl, methylene attach to, form a phenyl optionally substituted with one or dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, more groups, each of which can be the same or different, indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bro imidazothiazolyl, and quinoxalinyl, and the like, and is mine, and iodine), cyano, nitro, methyl, ethyl, t-butyl, triflu optionally substituted. omethyl, methoxy, ethoxy, t-butoxy, and —NHC(O)R. 50 For example, Q is pyridinyl. For example, R. and Ra, together with the atoms they For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, attach to, form a phenyl optionally substituted with two or cyclohexyl, or cycloheptyl, and is optionally Substituted. more groups, each of which can be the same or different, For example, Q is cycloheptyl. selected from hydroxyl, halogen (e.g., fluorine, chlorine, bro For example, Q is heterocycle selected from pyrrolidinyl, mine, and iodine), cyano, nitro, methyl, ethyl, t-butyl, triflu 55 imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, omethyl, methoxy, ethoxy, t-butoxy, and —C(O)R. triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, For example, R. and Ra, together with the atoms they morpholinyl, and pyrrolidinone, and the like, and is option attach to, form a heteroaryl selected from imidazolyl, thiaz ally Substituted with one or more groups, each of which can olyl pyridinyl, pyridinone, pyrimidinyl, furanyl, or thienyl, be the same or different, selected from hydroxyl, halogen each of which is optionally substituted with one or more 60 (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted groups, each of which can be the same or different, selected or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. from halogen (e.g., fluorine, chlorine, bromine, and iodine), i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and methyl, ethyl, t-butyl, trifluromethyl, methoxy, ethoxy, t-bu n-hexyl). toxy, phenyl, -NR, R2, and —SR. For example, Q is pyrrolidinyl, piperidinyl, morpholinyl, For example, both R. and R. are H. 65 or pyrrolidinone, and is optionally substituted with methyl, For example, at least one of R and R is unsubsti ethyl, or t-butyl. tuted or Substituted, straight-chain or branched C-C alkyl, For example, Q is —OR. US 8,263,610 B2 11 12 For example, R is H. dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz For example, R is unsubstituted or substituted, straight inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is chain or branched C-C alkyl, including but not limited to, optionally substituted. methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, For example, R is cyclopropyl, cyclobutyl, cyclopentyl, n-pentyl, S-pentyl, and n-hexyl. cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, R is phenyl, and is optionally Substituted. For example, R is heterocycle selected from pyrrolidi For example, R. and R, together with the atom they nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi attach to, form a 5- or 6-member ring selected from pyrro nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo morpholinyl, and pyrrolidinone, and the like, and is option lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi 10 ally substituted. nyl, and the like and is optionally substituted with one or more For example, R is pyrrolidinyl. groups, each of which can be the same or different, selected For example, R. and R, together with the atom they from -T-Q, wherein: attach to, form a 5- or 6-member ring selected from pyrro Ta is a bond, or unsubstituted or substituted C-C alkyl lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo linker; 15 lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi Q is H. unsubstituted or substituted phenyl, unsubstituted nyl, and the like and is optionally substituted with two or more or Substituted heteroaryl comprising one or two 5- or groups, any adjacent two of which, together with the atoms 6-member ring and 1-4 heteroatoms selected from N.O they attach to form a 5- or 6-member which optionally com and S, unsubstituted or Substitute C-C carbocycle, prises 1-4 heteroatoms selected from N, O and S and is unsubstituted or Substituted heterocycle comprising one optionally substituted. or two 5- or 6-member ring and 1-4 heteroatoms selected For example, R. and R, together with the atom they from N, O and S. —C(O)R. —C(O)OR, and attach to, form a 5- or 6-member ring selected from pyrro Ra is H. unsubstituted or substituted phenyl, unsubsti lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo tuted or substituted heteroaryl comprising one or two 5 lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi or 6-member ring and 1-4 heteroatoms selected from N. 25 nyl, and the like and is optionally substituted with two or more O and S, unsubstituted or substitute C-C carbocycle, groups, any adjacent two of which, together with the atoms unsubstituted or Substituted heterocycle comprising one they attach to form a phenyl ring, which is optionally Substi or two 5- or 6-member ring and 1-4 heteroatoms selected tuted. from N, O and S. For example, R. and Ra, together with the atoms they For example, R. and R, together with the atom they 30 attach to, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclo attach to, form a 5- or 6-member ring selected from a pyrro hexyl, or cycloheptyl, and is optionally substituted. lidinyl, piperidinyl, piperazinyl, or morpholinyl, and is For example, R. and R, together with the atoms they optionally substituted. attach to, form a heterocycle selected from pyrrolidinyl, imi For example, T is a bond. dazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, tria For example, T is unsubstituted or substituted C-C, 35 Zolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, mor alkyl linker, including but not limited to, methyl, ethyl, n-pro pholinyl, and pyrrolidinone, and the like, and is optionally pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and substituted. n-hexyl linker. For example, X-X is CRR. O. For example, T is a methyl linker. For example, X-X is CRR O where R and R', For example, Q is unsubstituted phenyl. 40 together with the atom they attach to, form a ring. For example, Q is heteroaryl selected from pyrrolyl, fura For example, X-X is CRR O where R and R', nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet together with the atom they attach to, forman unsubstituted or razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, substituted heterocycle. pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, For example, X-X is CRR O where R and R', benzothiazolyl, benzoimidazolyl, benzothienyl, methylene 45 together with the atom they attach to, forman unsubstituted or dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, Substituted piperidine ring. indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, For example, X-X, is CH, NR. imidazothiazolyl, and quinoxalinyl, and the like, and is For example, R, is H. optionally substituted. For example, R, is unsubstituted phenyl. For example, Q is pyridinyl. 50 For example, R, is phenyl substituted with one, two, three For example, Q is cyclopropyl, cyclobutyl, cyclopentyl, or more groups, each of which can be the same or different, cyclohexyl, or cycloheptyl, and is optionally substituted. selected from hydroxyl, halogen, nitro, cyano, unsubstituted For example, Q, is heterocycle selected from pyrrolidinyl, or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 55 n-hexyl, each of which is optionally substituted with halogen morpholinyl, and pyrrolidinone, and the like, and is option (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted ally substituted. or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy For example, Q is morpholinyl. loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene For example, Q is —C(O)R. dioxy, each of which is optionally substituted with halogen For example, R is H. 60 (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) For example, R is phenyl and is optionally substituted. R. —NHC(O)OR, —C(O)R, and —C(O)CR, For example, R is heteroaryl selected from pyrrolyl, wherein Riis H, or unsubstituted or Substituted C-C alkyl furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi tyl, n-pentyl, S-pentyl, and n-hexyl). nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox 65 For example, R, is phenyl substituted with one, two, three azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, or more groups, each of which can be the same or different, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry selected from halogen (e.g., fluorine, chlorine, bromine, and US 8,263,610 B2 13 14 iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, is unsubstituted naphthyl. For example, R, is cyclopropyl. For example, R, is naphthyl substituted with one, two, 5 For example, R, is heterocycle selected from pyrrolidinyl, three or more groups, each of which can be the same or imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, different, selected from hydroxyl, halogen, nitro, cyano, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, morpholinyl, and pyrrolidinone, and the like, and is option n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen ally Substituted with halogen (e.g., fluorine, chlorine, bro tyl, and n-hexyl, each of which is optionally substituted with 10 mine, and iodine)), unsubstituted or Substituted C-C alkoxy halogen (e.g., fluorine, chlorine, bromine, and iodine)), (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu unsubstituted or Substituted C-C alkoxy (e.g., methoxy, toxy, and t-butoxy, each of which is optionally substituted ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu with halogen (e.g., fluorine, chlorine, bromine, and iodine)). toxy, each of which is optionally substituted with halogen For example, R, is S(O).R, C(O)R, C(O)OR, (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) 15 —(CH2)R. R. —NHC(O)OR, —C(O)R and —C(O)OR, For example, o is 0. wherein Riis H, or unsubstituted or Substituted C-C alkyl For example, o is 1. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, R is H. tyl, n-pentyl, S-pentyl, and n-hexyl). For example, R is unsubstituted or Substituted, straight For example, R, is naphthyl substituted with one, two, chain or branched C-C alkyl, including but not limited to, three or more groups, each of which can be the same or methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, different, selected from halogen (e.g., fluorine, chlorine, bro n-pentyl, S-pentyl, and n-hexyl. mine, and iodine). For example, R is straight-chain or branched C-C alkyl For example, R, is heteroaryl selected from pyrrolyl, fura Substituted with one, two, three or more groups, each of nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet 25 which can be the same or different, selected from: razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 1) phenyl, which is optionally substituted with one or more pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox groups, each of which can be the same or different, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, selected from unsubstituted or substituted C-C alkyl benzoimidazolyl, benzothienyl, methylenedioxyphenyl, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura 30 t-butyl, n-pentyl, S-pentyl, and n-hexyl), and unsubsti nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, noxalinyl, and pyrrolopyrimidinyl, and the like, and is option propyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy); ally Substituted with one, two, three or more groups, each of 2) unsubstituted or substituted C-C alkoxy (e.g., meth which can be the same or different, selected from hydroxyl, oxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, halogen, nitro, cyano, unsubstituted or Substituted amino, 35 and t-butoxy); unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, 3) —C(O)OR; —C(O)R; and n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 4) —NRR, wherein: tyl, and n-hexyl, each of which is optionally substituted with R is H, or unsubstituted or substituted C-C alkyl: halogen (e.g., fluorine, chlorine, bromine, and iodine)), R12 and R1s are each independently H, -T2-Q2 or R2 unsubstituted or substituted C-C alkoxy (e.g., methoxy, 40 and R, together with the atom they attach to, form a ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu 5- or 6-member ring: toxy, each of which is optionally substituted with halogen T is a bond, or unsubstituted or substituted C-C alkyl (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) linker; Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, Q2 is H, hydroxyl, unsubstituted or substituted C-C, wherein R is H. unsubstituted or Substituted C-C alkyl 45 alkoxy, unsubstituted or Substituted Co-Co aryl, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu unsubstituted or Substituted heteroaryl comprising tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi one or two 5- or 6-member ring and 1-4 heteroatoms tuted C-C aryl, or unsubstituted or substituted heteroaryl selected from N, O and S, unsubstituted or substituted comprising one or two 5- or 6-member ring and 1-4 heteroa C-C carbocycle, unsubstituted or substituted het toms selected from N, O and S. 50 erocycle comprising one or two 5- or 6-member ring For example, R, is imidazolyl pyrazolyl, oxazolyl, isox and 1-4 heteroatoms selected from N, O and S, azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino —NRR', -C(O)R. —C(O)CRt.; and linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben R. and Rare each independently H, or unsubsti Zothiazolyl, benzothiadiazolyl, benzothienyl, O tuted or substituted C-C alkyl, unsubstituted or sub pyrrolopyrimidiyl, each of which is optionally substituted 55 stituted Co-Co aryl, or unsubstituted or Substituted with one, two, three or more groups, each of which can be the heteroaryl comprising one or two 5- or 6-member ring same or different, selected from selected from halogen (e.g., and 1-4 heteroatoms selected from N, O and S. fluorine, chlorine, bromine, and iodine), amino, methyl, For example, R is methyl substitute with unsubstituted ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein phenyl. R is H. methyl, ethyl, t-butyl, or phenyl. 60 For example, R is methyl substitute with phenyl substi For example, R, is cyclopropyl, cyclobutyl, cyclopentyl, tuted with one or more groups, each of which can be the same cyclohexyl, or cycloheptyl, and is optionally substituted with or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tyl, and n-hexyl, each of or which is optionally substituted 65 tyl, and n-hexyl, each of which is optionally substituted with with halogen (e.g., fluorine, chlorine, bromine, and iodine)), halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, US 8,263,610 B2 15 16 ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, toxy, each of which is optionally substituted with halogen imidazothiazolyl, and quinoxalinyl, and the like, and is (e.g., fluorine, chlorine, bromine, and iodine)). optionally substituted. For example, R is methyl substitute with methoxy, ethoxy, For example, Q2 is indolyl. or t-butoxy. For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is methyl substitute with two or more cyclohexyl, or cycloheptyl, and is optionally Substituted. groups, each of which can be the same or different, selected For example, Q2 is heterocycle selected from pyrrolidinyl, from: imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1) phenyl, which is optionally substituted with one or more triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, groups, each of which can be the same or different, 10 morpholinyl, and pyrrolidinone, and the like, and is option Selected from hydroxyl, halogen, nitro, cyano, unsubsti ally substituted. tuted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, Q2 is piperidinyl. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, For example, Q2 is —NR.R.'. s-pentyl, and n-hexyl, each of which is optionally Sub 15 For example, Q, is —C(O)OR. stituted with halogen (e.g., fluorine, chlorine, bromine, For example, both R. and Rare H. and iodine)), unsubstituted or Substituted C-C alkoxy For example, at least one of R and R is unsubsti (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, tuted or substituted, straight-chain or branched C-C alkyl, i-butoxy, and t-butoxy, each of which is optionally Sub including but not limited to, methyl, ethyl, n-propyl, i-propyl. stituted with halogen (e.g., fluorine, chlorine, bromine, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. and iodine)); and For example, at least one of R and R. is methyl or 2) one of the following: t-butyl. i) —C(O)OR; For example, R and R, together with the atom they ii) methoxy, ethoxy, i-propyloxy, or t-butoxy; or attach to, form a 5- or 6-member ring selected from pyrro iii) —NRR. 25 lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo For example, R is methyl substitute with —C(O)CR. lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi For example, R is H. nyl, and the like, and is optionally Substituted with halogen For example, R is unsubstituted or Substituted, straight (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted chain or branched C-C alkyl, including but not limited to, or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, 30 i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substituted C-C alkoxy (e.g., n-pentyl, S-pentyl, and n-hexyl. methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, For example, R is methyl substitute with —NRR. and t-butoxy), unsubstituted or substituted amino, —C(O) For example, both R and R are H. R, or—C(O)OR, wherein R is H, or unsubstituted For example, at least one of R12 and Ris is -T2-Q2. 35 or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. For example, T is a bond. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, T2 is unsubstituted or substituted C-C, n-hexyl). alkyl linker, including but not limited to, methyl, ethyl, n-pro For example, R and R, together with the atom they pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and attach to, form a piperidinyl or piperazinyl, and is optionally n-hexyl linker. 40 substituted with halogen, methyl, ethyl, t-butyl, methoxy, For example, T2 is a methyl ethyl, or propyl linker. ethoxy, i-propyloxy, t-butoxy, or —C(O)CR, wherein For example, Q, is H. R is methyl, ethyl, or t-butyl. For example, Q2 is hydroxyl. For example, R is -T-Q. For example, Q2 is unsubstituted or substituted C-C, For example, T is a bond. alkoxy, including but not limited to, methoxy, ethoxy, propy 45 For example, T is unsubstituted or substituted C-C, loxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy. alkyl linker, including but not limited to, methyl, ethyl, n-pro For example, Q, is methoxy. pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, Q2 is unsubstituted or substituted phenyl or n-hexyl linker. naphthyl. For example, T is a methyl, ethyl, propyl, or i-propyl For example, Q2 is unsubstituted phenyl. 50 linker. For example, Q2 is phenyl substituted with one or more For example, Q, is H. groups, each of which can be the same or different, selected For example, Q, is unsubstituted phenyl. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, Q, is phenyl substituted with one, two, three stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. or more groups, each of which can be the same or different, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 55 selected from hydroxyl, halogen, nitro, cyano, unsubstituted of which is optionally substituted with halogen (e.g., fluorine, or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. chlorine, bromine, and iodine)), and unsubstituted or Substi i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro n-hexyl, each of which is optionally substituted with halogen pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted optionally Substituted with halogen (e.g., fluorine, chlorine, 60 or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy bromine, and iodine)). loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene For example, Q2 is heteroaryl selected from pyrrolyl, fura dioxy, each of which is optionally substituted with halogen nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, R —NHC(O)OR, —C(O)R and —C(O)CR, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, 65 wherein Riis H, or unsubstituted or Substituted C-C alkyl benzothiazolyl, benzoimidazolyl, benzothienyl, methylene (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, tyl, n-pentyl, S-pentyl, and n-hexyl). US 8,263,610 B2 17 18 For example, Q, is phenyl substituted with one, two, three tyl, and n-hexyl, each of or which is optionally substituted or more groups, each of which can be the same or different, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), selected from halogen (e.g., fluorine, chlorine, bromine, and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, Q, is unsubstituted naphthyl. For example, Q, is cyclopropyl. For example, Q, is naphthyl substituted with one, two, For example, Q, is heterocycle selected from pyrrolidinyl, three or more groups, each of which can be the same or imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, different, selected from hydroxyl, halogen, nitro, cyano, 10 triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, morpholinyl, and pyrrolidinone, and the like, and is option n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen ally Substituted with halogen (e.g., fluorine, chlorine, bro tyl, and n-hexyl, each of which is optionally substituted with mine, and iodine)), unsubstituted or Substituted C-C alkoxy halogen (e.g., fluorine, chlorine, bromine, and iodine)), (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu unsubstituted or Substituted C-C alkoxy (e.g., methoxy, 15 toxy, and t-butoxy, each of which is optionally substituted ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu with halogen (e.g., fluorine, chlorine, bromine, and iodine)). toxy, each of which is optionally substituted with halogen For example, R, is C(=NH)NR.R.'. (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) For example, both R- and Rare H. Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, For example, R, is C(S)NR.R.'. wherein R is H, or unsubstituted or Substituted C-C alkyl For example, both R- and Rare phenyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, R, is C(=NH)NR.R., C(O)NR.R.', or tyl, n-pentyl, S-pentyl, and n-hexyl). - C(S)NRR". For example, Q, is naphthyl substituted with one, two, For example, both R and Rare H. three or more groups, each of which can be the same or For example, at least one of R and R is unsubstituted or different, selected from halogen (e.g., fluorine, chlorine, bro 25 Substituted, straight-chain or branched C-C alkyl, including mine, and iodine). but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, Q, is heteroaryl selected from pyrrolyl, fura S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, at least one of R and R. is -T-Qa. razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, Ts is a bond. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox 30 For example, Ts is unsubstituted or substituted C-C, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, alkyl linker, including but not limited to, methyl, ethyl, n-pro benzoimidazolyl, benzothienyl, methylenedioxyphenyl, pyl, i-propyl. n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura n-hexyl, and 2-methylpropyl linker. nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui For example, Ts is a methyl ethyl, propyl, or 2-methyl noxalinyl, and pyrrolopyrimidinyl, and the like, and is option 35 propyl linker. ally Substituted with one, two, three or more groups, each of For example, Q, is H. which can be the same or different, selected from hydroxyl, For example, Q, is unsubstituted phenyl. halogen, nitro, cyano, unsubstituted or Substituted amino, For example, Q, is phenyl substituted with one or more unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, groups, each of which can be the same or different, selected n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 40 from-Ta-Q, wherein: tyl, and n-hexyl, each of which is optionally substituted with Ta Ts and T are each independently a bond, or unsub halogen (e.g., fluorine, chlorine, bromine, and iodine)), stituted or substituted C-C alkyl linker; unsubstituted or Substituted C-C alkoxy (e.g., methoxy, Q, is H, unsubstituted or substituted C-C alkyl, unsub ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu stituted or Substituted C-C alkoxy, halogen, nitro, toxy, each of which is optionally substituted with halogen 45 unsubstituted or substituted phenyl, unsubstituted or (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) Substituted heteroaryl comprising one or two 5- or R. —NHC(O)OR, —C(O)R and —C(O)OR, 6-member ring and 1-4 heteroatoms selected from N.O wherein R is H. unsubstituted or Substituted C-C alkyl and S, unsubstituted or Substituted C-Cs carbocycle, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu unsubstituted or Substituted heterocycle comprising one tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi 50 or two 5- or 6-member ring and 1-4 heteroatoms selected tuted C-C aryl, or unsubstituted or substituted heteroaryl from N, O and S. —NRR", —NHC(O)R —NHC comprising one or two 5- or 6-member ring and 1-4 heteroa (O)OR. -C(O), —C(O)CR-2, -OR- —SR, toms selected from N, O and S. —C(O)NRR'; For example, Q, is imidazolyl pyrazolyl, oxazolyl, isox R and R are each independently H, unsubstituted or azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino 55 substituted C-C alkyl, unsubstituted or substituted linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben phenyl, unsubstituted or substituted heteroaryl compris Zothiazolyl, benzothiadiazolyl, benzothienyl, O ing one or two 5- or 6-member ring and 1-4 heteroatoms pyrrolopyrimidiyl, each of which is optionally substituted selected from N, O and S. -Ts-Qs, or Rs2 and Rs', with one, two, three or more groups, each of which can be the together with the atom they attach to, form a 5- or same or different, selected from selected from halogen (e.g., 60 6-member ring which optionally comprises 1-4 heteroa fluorine, chlorine, bromine, and iodine), amino, methyl, toms selected from N, O and S and is optionally substi ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein tuted with -To-Q.: R is H. methyl, ethyl, t-butyl, or phenyl. Qs is H, hydroxyl, unsubstituted or substituted phenyl, For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, unsubstituted or Substituted heteroaryl comprising one cyclohexyl, or cycloheptyl, and is optionally substituted with 65 or two 5- or 6-member ring and 1-4 heteroatoms selected unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, from N, O and S, unsubstituted or substituted C-Cs n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen carbocycle, unsubstituted or substituted heterocycle US 8,263,610 B2 19 20 comprising one or two 5- or 6-member ring and 1-4 or substituted amino, unsubstituted or substituted C-C alkyl heteroatoms selected from N, O and S. —OR, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu —NR,R,'. —NHC(O)R. —NHC(O)OR, tyl, n-pentyl, S-pentyl, and n-hexyl, each of which is option —C(O)NR'R''. —C(O)R, or—C(O)CR; ally Substituted with halogen (e.g., fluorine, chlorine, bro Q, is H, hydroxyl, unsubstituted or substituted phenyl, mine, and iodine)), and unsubstituted or Substituted C-C, unsubstituted or Substituted heteroaryl comprising one alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, or two 5- or 6-member ring and 1-4 heteroatoms selected butoxy, i-butoxy, and t-butoxy, each of which is optionally from N, O and S, unsubstituted or substituted C-Cs Substituted with halogen (e.g., fluorine, chlorine, bromine, carbocycle, unsubstituted or substituted heterocycle and iodine)). comprising one or two 5- or 6-member ring and 1-4 10 For example, Q, is thiazolyl, isothiazolyl, or oxadiazolyl, heteroatoms selected from N, O and S. —NRR, each of which is optionally substituted with one or more —C(O)NR'R'; groups, each of which can be the same or different, selected Rc and Rare each independently H, unsubstituted or from methyl, ethyl, and t-butyl. substituted C-C alkyl, unsubstituted or substituted For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, Co-Co aryl, or unsubstituted or Substituted heteroaryl 15 cyclohexyl, or cycloheptyl, and is optionally Substituted. comprising one or two 5- or 6-member ring and 1-4 For example, Q, is heterocycle selected from pyrrolidinyl, heteroatoms selected from N, O and S; imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, Ra and R are each independently H, unsubstituted or triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, Substituted C-C alkyl, or R and R', together with morpholinyl, and pyrrolidinone, and the like, and is option the atom they attach to, form a 5- or 6-member ring ally Substituted with halogen (e.g., fluorine, chlorine, bro which optionally comprises 1-4 heteroatoms selected mine, and iodine)), unsubstituted or substituted C-C alkoxy from N, O and S and is optionally substituted. (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu For example, Ta is a bond. toxy, and t-butoxy, each of which is optionally substituted For example, Ta is unsubstituted or substituted C-C, with halogen (e.g., fluorine, chlorine, bromine, and iodine)). alkyl linker, including but not limited to, methyl, ethyl, n-pro 25 For example, Q, is piperazinyl or piperazinyl, and is pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and optionally substituted with methyl, ethyl, or t-butyl. n-hexyl linker. For example, Q, is NRs.2Rs'. For example, T is a methyl ort-butyl linker. For example, both R- and Rare H. For example, Q, is H. For example, at least one of RandR is unsubstituted or For example, Q, is unsubstituted or substituted, straight 30 Substituted, straight-chain or branched C-C alkyl, including chain or branched C-C alkyl, including but not limited to, but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, s-butyl, t-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl. n-pentyl, S-pentyl, and n-hexyl, each of which is optionally For example, at least one of R and R' is methyl or ethyl. Substituted with halogen (e.g., fluorine, chlorine, bromine, For example, R and Rare both methyl or ethyl. and iodine). 35 For example, Q, is —ORs, or—SR-2. For example, Q, is methyl ethyl, t-butyl, or trifluorom For example, R is H. ethyl. For example, R is unsubstituted or Substituted, straight For example, Q, is unsubstituted or substituted C-C, chain or branched C-C alkyl, including but not limited to, alkoxy, including but not limited to, methoxy, ethoxy, propy methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and methylene 40 n-pentyl, S-pentyl, and n-hexyl, each of which is optionally dioxy. Substituted with halogen (e.g., fluorine, chlorine, bromine, For example, Q, is methoxy, ethoxy, or methylenedioxy. and iodine). For example, Q, is fluorine, chlorine, bromine, or iodine. For example, R is methyl, ethyl, t-butyl, or trifluorom For example, Q, is unsubstituted phenyl. ethyl. For example, Q, is phenyl substituted with one or more 45 For example, R is unsubstituted phenyl. groups, each of which can be the same or different, selected For example, R is phenyl Substituted with one or more from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub groups, each of which can be the same or different, selected stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. of which is optionally substituted with halogen (e.g., fluorine, 50 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each chlorine, bromine, and iodine)), and unsubstituted or Substi of which is optionally substituted with halogen (e.g., fluorine, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro chlorine, bromine, and iodine)), and unsubstituted or Substi pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro of which is optionally substituted with halogen (e.g., fluorine, pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each chlorine, bromine, and iodine)). 55 of which is optionally substituted with halogen (e.g., fluorine, For example, Q, is heteroaryl selected from heteroaryl chlorine, bromine, and iodine)). selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiaz For example, R is heteroaryl selected from pyrrolyl, fura olyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tri razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, azinyl, benzoxazolyl, benzodioxazolyl, benzoxadiazolyl, 60 pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, ben azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, Zothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura indolizinyl, imidazothiazolyl, quinoxalinyl, and pyrrolopyri nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, and midinyl, and the like, and is optionally substituted with one or 65 quinoxalinyl, and the like, and is optionally Substituted with more groups, each of which can be the same or different, one, two or more groups, each of which can be the same or selected from hydroxyl, halogen, nitro, cyano, unsubstituted different, selected from hydroxyl, halogen, nitro, cyano, US 8,263,610 B2 21 22 unsubstituted or substituted amino, unsubstituted or substi n-hexyl, each of which is optionally substituted with halogen tuted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro of which is optionally substituted with halogen (e.g., fluorine, pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of chlorine, bromine, and iodine)), and unsubstituted or Substi which is optionally Substituted with halogen (e.g., fluorine, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro chlorine, bromine, and iodine)). pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is For example, Qis is pyrazolyl, imidazolyl, isoxazolyl, optionally Substituted with halogen (e.g., fluorine, chlorine, oxazolyl, pyridinyl, furanyl, indolyl, or benzoimidazolyl, bromine, and iodine)). each of which is optionally substituted with one or more For example, R is pyrazinyl, and is optionally substituted 10 with methyl, ethyl or t-butyl. groups, each of which can be the same or different, selected For example, Q, is —C(O)Rs2. -C(O)CRs2. from methyl or ethyl. For example, R is H. For example, Qis is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is unsubstituted or substituted, straight cyclohexyl, or cycloheptyl, and is optionally substituted with chain or branched C-C alkyl, including but not limited to, 15 unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-pentyl, S-pentyl, and n-hexyl. tyl, and n-hexyl, each of or which is optionally substituted For example, R is methyl or ethyl. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, Q, is NHC(O)Rs, NHC(O)CRs, or unsubstituted or Substituted C-C alkoxy (e.g., methoxy, —C(O)NRR". ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, Q, is —C(O)NR'R''. toxy, each of which is optionally substituted with halogen For example, both R- and Rare H. (e.g., fluorine, chlorine, bromine, and iodine)). For example, at least one of Rs and Rs' is -Ts-Qs. For example, Q, is cyclohexyl or cycloheptyl, which is For example, Ts is a bond. optionally substituted with methyl or ethyl. For example, Ts is unsubstituted or substituted C-C, 25 For example, Qis is heterocycle selected from pyrrolidinyl, alkyl linker, including but not limited to, methyl, ethyl, n-pro pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, n-hexyl, 1,2-dimethylpropyl, and 1-methylbutyl linker. piperazinyl, morpholinyl, and pyrrolidinone, and the like, and For example, Ts is a methyl ethyl, propyl, i-propyl, butyl, is optionally substituted. 1,2-dimethylpropyl, or 1-methylbutyl linker. 30 For example, Q, is pyrrolidinyl, pyrrolidinone, piperidi For example, Qis is H. nyl, morpholinyl, or tetrahydrofuranyl, and is optionally Sub For example, Qs is unsubstituted phenyl. stituted. For example, Q, is phenyl substituted with one or more For example, Qs is —OR. groups, each of which can be the same or different, selected For example, R is H. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub 35 For example, Riis unsubstituted or substituted, straight stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. chain or branched C-C alkyl, including but not limited to, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, of which is optionally substituted with halogen (e.g., fluorine, n-pentyl, S-pentyl, and n-hexyl. chlorine, bromine, and iodine)), unsubstituted or substituted For example, R is methyl, ethyl, or t-butyl. C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, 40 For example, R is unsubstituted phenyl. butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each of which For example, R is phenyl Substituted with one or more is optionally substituted with halogen (e.g., fluorine, chlorine, groups, each of which can be the same or different, selected bromine, and iodine)), unsubstituted or substituted Co-Co from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub aryloxy (e.g., phenoxy), and —NHC(O)R, wherein R. stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. is H, or unsubstituted or Substituted C-C alkyl (e.g., methyl, 45 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, of which is optionally substituted with halogen (e.g., fluorine, s-pentyl, and n-hexyl). chlorine, bromine, and iodine)), and unsubstituted or Substi For example, Qs is phenyl substituted with one or more tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro groups, each of which can be the same or different, selected pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each from halogen (e.g., fluorine, chlorine, bromine, and iodine), 50 of which is optionally substituted with halogen (e.g., fluorine, methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, t-bu chlorine, bromine, and iodine)). toxy, phenoxy, and —NHC(O)R, wherein R is H. For example, Qs is —NR.R.". -NHC(O)R. methyl or ethyl. —NHC(O)OR, —C(O)NRR, —C(O)R, or For example, Q, is heteroaryl selected from pyrrolyl, fura —C(O)CR. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet 55 For example, Qis is —NR.R.', -NHC(O)R or razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, —C(O)NRR, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, both R. and Rare H. azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, For example, at least one of R and R is unsubsti benzoimidazolyl, benzothienyl, methylenedioxyphenyl, tuted or Substituted, straight-chain or branched C-C alkyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura 60 including but not limited to, methyl, ethyl, n-propyl, i-propyl. nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. noxalinyl, and pyrrolopyrimidinyl, and the like, and is option For example, at least one of R and R. is methyl or ally Substituted with one or more groups, each of which can ethyl. be the same or different, selected from hydroxyl, halogen, For example, R. and R. are both methyl or ethyl. nitro, cyano, unsubstituted or substituted amino, unsubsti 65 For example, R and R', together with the atom they tuted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. attach to, form a 5- or 6-member ring selected from pyrro i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo US 8,263,610 B2 23 24 lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, and is optionally substituted with-To-Q, piperazinyl, morpholinyl, and pyrrolidinone, and the like, and For example, R and R', together with the atom they is optionally substituted. attach to, form a 5- or 6-member ring selected from pyrro For example, Q, is —NR.R.'. lidinyl, piperidinyl, and piperazinyl, and is optionally Substi For example, both R. and Rare H. tuted with -To-Q, For example, at least one of R and R is unsubsti For example, T is a bond. tuted or substituted, straight-chain or branched C-C alkyl, For example, T is unsubstituted or substituted C-C, including but not limited to, methyl, ethyl, n-propyl, i-propyl. alkyl linker, including but not limited to, methyl, ethyl, n-pro n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. 10 For example, at least one of R and R. is methyl or pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and ethyl. n-hexyl linker. For example, R. and R. are both methyl or ethyl. For example, T is a methyl or ethyl linker. For example, Q, is —C(O)NR'R''. For example, Q, is H. For example, R and Rare both H. For example, Q, is unsubstituted phenyl. 15 For example, at least one of RandR is unsubstituted or For example, Q, is phenyl substituted with one or more Substituted, straight-chain or branched C-C alkyl, including groups, each of which can be the same or different, selected but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, R and R', together with the atom they n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each attach to, form a 5- or 6-member ring selected from pyrro of which is optionally substituted with halogen (e.g., fluorine, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo chlorine, bromine, and iodine)), and unsubstituted or Substi lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro and is optionally Substituted. pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each For example, R and R', together with the atom they of which is optionally substituted with halogen (e.g., fluorine, 25 attach to, form a pyrrolidinyl ring, and is optionally Substi chlorine, bromine, and iodine)). tuted. For example, Q, is phenyl substituted with one or more For example, Q, is unsubstituted naphthyl. groups, each of which can be the same or different, selected For example, Q, is heteroaryl selected from pyrrolyl, fura from methyl, ethyl, and t-butyl. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet 30 razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, Q, is heteroaryl selected from pyrrolyl, fura pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, 35 nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui benzoimidazolyl, benzothienyl, methylenedioxyphenyl, noxalinyl, dihydrobenzofuranyl, and pyrrolopyrimidinyl, and quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura the like, and is optionally substituted with one, two or more nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui groups, each of which can be the same or different, selected noxalinyl, benzodihydroimidazolone, and pyrrolopyrimidi from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub nyl, and the like, and is optionally substituted with one or 40 stituted amino, unsubstituted or substituted C-C alkyl (e.g., more groups, each of which can be the same or different, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, selected from hydroxyl, halogen, nitro, cyano, unsubstituted n-pentyl, S-pentyl, and n-hexyl, each of which is optionally or substituted amino, unsubstituted or substituted C-C alkyl Substituted with halogen (e.g., fluorine, chlorine, bromine, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu and iodine)), unsubstituted or Substituted C-C alkoxy (e.g., tyl, n-pentyl, S-pentyl, and n-hexyl, each of which is option 45 methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, ally Substituted with halogen (e.g., fluorine, chlorine, bro and t-butoxy, each of which is optionally substituted with mine, and iodine)), and unsubstituted or substituted C-C, halogen (e.g., fluorine, chlorine, bromine, and iodine)), and alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, unsubstituted or substituted phenyl. butoxy, i-butoxy, and t-butoxy, each of which is optionally For example, Q, is oxazolyl, isoxazolyl pyridinyl, pyrazi Substituted with halogen (e.g., fluorine, chlorine, bromine, 50 nyl, triazinyl, thienyl, benzothiadiazolyl, or dihydrobenzo and iodine)). furanyl, each of which is optionally substituted with one, two For example, Q, is pyridinyl, pyrazinyl, or benzodihy or more groups, each of which can be the same or different, droimidazolone, each of which is optionally substituted with selected from halogen (e.g., fluorine, chlorine, bromine, and one or more groups, each of which can be the same or differ iodine), methyl, ethyl, t-butyl, trifluoromethyl, and phenyl. ent, selected from methyl or ethyl. 55 For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted with cyclohexyl, or cycloheptyl, and is optionally substituted with unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tyl, and n-hexyl, each of or which is optionally substituted tyl, and n-hexyl, each of or which is optionally substituted 60 with halogen (e.g., fluorine, chlorine, bromine, and iodine)), with halogen (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted or substituted C-C alkoxy (e.g., methoxy, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu toxy, each of which is optionally substituted with halogen toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). (e.g., fluorine, chlorine, bromine, and iodine)). 65 For example, Q, is cyclohexyl. For example, Q, is heterocycle selected from pyrrolidinyl, For example, Q, is heterocycle selected from pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, US 8,263,610 B2 25 26 triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, of which is optionally substituted with halogen (e.g., fluorine, morpholinyl, and pyrrolidinone, and the like, and is option chlorine, bromine, and iodine)), and unsubstituted or Substi ally Substituted with halogen (e.g., fluorine, chlorine, bro tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro mine, and iodine)), unsubstituted or Substituted C-C alkoxy pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu of which is optionally substituted with halogen (e.g., fluorine, toxy, and t-butoxy, each of which is optionally substituted chlorine, bromine, and iodine)). with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, Q, is phenyl substituted with one or more For example, Q, is —C(O)ORs, -C(O)Rs –C(O) groups, each of which can be the same or different, selected NRR", or —NRR". from halogen (e.g., fluorine, chlorine, bromine, and iodine), For example, Q, is —C(O)CRs or -NRs Rs'. 10 methyl, ethyl, -t-butyl, methoxy, ethoxy and t-butoxy. For example, R and R' are both H. For example, at least one of R and Rs' is unsubstituted or For example, Q, is —C(O)NR'R' or -NRRs Substituted, straight-chain or branched C-C alkyl, including For example, R and Rare both H. but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, at least one of R and Rs' is unsubstituted or S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of which 15 Substituted, straight-chain or branched C-C alkyl, including is optionally substituted with halogen (e.g., fluorine, chlorine, but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, bromine, and iodine), hydroxyl, or unsubstituted or Substi S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro For example, at least one of R and R is unsubstituted or pyloxy, butoxy, i-butoxy, and t-butoxy). substituted phenyl. For example, at least one of R and Rs' is methyl or ethyl For example, at least one of R and R is heteroaryl optionally substituted with hydroxyl. selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiaz For example, R and R', together with the atom they attach olyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, to, form a 5-, 6- or 7-member ring selected from pyrrolidinyl, isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tri imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, azinyl, benzoxazolyl, benzodioxazolyl, benzoxadiazolyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepa 25 benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, ben nyl, and diazepanyl, and the like and is optionally substituted Zothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, with one or more groups, each of which can be the same or naphthrydinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, different, selected from -T7-Q7, wherein: indolizinyl, imidazothiazolyl, quinoxalinyl, and pyrrolopyri T, is a bond, or unsubstituted or substituted C-C alkyl midinyl, and the like, and is optionally Substituted. linker; 30 For example, at least one of R and R is cyclopropyl. Q, is H, unsubstituted or substituted phenyl, unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is or substituted heteroaryl comprising one or two 5- or optionally substituted. 6-member ring and 1-4 heteroatoms selected from N.O For example, at least one of R and R is heterocycle and S, unsubstituted or Substitute C-C carbocycle, selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, unsubstituted or Substituted heterocycle comprising one 35 oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl. or two 5- or 6-member ring and 1-4 heteroatoms selected piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and from N, O and S. —C(O)NR'R''. —C(O)ONRR", the like, and is optionally substituted. or —NRR'; and For example, R and R', together with the atom they R and Rs' are each independently H, unsubstituted or attach to, form a 5- or 6-member ring selected from pyrro substituted C-C alkyl, unsubstituted or substituted 40 lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo phenyl, unsubstituted or substituted heteroaryl compris lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl, ing one or two 5- or 6-member ring and 1-4 heteroatoms and pyrrolidinone, and the like, and is optionally Substituted. selected from N, O and S, unsubstituted or substitute For example, R and R', together with the atom they C-Cs carbocycle, unsubstituted or Substituted hetero attachto, form a 5- or 6-member ring selected from morpholi cycle comprising one or two 5- or 6-member ring and 45 nyl. 1-4 heteroatoms selected from N, O and S, or R and For example, X-X, is CH, CHR'. R", together with the atom they attach to, form a 5- or For example, R, is H. 6-member ring which optionally comprises 1-4 heteroa For example, R, is unsubstituted phenyl. toms selected from N, O and S and is optionally substi For example, R, is phenyl substituted with one, two, three tuted. 50 or more groups, each of which can be the same or different, For example, R and R', together with the atom they attach selected from hydroxyl, halogen, nitro, cyano, unsubstituted to, form a 5-, 6- or 7-member ring selected from piperidinyl, or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. piperazinyl, pyrrolidinyl, and diazepanyl, and is optionally i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and substituted with -T-Q7. n-hexyl, each of which is optionally substituted with halogen For example, T., is a bond. 55 (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted For example, T., is unsubstituted or substituted C-C, or substituted C-C alkoxy (e.g., methoxy, ethoxy, propy alkyl linker, including but not limited to, methyl, ethyl, n-pro loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and dioxy, each of which is optionally substituted with halogen n-hexyl linker. (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) For example, T., is a methyl ethyl, or propyl linker. 60 R —NHC(O)OR, —C(O)R and —C(O)CR, For example, Q, is H. wherein Riis H, or unsubstituted or substituted C-C alkyl For example, Q, is unsubstituted phenyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, Q, is phenyl substituted with one or more tyl, n-pentyl, S-pentyl, and n-hexyl). groups, each of which can be the same or different, selected For example, R, is phenyl substituted with one, two, three from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub 65 or more groups, each of which can be the same or different, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. selected from halogen (e.g., fluorine, chlorine, bromine, and n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, US 8,263,610 B2 27 28 ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, is unsubstituted naphthyl. For example, R, is heterocycle selected from pyrrolidinyl, For example, R, is naphthyl substituted with one, two, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, three or more groups, each of which can be the same or 5 triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, different, selected from hydroxyl, halogen, nitro, cyano, morpholinyl, and pyrrolidinone, and the like, and is option unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, ally Substituted with halogen (e.g., fluorine, chlorine, bro n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen mine, and iodine)), unsubstituted or Substituted C-C alkoxy tyl, and n-hexyl, each of which is optionally substituted with (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu halogen (e.g., fluorine, chlorine, bromine, and iodine)), 10 toxy, and t-butoxy, each of which is optionally substituted unsubstituted or Substituted C-C alkoxy (e.g., methoxy, with halogen (e.g., fluorine, chlorine, bromine, and iodine)). ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, R." is H. toxy, each of which is optionally substituted with halogen For example, R." is unsubstituted or substituted, straight (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) chain or branched C-C alkyl, including but not limited to, Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, 15 methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, wherein Riis H, or unsubstituted or substituted C-C alkyl n-pentyl, S-pentyl, and n-hexyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, both R and Rare H. tyl, n-pentyl, S-pentyl, and n-hexyl). For example, at least one of Rs and Rs' is -T'-Q,'. For example, R, is naphthyl substituted with one, two, For example, T' is a bond. three or more groups, each of which can be the same or 20 For example, T' is unsubstituted or substituted C-C, different, selected from halogen (e.g., fluorine, chlorine, bro alkyl linker, including but not limited to, methyl, ethyl, n-pro mine, and iodine). pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, R, is heteroaryl selected from pyrrolyl, fura n-hexyl linker. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, T' is a methyl, ethyl, propyl, or t-butyl razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 25 linker. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, Q,' is H. azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, For example, Q,' is unsubstituted phenyl. benzoimidazolyl, benzothienyl, methylenedioxyphenyl, For example, Q,' is phenyl substituted with one, two or quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura more groups, each of which can be the same or different, nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui- 30 selected from hydroxyl, halogen, nitro, cyano, unsubstituted noxalinyl, and pyrrolopyrimidinyl, and the like, and is option or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. ally substituted with one, two, three or more groups, each of i-propyl. n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and which can be the same or different, selected from hydroxyl, n-hexyl, each of which is optionally substituted with halogen halogen, nitro, cyano, unsubstituted or Substituted amino, (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, 35 tuted or substituted C-C alkoxy (e.g., methoxy, ethoxy, pro n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen pyloxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, methylene tyl, and n-hexyl, each of which is optionally substituted with dioxy, and ethylenedioxy, each of which is optionally halogen (e.g., fluorine, chlorine, bromine, and iodine)), Substituted with halogen (e.g., fluorine, chlorine, bromine, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, and iodine)), unsubstituted or Substituted phenyl, unsubsti ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu- 40 tuted or substituted C-C aryloxy (e.g., phenoxy). toxy, each of which is optionally substituted with halogen —NR.R. i.,s -C(O)R.R. i., S(O)2Rn, and (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) —NHC(O)R.R.", wherein R and R are each Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, independently H, unsubstituted or substituted C-C alkyl wherein R is H. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu- 45 tyl, n-pentyl, S-pentyl, and n-hexyl) tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi For example, Q,' is phenyl substituted with one, two or tuted C-C aryl, or unsubstituted or substituted heteroaryl more groups, each of which can be the same or different, comprising one or two 5- or 6-member ring and 1-4 heteroa selected from fluorine, chlorine, bromine, and iodine. toms selected from N, O and S. For example, Q,' is phenyl substituted with one, two or For example, R, is imidazolyl pyrazolyl, oxazolyl, isox- 50 more groups, each of which can be the same or different, azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino selected from methyl, ethyl, t-butyl, and trifluoromethyl. linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben For example, Q,' is phenyl substituted with one, two or Zothiazolyl, benzothiadiazolyl, benzothienyl, O more groups, each of which can be the same or different, pyrrolopyrimidiyl, each of which is optionally substituted selected from methoxy, ethoxy, trifluoromethoxy, and ethyl with one, two, three or more groups, each of which can be the 55 enedioxy. same or different, selected from selected from halogen (e.g., For example, Q,' is phenyl substituted with one, two or fluorine, chlorine, bromine, and iodine), amino, methyl, more groups, each of which can be the same or different, ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein Selected from —NRR', -C(O)R.R.", R is H. methyl, ethyl, t-butyl, or phenyl. —S(O).R., and —NHC(O)R.R., wherein at least For example, R, is cyclopropyl, cyclobutyl, cyclopentyl, 60 one of R and R. is methyl or ethyl. cyclohexyl, or cycloheptyl, and is optionally substituted with For example, Q,' is phenyl substituted with one, two or unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, more groups, each of which can be the same or different, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen selected from fluorine, chlorine, bromine, iodine, methyl, tyl, and n-hexyl, each of or which is optionally substituted ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, trifluo with halogen (e.g., fluorine, chlorine, bromine, and iodine)), 65 romethoxy, phenyl, phenoxy, —NRR', -C(O)R- unsubstituted or Substituted C-C alkoxy (e.g., methoxy, R., -S(O)2R, and —NHC(O)R.R., wherein at ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu least one of R and R. is methyl or ethyl. US 8,263,610 B2 29 30 For example, Q,' is unsubstituted naphthyl. ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu For example, Q,' is naphthyl substituted with one, two or tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of more groups, each of which can be the same or different, which is optionally Substituted with halogen (e.g., fluorine, selected from hydroxyl, halogen, nitro, cyano, unsubstituted chlorine, bromine, and iodine). or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. 5 For example, at least one of R and R is methyl, which i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and is optionally substituted with halogen (e.g., fluorine, chlorine, n-hexyl, each of which is optionally substituted with halogen bromine, and iodine). (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti For example, at least one of R and R is unsubstituted tuted or substituted C-C alkoxy (e.g., methoxy, ethoxy, pro phenyl. pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of 10 For example, at least one of R and R is phenyl Sub which is optionally Substituted with halogen (e.g., fluorine, stituted with one or more groups, each of which can be the chlorine, bromine, and iodine)). same or different, selected from hydroxyl, halogen, nitro, For example, Q,' is naphthyl substituted with one, two or cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, more groups, each of which can be the same or different, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, selected from methyl, ethyl, and halogen (e.g., fluorine, chlo 15 rine, bromine, and iodine). s-pentyl, and n-hexyl, each of which is optionally Substituted For example, Q,' is fluorenyl, and is optionally substi with halogen (e.g., fluorine, chlorine, bromine, and iodine)), tuted. and unsubstituted or substituted C-C alkoxy (e.g., methoxy, For example, Q,' is dihydroindenyl, and is optionally sub ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu stituted. toxy, each of which is optionally substituted with halogen For example, Q,' is heteroaryl selected from pyrrolyl, (e.g., fluorine, chlorine, bromine, and iodine)). furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, For example, at least one of R and R is phenyl Sub tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi stituted with two or more groups, each of which can be the nyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, ben same or different, selected from hydroxyl, halogen, nitro, Zoisoxazolyl, benzodioxazolyl, benzoxadiazolyl, benzothia 25 cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, Zolyl, benzothiadiazolyl, benzoimidazolyl, benzothienyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry s-pentyl, and n-hexyl, each of which is optionally Substituted dinyl, indolyl, benzofuranyl, purinyl, purinone, deaZapurinyl, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), indolizinyl, imidazothiazolyl, dihydrobenzofuranyl, quinox and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, alinyl, and pyrrolopyrimidinyl, and the like, and is optionally 30 ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu Substituted with one, two or more groups, each of which can toxy, each of which is optionally substituted with halogen be the same or different, selected from hydroxyl, halogen, (e.g., fluorine, chlorine, bromine, and iodine)). unsubstituted or substituted amino, unsubstituted or substi For example, R, is H. tuted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, R, is unsubstituted or Substituted, straight n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 35 chain or branched C-C alkyl, including but not limited to, of which is optionally substituted with halogen (e.g., fluorine, methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, chlorine, bromine, and iodine)), unsubstituted or substituted n-pentyl, S-pentyl, and n-hexyl. C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, For example, R, is unsubstituted phenyl. butoxy, i-butoxy, and t-butoxy, each of which is optionally For example, R, is phenyl Substituted with one or more Substituted with halogen (e.g., fluorine, chlorine, bromine, 40 groups, each of which can be the same or different, selected and iodine)), unsubstituted or Substituted Co-Co aryloxy from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub (e.g., phenoxy), and unsubstituted or Substituted phenyl. stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, Q,' is oxazolyl, isoxazolyl pyridinyl, pyri n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each midinyl, triazinyl, thienyl, purinyl, purinone, quinolinyl, ben of which is optionally substituted with halogen (e.g., fluorine, Zothienyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, 45 chlorine, bromine, and iodine)), and unsubstituted or Substi benzothiazolyl, benzothiadiazolyl pyrrolopyrimidinyl, or tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro dihydrobenzofuranyl, each of which is substituted with one, pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is two or more groups, each of which can be the same or differ optionally Substituted with halogen (e.g., fluorine, chlorine, ent, selected from halogen (e.g., fluorine, chlorine, bromine, bromine, and iodine)). and iodine), methyl, ethyl, amino, phenyl, and phenoxy. 50 For example, R, is phenyl substituted with two or more For example, Q,' is C(O)CR, C(O)R2, C(O) groups, each of which can be the same or different, selected NRR', or —NRR". from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, Q,' is —C(O)OR2. stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, R is H. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each For example, R is unsubstituted or Substituted C-C, 55 of which is optionally substituted with halogen (e.g., fluorine, alkyl, including but not limited to, methyl, ethyl, n-propyl. chlorine, bromine, and iodine)), and unsubstituted or Substi i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro n-hexyl. pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is For example, R is methyl or ethyl. optionally Substituted with halogen (e.g., fluorine, chlorine, For example, X-X is X-X'. 60 bromine, and iodine)). For example, X-X," is CHR-CHR CHR. O. For example, R is H. O—CHR, CHR, CHR-CHR-CHRs, CHR For example, R is unsubstituted or Substituted, straight CHR. O. O—CHR-CHR, CHR-O-CHR, chain or branched C-C alkyl, including but not limited to, CHR, S, or S CHR, methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, For example, both R and R are H. 65 n-pentyl, S-pentyl, and n-hexyl. For example, at least one of R and R is unsubstituted For example, R is methyl. or Substituted, straight-chain or branched C-C alkyl, includ For example, R is unsubstituted phenyl. US 8,263,610 B2 31 32 For example, R is phenyl substituted with one or more ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu groups, each of which can be the same or different, selected toxy, each of which is optionally substituted with halogen from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub (e.g., fluorine, chlorine, bromine, and iodine)). stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, at least one of R and R is phenyl Substi n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each tuted with two or more groups, each of which can be the same of which is optionally substituted with halogen (e.g., fluorine, or different, selected from hydroxyl, halogen, nitro, cyano, chlorine, bromine, and iodine)), and unsubstituted or Substi unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is tyl, and n-hexyl, each of which is optionally substituted with optionally Substituted with halogen (e.g., fluorine, chlorine, 10 bromine, and iodine)). halogen (e.g., fluorine, chlorine, bromine, and iodine)), and For example, R is phenyl substituted with two or more unsubstituted or substituted C-C alkoxy (e.g., methoxy, groups, each of which can be the same or different, selected ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub toxy, each of which is optionally substituted with halogen stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. 15 (e.g., fluorine, chlorine, bromine, and iodine)). n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each For example, Riis H. of which is optionally substituted with halogen (e.g., fluorine, For example, R is unsubstituted or substituted, straight chlorine, bromine, and iodine)), and unsubstituted or Substi chain or branched C-C alkyl, including but not limited to, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is n-pentyl, S-pentyl, and n-hexyl. optionally Substituted with halogen (e.g., fluorine, chlorine, For example, R is unsubstituted phenyl. bromine, and iodine)). For example, R is phenyl substituted with one or more For example, all of R. R. and Rs are H. groups, each of which can be the same or different, selected For example, at least one of R, R2 and Rs is unsub from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub stituted or Substituted, straight-chain or branched C-C, 25 stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. alkyl, including but not limited to, methyl, ethyl, n-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and of which is optionally substituted with halogen (e.g., fluorine, n-hexyl. chlorine, bromine, and iodine)), and unsubstituted or Substi For example, at least one of R, R2 and Rs is unsub tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro stituted phenyl. 30 pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is For example, at least one of R, R2 and Rs is phenyl optionally Substituted with halogen (e.g., fluorine, chlorine, substituted with one or more groups, each of which can be the bromine, and iodine)). same or different, selected from hydroxyl, halogen, nitro, For example, R is phenyl substituted with two or more cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, groups, each of which can be the same or different, selected ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, 35 from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub s-pentyl, and n-hexyl, each of which is optionally Substituted stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, of which is optionally substituted with halogen (e.g., fluorine, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu chlorine, bromine, and iodine)), and unsubstituted or Substi toxy, each of which is optionally substituted with halogen 40 tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro (e.g., fluorine, chlorine, bromine, and iodine)). pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is For example, at least one of R. R. and R is phenyl optionally Substituted with halogen (e.g., fluorine, chlorine, substituted with two or more groups, each of which can be the bromine, and iodine)). same or different, selected from hydroxyl, halogen, nitro, The present invention also provides the compounds of cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, 45 ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, Formula II: s-pentyl, and n-hexyl, each of which is optionally Substituted

with halogen (e.g., fluorine, chlorine, bromine, and iodine)), (II) and unsubstituted or substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu 50 toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, both R and R2 are H. For example, at least one of R and R is unsubstituted or Substituted, straight-chain or branched C-C alkyl, includ 55 ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, at least one of R and R is unsubstituted phenyl. For example, at least one of R and R is phenyl Substi 60 or a salt, Solvate, hydrate or prodrug thereof, wherein: tuted with one or more groups, each of which can be the same R is H. halogen, unsubstituted or substituted C-C alkyl, or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or substituted phenyl, or unsubstituted or sub unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, stituted heteroaryl comprising one or two 5- or 6-member ring n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen and 1-4 heteroatoms selected from N, O and S; tyl, and n-hexyl, each of which is optionally substituted with 65 R is H, or unsubstituted or substituted C-C alkyl: halogen (e.g., fluorine, chlorine, bromine, and iodine)), and each R, is independently halogen, hydroxyl, cyano, nitro, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, amino, unsubstituted or Substituted C-C alkoxy, unsubsti US 8,263,610 B2 33 34 tuted or Substituted C-C alkyl, —C(O)R. from hydroxyl, cyano, methyl, ethyl, t-butyl, trifluoromethyl, C(O)OR, —NHC(O)R —NHC(O)OR; methoxy, t-butoxy, trifluoromethoxy, and halogen. n is 0, 1, 2, 3, or 4: For example, R is heteroaryl selected from pyrrolyl, fura X-X" is CHR-CHR CHR, O, O CHR, nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet CHR CHR-CHR-CHR, CHR-CHR. O. 5 razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, O—CHR-CHR2, CHR-O-CHR2, CHR, S, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, S CHR CHR-CHR, NR, CHR, NR, benzothiazolyl, benzoimidazolyl, benzothienyl, methylene CHR, or NR, CHR-CHR; dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, Ryal, Rya2. Rt. Re. Rya, Ryaz, Rya. Rye. Re2, O Rare indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, each independently H, unsubstituted or substituted C-C, 10 imidazothiazolyl, quinoxalinyl, tetrahydropyridinyl, pyrrol alkyl, or unsubstituted or substituted phenyl; and opyrimidinyl, and the like, and is optionally substituted with Riis H. unsubstituted or Substituted C-C alkyl, unsub halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub stituted or Substituted Co-Co aryl, or unsubstituted or Substi stituted or substituted amino, unsubstituted or substituted tuted heteroaryl comprising one or two 5- or 6-member ring 15 C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, and 1-4 heteroatoms selected from N, O and S. S-butyl, t-butyl, n-pentyl, S-pentyl and n-hexyl, each of which For example, R is H. is optionally substituted with halogen (e.g., fluorine, chlorine, For example, R is fluorine, chlorine, bromine, or iodine. bromine and iodine)), C-C aryl (e.g., phenyl, which is For example, R is unsubstituted or Substituted, straight optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. chain or branched C-C alkyl, including but not limited to, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, n-pentyl, S-pentyl, and n-hexyl. pyridazinyl, and pyrimidinyl, and the like, and is optionally For example, R is methyl. Substituted), C-C carbocycle (e.g., cyclopropyl, cyclobutyl, For example, R is unsubstituted phenyl. cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally For example, R is phenyl substituted with one or more 25 Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi groups, each of which can be the same or different, selected nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. and the like, and is optionally Substituted). n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each For example, R is heteroaryl selected from furanyl, pyra of which is optionally substituted with halogen (e.g., fluorine, 30 Zolyl, purinyl, indolyl, tetrahydropyridinyl, and pyrrolopyri chlorine, bromine, and iodine)), unsubstituted or substituted midinyl, and is optionally Substituted with one or more C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, groups, each of which can be the same of different, selected butoxy, i-butoxy, and t-butoxy, each of which is optionally from methyl, ethyl, t-butyl, amino, and heterocycle (e.g., Substituted with halogen (e.g., fluorine, chlorine, bromine, piperidinyl, which is optionally substituted with e.g., C(O) and iodine)), and -T-Q, wherein: 35 O—(C-Calkyl)). T is a bond, or unsubstituted or Substituted C-C alkyl For example, R is H. linker; For example, R is unsubstituted or Substituted, straight Q is H. —NRR', C(O)NR'R''. —NHC(O) chain or branched C-C alkyl, including but not limited to, R. —NHC(O)OR, NHC(O)NR'R'', or methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, —S(O).R. and 40 n-pentyl, S-pentyl, and n-hexyl. R, and Rare each independently H, or unsubstituted For example, R is methyl substituted with unsubstituted or substituted C-C alkyl. phenyl. For example, R is phenyl substituted with one or more For example, R is methyl substituted with phenyl substi groups, each of which can be the same or different, selected tuted with one or more groups, each of which can be the same from -T-Q. 45 or different, selected from hydroxyl, halogen, nitro, cyano, For example, T is a bond. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, T is unsubstituted or substituted C-C, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen alkyl linker, including but not limited to, methyl, ethyl, n-pro tyl, and n-hexyl, each of which is optionally substituted with pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and halogen (e.g., fluorine, chlorine, bromine, and iodine)), and n-hexyl linker. 50 unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, T is a methyl linker. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, Q is H. toxy, each of which is optionally substituted with halogen For example, both R and Rare H. (e.g., fluorine, chlorine, bromine, and iodine)). For example, at least one of R and R is unsubstituted For example, R is methyl substituted with phenyl substi or Substituted, straight-chain or branched C-C alkyl, includ 55 tuted with one or more groups, each of which can be the same ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu or different, selected from methyl, ethyl, t-butyl, and trifluo tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. romethyl. For example, at least one of R and R' is methyl, ethyl For example, R is methyl substituted with phenyl substi or t-butyl. tuted with one or more groups, each of which can be the same For example, R is phenyl substituted with one or more 60 or different, selected from methoxy, ethoxy, i-propyloxy, and groups, each of which can be the same or different, selected t-butoxy. For example, R is methyl substituted with phenyl from methyl, ethyl, t-butyl and trifluoromethyl. substituted with one methoxy. For example, R is phenyl substituted with one or more For example, n is 0. groups, each of which can be the same or different, selected For example, n is 1. from methoxy, t-butoxy and trifluoromethoxy. 65 For example, n is 2. For example, R is phenyl substituted with two or more For example, each R, is independently fluorine, chlorine, groups, each of which can be the same or different, selected bromine, or iodine. US 8,263,610 B2 35 36 For example, each R, is independently unsubstituted or For example, R, is unsubstituted phenyl. Substituted, straight-chain or branched C-C alkyl, including For example, R, is phenyl substituted with one or more but not limited to, methyl, ethyl, n-propyl, i-propyl, -butyl, groups, each of which can be the same or different, selected S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, each R, is independently unsubstituted or 5 stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. Substituted C-C alkoxy, including but not limited to, meth n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each oxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, t-butoxy. of which is optionally substituted with halogen (e.g., fluorine, For example, each R is independently —NHC(O)R. chlorine, bromine, and iodine)), and unsubstituted or Substi For example, R is H. tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro For example, Riis unsubstituted or Substituted, straight 10 pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is chain or branched C-C alkyl, including but not limited to, optionally Substituted with halogen (e.g., fluorine, chlorine, methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, bromine, and iodine)). n-pentyl, S-pentyl, and n-hexyl. For example, R, is phenyl substituted with two or more For example, R is methyl. groups, each of which can be the same or different, selected For example, at least one R is hydroxyl, methyl, ethyl, 15 from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub t-butyl, trifluoromethyl, methoxy, ethoxy, i-propyloxy, t-bu stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. toxy, nitro, halogen (e.g., fluorine, chlorine, bromine, and n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each iodine), or —NHC(O)R, wherein R is methyl. of which is optionally substituted with halogen (e.g., fluorine, For example, at least two R, each of which is independent chlorine, bromine, and iodine)), and unsubstituted or Substi from the other, are hydroxyl, methyl, ethyl, t-butyl, trifluo tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro romethyl, methoxy, ethoxy, i-propyloxy, t-butoxy, nitro, halo pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is gen (e.g., fluorine, chlorine, bromine, and iodine), or—NHC optionally Substituted with halogen (e.g., fluorine, chlorine, (O)R, wherein R is methyl. bromine, and iodine)). For example, at least three R, each of which is indepen For example, R is H. dent from the other, are hydroxyl, methyl, ethyl, t-butyl, tri 25 For example, R is unsubstituted or Substituted, straight fluoromethyl, methoxy, ethoxy, i-propyloxy, t-butoxy, nitro, chain or branched C-C alkyl, including but not limited to, halogen (e.g., fluorine, chlorine, bromine, and iodine), or methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, —NHC(O)R, wherein R is methyl. n-pentyl, S-pentyl, and n-hexyl. For example, both R and R are H. For example, R is methyl. For example, at least one of R and R is unsubstituted 30 For example, R is unsubstituted phenyl. or Substituted, straight-chain or branched C-C alkyl, includ For example, R is phenyl substituted with one or more ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu groups, each of which can be the same or different, selected tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub which is optionally Substituted with halogen (e.g., fluorine, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. chlorine, bromine, and iodine). 35 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each For example, at least one of RandR is methyl, which of which is optionally substituted with halogen (e.g., fluorine, is optionally substituted with halogen (e.g., fluorine, chlorine, chlorine, bromine, and iodine)), and unsubstituted or Substi bromine, and iodine). tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro For example, at least one of R and R. is unsubstituted pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is phenyl. 40 optionally Substituted with halogen (e.g., fluorine, chlorine, For example, at least one of R and R is phenyl Sub bromine, and iodine)). stituted with one or more groups, each of which can be the For example, R is phenyl substituted with two or more same or different, selected from hydroxyl, halogen, nitro, groups, each of which can be the same or different, selected cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, 45 stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. s-pentyl, and n-hexyl, each of which is optionally Substituted n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each with halogen (e.g., fluorine, chlorine, bromine, and iodine)), of which is optionally substituted with halogen (e.g., fluorine, and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, chlorine, bromine, and iodine)), and unsubstituted or Substi ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro toxy, each of which is optionally substituted with halogen 50 pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is (e.g., fluorine, chlorine, bromine, and iodine)). optionally Substituted with halogen (e.g., fluorine, chlorine, For example, at least one of R and R is phenyl Sub bromine, and iodine)). stituted with two or more groups, each of which can be the For example, all of R, R2 and Rs are H. same or different, selected from hydroxyl, halogen, nitro, For example, at least one of R. R. and R is unsub cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, 55 stituted or Substituted, straight-chain or branched C-C, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, alkyl, including but not limited to, methyl, ethyl, n-propyl. s-pentyl, and n-hexyl, each of which is optionally Substituted i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and with halogen (e.g., fluorine, chlorine, bromine, and iodine)), n-hexyl. and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, at least one of R, R2 and Rs is unsub ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu 60 stituted phenyl. toxy, each of which is optionally substituted with halogen For example, at least one of R. R. and R is phenyl (e.g., fluorine, chlorine, bromine, and iodine)). substituted with one or more groups, each of which can be the For example, R, is H. same or different, selected from hydroxyl, halogen, nitro, For example, R, is unsubstituted or Substituted, straight cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, chain or branched C-C alkyl, including but not limited to, 65 ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, s-pentyl, and n-hexyl, each of which is optionally Substituted n-pentyl, S-pentyl, and n-hexyl. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), US 8,263,610 B2 37 38 and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, chlorine, bromine, and iodine)), and unsubstituted or Substi ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro toxy, each of which is optionally substituted with halogen pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is (e.g., fluorine, chlorine, bromine, and iodine)). optionally Substituted with halogen (e.g., fluorine, chlorine, For example, at least one of R, R2 and Rs is phenyl bromine, and iodine)). substituted with two or more groups, each of which can be the For example, X-X, is CRR. O. same or different, selected from hydroxyl, halogen, nitro, For example, X-X" is CRR O where R and R', cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, together with the atom they attach to, form a ring. ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, For example, X-X" is CRR O where R and R', together with the atom they attach to, forman unsubstituted or s-pentyl, and n-hexyl, each of which is optionally Substituted 10 substituted heterocycle. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, X-X, is CRR O where R and R', and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, together with the atom they attach to, forman unsubstituted or ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu Substituted piperidine ring. toxy, each of which is optionally substituted with halogen The present invention also provides the compounds of (e.g., fluorine, chlorine, bromine, and iodine)). 15 Formulae IIal, IIa2, IIb, IIc, IId, IIe and IIf: For example, both R and R are H. For example, at least one of R and R is unsubstituted or Substituted, straight-chain or branched C-C alkyl, includ (IIa1) ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, at least one of R and R is unsubstituted phenyl. For example, at least one of R and R is phenyl substi tuted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, 25 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tyl, and n-hexyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubstituted or substituted C-C alkoxy (e.g., methoxy, 30 (IIa2) ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, at least one of R and R is phenyl Substi tuted with two or more groups, each of which can be the same 35 or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tyl, and n-hexyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)), and 40 unsubstituted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, R is H. 45

For example, R is unsubstituted or substituted, straight (IIb) chain or branched C-C alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is unsubstituted phenyl. 50 For example, R is phenyl substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 55 of which is optionally substituted with halogen (e.g., fluorine, (IIc) chlorine, bromine, and iodine)), and unsubstituted or Substi R tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is - optionally Substituted with halogen (e.g., fluorine, chlorine, 60 Rel 21 N, bromine, and iodine)). For example, R is phenyl substituted with two or more S groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub / \ stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. 65 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each (R)\- Rye of which is optionally substituted with halogen (e.g., fluorine, US 8,263,610 B2 39 40 -continued For example, R is methyl. (IId) For example, R is heteroaryl selected from pyrrolyl, fura nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, W pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, Rel a NN benzothiazolyl, benzoimidazolyl, benzothienyl, methylene dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, e (R) is N indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, imidazothiazolyl, quinoxalinyl, tetrahydropyridinyl, pyrrol N-4 10 opyrimidinyl, and the like, and is optionally substituted with Rd1, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub stituted or substituted amino, unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, (IIe) S-butyl, t-butyl, n-pentyl, S-pentyl and n-hexyl, each of which 15 is optionally substituted with halogen (e.g., fluorine, chlorine, bromine and iodine)), C-C aryl (e.g., phenyl, which is optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, and the like, and is optionally Substituted), C-C carbocycle (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally Rel, or Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, 25 tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, (IIf) and the like, and is optionally Substituted). For example, R is pyrazolyl, and is optionally substituted with (e.g., piperidinyl, which is optionally Substituted). For example, R is H. 30 For example, R is unsubstituted or substituted, straight chain or branched C-C alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl. n-butyl, s-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is methyl substituted with unsubstituted 35 phenyl. For example, R is methyl substituted with phenyl substi tuted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, or a salt, Solvate, hydrate or prodrug thereof, wherein: unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, R is H. halogen, unsubstituted or substituted C-C alkyl, 40 n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen unsubstituted or substituted phenyl, or unsubstituted or sub tyl, and n-hexyl, each of which is optionally substituted with stituted heteroaryl comprising one or two 5- or 6-member ring halogen (e.g., fluorine, chlorine, bromine, and iodine)), and and 1-4 heteroatoms selected from N, O and S; unsubstituted or Substituted C-C alkoxy (e.g., methoxy, R is H, or unsubstituted or substituted C-C alkyl: ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu each R, is independently halogen, hydroxyl, cyano, nitro, 45 toxy, each of which is optionally substituted with halogen amino, unsubstituted or Substituted C-C alkoxy, unsubsti (e.g., fluorine, chlorine, bromine, and iodine)). tuted or substituted C-C alkyl, -C(O)R. For example, R is methyl substituted with phenyl substi C(O)CR —NHC(O)R, or —NHC(O)CR; tuted with one or more groups, each of which can be the same n is 0, 1, 2, 3, or 4: or different, selected from methyl, ethyl, t-butyl, and trifluo Ryal, Rya2. Rt. Re. Rya, Ryaz, Rya. Rye. Re2, O Rare 50 romethyl. each independently H, unsubstituted or substituted C-C, For example, R is methyl substituted with phenyl substi alkyl, or unsubstituted or substituted phenyl: tuted with one or more groups, each of which can be the same Riis H. unsubstituted or Substituted C-C alkyl, unsub or different, selected from methoxy, ethoxy, i-propyloxy, and stituted or substituted C-C aryl, or unsubstituted or substi t-butoxy. tuted heteroaryl comprising one or two 5- or 6-member ring 55 For example, n is 0. and 1-4 heteroatoms selected from N, O and S; and For example, n is 1. R, R2, Rs. R4 and Rs are each independently H. For example, n is 2. hydroxyl, halogen, cyano, nitro, unsubstituted or Substituted For example, each R, is independently fluorine, chlorine, amino, unsubstituted or Substituted C-C alkyl, unsubsti bromine, or iodine. tuted or substituted C-C alkoxy, or unsubstituted or substi 60 For example, each R, is independently unsubstituted or tuted phenyl. Substituted, straight-chain or branched C-C alkyl, including For example, R is H. but not limited to, methyl, ethyl, n-propyl, i-propyl, -butyl, For example, R is fluorine, chlorine, bromine, or iodine. S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is unsubstituted or Substituted, straight For example, each R, is independently unsubstituted or chain or branched C-C alkyl, including but not limited to, 65 Substituted C-C alkoxy, including but not limited to, meth methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, oxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, t-butoxy. n-pentyl, S-pentyl, and n-hexyl. For example, each R, is independently —NHC(O)R. US 8,263,610 B2 41 42 For example, R is H. pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is For example, R is unsubstituted or substituted, straight optionally Substituted with halogen (e.g., fluorine, chlorine, chain or branched C-C alkyl, including but not limited to, bromine, and iodine)). methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R, is phenyl substituted with two or more For example, R is methyl. groups, each of which can be the same or different, selected For example, at least one R is hydroxyl, methyl, ethyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub t-butyl, trifluoromethyl, methoxy, ethoxy, i-propyloxy, t-bu stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. toxy, nitro, halogen (e.g., fluorine, chlorine, bromine, and n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each iodine), or —NHC(O)R, wherein R is methyl. 10 of which is optionally substituted with halogen (e.g., fluorine, For example, at least two R, each of which is independent chlorine, bromine, and iodine)), and unsubstituted or Substi from the other, are hydroxyl, methyl, ethyl, t-butyl, trifluo tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro romethyl, methoxy, ethoxy, i-propyloxy, t-butoxy, nitro, halo pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is optionally Substituted with halogen (e.g., fluorine, chlorine, gen (e.g., fluorine, chlorine, bromine, and iodine), or—NHC 15 (O)R, wherein R is methyl. bromine, and iodine)). For example, at least three R, each of which is indepen For example, R is H. dent from the other, are hydroxyl, methyl, ethyl, t-butyl, tri For example, R is unsubstituted or Substituted, straight fluoromethyl, methoxy, ethoxy, i-propyloxy, t-butoxy, nitro, chain or branched C-C alkyl, including but not limited to, halogen (e.g., fluorine, chlorine, bromine, and iodine), or methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, —NHC(O)R, wherein R is methyl. n-pentyl, S-pentyl, and n-hexyl. For example, both R and R are H. For example, R is methyl. For example, at least one of R and R is unsubstituted or substituted, straight-chain or branched C-C alkyl, includ For example, all of R, RR2 and Rs are H. ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu 25 For example, at least one of R, R2 and Rs is unsub tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of stituted or substituted, straight-chain or branched C-C, which is optionally Substituted with halogen (e.g., fluorine, alkyl, including but not limited to, methyl, ethyl, n-propyl. chlorine, bromine, and iodine). i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, at least one of R and R is methyl, which n-hexyl. 30 is optionally substituted with halogen (e.g., fluorine, chlorine, For example, both R and R2 are H. bromine, and iodine). For example, at least one of R and R is unsubstituted For example, at least one of R and R. is unsubstituted or substituted, straight-chain or branched C-C alkyl, includ phenyl. ing but not limited to, methyl, ethyl, n-propyl, i-propyl, -bu For example, at least one of R and R is phenyl Sub 35 tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. stituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, For example, Reis H. cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, For example, R is unsubstituted or substituted, straight ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, chain or branched C-C alkyl, including but not limited to, s-pentyl, and n-hexyl, each of which is optionally Substituted 40 methyl, ethyl, n-propyl, i-propyl, -butyl, S-butyl, t-butyl, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), n-pentyl, S-pentyl, and n-hexyl. and unsubstituted or substituted C-C alkoxy (e.g., methoxy, For example, all of R,p1: R p.2: R.is R4R and Rs are H. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, at least one of R, R2, Rs.p33 R4 and Rs is toxy, each of which is optionally substituted with halogen fluorine, chlorine, bromine, or iodine. (e.g., fluorine, chlorine, bromine, and iodine)). 45 For example, at least one of R, R2, Rs. Ra and Rs is For example, at least one of R and R is phenyl Sub unsubstituted or substituted, straight-chain or branched stituted with two or more groups, each of which can be the C-C alkyl, including but not limited to, methyl, ethyl, n-pro same or different, selected from hydroxyl, halogen, nitro, pyl, i-propyl, -butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, n-hexyl. ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, 50 For example, at least one of Rp13 p25 p33 Ra and Rs is s-pentyl, and n-hexyl, each of which is optionally Substituted methyl. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, at least one of R, R2, Rs. Ra and Rs is ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu unsubstituted or substituted C-C alkoxy, including but not toxy, each of which is optionally substituted with halogen 55 limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-bu (e.g., fluorine, chlorine, bromine, and iodine)). toxy, t-butoxy. For example, R, is H. For example, at least one of R, R2, Rs. Ra and Rs is For example, R, is unsubstituted phenyl. unsubstituted or substituted phenyl. For example, R, is phenyl Substituted with one or more 60 For example, at least two of R. R. R. R. and Rs. groups, each of which can be the same or different, selected each of which is independent from the other, are methyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, i-propyloxy, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. t-butoxy, hydroxyl, halogen, nitro, or cyano. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each For example, at least three of R, R2, Rs. Ra and Rs. of which is optionally substituted with halogen (e.g., fluorine, 65 each of which is independent from the other, are methyl, chlorine, bromine, and iodine)), and unsubstituted or Substi ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, i-propyloxy, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro t-butoxy, hydroxyl, halogen, nitro, or cyano. US 8,263,610 B2 43 44 The present invention also provides the compounds of For example, T is unsubstituted or Substituted C-C, Formula III: alkyl linker, including but not limited to, methyl, ethyl, n-pro pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl linker. (III) 5 For example, T is a methyl linker. Rc2 For example, Q is H. N-y For example, both R and Rare H. W For example, at least one of R and R' is unsubstituted Rel 21 NN or substituted, straight-chain or branched C-C alkyl, includ 10 ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu N tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, at least one of R and R' is methyl, ethyl or t-butyl. Rc6, For example, R is phenyl substituted with one or more 15 groups, each of which can be the same or different, selected Rc5 from methyl, ethyl, t-butyl and trifluoromethyl. For example, R is phenyl substituted with one or more groups, each of which can be the same or different, selected or a salt, Solvate, hydrate or prodrug thereof, wherein: from methoxy, t-butoxy and trifluoromethoxy. For example, R is phenyl substituted with two or more groups, each of which can be the same or different, selected from hydroxyl, cyano, methyl, ethyl, t-butyl, trifluoromethyl, O methoxy, t-butoxy, trifluoromethoxy, and halogen. For example, R is heteroaryl selected from pyrrolyl, fura 25 nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet is a 5- or 6-member ring which optionally comprises 1-4 razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, heteroatoms selected from N, O and S, and is optionally pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, substituted; benzothiazolyl, benzoimidazolyl, benzothienyl, methylene R is H. halogen, unsubstituted or substituted C-C alkyl, dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, unsubstituted or substituted phenyl, or unsubstituted or sub 30 indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, stituted heteroaryl comprising one or two 5- or 6-member ring imidazothiazolyl, quinoxalinyl, tetrahydropyridinyl, pyrrol and 1-4 heteroatoms selected from N, O and S. opyrimidinyl, and the like, and is optionally substituted with R is H or unsubstituted or substituted C-C alkyl; and halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub Rs and R are each independently H, unsubstituted or stituted or substituted amino, unsubstituted or substituted substituted C-C alkyl, or unsubstituted or substituted 35 C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, Co-Co aryl. S-butyl, t-butyl, n-pentyl, S-pentyl and n-hexyl, each of which For example, R is H. is optionally substituted with halogen (e.g., fluorine, chlorine, For example, R is fluorine, chlorine, bromine, or iodine. bromine and iodine)), Co-Co aryl (e.g., phenyl, which is For example, R is unsubstituted or Substituted, straight optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. chain or branched C-C alkyl, including but not limited to, 40 thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, n-pentyl, S-pentyl, and n-hexyl. pyridazinyl, and pyrimidinyl, and the like, and is optionally For example, R is methyl. Substituted), C-Cs carbocycle (e.g., cyclopropyl, cyclobutyl, For example, R is unsubstituted phenyl. cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally 45 Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi For example, R is phenyl substituted with one or more nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, groups, each of which can be the same or different, selected tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub and the like, and is optionally Substituted). stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, R is heteroaryl selected from furanyl, pyra n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 50 Zolyl, purinyl, indolyl, tetrahydropyridinyl, and pyrrolopyri of which is optionally substituted with halogen (e.g., fluorine, midinyl, and is optionally Substituted with one or more chlorine, bromine, and iodine)), unsubstituted or substituted groups, each of which can be the same of different, selected C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, from methyl, ethyl, t-butyl, amino, and heterocycle (e.g., butoxy, i-butoxy, and t-butoxy, each of which is optionally piperidinyl, which is optionally substituted). Substituted with halogen (e.g., fluorine, chlorine, bromine, 55 For example, R is H. and iodine)), and -T-Q, wherein: For example, R is unsubstituted or substituted, straight T is a bond, or unsubstituted or Substituted C-C alkyl chain or branched C-C alkyl, including but not limited to, linker; methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, Q is H. —NRR', C(O)NR'R''. —NHC(O) n-pentyl, S-pentyl, and n-hexyl. R. —NHC(O)OR, NHC(O)NR'R'', or 60 For example, R is methyl substituted with unsubstituted —S(O).R. and phenyl. R, and Rare each independently H, or unsubstituted For example, R is methyl substituted with phenyl substi or substituted C-C alkyl. tuted with one or more groups, each of which can be the same For example, R is phenyl substituted with one or more or different, selected from hydroxyl, halogen, nitro, cyano, groups, each of which can be the same or different, selected 65 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, from -T-Q. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, T is a bond. tyl, and n-hexyl, each of which is optionally substituted with US 8,263,610 B2 45 46 halogen (e.g., fluorine, chlorine, bromine, and iodine)), and form a 5- or 6-member ring which optionally comprises unsubstituted or substituted C-C alkoxy (e.g., methoxy, 1-4 heteroatoms selected from N, O and S and is option ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ally substituted; toxy, each of which is optionally substituted with halogen T is a bond, or unsubstituted or Substituted C-C alkyl (e.g., fluorine, chlorine, bromine, and iodine)). linker; For example, R is methyl substituted with phenyl substi Q, is H. unsubstituted or Substituted phenyl, unsubsti tuted with one or more groups, each of which can be the same tuted or substituted heteroaryl comprising one or two 5 or different, selected from methyl, ethyl, t-butyl, and trifluo or 6-member ring and 1-4 heteroatoms selected from N. romethyl. O and S, unsubstituted or substitute C-C carbocycle, For example, R is methyl substituted with phenyl substi 10 unsubstituted or Substituted heterocycle comprising one tuted with one or more groups, each of which can be the same or two 5- or 6-member ring and 1-4 heteroatoms selected or different, selected from methoxy, ethoxy, i-propyloxy, and from N, O and S, or —OR, and t-butoxy. R is H. unsubstituted or Substituted C-C alkyl, or For example, both Rs and R are H. 15 unsubstituted or substituted phenyl. For example, at least one of Rs and R is unsubstituted or For example, Substituted, straight-chain or branched C-C alkyl, including but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, at least one of Rs and R is unsubstituted or substituted phenyl. For example, is a phenyl optionally Substituted with one or more groups, each of which can be the same or different, selected from 25 hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), cyano, nitro, methyl, ethyl, t-butyl, trifluomethyl, O methoxy, ethoxy, t-butoxy, and —NHC(O)R. For example, is a 5- or 6-member ring selected from: 1) phenyl, which is optionally substituted with one or more 30 groups, each of which can be the same or different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), cyano, nitro, unsubstituted or Substituted amino, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 35 is a phenyl optionally Substituted with two or more groups, tyl, and n-hexyl), unsubstituted or Substituted C-C alkoxy each of which can be the same or different, selected from (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and toxy, and t-butoxy), —C(O)R. —C(O)CR —NHC iodine), cyano, nitro, methyl, ethyl, t-butyl, trifluomethyl, (O)R —NHC(O)CR, and —C(O)NRR): methoxy, ethoxy, t-butoxy, and —NHC(O)R. 2) heteroaryl (e.g., pyrrolyl pyrazolyl, imidazolyl, 40 For example, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxa diazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thienyl, and pyridinone, and the like, and is optionally Substituted with one or more groups, each of which can be the same or 45 different, selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted or substituted is heteroaryl selected from imidazolyl, thiazolyl pyridinyl, C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, pyrazoyl pyridinone, pyrimidinyl, furanyl, or thienyl, each of S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl), unsubsti which is optionally Substituted with one or more groups, each tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro 50 of which can be the same or different, selected from halogen pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy), unsub (e.g., fluorine, chlorine, bromine, and iodine), methyl, ethyl, stituted or Substituted phenyl, —NR, R2, and t-butyl, trifluomethyl, methoxy, ethoxy, t-butoxy, phenyl, —SR); NR, R2, and SR,. 3) carbocycle (e.g., cyclopropyl, cyclobutyl, cyclopentyl, For example, both R and Rare H. cyclohexyl, or cycloheptyl, and is optionally Substituted); or 55 For example, at least one of R and R is unsubsti 4) heterocycle (e.g., pyrrolidinyl, imidazolidinyl, pyrazo tuted or substituted, straight-chain or branched C-C alkyl, lidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahy including but not limited to, methyl, ethyl, n-propyl, i-propyl. drofuranyl, piperidinyl, piperazinyl, and morpholinyl, and the n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. like, and is optionally substituted), For example, R is H. wherein: 60 For example, Riis unsubstituted or Substituted, straight Rand Rare each independently H, unsubstituted or chain or branched C-C alkyl, including but not limited to, substituted C-C alkyl, unsubstituted or substituted methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, C-C aryl, or unsubstituted or substituted heteroaryl n-pentyl, S-pentyl, and n-hexyl. comprising one or two 5- or 6-member ring and 1-4 For example, R is methyl. heteroatoms selected from N, O and S; 65 For example, both of R, and R2 are H. R, and R2 are each independently H.-Ti-Qi, or For example, at least one of R and R 1S - R, and R apaa23 together with the atom they attach to, Qin, US 8,263,610 B2 47 48 For example, T is a bond. Q, is H. unsubstituted or Substituted phenyl, unsubsti For example, T is unsubstituted or substituted C-C, tuted or substituted heteroaryl comprising one or two 5 alkyl linker, including but not limited to, methyl, ethyl, n-pro or 6-member ring and 1-4 heteroatoms selected from N. pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and O and S, unsubstituted or substitute C-C carbocycle, n-hexyl linker. unsubstituted or Substituted heterocycle comprising one For example, T is a methyl, ethyl, or propyl linker. or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S. —C(O)R. —C(O)OR; and For example, Q, is H. R is H. unsubstituted or Substituted phenyl, unsubsti For example, Q, is unsubstituted phenyl. tuted or substituted heteroaryl comprising one or two 5 For example, Q, is phenyl Substituted with one or more or 6-member ring and 1-4 heteroatoms selected from N. groups, each of which can be the same or different, selected 10 O and S, unsubstituted or substitute C-C carbocycle, from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and unsubstituted or Substituted heterocycle comprising one iodine), cyano, nitro, unsubstituted or Substituted amino, or two 5- or 6-member ring and 1-4 heteroatoms selected unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, from N, O and S. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, R, and R, together with the atom they tyl, and n-hexyl, each of which is optionally substituted with 15 attach to, form a 5- or 6-member ring selected from a pyrro halogen (e.g., fluorine, chlorine, bromine, and iodine)), and lidinyl, piperidinyl, piperazinyl, or morpholinyl, and is unsubstituted or Substituted C-C alkoxy (e.g., methoxy, optionally substituted. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, T is a bond. toxy, each of which is optionally substituted with halogen For example, T is unsubstituted or substituted C-C, (e.g., fluorine, chlorine, bromine, and iodine)). alkyl linker, including but not limited to, methyl, ethyl, n-pro For example, Q, is phenyl Substituted with one or more pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and groups, each of which can be the same or different, selected n-hexyl linker. from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, For example, T is a methyl linker. t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and For example, Q, is unsubstituted phenyl. iodine). For example, Q, is heteroaryl selected from pyrrolyl, For example, Q, is phenyl substituted with two or more 25 furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, groups, each of which can be the same or different, selected tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, iodine). methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry For example, Q, is heteroaryl selected from pyrrolyl, dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, 30 inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi optionally substituted. nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox For example, Q2 is pyridinyl. azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, For example, Q, is cyclopropyl, cyclobutyl, cyclopen methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz 35 For example, Q, is heterocycle selected from pyrrolidi inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi optionally substituted. nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, For example, Q, is pyridinyl. morpholinyl, and pyrrolidinone, and the like, and is option For example, Q, is cyclopropyl, cyclobutyl, cyclopen ally substituted. tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, Q2 is morpholinyl. For example, Q, is cycloheptyl. 40 For example, Q, is —C(O)R. For example, Q, is heterocycle selected from pyrrolidi For example, R, is H. nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi For example, R, is phenyl and is optionally Substituted. nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, For example, R, is heteroaryl selected from pyrrolyl, morpholinyl, and pyrrolidinone, and the like, and is option furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, ally Substituted with one or more groups, each of which can 45 tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi be the same or different, selected from hydroxyl, halogen nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox (e.g., fluorine, chlorine, bromine, and iodine), and unsubsti azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, tuted or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz n-hexyl). inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is For example, Q, is pyrrolidinyl, piperidinyl, morpholi 50 optionally substituted. nyl, or pyrrolidinone, and is optionally Substituted with For example, R, is cyclopropyl, cyclobutyl, cyclopen methyl, ethyl, or t-butyl. tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, Q, is —ORs. For example, R, is heterocycle selected from pyrrolidi For example, R, is H. nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi For example, R is unsubstituted or substituted, straight 55 nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, chain or branched C-C alkyl, including but not limited to, morpholinyl, and pyrrolidinone, and the like, and is option methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, ally substituted. n-pentyl, S-pentyl, and n-hexyl. For example, R, is pyrrolidinyl. For example, R is phenyl, and is optionally substituted. For example, R, and R, together with the atom they For example, R, and R apaa23 together with the atom they attach to, form a 5- or 6-member ring selected from pyrro 60 attach to, form a 5- or 6-member ring selected from pyrro lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi nyl, and the like and is optionally substituted with one or more nyl, and the like and is optionally substituted with two or more groups, each of which can be the same or different, selected groups, any adjacent two of which, together with the atoms from -T2-Q2, wherein: 65 they attach to form a 5- or 6-member ring which optionally T is a bond, or unsubstituted or Substituted C-C alkyl comprises 1-4 heteroatoms selected from N, O and S and is linker; optionally substituted. US 8,263,610 B2 49 50 For example, R, and R, together with the atom they -continued

attach to, form a 5- or 6-membered ring selected from pyrro (IIIb) lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi nyl, and the like and is optionally substituted with two or more groups, any adjacent two of which, together with the atoms they attach to form a phenyl ring, which is optionally Substi tuted e.g., with heteroaryl or heterocycle (e.g., morpholine or pyridine) or with C-C alkyl linker-unsubstituted phenyl (e.g., benzyl), C-C alkyl linker-Substituted phenyl e.g., Sub 10 stituted with halogen, C-C alkyl linker-C(O)-heterocycle (e.g., pyrrolidine). For example, the 5- or 6-membered ring is Substituted with a fused aryl ring e.g., (IIIc) 15 --

25

(IIId) Rc2 For example, N-- N^ 30 W 21 NN G) S. 35 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclo Rc6 s heptyl, and is optionally Substituted. For example, 40

(IIIc1) G) 45 is heterocycle selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tet rahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and the like, and is optionally Substituted. 50 The present invention also provides the compounds of Formulae IIIa, IIIb, IIIc, IIId, IIIel, IIIe2, and IIIf:

(IIIa) 55 (IIIc2)

60

Rc6, or 65 US 8,263,610 B2 51 52 -continued unsubstituted or Substituted C-C alkoxy (e.g., methoxy,

(IIIf ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, R is methyl substituted with phenyl substi tuted with one or more groups, each of which can be the same or different, selected from methyl, ethyl, t-butyl, and trifluo romethyl. For example, R is methyl substituted with phenyl substi 10 tuted with one or more groups, each of which can be the same or different, selected from methoxy, ethoxy, i-propyloxy, and t-butoxy. For example, both Rs and R are H. For example, at least one of Rs and R is unsubstituted or or a salt, Solvate, hydrate or prodrug thereof, wherein: 15 Substituted, straight-chain or branched C-C alkyl, including R is H: but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, R is H, or unsubstituted or substituted C-C alkyl: S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. Rs and R are each independently H, unsubstituted or For example, at least one of Rs and R is unsubstituted or substituted phenyl. substituted C-C alkyl, or unsubstituted or substituted For example, m is 0. Co-Co aryl; For example, each of R is independently unsubstituted or each R, is eachindependently unsubstituted or Substituted Substituted, straight-chain or branched C-C alkyl, including C-C alkyl; but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, m is 0, 1, 2, or 3: S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. Rs and R. are each independently H, unsubstituted or 25 For example, all of R. R. and R. are H. substituted C-C alkyl, or unsubstituted or substituted phe For example, at least one of R. R. and R, is unsubsti nyl: tuted or Substituted, straight-chain or branched C-C alkyl, R. R., and R are each independently H, or unsubsti including but not limited to, methyl, ethyl, n-propyl, i-propyl. tuted or substituted C-C alkyl: n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. R. R.s, and R. are each independently H, unsubstituted 30 For example, both of Rs and R. are H. or substituted C-C alkyl, unsubstituted or substituted For example, at least one of Rs and R, is unsubstituted or C-C aryl, or unsubstituted or substituted heteroaryl com substituted, straight-chain or branched C-C alkyl, including prising one or two 5- or 6-member ring and 1-4 heteroatoms but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, selected from N, O and S. S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. R, and R. are each independently H, unsubstituted or 35 For example, at least one of Rs and R is unsubstituted Substituted C-C alkyl, -NR, R2, or—SR; phenyl. R is H, or unsubstituted or Substituted C-C alkyl, For example, R, is unsubstituted phenyl. R, and R2 are each independently H.-Ti-Qi, or For example, R., is H. R, and R, together with the atom they attach to, form a For example, R., is unsubstituted or Substituted, straight 5- or 6-member ring which optionally comprises 1-4 heteroa 40 chain or branched C-C alkyl, including but not limited to, toms selected from N, O and Sand is optionally substituted; methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, T is a bond, or unsubstituted or substituted C-C alkyl n-pentyl, S-pentyl, and n-hexyl. linker; For example, R., is methyl. Q, is H. unsubstituted or Substituted phenyl, unsubsti For example, both of Rs and R. are H. tuted or substituted heteroaryl comprising one or two 5- or 45 For example, at least one of Rs and R is unsubstituted or 6-member ring and 1-4 heteroatoms selected from N, O and S. Substituted, straight-chain or branched C-C alkyl, including unsubstituted or substitute C-C carbocycle, unsubstituted but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, or Substituted heterocycle comprising one or two 5- or S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. 6-member ring and 1-4 heteroatoms selected from N, O and S. For example, both of R and R. are H. or —ORs, and 50 For example, at least one of R and R is unsubstituted R is H. unsubstituted or Substituted C-C alkyl, or or Substituted, straight-chain or branched C-C alkyl, includ unsubstituted or substituted phenyl. ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu For example, R is H. tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is H. For example, at least one of R, and R, is —SR. For example, R is unsubstituted or Substituted, straight 55 For example, R, is H and R2 is —SR. chain or branched C-C alkyl, including but not limited to, For example, R is H. methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, For example, Riis unsubstituted or Substituted, straight n-pentyl, S-pentyl, and n-hexyl. chain or branched C-C alkyl, including but not limited to, For example, R is methyl substituted with unsubstituted methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, phenyl. 60 n-pentyl, S-pentyl, and n-hexyl. For example, R is methyl substituted with phenyl substi For example, R is methyl. tuted with one or more groups, each of which can be the same For example, at least one of R, and R apa2 is or different, selected from hydroxyl, halogen, nitro, cyano, NR, R2. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, R, is H and R is —NRRY2 n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 65 For example, both of R, and R2 are H. tyl, and n-hexyl, each of which is optionally substituted with For example, at least one of R and R 1S - nnn1 halogen (e.g., fluorine, chlorine, bromine, and iodine)), and Qin, US 8,263,610 B2 53 54 For example, T is a bond. nyl, and the like and is optionally substituted with one or more For example, T is unsubstituted or substituted C-C, groups, each of which can be the same or different, selected alkyl linker, including but not limited to, methyl, ethyl, n-pro from -T2-Q2, wherein: pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and T is a bond, or unsubstituted or Substituted C-C alkyl n-hexyl linker. 5 linker; For example, T is a methyl, ethyl, or propyl linker. Q, is H. unsubstituted or Substituted phenyl, unsubsti For example, Q, is H. tuted or substituted heteroaryl comprising one or two 5 For example, Q, is unsubstituted phenyl. or 6-member ring and 1-4 heteroatoms selected from N. For example, Q, is phenyl substituted with one or more O and S, unsubstituted or substitute C-C carbocycle, groups, each of which can be the same or different, selected 10 unsubstituted or Substituted heterocycle comprising one from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and or two 5- or 6-member ring and 1-4 heteroatoms selected iodine), cyano, nitro, unsubstituted or Substituted amino, from N, O and S. —C(O)R. —C(O)CR, and unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, R is H. unsubstituted or Substituted phenyl, unsubsti n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tuted or substituted heteroaryl comprising one or two 5 tyl, and n-hexyl, each of which is optionally substituted with 15 or 6-member ring and 1-4 heteroatoms selected from N. halogen (e.g., fluorine, chlorine, bromine, and iodine)), and O and S, unsubstituted or substitute C-C carbocycle, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, unsubstituted or Substituted heterocycle comprising one ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu or two 5- or 6-member ring and 1-4 heteroatoms selected toxy, each of which is optionally substituted with halogen from N, O and S. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, and R, together with the atom they For example, Q, is phenyl substituted with one or more attach to, form a 5- or 6-member ring selected from pyrro groups, each of which can be the same or different, selected lidinyl, piperidinyl, piperazinyl, or morpholinyl, and is from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, optionally substituted. t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and For example, T2 is a bond. iodine). 25 For example, T is unsubstituted or Substituted C-C, For example, Q, is phenyl Substituted with two or more alkyl linker, including but not limited to, methyl, ethyl, n-pro groups, each of which can be the same or different, selected pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-hexyl linker. t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and For example, T is a methyl linker. iodine). 30 For example, Q, is unsubstituted phenyl. For example, Q, is heteroaryl selected from pyrrolyl, For example, Q, is heteroaryl selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, 35 azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is optionally substituted. optionally substituted. For example, Q, is pyridinyl. 40 For example, Q, is pyridinyl. For example, Q, is cyclopropyl, cyclobutyl, cyclopen For example, Q, is cyclopropyl, cyclobutyl, cyclopen tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, Q, is cycloheptyl. For example, Q, is heterocycle selected from pyrrolidi For example, Q, is heterocycle selected from pyrrolidi nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi 45 nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and the like, and is option morpholinyl, and pyrrolidinone, and the like, and is option ally substituted. ally Substituted with one or more groups, each of which can For example, Q2 is morpholinyl. be the same or different, selected from hydroxyl, halogen For example, Q, is —C(O)R. (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted 50 For example, R, is H. or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. For example, R, is phenyl and is optionally Substituted. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, R, is heteroaryl selected from pyrrolyl, n-hexyl). furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, For example, Q, is pyrrolidinyl, piperidinyl, morpholi tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi nyl, or pyrrolidinone, and is optionally Substituted with 55 nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox methyl, ethyl, or t-butyl. azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, For example, Q, is —ORs. methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry For example, R, is H. dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz For example, R is unsubstituted or Substituted, straight inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is chain or branched C-C alkyl, including but not limited to, 60 optionally substituted. methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, For example, R, is cyclopropyl, cyclobutyl, cyclopen n-pentyl, S-pentyl, and n-hexyl. tyl, cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, R is phenyl, and is optionally substituted. For example, R, is heterocycle selected from pyrrolidi For example, R, and R, together with the atom they nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi attach to, form a 5- or 6-member ring selected from pyrro 65 nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo morpholinyl, and pyrrolidinone, and the like, and is option lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi ally substituted. US 8,263,610 B2 55 56 For example, R, is pyrrolidinyl. Rs and Rs' are each independently H, or-T'-Q,"; For example, R, and R, together with the atom they R" is H, or unsubstituted or substituted C-C alkyl: attach to, form a 5- or 6-member ring selected from pyrro T.T., and Ts are each independently a bond, or unsub lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo stituted or substituted C-C alkyl linker; lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi Q, is H, unsubstituted or substituted Co-Co aryl, unsub nyl, and the like and is optionally substituted with two or more stituted or substituted heteroaryl comprising one or two 5- or groups, any adjacent two of which, together with the atoms 6-member ring and 1-4 heteroatoms selected from N, O and S. they attach to form a 5- or 6-member which optionally com unsubstituted or Substituted C-Cs carbocycle, unsubstituted prises 1-4 heteroatoms selected from N, O and S and is or Substituted heterocycle comprising one or two 5- or optionally substituted. 10 6-member ring and 1-4 heteroatoms selected from N, O and S. —C(O)CR, —C(O)R. —C(O)NR'R'', or—NRR'; For example, R, and R, together with the atom they Q," is H, unsubstituted or substituted Co-Co aryl, unsub attach to, form a 5- or 6-member ring selected from pyrro stituted or substituted heteroaryl comprising one or two 5- or lidinyl, piperidinyl, piperazinyl, and morpholinyl, and is 6-member ring and 1-4 heteroatoms selected from N, O and S. optionally Substituted with two or more groups, any adjacent 15 unsubstituted or Substituted C-Cs carbocycle, unsubstituted two of which, together with the atoms they attach to form a or Substituted heterocycle comprising one or two 5- or phenyl ring, which is optionally substituted. 6-member ring and 1-4 heteroatoms selected from N, O and S. The present invention also provides the compounds of —C(O)CR, —C(O)R. —C(O)NR'R'', or—NRR'; Formula IV': Q, is H, unsubstituted or substituted Co-Co aryl, unsub stituted or substituted heteroaryl comprising one or two 5- or (IV) 6-member ring and 1-4 heteroatoms selected from N, O and S. Rc2 unsubstituted or Substituted C-Cs carbocycle, unsubstituted NN- N^ or Substituted heterocycle comprising one or two 5- or W 6-member ring and 1-4 heteroatoms selected from N, O and S. R 21 NN 25 OOR, , —C(O)R. —C(O)NR'R'', or—NRR'; al R. R. R. and R' are each independently H, unsub R4 N stituted or substituted C-C alkyl, unsubstituted or substi tuted C-C aryl, or unsubstituted or substituted heteroaryl 30 comprising one or two 5- or 6-member ring and 1-4 heteroa R Y Rc6, toms selected from N, O and S. For example, R is H. or a salt, Solvate, hydrate or prodrug thereof, wherein: For example, R is fluorine, chlorine, bromine, or iodine. R is H. halogen, unsubstituted or Substituted C-C alkyl, For example, R is unsubstituted or Substituted, straight unsubstituted or substituted phenyl, or unsubstituted or sub 35 chain or branched C-C alkyl, including but not limited to, stituted heteroaryl comprising one or two 5- or 6-member ring methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, and 1-4 heteroatoms selected from N, O and S; n-pentyl, S-pentyl, and n-hexyl. R is H, or unsubstituted or substituted C-C alkyl: For example, R is methyl. R, and R are each independently H, unsubstituted or For example, R is unsubstituted phenyl. substituted C-C alkyl; 40 For example, R is phenyl substituted with one or more R is H, or unsubstituted or substituted C-C alkyl, or groups, each of which can be the same or different, selected unsubstituted or substituted C-C aryl; from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub Y is NR, or CHR,'; stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. R is H, unsubstituted or substituted Co-Co aryl, unsubsti n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each tuted or substituted heteroaryl comprising one or two 5- or 45 of which is optionally substituted with halogen (e.g., fluorine, 6-member ring and 1-4 heteroatoms selected from N, O and S. chlorine, bromine, and iodine)), unsubstituted or substituted unsubstituted or substituted C-C carbocycle, unsubstituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, or Substituted heterocycle comprising one or two 5- or butoxy, i-butoxy, and t-butoxy, each of which is optionally 6-member ring and 1-4 heteroatoms selected from N, O and S. Substituted with halogen (e.g., fluorine, chlorine, bromine, —S(O).R. —C(O)R. —C(O)CR, —(CH2)R. 50 and iodine)), and -T-Q, wherein: —C(=NH)NRR', —C(O)NRR', or - C(S)NRR'; T is a bond, or unsubstituted or Substituted C-C alkyl o is 0, 1, 2, 3, or 4: linker; R is H. unsubstituted or substituted C-C alkyl, or-T- Q is H. —NRR", —C(O)NR'R'', NHC(O) Q.: R. —NHC(O)CR, NHC(O)NR'R'', or R. and R are each independently H, unsubstituted or 55 —S(O).R., and substituted C-C alkyl, -T-Qs, or RandR', together with R. and R' are each independently H, or unsubstituted the atom they attach to, form a 5-, 6- or 7-member ring which or substituted C-C alkyl. comprises 1-4 heteroatoms selected from N, O and S and is For example, R is phenyl substituted with one or more optionally substituted; groups, each of which can be the same or different, selected R, is H. unsubstituted or substituted Co-Co aryl, unsub 60 from -T-Q. stituted or substituted heteroaryl comprising one or two 5- or For example, T is a bond. 6-member ring and 1-4 heteroatoms selected from N, O and S. For example, T is unsubstituted or Substituted C-C, unsubstituted or substituted C-C carbocycle, unsubstituted alkyl linker, including but not limited to, methyl, ethyl, n-pro or Substituted heterocycle comprising one or two 5- or pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and 6-member ring and 1-4 heteroatoms selected from N, O and S. 65 n-hexyl linker. —NRR", NR"C(O)NR'R', NR"C(O)R - NR"C For example, T is a methyl linker. (O)OR - NR"S(O).R., or - C(O)NR'R'': For example, Q is H. US 8,263,610 B2 57 58 For example, both R and Rare H. For example, R is methyl substituted with phenyl substi For example, at least one of R and R is unsubstituted tuted with one or more groups, each of which can be the same or Substituted, straight-chain or branched C-C alkyl, includ or different, selected from methyl, ethyl, t-butyl, and trifluo ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu romethyl. tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R is methyl substituted with phenyl substi For example, at least one of R and R' is methyl, ethyl tuted with one or more groups, each of which can be the same or t-butyl. or different, selected from methoxy, ethoxy, i-propyloxy, and For example, R is phenyl substituted with one or more t-butoxy. groups, each of which can be the same or different, selected For example, R is H. from methyl, ethyl, t-butyl and trifluoromethyl. 10 For example, R is unsubstituted or Substituted, straight chain or branched C-C alkyl, including but not limited to, For example, R is phenyl substituted with one or more methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, groups, each of which can be the same or different, selected n-pentyl, S-pentyl, and n-hexyl. from methoxy, t-butoxy and trifluoromethoxy. For example, R is H. For example, R is phenyl substituted with two or more 15 For example, R is unsubstituted or Substituted, straight groups, each of which can be the same or different, selected chain or branched C-C alkyl, including but not limited to, from hydroxyl, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, methoxy, t-butoxy, trifluoromethoxy, and halogen. n-pentyl, S-pentyl, and n-hexyl. For example, R is heteroaryl selected from pyrrolyl, fura For example, R is H. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, R is unsubstituted or Substituted, straight razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, chain or branched C-C alkyl, including but not limited to, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, benzothiazolyl, benzoimidazolyl, benzothienyl, methylene n-pentyl, S-pentyl, and n-hexyl. dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, For example, all of R. R. and R are H. indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, 25 For example, both R. and Rare H. imidazothiazolyl, quinoxalinyl, tetrohydropyridinyl, pyrrol For example, at least one of R and R is unsubsti opyrimidinyl, and the like, and is optionally substituted with tuted or Substituted, straight-chain or branched C-C alkyl, halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub including but not limited to, methyl, ethyl, n-propyl, i-propyl. stituted or substituted amino, unsubstituted or substituted n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, 30 For example, R is H. S-butyl, t-butyl, n-pentyl, S-penty1 and n-hexyl, each of which For example, Riis unsubstituted or Substituted, straight is optionally substituted with halogen (e.g., fluorine, chlorine, chain or branched C-C alkyl, including but not limited to, bromine and iodine)), C-C aryl (e.g., phenyl, which is methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. n-pentyl, S-pentyl, and n-hexyl. thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet 35 For example, R is methyl. razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, both of R and R are H. pyridazinyl, and pyrimidinyl, and the like, and is optionally For example, at least one of Rs 1 and R2 is -T-Qs. Substituted), C-Cs carbocycle (e.g., cyclopropyl, cyclobutyl, For example, T is a bond. cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally For example, T is unsubstituted or Substituted C-C, Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi 40 alkyl linker, including but not limited to, methyl, ethyl, n-pro nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, n-hexyl linker. and the like, and is optionally Substituted). For example, Q is a methyl, ethyl, or propyl linker. For example, R is heteroaryl selected from furanyl, pyra For example, Q is H. Zolyl, purinyl, indolyl, tetrahydropyridinyl, and pyrrolopyri 45 For example, Q is unsubstituted phenyl. midinyl, and is optionally Substituted with one or more For example, Q is phenyl Substituted with one or more groups, each of which can be the same of different, selected groups, each of which can be the same or different, selected from methyl, ethyl, t-butyl, amino, and heterocycle (e.g., from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, and piperidinyl, which is optionally substituted). iodine), cyano, nitro, unsubstituted or Substituted amino, For example, R is H. 50 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, R is unsubstituted or Substituted, straight n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen chain or branched C-C alkyl, including but not limited to, tyl, and n-hexyl, each of which is optionally substituted with methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, halogen (e.g., fluorine, chlorine, bromine, and iodine)), n-pentyl, S-pentyl, and n-hexyl. unsubstituted or substituted C-C alkoxy (e.g., methoxy, For example, R is methyl substituted with unsubstituted 55 ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu phenyl. toxy, each of which is optionally substituted with halogen For example, R is methyl substituted with phenyl substi (e.g., fluorine, chlorine, bromine, and iodine)). tuted with one or more groups, each of which can be the same For example, Q is phenyl Substituted with one or more or different, selected from hydroxyl, halogen, nitro, cyano, groups, each of which can be the same or different, selected unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, 60 from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and tyl, and n-hexyl, each of which is optionally substituted with iodine). halogen (e.g., fluorine, chlorine, bromine, and iodine)), and For example, Q is phenyl substituted with two or more unsubstituted or Substituted C-C alkoxy (e.g., methoxy, groups, each of which can be the same or different, selected ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu 65 from methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, toxy, each of which is optionally substituted with halogen t-butoxy, and halogen (e.g. fluorine, chlorine, bromine and (e.g., fluorine, chlorine, bromine, and iodine)). iodine). US 8,263,610 B2 59 60 For example, Q is heteroaryl selected from pyrrolyl, fura For example, Q is heteroaryl selected from pyrrolyl, fura nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, methylene benzothiazolyl, benzoimidazolyl, benzothienyl, methylene dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, imidazothiazolyl, and quinoxalinyl, and the like, and is imidazothiazolyl, and quinoxalinyl, and the like, and is optionally substituted. optionally substituted. For example, Q is pyridinyl. 10 For example, Q is pyridinyl. For example, Q is cyclopropyl, cyclobutyl, cyclopentyl, For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted. cyclohexyl, or cycloheptyl, and is optionally Substituted. For example, Q is cycloheptyl. For example, Q is heterocycle selected from pyrrolidinyl, For example, Q, is heterocycle selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 15 triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and the like, and is option morpholinyl, and pyrrolidinone, and the like, and is option ally substituted. ally Substituted with one or more groups, each of which can For example, Q is morpholinyl. be the same or different, selected from hydroxyl, halogen For example, Q is —C(O)R. (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted For example, R is H. or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. For example, R is phenyl and is optionally substituted. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, R is heteroaryl selected from pyrrolyl, n-hexyl). furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, For example, Q is pyrrolidinyl, piperidinyl, morpholinyl, tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi or pyrrolidinone, and is optionally substituted with methyl, 25 nyl, pyridazinyl, pyrimidinyl, benzoxazolyl, benzodiox ethyl, or t-butyl. azolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, For example, Q is —OR. methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry For example, R is H. dinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, indoliz For example, R is unsubstituted or Substituted, straight inyl, imidazothiazolyl, and quinoxalinyl, and the like, and is chain or branched C-C alkyl, including but not limited to, 30 optionally substituted. methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, For example, R is cyclopropyl, cyclobutyl, cyclopentyl, n-pentyl, s-pentyl, and n-hexyl. cyclohexyl, or cycloheptyl, and is optionally substituted. For example, R is phenyl, and is optionally substituted. For example, R is heterocycle selected from pyrrolidi For example, R. and R, together with the atom they nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidi attach to, form a 5- or 6-member ring selected from pyrro 35 nyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo morpholinyl, and pyrrolidinone, and the like, and is option lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi ally substituted. nyl, and the like and is optionally substituted with one or more For example, R is pyrrolidinyl. groups, each of which can be the same or different, selected For example, R. and R, together with the atom they from -T-Q, wherein: 40 attach to, form a 5- or 6-member ring selected from pyrro T is a bond, or unsubstituted or Substituted C-C alkyl lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo linker; lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi Q is H. unsubstituted or Substituted phenyl, unsubstituted nyl, and the like and is optionally substituted with two or more or Substituted heteroaryl comprising one or two 5- or groups, any adjacent two of which, together with the atoms 6-member ring and 1-4 heteroatoms selected from N.O 45 they attach to form a 5- or 6-member which optionally com and S, unsubstituted or Substitute C-C carbocycle, prises 1-4 heteroatoms selected from N, O and S and is unsubstituted or Substituted heterocycle comprising one optionally substituted. or two 5- or 6-member ring and 1-4 heteroatoms selected For example, R. and R, together with the atom they from N, O and S. —C(O)R. —C(O)CR; and attach to, form a 5- or 6-member ring selected from pyrro R is H. unsubstituted or Substituted phenyl, unsubsti 50 lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo tuted or substituted heteroaryl comprising one or two 5 lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi or 6-member ring and 1-4 heteroatoms selected from N. nyl, and the like and is optionally substituted with two or more O and S, unsubstituted or substitute C-C carbocycle, groups, any adjacent two of which, together with the atoms unsubstituted or Substituted heterocycle comprising one they attach to form a phenyl ring, which is optionally Substi or two 5- or 6-member ring and 1-4 heteroatoms selected 55 tuted. from N, O and S. For example, Y is NR. For example, R. and R, together with the atom they For example, R, is H. attach to, form a 5- or 6-member ring selected from a pyrro For example, R, is unsubstituted phenyl. lidinyl, piperidinyl, piperazinyl, or morpholinyl, and is For example, R, is phenyl substituted with one, two, three optionally substituted. 60 or more groups, each of which can be the same or different, For example, Ta is a bond. selected from hydroxyl, halogen, nitro, cyano, unsubstituted For example, T is unsubstituted or substituted C-C, or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. alkyl linker, including but not limited to, methyl, ethyl, n-pro i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of which is optionally substituted with halogen n-hexyl linker. 65 (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted For example, T is a methyl linker. or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy For example, Q is unsubstituted phenyl. loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene US 8,263,610 B2 61 62 dioxy, each of which is optionally substituted with halogen ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) R is H. methyl, ethyl, t-butyl, or phenyl. Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, For example, R is cyclopropyl, cyclobutyl, cyclopentyl, wherein Riis H, or unsubstituted or Substituted C-C alkyl cyclohexyl, or cycloheptyl, and is optionally substituted with (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu- 5 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, tyl, n-pentyl, S-pentyl, and n-hexyl). n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, R, is phenyl substituted with one, two, three tyl, and n-hexyl, each of or which is optionally substituted or more groups, each of which can be the same or different, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), selected from halogen (e.g., fluorine, chlorine, bromine, and unsubstituted or substituted C-C alkoxy (e.g., methoxy, iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, 10 ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, is unsubstituted naphthyl. For example, R, is cyclopropyl. For example, R, is naphthyl substituted with one, two, For example, R, is heterocycle selected from pyrrolidinyl, three or more groups, each of which can be the same or 15 imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, different, selected from hydroxyl, halogen, nitro, cyano, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, morpholinyl, and pyrrolidinone, and the like, and is option n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen ally Substituted with halogen (e.g., fluorine, chlorine, bro tyl, and n-hexyl, each of which is optionally substituted with mine, and iodine)), unsubstituted or Substituted C-C alkoxy halogen (e.g., fluorine, chlorine, bromine, and iodine)), 20 (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu unsubstituted or substituted C-C alkoxy (e.g., methoxy, toxy, and t-butoxy, each of which is optionally substituted ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu with halogen (e.g., fluorine, chlorine, bromine, and iodine)). toxy, each of which is optionally substituted with halogen For example, R, is S(O).R, C(O)R, C(O)OR, (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) —(CH2)R. Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, 25 For example, o is 0. wherein Riis H, or unsubstituted or Substituted C-C alkyl For example, o is 1. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, R is H. tyl, n-pentyl, S-pentyl, and n-hexyl). For example, R is unsubstituted or substituted, straight For example, R, is naphthyl substituted with one, two, chain or branched C-C alkyl, including but not limited to, three or more groups, each of which can be the same or 30 methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, different, selected from halogen (e.g., fluorine, chlorine, bro n-pentyl, S-pentyl, and n-hexyl. mine, and iodine). For example, R is straight-chain or branched C-C alkyl For example, R, is heteroaryl selected from pyrrolyl, fura Substituted with one, two, three or more groups, each of nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet which can be the same or different, selected from: razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 35 1) phenyl, which is optionally substituted with one or more pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox groups, each of which can be the same or different, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, selected from unsubstituted or substituted C-C alkyl benzoimidazolyl, benzothienyl, methylenedioxyphenyl, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura t-butyl, n-pentyl, S-pentyl, and n-hexyl), and unsubsti nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui- 40 tuted or substituted C-C alkoxy (e.g., methoxy, ethoxy, noxalinyl, and pyrrolopyrimidinyl, and the like, and is option propyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy); ally Substituted with one, two, three or more groups, each of 2) unsubstituted or substituted C-C alkoxy (e.g., meth which can be the same or different, selected from hydroxyl, oxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, halogen, nitro, cyano, unsubstituted or Substituted amino, and t-butoxy); unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, 45 3) —C(O)OR; —C(O)R; and n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 4) —NRR, wherein: tyl, and n-hexyl, each of which is optionally substituted with R is H, or unsubstituted or substituted C-C alkyl; halogen (e.g., fluorine, chlorine, bromine, and iodine)), R12 and R1s are each independently H, -T2-Q2 or R2 unsubstituted or substituted C-C alkoxy (e.g., methoxy, and R, together with the atom they attach to, form a ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu- 50 5- or 6-member ring, optionally Substituted with e.g., toxy, each of which is optionally substituted with halogen C(O)O(C-Calkyl) or CH-heteroaryl; (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) T2 is a bond, or unsubstituted or substituted C-C alkyl Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, linker; wherein R is H. unsubstituted or substituted C-C alkyl Q, is H, hydroxyl, unsubstituted or substituted C-C, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu- 55 alkoxy, unsubstituted or Substituted Co-Co aryl, tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi unsubstituted or Substituted heteroaryl comprising tuted C-C aryl, or unsubstituted or substituted heteroaryl one or two 5- or 6-member ring and 1-4 heteroatoms comprising one or two 5- or 6-member ring and 1-4 heteroa selected from N, O and S, unsubstituted or substituted toms selected from N, O and S. C-Cs carbocycle, unsubstituted or Substituted het For example, R, is imidazolyl pyrazolyl, oxazolyl, isox- 60 erocycle comprising one or two 5- or 6-member ring azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino and 1-4 heteroatoms selected from N, O and S, linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben —NRR', -C(O)R. —C(O)CRt.; and Zothiazolyl, benzothiadiazolyl, benzothienyl, O RandR are each independently H, unsubstituted pyrrolopyrimidiyl, each of which is optionally substituted or substituted C-C alkyl, unsubstituted or substi with one, two, three or more groups, each of which can be the 65 tuted Co-Co aryl, or unsubstituted or Substituted het same or different, selected from selected from halogen (e.g., eroaryl comprising one or two 5- or 6-member ring fluorine, chlorine, bromine, and iodine), amino, methyl, and 1-4 heteroatoms selected from N, O and S. US 8,263,610 B2 63 64 For example, R is methyl substitute with unsubstituted pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is phenyl. optionally Substituted with halogen (e.g., fluorine, chlorine, For example, R is methyl substitute with phenyl substi bromine, and iodine)). tuted with one or more groups, each of which can be the same For example, Q2 is heteroaryl selected from pyrrolyl, fura or different, selected from hydroxyl, halogen, nitro, cyano, nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, tyl, and n-hexyl, each of which is optionally substituted with benzothiazolyl, benzoimidazolyl, benzothienyl, methylene halogen (e.g., fluorine, chlorine, bromine, and iodine)), and dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, 10 indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, imidazothiazolyl, and quinoxalinyl, and the like, and is ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu optionally substituted. toxy, each of which is optionally substituted with halogen For example, Q2 is indolyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is methylsubstitute with methoxy, ethoxy, 15 cyclohexyl, or cycloheptyl, and is optionally Substituted. or t-butoxy. For example, Q, is heterocycle selected from pyrrolidinyl, For example, R is methyl substitute with two or more imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, groups, each of which can be the same or different, selected triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, from: morpholinyl, and pyrrolidinone, and the like, and is option 1) phenyl, which is optionally substituted with one or more ally substituted. groups, each of which can be the same or different, For example, Q, is piperidinyl. Selected from hydroxyl, halogen, nitro, cyano, unsubsti For example, Q2 is —NR.R.'. tuted or substituted C-C alkyl (e.g., methyl, ethyl, For example, Q, is —C(O)OR. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, For example, both R. and Rare H. s-pentyl, and n-hexyl, each of which is optionally Sub 25 For example, at least one of R and R is unsubsti stituted with halogen (e.g., fluorine, chlorine, bromine, tuted or Substituted, straight-chain or branched C-C alkyl, and iodine)), unsubstituted or Substituted C-C alkoxy including but not limited to, methyl, ethyl, n-propyl, i-propyl. (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. i-butoxy, and t-butoxy, each of which is optionally Sub For example, at least one of R and R. is methyl or stituted with halogen (e.g., fluorine, chlorine, bromine, 30 t-butyl. and iodine)); and For example, R and R, together with the atom they 2) one of the following: attach to, form a 5- or 6-member ring selected from pyrro i) —C(O)CR; lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo ii) methoxy, ethoxy, i-propyloxy, or t-butoxy; or lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi iii)-NRR. 35 nyl, and the like, and is optionally Substituted with halogen For example, R is methyl substitute with —C(O)CR. (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted For example, R is H. or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. For example, R is unsubstituted or Substituted, straight i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and chain or branched C-C alkyl, including but not limited to, n-hexyl), unsubstituted or Substituted C-C alkoxy (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, 40 methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, n-pentyl, S-pentyl, and n-hexyl. and t-butoxy), unsubstituted or substituted amino, —C(O) For example, R is methyl substitute with —NRR. R, or—C(O)OR, wherein R is H, or unsubstituted For example, both R and R are H. or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. For example, at least one of R12 and Ris is -T2-Q2. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, T2 is a bond. 45 n-hexyl). For example, T2 is unsubstituted or substituted C-C, For example, R and R, together with the atom they alkyl linker, including but not limited to, methyl, ethyl, n-pro attach to, form a piperidinyl or piperazinyl, and is optionally pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and substituted with halogen, methyl, ethyl, t-butyl, methoxy, n-hexyl linker. ethoxy, i-propyloxy, t-butoxy, or —C(O)CR, wherein For example, T2 is a methyl ethyl, or propyl linker. 50 R is methyl, ethyl, or t-butyl. For example, Q2 is H. For example, R is -T-Q. For example, Q2 is hydroxyl. For example, T is a bond. For example, Q2 is unsubstituted or substituted C-C, For example, T is unsubstituted or substituted C-C, alkoxy, including but not limited to, methoxy, ethoxy, propy alkyl linker, including but not limited to, methyl, ethyl, n-pro loxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy. 55 pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, Q, is methoxy. n-hexyl linker. For example, Q2 is unsubstituted or substituted phenyl or For example, T is a methyl ethyl, propyl, or i-propyl naphthyl. linker. For example, Q2 is unsubstituted phenyl. For example, Q, is H. For example, Q2 is phenyl substituted with one or more 60 For example, Q, is unsubstituted phenyl. groups, each of which can be the same or different, selected For example, Q, is phenyl substituted with one, two, three from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub or more groups, each of which can be the same or different, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. selected from hydroxyl, halogen, nitro, cyano, unsubstituted n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. of which is optionally substituted with halogen (e.g., fluorine, 65 i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and chlorine, bromine, and iodine)), and unsubstituted or Substi n-hexyl, each of which is optionally substituted with halogen tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted US 8,263,610 B2 65 66 or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene tuted C-C aryl, or unsubstituted or substituted heteroaryl dioxy, each of which is optionally substituted with halogen comprising one or two 5- or 6-member ring and 1-4 heteroa (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) toms selected from N, O and S. R. —NHC(O)OR, —C(O)R and —C(O)OR, For example, Q, is imidazolyl pyrazolyl, oxazolyl, isox wherein Riis H, or unsubstituted or Substituted C-C alkyl azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben tyl, n-pentyl, s-pentyl, and n-hexyl). For example, Q, is Zothiazolyl, benzothiadiazolyl, benzothienyl, O phenyl Substituted with two groups that connect to form a pyrrolopyrimidiyl, each of which is optionally substituted 10 with one, two, three or more groups, each of which can be the fused six membered ring: same or different, selected from selected from halogen (e.g., fluorine, chlorine, bromine, and iodine), amino, methyl, ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein R is H. methyl, ethyl, t-butyl, or phenyl. 15 For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, X) cyclohexyl, or cycloheptyl, and is optionally substituted with Së, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, Q, is phenyl substituted with one, two, three tyl, and n-hexyl, each of or which is optionally substituted or more groups, each of which can be the same or different, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), selected from halogen (e.g., fluorine, chlorine, bromine, and unsubstituted or substituted C-C alkoxy (e.g., methoxy, iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, Q, is unsubstituted naphthyl. 25 For example, Q, is cyclopropyl. For example, Q, is naphthyl substituted with one, two, For example, Q, is heterocycle selected from pyrrolidinyl, three or more groups, each of which can be the same or imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, different, selected from hydroxyl, halogen, nitro, cyano, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, morpholinyl, and pyrrolidinone, and the like, and is option n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 30 ally Substituted with halogen (e.g., fluorine, chlorine, bro tyl, and n-hexyl, each of which is optionally substituted with mine, and iodine)), unsubstituted or Substituted C-C alkoxy halogen (e.g., fluorine, chlorine, bromine, and iodine)), (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu unsubstituted or substituted C-C alkoxy (e.g., methoxy, toxy, and t-butoxy, each of which is optionally substituted ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu with halogen (e.g., fluorine, chlorine, bromine, and iodine)). toxy, each of which is optionally substituted with halogen 35 For example, R, is C(=NH)NR.R.'. (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) For example, both R- and Rare H. R —NHC(O)CR, —C(O)R and —C(O)CR, For example, R, is C(S)NR.R.'. wherein Riis H, or unsubstituted or Substituted C-C alkyl For example, both R- and Rare phenyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, R, is C(=NH)NR2R3', C(O)NR.R.', or tyl, n-pentyl, S-pentyl, and n-hexyl). 40 - C(S)NRR". For example, Q, is naphthyl substituted with one, two, For example, both R- and Rare H. three or more groups, each of which can be the same or For example, at least one of R and R is unsubstituted or different, selected from halogen (e.g., fluorine, chlorine, bro Substituted, straight-chain or branched C-C alkyl, including mine, and iodine). but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, Q, is heteroaryl selected from pyrrolyl, fura 45 S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, at least one of R2 and R2 is -Ts-Qs. razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, T is a bond. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, Ts is unsubstituted or substituted C-C, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, alkyl linker, including but not limited to, methyl, ethyl, n-pro benzoimidazolyl, benzothienyl, methylenedioxyphenyl, 50 pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura n-hexyl, and 2-methylpropyl linker. nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui For example, Ts is a methyl ethyl, propyl, or 2-methyl noxalinyl, and pyrrolopyrimidinyl, and the like, and is option propyl linker. ally Substituted with one, two, three or more groups, each of For example, Q, is H. which can be the same or different, selected from hydroxyl, 55 For example, Q, is unsubstituted phenyl. halogen, nitro, cyano, unsubstituted or Substituted amino, For example, Q, is phenyl substituted with one or more unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, groups, each of which can be the same or different, selected n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen from-Ta-Q, wherein: tyl, and n-hexyl, each of which is optionally substituted with Ta Ts and T are each independently a bond, or unsub halogen (e.g., fluorine, chlorine, bromine, and iodine)), 60 stituted or substituted C-C alkyl linker; unsubstituted or substituted C-C alkoxy (e.g., methoxy, Q, is H, unsubstituted or substituted C-C alkyl, unsub ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu stituted or Substituted C-C alkoxy, halogen, nitro, toxy, each of which is optionally substituted with halogen unsubstituted or substituted phenyl, unsubstituted or (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) Substituted heteroaryl comprising one or two 5- or Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, 65 6-member ring and 1-4 heteroatoms selected from N.O wherein R is H. unsubstituted or Substituted C-C alkyl and S, unsubstituted or Substituted C-Cs carbocycle, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu unsubstituted or Substituted heterocycle comprising one US 8,263,610 B2 67 68 or two 5- or 6-member ring and 1-4 heteroatoms selected For example, Q, is unsubstituted or substituted C-C, from N, O and S, NRR', NHC(O)R. NHC alkoxy, including but not limited to, methoxy, ethoxy, propy (O)OR. -C(O)R —C(O)OR. --OR - SR, loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and methylene —C(O)NRR'; dioxy. For example, Q, is phenyl, wherein phenyl is substituted For example, Q, is methoxy, ethoxy, or methylenedioxy. with two groups that connect to form a fused 5-mem For example, Q, is fluorine, chlorine, bromine, or iodine. bered ring e.g., For example, Q, is unsubstituted phenyl. For example, Q, is phenyl substituted with one or more groups, each of which can be the same or different, selected 10 from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each Y.) O.O of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubstituted or Substi 15 tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro R and R2 are each independently H, unsubstituted or pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each substituted C-C alkyl, unsubstituted or substituted of which is optionally substituted with halogen (e.g., fluorine, phenyl, unsubstituted or substituted heteroaryl compris chlorine, bromine, and iodine)). ing one or two 5- or 6-member ring and 1-4 heteroatoms For example, Q, is heteroaryl selected from selected from selected from N, O and S. -Ts-Qs, or Rs2 and Rs.", heteroaryl selected from pyrrolyl, furanyl, thienyl, thiazolyl, together with the atom they attach to, form a 5- or isothiazolyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, 6-member ring which optionally comprises 1-4 heteroa oxazolyl, isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyri toms selected from N, O and S and is optionally substi midinyl, triazinyl, benzoxazolyl, benzodioxazolyl, benzoxa tuted with -To-Q.: diazolyl, benzothiazolyl, benzothiadiazolyl, benzoimida Qs is H, hydroxyl, unsubstituted or substituted phenyl, 25 Zolyl, benzothienyl, methylenedioxyphenyl, quinolinyl, unsubstituted or Substituted heteroaryl comprising one isoquinolinyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, or two 5- or 6-member ring and 1-4 heteroatoms selected deazapurinyl, indolizinyl, imidazothiazolyl, quinoxalinyl, from N, O and S, unsubstituted or substituted C-Cs oxadiazolyl, and pyrrolopyrimidinyl, and the like, and is carbocycle, unsubstituted or substituted heterocycle optionally Substituted with one or more groups, each of which comprising one or two 5- or 6-member ring and 1-4 30 can be the same or different, selected from hydroxyl, halogen, heteroatoms selected from N, O and S. —OR, nitro, cyano, unsubstituted or Substituted amino, unsubsti —NR,R,'. —NHC(O)R. —NHC(O)OR, tuted or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. —C(O)NR'R''. —C(O)R, or—C(O)CR; i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and Q, is H, hydroxyl, unsubstituted or substituted phenyl, n-hexyl, each of which is optionally substituted with halogen 35 (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti unsubstituted or Substituted heteroaryl comprising one tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro or two 5- or 6-member ring and 1-4 heteroatoms selected pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of from N, O and S, unsubstituted or substituted C-Cs which is optionally Substituted with halogen (e.g., fluorine, carbocycle, unsubstituted or substituted heterocycle chlorine, bromine, and iodine)). comprising one or two 5- or 6-member ring and 1-4 40 For example, Q, is thiazolyl, isothiazolyl, or oxadiazolyl, heteroatoms selected from N, O and S. —NR.R.", each of which is optionally substituted with one or more —C(O)NR'R'; groups, each of which can be the same or different, selected c and Rare each independently H, unsubstituted or from methyl, ethyl, and t-butyl. substituted C-C alkyl, unsubstituted or substituted For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, Co-Co aryl, or unsubstituted or Substituted heteroaryl 45 cyclohexyl, or cycloheptyl, and is optionally Substituted. comprising one or two 5- or 6-member ring and 1-4 For example, Q, is heterocycle selected from pyrrolidinyl, heteroatoms selected from N, O and S; imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, Ra and R are each independently H, unsubstituted or triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, Substituted C-C alkyl, or R and R', together with morpholinyl, and pyrrolidinone, and the like, and is option the atom they attach to, form a 5- or 6-member ring 50 ally Substituted with halogen (e.g., fluorine, chlorine, bro which optionally comprises 1-4 heteroatoms selected mine, and iodine)), unsubstituted or Substituted C-C alkoxy from N, O and S and is optionally substituted. (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu For example, Ta is a bond. toxy, and t-butoxy, each of which is optionally substituted For example, Ta is unsubstituted or substituted C-C, with halogen (e.g., fluorine, chlorine, bromine, and iodine)). alkyl linker, including but not limited to, methyl, ethyl, n-pro 55 For example, Q, is piperazinyl or piperazinyl, and is pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and optionally substituted with methyl, ethyl, or t-butyl. n-hexyl linker. For example, Q, is NRs.2Rs'. For example, Ta is a methyl ort-butyl linker. For example, both R- and Rare H. For example, Q, is H. For example, at least one of RandR is unsubstituted or For example, Q, is unsubstituted or substituted, straight 60 Substituted, straight-chain or branched C-C alkyl, including chain or branched C-C alkyl, including but not limited to, but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, n-pentyl, S-pentyl, and n-hexyl, each of which is optionally at least one of R and R is C-C alkyl Substituted with Substituted with halogen (e.g., fluorine, chlorine, bromine, —CH2OH. and iodine). 65 For example, at least one of R and R is methyl or ethyl. For example, Q, is methyl ethyl, t-butyl, or trifluorom For example, R and Rare both methyl or ethyl. ethyl. For example, Q, is —ORs, or—SR-2. US 8,263,610 B2 69 70 For example, R is H. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, R is unsubstituted or substituted, straight stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. chain or branched C-C alkyl, including but not limited to, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, of which is optionally substituted with halogen (e.g., fluorine, n-pentyl, S-pentyl, and n-hexyl, each of which is optionally chlorine, bromine, and iodine)), unsubstituted or substituted Substituted with halogen (e.g., fluorine (e.g., —CF), chlo C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, rine, bromine, and iodine) or hydroxyl. butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each of which For example, R is methyl, ethyl, t-butyl, or trifluorom is optionally substituted with halogen (e.g., fluorine, chlorine, ethyl. bromine, and iodine)), unsubstituted or substituted C-Co For example, R is unsubstituted phenyl. 10 aryloxy (e.g., phenoxy), and —NHC(O)R, wherein R. For example, R is phenyl Substituted with one or more is H, or unsubstituted or Substituted C-C alkyl (e.g., methyl, groups, each of which can be the same or different, selected ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub s-pentyl, and n-hexyl). stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, Q, is phenyl substituted with one or more n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 15 groups, each of which can be the same or different, selected of which is optionally substituted with halogen (e.g., fluorine, from halogen (e.g., fluorine, chlorine, bromine, and iodine), chlorine, bromine, and iodine)), and unsubstituted or Substi methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, t-bu tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro toxy, phenoxy, and —NHC(O)R, wherein R is H. pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each methyl or ethyl. of which is optionally substituted with halogen (e.g., fluorine, For example, Qis is heteroaryl selected from pyrrolyl, fura chlorine, bromine, and iodine)). nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, R is heteroaryl selected from pyrrolyl, fura razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox 25 benzoimidazolyl, benzothienyl, methylenedioxyphenyl, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura benzoimidazolyl, benzothienyl, methylenedioxyphenyl, nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura noxalinyl, and pyrrolopyrimidinyl, and the like, and is option nyl, purinyl, deaZapurinyl, indolizinyl, imidazothiazolyl, and ally Substituted with one or more groups, each of which can quinoxalinyl, and the like, and is optionally substituted with 30 be the same or different, selected from hydroxyl, halogen, one, two or more groups, each of which can be the same or nitro, cyano, unsubstituted or Substituted amino, unsubsti different, selected from hydroxyl, halogen, nitro, cyano, tuted or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. unsubstituted or substituted amino, unsubstituted or substi i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and tuted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-hexyl, each of which is optionally substituted with halogen n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 35 (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti of which is optionally substituted with halogen (e.g., fluorine, tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro chlorine, bromine, and iodine)), and unsubstituted or Substi pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro which is optionally Substituted with halogen (e.g., fluorine, pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is chlorine, bromine, and iodine)). optionally Substituted with halogen (e.g., fluorine, chlorine, 40 For example, Q, is pyrazolyl, imidazolyl, isoxazolyl, bromine, and iodine)). oxazolyl, pyridinyl, furanyl, indolyl, or benzoimidazolyl, For example, R is pyrazinyl, and is optionally substituted each of which is optionally substituted with one or more with methyl, ethyl or t-butyl. groups, each of which can be the same or different, selected For example, Q, is —C(O)Rs2. -C(O)CRs2. from methyl or ethyl. For example, R is H. 45 For example, Qis is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is unsubstituted or Substituted, straight cyclohexyl, or cycloheptyl, and is optionally substituted with chain or branched C-C alkyl, including but not limited to, unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-pentyl, S-pentyl, and n-hexyl. tyl, and n-hexyl, each of or which is optionally substituted For example, R is methyl or ethyl. 50 with halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, Q, is NHC(O)Rs, NHC(O)CRs, or unsubstituted or Substituted C-C alkoxy (e.g., methoxy, —C(O)NRR". ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, Q, is —C(O)NR2Rs.'. toxy, each of which is optionally substituted with halogen For example, both R and Rare H. (e.g., fluorine, chlorine, bromine, and iodine)). For example, at least one of Rs.2 and Rs' is -Ts-Qs. 55 For example, Qs is cyclohexyl or cycloheptyl, which is For example, Ts is a bond. optionally substituted with methyl or ethyl. For example, Ts is unsubstituted or substituted C-C, For example, Qis is heterocycle selected from pyrrolidinyl, alkyl linker, including but not limited to, methyl, ethyl, n-pro pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, n-hexyl, 1,2-dimethylpropyl, and 1-methylbutyl linker. 60 piperazinyl, morpholinyl, and pyrrolidinone, and the like, and For example, Ts is a methyl, ethyl, propyl, i-propyl, butyl, is optionally substituted. For example, Q, is substituted with 1,2-dimethylpropyl, or 1-methylbutyl linker. For example, CHOH. Ts is ethyl substituted with C(O)NH2. For example, Q, is pyrrolidinyl, pyrrolidinone, piperidi For example, Qis is H. nyl, morpholinyl, or tetrahydrofuranyl, and is optionally Sub For example, Qis is unsubstituted phenyl. 65 stituted. For example, Qs is phenyl substituted with one or more For example, Qs is —OR. groups, each of which can be the same or different, selected For example, R is H. US 8,263,610 B2 71 72 For example, Riis unsubstituted or Substituted, straight quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura chain or branched C-C alkyl, including but not limited to, nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, noxalinyl, benzoimidazolonyl, benzodihydroimidazolone, n-pentyl, S-pentyl, and n-hexyl. and pyrrolopyrimidinyl, and the like, and is optionally Sub For example, R is methyl, ethyl, or t-butyl. stituted with one or more groups, each of which can be the For example, R is unsubstituted phenyl. same or different, selected from hydroxyl, halogen, nitro, For example, R is phenyl substituted with one or more cyano, unsubstituted or Substituted amino, unsubstituted or groups, each of which can be the same or different, selected Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-pro from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub pyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. 10 each of which is optionally Substituted with halogen (e.g., n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each fluorine, chlorine, bromine, and iodine)), and unsubstituted or of which is optionally substituted with halogen (e.g., fluorine, Substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, chlorine, bromine, and iodine)), and unsubstituted or Substi i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of which is tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro optionally Substituted with halogen (e.g., fluorine, chlorine, pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each 15 bromine, and iodine)). of which is optionally substituted with halogen (e.g., fluorine, For example, Q, is pyridinyl, pyrazinyl, or benzodihy chlorine, bromine, and iodine)). droimidazolone, each of which is optionally substituted with For example, Qs is —NR.R.', -NHC(O)R. one or more groups, each of which can be the same or differ —NHC(O)OR, —C(O)NR'R''. —C(O)R, or ent, selected from methyl or ethyl. —C(O)OR. For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, Q, is —NR.R.', -NHC(O)R, or cyclohexyl, or cycloheptyl, and is optionally substituted with —C(O)NRR, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, both R and R. are H. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, at least one of R and R is unsubsti tyl, and n-hexyl, each of or which is optionally substituted tuted or Substituted, straight-chain or branched C-C alkyl, 25 with halogen (e.g., fluorine, chlorine, bromine, and iodine)), including but not limited to, methyl, ethyl, n-propyl, i-propyl. unsubstituted or Substituted C-C alkoxy (e.g., methoxy, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, at least one of R and R. is methyl or toxy, each of which is optionally substituted with halogen ethyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R. and R. are both methyl or ethyl. 30 For example, Q, is heterocycle selected from pyrrolidinyl, For example, R and R', together with the atom they pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, attach to, form a 5- or 6-member ring selected from pyrro isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo piperazinyl, morpholinyl, and pyrrolidinone, and the like, and lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl is optionally substituted. and is optionally substituted with-To-Q, 35 For example, Q, is —NR.R.'. For example, R and R', together with the atom they For example, both R. and Rare H. attach to, form a 5- or 6-member ring selected from pyrro For example, at least one of R and R is unsubsti lidinyl, piperidinyl, and piperazinyl, and is optionally Substi tuted or Substituted, straight-chain or branched C-C alkyl, tuted with -To-Q, including but not limited to, methyl, ethyl, n-propyl, i-propyl. For example, T is a bond. 40 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, T is unsubstituted or substituted C-C, For example, at least one of R and R. is methyl or alkyl linker, including but not limited to, methyl, ethyl, n-pro ethyl. pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, R. and R. are both methyl or ethyl. n-hexyl linker. For example, Q, is —C(O)NR'R''. For example, T is a methyl or ethyl linker. 45 For example, R and Rare both H. For example, Q, is H. For example, at least one of RandR is unsubstituted or For example, Q, is unsubstituted phenyl. Substituted, straight-chain or branched C-C alkyl, including For example, Q, is phenyl substituted with one or more but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, groups, each of which can be the same or different, selected S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub 50 For example, R and R', together with the atom they stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. attach to, form a 5- or 6-member ring selected from pyrro n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo of which is optionally substituted with halogen (e.g., fluorine, lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl chlorine, bromine, and iodine)), and unsubstituted or Substi and is optionally Substituted. tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro 55 For example, R and R', together with the atom they pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each attach to, form a pyrrolidinyl ring, and is optionally Substi of which is optionally substituted with halogen (e.g., fluorine, tuted. chlorine, bromine, and iodine)). For example, Q, is unsubstituted naphthyl. For example, Q, is phenyl substituted with one or more For example, Q, is heteroaryl selected from pyrrolyl, fura groups, each of which can be the same or different, selected 60 nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet from methyl, ethyl, and t-butyl. razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, Q, is heteroaryl selected from pyrrolyl, fura pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox 65 quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui benzoimidazolyl, benzothienyl, methylenedioxyphenyl, noxalinyl, dihydrobenzofuranyl, and pyrrolopyrimidinyl, and US 8,263,610 B2 73 74 the like, and is optionally substituted with one, two or more or two 5- or 6-member ring and 1-4 heteroatoms selected groups, each of which can be the same or different, selected from N, O and S. —C(O)NR'R'', —C(O)ONRR", from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub or —NRR'; and stituted amino, unsubstituted or Substituted C-C alkyl (e.g., R and Rs' are each independently H, unsubstituted or methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, substituted C-C alkyl, unsubstituted or substituted n-pentyl, S-pentyl, and n-hexyl, each of which is optionally phenyl, unsubstituted or substituted heteroaryl compris Substituted with halogen (e.g., fluorine, chlorine, bromine, ing one or two 5- or 6-member ring and 1-4 heteroatoms and iodine)), unsubstituted or substituted C-C alkoxy (e.g., selected from N, O and S, unsubstituted or substitute methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, C-C carbocycle, unsubstituted or substituted hetero and t-butoxy, each of which is optionally substituted with 10 cycle comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S, or R and halogen (e.g., fluorine, chlorine, bromine, and iodine)), and R", together with the atom they attach to, form a 5- or unsubstituted or substituted phenyl. 6-member ring which optionally comprises 1-4 heteroa For example, Q, is oxazolyl, isoxazolyl pyridinyl, pyrazi toms selected from N, O and S and is optionally substi nyl, triazinyl, thienyl, benzothiadiazolyl, or dihydrobenzo 15 tuted. furanyl, each of which is optionally substituted with one, two For example, RandR', together with the atom they attach or more groups, each of which can be the same or different, to, form a 5-, 6- or 7-member ring selected from piperidinyl, selected from halogen (e.g., fluorine, chlorine, bromine, and piperazinyl, pyrrolidinyl, and diazepanyl, and is optionally iodine), methyl, ethyl, t-butyl, trifluoromethyl, and phenyl. substituted with -T7-Q7. For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, T., is a bond. cyclohexyl, or cycloheptyl, and is optionally substituted with For example, T, is unsubstituted or substituted C-C, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, alkyl linker, including but not limited to, methyl, ethyl, n-pro n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and tyl, and n-hexyl, each of or which is optionally substituted n-hexyl linker. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), 25 For example, T, is a methyl, ethyl, or propyl linker. unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, Q, is H. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, Q, is unsubstituted phenyl. toxy, each of which is optionally substituted with halogen For example, Q, is phenyl substituted with one or more (e.g., fluorine, chlorine, bromine, and iodine)). groups, each of which can be the same or different, selected For example, Q, is cyclohexyl. 30 from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, Q, is heterocycle selected from pyrrolidinyl, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl, each triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, of which is optionally substituted with halogen (e.g., fluorine, morpholinyl, and pyrrolidinone, and the like, and is option chlorine, bromine, and iodine)), and unsubstituted or Substi ally Substituted with halogen (e.g., fluorine, chlorine, bro 35 tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro mine, and iodine)), unsubstituted or Substituted C-C alkoxy pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu of which is optionally substituted with halogen (e.g., fluorine, toxy, and t-butoxy, each of which is optionally substituted chlorine, bromine, and iodine)). with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, Q, is phenyl substituted with one or more For example, Q, is —C(O)ORs, -C(O)Rs –C(O) 40 groups, each of which can be the same or different, selected NRR', or —NRR". from halogen (e.g., fluorine, chlorine, bromine, and iodine), For example, Q, is —C(O)CRs or—NRRs'. methyl, ethyl, -t-butyl, methoxy, ethoxy and t-butoxy. For example, R and R' are both H. For example, Q, is heteroaryl e.g., indole. For example, at least one of R and Rs' is unsubstituted or For example, Q, is —C(O)NRRs, or—NRss Ras' Substituted, straight-chain or branched C-C alkyl, including 45 For example, R and Rare both H. but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, at least one of R and Rs' is unsubstituted or S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of which Substituted, straight-chain or branched C-C alkyl, including is optionally substituted with halogen (e.g., fluorine, chlorine, but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, bromine, and iodine), hydroxyl, or unsubstituted or Substi S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro 50 For example, at least one of R and Rs' is unsubstituted or pyloxy, butoxy, i-butoxy, and t-butoxy). substituted phenyl. For example, at least one of R and Rs' is methyl or ethyl For example, at least one of R and R is heteroaryl optionally substituted with hydroxyl. selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiaz For example, R and R', together with the atom they attach olyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, to, form a 5-, 6- or 7-member ring selected from pyrrolidinyl, 55 isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tri imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, azinyl, benzoxazolyl, benzodioxazolyl, benzoxadiazolyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepa benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, ben nyl, and diazepanyl, and the like and is optionally substituted Zothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, with one or more groups, each of which can be the same or naphthrydinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, different, selected from -T7-Q7, wherein: 60 indolizinyl, imidazothiazolyl, quinoxalinyl, and pyrrolopyri T, is a bond, or unsubstituted or substituted C-C alkyl midinyl, and the like, and is optionally Substituted. linker; For example, at least one of R and Rs' is cyclopropyl. Q, is H, unsubstituted or substituted phenyl, unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is or Substituted heteroaryl comprising one or two 5- or optionally substituted. 6-member ring and 1-4 heteroatoms selected from N.O 65 For example, at least one of R and R is heterocycle and S, unsubstituted or Substitute C-C carbocycle, selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, unsubstituted or Substituted heterocycle comprising one oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl. US 8,263,610 B2 75 76 piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen the like, and is optionally substituted. tyl, and n-hexyl, each of which is optionally substituted with For example, R and R', together with the atom they halogen (e.g., fluorine, chlorine, bromine, and iodine)), attach to, form a 5- or 6-member ring selected from pyrro unsubstituted or Substituted C-C alkoxy (e.g., methoxy, lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl, toxy, each of which is optionally substituted with halogen and pyrrolidinone, and the like, and is optionally Substituted. (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) For example, R and R', together with the atom they R —NHC(O)OR, —C(O)R and —C(O)CR, attach to, form a 5- or 6-member ring selected from morpholi wherein R is H. unsubstituted or substituted C-C alkyl nyl. 10 (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, Y is CHR,'. tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi For example, R, is H. tuted C-C aryl, or unsubstituted or substituted heteroaryl For example, R, is unsubstituted phenyl. comprising one or two 5- or 6-member ring and 1-4 heteroa For example, R, is phenyl substituted with one, two, three toms selected from N, O and S. or more groups, each of which can be the same or different, 15 For example, R, is imidazolyl pyrazolyl, oxazolyl, isox selected from hydroxyl, halogen, nitro, cyano, unsubstituted azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and Zothiazolyl, benzothiadiazolyl, benzothienyl, O n-hexyl, each of which is optionally substituted with halogen pyrrolopyrimidiyl, each of which is optionally substituted (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted with one, two, three or more groups, each of which can be the or substituted C-C alkoxy (e.g., methoxy, ethoxy, propy same or different, selected from selected from halogen (e.g., loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene fluorine, chlorine, bromine, and iodine), amino, methyl, dioxy, each of which is optionally substituted with halogen ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) R is H. methyl, ethyl, t-butyl, or phenyl. Rakhr —NHC(O)OR, —C(O)R. and —C(O)OR, 25 For example, R, is cyclopropyl, cyclobutyl, cyclopentyl, wherein Riis H, or unsubstituted or Substituted C-C alkyl cyclohexyl, or cycloheptyl, and is optionally substituted with (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, tyl, n-pentyl, S-pentyl, and n-hexyl). n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, R, is phenyl substituted with one, two, three tyl, and n-hexyl, each of or which is optionally substituted or more groups, each of which can be the same or different, 30 with halogen (e.g., fluorine, chlorine, bromine, and iodine)), selected from halogen (e.g., fluorine, chlorine, bromine, and unsubstituted or Substituted C-C alkoxy (e.g., methoxy, iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. toxy, each of which is optionally substituted with halogen wherein R is H. methyl, ethyl, or t-butyl. (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, is unsubstituted naphthyl. 35 For example, R, is heterocycle selected from pyrrolidinyl, For example, R, is naphthyl substituted with one, two, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, three or more groups, each of which can be the same or triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, different, selected from hydroxyl, halogen, nitro, cyano, morpholinyl, and pyrrolidinone, and the like, and is option unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, ally Substituted with halogen (e.g., fluorine, chlorine, bro n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen 40 mine, and iodine)), unsubstituted or substituted C-C alkoxy tyl, and n-hexyl, each of which is optionally substituted with (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu halogen (e.g., fluorine, chlorine, bromine, and iodine)), toxy, and t-butoxy, each of which is optionally substituted unsubstituted or Substituted C-C alkoxy (e.g., methoxy, with halogen (e.g., fluorine, chlorine, bromine, and iodine)). ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, R." is H. toxy, each of which is optionally substituted with halogen 45 For example, R." is unsubstituted or substituted, straight (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) chain or branched C-C alkyl, including but not limited to, R. —NHC(O)OR, —C(O)R and —C(O)OR, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, wherein Riis H, or unsubstituted or Substituted C-C alkyl n-pentyl, S-pentyl, and n-hexyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, both R and Rare H. tyl, n-pentyl, S-pentyl, and n-hexyl). 50 For example, at least one of Rs and Rs' is -T-Q,'. For example, R, is naphthyl substituted with one, two, For example, T' is a bond. three or more groups, each of which can be the same or For example, T' is unsubstituted or substituted C-C, different, selected from halogen (e.g., fluorine, chlorine, bro alkyl linker, including but not limited to, methyl, ethyl, n-pro mine, and iodine). pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, R, is heteroaryl selected from pyrrolyl, fura 55 n-hexyl linker. nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet For example, T' is a methyl ethyl, propyl, or t-butyl razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, linker. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, Q,' is H. azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, For example, Q,' is unsubstituted phenyl. benzoimidazolyl, benzothienyl, methylenedioxyphenyl, 60 For example, Q,' is phenyl substituted with one, two or quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura more groups, each of which can be the same or different, nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui selected from hydroxyl, halogen, nitro, cyano, unsubstituted noxalinyl, and pyrrolopyrimidinyl, and the like, and is option or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. ally Substituted with one, two, three or more groups, each of i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and which can be the same or different, selected from hydroxyl, 65 n-hexyl, each of which is optionally substituted with halogen halogen, nitro, cyano, unsubstituted or Substituted amino, (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro US 8,263,610 B2 77 78 pyloxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, methylene Zolyl, benzothiadiazolyl, benzoimidazolyl, benzothienyl, dioxy, and ethylenedioxy, each of which is optionally methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry Substituted with halogen (e.g., fluorine (e.g., —OCF), chlo dinyl, indolyl, benzofuranyl, purinyl, purinone, deazapurinyl, rine, bromine, and iodine)), unsubstituted or Substituted phe indolizinyl, imidazothiazolyl, dihydrobenzofuranyl, quinox nyl, unsubstituted or substituted C-C aryloxy (e.g., phe alinyl, and pyrrolopyrimidinyl, dihydrobenzofuran, dihy noxy), —NRR, -C(O)R.R., -C(O)CR, drobenzothiophene, pyrazolopyrimidinyl, and the like, and is —S(O)2R, and —NHC(O).R.R.", wherein R. and optionally Substituted with one, two or more groups, each of Rare each independently H, unsubstituted or substituted which can be the same or different, selected from hydroxyl, C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, halogen, unsubstituted or Substituted amino, unsubstituted or S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl) 10 Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-pro For example, Q,' is phenyl substituted with one, two or pyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, more groups, each of which can be the same or different, each of which is optionally Substituted with halogen (e.g., selected from fluorine, chlorine, bromine, and iodine. fluorine, chlorine, bromine, and iodine)), unsubstituted or For example, Q,' is phenyl substituted with one, two or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, more groups, each of which can be the same or different, 15 i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of which is selected from methyl, ethyl, t-butyl, and trifluoromethyl. optionally Substituted with halogen (e.g., fluorine, chlorine, For example, Q,' is phenyl substituted with one, two or bromine, and iodine)), unsubstituted or substituted C-Co more groups, each of which can be the same or different, aryloxy (e.g., phenoxy), and unsubstituted or Substituted phe selected from methoxy, ethoxy, trifluoromethoxy, phenoxy, nyl. and ethylenedioxy. For example, Q,' is phenyl substituted For example, Q,' is oxazolyl, isoxazolyl pyridinyl, pyri with two groups that connect to form a fused 6-membered midinyl, triazinyl, thienyl, purinyl, purinone, quinolinyl, ben Zothienyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl pyrrolopyrimidinyl, or 25 dihydrobenzofuranyl, each of which is substituted with one, two or more groups, each of which can be the same or differ ent, selected from halogen (e.g., fluorine, chlorine, bromine, and iodine), methyl, ethyl, amino, phenyl, and phenoxy. D For example, Q, is cyclopropyl. 30 For example, Q,' is C(O)OR2, C(O)R2, C(O) For example, Q,' is phenyl substituted with one, two or NRR', or —NRR". more groups, each of which can be the same or different, For example, Q,' is —C(O)OR. Selected from —NRR', -C(O)R.R.", For example, R is H. —S(O).R., and —NHC(O)R.R., wherein at least For example, R is unsubstituted or substituted C-C, one of R and R is methyl or ethyl. 35 alkyl, including but not limited to, methyl, ethyl, n-propyl. For example, Q,' is phenyl substituted with one, two or i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and more groups, each of which can be the same or different, n-hexyl. selected from fluorine, chlorine, bromine, iodine, methyl, For example, R is methyl or ethyl. ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, trifluo The present invention also provides the compounds of romethoxy, phenyl, phenoxy, —NRR', -C(O)R- 40 Formulae IVa and IVb: R., -S(O)2R, and —NHC(O)R.R., wherein at least one of R and R. is methyl or ethyl. For example, Q,' is unsubstituted naphthyl. R (IVa) For example, Q,' is naphthyl substituted with one, two or N-N? 2 more groups, each of which can be the same or different, 45 selected from hydroxyl, halogen, nitro, cyano, unsubstituted W or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. R 21 NN i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of which is optionally substituted with halogen Rc4 S (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti 50 tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of R3 Rc6 which is optionally Substituted with halogen (e.g., fluorine, R O chlorine, bromine, and iodine)). R (IVb) For example, Q,' is naphthyl substituted with one, two or 55 2 more groups, each of which can be the same or different, N-N? selected from methyl, ethyl, and halogen (e.g., fluorine, chlo W rine, bromine, and iodine). For example, Q,' is fluorenyl, and is optionally substi R 21 NN tuted. 60 For example, Q,' is dihydroindenyl, and is optionally sub stituted. For example, Q,' is heteroaryl selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, R3 Rc6, tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi 65 nyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, ben Zoisoxazolyl, benzodioxazolyl, benzoxadiazolyl, benzothia US 8,263,610 B2 79 80 or a salt, Solvate, hydrate or prodrug thereof, wherein: comprising one or two 5- or 6-member ring and 1-4 heteroa R is H. halogen, unsubstituted or substituted C-C alkyl, toms selected from N, O and S. unsubstituted or substituted phenyl, or unsubstituted or sub For example, R is H. stituted heteroaryl comprising one or two 5- or 6-member ring For example, R is fluorine, chlorine, bromine, or iodine. and 1-4 heteroatoms selected from N, O and S; For example, R is unsubstituted or Substituted, straight R is H, or unsubstituted or substituted C-C alkyl: chain or branched C-C alkyl, including but not limited to, R. and Ra are each independently H, unsubstituted or methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, Substituted C-C alkyl, or R and Ra, together with the n-pentyl, S-pentyl, and n-hexyl. atoms they attach to, form a 5-, 6- or 7-member ring which For example, R is methyl. optionally comprises 1-4 heteroatoms selected from N, O and 10 For example, R is unsubstituted phenyl. Sand is optionally substituted; For example, R is phenyl substituted with one or more R is H. unsubstituted or Substituted C-C alkyl, or groups, each of which can be the same or different, selected unsubstituted or Substituted Co-Co aryl; from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub R is H. unsubstituted or substituted Co-Co aryl, unsubsti stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. tuted or substituted heteroaryl comprising one or two 5- or 15 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each 6-member ring and 1-4 heteroatoms selected from N, O and S. of which is optionally substituted with halogen (e.g., fluorine, unsubstituted or Substituted C-Cs carbocycle, unsubstituted chlorine, bromine, and iodine)), unsubstituted or substituted or Substituted heterocycle comprising one or two 5- or C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, 6-member ring and 1-4 heteroatoms selected from N, O and S. butoxy, i-butoxy, and t-butoxy, each of which is optionally —S(O).R. —C(O)R. —C(O)CR, —(CH2)R. Substituted with halogen (e.g., fluorine, chlorine, bromine, —C(=NH)NRR', —C(O)NRR', or - C(S)NRR'; and iodine)), and -T-Q, wherein: o is 0, 1, 2, 3, or 4: T is a bond, or unsubstituted or Substituted C-C alkyl R is H, unsubstituted or substituted C-C alkyl, or -T- linker; Q.: Q is H. —NRR", —C(O)NR'R'', NHC(O) R. and R are each independently H, unsubstituted or 25 R. —NHC(O)CR, NHC(O)NR'R'', or substituted C-C alkyl, -Ts-Qs, or R2 and R2', together with —S(O).R., and the atom they attach to, form a 5-, 6- or 7-member ring which R. and Rare each independently H, or unsubstituted comprises 1-4 heteroatoms selected from N, O and S and is or substituted C-C alkyl. optionally substituted; For example, R is phenyl substituted with one or more R. is H. unsubstituted or substituted Co-Co aryl, unsub 30 groups, each of which can be the same or different, selected stituted or substituted heteroaryl comprising one or two 5- or from -T-Q. 6-member ring and 1-4 heteroatoms selected from N, O and S. For example, T is a bond. unsubstituted or substituted C-C carbocycle, unsubstituted For example, T is unsubstituted or substituted C-C, or Substituted heterocycle comprising one or two 5- or alkyl linker, including but not limited to, methyl, ethyl, n-pro 6-member ring and 1-4 heteroatoms selected from N, O and S. 35 pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and —NRR", NR"C(O)NR'R', NR"C(O)R - NR"C n-hexyl linker. (O)OR - NR"S(O).R., or - C(O)NR'R'': For example, T is a methyl linker. Rs and Rs' are each independently H, or -T'-Q,"; For example, Q is H. R" is H, or unsubstituted or substituted C-C alkyl: For example, both R. and Rare H. T.T., and Ts are each independently a bond, or unsub 40 For example, at least one of R and R' is unsubstituted stituted or substituted C-C alkyl linker; or Substituted, straight-chain or branched C-C alkyl, includ Q, is H. unsubstituted or substituted Co-Co aryl, unsub ing but not limited to, methyl, ethyl, n-propyl. i-propyl. n-bu stituted or substituted heteroaryl comprising one or two 5- or tyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. 6-member ring and 1-4 heteroatoms selected from N, O and S. For example, at least one of R and R' is methyl, ethyl unsubstituted or Substituted C-Cs carbocycle, unsubstituted 45 or t-butyl. or Substituted heterocycle comprising one or two 5- or For example, R is phenyl substituted with one or more 6-member ring and 1-4 heteroatoms selected from N, O and groups, each of which can be the same or different, selected S; —C(O)OR; —C(O)R. —C(O)NR'R'', or from methyl, ethyl, t-butyl and trifluoromethyl. —NRR'; For example, R is phenyl substituted with one or more Q," is H, unsubstituted or substituted Co-Cs aryl, unsub 50 groups, each of which can be the same or different, selected stituted or substituted heteroaryl comprising one or two 5- or from methoxy, t-butoxy and trifluoromethoxy. 6-member ring and 1-4 heteroatoms selected from N, O and S. For example, R is phenyl substituted with two or more unsubstituted or Substituted C-Cs carbocycle, unsubstituted groups, each of which can be the same or different, selected or Substituted heterocycle comprising one or two 5- or from hydroxyl, cyano, methyl, ethyl, t-butyl, trifluoromethyl, 6-member ring and 1-4 heteroatoms selected from N, O and S. 55 methoxy, t-butoxy, trifluoromethoxy, and halogen. —C(O)CR, —C(O)R. —C(O)NR'R'', or NRR"; For example, R is heteroaryl selected from pyrrolyl, fura Q, is H. unsubstituted or substituted Co-Co aryl, unsub nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet stituted or substituted heteroaryl comprising one or two 5- or razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 6-member ring and 1-4 heteroatoms selected from N, O and S. pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, unsubstituted or Substituted C-Cs carbocycle, unsubstituted 60 benzothiazolyl, benzoimidazolyl, benzothienyl, methylene or Substituted heterocycle comprising one or two 5- or dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, 6-member ring and 1-4 heteroatoms selected from N, O and S. indolyl, benzofuranyl, purinyl, deaZapurinyl, indolizinyl, OOR, , —C(O)R. —C(O)NR'R'', or—NRR'; imidazothiazolyl, quinoxalinyl, tetrahydropyridinyl, pyrrol al opyrimidinyl, and the like, and is optionally substituted with R. R. R. and R' are each independently H, unsub 65 halogen (e.g., fluorine, chlorine, bromine, and iodine), unsub stituted or substituted C-C alkyl, unsubstituted or substi stituted or substituted amino, unsubstituted or substituted tuted C-C aryl, or unsubstituted or substituted heteroaryl C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, US 8,263,610 B2 81 82 S-butyl, t-butyl, n-pentyl, S-penty1 and n-hexyl, each of which i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and is optionally substituted with halogen (e.g., fluorine, chlorine, n-hexyl, each of which is optionally substituted with halogen bromine and iodine)), Co-Co aryl (e.g., phenyl, which is (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted optionally Substituted), heteroaryl (e.g., pyrrolyl, furanyl. or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, dioxy, each of which is optionally substituted with halogen pyridazinyl, and pyrimidinyl, and the like, and is optionally (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) Substituted), C-Cs carbocycle (e.g., cyclopropyl, cyclobutyl, R —NHC(O)OR, —C(O)R and —C(O)CR, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally wherein Riis H, or unsubstituted or substituted C-C alkyl Substituted), or heterocycle (e.g., pyrrolidinyl, imidazolidi 10 (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu nyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tyl, n-pentyl, S-pentyl, and n-hexyl). tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, For example, R, is phenyl substituted with one, two, three and the like, and is optionally Substituted). or more groups, each of which can be the same or different, For example, R is heteroaryl selected from furanyl, pyra selected from halogen (e.g., fluorine, chlorine, bromine, and Zolyl, purinyl, indolyl, tetrahydropyridinyl, and pyrrolopyri 15 iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, midinyl, and is optionally Substituted with one or more ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. groups, each of which can be the same of different, selected wherein R is H. methyl, ethyl, or t-butyl. from methyl, ethyl, t-butyl, amino, and heterocycle (e.g., For example, R, is unsubstituted naphthyl. piperidinyl, which is optionally substituted). For example, R, is naphthyl substituted with one, two, For example, R is H. three or more groups, each of which can be the same or For example, R is unsubstituted or substituted C-C, different, selected from hydroxyl, halogen, nitro, cyano, alkyl, including but not limited to, methyl, ethyl, n-propyl. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-hexyl. tyl, and n-hexyl, each of which is optionally substituted with For example, R is methyl substituted with unsubstituted 25 halogen (e.g., fluorine, chlorine, bromine, and iodine)), phenyl. unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, R is methyl substituted with phenyl substi ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu tuted with one or more groups, each of which can be the same toxy, each of which is optionally substituted with halogen or different, selected from hydroxyl, halogen, nitro, cyano, (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, 30 R. —NHC(O)OR, —C(O)R, and —C(O)CR, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen wherein Riis H, or unsubstituted or Substituted C-C alkyl tyl, and n-hexyl, each of which is optionally substituted with (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, s-butyl, t-bu halogen (e.g., fluorine, chlorine, bromine, and iodine)), and tyl, n-pentyl, S-pentyl, and n-hexyl). unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, R, is naphthyl substituted with one, two, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu 35 three or more groups, each of which can be the same or toxy, each of which is optionally substituted with halogen different, selected from halogen (e.g., fluorine, chlorine, bro (e.g., fluorine, chlorine, bromine, and iodine)). mine, and iodine). For example, R is methyl substituted with phenyl substi For example, R, is heteroaryl selected from pyrrolyl, fura tuted with one or more groups, each of which can be the same nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet or different, selected from methyl, ethyl, t-butyl, and trifluo 40 razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, romethyl. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, R is methyl substituted with phenyl substi azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, tuted with one or more groups, each of which can be the same benzoimidazolyl, benzothienyl, methylenedioxyphenyl, or different, selected from methoxy, ethoxy, i-propyloxy, and quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura t-butoxy. 45 nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui For example, R is H. noxalinyl, and pyrrolopyrimidinyl, and the like, and is option For example, R is unsubstituted or substituted, straight ally Substituted with one, two, three or more groups, each of chain or branched C-C alkyl, including but not limited to, which can be the same or different, selected from hydroxyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, halogen, nitro, cyano, unsubstituted or Substituted amino, n-pentyl, S-pentyl, and n-hexyl. 50 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, R is H. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, R is unsubstituted or Substituted, straight tyl, and n-hexyl, each of which is optionally substituted with chain or branched C-C alkyl, including but not limited to, halogen (e.g., fluorine, chlorine, bromine, and iodine)), methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, unsubstituted or substituted C-C alkoxy (e.g., methoxy, n-pentyl, S-pentyl, and n-hexyl. 55 ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, R is H. toxy, each of which is optionally substituted with halogen For example, R is unsubstituted or Substituted, straight (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) chain or branched C-C alkyl, including but not limited to, R —NHC(O)OR, —C(O)R and —C(O)CR, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, wherein R is H. unsubstituted or Substituted C-C alkyl n-pentyl, S-pentyl, and n-hexyl. 60 (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, all of R. R. and R are H. tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi For example, R, is H. tuted C-C aryl, or unsubstituted or substituted heteroaryl For example, R, is unsubstituted phenyl. comprising one or two 5- or 6-member ring and 1-4 heteroa For example, R, is phenyl substituted with one, two, three toms selected from N, O and S. or more groups, each of which can be the same or different, 65 For example, R, is imidazolyl pyrazolyl, oxazolyl, isox selected from hydroxyl, halogen, nitro, cyano, unsubstituted azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben US 8,263,610 B2 83 84 Zothiazolyl, benzothiadiazolyl, benzothienyl, O RandR are each independently H, unsubstituted pyrrolopyrimidiyl, each of which is optionally substituted or substituted C-C alkyl, unsubstituted or substi with one, two, three or more groups, each of which can be the tuted Co-Co aryl, or unsubstituted or Substituted het same or different, selected from selected from halogen (e.g., eroaryl comprising one or two 5- or 6-member ring fluorine, chlorine, bromine, and iodine), amino, methyl, and 1-4 heteroatoms selected from N, O and S. ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein For example, R is methyl substitute with unsubstituted R is H. methyl, ethyl, t-butyl, or phenyl. phenyl. For example, R, is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is methyl substitute with phenyl substi cyclohexyl, or cycloheptyl, and is optionally substituted with tuted with one or more groups, each of which can be the same 10 or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tyl, and n-hexyl, each of or which is optionally substituted tyl, and n-hexyl, each of which is optionally substituted with with halogen (e.g., fluorine, chlorine, bromine, and iodine)), halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubstituted or substituted C-C alkoxy (e.g., methoxy, 15 unsubstituted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu toxy, each of which is optionally substituted with halogen toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). (e.g., fluorine, chlorine, bromine, and iodine)). For example, R, is cyclopropyl. For example, R is methyl substitute with methoxy, ethoxy, For example, R, is heterocycle selected from pyrrolidinyl, or t-butoxy. imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, For example, R is methyl substitute with two or more triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, groups, each of which can be the same or different, selected morpholinyl, and pyrrolidinone, and the like, and is option from: ally Substituted with halogen (e.g., fluorine, chlorine, bro 1) phenyl, which is optionally substituted with one or more mine, and iodine)), unsubstituted or Substituted C-C alkoxy 25 groups, each of which can be the same or different, (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu Selected from hydroxyl, halogen, nitro, cyano, unsubsti toxy, and t-butoxy, each of which is optionally substituted tuted or Substituted C-C alkyl (e.g., methyl, ethyl, with halogen (e.g., fluorine, chlorine, bromine, and iodine)). n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, For example, R, is S(O).R, C(O)R, C(O)OR, s-pentyl, and n-hexyl, each of which is optionally Sub —(CH).R. 30 stituted with halogen (e.g., fluorine, chlorine, bromine, For example, o is 0. and iodine)), unsubstituted or Substituted C-C alkoxy For example, o is 1. (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, For example, R is H. i-butoxy, and t-butoxy, each of which is optionally Sub For example, R is unsubstituted or Substituted, straight stituted with halogen (e.g., fluorine, chlorine, bromine, chain or branched C-C alkyl, including but not limited to, 35 and iodine)); and methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, 2) one of the following: n-pentyl, S-pentyl, and n-hexyl. i) —C(O)OR; For example, R is straight-chain or branched C-C alkyl ii) methoxy, ethoxy, i-propyloxy, or t-butoxy; or Substituted with one, two, three or more groups, each of iii) —NRR. which can be the same or different, selected from: 40 For example, R is methyl substitute with —C(O)CR. 1) phenyl, which is optionally substituted with one or more For example, R is H. groups, each of which can be the same or different, For example, R is unsubstituted or substituted, straight selected from unsubstituted or substituted C-C alkyl chain or branched C-C alkyl, including but not limited to, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl), and unsubsti 45 n-pentyl, S-pentyl, and n-hexyl. tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, For example, R is methyl substitute with —NRR. propyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy); For example, both R and R are H. 2) unsubstituted or Substituted C-C alkoxy (e.g., meth For example, at least one of R12 and R1s is -To-Q2. oxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, For example, T is a bond. and t-butoxy); 50 For example, T2 is unsubstituted or substituted C-C, 3) —C(O)OR; —C(O)R; and alkyl linker, including but not limited to, methyl, ethyl, n-pro 4) —NRR, wherein: pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and R is H, or unsubstituted or substituted C-C alkyl: n-hexyl linker. R2 and R1s are each independently H, -To-Q2 or R2 For example, T is a methyl ethyl, or propyl linker. and R, together with the atom they attach to, form a 55 For example, Q2 is H. 5- or 6-member ring: For example, Q, is hydroxyl. T2 is a bond, or unsubstituted or substituted C-C alkyl For example, Q2 is unsubstituted or substituted C-C, linker; alkoxy, including but not limited to, methoxy, ethoxy, propy Q2 is H, hydroxyl, unsubstituted or substituted C-C, loxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy. alkoxy, unsubstituted or Substituted Co-Co aryl, 60 For example, Q2 is methoxy. unsubstituted or Substituted heteroaryl comprising For example, Q, is unsubstituted or substituted phenyl or one or two 5- or 6-member ring and 1-4 heteroatoms naphthyl. selected from N, O and S, unsubstituted or substituted For example, Q, is unsubstituted phenyl. C-Cs carbocycle, unsubstituted or Substituted het For example, Q2 is phenyl substituted with one or more erocycle comprising one or two 5- or 6-member ring 65 groups, each of which can be the same or different, selected and 1-4 heteroatoms selected from N, O and S, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub —NRR', -C(O)R. —C(O)CRt.; and stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. US 8,263,610 B2 85 86 n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. of which is optionally substituted with halogen (e.g., fluorine, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and chlorine, bromine, and iodine)), and unsubstituted or Substi n-hexyl, each of which is optionally substituted with halogen tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy optionally Substituted with halogen (e.g., fluorine, chlorine, loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene bromine, and iodine)). dioxy, each of which is optionally substituted with halogen For example, Q2 is heteroaryl selected from pyrrolyl, fura (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet R. —NHC(O)OR, —C(O)R, and —C(O)CR, razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 10 wherein Riis H, or unsubstituted or Substituted C-C alkyl pyridazinyl, pyrimidinyl, benzoxazolyl, benzodioxazolyl, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu benzothiazolyl, benzoimidazolyl, benzothienyl, methylene tyl, n-pentyl, S-pentyl, and n-hexyl). dioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, For example, Q, is phenyl substituted with one, two, three indolyl, benzofuranyl, purinyl, deazapurinyl, indolizinyl, or more groups, each of which can be the same or different, imidazothiazolyl, and quinoxalinyl, and the like, and is 15 selected from halogen (e.g., fluorine, chlorine, bromine, and optionally substituted. iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, For example, Q2 is indolyl. ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. For example, Q2 is cyclopropyl, cyclobutyl, cyclopentyl, wherein R is H. methyl, ethyl, or t-butyl. cyclohexyl, or cycloheptyl, and is optionally substituted. For example, Q, is unsubstituted naphthyl. For example, Q2 is heterocycle selected from pyrrolidinyl, For example, Q, is naphthyl substituted with one, two, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, three or more groups, each of which can be the same or triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, different, selected from hydroxyl, halogen, nitro, cyano, morpholinyl, and pyrrolidinone, and the like, and is option unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, ally substituted. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, Q2 is piperidinyl. 25 tyl, and n-hexyl, each of which is optionally substituted with For example, Q2 is —NR.R.'. halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, Q2 is —C(O)OR. unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, both R and R. are H. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, at least one of R and R is unsubsti toxy, each of which is optionally substituted with halogen tuted or substituted, straight-chain or branched C-C alkyl, 30 (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) including but not limited to, methyl, ethyl, n-propyl, i-propyl. R —NHC(O)OR, —C(O)R and —C(O)CR, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl. wherein Riis H, or unsubstituted or substituted C-C alkyl For example, at least one of R and R. is methyl or (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu t-butyl. tyl, n-pentyl, S-pentyl, and n-hexyl). For example, R and R, together with the atom they 35 For example, Q, is naphthyl substituted with one, two, attach to, form a 5- or 6-member ring selected from pyrro three or more groups, each of which can be the same or lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo different, selected from halogen (e.g., fluorine, chlorine, bro lidinyl, triazolidinyl, piperidinyl, piperazinyl, and morpholi mine, and iodine). nyl, and the like, and is optionally Substituted with halogen For example, Q, is heteroaryl selected from pyrrolyl, fura (e.g., fluorine, chlorine, bromine, and iodine), unsubstituted 40 nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox n-hexyl), unsubstituted or Substituted C-C alkoxy (e.g., azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, and t-butoxy), unsubstituted or substituted amino, —C(O) 45 quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura R, or—C(O)CR, wherein R is H, or unsubstituted nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. noxalinyl, and pyrrolopyrimidinyl, and the like, and is option i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and ally Substituted with one, two, three or more groups, each of n-hexyl). which can be the same or different, selected from hydroxyl, For example, R and R, together with the atom they 50 halogen, nitro, cyano, unsubstituted or Substituted amino, attach to, form a piperidinyl or piperazinyl, and is optionally unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, substituted with halogen, methyl, ethyl, t-butyl, methoxy, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen ethoxy, i-propyloxy, t-butoxy, or —C(O)OR, wherein tyl, and n-hexyl, each of which is optionally substituted with R is methyl, ethyl, or t-butyl. halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, R is -T-Q. 55 unsubstituted or Substituted C-C alkoxy (e.g., methoxy, For example, T is a bond. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, T, is unsubstituted or substituted C-C, toxy, each of which is optionally substituted with halogen alkyl linker, including but not limited to, methyl, ethyl, n-pro (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and R —NHC(O)OR, —C(O)R and —C(O)CR, n-hexyl linker. 60 wherein R is H. unsubstituted or Substituted C-C alkyl For example, T is a methyl, ethyl, propyl, or i-propyl (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu linker. tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi For example, Q, is H. tuted C-C aryl, or unsubstituted or substituted heteroaryl For example, Q, is unsubstituted phenyl. comprising one or two 5- or 6-member ring and 1-4 heteroa For example, Q, is phenyl substituted with one, two, three 65 toms selected from N, O and S. or more groups, each of which can be the same or different, For example, Q, is imidazolyl pyrazolyl, oxazolyl, isox selected from hydroxyl, halogen, nitro, cyano, unsubstituted azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino US 8,263,610 B2 87 88 linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben phenyl, unsubstituted or substituted heteroaryl compris Zothiazolyl, benzothiadiazolyl, benzothienyl, O ing one or two 5- or 6-member ring and 1-4 heteroatoms pyrrolopyrimidiyl, each of which is optionally substituted selected from N, O and S. -Ts-Qs, or Rs2 and Rs', with one, two, three or more groups, each of which can be the together with the atom they attach to, form a 5- or same or different, selected from selected from halogen (e.g., 6-member ring which optionally comprises 1-4 heteroa fluorine, chlorine, bromine, and iodine), amino, methyl, toms selected from N, O and S and is optionally substi ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein tuted with-To-Q.: R is H. methyl, ethyl, t-butyl, or phenyl. Qs is H, hydroxyl, unsubstituted or substituted phenyl, For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, unsubstituted or Substituted heteroaryl comprising one cyclohexyl, or cycloheptyl, and is optionally substituted with 10 or two 5- or 6-member ring and 1-4 heteroatoms selected unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, from N, O and S, unsubstituted or substituted C-Cs n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen carbocycle, unsubstituted or substituted heterocycle tyl, and n-hexyl, each of or which is optionally substituted comprising one or two 5- or 6-member ring and 1-4 with halogen (e.g., fluorine, chlorine, bromine, and iodine)), heteroatoms selected from N, O and S. —OR, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, 15 —NR.R.'. —NHC(O)R. —NHC(O)OR, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu —C(O)NR'R''. —C(O)R, or—C(O)OR; toxy, each of which is optionally substituted with halogen Q, is H, hydroxyl, unsubstituted or substituted phenyl, (e.g., fluorine, chlorine, bromine, and iodine)). unsubstituted or Substituted heteroaryl comprising one For example, Q, is cyclopropyl. or two 5- or 6-member ring and 1-4 heteroatoms selected For example, Q, is heterocycle selected from pyrrolidinyl, from N, O and S, unsubstituted or substituted C-Cs imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, carbocycle, unsubstituted or substituted heterocycle triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, comprising one or two 5- or 6-member ring and 1-4 morpholinyl, and pyrrolidinone, and the like, and is option heteroatoms selected from N, O and S. —NR.R.", ally Substituted with halogen (e.g., fluorine, chlorine, bro —C(O)NR'R''. mine, and iodine)), unsubstituted or Substituted C-C alkoxy 25 RandR are each independently H, unsubstituted or (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu substituted C-C alkyl, unsubstituted or substituted toxy, and t-butoxy, each of which is optionally substituted Co-Co aryl, or unsubstituted or Substituted heteroaryl with halogen (e.g., fluorine, chlorine, bromine, and iodine)). comprising one or two 5- or 6-member ring and 1-4 For example, R, is C(=NH)NR.R.'. heteroatoms selected from N, O and S: For example, both R and Rare H. 30 Ra and R are each independently H, unsubstituted or For example, R, is C(S)NR.R.'. Substituted C-C alkyl, or R and R', together with For example, both R- and Rare phenyl. the atom they attach to, form a 5- or 6-member ring For example, R, is C(=NH)NR.R., C(O)NR.R.', or which optionally comprises 1-4 heteroatoms selected —C(S)NRR". from N, O and S and is optionally substituted. For example, both R and Rare H. 35 For example, T is a bond. For example, at least one of R and R is unsubstituted or For example, Ta is unsubstituted or substituted C-C, Substituted, straight-chain or branched C-C alkyl, including alkyl linker, including but not limited to, methyl, ethyl, n-pro but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. n-hexyl linker. For example, at least one of R and R. is -T-Qa. 40 For example, Ta is a methyl ort-butyl linker. For example, Ts is a bond. For example, Q, is H. For example, T is unsubstituted or substituted C-C, For example, Q, is unsubstituted or substituted, straight alkyl linker, including but not limited to, methyl, ethyl, n-pro chain or branched C-C alkyl, including but not limited to, pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-hexyl, and 2-methylpropyl linker. 45 n-pentyl, S-pentyl, and n-hexyl, each of which is optionally For example, Ts is a methyl, ethyl, propyl, or 2-methyl Substituted with halogen (e.g., fluorine, chlorine, bromine, propyl linker. and iodine). For example, Q, is H. For example, Q, is methyl, ethyl, t-butyl, or trifluorom For example, Q, is unsubstituted phenyl. ethyl. For example, Q, is phenyl substituted with one or more 50 For example, Q, is unsubstituted or substituted C-C, groups, each of which can be the same or different, selected alkoxy, including but not limited to, methoxy, ethoxy, propy from-Ta-Q4, wherein: loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and methylene T.T.s and T are each independently a bond, or unsub dioxy. stituted or substituted C-C alkyl linker; For example, Q, is methoxy, ethoxy, or methylenedioxy. Q, is H. unsubstituted or substituted C-C alkyl, unsub 55 For example, Q, is fluorine, chlorine, bromine, or iodine. stituted or substituted C-C alkoxy, halogen, nitro, For example, Q, is unsubstituted phenyl. unsubstituted or substituted phenyl, unsubstituted or For example, Q, is phenyl substituted with one or more Substituted heteroaryl comprising one or two 5- or groups, each of which can be the same or different, selected 6-member ring and 1-4 heteroatoms selected from N.O from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub and S, unsubstituted or Substituted C-Cs carbocycle, 60 stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. unsubstituted or Substituted heterocycle comprising one n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each or two 5- or 6-member ring and 1-4 heteroatoms selected of which is optionally substituted with halogen (e.g., fluorine, from N, O and S, NRR', NHC(O)R. NHC chlorine, bromine, and iodine)), and unsubstituted or Substi (O)OR. -C(O)CR-2, -C(O)CR -OR, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro —SR-2, —C(O)NRR'; 65 pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each R and R2 are each independently H, unsubstituted or of which is optionally substituted with halogen (e.g., fluorine, substituted C-C alkyl, unsubstituted or substituted chlorine, bromine, and iodine)). US 8,263,610 B2 89 90 For example, Q, is heteroaryl selected from heteroaryl of which is optionally substituted with halogen (e.g., fluorine, selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiaz chlorine, bromine, and iodine)). olyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, For example, R is heteroaryl selected from pyrrolyl, fura isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tri nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet azinyl, benzoxazolyl, benzodioxazolyl, benzoxadiazolyl, razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, ben pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox Zothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, naphthrydinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, indolizinyl, imidazothiazolyl, quinoxalinyl, and pyrrolopyri quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura midinyl, and the like, and is optionally substituted with one or 10 nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, and more groups, each of which can be the same or different, quinoxalinyl, and the like, and is optionally Substituted with selected from hydroxyl, halogen, nitro, cyano, unsubstituted one, two or more groups, each of which can be the same or or substituted amino, unsubstituted or substituted C-C alkyl different, selected from hydroxyl, halogen, nitro, cyano, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu unsubstituted or substituted amino, unsubstituted or substi tyl, n-pentyl, S-pentyl, and n-hexyl, each of which is option 15 tuted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. ally Substituted with halogen (e.g., fluorine, chlorine, bro n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each mine, and iodine)), and unsubstituted or substituted C-C, of which is optionally substituted with halogen (e.g., fluorine, alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, chlorine, bromine, and iodine)), and unsubstituted or Substi butoxy, i-butoxy, and t-butoxy, each of which is optionally tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro Substituted with halogen (e.g., fluorine, chlorine, bromine, pyloxy, butoxy, i-butoxy, and t-butoxy, each of which is and iodine)). optionally Substituted with halogen (e.g., fluorine, chlorine, For example, Q, is thiazolyl, isothiazolyl, or oxadiazolyl, bromine, and iodine)). each of which is optionally substituted with one or more For example, R is pyrazinyl, and is optionally Substituted groups, each of which can be the same or different, selected 25 with methyl, ethyl or t-butyl. from methyl, ethyl, and t-butyl. For example, Q, is —C(O)Rs2. -C(O)ORs. For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, For example, R is H. cyclohexyl, or cycloheptyl, and is optionally substituted. For example, R is unsubstituted or substituted, straight For example, Q, is heterocycle selected from pyrrolidinyl, chain or branched C-C alkyl, including but not limited to, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 30 methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, n-pentyl, S-pentyl, and n-hexyl. morpholinyl, and pyrrolidinone, and the like, and is option For example, R is methyl or ethyl. ally Substituted with halogen (e.g., fluorine, chlorine, bro For example, Q, is NHC(O)Rs, NHC(O)ORs, or mine, and iodine)), unsubstituted or Substituted C-C alkoxy —C(O)NRR". (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu 35 For example, Q, is —C(O)NR2Rs'. toxy, and t-butoxy, each of which is optionally substituted For example, both R- and Rare H. with halogen (e.g., fluorine, chlorine, bromine, and iodine)). For example, at least one of Rs and Rs2' is -Ts-Qs. For example, Q, is piperazinyl or piperazinyl, and is For example, Ts is a bond. optionally substituted with methyl, ethyl, or t-butyl. For example, Ts is unsubstituted or substituted C-C, For example, Q, is —NR.R.'. 40 alkyl linker, including but not limited to, methyl, ethyl, n-pro For example, both R- and Rare H. pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, For example, at least one of RandR is unsubstituted or n-hexyl, 1,2-dimethylpropyl, and 1-methylbutyl linker. Substituted, straight-chain or branched C-C alkyl, including For example, Ts is a methyl, ethyl, propyl, i-propyl, butyl, but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, 1,2-dimethylpropyl, or 1-methylbutyl linker. S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. 45 For example, Qs is H. For example, at least one of R and R' is methyl or ethyl. For example, Qs is unsubstituted phenyl. For example, R and Rare both methyl or ethyl. For example, Q, is phenyl substituted with one or more For example, Q, is —ORs, or —SR-2. groups, each of which can be the same or different, selected For example, R is H. from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, R is unsubstituted or Substituted, straight 50 stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. chain or branched C-C alkyl, including but not limited to, n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, of which is optionally substituted with halogen (e.g., fluorine, n-pentyl, S-pentyl, and n-hexyl, each of which is optionally chlorine, bromine, and iodine)), unsubstituted or substituted Substituted with halogen (e.g., fluorine, chlorine, bromine, C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, and iodine). 55 butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each of which For example, R is methyl, ethyl, t-butyl, or trifluorom is optionally substituted with halogen (e.g., fluorine, chlorine, ethyl. bromine, and iodine)), unsubstituted or substituted Co-Co For example, R is unsubstituted phenyl. aryloxy (e.g., phenoxy), and —NHC(O)R, wherein R. For example, R is phenyl Substituted with one or more is H, or unsubstituted or Substituted C-C alkyl (e.g., methyl, groups, each of which can be the same or different, selected 60 ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub s-pentyl, and n-hexyl). stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. For example, Qis is phenyl substituted with one or more n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each groups, each of which can be the same or different, selected of which is optionally substituted with halogen (e.g., fluorine, from halogen (e.g., fluorine, chlorine, bromine, and iodine), chlorine, bromine, and iodine)), and unsubstituted or Substi 65 methyl, ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, t-bu tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro toxy, phenoxy, and —NHC(O)R, wherein R is H. pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each methyl or ethyl. US 8,263,610 B2 91 92 For example, Qs is heteroaryl selected from pyrrolyl, fura For example, Qis is —NR.R.', -NHC(O)R or nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet —C(O)NRR, razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, both R. and Rare H. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, at least one of R and R is unsubsti azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, tuted or substituted, straight-chain or branched C-C alkyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl. quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui For example, at least one of R and R. is methyl or noxalinyl, and pyrrolopyrimidinyl, and the like, and is option ethyl. ally Substituted with one or more groups, each of which can 10 be the same or different, selected from hydroxyl, halogen, For example, R. and R. are both methyl or ethyl. nitro, cyano, unsubstituted or substituted amino, unsubsti For example, R and R', together with the atom they tuted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. attach to, form a 5- or 6-member ring selected from pyrro i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl n-hexyl, each of which is optionally substituted with halogen 15 (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti and is optionally substituted with -To-Q, tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro For example, R and R', together with the atom they pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of attach to, form a 5- or 6-member ring selected from pyrro which is optionally Substituted with halogen (e.g., fluorine, lidinyl, piperidinyl, and piperazinyl, and is optionally Substi chlorine, bromine, and iodine)). tuted with -To-Q, For example, Q, is pyrazolyl, imidazolyl, isoxazolyl, For example, T is a bond. oxazolyl pyridinyl, furanyl, indolyl, or benzoimidazolyl, For example, T is unsubstituted or substituted C-C, each of which is optionally substituted with one or more alkyl linker, including but not limited to, methyl, ethyl, n-pro groups, each of which can be the same or different, selected pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and from methyl or ethyl. 25 n-hexyl linker. For example, Qis is cyclopropyl, cyclobutyl, cyclopentyl, For example, T is a methyl or ethyl linker. cyclohexyl, or cycloheptyl, and is optionally substituted with For example, Q, is H. unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, For example, Q, is unsubstituted phenyl. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, Q, is phenyl substituted with one or more tyl, and n-hexyl, each of or which is optionally substituted 30 groups, each of which can be the same or different, selected with halogen (e.g., fluorine, chlorine, bromine, and iodine)), from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub unsubstituted or substituted C-C alkoxy (e.g., methoxy, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each toxy, each of which is optionally substituted with halogen of which is optionally substituted with halogen (e.g., fluorine, (e.g., fluorine, chlorine, bromine, and iodine)). 35 chlorine, bromine, and iodine)), and unsubstituted or Substi For example, Qs is cyclohexyl or cycloheptyl, which is tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro optionally substituted with methyl or ethyl. pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each For example, Qs is heterocycle selected from pyrrolidinyl, of which is optionally substituted with halogen (e.g., fluorine, pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, chlorine, bromine, and iodine)). isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, 40 For example, Q, is phenyl substituted with one or more piperazinyl, morpholinyl, and pyrrolidinone, and the like, and groups, each of which can be the same or different, selected is optionally substituted. from methyl, ethyl, and t-butyl. For example, Qis is pyrrolidinyl, pyrrolidinone, piperidi For example, Q, is heteroaryl selected from pyrrolyl, fura nyl, morpholinyl, or tetrahydrofuranyl, and is optionally Sub nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet stituted. 45 razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, Qs is —OR. pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox For example, R is H. azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, For example, Riis unsubstituted or Substituted, straight benzoimidazolyl, benzothienyl, methylenedioxyphenyl, chain or branched C-C alkyl, including but not limited to, quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, 50 nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui n-pentyl, S-pentyl, and n-hexyl. noxalinyl, benzodihydroimidazolone, and pyrrolopyrimidi For example, R is methyl, ethyl, or t-butyl. nyl, and the like, and is optionally substituted with one or For example, R is unsubstituted phenyl. more groups, each of which can be the same or different, For example, R is phenyl substituted with one or more selected from hydroxyl, halogen, nitro, cyano, unsubstituted groups, each of which can be the same or different, selected 55 or substituted amino, unsubstituted or substituted C-C alkyl from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. tyl, n-pentyl, S-pentyl, and n-hexyl, each of which is option n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each ally Substituted with halogen (e.g., fluorine, chlorine, bro of which is optionally substituted with halogen (e.g., fluorine, mine, and iodine)), and unsubstituted or Substituted C-C, chlorine, bromine, and iodine)), and unsubstituted or Substi 60 alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro butoxy, i-butoxy, and t-butoxy, each of which is optionally pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each Substituted with halogen (e.g., fluorine, chlorine, bromine, of which is optionally substituted with halogen (e.g., fluorine, and iodine)). chlorine, bromine, and iodine)). For example, Q, is pyridinyl, pyrazinyl, or benzodihy For example, Qs is —NR.R.', -NHC(O)R. 65 droimidazolone, each of which is optionally substituted with —NHC(O)OR, —C(O)NR'R''. —C(O)R, or one or more groups, each of which can be the same or differ —C(O)OR. ent, selected from methyl or ethyl. US 8,263,610 B2 93 94 For example, Q, is cyclopropyl, cyclobutyl, cyclopentyl, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), cyclohexyl, or cycloheptyl, and is optionally substituted with unsubstituted or Substituted C-C alkoxy (e.g., methoxy, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen toxy, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)). tyl, and n-hexyl, each of or which is optionally substituted For example, Q, is cyclohexyl. with halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, Q, is heterocycle selected from pyrrolidinyl, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, toxy, each of which is optionally substituted with halogen 10 morpholinyl, and pyrrolidinone, and the like, and is option (e.g., fluorine, chlorine, bromine, and iodine)). ally Substituted with halogen (e.g., fluorine, chlorine, bro For example, Q, is heterocycle selected from pyrrolidinyl, mine, and iodine)), unsubstituted or substituted C-C alkoxy pyrrolidinone, imidazolidinyl, pyrazolidinyl, oxazolidinyl, (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, toxy, and t-butoxy, each of which is optionally substituted piperazinyl, morpholinyl, and pyrrolidinone, and the like, and with halogen (e.g., fluorine, chlorine, bromine, and iodine)). is optionally substituted. 15 For example, Q, is C(O)ORs. -C(O)Rs –C(O) For example, Q, is —NR.R.'. NRR', or —NRR". For example, both R and R. are H. For example, Q, is C(O)ORs, or NRs Rs. For example, at least one of R and R is unsubsti For example, R, and Rare both H. tuted or Substituted, straight-chain or branched C-C alkyl, For example, at least one of R and R' is unsubstituted or including but not limited to, methyl, ethyl, n-propyl, i-propyl. Substituted, straight-chain or branched C-C alkyl, including n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, at least one of R and R. is methyl or S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each of which ethyl. is optionally substituted with halogen (e.g., fluorine, chlorine, For example, R. and Rare both methyl or ethyl. bromine, and iodine), hydroxyl, or unsubstituted or Substi For example, Q, is C(O)NR'R''. 25 tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro For example, R and Ra'are both H. pyloxy, butoxy, i-butoxy, and t-butoxy). For example, at least one of RandR is unsubstituted or For example, at least one of R and R' is methyl or ethyl Substituted, straight-chain or branched C-C alkyl, including optionally substituted with hydroxyl. but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, For example, RandR', together with the atom they attach S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. to, form a 5-, 6- or 7-member ring selected from pyrrolidinyl, For example, R and R', together with the atom they 30 imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, attach to, form a 5- or 6-member ring selected from pyrro triazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepa lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo nyl, and diazepanyl, and the like and is optionally substituted lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl with one or more groups, each of which can be the same or and is optionally Substituted. different, selected from T-Q, wherein: For example, R and R', together with the atom they 35 T is a bond, or unsubstituted or substituted C-C alkyl attach to, form a pyrrolidinyl ring, and is optionally Substi linker; tuted. Q7 is H, unsubstituted or substituted phenyl, unsubstituted For example, Q, is unsubstituted naphthyl. or Substituted heteroaryl comprising one or two 5- or For example, Q, is heteroaryl selected from pyrrolyl, fura 6-member ring and 1-4 heteroatoms selected from N.O nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet and S, unsubstituted or Substitute C-C carbocycle, razolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, 40 unsubstituted or Substituted heterocycle comprising one pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox or two 5- or 6-member ring and 1-4 heteroatoms selected azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, from N, O and S. —C(O)NR'R''. —C(O)ONRR", benzoimidazolyl, benzothienyl, methylenedioxyphenyl, or —NRR'; and quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura R and Rs' are each independently H, unsubstituted or nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui 45 substituted C-C alkyl, unsubstituted or substituted noxalinyl, dihydrobenzofuranyl, and pyrrolopyrimidinyl, and phenyl, unsubstituted or substituted heteroaryl compris the like, and is optionally substituted with one, two or more ing one or two 5- or 6-member ring and 1-4 heteroatoms groups, each of which can be the same or different, selected selected from N, O and S, unsubstituted or substitute from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub C-C carbocycle, unsubstituted or substituted hetero stituted amino, unsubstituted or Substituted C-C alkyl (e.g., cycle comprising one or two 5- or 6-member ring and methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, 50 1-4 heteroatoms selected from N, O and S, or R and n-pentyl, S-pentyl, and n-hexyl, each of which is optionally R", together with the atom they attach to, form a 5- or Substituted with halogen (e.g., fluorine, chlorine, bromine, 6-member ring which optionally comprises 1-4 heteroa and iodine)), unsubstituted or Substituted C-C alkoxy (e.g., toms selected from N, O and S and is optionally substi methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, tuted. and t-butoxy, each of which is optionally substituted with 55 For example, RandR', together with the atom they attach halogen (e.g., fluorine, chlorine, bromine, and iodine)), and to, form a 5-, 6- or 7-member ring selected from piperidinyl, unsubstituted or substituted phenyl. piperazinyl, pyrrolidinyl, and diazepanyl, and is optionally For example, Q, is oxazolylisoxazolyl pyridinyl, pyrazi substituted with-T-Q7. nyl, triazinyl, thienyl, benzothiadiazolyl, or dihydrobenzo For example, T, is a bond. furanyl, each of which is optionally substituted with one, two For example, T., is unsubstituted or substituted C-C, or more groups, each of which can be the same or different, 60 alkyl linker, including but not limited to, methyl, ethyl, n-pro selected from halogen (e.g., fluorine, chlorine, bromine, and pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and iodine), methyl, ethyl, t-butyl, trifluoromethyl, and phenyl. n-hexyl linker. For example, Q, is cyclopropyl, cyclobutyl cyclopentyl, For example, T, is a methyl ethyl, or propyl linker. cyclohexyl, or cycloheptyl, and is optionally substituted with For example, Q, is H. unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, 65 For example, Q, is unsubstituted phenyl. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen For example, Q, is phenyl Substituted with one or more tyl, and n-hexyl, each of or which is optionally substituted groups, each of which can be the same or different, selected US 8,263,610 B2 95 96 from hydroxyl, halogen, nitro, cyano, unsubstituted or Sub For example, R, is naphthyl substituted with one, two, stituted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. three or more groups, each of which can be the same or n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each different, selected from hydroxyl, halogen, nitro, cyano, of which is optionally substituted with halogen (e.g., fluorine, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, chlorine, bromine, and iodine)), and unsubstituted or Substi n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen tuted C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-pro tyl, and n-hexyl, each of which is optionally substituted with pyloxy, butoxy, i-butoxy, t-butoxy, and ethylenedioxy, each halogen (e.g., fluorine, chlorine, bromine, and iodine)), of which is optionally substituted with halogen (e.g., fluorine, unsubstituted or Substituted C-C alkoxy (e.g., methoxy, chlorine, bromine, and iodine)). ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu For example, Q, is phenyl substituted with one or more 10 toxy, each of which is optionally substituted with halogen groups, each of which can be the same or different, selected (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) from halogen (e.g., fluorine, chlorine, bromine, and iodine), R —NHC(O)OR, —C(O)R and —C(O)CR, methyl, ethyl, -t-butyl, methoxy, ethoxy and t-butoxy. wherein Riis H, or unsubstituted or Substituted C-C alkyl For example, Q, is —C(O)NRRss' or —NRssRss'. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, R and Rare both H. tyl, n-pentyl, S-pentyl, and n-hexyl). 15 For example, R, is naphthyl substituted with one, two, For example, at least one of R and R is unsubstituted or three or more groups, each of which can be the same or Substituted, straight-chain or branched C-C alkyl, including different, selected from halogen (e.g., fluorine, chlorine, bro but not limited to, methyl, ethyl, n-propyl. i-propyl. n-butyl, mine, and iodine). S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl. For example, R, is heteroaryl selected from pyrrolyl, fura For example, at least one of R and R is unsubstituted or nyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tet substituted phenyl. razolyl, pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazinyl, For example, at least one of R and R is heteroaryl pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, benzodiox selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiaz azolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, olyl, imidazolyl, triazolyl, tetrazolyl pyrazolyl, oxazolyl, benzoimidazolyl, benzothienyl, methylenedioxyphenyl, isoxazolyl pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tri quinolinyl, isoquinolinyl, naphthrydinyl, indolyl, benzofura azinyl, benzoxazolyl, benzodioxazolyl, benzoxadiazolyl, 25 nyl, purinyl, deazapurinyl, indolizinyl, imidazothiazolyl, qui benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, ben noxalinyl, and pyrrolopyrimidinyl, and the like, and is option Zothienyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, ally Substituted with one, two, three or more groups, each of naphthrydinyl, indolyl, benzofuranyl, purinyl, deaZapurinyl, which can be the same or different, selected from hydroxyl, indolizinyl, imidazothiazolyl, quinoxalinyl, and pyrrolopyri halogen, nitro, cyano, unsubstituted or Substituted amino, midinyl, and the like, and is optionally Substituted. 30 unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, For example, at least one of R and Rs' is cyclopropyl. n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is tyl, and n-hexyl, each of which is optionally substituted with optionally substituted. halogen (e.g., fluorine, chlorine, bromine, and iodine)), For example, at least one of R and R is heterocycle unsubstituted or Substituted C-C alkoxy (e.g., methoxy, selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl. 35 toxy, each of which is optionally substituted with halogen piperidinyl, piperazinyl, morpholinyl, and pyrrolidinone, and (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) the like, and is optionally substituted. R —NHC(O)OR, —C(O)R and —C(O)CR, For example, R and R', together with the atom they wherein R is H. unsubstituted or Substituted C-C alkyl attach to, form a 5- or 6-member ring selected from pyrro (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu lidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazo 40 tyl, n-pentyl, S-pentyl, and n-hexyl), unsubstituted or Substi lidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl, tuted C-C aryl, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member ring and 1-4 heteroa and pyrrolidinone, and the like, and is optionally Substituted. toms selected from N, O and S. For example, R and R', together with the atom they For example, R. is imidazolyl pyrazolyl, oxazolyl, isox attach to, form a 5- or 6-member ring selected from morpholi azolyl, thiazolyl, isothiazolyl pyrimidinyl, triazinyl, quino nyl. 45 For example, R, is H. linyl, purinyl, thienyl, quinolinyl, benzoxadiazolyl, ben For example, R, is unsubstituted phenyl. Zothiazolyl, benzothiadiazolyl, benzothienyl, O For example, R, is phenyl substituted with one, two, three pyrrolopyrimidiyl, each of which is optionally substituted or more groups, each of which can be the same or different, with one, two, three or more groups, each of which can be the selected from hydroxyl, halogen, nitro, cyano, unsubstituted same or different, selected from selected from halogen (e.g., or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. 50 fluorine, chlorine, bromine, and iodine), amino, methyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and ethyl, t-butyl, trifluoromethyl, and —C(O)R, wherein n-hexyl, each of which is optionally substituted with halogen R is H. methyl, ethyl, t-butyl, or phenyl. (e.g., fluorine, chlorine, bromine, and iodine)), unsubstituted For example, R is cyclopropyl, cyclobutyl, cyclopentyl, or Substituted C-C alkoxy (e.g., methoxy, ethoxy, propy cyclohexyl, or cycloheptyi, and is optionally substituted with loxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, and ethylene 55 unsubstituted or substituted C-C alkyl (e.g., methyl, ethyl, dioxy, each of which is optionally substituted with halogen n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pen (e.g., fluorine, chlorine, bromine, and iodine)), —NHC(O) tyl, and n-hexyl, each of or which is optionally substituted R —NHC(O)OR, —C(O)R, and —C(O)OR, with halogen (e.g., fluorine, chlorine, bromine, and iodine)), wherein Riis H, or unsubstituted or substituted C-C alkyl unsubstituted or substituted C-C alkoxy (e.g., methoxy, (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, and t-bu tyl, n-pentyl, S-pentyl, and n-hexyl). 60 toxy, each of which is optionally substituted with halogen For example, R, is phenyl substituted with one, two, three (e.g., fluorine, chlorine, bromine, and iodine)). or more groups, each of which can be the same or different, For example, R, is heterocycle selected from pyrrolidinyl, selected from halogen (e.g., fluorine, chlorine, bromine, and imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, iodine), methyl, ethyl, t-butyl, trifluoromethyl, methoxy, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, ethoxy, trifluoromethoxy, cyano, and —NHC(O)R. 65 morpholinyl, and pyrrolidinone, and the like, and is option wherein R is H. methyl, ethyl, or t-butyl. ally Substituted with halogen (e.g., fluorine, chlorine, bro For example, R, is unsubstituted naphthyl. mine, and iodine)), unsubstituted or substituted C-C alkoxy US 8,263,610 B2 97 98 (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-bu tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro toxy, and t-butoxy, each of which is optionally substituted pyloxy, i-propyloxy, butoxy, i-butoxy, and t-butoxy, each of with halogen (e.g., fluorine, chlorine, bromine, and iodine)). which is optionally Substituted with halogen (e.g., fluorine, For example, R." is H. chlorine, bromine, and iodine)). For example, R." is unsubstituted or substituted, straight For example, Q,' is naphthyl substituted with one, two or chain or branched C-C alkyl, including but not limited to, more groups, each of which can be the same or different, methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, selected from methyl, ethyl, and halogen (e.g., fluorine, chlo n-pentyl, S-pentyl, and n-hexyl. rine, bromine, and iodine). For example, both R and Rare H. For example, Q,' is fluorenyl, and is optionally substi For example, at least one of Rs and Rs' is -T'-Q. 10 For example, T' is a bond. tuted. For example, T' is unsubstituted or substituted C-C, For example, Q, is dihydroindenyl, and is optionally sub alkyl linker, including but not limited to, methyl, ethyl, n-pro stituted. pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and For example, Q,' is heteroaryl selected from pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, n-hexyl linker. 15 For example, T' is a methyl ethyl, propyl, or t-butyl tetrazolyl pyrazolyl, oxazolyl, isoxazolyl pyridinyl, pyrazi linker. nyl, pyridazinyl, pyrimidinyl, triazinyl, benzoxazolyl, ben For example, Q,' is H. Zoisoxazolyl, benzodioxazolyl, benzoxadiazolyl, benzothia For example, Q,' is unsubstituted phenyl. Zolyl, benzothiadiazolyl, benzoimidazolyl, benzothienyl, For example, Q,' is phenyl substituted with one, two or methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthry more groups, each of which can be the same or different, dinyl, indolyl, benzofuranyl, purinyl, purinone, deazapurinyl, selected from hydroxyl, halogen, nitro, cyano, unsubstituted indolizinyl, imidazothiazolyl, dihydrobenzofuranyl, quinox or substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. alinyl, and pyrrolopyrimidinyl, and the like, and is optionally i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and Substituted with one, two or more groups, each of which can n-hexyl, each of which is optionally substituted with halogen 25 be the same or different, selected from hydroxyl, halogen, (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti unsubstituted or substituted amino, unsubstituted or substi tuted or Substituted C-C alkoxy (e.g., methoxy, ethoxy, pro tuted C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl. pyloxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, methylene n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and n-hexyl, each dioxy, and ethylenedioxy, each of which is optionally of which is optionally substituted with halogen (e.g., fluorine, Substituted with halogen (e.g., fluorine, chlorine, bromine, 30 chlorine, bromine, and iodine)), unsubstituted or substituted and iodine)), unsubstituted or Substituted phenyl, unsubsti C-C alkoxy (e.g., methoxy, ethoxy, propyloxy, i-propyloxy, tuted or substituted C-C aryloxy (e.g., phenoxy), butoxy, i-butoxy, and t-butoxy, each of which is optionally —NR.R., -C(O)R.R., S(O)2R, and Substituted with halogen (e.g., fluorine, chlorine, bromine, —NHC(O)R.R., wherein R. and R. are each and iodine)), unsubstituted or Substituted Co-Co aryloxy independently H, unsubstituted or substituted C-C alkyl 35 (e.g., phenoxy), and unsubstituted or Substituted phenyl. (e.g., methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-bu For example, Q,' is oxazolyl, isoxazolyl pyridinyl, pyri tyl, n-pentyl, S-pentyl, and n-hexyl) midinyl, triazinyl, thienyl, purinyl, purinone, quinolinyl, ben For example, Q,' is phenyl substituted with one, two or Zothienyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, more groups, each of which can be the same or different, benzothiazolyl, benzothiadiazolyl pyrrolopyrimidinyl, or selected from fluorine, chlorine, bromine, and iodine. 40 dihydrobenzofuranyl, each of which is substituted with one, For example, Q,' is phenyl substituted with one, two or two or more groups, each of which can be the same or differ more groups, each of which can be the same or different, ent, selected from halogen (e.g., fluorine, chlorine, bromine, selected from methyl, ethyl, t-butyl, and trifluoromethyl. and iodine), methyl, ethyl, amino, phenyl, and phenoxy. For example, Q,' is phenyl substituted with one, two or For example, Q,' is C(O)OR2, C(O)R2, C(O) more groups, each of which can be the same or different, 45 NRR", or —NRR". selected from methoxy, ethoxy, trifluoromethoxy, and ethyl For example, Q,' is —C(O)OR2. enedioxy. For example, R is H. For example, Q,' is phenyl substituted with one, two or For example, R is unsubstituted or Substituted C-C, more groups, each of which can be the same or different, alkyl, including but not limited to, methyl, ethyl, n-propyl. Selected from —NRR', -C(O)R.R.", 50 i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and —S(O).R., and —NHC(O)R.R., wherein at least n-hexyl. one of R and R. is methyl or ethyl. For example, R is methyl or ethyl. For example, Q,' is phenyl substituted with one, two or The present invention also provides Formula IVal, IVb1, more groups, each of which can be the same or different, IVc1, IVd1, IVe1, and IVf1. selected from fluorine, chlorine, bromine, iodine, methyl, 55 ethyl, t-butyl, trifluoromethyl, methoxy, ethoxy, trifluo romethoxy, phenyl, phenoxy, —NRR', -C(O)R- (IVal) R., -S(O)2R, and —NHC(O)R.R., wherein at least one of R and R. is methyl or ethyl. For example, Q,' is unsubstituted naphthyl. 60 For example, Q,' is naphthyl substituted with one, two or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or Substituted C-C alkyl (e.g., methyl, ethyl, n-propyl. i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl, and 65 n-hexyl, each of which is optionally substituted with halogen (e.g., fluorine, chlorine, bromine, and iodine)), and unsubsti

US 8,263,610 B2 109 TABLE 2-continued

Compound LCMS No. Structure IUPAC Name IM+ H 24 NO 3-(4-methoxybenzyl)-9-nitro- 387 6,7-dihydro-3H benzof pyrazolo 3,4- cisoquinohne

N KN % Y.

25 3-(4-methoxybenzyl)-3,6,7,8- 359

tetrahydro-9H-pyrazolo 4,3- a3,7phenanthrolin-9-one

As used herein, “alkyl”, “C, C, C, C, Cs or C alkyl or carbonylamino, arylcarbonylamino, carbamoyl and ureido), "C-C alkyl is intended to include C, C, C, C, Cs or C amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy straight chain (linear) saturated aliphatic hydrocarbon groups late, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfona 35 mido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky and C, C, Cs or C. branched saturated aliphatic hydrocar laryl, or an aromatic or heteroaromatic moiety. Cycloalkyls bon groups. For example, C-C alkyl is intended to include can be further substituted, e.g., with the substituents C1, C2, Cs, Ca, Cs and C alkyl groups. For example, C-C, described above. An “alkylaryl or an “aralkyl moiety is an alkyl is intended to include C. C. and C alkyl groups. alkyl Substituted with an aryl (e.g., phenylmethyl (benzyl)). Examples of alkyl include, moieties having from one to six 40 Unless the number of carbons is otherwise specified, carbonatoms, such as, but not limited to, methyl, ethyl, n-pro “lower alkyl includes an alkyl group, as defined above, hav pyl, i-propyl. n-butyl, S-butyl, t-butyl, n-pentyl, S-pentyl or ing from one to six, or in another embodiment from one to n-hexyl. four, carbonatoms in its backbone structure. “Lower alkenyl In certain embodiments, a straight chain or branched alkyl and “lower alkynyl have chain lengths of, for example, two has six or fewer carbon atoms (e.g., C-C for straight chain, 45 to six or of two to four carbon atoms. C-C for branched chain), and in another embodiment, a Alkenyl' includes unsaturated aliphatic groups analogous straight chain or branched alkyl has four or fewer carbon in length and possible substitution to the alkyls described atOmS. above, but that contain at least one double bond. For example, “Heteroalkyl groups are alkyl groups, as defined above, the term “alkenyl' includes straight chain alkenyl groups that have an oxygen, nitrogen, Sulfur or phosphorous atom 50 (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, replacing one or more hydrocarbon backbone carbon atoms. octenyl, nonenyl, decenyl), branched alkenyl groups, As used herein, the term "cycloalkyl”, “C, C, Cs, C, C, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, or Cs cycloalkyl or "C-C cycloalkyl is intended to include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), hydrocarbon rings having from three to eight carbon atoms in alkyl or alkenyl Substituted cycloalkenyl groups, and their ring structure. In one embodiment, a cycloalkyl group 55 cycloalkyl or cycloalkenyl Substituted alkenyl groups. In cer has five or six carbons in the ring structure. tain embodiments, a straight chain or branched alkenyl group The term “substituted alkyl refers to alkyl moieties having has six or fewer carbonatoms in its backbone (e.g., C-C for Substituents replacing one or more hydrogenatoms on one or straight chain, C-C for branched chain). Likewise, more carbons of the hydrocarbon backbone. Such substitu cycloalkenyl groups may have from five to eight carbon ents can include, for example, alkyl, alkenyl, alkynyl, halo 60 atoms in their ring structure, and in one embodiment, gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy cycloalkenyl groups have five or six carbons in the ring struc carbonyloxy, aryloxycarbonyloxy, carboxylate, ture. The term "C-C includes alkenyl groups containing alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbo two to six carbon atoms. The term "C-C includes alkenyl nyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio groups containing three to six carbon atoms. carbonyl, alkoxyl, phosphate, phosphonato, phosphinato, 65 “Heteroalkenyl' includes alkenyl groups, as defined amino (including alkylamino, dialkylamino, arylamino, dia herein, having an oxygen, nitrogen, Sulfur or phosphorous rylamino and alkylarylamino), acylamino (including alkyl atom replacing one or more hydrocarbon backbone carbons. US 8,263,610 B2 111 112 The term “substituted alkenyl refers to alkenyl moieties Examples of heteroaryl groups include pyrrole, furan, having Substituents replacing one or more hydrogenatoms on thiophene, thiazole, isothiazole, imidazole, triazole, tetra one or more hydrocarbon backbone carbonatoms. Such sub Zole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, stituents can include, for example, alkyl, alkenyl, alkynyl, pyridazine, pyrimidine, and the like. halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, Furthermore, the terms “aryl and "heteroaryl' include alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicy carbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, clic, e.g., naphthalene, benzoxazole, benzodioxazole, ben alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbo Zothiazole, benzoimidazole, benzothiophene, methylene nyl, alkoxyl, phosphate, phosphonato, phosphinato, amino dioxyphenyl, quinoline, isoquinoline, naphthridine, indole, (including alkylamino, dialkylamino, arylamino, diary 10 benzofuran, purine, benzofuran, deaZapurine, indolizine. In the case of multicyclic aromatic rings, only one of the lamino and alkylarylamino), acylamino (including alkylcar rings needs to be aromatic (e.g., 2,3-dihydroindole), although bonylamino, arylcarbonylamino, carbamoyl and ureido), all of the rings may be aromatic (e.g., quinoline). The second amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy ring can also be fused or bridged. late, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfona 15 The aryl or heteroaryl aromatic ring can be substituted at mido, nitro, trifluoromethyl, cyano, heterocyclyl alkylaryl, one or more ring positions with Such Substituents as described or an aromatic or heteroaromatic moiety. above, for example, alkyl, alkenyl, alkynyl, halogen, Alkynyl includes unsaturated aliphatic groups analogous hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, in length and possible substitution to the alkyls described alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl above, but which contain at least one triple bond. For carbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alk example, "alkynyl' includes straight chain alkynyl groups enylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcar (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, hepty bonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, nyl, octynyl, nonynyl, decynyl), branched alkynyl groups, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, and cycloalkyl or cycloalkenyl Substituted alkynyl groups. In amino (including alkylamino, dialkylamino, arylamino, dia certain embodiments, a straight chain or branched alkynyl 25 rylamino and alkylarylamino), acylamino (including alkyl group has six or fewer carbon atoms in its backbone (e.g., carbonylamino, arylcarbonylamino, carbamoyl and ureido), C-C for straight chain, C-C for branched chain). The term amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy "C-C includes alkynyl groups containing two to six carbon late, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfona atoms. The term "C-C includes alkynyl groups containing mido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky three to six carbon atoms. 30 laryl, or an aromatic or heteroaromatic moiety. Aryl groups “Heteroalkynyl' includes alkynyl groups, as defined can also be fused or bridged with alicyclic or heterocyclic herein, having an oxygen, nitrogen, Sulfur or phosphorous rings, which are not aromatic so as to form a multicyclic atom replacing one or more hydrocarbon backbone carbons. system (e.g., tetralin, methylenedioxyphenyl). The term “substituted alkynyl refers to alkynyl moieties As used herein, "carbocycle' or “carbocyclic ring is having Substituents replacing one or more hydrogenatoms on 35 intended to include any stable monocyclic, bicyclic or tricy one or more hydrocarbon backbone carbonatoms. Such sub clic ring having the specified number of carbons, any of which stituents can include, for example, alkyl, alkenyl, alkynyl, may be saturated, unsaturated, or aromatic. For example, a halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, C-C carbocycle is intended to include a monocyclic, bicy alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl clic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or carbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, 40 14 carbon atoms. Examples of carbocycles include, but are alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbo not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclo nyl, alkoxyl, phosphate, phosphonato, phosphinato, amino pentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cyclohep (including alkylamino, dialkylamino, arylamino, diary tyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, lamino and alkylarylamino), acylamino (including alkylcar cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, ada bonylamino, arylcarbonylamino, carbamoyl and ureido), 45 manty1 and tetrahydronaphthyl. Bridged rings are also amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy included in the definition of carbocycle, including, for late, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfona example, 3.3.0 bicyclooctane, 4.3.0cyclononane, 4.4.0 mido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky bicyclodecane and 2.2.2 bicyclooctane. A bridged ring laryl, or an aromatic or heteroaromatic moiety. occurs when one or more carbonatoms link two non-adjacent Aryl includes groups with aromaticity, including “con 50 carbonatoms. In one embodiment, bridge rings are one or two jugated, or multicyclic, systems with at least one aromatic carbon atoms. It is noted that a bridge always converts a ring. Examples include phenyl, benzyl, etc. monocyclic ring into a tricyclic ring. When a ring is bridged, “Heteroaryl groups are aryl groups, as defined above, the substituents recited for the ring may also be present on the having from one to four heteroatoms in the ring structure, and bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro may also be referred to as “arylheterocycles' or "heteroaro 55 rings are also included. matics’. As used herein, the term "heteroaryl is intended to As used herein, "heterocycle includes any ring structure include a stable 5-, 6-, or 7-membered monocyclic or 7-8- (saturated or partially unsaturated) which contains at least 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic one ring heteroatom (e.g., N, O or S). Examples of hetero ring which consists of carbon atoms and one or more heteroa cycles include, but are not limited to, morpholine, pyrroli toms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, 60 dine, tetrahydrothiophene, piperidine, piperazine and tet independently selected from the group consisting of nitrogen, rahydrofuran. oxygen and Sulfur. The nitrogen atom may be substituted or Examples of heterocyclic groups include, but are not lim unsubstituted (i.e., Nor NR wherein R is H or other substitu ited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl. ents, as defined). The nitrogen and Sulfur heteroatoms may benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzox optionally be oxidized (i.e., N->O and S(O), where p=1 or 65 azolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, ben 2). It is to be noted that total number of S and O atoms in the Zisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, aromatic heterocycle is not more than 1. 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnoli US 8,263,610 B2 113 114 nyl, decahydroquinolinyl, 2H,6H-1.5.2-dithiazinyl, dihydro carbonyl include, but are not limited to, aldehydes, ketones, furo2.3-btetrahydrofuran, furanyl, furazanyl, imidazolidi carboxylic acids, amides, esters, anhydrides, etc. nyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, Acyl' includes moieties that contain the acyl radical ( C indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isoben (O)—) or a carbonyl group. “Substituted acyl includes acyl Zofuranyl, isochromanyl, isolindazolyl, isoindolinyl, isoin 5 groups where one or more of the hydrogenatoms are replaced dolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenediox by, for example, alkyl groups, alkynyl groups, halogen, yphenyl, morpholinyl, naphthyridinyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbo octahydroisoquinolinyl, oxadiazolyl, 1.2.3-oxadiazolyl, 1.2, nyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1.3,4-oxadiazolyl, 1,2,4- arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylami oxadiazols(4H)-one, oxazolidinyl, oxazolyl, oxindolyl pyri 10 nocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, midinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (in phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, cluding alkylamino, dialkylamino, arylamino, diarylamino piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, pipero and alkylarylamino), acylamino (including alkylcarbony nyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, lamino, arylcarbonylamino, carbamoylandureido), amidino, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyri 15 imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, fates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl pyrrolyl, quinazolinyl, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tet aromatic or heteroaromatic moiety. rahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoli “Aroyl includes moieties with an aryl or heteroaromatic nyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1.2, moiety bound to a carbonyl group. Examples of aroyl groups 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, include phenylcarboxy, naphthyl carboxy, etc. thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoox “Alkoxyalkyl”, “alkylaminoalkyl and “thioalkoxyalkyl azolyl, thienoimidazolyl, thiophenyl, triazinyl, 1.2.3-triaz include alkyl groups, as described above, wherein oxygen, olyl, 1,2,4-triazolyl, 1.2.5-triazolyl, 1,3,4-triazolyl and Xan nitrogen or Sulfur atoms replace one or more hydrocarbon thenyl. 25 backbone carbon atoms. The term “substituted, as used herein, means that any one The term “alkoxy' or “alkoxyl includes substituted and or more hydrogen atoms on the designated atom is replaced unsubstituted alkyl, alkenyl and alkynyl groups covalently with a selection from the indicated groups, provided that the linked to an oxygen atom. Examples of alkoxy groups or designated atoms normal Valency is not exceeded, and that alkoxyl radicals include, but are not limited to, methoxy, the substitution results in a stable compound. When a sub 30 ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. stituent is keto (i.e., =O), then 2 hydrogenatoms on the atom Examples of Substituted alkoxy groups include halogenated are replaced. Keto substituents are not present on aromatic alkoxy groups. The alkoxy groups can be substituted with moieties. Ring double bonds, as used herein, are double groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcar bonds that are formed between two adjacent ring atoms (e.g., bonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycar C—C, C=N or N=N). “Stable compound” and “stable 35 bonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy structure' are meant to indicate a compound that is suffi carbonyl, aminocarbonyl, alkylaminocarbonyl, ciently robust to survive isolation to a useful degree of purity dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos from a reaction mixture, and formulation into an efficacious phate, phosphonato, phosphinato, amino (including alky therapeutic agent. lamino, dialkylamino, arylamino, diarylamino, and alkylary When a bond to a substituent is shown to cross a bond 40 lamino), acylamino (including alkylcarbonylamino, connecting two atoms in a ring, then such Substituent may be arylcarbonylamino, carbamoyl and ureido), amidino, imino, bonded to any atom in the ring. When a substituent is listed sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, without indicating the atom via which Such substituent is alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif bonded to the rest of the compound of a given formula, then luoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aro Such substituent may be bonded via any atom in Such formula. 45 matic or heteroaromatic moieties. Examples of halogen Sub Combinations of substituents and/or variables are permis stituted alkoxy groups include, but are not limited to, sible, but only if such combinations result in stable com fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlo pounds. romethoxy, dichloromethoxy and trichloromethoxy. When any variable (e.g., R) occurs more than one time in The term “ether' or “alkoxy' includes compounds or moi any constituent or formula for a compound, its definition at 50 eties which contain an oxygenbonded to two carbonatoms or each occurrence is independent of its definition at every other heteroatoms. For example, the term includes “alkoxyalkyl, occurrence. Thus, for example, if a group is shown to be which refers to an alkyl, alkenyl, or alkynyl group covalently Substituted with 0-2 R moieties, then the group may option bonded to an oxygen atom which is covalently bonded to an ally be substituted with up to two R moieties and R at each alkyl group. occurrence is selected independently from the definition of 55 The term “ester includes compounds or moieties which R. Also, combinations of substituents and/or variables are contain a carbon or a heteroatom bound to an oxygen atom permissible, but only if such combinations result in stable which is bonded to the carbon of a carbonyl group. The term compounds. 'ester” includes alkoxycarboxy groups such as methoxycar The term “hydroxy' or “hydroxyl includes groups with an bonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, - OH or - OT. 60 pentoxycarbonyl, etc. As used herein, “halo' or “halogen refers to fluoro, The term “thioalkyl includes compounds or moieties chloro, bromo and iodo. The term “perhalogenated' gener which contain an alkyl group connected with a Sulfur atom. ally refers to a moiety wherein all hydrogen atoms are The thioalkyl groups can be substituted with groups such as replaced by halogen atoms. alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, The term "carbonyl' or “carboxy” includes compounds 65 arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, and moieties which contain a carbon connected with a double carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, bond to an oxygen atom. Examples of moieties containing a alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, US 8,263,610 B2 115 116 dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino N-oxide derivative (which can be designated as N->O or (including alkylamino, dialkylamino, arylamino, diary N" O). Furthermore, in other instances, the nitrogens in lamino and alkylarylamino), acylamino (including alkylcar the compounds of the present invention can be converted to bonylamino, arylcarbonylamino, carbamoyl and ureido), N-hydroxy or N-alkoxy compounds. For example, N-hy amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy droxy compounds can be prepared by oxidation of the parent late, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfona amine by an oxidizing agent such as m-CPBA. All shown and mido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky claimed nitrogen-containing compounds are also considered, laryl, or an aromatic or heteroaromatic moieties. when allowed by valency and structure, to cover both the The term “thiocarbonyl or “thiocarboxy' includes com compound as shown and its N-hydroxy (i.e., N—OH) and pounds and moieties which contain a carbon connected with 10 a double bond to a sulfur atom. N-alkoxy (i.e., N—OR, wherein R is substituted or unsubsti The term “thioether' includes moieties which contain a tuted C-C alkyl, C-C alkenyl, C-C alkynyl, 3-14-mem Sulfur atom bonded to two carbon atoms or heteroatoms. bered carbocycle or 3-14-membered heterocycle) derivatives. Examples of thioethers include, but are not limited to alkthio In the present specification, the structural formula of the alkyls, alkthioalkenyls and alkthioalkynyls. The term “alk 15 compound represents a certain isomer for convenience in thioalkyls' include moieties with an alkyl, alkenyl or alkynyl Some cases, but the present invention includes all isomers, group bonded to a sulfur atom which is bonded to an alkyl Such as geometrical isomers, optical isomers based on an group. Similarly, the term “alkthioalkenyls' refers to moi asymmetrical carbon, Stereoisomers, tautomers, and the like. eties wherein an alkyl, alkenyl or alkynyl group is bonded to In addition, a crystal polymorphism may be present for the a Sulfur atom which is covalently bonded to an alkenyl group; compounds represented by the formula. It is noted that any and alkthioalkynyls' refers to moieties wherein an alkyl, crystal form, crystal form mixture, or anhydride or hydrate alkenyl or alkynyl group is bonded to a Sulfur atom which is thereof is included in the scope of the present invention. covalently bonded to an alkynyl group. Furthermore, so-called metabolite which is produced by deg As used herein, “amine' or "amino” includes moieties radation of the present compound in vivo is included in the where a nitrogen atom is covalently bonded to at least one 25 Scope of the present invention. carbon or heteroatom. Alkylamino' includes groups of com “Isomerism” means compounds that have identical pounds wherein nitrogen is bound to at least one alkyl group. molecular formulae but differ in the sequence of bonding of Examples of alkylamino groups include benzylamino, their atoms or in the arrangement of their atoms in space. methylamino, ethylamino, phenethylamino, etc. “Dialky Isomers that differ in the arrangement of their atoms in space lamino' includes groups wherein the nitrogen atom is bound 30 to at least two additional alkyl groups. Examples of dialky are termed “stereoisomers'. Stereoisomers that are not mirror lamino groups include, but are not limited to, dimethylamino images of one another are termed "diastereoisomers', and and diethylamino Arylamino” and “diarylamino' include Stereoisomers that are non-Superimposable mirror images of groups wherein the nitrogen is bound to at least one or two each other are termed “enantiomers' or sometimes optical aryl groups, respectively. “alkylarylamino', 'alkylami 35 isomers. A mixture containing equal amounts of individual noaryl' or “arylaminoalkyl refers to an amino group which enantiomeric forms of opposite chirality is termed a “racemic is bound to at least one alkyl group and at least one aryl group. mixture'. Alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group A carbonatom bonded to four nonidentical substituents is bound to a nitrogen atom which is also bound to an alkyl termed a "chiral center'. group. Acylamino' includes groups wherein nitrogen is 40 “Chiral isomer means a compound with at least one chiral bound to an acyl group. Examples of acylamino include, but center. Compounds with more than one chiral center may are not limited to, alkylcarbonylamino, arylcarbonylamino, exist either as an individual diastereomer or as a mixture of carbamoyl and ureido groups. diastereomers, termed "diastereomeric mixture'. When one The term "amide' or "aminocarboxy” includes compounds chiral center is present, a stereoisomer may be characterized or moieties that contain a nitrogen atom that is bound to the 45 by the absolute configuration (R or S) of that chiral center. carbon of a carbonyl or a thiocarbonyl group. The term Absolute configuration refers to the arrangement in space of includes "alkaminocarboxy' groups that include alkyl, alk the substituents attached to the chiral center. The substituents enyl or alkynyl groups bound to an amino group which is attached to the chiral center under consideration are ranked in bound to the carbon of a carbonyl or thiocarbonyl group. It accordance with the Sequence Rule of Cahn, Ingold and also includes “arylaminocarboxy groups that include aryl or 50 Prelog. (Cahn et al., Angew. Chem. Inter: Edit. 1966, 5,385; heteroaryl moieties bound to an amino group that is bound to errata 511; Cahn et al., Angew. Chem. 1966, 78, 413: Cahn the carbon of a carbonyl or thiocarbonyl group. The terms and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., “alkylaminocarboxy”, “alkenylaminocarboxy”, “alkyny Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, laminocarboxy” and “arylaminocarboxy” include moieties 116). wherein alkyl, alkenyl, alkynyl and aryl moieties, respec 55 “Geometric isomer means the diastereomers that owe tively, are bound to a nitrogen atom which is in turn bound to their existence to hindered rotation about double bonds. the carbon of a carbonyl group. Amides can be substituted These configurations are differentiated in their names by the with Substituents such as Straight chain alkyl, branched alkyl, prefixes cis and trans, or Z and E, which indicate that the cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on groups are on the same or opposite side of the double bond in amide groups may be further Substituted. 60 the molecule according to the Cahn-Ingold-Prelog rules. Compounds of the present invention that contain nitrogens Furthermore, the structures and other compounds dis can be converted to N-oxides by treatment with an oxidizing cussed in this invention include all atropic isomers thereof agent (e.g., 3-chloroperoxybenzoic acid (m-CPBA) and/or Atropic isomers' are a type of stereoisomer in which the hydrogen peroxides) to afford other compounds of the present atoms of two isomers are arranged differently in space. Atro invention. Thus, all shown and claimed nitrogen-containing 65 pic isomers owe their existence to a restricted rotation caused compounds are considered, when allowed by Valency and by hindrance of rotation of large groups about a central bond. structure, to include both the compound as shown and its Such atropic isomers typically exist as a mixture, however as US 8,263,610 B2 117 118 a result of recent advances in chromatography techniques, it compound that is similar or comparable in function and has been possible to separate mixtures of two atropic isomers appearance, but not in structure or origin to the reference in select cases. compound. "Tautomer' is one of two or more structural isomers that As defined herein, the term "derivative' refers to com exist in equilibrium and is readily converted from one iso 5 pounds that have a common core structure, and are substituted meric form to another. This conversion results in the formal with various groups as described herein. For example, all of migration of a hydrogen atom accompanied by a Switch of the compounds represented by Formula I are 5,6-dihydro-6- adjacent conjugated double bonds. Tautomers exist as a mix phenylbenzofisoquinolin-2-amine derivatives, and have ture of a tautomeric set in solution. In solid form, usually one Formula I as a common core. tautomer predominates. In solutions where tautomerization is 10 The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, possible, a chemical equilibrium of the tautomers will be broadly similar, atom or group of atoms. The objective of a reached. The exact ratio of the tautomers depends on several bioisosteric replacement is to create a new compound with factors, including temperature, solvent and pH. The concept similar biological properties to the parent compound. The of tautomers that are interconvertable by tautomerizations is 15 bioisosteric replacement may be physicochemically or topo called tautomerism. logically based. Examples of carboxylic acid bioisosteres Of the various types of tautomerism that are possible, two include, but are not limited to, acyl Sulfonimides, tetrazoles, are commonly observed. In keto-enol tautomerism a simul Sulfonates and phosphonates. See, e.g., Patani and LaVoie, taneous shift of electrons and a hydrogen atom occurs. Ring Chem. Rev. 96, 3147-3176, 1996. chain tautomerism arises as a result of the aldehyde group The present invention is intended to include all isotopes of (—CHO) in a Sugar chain molecule reacting with one of the atoms occurring in the present compounds. Isotopes include hydroxy groups (-OH) in the same molecule to give it a those atoms having the same atomic number but different cyclic (ring-shaped) form as exhibited by glucose. mass numbers. By way of general example and without limi Common tautomeric pairs are: ketone-enol, amide-nitrile, tation, isotopes of hydrogen include tritium and deuterium, lactam-lactim, amide-imidic acid tautomerism in heterocy 25 and isotopes of carbon include C-13 and C-14. clic rings (e.g., in nucleobases such as guanine, thymine and It is understood that in the chemical structures or formulae cytosine), amine-enamine and enamine-enamine shown in the specification hydrogen atoms are assumed to be It is to be understood that the compounds of the present bonded to atoms (e.g., C, N, O, and S) to complete their invention may be depicted as different tautomers. It should Valency. also be understood that when compounds have tautomeric 30 forms, all tautomeric forms are intended to be included in the 2. Synthesis of Substituted scope of the present invention, and the naming of the com Imidazolyl-5,6-Dihydrobenzon Isoquinoline pounds does not exclude any tautomer form. Compounds The term “crystal polymorphs”, “polymorphs' or “crystal forms' means crystal structures in which a compound (or a 35 The present invention provides methods for the synthesis salt or solvate thereof) can crystallize in different crystal of the compounds of Formula I-IV. The present invention also packing arrangements, all of which have the same elemental provides detailed methods for the synthesis of various dis composition. Different crystal forms usually have different closed compounds of the present invention according to the X-ray diffraction patterns, infrared spectral, melting points, following schemes as shown in the Examples. density hardness, crystal shape, optical and electrical proper 40 Throughout the description, where compositions are ties, stability and solubility. Recrystallization solvent, rate of described as having, including, or comprising specific com crystallization, storage temperature, and other factors may ponents, it is contemplated that compositions also consist cause one crystal form to dominate. Crystal polymorphs of essentially of or consist of the recited components. Simi the compounds can be prepared by crystallization under dif larly, where methods or processes are described as having, ferent conditions. 45 including, or comprising specific process steps, the processes Additionally, the compounds of the present invention, for also consistessentially of, or consist of the recited processing example, the salts of the compounds, can exist in either steps. Further, it should be understood that the order of steps hydrated or unhydrated (the anhydrous) form or as solvates or order for performing certain actions is immaterial so long with other solvent molecules. Nonlimiting examples of as the invention remains operable. Moreover, two or more hydrates include monohydrates, dihydrates, etc. Nonlimiting 50 steps or actions can be conducted simultaneously. examples of Solvates include ethanol Solvates, acetone sol The synthetic processes of the invention can tolerate a wide Vates, etc. variety of functional groups, therefore various substituted “Solvate” means solvent addition forms that contain either starting materials can be used. The processes generally pro Stoichiometric or non Stoichiometric amounts of solvent. vide the desired final compound at or near the end of the Some compounds have a tendency to trap a fixed molar ratio 55 overall process, although it may be desirable in certain of solvent molecules in the crystalline solid state, thus form instances to further convert the compound to a pharmaceuti ing a solvate. If the solvent is water the solvate formed is a cally acceptable salt, ester or prodrug thereof hydrate; and if the solvent is alcohol, the solvate formed is an Compounds of the present invention can be prepared in a alcoholate. Hydrates are formed by the combination of one or variety of ways using commercially available starting mate more molecules of water with one molecule of the substance 60 rials, compounds known in the literature, or from readily in which the water retains its molecular state as H.O. prepared intermediates, by employing standard synthetic As used herein, the term “analog refers to a chemical methods and procedures either known to those skilled in the compound that is structurally similar to another but differs art, or which will be apparent to the skilled artisan in light of slightly in composition (as in the replacement of one atom by the teachings herein. Standard synthetic methods and proce an atom of a different element or in the presence of a particu 65 dures for the preparation of organic molecules and functional lar functional group, or the replacement of one functional group transformations and manipulations can be obtained group by another functional group). Thus, an analog is a from the relevant scientific literature or from standard text US 8,263,610 B2 119 120 books in the field. Although not limited to any one or several -continued sources, classic texts such as Smith, M.B., March, J., March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5' edition, John Wiley & Sons: New York, 2001; N-N and Greene, T. W. Wuts, P. G. M., Protective Groups in Organic Synthesis, 3" edition, John Wiley & Sons: NewYork, CFCOOH 1999, incorporated by reference herein, are useful and recog --- nized reference textbooks of organic synthesis known to those in the art. The following description of synthetic meth ods are designed to illustrate, but not to limit, general proce 10 dures for the preparation of compounds of the present inven tion. Compounds of the present invention can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this invention with Formula I-IV may be prepared according to the following procedures from 15 N-NH commercially available starting materials or starting materi als which can be prepared using literature procedures. These procedures show the preparation of representative com pounds of this invention. The compounds of this invention with Formula I-IV may be also be prepared according to the following schemes from commercially available starting materials or starting materi als, which can be prepared using literature procedures. Compounds of formula (I) can be conveniently prepared by 25 a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Ketone compounds such as formula (II) are either available commercially, can be prepared by known methods or readily prepared by methods described in the literature and known to Scheme 1 30 those skilled in art as shown in Scheme 2. The ketone (II) is O treated with DMFacetal at 100° C. for a period of 12-24 hours to give the enaminone (III). Alternatively reagents such as Brederick's reagent and hexamethylmethanetraiamine can N DMF-DMA R-i- Her also be used to prepare the enaminone (III). The enaminone 35 (III) is heated thermally or in a microwave with p-methoxy 21 X R benzyl protected amino pyrazole (IV) in the presence of acids II Such as trifluoroacetic acid or acetic acid in range between 100° C. to 150° C. to give the PMB protected pyrazolopyri W N dine compounds with formula (V). The p-methoxybenzyl HN N protecting group can be removed by heating intrifluoroacetic acid at 100° C. for a period of 12-24 hours to give the com O pounds with formula (I). Alternatively conditions outlined in N Protective Groups in Organic Synthesis, Third Edition, The N 21 N1 O 45 odora W. Greene and Peter M. Wuts, Wiley Interscience, 1999 R-t IV can be used to remove the p-methoxybenzyl protecting group. 4n. R CFCOOH Some ketones (II) used as shown in the scheme 1 to make the compounds with formula (I) can be prepared as shown in scheme 2. US 8,263,610 B2 121 122 -continued

N 1. NH O O O O R. ul n DMF-DMA Ns NH2 N --- NaOAc, DMF S -R7

VI VII IX

R1 N NH2

VIII

Cyclohexane-1,3-dione (VI) can be treated with DMF These ketones (VIII-XI) can then be converted to compounds acetal to give the enamonine (VII). The enaminone (VII) can 35 with the formula (I) as shown in Scheme 1. Many guanidines, be treated with guanidines Such as methylguanidine to give hydrazines, thioamides are commercially available or readily the ketone (VIII). Alternatively, the enaminone (VII) can be prepared by methods described in the literature (Comprehen treated with thiomethyl amidine to give the ketone (IX). sive Organic Transformations, Richard C. Larock, Second Alternatively, the enaminone (VII) can be treated with hydra Edition, Wiley-VCH, 1999) and known to those skilled in art. Zine to give the ketone (X). Alternatively, the enaminone 40 The compounds of formula (XII-XIV) can be prepared as (VII) can be treated with thioamide to give the ketone (XI). shown in Scheme 3.

Scheme 3 NH2 N Pg N. O O N OS N "SaBMX. 1N4N1 O IV 4N-r N N N s N

Pg

XV XVI NBS No XVII CFCOOH CHCl2 US 8,263,610 B2 123 124 -continued Pg NN Br HN HN Br \ 21 21 N CFCOOH S. M N N S. N N CH.Cl, N N

O NO XII XIV

The ketone (XV) where Pg is protecting group Such as -continued tert-butyl carbamate (t-BOC) or benzyloxycarbamate (CBZ) O NH and mand n can be 1-2 is heated with DMF acetal in DMF at 100° C. for a period of 24–48 hours to give the enaminone (XVI). The enaminone (XVI) is heated with p-methoxyben Zyl protected amino pyrazole (IV) at 100° C. for a period of 25 No NS 10-24 hours to give PMB protected pyrazolopyridine (XVII). AcOH The tert-butyl carbamate (t-BOC) protecting group is removed using trifluoroacetic acid at ambient temperature for n Pg a period of 2-12 hours to give the amine with the formula 30 (XII). The tert-butyl carbamate (t-BOC) protecting group can XX also be removed by using the conditions outlined in Protective Groups in Organic Synthesis. Third Edition, Theodora W. Greene and Peter M. Wuts, Wiley Interscience, 1999. The n-t-BOC protected pyrazolopyridine (XVII) can also be 35 HN bominated using N-bromosuccinimide (NBS) in solvents Such as dichloromethane at ambient temperatures for a period of 2-12 hours or other conditions outlined in Comprehensive 21 N N (BOC)2O, THF Organic Transformations, Richard C. Larock, Second Edi He 40 Sa M tion, Wiley-VCH, 1999 to give the 3-bromo-pyrazolopyri N N dine (XIII). The tert-butyl carbamate (t-BOC) protecting group in the compound (XIII) is removed using acidic con ditions such as trifluoroacetic acid at ambient temperatures for a period of 2-12 hours to give the amine with the formula (XIV). The tert-butyl carbamate (t-BOC) protecting group 45 can also be removed by using the conditions outlined in Noy Protective Groups in Organic Synthesis, Third Edition, The XVIII odora W. Greene and Peter M. Wuts, Wiley Interscience, 1999. 50 The compounds of formula (XVIII) can be prepared as shown in Scheme 4. P.1 55 Scheme 4 21 CF3COOH, CHCl2 O He Sa Y. N N DMF-DMA Her 60

HN n Pg Noy 65 XIX XXI US 8,263,610 B2 125 126 -continued -continued HN O 21 5 Ol N s oN C 21 N. CFCOOH S. N Y". N N 10

No XVIII 15 No The aminoketone (XIX) where Pg is protecting group Such XXIV as tert-butyl carbamate (t-BOC) or benzyloxycarbamate (CBZ) is heated with DMF acetal to give the enaminone O (XX). The enaminone (XX) is heated with p-methoxybenzyl protected amino pyrazole (IV) in acids Such as acetic acid at N 100° C. for a period of 24-48 hours to give PMB protected C pyrazolopyridine (XVIII). Alternatively, trifluoroacetic acid 21 N NBS, CH2Cl2 can be used at 100° C. for a period of 10-24 hours to give the N -ss PMB protected pyrazolopyridine (XVIII). During the reac 25 N N^ tion the tert-butyl carbamate (t-BOC) was removed. The N H amine (XVIII) was treated with t-BOC anhydride at ambient temperature for a period of 2-10 hours to protect the amine XXV with tert-butyl carbamate (t-BOC) to aid with the purification of the compound (XXI). The tert-butyl carbamate (t-BOC) 30 protecting group from the compound (XXI) is removed using N trifluoroacetic acid at ambient temperatures for a period of Br 2-10 hours to give the amine (XVIII). The tert-butyl carbam OlC ate (t-BOC) protecting group can also be removed by using 21 N the conditions outlined in Protective Groups in Organic Syn N thesis, Third Edition, Theodora W. Greene and Peter M. Wuts, 35 N \ Wiley Interscience, 1999. N H The C-chloroamides of pyrazolopyridines (XXII) can be XXII prepared as shown in schemes 5 and 6. The PMB protected pyrazolo pyridine amine (XII) is reacted with a-chloroacyl Alternatively the 3-phenyl C-chloroamide of pyrazolopy chloride (XXIII) in the presence of tertiary amines bases such 40 as triethylamine, diisopropylethyl amine in chlorinated Sol ridine (XXVI) is prepared as shown in scheme 6. The PMB vents such as dichloromethane at ambient temperatures for protected pyrazolo pyridine (XII) is first deprotected by heat 1-4 hours. The PMB protecting group of the resulting C-chlo ing intrifluoroacetic acid at 65°C. for a period of 16-24 hours. roamide (XXIV) is then removed by heating intrifluoroacetic The piperidine nitrogen of the resulting pyrazolopyridine acid at 100° C. for 16-24 hours to give the compounds with 45 amine is protected with tert-butyl carbamate (t-BOC) using formula (XXV). The O.-chloroamides pyrazolopyridine N-t-Boc anhydride, tertiary amine sbases such as triethy (XXV) is then bominated in the 3 position using N-bromo lamine, Hunig's Base at ambient temperature for period of succinimide (NBS) in chlorinated solvents such as dichlo 2-6 hours to give the tert-butyl carbamate of the pyrazolo romethane under ambient temperatures for 1-6 hours to give pyridine amine (XXVII). The t-BOC protected pyrazole pyri the 3-bromo-O-chloroamides pyrazolopyridine (XXII). 50 dine (XXVII) is brominated on the 3-position using N-bro mosuccinimide (NBS) in chlorinated solvents such as dichlo romethane under ambient temperatures for 1-6 hours to give Scheme 5 the t-BOC protected 3-bromo-pyrazolopyridine amine (XX HN O VIII). Suzuki coupling reactions are carried out at 90° C. for 55 a period of 16-24 hours using boronic acids such as phenyl boronic acid in the presence palladium coupling agents such 21 C as dichloro-((bis diphenylphosphino) ferrocenyl)palladium (II), aqueous bases Such as Sodium carbonate and in solvents N Y. C N N Such as toluene, and protic solvents such as ethanol to give the XXIII 60 He compounds with formula (XXIX). The t-BOC group on the Et3N, CHCl2 compounds with formula (XXIX) is then removed under acidic condition Such as HCl(g) in dioxane in Solvents such as dichloromethane, ethyl acetate, 1,4-dioxane at ambient tem peratures for a period of 2-24 hours to give the HCl salt of 65 3-phenyl pyrazolo pyridine amine (XXX). The 3-phenyl XII pyrazolo pyridine amine is reacted with C-chloroacyl chlo ride (XXIII) in the presence of tertiary amines bases such as US 8,263,610 B2 127 128 triethylamine, diisopropylethylamine in chlorinated solvents -continued Such as dichloromethane at ambient temperatures for 1-2 hours to give the desired C-chloroamide of 3-phenyl pyrazol O opyridine (XXVI). N

C Scheme 6 21 N

HN S. N 10 N1 N 21 N (i) CFCOOH XXVI N He N M (ii) (BOC)2O, Et3N, CH2Cl2 N N 15

No Scheme 7 and 8 illustrates a variety of chemical transfor mation of pyrazolopyridine amine (XII, XIII, XVIII) to pro XII vide compounds (XXXIa,b-XXXVIIa,b, XXXVIII XXXXIII). The following methods are provided by way of > O exemplification. Alternative methods may be employed and 1. 25 are described in reference texts such as Comprehensive 21 \ NBS, CHCl2 Organic Transformations, Richard C. Larock, Second Edi He tion, Wiley-VCH, 1999; Protective Groups in Organic Syn N N? N H thesis, Third Edition, Theodora W. Greene and Peter M. Wuts, 30 Wiley Interscience, 1999: The Practice of Peptide Synthesis, XXVII M. Bodanszky and A. Bodanzsky, Springer-Verlag, 1984. The pyrazolopyridine amides (XXXIa, b, XXXVIII) can > ul be conveniently prepared by treating pyrazolopyridine amine O N DtBPFPdCl2. 35 PhB(OH) (XII, XIII, XVIII) with the corresponding carboxylic acid in 21 HeToluene, presence of amide coupling agents such as HBTU (O-(ben N EtOH, Aq. Zotriazo-1-yl)-N.N.N',N'-tetramethyluronium hexafluoro N N^ Na2CO3 phosphate), tertiary amine bases such as dimethylaminopyri N H 40 dine and solvents such as dimethylformamide at ambient XXVIII temperature for 4-24 hours followed by the removal of the PMB protecting group by heating the intermediate in trifluo roacetic acid at 65° C. for a period of 12-24 hours. Alterna 45 tively amide coupling agents such as DCC (dicyclohexycar bodiimide), BOP ((benzotriazo-1-yloxy)tris(dimethylamino) > O l N HCl (g) in phosphonium hexafluorophosphate, EDCI.HCl (1-(3-Dim Dioxane -> ethyl aminopropyl)-3-ethylcarbodiimide hydrochloride), 21 N CHCl2 DMC (2-chloro-1,3-dimethylimidazolinium chloride) and N Sa N^ tertiary amines bases such as triethylamine, diisopropylethyl N H amine can also be used. Many carboxylic acids are commer XXIX cially available or readily prepared by methods described in the literature and known to those skilled in art. 55 Alternatively, the pyrazolopyridine amides (XXXIa, b, O XXXVIII) can be conveniently prepared by treating pyrazol opyridine amine (XII, XIII, XVIII) with acid chlorides such G G as m-trifluoromethylbenzoyl chloride in presence of tertiary CI HN C 60 amine bases such as triethylamine, diisopropylethyl amine 21 N C and solvents such as dichloromethane at ambient temperature N XXIII for 1-12 hours followed by the removal of the PMB protecting N N^ Hunig's Base, CH2Cl2 group by heating the intermediate in trifluoroacetic acid at N H 65 65° C. for a period of 12-24 hours. Many acid chlorides are XXX commercially available or readily prepared by methods described in the literature and known to those skilled in art.

US 8,263,610 B2 131 132

Scheme 8 R 15n1 R 151 N O N 4. Y.N 4. Y.N XXXXIII XXXVIII (i) RsCOOH (ii)(i) BigCFCOOH (ii) sy

H. H. HN H -Na-N R9 n-N Rir N (i) RoSOCl, iv. O (i) RNCO W EtN O O N-V N (ii) CFCOOH 2NN N (ii) CFCOOH N-V N Nra N N OCH Nra N W XXXX XVIII C XXXIX

sh| Rio lsa (i) R2NCS (ii) RICOCI (i) DMSO, Heat (ii) CFCOOH (ii) CFCOOH R1 r R 1 N. N S O N 1. N N R10 N 4. NH 4. NH % NH XXXXII XXXVIII XXXXI

Pyrazolo-pyridine sulfonamide (XXXIIa, b, XXXIX) can 40 ureas (XXXIIIa, b) as described above. Alternatively, the be conveniently prepared by treating pyrazolopyridine amine pyrazolopyridine amine (XII, XIII) can be converted to pyra (XII, XIII, XVIII) with sulfonyl chlorides such as methane Zolopyridine amine carbamoyl chloride (XXXIVa, b) which Sulfonyl chloride in presence of tertiary amine bases such as can then be reacted with amines followed by the removal of the PMB protecting group by heating the intermediate in triethylamine and solvents such as dichloromethane at ambi 45 trifluoroacetic acid at 65° C. for a period of 12-24 hours to ent temperature for 1-12 hours followed by the removal of the give pyrazolo-pyridine ureas (XXXIIIa, b). PMB protecting group by heating the intermediate in trifluo Pyrazolopyridine amine heterocycle (XXXVa, b, XXXXI) roacetic acid at 65° C. for a period of 12-24 hours. Alterna can be conveniently prepared by treating pyrazolopyridine tively tertiary amines bases such as diisopropylethyl amine amine (XII, XIII, XVIII) with heterocyclic halides such as can also be used. Many Sulfonyl chlorides are commercially 50 2-chloropyrazine, tertiary amine bases such as triethylamine, available or readily prepared by methods described in the diisopropylethylamies in polar aprotic solvent such as dim literature and known to those skilled in art. ethylsulfoxide, dimethylformamide at 80-110° C. for 1-12 Pyrazolopyridine urea (XXXIIIa, b, XXXX) can be con hours followed by the removal of the PMB protecting group Veniently prepared by treating pyrazolopyridine amine (XII, by heating the intermediate intrifluoroacetic acid at 65° C. for XIII, XVIII) with isocyanates such as phenylisocyanate in 55 a period of 12-24 hours. Many heterocyclic halides are com Solvents such as dichloromethane at ambient temperature for mercially available or readily prepared by methods described 1-12 hours followed by the removal of the PMB protecting in the literature and known to those skilled in art. group by heating the intermediate in trifluoroacetic acid at Pyrazolopyridine thiourea (XXXVIa, b, XXXXII) can be 65° C. for a period of 12-24 hours. Many isocyanates are conveniently prepared by treating pyrazolopyridine amine commercially available or readily prepared by methods 60 (XII, XIII, XVIII) with thioisocyanates such as phenylthio described in the literature and known to those skilled in art. isocyanate in solvents such as dichloromethane at ambient Isocyantes can also be prepared in situ from carboxylic acids temperature for 1-12 hours followed by the removal of the by a variety of methods familiar to those skilled in the art. PMB protecting group by heating the intermediate in trifluo Carboxylic acids are treated with diphenyl phosphoryl azide roacetic acid at 65° C. for a period of 12-24 hours. Many in solvents such as toluene at reflux for 1-5 hours. The isocy 65 isocyanates are commercially available or readily prepared anates are used in situ as solution to react with the pyrazol by methods described in the literature and known to those opyridine amine (XII, XIII) to prepare pyrazolo-pyridine skilled in art. US 8,263,610 B2 133 134 The compounds of the formula (XXXVIIa, b, XXXXIII) -continued can be conveniently prepared by treating pyrazolopyridine Ar-NH 21 amine (XII, XIII, XVIII) with aldehydes such as benzalde hyde and reducing agents such sodium triacetoxyborohydride or tetramethylammoniumborohydride in solvents such as Sull N dichloromethane at ambient temperature for 1-12 hours fol lowed by the removal of the PMB protecting group by heating N the intermediate intrifluoroacetic acid at 65° C. for a period of 12-24 hours. Many aldehydes are commercially available or 2 Y. readily prepared by methods described in the literature and 10 N N known to those skilled in art. XXXXIV Pyrazolopyridine urea amides of formula (XXXXIV) formed using anilines or heterocyclic amines can be prepared as shown in Scheme 9. PMB protected pyrazolo pyridine urea ester (XXXXV) can 15 be prepared by treating pyrazolopyridine (XII) with isocyan ates with carboxylic esters in solvents such as dichlo Scheme 9 romethane at ambient temperature for 1-12 hours. Many iso cyanates with carboxylic esters are commercially available or HN readily prepared by methods described in the literature and known to those skilled in art. The ester group on the PMB 21 21 protected pyrazolopyridine urea ester (XXXXV) is converted EtOOC-H to carboxylic compound (XXXXVI) by hydrolysis using N NY. Sodium hydroxide, water and protic solvent like methanol, NCO ethanol at ambient temperatures for a period of 12-24 hours. CHCl2 25 The PMB protected pyrazolopyridine urea acid (XXXXVI) is then converted to pyrozolopyridine urea amides (XXXXIV) by reacting with coupling agent DMC (2-chloro-1,3-dimeth ylimidazolinium chloride) and amines like anilines, hetero No 30 cyclic amines in solvents such as dichloromethane at ambient XII temperatures for a period of 12-24 hours followed by the removal of the PMB protecting group by heating the interme diate in trifluoroacetic acid at 65° C. for a period of 12-24 hours. Many anilines and heterocyclic amines are commer 35 cially available or readily prepared by methods described in EtOOC-H the literature and known to those skilled in art. CluNulls, Alternatively, the pyrazolopyridine urea amide (XXXX H VII) of primary or secondary amines, which are more reactive NaOH, than anilines, can be prepared as shown in Scheme 10. N-V H2O, 40 MeOH -e- N N Scheme 10

HN 45 21 \ (i) CFCOOH No s NM (ii) OCN N XXXXV --COOEt 50 21 Hunig's Base, CH2Cl2, DMA HOOC-H No (i) DMC, CH2Cl2. 55 CluS-s-s DMA XII Ar-NH2 21 O N Hunig's Base -e- EtOOC-H ls 4SN (ii) CFCOOH N N N 60 H NaOH, H2O, N N CH-OH N -ss

N2N/ H NO 65 XXXXVI XXXXVIII US 8,263,610 B2 135 136 -continued such as dichloromethane at ambient temperature for 1-12 21 O hours to give the pyrazolopyridine urea ester (XXXXVIII). HOOC-H Many isocyanates with carboxylic esters are commercially N available or readily prepared by methods described in the H-- literature and known to those skilled in art. The pyrazolopy na ridine urea ester (XXXXVIII) can then be converted to pyra N N R1R Zolopyridine urea carboxylic acid (XXXXIX) by hydrolysis N HBTU, 2 N Hunig's Base, using Sodium hydroxide, water and protic solvent like metha N H DMA, nol, ethanol at ambient temperatures for a period of 12-24 XXXXIX 10 hours. The pyrazolopyridine urea amide (XXXXVII) can be R14 conveniently prepared by treating pyrazolopyridine urea acid (XXXXIX) with the corresponding primary or secondary R-y amines in presence of amide coupling agents such as HBTU (O-(benzotriazo-1-yl)-N.N.N',N'-tetramethyluronium hexafluorophosphate), tertiary amine bases such as dimethy ) Ou laminopyridine and solvents such as dimethylformamide at / Sulls, ambient temperature for 4-24 hours. Alternatively amide cou pling agents such as DCC (dicyclohexycarbodiimide), BOP N-\ ((benzotriaZo-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate, EDCI.HCl (1-(3-Dimethyl aminopro N N H pyl)-3-ethylcarbodiimide hydrochloride), DMC (2-chloro-1, 3-dimethylimidazolinium chloride) and tertiary amines bases XXXXVII Such as triethylamine, diisopropylethyl amine can also be used. Many primary and secondary amines are commercially The PMB protected pyrazolo pyridine amine (XII) is 25 available or readily prepared by methods described in the deprotected in acids such as trifluoroacetic acid at 65° C. for literature and known to those skilled in art. 12-24 hours to give the pyrazolopyridine amine followed by The compounds of the formula (XXXXXa-c) can be pre reaction with isocyanates with carboxylic esters in solvents pared as shown in Scheme 11.

Scheme 11

O O N W N C n 21 R1 R14 e- N W Condition 1: Hunig's Base, 1,4-Dioxane - Na Y. Condition 2: nBuNI, Hunig's Base, DMSO R13 R14 21 N s N N Sa N^ XXV (W = H) N H XXII (W = Br) XXVI (W =Ph) XXXXXa (W = H) XXXXXb (W =Br) H N XXXXXc (W =Ph) C D Condition 1

BOC

O

N W N Ol W s HCl (g) in Dioxane N 21 M Sa Y. N N N O H XXXXXIa (W = H) XXXXXa (W = H) XXXXXIb (W = Br) XXXXXb (W = Br) XXXXXIc (W = Ph) XXXXXc (W = Ph) US 8,263,610 B2 137 138 The compounds of the formula (XXXXXa-c) can be pre -continued pared using two conditions. In condition 1, a primary or secondary amine such as N-Methyl piperazine or benzyl O amine is heated with the C-chloroamide of pyrazolopyridine amine (XXV. XXII, XXVI) in presence of tertiary amines N bases such as triethylamine, diisopropylethyl amine in Sol CF 3 co5 93 vents such as 1,4-dioxane for at 100° C. for a period of 2-18 21 N CFCOOH hours to give the compound (XXXXXa-c). If the amine used N N is." is a protected diamine such N-t-BOC-piperazine then a com N N pound with the formula (XXXXXIa-c) is obtained. The pro 10 tecting group (N-t-BOC) can be removed under acid condi tions such as HCl (g) in Dioxane or trifluoroacetic at ambient temperatures for a period 2-16 hours to give the desired com pounds with the formula (XXXXXa-c). Alternatively condi 15 tion 2 can be utilized where the amino amides of pyrazolopy No ridines (XXXXXa-c) are prepared by heating chloroamide of XXXXXV pyrazolopyridine amine (XXV. XXII, XXVI) in presence of phase transfer catalyst Such as n-butylammonium iodide and tertiary amines bases such as triethylamine, diisopropylethyl amine in solvents such as 1,4-dioxane at 100° C. for a period O of 2-18 hours. Many primary and secondary amines are com mercially available or readily prepared by methods described N in the literature and known to those skilled in art. CF co5 The compounds of the formula (XXXXXII) can be pre 25 3 3 21 N pared as shown in Scheme 12. N N N^ N H Scheme 12 XXXXXII 30 O O The PMB protected pyrazolopyridine amine (XII) is o1 N reacted with the t-BOC protected succinimide ester of amino acid (XXXXXIII) such as phenylalanine in solvent such as O 35 dichloromethane under ambient temperatures for a period of 1-10 hours to give the compounds of formula (XXXXXIV). in The t-BOC protecting group is then removed under acid HN conditions such as trifluoroacetic acid in dichloromethane or Sk 40 HCl gas as a solution in 1,4-dioxane at ambient temperatures 21 XXXXXIII for a period 4-18 hours to give the compounds of formula CHCl2 (XXXXXV). The PMB protecting of the compound with the s NY. formula (XXXXXV) is then removed by heating in trifluoro acetic acid at 65° C. for a period of 16-24 hours to give the 45 compound of formula (XXXXXII). Many N-protected suc cinimyl esters of amino acids are commercially available or readily prepared by methods described in the literature and known to those skilled in art. No The compounds of the formula (XXXXXVI) were pre XII 50 pared as shown in scheme 13. The thiomethyl pyrimidine O pyrazolopyridine (XXXXXXVII) was treated with an oxi dant such as Oxone in a mixture of water and a protic solvent Such as methanol at ambient temperature for 12-24 hours to N give the corresponding sulfone (XXXXXVIII). Alternatively, 55 m-CPBA can be utilized at ambient temperatures for a period 21 CFCOOH --- 12-24 hours to prepare compounds with the formula N N NY. CHCl2 (XXXXXXVIII), The sulfone (XXXXXVIII) can then be N reacted with the primary or secondary amines or anilines in 60 solvents such as DMSO at 100° C. for a period of 1-24 hours Sk followed by the removal of the PMB protecting group by heating the intermediate in trifluoroacetic acid at 65° C. for a period of 12-24 hours to give the desired compounds with the No formula (XXXXXVI). Many primary, secondary amines and 65 anilines are commercially available or readily prepared by XXXXXIV methods described in the literature and knownto those skilled in art. US 8,263,610 B2 139 140 -continued Scheme 13 EtOC

LiOH, CHOH, N-N / Oxone(R), N N THF, HO W O MeOH, N He 2 M 21 NN - I - N N

N1 n N 10

Ns N 2 XXXXXVII XXXXXXII 15 H NH2 N-N / N HOC W yO - (i) R16R4. R16 agn aYN HeDMSO (i) CFCOOH N 1s1s 21, HBTU Y. Hunig's Base, Ns 2 4. DMF 4.Y,AW XXXXXVIII 25

No 21 N XXXXXXIII N1 N S 30 21 O R-- R13 l 2 N N N H

R14 35 N N CFCOOH N Ho XXXXXVI 2 M N N The compounds of formula (XXXXXIX) can be prepared as shown in Scheme 14. 40 s XXXXXXIV 45 21 O R-- DMF-DMA He S N H 50 N COEt es% N XXXXXIX 55 NH2 The ketone ethyl ester (XXXXXX) is heated with DMF acetal in DMF at 120° C. for a period of 12–48 hours to give No NS the enaminone (XXXXXXI). The enaminone (XXXXXXI) CS 60 is heated with p-methoxybenzyl protected amino pyrazole IV (IV) in acid such as glacial acetic acid at 100° C. for a period ~ CH3COOH of 12-36 hours to give PMB protected pyrazolopyridine ethyl ester (XXXXXXII). The ethyl ester is hydrolyzed using base Such as lithium hydroxide in water and protic solvent Such as COEt 65 methanol at ambient temperature for 1 to 12 hours to give the XXXXXXI compound with the formula (XXXXXXIII). The pyrazolopy ridine amide (XXXXXIX) can be conveniently prepared by US 8,263,610 B2 141 142 treating pyrazolo-pyridine acids (XXXXXXIII) with the cor using Substituted phenylboronic acids, palladium coupling responding primary, secondary amine oranilines in presence agents such as dichloro-((bis diphenylphosphino) ferrocenyl) of amide coupling agents such as HBTU (O-(benzotriazo-1- palladium, aqueous bases such as Sodium carbonate and in yl)-N.N.N',N'-tetramethyluronium hexafluorophosphate), Solvents such as toluene, and protic solvents such as ethanol tertiary amine bases such as dimethylaminopyridine and sol to give the compound with formula (XXXXXXVII). Many vents such as dimethylformamide at ambient temperature for boronic acids are commercially available or readily prepared 4-24 hours followed by the removal of the PMB protecting group by heating the intermediate (XXXXXXIV) in trifluo by methods described in the literature and known to those roacetic acid at 65° C. for a period of 12-24 hours. Alterna skilled in art. The t-BOC-protecting group on compounds tively amide coupling agents such as DCC (dicyclohexycar with formula (XXXXXXVII) is then removed under acid bodiimide), BOP ((benzotriazo-1-yloxy)tris(dimethylamino) 10 conditions such as HCl gas as a solution in 1,4-dioxane at 55° phosphonium hexafluorophosphate, EDCI.HCl (1-(3-Dim C. for a period 10-24 hours to give the compounds of formula ethyl aminopropyl)-3-ethylcarbodiimide hydrochloride), (XXXXXXVIII). The amines of the formula (XXXXXX DMC (2-chloro-1,3-dimethylimidazolinium chloride) and VIII) can then be reacted with isocyanates such as phenyl tertiary amines bases such as triethylamine, diisopropylethyl isocyanate in Solvents such as tetrahydrofuran at ambient amine can also be used. Many amines (primary, secondary, 15 temperature for 1-12 hours to give compounds of formula and aniline) are commercially available or readily prepared (XXXXXXV). Many isocyanates are commercially available by methods described in the literature and known to those or readily prepared by methods described in the literature and skilled in art. known to those skilled in art. The compounds of formula (XXXXXXV) can be prepared 3. Methods of Treatment as shown in scheme 15. The present invention provides methods for the treatment of a cell proliferative disorder in a subject in need thereof by Scheme 15 administering to a subject in need of such treatment, a thera 25 peutically effective amount of a compound of Formula I-IV. > usO B(OH)2 The cell proliferative disorder can be cancer or a precancer O N Br N ous condition. The present invention further provides the use --R of a compound of Formula I-IV for the preparation of a 21 2 medicament useful for the treatment of a cell proliferative 30 disorder. N Pd(Di-tBuppf)PdCl2. The present invention also provides methods of protecting s Na2CO3, Toluene, H EtOH, against a cell proliferative disorder in a subject in need thereof Water by administering atherapeutically effective amount of a com pound of Formula I-IV to a subject in need of such treatment. 35 The cell proliferative disorder can be cancer or a precancer ous condition. The present invention also provides the use of a compound of Formula I-IV for the preparation of a medi cament useful for the prevention of a cell proliferative disor HCl (g), Dioxane der. -- 40 As used herein, a “subject in need thereof is a subject having a cell proliferative disorder, or a Subject having an increased risk of developing a cell proliferative disorder rela tive to the population at large. A subject in need thereof can have a precancerous condition. Preferably, a Subject in need 45 thereof has cancer. A “subject' includes a mammal. The NCO mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep R1s EtN, THF or a pig. Preferably, the mammal is a human. As used herein, the term “cell proliferative disorder” refers 50 to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary cell proliferative disorders of the invention encompass a variety of conditions wherein cell division is 55 deregulated. Exemplary cell proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsu lated tumors, metastatic tumors, liquid tumors, Solid tumors, immunological tumors, hematological tumors, cancers, car 60 cinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A cell proliferative 65 disorder includes a precancer or a precancerous condition. A Suzuki reaction is carried out on 3-bromo-pyrazolopyri cell proliferative disorder includes cancer. Preferably, the dine (XXXXXXVI) at 100° C. for a period of 16-24 hours methods provided herein are used to treat oralleviate a symp US 8,263,610 B2 143 144 tom of cancer. The term "cancer includes solid tumors, as kidney cancer, renal cancer, kidney cancer, laryngeal cancer, well as, hematologic tumors and/or malignancies. A "precan acute lymphoblastic leukemia, acute myeloid leukemia, cer cell' or “precancerous cell' is a cell manifesting a cell chronic lymphocytic leukemia, chronic myelogenous leuke proliferative disorder that is a precancer or a precancerous mia, hairy cell leukemia, lip and oral cavity cancer, liver condition. A "cancer cell' or “cancerous cell' is a cell mani cancer, lung cancer, non-small cell lung cancer, Small cell festing a cell proliferative disorder that is a cancer. Any repro lung cancer, AIDS-related lymphoma, non-Hodgkin lym ducible means of measurement may be used to identify can phoma, primary central nervous system lymphoma, Walden cer cells or precancerous cells. Cancer cells or precancerous stram macroglobulinemia, medulloblastoma, melanoma, cells can be identified by histological typing or grading of a intraocular (eye) melanoma, merkel cell carcinoma, mesothe tissue sample (e.g., a biopsy sample). Cancer cells or precan 10 lioma malignant, mesothelioma, metastatic squamous neck cerous cells can be identified through the use of appropriate cancer, mouth cancer, cancer of the tongue, multiple endo molecular markers. crine neoplasia syndrome, mycosis fungoides, myelodys Exemplary non-cancerous conditions or disorders include, plastic syndromes, myelodysplastic/myeloproliferative dis but are not limited to, rheumatoid arthritis; inflammation; eases, chronic myelogenous leukemia, acute myeloid autoimmune disease; lymphoproliferative conditions; 15 leukemia, multiple myeloma, chronic myeloproliferative dis acromegaly; rheumatoid spondylitis; osteoarthritis; gout, orders, nasopharyngeal cancer, neuroblastoma, oral cancer, other arthritic conditions; sepsis; septic shock; endotoxic oral cavity cancer, oropharyngeal cancer, ovarian cancer, ova shock, gram-negative sepsis: toxic shock syndrome; asthma, rian epithelial cancer, ovarian low malignant potential tumor, adult respiratory distress syndrome; chronic obstructive pull pancreatic cancer, islet cell pancreatic cancer, paranasal sinus monary disease; chronic pulmonary inflammation; inflam and nasal cavity cancer, parathyroid cancer, penile cancer, matory bowel disease; Crohn's disease; psoriasis: eczema: pharyngeal cancer, pheochromocytoma, pineoblastoma and ulcerative colitis; pancreatic fibrosis; hepatic fibrosis: acute Supratentorial primitive neuroectodermal tumors, pituitary and chronic renal disease; irritable bowel syndrome; pyresis; tumor, plasma cell neoplasm/multiple myeloma, pleuropul restenosis; cerebral malaria; stroke and ischemic injury; neu monary blastoma, prostate cancer, rectal cancer, renal pelvis ral trauma; Alzheimer's disease; Huntington's disease; Par 25 and ureter, transitional cell cancer, retinoblastoma, rhab kinson's disease; acute and chronic pain; allergic rhinitis; domyosarcoma, salivary gland cancer, ewing family of Sar allergic conjunctivitis; chronic heart failure; acute coronary coma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine syndrome; cachexia; malaria, leprosy; leishmaniasis; Lyme cancer, uterine sarcoma, skin cancer (non-melanoma), skin disease; Reiter's syndrome; acute synovitis; muscle degen cancer (melanoma), merkel cell skin carcinoma, Small intes eration, bursitis; tendonitis; tenosynovitis; herniated, rup 30 tine cancer, Soft tissue sarcoma, squamous cell carcinoma, tures, or prolapsed intervertebral disk syndrome; osteopetro stomach (gastric) cancer, Supratentorial primitive neuroecto sis; thrombosis; restenosis; silicosis: pulmonary sarcosis: dermal tumors, testicular cancer, throat cancer, thymoma, bone resorption diseases, such as osteoporosis; graft-Versus thymoma and thymic carcinoma, thyroid cancer, transitional host reaction; Multiple Sclerosis; lupus; fibromyalgia: AIDS cell cancer of the renal pelvis and ureter and other urinary and other viral diseases such as Herpes Zoster, Herpes Sim 35 organs, gestational trophoblastic tumor, urethral cancer, plex I or II, influenza virus and cytomegalovirus; and diabetes endometrial uterine cancer, uterine sarcoma, uterine corpus mellitus. cancer, vaginal cancer, Vulvar cancer, and Wilm's Tumor. Exemplary cancers include, but are not limited to, adreno A “cell proliferative disorder of the hematologic system” is cortical carcinoma, AIDS-related cancers, AIDS-relatedlym a cell proliferative disorder involving cells of the hematologic phoma, anal cancer, anorectal cancer, cancer of the anal canal, 40 system. A cell proliferative disorder of the hematologic sys appendix cancer, childhood cerebellar astrocytoma, child tem can include lymphoma, leukemia, myeloid neoplasms, hood cerebral astrocytoma, basal cell carcinoma, skin cancer mast cell neoplasms, myelodysplasia, benign monoclonal (non-melanoma), biliary cancer, extrahepatic bile duct can gammopathy, lymphomatoid granulomatosis, lymphomatoid cer, intrahepatic bile duct cancer, bladder cancer, uringary papulosis, polycythemia Vera, chronic myelocytic leukemia, bladder cancer, bone and joint cancer, osteosarcoma and 45 agnogenic myeloid metaplasia, and essential thromb malignant fibrous histiocytoma, brain cancer, brain tumor, ocythemia. A cell proliferative disorder of the hematologic brain stem glioma, cerebellar astrocytoma, cerebral astrocy system can include hyperplasia, dysplasia, and metaplasia of toma/malignant glioma, ependymoma, medulloblastoma, cells of the hematologic system. Preferably, compositions of Supratentorial primitive neuroectodeimal tumors, visual the present invention may be used to treat a cancer selected pathway and hypothalamic glioma, breast cancer, bronchial 50 from the group consisting of a hematologic cancer of the adenomas/carcinoids, carcinoid tumor, gastrointestinal, ner present invention or a hematologic cell proliferative disorder Vous system cancer, nervous system lymphoma, central ner of the present invention. A hematologic cancer of the present Vous system cancer, central nervous system lymphoma, cer invention can include multiple myeloma, lymphoma (includ Vical cancer, childhood cancers, chronic lymphocytic ing Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, child leukemia, chronic myelogenous leukemia, chronic myelo 55 hood lymphomas, and lymphomas of lymphocytic and cuta proliferative disorders, colon cancer, colorectal cancer, cuta neous origin), leukemia (including childhood leukemia, neous T-cell lymphoma, lymphoid neoplasm, mycosis fun hairy-cell leukemia, acute lymphocytic leukemia, acute goides, Seziary Syndrome, endometrial cancer, esophageal myelocytic leukemia, chronic lymphocytic leukemia, chronic cancer, extracranial germ cell tumor, extragonadal germ cell myelocytic leukemia, chronic myelogenous leukemia, and tumor, extrahepatic bile duct cancer, eye cancer, intraocular 60 mast cell leukemia), myeloid neoplasms and mast cell neo melanoma, retinoblastoma, gallbladder cancer, gastric (stom plasms. ach) cancer, gastrointestinal carcinoid tumor, gastrointestinal A “cell proliferative disorder of the lung is a cell prolif stromal tumor (GIST), germ cell tumor, ovarian germ cell erative disorder involving cells of the lung. Cell proliferative tumor, gestational trophoblastic tumor glioma, head and neck disorders of the lung can include all forms of cell proliferative cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, 65 disorders affecting lung cells. Cell proliferative disorders of hypopharyngeal cancer, intraocular melanoma, ocular can the lung can include lung cancer, a precancer or precancerous cer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, condition of the lung, benign growths or lesions of the lung, US 8,263,610 B2 145 146 and malignant growths or lesions of the lung, and metastatic prior colon cancer. Current disease that may predispose indi lesions in tissue and organs in the body other than the lung. viduals to development of cell proliferative disorders of the Preferably, compositions of the present invention may be colon can include Crohn's disease and ulcerative colitis. A used to treat lung cancer or cell proliferative disorders of the cell proliferative disorder of the colon can be associated with lung. Lung cancer can include all forms of cancer of the lung. a mutation in a gene selected from the group consisting of Lung cancer can include malignant lung neoplasms, carci p53, ras, FAP and DCC. An individual can have an elevated noma in situ, typical carcinoid tumors, and atypical carcinoid risk of developing a cell proliferative disorder of the colon tumors. Lung cancer can include Small cell lung cancer due to the presence of a mutation in a gene selected from the ('SCLC), non-small cell lung cancer (“NSCLC), squa group consisting of p53, ras, FAP and DCC. mous cell carcinoma, adenocarcinoma, Small cell carcinoma, 10 A “cell proliferative disorder of the pancreas” is a cell large cell carcinoma, adenosquamous cell carcinoma, and proliferative disorder involving cells of the pancreas. Cell mesothelioma. Lung cancer can include “scar carcinoma’. proliferative disorders of the pancreas can include all forms of bronchioalveolar carcinoma, giant cell carcinoma, spindle cell proliferative disorders affecting pancreatic cells. Cell cell carcinoma, and large cell neuroendocrine carcinoma. proliferative disorders of the pancreas can include pancreas Lung cancer can include lung neoplasms having histologic 15 cancer, a precancer or precancerous condition of the pan and ultrastructual heterogeneity (e.g., mixed cell types). creas, hyperplasia of the pancreas, and dysaplasia of the pan Cell proliferative disorders of the lung can include all creas, benign growths or lesions of the pancreas, and malig forms of cell proliferative disorders affecting lung cells. Cell nant growths or lesions of the pancreas, and metastatic lesions proliferative disorders of the lung can include lung cancer, in tissue and organs in the body other than the pancreas. precancerous conditions of the lung. Cell proliferative disor Pancreatic cancer includes all forms of cancer of the pan ders of the lung can include hyperplasia, metaplasia, and creas. Pancreatic cancer can include ductal adenocarcinoma, dysplasia of the lung. Cell proliferative disorders of the lung adenosquamous carcinoma, pleomorphic giant cell carci can include asbestos-induced hyperplasia, squamous meta noma, mucinous adenocarcinoma, osteoclast-like giant cell plasia, and benign reactive mesothelial metaplasia. Cell pro carcinoma, mucinous cystadenocarcinoma, acinar carci liferative disorders of the lung can include replacement of 25 noma, unclassified large cell carcinoma, Small cell carci columnar epithelium with stratified squamous epithelium, noma, pancreatoblastoma, papillary neoplasm, mucinous and mucosal dysplasia. Individuals exposed to inhaled inju cystadenoma, papillary cystic neoplasm, and serous cystad rious environmental agents such as cigarette Smoke and enoma. Pancreatic cancer can also include pancreatic neo asbestos may be at increased risk for developing cell prolif plasms having histologic and ultrastructual heterogeneity erative disorders of the lung. Prior lung diseases that may 30 (e.g., mixed cell types). predispose individuals to development of cell proliferative A “cell proliferative disorder of the prostate' is a cell disorders of the lung can include chronic interstitial lung proliferative disorder involving cells of the prostate. Cell disease, necrotizing pulmonary disease, Scleroderma, rheu proliferative disorders of the prostate can include all forms of matoid disease, sarcoidosis, interstitial pneumonitis, tubercu cell proliferative disorders affecting prostate cells. Cell pro losis, repeated pneumonias, idiopathic pulmonary fibrosis, 35 liferative disorders of the prostate can include prostate cancer, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin’s a precancer or precancerous condition of the prostate, benign disease. growths or lesions of the prostate, and malignant growths or A “cell proliferative disorder of the colon' is a cell prolif lesions of the prostate, and metastatic lesions in tissue and erative disorder involving cells of the colon. Preferably, the organs in the body other than the prostate. Cell proliferative cell proliferative disorder of the colon is colon cancer. Pref 40 disorders of the prostate can include hyperplasia, metaplasia, erably, compositions of the present invention may be used to and dysplasia of the prostate. treat colon cancer or cell proliferative disorders of the colon. A “cell proliferative disorder of the skin' is a cell prolif Colon cancer can include all forms of cancer of the colon. erative disorder involving cells of the skin. Cell proliferative Colon cancer can include sporadic and hereditary colon can disorders of the skin can include all forms of cell proliferative cers. Colon cancer can include malignant colon neoplasms, 45 disorders affecting skin cells. Cell proliferative disorders of carcinoma in situ, typical carcinoid tumors, and atypical car the skin can include a precancer or precancerous condition of cinoid tumors. Colon cancer can include adenocarcinoma, the skin, benign growths or lesions of the skin, melanoma, squamous cell carcinoma, and adenosquamous cell carci malignant melanoma and other malignant growths or lesions noma. Colon cancer can be associated with a hereditary Syn of the skin, and metastatic lesions in tissue and organs in the drome selected from the group consisting of hereditary non 50 body other than the skin. Cell proliferative disorders of the polyposis colorectal cancer, familial adenomatous polyposis, skin can include hyperplasia, metaplasia, and dysplasia of the Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's Syn skin. drome and juvenile polyposis. Colon cancer can be caused by A “cell proliferative disorder of the ovary” is a cell prolif a hereditary syndrome selected from the group consisting of erative disorder involving cells of the ovary. Cell proliferative hereditary nonpolyposis colorectal cancer, familial adenoma 55 disorders of the ovary can include all forms of cell prolifera tous polyposis, Gardner's syndrome, Peutz-Jeghers Syn tive disorders affecting cells of the ovary. Cell proliferative drome, Turcot's syndrome and juvenile polyposis. disorders of the ovary can include a precancer or precancer Cell proliferative disorders of the colon can include all ous condition of the ovary, benign growths or lesions of the forms of cell proliferative disorders affecting colon cells. Cell ovary, ovarian cancer, malignant growths or lesions of the proliferative disorders of the colon can include colon cancer, 60 ovary, and metastatic lesions in tissue and organs in the body precancerous conditions of the colon, adenomatous polyps of other than the ovary. Cell proliferative disorders of the skin the colon and metachronous lesions of the colon. A cell pro can include hyperplasia, metaplasia, and dysplasia of cells of liferative disorder of the colon can include adenoma. Cell the ovary. proliferative disorders of the colon can be characterized by A “cell proliferative disorder of the breast’ is a cell prolif hyperplasia, metaplasia, and dysplasia of the colon. Prior 65 erative disorder involving cells of the breast. Cell prolifera colon diseases that may predispose individuals to develop tive disorders of the breast can include all forms of cell ment of cell proliferative disorders of the colon can include proliferative disorders affecting breast cells. Cell prolifera US 8,263,610 B2 147 148 tive disorders of the breast can include breast cancer, a pre HER2/neu, or as having a low, intermediate or high level of cancer or precancerous condition of the breast, benign HER2/neu expression. A breast cancer that is to be treated can growths or lesions of the breast, and malignant growths or be typed for a marker selected from the group consisting of lesions of the breast, and metastatic lesions in tissue and estrogen receptor (ER), progesterone receptor (PR), human organs in the body other than the breast. Cell proliferative epidermal growth factor receptor-2, Ki-67, CA15-3, CA disorders of the breast can include hyperplasia, metaplasia, 27-29, and c-Met. A breast cancer that is to be treated can be and dysplasia of the breast. typed as ER-unknown, ER-rich or ER-poor. A breast cancer A cell proliferative disorder of the breast can be a precan that is to be treated can be typed as ER-negative or ER cerous condition of the breast. Compositions of the present positive. ER-typing of a breast cancer may be performed by invention may be used to treat a precancerous condition of the 10 any reproducible means. ER-typing of a breast cancer may be breast. A precancerous condition of the breast can include performed as set forth in Onkologie 27: 175-179 (2004). A atypical hyperplasia of the breast, ductal carcinoma in situ breast cancer that is to be treated can be typed as PR-un (DCIS), intraductal carcinoma, lobular carcinoma in situ known, PR-rich or PR-poor. A breast cancer that is to be (LCIS), lobular neoplasia, and stage 0 or grade 0 growth or treated can be typed as PR-negative or PR-positive. A breast lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or 15 cancer that is to be treated can be typed as receptor positive or carcinoma in situ). A precancerous condition of the breast can receptor negative. A breast cancer that is to be treated can be be staged according to the TNM classification scheme as typed as being associated with elevated blood levels of CA accepted by the American Joint Committee on Cancer 15-3, or CA 27-29, or both. (AJCC), where the primary tumor (T) has been assigned a A breast cancer that is to be treated can include a localized stage of TO or T is; and where the regional lymph nodes (N) tumor of the breast. A breast cancer that is to be treated can have been assigned a stage of NO; and where distant metasta include a tumor of the breast that is associated with a negative sis (M) has been assigned a stage of M0. sentinel lymph node (SLN) biopsy. A breast cancer that is to The cell proliferative disorder of the breast can be breast be treated can include a tumor of the breast that is associated cancer. Preferably, compositions of the present invention may with a positive sentinel lymph node (SLN) biopsy. A breast be used to treat breast cancer. Breast cancer includes all forms 25 cancer that is to be treated can include a tumor of the breast of cancer of the breast. Breast cancer can include primary that is associated with one or more positive axillary lymph epithelial breast cancers. Breast cancer can include cancers in nodes, where the axillary lymph nodes have been staged by which the breast is involved by other tumors such as lym any applicable method. A breast cancer that is to be treated phoma, sarcoma or melanoma. Breast cancer can include can include a tumor of the breast that has been typed as having carcinoma of the breast, ductal carcinoma of the breast, lobu 30 nodal negative status (e.g., node-negative) or nodal positive lar carcinoma of the breast, undifferentiated carcinoma of the status (e.g., node-positive). A breast cancer that is to be breast, cystosarcoma phyllodes of the breast, angiosarcoma treated can include a tumor of the breast that has metastasized of the breast, and primary lymphoma of the breast. Breast to other locations in the body. A breast cancer that is to be cancer can include Stage I, II, IIIA, IIIB, IIIC and IV breast treated can be classified as having metastasized to a location cancer. Ductal carcinoma of the breast can include invasive 35 selected from the group consisting of bone, lung, liver, or carcinoma, invasive carcinoma in situ with predominant brain. A breast cancer that is to be treated can be classified intraductal component, inflammatory breast cancer, and a according to a characteristic selected from the group consist ductal carcinoma of the breast with a histologic type selected ing of metastatic, localized, regional, local-regional, locally from the group consisting of comedo, mucinous (colloid), advanced, distant, multicentric, bilateral, ipsilateral, con medullary, medullary with lymphcytic infiltrate, papillary, 40 tralateral, newly diagnosed, recurrent, and inoperable. Scirrhous, and tubular. Lobular carcinoma of the breast can A compound of the present invention may be used to treat include invasive lobular carcinoma with predominant in situ or prevent a cell proliferative disorder of the breast, or to treat component, invasive lobular carcinoma, and infiltrating lobu or prevent breast cancer, in a subject having an increased risk lar carcinoma. Breast cancer can include Paget’s disease, of developing breast cancer relative to the population at large. Paget’s disease with intraductal carcinoma, and Paget’s dis 45 A subject with an increased risk of developing breast cancer ease with invasive ductal carcinoma. Breast cancer can relative to the population at large is a female Subject with a include breast neoplasms having histologic and ultrastructual family history or personal history of breast cancer. A subject heterogeneity (e.g., mixed cell types). with an increased risk of developing breast cancer relative to Preferably, a compound of the present invention may be the population at large is a female Subject having a germ-line used to treat breast cancer. A breast cancer that is to be treated 50 or spontaneous mutation in BRCA1 or BRCA2, or both. A can include familial breast cancer. A breast cancer that is to be Subject with an increased risk of developing breast cancer treated can include sporadic breast cancer. A breast cancer relative to the population at large is a female Subject with a that is to be treated can arise in a male Subject. A breast cancer family history of breast cancer and a germ-line or spontane that is to be treated can arise in a female subject. A breast ous mutation in BRCA1 or BRCA2, or both. A subject with an cancer that is to be treated can arise in a premenopausal 55 increased risk of developing breast cancer relative to the female Subject or a postmenopausal female Subject. A breast population at large is a female who is greater than 30 years cancer that is to be treated can arise in a subject equal to or old, greater than 40 years old, greater than 50 years old, older than 30 years old, or a subject younger than 30years old. greater than 60 years old, greater than 70 years old, greater A breast cancer that is to be treated has arisen in a subject than 80 years old, or greater than 90 years old. A subject with equal to or older than 50 years old, or a subject younger than 60 an increased risk of developing breast cancer relative to the 50 years old. A breast cancer that is to be treated can arise in population at large is a Subject with atypical hyperplasia of a subject equal to or older than 70 years old, or a subject the breast, ductal carcinoma in situ (DCIS), intraductal car younger than 70 years old. cinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, A breast cancer that is to be treated can be typed to identify or a stage 0 growth or lesion of the breast (e.g., stage 0 or a familial or spontaneous mutation in BRCA1, BRCA2, or 65 grade Obreast cancer, or carcinoma in situ). p53. A breast cancer that is to be treated can be typed as A breast cancer that is to be treated can histologically having a HER2/neu gene amplification, as overexpressing graded according to the Scarff-Bloom-Richardson system, US 8,263,610 B2 149 150 wherein a breast tumor has been assigned a mitosis count As used herein, "contacting a cell refers to a condition in score of 1, 2, or 3; a nuclear pleiomorphism score of 1, 2, or which a compound or other composition of matter is in direct 3; a tubule formation score of 1, 2, or 3; and a total Scarff contact with a cell, or is close enough to induce a desired Bloom-Richardson score of between 3 and 9. A breast cancer biological effect in a cell. that is to be treated can be assigned a tumor grade according 5 As used herein, "candidate compound” refers to a com to the International Consensus Panel on the Treatment of pound of the present invention that has been or will be tested Breast Cancer selected from the group consisting of grade 1. in one or more in vitro or in vivo biological assays, in order to grade 1-2, grade 2, grade 2-3, or grade 3. determine if that compound is likely to elicit a desired bio A cancer that is to be treated can be staged according to the logical or medical response in a cell, tissue, system, animal or 10 human that is being sought by a researcher or clinician. A American Joint Committee on Cancer (AJCC) TNM classi candidate compound is a compound of Formula I-IV. The fication system, where the tumor (T) has been assigned a biological or medical response can be the treatment of cancer. stage of TX, T1, T1 mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, The biological or medical response can be treatment or pre T4c, or T4d; and where the regional lymph nodes (N) have vention of a cell proliferative disorder. In vitro or in vivo been assigned a stage of NX, NO, N1, N2, N2a, N2b, N3, N3a, 15 biological assays can include, but are not limited to, enzy N3b, or N3c; and where distant metastasis (M) can be matic activity assays, electrophoretic mobility shift assays, assigned a stage of MX, MO, or M1. A cancer that is to be reporter gene assays, in vitro cell viability assays, and the treated can be staged according to an American Joint Com assays described herein. mittee on Cancer (AJCC) classification as Stage I, Stage IIA, As used herein, "monotherapy” refers to the administration Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. A ofa single active ortherapeutic compound to a subject in need cancer that is to be treated can be assigned a grade according thereof. Preferably, monotherapy will involve administration to an AJCC classification as Grade GX (e.g., grade cannot be of a therapeutically effective amount of an active compound. assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that For example, cancer monotherapy with one of the compound is to be treated can be staged according to an AJCC pathologic of the present invention, or a pharmaceutically acceptable classification (pN) of pNX, pN0, PNO (I-), PNO (I+), PNO 25 salt, prodrug, metabolite, analog or derivative thereof, to a (mol-), PNO (mol+), PN1, PN1 (mi), PN1a, PN1b, PN1c, subject in need of treatment of cancer. Monotherapy may be pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c. contrasted with combination therapy, in which a combination A cancer that is to be treated can include a tumor that has of multiple active compounds is administered, preferably been determined to be less than or equal to about 2 centime with each component of the combination present in a thera ters in diameter. A cancer that is to be treated can include a 30 peutically effective amount. In one aspect, monotherapy with a compound of the present invention is more effective than tumor that has been determined to be from about 2 to about 5 combination therapy in inducing a desired biological effect. centimeters in diameter. A cancer that is to be treated can As used herein, “treating or “treat describes the manage include a tumor that has been determined to be greater than or ment and care of a patient for the purpose of combating a equal to about 3 centimeters in diameter. A cancer that is to be 35 disease, condition, or disorder and includes the administra treated can include a tumor that has been determined to be tion of a compound of the present invention to alleviate the greater than 5 centimeters in diameter. A cancer that is to be symptoms or complications of a disease, condition or disor treated can be classified by microscopic appearance as well der, or to eliminate the disease, condition or disorder. differentiated, moderately differentiated, poorly differenti A compound of the present invention, or a pharmaceuti ated, or undifferentiated. A cancer that is to be treated can be 40 cally acceptable salt, prodrug, metabolite, polymorph or Sol classified by microscopic appearance with respect to mitosis vate thereof, can also be used to prevent a disease, condition count (e.g., amount of cell division) or nuclear pleiomor or disorder. As used herein, “preventing or “prevent phism (e.g., change in cells). A cancer that is to be treated can describes reducing or eliminating the onset of the symptoms be classified by microscopic appearance as being associated or complications of the disease, condition or disorder. with areas of necrosis (e.g., areas of dying or degenerating 45 As used herein, the term “alleviate' is meant to describe a cells). A cancer that is to be treated can be classified as having process by which the severity of a sign or symptom of a an abnormal karyotype, having an abnormal number of chro disorder is decreased. Importantly, a sign or symptom can be mosomes, or having one or more chromosomes that are alleviated without being eliminated. In a preferred embodi abnormal in appearance. A cancer that is to be treated can be ment, the administration of pharmaceutical compositions of classified as being aneuploid, triploid, tetraploid, or as having 50 the invention leads to the elimination of a sign or symptom, an altered ploidy. A cancer that is to be treated can be classi however, elimination is not required. Effective dosages are fied as having a chromosomal translocation, or a deletion or expected to decrease the severity of a sign or symptom. For duplication of an entire chromosome, or a region of deletion, instance, a sign or symptom of a disorder Such as cancer, duplication or amplification of a portion of a chromosome. which can occur in multiple locations, is alleviated if the A cancer that is to be treated can be evaluated by DNA 55 severity of the cancer is decreased within at least one of cytometry, flow cytometry, or image cytometry. A cancer that multiple locations. is to be treated can be typed as having 10%, 20%, 30%, 40%, As used herein, the term “severity” is meant to describe the 50%. 60%, 70%, 80%, or 90% of cells in the synthesis stage potential of cancer to transform from a precancerous, or of cell division (e.g., in S phase of cell division). A cancer that benign, state into a malignant state. Alternatively, or in addi is to be treated can be typed as having a low S-phase fraction 60 tion, severity is meant to describe a cancer stage, for example, or a high S-phase fraction. according to the TNM system (accepted by the International As used herein, a “normal cell' is a cell that cannot be Union Against Cancer (UICC) and the American Joint Com classified as part of a “cell proliferative disorder. A normal mittee on Cancer (AJCC)) or by other art-recognized meth cell lacks unregulated or abnormal growth, or both, that can ods. Cancer stage refers to the extent or severity of the cancer, lead to the development of an unwanted condition or disease. 65 based on factors such as the location of the primary tumor, Preferably, a normal cell possesses normally functioning cell tumor size, number of tumors, and lymph node involvement cycle checkpoint control mechanisms. (spread of cancer into lymph nodes). Alternatively, or in addi US 8,263,610 B2 151 152 tion, severity is meant to describe the tumor grade by art Sometimes, cancer cells release Substances into the blood recognized methods (see, National Cancer Institute, stream that cause symptoms not usually thought to result www.cancer.gov). Tumor grade is a system used to classify from cancers. For example, Some cancers of the pancreas can cancer cells in terms of how abnormal they look under a release substances which cause blood clots to develop in microscope and how quickly the tumor is likely to grow and veins of the legs. Some lung cancers make hormone-like spread. Many factors are considered when determining tumor substances that affect blood calcium levels, affecting nerves grade, including the structure and growth pattern of the cells. and muscles and causing weakness and dizziness The specific factors used to determine tumor grade vary with Cancer presents several general signs or symptoms that each type of cancer. Severity also describes a histologic occur when a variety of Subtypes of cancer cells are present. grade, also called differentiation, which refers to how much 10 Most people with cancer will lose weight at some time with the tumor cells resemble normal cells of the same tissue type their disease. An unexplained (unintentional) weight loss of (see, National Cancer Institute, www.cancer.gov). Further 10 pounds or more may be the first sign of cancer, particularly more, severity describes a nuclear grade, which refers to the cancers of the pancreas, stomach, esophagus, or lung. size and shape of the nucleus in tumor cells and the percent Fever is very common with cancer, but is more often seen age of tumor cells that are dividing (see, National Cancer 15 inadvanced disease. Almost all patients with cancer will have Institute, www.cancer.gov). fever at Some time, especially if the cancer or its treatment In another aspect of the invention, severity describes the affects the immune system and makes it harder for the body to degree to which a tumor has secreted growth factors, fight infection. Less often, fever may be an early sign of degraded the extracellular matrix, become vascularized, lost cancer. Such as with leukemia or lymphoma. adhesion to juxtaposed tissues, or metastasized. Moreover, Fatigue may be an important symptom as cancer severity describes the number of locations to which a primary progresses. It may happen early, though, in cancers such as tumor has metastasized. Finally, severity includes the diffi with leukemia, or if the cancer is causing an ongoing loss of culty of treating tumors of varying types and locations. For blood, as in Some colon or stomach cancers. example, inoperable tumors, those cancers which have Pain may be an early symptom with Some cancers such as greater access to multiple body systems (hematological and 25 bone cancers or testicular cancer. But most often pain is a immunological tumors), and those which are the most resis symptom of advanced disease. tant to traditional treatments are considered most severe. In Along with cancers of the skin (see next section), some these situations, prolonging the life expectancy of the Subject internal cancers can cause skin signs that can be seen. These and/or reducing pain, decreasing the proportion of cancerous changes include the skin looking darker (hyperpigmenta cells or restricting cells to one system, and improving cancer 30 tion), yellow (jaundice), or red (erythema); itching; or exces stage/tumor grade/histological grade/nuclear grade are con sive hair growth. sidered alleviating a sign or symptom of the cancer. Alternatively, or in addition, cancer subtypes present spe As used herein the term “symptom' is defined as an indi cific signs or symptoms. Changes in bowel habits or bladder cation of disease, illness, injury, or that something is not right function could indicate cancer. Long-term constipation, diar in the body. Symptoms are felt or noticed by the individual 35 rhea, or a change in the size of the stool may be a sign of colon experiencing the symptom, but may not easily be noticed by cancer. Pain with urination, blood in the urine, or a change in others. Others are defined as non-health-care professionals. bladder function (such as more frequent or less frequent uri As used herein the term “sign” is also defined as an indi nation) could be related to bladder or prostate cancer. cation that something is not right in the body. But signs are Changes in skin condition or appearance of a new skin defined as things that can be seen by a doctor, nurse, or other 40 condition could indicate cancer. Skin cancers may bleed and health care professional. look like Sores that do not heal. A long-lasting Sore in the Cancer is a group of diseases that may cause almost any mouth could be an oral cancer, especially in patients who sign or symptom. The signs and symptoms will depend on Smoke, chew tobacco, or frequently drink alcohol. Sores on where the cancer is, the size of the cancer, and how much it the penis or vagina may either besigns of infection oran early affects the nearby organs or structures. If a cancer spreads 45 CaCC. (metastasizes), then symptoms may appear in different parts Unusual bleeding or discharge could indicate cancer. of the body. Unusual bleeding can happen in either early or advanced As a cancer grows, it begins to push on nearby organs, cancer. Blood in the sputum (phlegm) may be a sign of lung blood vessels, and nerves. This pressure creates some of the cancer. Blood in the stool (or a dark or black stool) could be signs and symptoms of cancer. If the cancer is in a critical 50 a sign of colon or rectal cancer. Cancer of the cervix or the area, such as certain parts of the brain, even the Smallest tumor endometrium (lining of the uterus) can cause vaginal bleed can cause early symptoms. ing. Blood in the urine may be a sign of bladder or kidney But sometimes cancers start in places where it does not cancer. A bloody discharge from the nipple may be a sign of cause any symptoms until the cancer has grown quite large. breast cancer. Pancreas cancers, for example, do not usually grow large 55 A thickening or lump in the breast or in other parts of the enough to be felt from the outside of the body. Some pancre body could indicate the presence of a cancer. Many cancers atic cancers do not cause symptoms until they begin to grow can be felt through the skin, mostly in the breast, testicle, around nearby nerves (this causes a backache). Others grow lymph nodes (glands), and the soft tissues of the body. A lump around the bile duct, which blocks the flow of bile and leads or thickening may be an early or late sign of cancer. Any lump to a yellowing of the skin known as jaundice. By the time a 60 or thickening could be indicative of cancer, especially if the pancreatic cancer causes these signs or symptoms, it has formation is new or has grown in size. usually reached an advanced Stage. Indigestion or trouble Swallowing could indicate cancer. A cancer may also cause symptoms such as fever, fatigue, While these symptoms commonly have other causes, indiges or weight loss. This may be because cancer cells use up much tion or Swallowing problems may be a sign of cancer of the of the body's energy Supply or release Substances that change 65 esophagus, stomach, or pharynx (throat). the body's metabolism. Or the cancer may cause the immune Recent changes in a wart or mole could be indicative of system to react in ways that produce these symptoms. cancer. Any wart, mole, or freckle that changes in color, size, US 8,263,610 B2 153 154 or shape, or loses its definite borders indicates the potential 90 days; and most preferably, by more than 120 days. An development of cancer. For example, the skin lesion may be a increase in average Survival time of a population may be melanoma. measured by any reproducible means. An increase in average A persistent cough or hoarseness could be indicative of Survival time of a population may be measured, for example, cancer. A cough that does not go away may be a sign of lung 5 by calculating for a population the average length of Survival cancer. Hoarseness can be a sign of cancer of the larynx (voice following initiation of treatment with an active compound. An box) or thyroid. increase in average Survival time of a population may also be While the signs and symptoms listed above are the more measured, for example, by calculating for a population the common ones seen with cancer, there are many others that are average length of Survival following completion of a first less common and are not listed here. However, all art-recog 10 nized signs and symptoms of cancer are contemplated and round of treatment with an active compound. encompassed by the instant invention. Treating cancer can result in an increase in average Survival Treating cancer can result in a reduction in size of a tumor. time of a population of treated Subjects in comparison to a A reduction in size of a tumor may also be referred to as population of untreated subjects. Preferably, the average sur “tumor regression’. Preferably, after treatment, tumor size is 15 vival time is increased by more than 30 days; more preferably, reduced by 5% or greater relative to its size prior to treatment; by more than 60 days; more preferably, by more than 90 days; more preferably, tumor size is reduced by 10% or greater; and most preferably, by more than 120 days. An increase in more preferably, reduced by 20% or greater; more preferably, average Survival time of a population may be measured by any reduced by 30% or greater; more preferably, reduced by 40% reproducible means. An increase in average Survival time of a or greater; even more preferably, reduced by 50% or greater; population may be measured, for example, by calculating for and most preferably, reduced by greater than 75% or greater. a population the average length of Survival following initia Size of a tumor may be measured by any reproducible means tion of treatment with an active compound. An increase in of measurement. The size of a tumor may be measured as a average Survival time of a population may also be measured, diameter of the tumor. for example, by calculating for a population the average Treating cancer can result in a reduction in tumor Volume. 25 length of survival following completion of a first round of Preferably, after treatment, tumor volume is reduced by 5% or treatment with an active compound. greater relative to its size prior to treatment; more preferably, Treating cancer can result in increase in average Survival tumor volume is reduced by 10% or greater; more preferably, time of a population of treated Subjects in comparison to a reduced by 20% or greater; more preferably, reduced by 30% population receiving monotherapy with a drug that is not a or greater; more preferably, reduced by 40% or greater; even 30 compound of the present invention, or a pharmaceutically more preferably, reduced by 50% or greater; and most pref acceptable salt, prodrug, metabolite, analog or derivative erably, reduced by greater than 75% or greater. Tumor volume thereof. Preferably, the average survival time is increased by may be measured by any reproducible means of measure more than 30 days; more preferably, by more than 60 days; ment. more preferably, by more than 90 days; and most preferably, Treating cancer results in a decrease in number of tumors. 35 by more than 120 days. An increase in average Survival time Preferably, after treatment, tumor number is reduced by 5% or of a population may be measured by any reproducible means. greater relative to number prior to treatment; more preferably, An increase in average Survival time of a population may be tumor number is reduced by 10% or greater; more preferably, measured, for example, by calculating for a population the reduced by 20% or greater; more preferably, reduced by 30% average length of Survival following initiation of treatment or greater; more preferably, reduced by 40% or greater; even 40 with an active compound. An increase in average Survival more preferably, reduced by 50% or greater; and most pref time of a population may also be measured, for example, by erably, reduced by greater than 75%. Number of tumors may calculating for a population the average length of Survival be measured by any reproducible means of measurement. The following completion of a first round of treatment with an number of tumors may be measured by counting tumors active compound. visible to the naked eye or at a specified magnification. Pref 45 Treating cancer can result in a decrease in the mortality rate erably, the specified magnification is 2x. 3x, 4x, 5x, 10x, or of a population of treated Subjects in comparison to a popu 50X. lation receiving carrier alone. Treating cancer can result in a Treating cancer can result in a decrease in number of meta decrease in the mortality rate of a population of treated sub static lesions in other tissues or organs distant from the pri jects in comparison to an untreated population. Treating can mary tumor site. Preferably, after treatment, the number of 50 cer can result in a decrease in the mortality rate of a popula metastatic lesions is reduced by 5% or greater relative to tion of treated Subjects in comparison to a population number prior to treatment; more preferably, the number of receiving monotherapy with a drug that is not a compound of metastatic lesions is reduced by 10% or greater; more pref the present invention, or a pharmaceutically acceptable salt, erably, reduced by 20% or greater; more preferably, reduced prodrug, metabolite, analog or derivative thereof. Preferably, by 30% or greater; more preferably, reduced by 40% or 55 the mortality rate is decreased by more than 2%: more pref greater; even more preferably, reduced by 50% or greater; and erably, by more than 5%; more preferably, by more than 10%: most preferably, reduced by greater than 75%. The number of and most preferably, by more than 25%. A decrease in the metastatic lesions may be measured by any reproducible mortality rate of a population of treated Subjects may be means of measurement. The number of metastatic lesions measured by any reproducible means. A decrease in the mor may be measured by counting metastatic lesions visible to the 60 tality rate of a population may be measured, for example, by naked eye or at a specified magnification. Preferably, the calculating for a population the average number of disease specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x. related deaths per unit time following initiation of treatment Treating cancer can result in an increase in average Survival with an active compound. A decrease in the mortality rate of time of a population of treated Subjects in comparison to a a population may also be measured, for example, by calcu population receiving carrier alone. Preferably, the average 65 lating for a population the average number of disease-related survival time is increased by more than 30 days; more pref deaths per unit time following completion of a first round of erably, by more than 60 days; more preferably, by more than treatment with an active compound. US 8,263,610 B2 155 156 Treating cancer can result in a decrease in tumor growth after treatment, the number of cells having an abnormal mor rate. Preferably, after treatment, tumor growth rate is reduced phology is reduced by at least 5% relative to its size prior to by at least 5% relative to number prior to treatment; more treatment; more preferably, reduced by at least 10%: more preferably, tumor growth rate is reduced by at least 10%: preferably, reduced by at least 20%; more preferably, reduced more preferably, reduced by at least 20%; more preferably, by at least 30%; more preferably, reduced by at least 40%; reduced by at least 30%; more preferably, reduced by at least more preferably, reduced by at least 50%; even more prefer 40%: more preferably, reduced by at least 50%; even more ably, reduced by at least 50%; and most preferably, reduced preferably, reduced by at least 50%; and most preferably, by at least 75%. An abnormal cellular appearance or morphol reduced by at least 75%. Tumor growth rate may be measured ogy may be measured by any reproducible means of measure by any reproducible means of measurement. Tumor growth 10 rate can be measured according to a change in tumor diameter ment. An abnormal cellular morphology can be measured by per unit time. microscopy, e.g., using an inverted tissue culture microscope. Treating cancer can result in a decrease in tumor regrowth. An abnormal cellular morphology can take the form of Preferably, after treatment, tumor regrowth is less than 5%; nuclear pleiomorphism. more preferably, tumor regrowth is less than 10%: more pref 15 As used herein, the term “selectively’ means tending to erably, less than 20%; more preferably, less than 30%; more occurat a higher frequency in one population than in another preferably, less than 40%; more preferably, less than 50%: population. The compared populations can be cell popula even more preferably, less than 50%; and most preferably, tions. Preferably, a compound of the present invention, or a less than 75%. Tumor regrowth may be measured by any pharmaceutically acceptable salt, prodrug, metabolite, ana reproducible means of measurement. Tumor regrowth is mea log or derivative thereof, acts selectively on a cancer or pre Sured, for example, by measuring an increase in the diameter cancerous cell but not on a normal cell. Preferably, a com of a tumor after a prior tumor shrinkage that followed treat pound of the present invention, or a pharmaceutically ment. A decrease in tumor regrowth is indicated by failure of acceptable salt, prodrug, metabolite, analog or derivative tumors to reoccur after treatment has stopped. thereof, acts selectively to modulate one molecular target Treating or preventing a cell proliferative disorder can 25 (e.g., a target kinase) but does not significantly modulate result in a reduction in the rate of cellular proliferation. Pref another molecular target (e.g., a non-target kinase). The erably, after treatment, the rate of cellular proliferation is invention also provides a method for selectively inhibiting the reduced by at least 5%: more preferably, by at least 10%: activity of an enzyme. Such as a kinase. Preferably, an event more preferably, by at least 20%; more preferably, by at least occurs selectively in population A relative to population B if 30%: more preferably, by at least 40%; more preferably, by at 30 it occurs greater than two times more frequently in population least 50%; even more preferably, by at least 50%; and most Aas compared to population B. An event occurs selectively if preferably, by at least 75%. The rate of cellular proliferation it occurs greater than five times more frequently in population may be measured by any reproducible means of measure A. An event occurs selectively if it occurs greater than ten ment. The rate of cellular proliferation is measured, for times more frequently in population A; more preferably, example, by measuring the number of dividing cells in a 35 greater than fifty times; even more preferably, greater than tissue sample per unit time. 100 times; and most preferably, greater than 1000 times more Treating or preventing a cell proliferative disorder can frequently in population A as compared to population B. For result in a reduction in the proportion of proliferating cells. example, cell death would be said to occur selectively in Preferably, after treatment, the proportion of proliferating cancer cells if it occurred greater than twice as frequently in cells is reduced by at least 5%: more preferably, by at least 40 cancer cells as compared to normal cells. 10%; more preferably, by at least 20%; more preferably, by at A compound of the present invention or a pharmaceutically least 30%; more preferably, by at least 40%; more preferably, acceptable salt, prodrug, metabolite, analog or derivative by at least 50%; even more preferably, by at least 50%; and thereof, can modulate the activity of a molecular target (e.g., most preferably, by at least 75%. The proportion of prolifer a target kinase). Modulating refers to stimulating or inhibiting ating cells may be measured by any reproducible means of 45 an activity of a molecular target. Preferably, a compound of measurement. Preferably, the proportion of proliferating cells the present invention modulates the activity of a molecular is measured, for example, by quantifying the number of divid target if it stimulates or inhibits the activity of the molecular ing cells relative to the number of nondividing cells in a tissue target by at least 2-fold relative to the activity of the molecular sample. The proportion of proliferating cells can be equiva target under the same conditions but lacking only the pres lent to the mitotic index. 50 ence of said compound. More preferably, a compound of the Treating or preventing a cell proliferative disorder can present invention modulates the activity of a molecular target result in a decrease in size of an area or Zone of cellular if it stimulates or inhibits the activity of the molecular target proliferation. Preferably, after treatment, size of an area or by at least 5-fold, at least 10-fold, at least 20-fold, at least Zone of cellular proliferation is reduced by at least 5% relative 50-fold, at least 100-fold relative to the activity of the molecu to its size prior to treatment; more preferably, reduced by at 55 lar target under the same conditions but lacking only the least 10%: more preferably, reduced by at least 20%; more presence of said compound. The activity of a molecular target preferably, reduced by at least 30%; more preferably, reduced may be measured by any reproducible means. The activity of by at least 40%; more preferably, reduced by at least 50%: a molecular target may be measured in vitro or in vivo. For even more preferably, reduced by at least 50%; and most example, the activity of a molecular target may be measured preferably, reduced by at least 75%. Size of an area or Zone of 60 in vitro by an enzymatic activity assay or a DNA binding cellular proliferation may be measured by any reproducible assay, or the activity of a molecular target may be measured in means of measurement. The size of an area or Zone of cellular Vivo by assaying for expression of a reporter gene. proliferation may be measured as a diameter or width of an A compound of the present invention, or a pharmaceuti area or Zone of cellular proliferation. cally acceptable salt, prodrug, metabolite, analog or deriva Treating or preventing a cell proliferative disorder can 65 tive thereof, does not significantly modulate the activity of a result in a decrease in the number or proportion of cells molecular target if the addition of the compound does not having an abnormal appearance or morphology. Preferably, stimulate or inhibit the activity of the molecular target by US 8,263,610 B2 157 158 greater than 10% relative to the activity of the molecular log or derivative thereof, to a cell or a subject in need thereof target under the same conditions but lacking only the pres results in modulation (i.e., stimulation or inhibition) of an ence of said compound. activity of an intracellular target (e.g., Substrate). Several As used herein, the term “isozyme selective” means pref intracellular targets can be modulated with the compounds of erential inhibition or stimulation of a first isoform of an the present invention, including, but not limited to, adaptor enzyme in comparison to a second isoform of an enzyme proteins such as Gab-1, Grb-2, Shc, SHP2 and c-Cb1, and (e.g., preferential inhibition or stimulation of a kinase signal transducers such as Ras, Src, PI3K, PLC-Y, STATs, isozyme alpha in comparison to a kinase isozyme beta). Pref ERK1 and 2 and FAK. erably, a compound of the present invention demonstrates a Activating refers to placing a composition of matter (e.g., minimum of a four fold differential, preferably a ten fold 10 protein or nucleic acid) in a state Suitable for carrying out a differential, more preferably a fifty fold differential, in the desired biological function. A composition of matter capable dosage required to achieve a biological effect. Preferably, a of being activated also has an unactivated State. An activated compound of the present invention demonstrates this differ composition of matter may have an inhibitory or stimulatory ential across the range of inhibition, and the differential is biological function, or both. exemplified at the ICs, i.e., a 50% inhibition, for a molecular 15 Elevation refers to an increase in a desired biological activ target of interest. ity of a composition of matter (e.g., a protein or a nucleic Administering a compound of the present invention, or a acid). Elevation may occur through an increase in concentra pharmaceutically acceptable salt, prodrug, metabolite, ana tion of a composition of matter. log or derivative thereof, to a cell or a subject in need thereof As used herein, “a cell cycle checkpoint pathway' refers to can result in modulation (i.e., stimulation or inhibition) of an a biochemical pathway that is involved in modulation of a cell activity of a kinase of interest. cycle checkpoint. A cell cycle checkpoint pathway may have The present invention provides methods to assess biologi stimulatory or inhibitory effects, or both, on one or more cal activity of the compounds of Formula I-IV. In one method, functions comprising a cell cycle checkpoint. A cell cycle an assay based on enzymatic activity can be utilized. In one checkpoint pathway is comprised of at least two composi specific enzymatic activity assay, the enzymatic activity is 25 tions of matter, preferably proteins, both of which contribute from a kinase. As used herein, "kinase' refers to a large class to modulation of a cell cycle checkpoint. A cell cycle check of enzymes which catalyze the transfer of the Y-phosphate point pathway may be activated through an activation of one from ATP to the hydroxyl group on the side chain of Ser/Thr or more members of the cell cycle checkpoint pathway. Pref or Tyr in proteins and peptides and are intimately involved in erably, a cell cycle checkpoint pathway is a biochemical the control of various important cell functions, perhaps most 30 signaling pathway. notably: signal transduction, differentiation, and prolifera As used herein, “cell cycle checkpoint regulator” refers to tion. There are estimated to be about 2,000 distinct protein a composition of matter that can function, at least in part, in kinases in the human body, and although each of these phos modulation of a cell cycle checkpoint. A cell cycle checkpoint phorylate particular protein/peptide substrates, they all bind regulator may have stimulatory or inhibitory effects, or both, the same second substrate ATP in a highly conserved pocket. 35 on one or more functions comprising a cell cycle checkpoint. About 50% of the known oncogene products are protein A cell cycle checkpoint regulator can be a protein or not a tyrosine kinases (PTKs), and their kinase activity has been protein. shown to lead to cell transformation. Preferably, the kinase Treating cancer or a cell proliferative disorder can result in assayed is a tyrosine kinase. cell death, and preferably, cell death results in a decrease of at A change in enzymatic activity caused by compounds of 40 least 10% in number of cells in a population. More preferably, the present invention can be measured in the disclosed assays. cell death means a decrease of at least 20%; more preferably, The change in enzymatic activity can be characterized by the a decrease of at least 30%; more preferably, a decrease of at change in the extent of phosphorylation of certain Substrates. least 40%; more preferably, a decrease of at least 50%; most As used herein, phosphorylation” refers to the addition of preferably, a decrease of at least 75%. Number of cells in a phosphate groups to a Substrate, including proteins and 45 population may be measured by any reproducible means. A organic molecules; and, plays an important role in regulating number of cells in a population can be measured by fluores the biological activities of proteins. Preferably, the phospho cence activated cell sorting (FACS), immunofluorescence rylation assayed and measured involves the addition of phos microscopy and light microscopy. Methods of measuring cell phate groups to tyrosine residues. The Substrate can be a death are as shown in Li et al., Proc Natl Acad Sci USA. peptide or protein. 50 100(5): 2674-8, 2003. In an aspect, cell death occurs by In some assays, immunological reagents, e.g., antibodies apoptosis. and antigens, are employed. Fluorescence can be utilized in Preferably, an effective amount of a compound of the the measurement of enzymatic activity in Some assays. As present invention, or a pharmaceutically acceptable salt, pro used herein, “fluorescence” refers to a process through which drug, metabolite, analog or derivative thereof is not signifi a molecule emits a photon as a result of absorbing an incom 55 cantly cytotoxic to normal cells. A therapeutically effective ing photon of higher energy by the same molecule. Specific amount of a compound is not significantly cytotoxic to nor methods for assessing the biological activity of the disclosed mal cells if administration of the compound in a therapeuti compounds are described in the examples. cally effective amount does not induce cell death in greater As used herein, an activity of c-Met refers to any biological than 10% of normal cells. A therapeutically effective amount function or activity that is carried out by c-Met. For example, 60 of a compound does not significantly affect the viability of a function of c-Met includes phosphorylation of downstream normal cells if administration of the compound in a therapeu target proteins. Other functions of c-Met include autophos tically effective amount does not induce cell death in greater phorylation, binding of adaptor proteins such as Gab-1, Grb than 10% of normal cells. In an aspect, cell death occurs by 2, Shc, SHP2 and c-Cb1, and activation of signal transducers apoptosis. such as Ras, Src, PI3K, PLC-Y, STATs, ERK1 and 2 and FAK. 65 Contacting a cell with a compound of the present invention, Administering a compound of the present invention, or a or a pharmaceutically acceptable salt, prodrug, metabolite, pharmaceutically acceptable salt, prodrug, metabolite, ana analog or derivative thereof, can induce or activate cell death US 8,263,610 B2 159 160 selectively in cancer cells. Administering to a subject in need administration of each therapeutic agent can be effected by thereof a compound of the present invention, or a pharmaceu any appropriate route including, but not limited to, oral tically acceptable salt, prodrug, metabolite, analog or deriva routes, intravenous routes, intramuscular routes, and direct tive thereof, can induce or activate cell death selectively in absorption through mucous membrane tissues. The therapeu cancer cells. Contacting a cell with a compound of the present 5 tic agents can be administered by the same route or by differ invention, or a pharmaceutically acceptable salt, prodrug, ent routes. For example, a first therapeutic agent of the com metabolite, analog orderivative thereof, can induce cell death bination selected may be administered by intravenous selectively in one or more cells affected by a cell proliferative injection while the other therapeutic agents of the combina disorder. Preferably, administering to a subject in need tion may be administered orally. Alternatively, for example, thereof a compound of the present invention, or a pharmaceu 10 all therapeutic agents may be administered orally or all thera tically acceptable salt, prodrug, metabolite, analog or deriva peutic agents may be administered by intravenous injection. tive thereof, induces cell death selectively in one or more cells The sequence in which the therapeutic agents are adminis affected by a cell proliferative disorder. tered is not narrowly critical. The present invention relates to a method of treating or “Combination therapy' also embraces the administration preventing cancer by administering a compound of the 15 of the therapeutic agents as described above in further com present invention, or a pharmaceutically acceptable salt, pro bination with other biologically active ingredients and non drug, metabolite, analog or derivative thereof to a subject in drug therapies (e.g., Surgery or radiation treatment). Where need thereof, where administration of the compound of the the combination therapy further comprises a non-drug treat present invention, or a pharmaceutically acceptable salt, pro ment, the non-drug treatment may be conducted at any Suit drug, metabolite, analog orderivative thereof results in one or able time so long as a beneficial effect from the co-action of more of the following: accumulation of cells in G1 and/or S the combination of the therapeutic agents and non-drug treat phase of the cell cycle, cytotoxicity via cell death in cancer ment is achieved. For example, in appropriate cases, the ben cells without a significant amount of cell death in normal eficial effect is still achieved when the non-drug treatment is cells, antitumor activity in animals with atherapeutic index of temporally removed from the administration of the therapeu at least 2, and activation of a cell cycle checkpoint. As used 25 tic agents, perhaps by days or even weeks. herein, “therapeutic index' is the maximum tolerated dose A compound of the present invention, or a pharmaceuti divided by the efficacious dose. cally acceptable salt, prodrug, metabolite, analog or deriva One skilled in the art may refer to general reference texts tive thereof, may be administered in combination with a sec for detailed descriptions of known techniques discussed ond chemotherapeutic agent. The second chemotherapeutic herein or equivalent techniques. These texts include Ausubel 30 agent (also referred to as an anti-neoplastic agent or anti et al., Current Protocols in Molecular Biology, John Wiley proliferative agent) can be an alkylating agent; an antibiotic; and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A an anti-metabolite; a detoxifying agent; an interferon; a poly Laboratory Manual (3" edition), Cold Spring Harbor Press, clonal or monoclonal antibody; an EGFR inhibitor; a HER2 Cold Spring Harbor, N.Y. (2000); Coligan et al., Current inhibitor; a histone deacetylase inhibitor; a hormone; a Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et 35 mitotic inhibitor, an MTOR inhibitor; a multi-kinase inhibi al., Current Protocols in Pharmacology, John Wiley & Sons, tor, a serine/threonine kinase inhibitor, a tyrosine kinase N.Y.; Fingletal. The Pharmacological Basis of Therapeutics inhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane (1975), Remington's Pharmaceutical Sciences, Mack Pub derivative, an aromatase inhibitor, an anthracycline, a micro lishing Co., Easton, Pa., 18" edition (1990). These texts can, tubule targeting drug, atopoisomerase poison drug, an inhibi of course, also be referred to in making or using an aspect of 40 tor of a molecular target or enzyme (e.g., a kinase inhibitor), the invention a cytidine analogue drug or any chemotherapeutic, anti-neo As used herein, “combination therapy’ or “co-therapy' plastic or anti-proliferative agent listed in www.cancer.org/ includes the administration of a compound of the present docroot/cdg/cdg 0.asp. invention and at least a second agent as part of a specific Exemplary alkylating agents include, but are not limited to, treatment regimen intended to provide the beneficial effect 45 cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leuke from the co-action of these therapeutic agents. The beneficial ran); melphalan (Alkeran); carmustine (BiCNU); busulfan effect of the combination includes, but is not limited to, (Busulfex); lomustine (CeeNU); dacarbazine (DTIC-Dome); pharmacokinetic or pharmacodynamic co-action resulting oxaliplatin (Eloxatin); carmustine (Gliadel); ifosfamide from the combination of therapeutic agents. Administration (Ifex); mechlorethamine (Mustargen); busulfan (Myleran); of these therapeutic agents in combination typically is carried 50 carboplatin (Paraplatin); cisplatin (CDDP: Platinol); temozo out over a defined time period (usually minutes, hours, days lomide (Temodar); thiotepa (Thioplex); bendamustine (Tre or weeks depending upon the combination selected). “Com anda); or Streptozocin (Zanosar). bination therapy may be, but generally is not, intended to Exemplary antibiotics include, but are not limited to, doxo encompass the administration of two or more of these thera rubicin (Adriamycin); doxorubicin liposomal (Doxil); mitox peutic agents as part of separate monotherapy regimens that 55 antrone (Novantrone); bleomycin (Blenoxane); daunorubicin incidentally and arbitrarily result in the combinations of the (Cerubidine); daunorubicin liposomal (DaunoXome); dacti present invention. nomycin (Cosmegen); epirubicin (Ellence); idarubicin (Ida “Combination therapy” is intended to embrace administra mycin); plicamycin (Mithracin); mitomycin (Mutamycin); tion of these therapeutic agents in a sequential manner, pentostatin (Nipent); or valrubicin (Valstar). wherein each therapeutic agent is administered at a different 60 Exemplary anti-metabolites include, but are not limited to, time, as well as administration of these therapeutic agents, or fluorouracil (Adrucil); capecitabine (Xeloda): hydroxyurea at least two of the therapeutic agents, in a Substantially simul (Hydrea); mercaptopurine (Purinethol); pemetrexed (Al taneous manner. Substantially simultaneous administration imta); fludarabine (Fludara); nelarabine (Arranon); cladrib can be accomplished, for example, by administering to the ine (Cladribine Novaplus); clofarabine (Clolar); cytarabine Subject a single capsule having a fixed ratio of each therapeu 65 (Cytosar-U); decitabine (Dacogen); cytarabine liposomal tic agent or in multiple, single capsules for each of the thera (DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); peutic agents. Sequential or Substantially simultaneous floxuridine (FUDR); gemcitabine (Gemzar); cladribine US 8,263,610 B2 161 162 (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheu Exemplary VEGF/VEGFR inhibitors include, but are not matrex); methotrexate (Trexall); thioguanine (Tabloid); TS-1 limited to, bevacizumab (Avastin): Sorafenib (Nexavar); Suni or cytarabine (Tarabine PFS). tinib (Sutent); ranibizumab: pegaptanib; or vandetinib. Exemplary detoxifying agents include, but are not limited Exemplary microtubule targeting drugs include, but are not to, amifostine (Ethyol) or mesna (Mesnex). limited to, paclitaxel, docetaxel, Vincristin, vinblastin, Exemplary interferons include, but are not limited to, inter nocodazole, epothilones and navelbine. feron alfa-2b (Intron A) or interferon alfa-2a (Roferon-A). Exemplary topoisomerase poison drugs include, but are Exemplary polyclonal or monoclonal antibodies include, not limited to, teniposide, etoposide, adriamycin, camptoth but are not limited to, trastuzumab (Herceptin); ofatumumab ecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, 10 epirubicin and idarubicin. (Arzerra); bevacizumab (Avastin); rituximab (Rituxan); Exemplary taxanes or taxane derivatives include, but are cetuximab (Erbitux); panitumumab (Vectibix); to situmomab/ not limited to, paclitaxel and docetaxol. iodine'' to situmomab (Bexxar); alemtuzumab (Campath); Exemplary general chemotherapeutic, anti-neoplastic, anti ibritumomab (Zevalin: In-111; Y-90 Zevalin); gemtuzumab proliferative agents include, but are not limited to, altretamine (Mylotarg); eculizumab (Soliris) ordenosumab. 15 (Hexylen); isotretinoin (Accutane; Amnesteem; Claravis; Exemplary EGFR inhibitors include, but are not limited to, Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bort gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); eZomib (Velcade)asparaginase (Elspar); levamisole (Ergami erlotinib (Tarceva); panitumumab (Vectibix); PKI-166; can Sol); mitotane (LySodren); procarbazine (Matulane); pegas ertinib (CI-1033); matuzumab (Emd7200) or EKB-569. pargase (Oncaspar); denileukin diftitox (Ontak); porfimer Exemplary HER2 inhibitors include, but are not limited to, (Photofrin); aldesleukin (Proleukin); lenalidomide (Rev trastuzumab (Herceptin); lapatinib (Tykerb) or AC-480. limid); bexarotene (Targretin); thalidomide (Thalomid); tem Histone Deacetylase Inhibitors include, but are not limited sirolimus (Torisel); arsenic trioxide (Trisenox); verteporfin to, Vorinostat (Zollinza). (Visudyne); mimosine (Leucenol); (1 M tegafur 0.4 M Exemplary hormones include, but are not limited to, 5-chloro-2,4-dihydroxypyrimidine—1 M potassium tamoxifen (Soltamox; Nolvadex); raloxifene (Evista); mege 25 oXonate) or lovastatin. strol (Megace); leuprolide (Lupron; Lupron Depot; Eligard; In another aspect, the second chemotherapeutic agent can Viadur); fulvestrant (Faslodex); letrozole (Femara); triptore be a cytokine such as G-CSF (granulocyte colony stimulating lin (Trelstar LA; Trelstar Depot); exemestane (Aromasin): factor). In another aspect, a compound of the present inven goserelin (Zoladex); bicalutamide (CaSodex); anastroZole tion, or a pharmaceutically acceptable salt, prodrug, metabo (Arimidex); fluoxymesterone (Androxy: Halotestin): 30 lite, analog or derivative thereof, may be administered in medroxyprogesterone (Provera; Depo-Provera); estramus combination with radiation therapy. Radiation therapy can also be administered in combination with a compound of the tine (Emcyt); flutamide (Eulexin); toremifene (Fareston); present invention and another chemotherapeutic agent degarelix (Firmagon); nilutamide (Nilandron); abarelix described herein as part of a multiple agent therapy. In yet (Plenaxis); or testolactone (Teslac). 35 another aspect, a compound of the present invention, or a Exemplary mitotic inhibitors include, but are not limited pharmaceutically acceptable salt, prodrug, metabolite, ana to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxo log orderivative thereof, may be administered in combination tere); Vincristine (Oncovin; Vincasar PFS); vinblastine (Vel with standard chemotherapy combinations such as, but not ban): etoposide (Toposar; Etopophos; VePesid); teniposide restricted to, CMF (cyclophosphamide, methotrexate and (Vumon); ixabepilone (Ixempra); nocodazole; epothilone; 40 5-fluorouracil), CAF (cyclophosphamide, adriamycin and vinorelbine (Navelbine); camptothecin (CPT); irinotecan 5-fluorouracil), AC (adriamycin and cyclophosphamide), (Camptosar); topotecan (Hycamtin); amsacrine or lamellarin FEC (5-fluorouracil, epirubicin, and cyclophosphamide), D (LAM-D). ACT or ATC (adriamycin, cyclophosphamide, and pacli Exemplary MTOR inhibitors include, but are not limited taxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP), to, everolimus (Afinitor) or temsirolimus (Torisel); rapam 45 Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at une, ridaforolimus; or AP23573. a molar ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinote Exemplary multi-kinase inhibitors include, but are not lim can or CamptosarTM) or CMFP (cyclophosphamide, methotr ited to, Sorafenib (Nexavar); Sunitinib (Sutent); BIBW 2992: exate, 5-fluorouracil and prednisone). E7080; Zdé474; PKC-412; motesanib; or AP24534. In preferred embodiments, a compound of the present Exemplary serine/threonine kinase inhibitors include, but 50 invention, or a pharmaceutically acceptable salt, prodrug, are not limited to, ruboxistaurin; eril/easudil hydrochloride: metabolite, polymorph or Solvate thereof, may be adminis flavopiridol; seliciclib (CYC202; Roscovitrine); SNS-032 tered with an inhibitor of an enzyme. Such as a receptor or (BMS-387032); Pkc412; bryostatin: KAI-9803; SF1126; non-receptor kinase. Receptor and non-receptor kinases of VX-680: Azd 1152: Arry-142886 (AZD-6244); SCIO-469; the invention are, for example, tyrosine kinases or serine/ GW681323; CC-401; CEP-1347 or PD 332991. 55 threonine kinases. Kinase inhibitors of the invention are small Exemplary tyrosine kinase inhibitors include, but are not molecules, polynucleic acids, polypeptides, or antibodies. limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib Exemplary kinase inhibitors include, but are not limited to, (Gleevec); Sorafenib (Nexavar); Sunitinib (Sutent); trastu Bevacizumab (targets VEGF), BIBW 2.992 (targets EGFR Zumab (Herceptin); bevacizumab (Avastin); rituximab (Rit and Erb2), Cetuximab/Erbitux (targets Erb1), Imatinib/ uxan); lapatinib (Tykerb); cetuximab (Erbitux); panitu 60 Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2), Gefi mumab (Vectibix); everolimus (Afinitor); alemtuzumab tinib/Iressa (targets EGFR), Ranibizumab (targets VEGF), (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); Pegaptainib (targets VEGF), Erlotinib/Tarceva (targets Erb 1), pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasi Nilotinib (targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/ gna); vatalanib (Ptk787; ZK222584); CEP-701: SU5614; Her2), GW-572016/lapatinib ditosylate (targets HER2/ MLN518; XL999; VX-322: Azd0530; BMS-354825; SKI 65 Erb2), Panitumumab/Vectibix (targets EGFR), Vandetinib 606 CP-690; AG-490; WHI-P154: WHI-P131; AC-220; or (targets RET/VEGFR), E7080 (multiple targets including AMG888. RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166 US 8,263,610 B2 163 164 (targets EGFR), Canertinib/CI-1033 (targets EGFR), Suni medical judgment, Suitable for use in contact with the tissues tinib/SU-11464/Sutent (targets EGFR and FLT3), Matu of human beings and animals without excessive toxicity, irri Zumab/Emd7200 (targets EGFR), EKB-569 (targets EGFR), tation, allergic response, or other problem or complication, Zdé474 (targets EGFR and VEGFR), PKC-412 (targets commensurate with a reasonable benefit/risk ratio. VEGR and FLT3), Vatalanib/Ptk787/ZK222584 (targets "Pharmaceutically acceptable excipient’ means an excipi VEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), ent that is useful in preparing a pharmaceutical composition MLN518 (targets FLT3), XL999 (targets FLT3), VX-322 that is generally safe, non-toxic and neither biologically nor (targets FLT3), AZd0530 (targets SRC), BMS-354825 (tar otherwise undesirable, and includes excipient that is accept gets SRC), SKI-606 (targets SRC), CP-690 (targets JAK), able for veterinary use as well as human pharmaceutical use. AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 10 A "pharmaceutically acceptable excipient’ as used in the (targets JAK), Sorafenib/Nexavar (targets RAF kinase, specification and claims includes both one and more than one VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3, Such excipient. and RET), Dasatinib/Sprycel (BCR/ABL and Src), AC-220 A pharmaceutical composition of the invention is formu (targets Flt3), AC-480 (targets all HER proteins, “panHER”), lated to be compatible with its intended route of administra Motesanib diphosphate (targets VEGF1-3, PDGFR, and 15 tion. Examples of routes of administration include parenteral, c-kit), Denosumab (targets RANKL, inhibits SRC), e.g., intravenous, intradermal. Subcutaneous, oral (e.g., inha AMG888 (targets HER3), and AP24534 (multiple targets lation), transdermal (topical), and transmucosal administra including Flt3). tion. Solutions or Suspensions used for parenteral, intrader Exemplary serine/threonine kinase inhibitors include, but mal, or Subcutaneous application can include the following are not limited to, Rapamune (targets mTOR/FRAP1), components: a sterile diluent such as water for injection, Deforolimus (targets mTOR), Certican/Everolimus (targets saline solution, fixed oils, polyethylene glycols, glycerine, mTOR/FRAP1), AP23573 (targets mTOR/FRAP1), Eril/Fa propylene glycol or other synthetic solvents; antibacterial Sudil hydrochloride (targets RHO), Flavopiridol (targets agents such as benzyl alcohol or methyl parabens; antioxi CDK), Seliciclib/CYC202/Roscovitrine (targets CDK), dants such as ascorbic acid or sodium bisulfite; chelating SNS-032/BMS-387032 (targets CDK), Ruboxistaurin (tar 25 agents such as ethylenediaminetetraacetic acid; buffers such gets PKC). Pkc412 (targets PKC), Bryostatin (targets PKC). as acetates, citrates or phosphates, and agents for the adjust KAI-9803 (targets PKC), SF1126 (targets PI3K), VX-680 ment oftonicity such as sodium chloride or dextrose. The pH (targets Aurora kinase), AZd 1152 (targets Aurora kinase), can be adjusted with acids or bases, such as hydrochloric acid Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 or Sodium hydroxide. The parenteral preparation can be (targets MAP/MEK), GW681323 (targets MAP/MEK), 30 enclosed in ampoules, disposable Syringes or multiple dose CC-401 (targets JNK), CEP-1347 (targets JNK), and PD vials made of glass or plastic. 332991 (targets CDK). A compound or pharmaceutical composition of the inven tion can be administered to a subject in many of the well 4. Pharmaceutical Compositions known methods currently used for chemotherapeutic treat 35 ment. For example, for treatment of cancers, a compound of The present invention also provides pharmaceutical com the invention may be injected directly into tumors, injected positions comprising a compound of Formula I-IV in combi into the blood stream or body cavities or taken orally or nation with at least one pharmaceutically acceptable excipi applied through the skin with patches. The dose chosen ent or carrier. should be sufficient to constitute effective treatment but not so A "pharmaceutical composition' is a formulation contain 40 high as to cause unacceptable side effects. The state of the ing the compounds of the present invention in a form Suitable disease condition (e.g., cancer, precancer, and the like) and for administration to a Subject. In one embodiment, the phar the health of the patient should preferably be closely moni maceutical composition is in bulk or in unit dosage form. The tored during and for a reasonable period after treatment. unit dosage form is any of a variety of forms, including, for The term “therapeutically effective amount’, as used example, a capsule, an IV bag, a tablet, a single pump on an 45 herein, refers to an amount of a pharmaceutical agent to treat, aerosol inhaler or a vial. The quantity of active ingredient ameliorate, or prevent an identified disease or condition, or to (e.g., a formulation of the disclosed compound or salt, exhibit a detectable therapeutic or inhibitory effect. The effect hydrate, Solvate or isomer thereof) in a unit dose of compo can be detected by any assay method known in the art. The sition is an effective amount and is varied according to the precise effective amount for a subject will depend upon the particular treatment involved. One skilled in the art will 50 Subject's body weight, size, and health; the nature and extent appreciate that it is sometimes necessary to make routine of the condition; and the therapeutic or combination of thera variations to the dosage depending on the age and condition peutics selected for administration. Therapeutically effective of the patient. The dosage will also depend on the route of amounts for a given situation can be determined by routine administration. A variety of routes are contemplated, includ experimentation that is within the skill and judgment of the ing oral, pulmonary, rectal, parenteral, transdermal, Subcuta 55 clinician. In a preferred aspect, the disease or condition to be neous, intravenous, intramuscular, intraperitoneal, inhala treated is cancer. In another aspect, the disease or condition to tional, buccal, Sublingual, intrapleural, intrathecal, intranasal, be treated is a cell proliferative disorder. and the like. Dosage forms for the topical or transdermal For any compound, the therapeutically effective amount administration of a compound of this invention include pow can be estimated initially either in cell culture assays, e.g., of ders, sprays, ointments, pastes, creams, lotions, gels, solu 60 neoplastic cells, or in animal models, usually rats, mice, rab tions, patches and inhalants. In one embodiment, the active bits, dogs, or pigs. The animal model may also be used to compound is mixed under sterile conditions with a pharma determine the appropriate concentration range and route of ceutically acceptable carrier, and with any preservatives, administration. Such information can then be used to deter buffers or propellants that are required. mine useful doses and routes for administration in humans. As used herein, the phrase “pharmaceutically acceptable' 65 Therapeutic/prophylactic efficacy and toxicity may be deter refers to those compounds, materials, compositions, carriers, mined by standard pharmaceutical procedures in cell cultures and/or dosage forms which are, within the scope of Sound or experimental animals, e.g., EDs (the dose therapeutically US 8,263,610 B2 165 166 effective in 50% of the population) and LDs (the dose lethal ration are vacuum drying and freeze-drying that yields a to 50% of the population). The dose ratio between toxic and powder of the active ingredient plus any additional desired therapeutic effects is the therapeutic index, and it can be ingredient from a previously sterile-filtered solution thereof. expressed as the ratio, LDso/EDso. Pharmaceutical composi Oral compositions generally include an inert diluent or an tions that exhibit large therapeutic indices are preferred. The edible pharmaceutically acceptable carrier. They can be dosage may vary within this range depending upon the dosage enclosed in gelatin capsules or compressed into tablets. For form employed, sensitivity of the patient, and the route of the purpose of oral therapeutic administration, the active administration. compound can be incorporated with excipients and used in Dosage and administration are adjusted to provide suffi the form of tablets, troches, or capsules. Oral compositions cient levels of the active agent(s) or to maintain the desired 10 can also be prepared using a fluid carrier for use as a mouth effect. Factors which may be taken into account include the wash, wherein the compound in the fluid carrier is applied severity of the disease state, general health of the Subject, age, orally and Swished and expectorated or swallowed. Pharma weight, and gender of the Subject, diet, time and frequency of ceutically compatible binding agents, and/or adjuvant mate administration, drug combination(s), reaction sensitivities, rials can be included as part of the composition. The tablets, and tolerance/response to therapy. Long-acting pharmaceuti 15 pills, capsules, troches and the like can contain any of the cal compositions may be administered every 3 to 4 days, following ingredients, or compounds of a similar nature: a every week, or once every two weeks depending on half-life binder Such as microcrystalline cellulose, gum tragacanth or and clearance rate of the particular formulation. gelatin; an excipient Such as starch or lactose, a disintegrating The pharmaceutical compositions containing active com agent such as alginic acid, Primogel, or corn starch; a lubri pounds of the present invention may be manufactured in a cant such as magnesium Stearate or Sterotes; a glidant Such as manner that is generally known, e.g., by means of conven colloidal silicon dioxide; a Sweetening agent such as Sucrose tional mixing, dissolving, granulating, dragee-making, levi or saccharin; or a flavoring agent Such as peppermint, methyl gating, emulsifying, encapsulating, entrapping, or lyophiliz salicylate, or orange flavoring. ing processes. Pharmaceutical compositions may be For administration by inhalation, the compounds are deliv formulated in a conventional manner using one or more phar 25 ered in the form of an aerosol spray from pressured container maceutically acceptable carriers comprising excipients and/ or dispenser, which contains a suitable propellant, e.g., a gas or auxiliaries that facilitate processing of the active com Such as carbon dioxide, or a nebulizer. pounds into preparations that can be used pharmaceutically. Systemic administration can also be by transmucosal or Of course, the appropriate formulation is dependent upon the transdermal means. For transmucosal or transdermal admin route of administration chosen. 30 istration, penetrants appropriate to the barrier to be permeated Pharmaceutical compositions suitable for injectable use are used in the formulation. Such penetrants are generally include sterile aqueous solutions (where water soluble) or known in the art, and include, for example, for transmucosal dispersions and sterile powders for the extemporaneous administration, detergents, bile salts, and fusidic acid deriva preparation of sterile injectable solutions or dispersion. For tives. Transmucosal administration can be accomplished intravenous administration, Suitable carriers include physi 35 through the use of nasal sprays or Suppositories. For trans ological saline, bacteriostatic water, Cremophor ELTM dermal administration, the active compounds are formulated (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS). into ointments, salves, gels, or creams as generally known in In all cases, the composition must be sterile and should be the art. fluid to the extent that easy syringeability exists. It must be The active compounds can be prepared with pharmaceuti stable under the conditions of manufacture and storage and 40 cally acceptable carriers that will protect the compound must be preserved against the contaminating action of micro against rapid elimination from the body, Such as a controlled organisms such as bacteria and fungi. The carrier can be a release formulation, including implants and microencapsu Solvent or dispersion medium containing, for example, water, lated delivery systems. Biodegradable, biocompatible poly ethanol, polyol (for example, glycerol, propylene glycol, and mers can be used, such as ethylene vinyl acetate, polyanhy liquid polyethylene glycol, and the like), and Suitable mix 45 drides, polyglycolic acid, collagen, polyorthoesters, and tures thereof. The proper fluidity can be maintained, for polylactic acid. Methods for preparation of such formulations example, by the use of a coating Such as lecithin, by the will be apparent to those skilled in the art. The materials can maintenance of the required particle size in the case of dis also be obtained commercially from Alza Corporation and persion and by the use of surfactants. Prevention of the action Nova Pharmaceuticals, Inc. Liposomal Suspensions (includ of microorganisms can be achieved by various antibacterial 50 ing liposomes targeted to infected cells with monoclonal and antifungal agents, for example, parabens, chlorobutanol, antibodies to viral antigens) can also be used as pharmaceu phenol, ascorbic acid, thimerosal, and the like. In many cases, tically acceptable carriers. These can be prepared according it will be preferable to include isotonic agents, for example, to methods known to those skilled in the art, for example, as Sugars, polyalcohols such as manitol, Sorbitol, Sodium chlo described in U.S. Pat. No. 4,522,811. ride in the composition. Prolonged absorption of the inject 55 It is especially advantageous to formulate oral or parenteral able compositions can be brought about by including in the compositions in dosage unit form for ease of administration composition an agent which delays absorption, for example, and uniformity of dosage. Dosage unit form as used herein aluminum monostearate and gelatin. refers to physically discrete units Suited as unitary dosages for Sterile injectable solutions can be prepared by incorporat the Subject to be treated; each unit containing a predetermined ing the active compound in the required amount in an appro 60 quantity of active compound calculated to produce the priate solvent with one or a combination of ingredients enu desired therapeutic effect in association with the required merated above, as required, followed by filtered sterilization. pharmaceutical carrier. The specification for the dosage unit Generally, dispersions are prepared by incorporating the forms of the invention are dictated by and directly dependent active compound into a sterile vehicle that contains a basic on the unique characteristics of the active compound and the dispersion medium and the required other ingredients from 65 particular therapeutic effect to be achieved. those enumerated above. In the case of sterile powders for the In therapeutic applications, the dosages of the pharmaceu preparation of sterile injectable solutions, methods of prepa tical compositions used in accordance with the invention vary US 8,263,610 B2 167 168 depending on the agent, the age, weight, and clinical condi alkali metalion, an alkaline earth ion, oran aluminum ion; or tion of the recipient patient, and the experience and judgment coordinates with an organic base Such as ethanolamine, of the clinician or practitioner administering the therapy, diethanolamine, triethanolamine, tromethamine, N-methyl among other factors affecting the selected dosage. Generally, glucamine, and the like. the dose should be sufficient to result in slowing, and prefer It should be understood that all references to pharmaceu ably regressing, the growth of the tumors and also preferably tically acceptable salts include solvent addition forms (sol causing complete regression of the cancer. Dosages can range Vates) or crystal forms (polymorphs) as defined herein, of the from about 0.01 mg/kg per day to about 5000 mg/kg per day. same salt. In preferred aspects, dosages can range from about 1 mg/kg The compounds of the present invention can also be pre per day to about 1000 mg/kg per day. In an aspect, the dose 10 pared as esters, for example, pharmaceutically acceptable will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to esters. For example, a carboxylic acid function group in a about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 compound can be converted to its corresponding ester, e.g., a mg to about 1 g/day, in single, divided, or continuous doses methyl, ethyl or other ester. Also, an alcohol group in a (which dose may be adjusted for the patients weight in kg, 15 compound can be converted to its corresponding ester, e.g., an body surface area in m, and age in years). An effective acetate, propionate or other ester. amount of a pharmaceutical agent is that which provides an The compounds of the present invention can also be pre objectively identifiable improvement as noted by the clinician pared as prodrugs, for example, pharmaceutically acceptable or other qualified observer. For example, regression of a prodrugs. The terms “pro-drug and “prodrug” are used inter tumor in a patient may be measured with reference to the changeably herein and refer to any compound which releases diameter of a tumor. Decrease in the diameter of a tumor an active parent drug in vivo. Since prodrugs are known to indicates regression. Regression is also indicated by failure of enhance numerous desirable qualities of pharmaceuticals tumors to reoccur after treatment has stopped. As used herein, (e.g., Solubility, bioavailability, manufacturing, etc.), the the term “dosage effective manner” refers to amount of an compounds of the present invention can be delivered in pro active compound to produce the desired biological effect in a 25 drug form. Thus, the present invention is intended to cover subject or cell. prodrugs of the presently claimed compounds, methods of The pharmaceutical compositions can be included in a delivering the same and compositions containing the same. container, pack, or dispenser together with instructions for “Prodrugs are intended to include any covalently bonded administration. carriers that release an active parent drug of the present inven The compounds of the present invention are capable of 30 tion in vivo when Such prodrug is administered to a Subject. further forming salts. All of these forms are also contemplated Prodrugs in the present invention are prepared by modifying within the scope of the claimed invention. functional groups present in the compound in such away that As used herein, “pharmaceutically acceptable salts' refer the modifications are cleaved, either in routine manipulation to derivatives of the compounds of the present invention or in vivo, to the parent compound. Prodrugs include com wherein the parent compound is modified by making acid or 35 pounds of the present invention wherein a hydroxy, amino, base salts thereof. Examples of pharmaceutically acceptable Sulfhydryl, carboxy or carbonyl group is bonded to any group salts include, but are not limited to, mineral or organic acid that may be cleaved in vivo to form a free hydroxyl, free salts of basic residues such as amines, alkali or organic salts of amino, free Sulfhydryl, free carboxy or free carbonyl group, acidic residues such as carboxylic acids, and the like. The respectively. pharmaceutically acceptable salts include the conventional 40 Examples of prodrugs include, but are not limited to, esters non-toxic salts or the quaternary ammonium salts of the par (e.g., acetate, dialkylaminoacetates, formates, phosphates, ent compound formed, for example, from non-toxic inorganic Sulfates and benzoate derivatives) and carbamates (e.g., N.N- or organic acids. For example, such conventional non-toxic dimethylaminocarbonyl) of hydroxy functional groups, salts include, but are not limited to, those derived from inor esters (e.g., ethyl esters, morpholinoethanol esters) of car ganic and organic acids selected from 2-acetoxybenzoic, 45 boxyl functional groups, N-acyl derivatives (e.g., N-acetyl) 2-hydroxyethane Sulfonic, acetic, ascorbic, benzene Sulfonic, N-Mannich bases, Schiff bases and enaminones of amino benzoic, bicarbonic, carbonic, citric, edetic, ethane disul functional groups, oximes, acetals, ketals and enol esters of fonic, 1.2-ethane Sulfonic, fumaric, glucoheptonic, gluconic, ketone and aldehyde functional groups in compounds of the glutamic, glycolic, glycolyarsanilic, hexylresorcinic, hydra invention, and the like, See Bundegaard, H., Design of Pro bamic, hydrobromic, hydrochloric, hydroiodic, hydroxyma 50 drugs, p 1-92, Elesevier, N.Y.-Oxford (1985). leic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl The compounds, or pharmaceutically acceptable salts, Sulfonic, maleic, malic, mandelic, methane Sulfonic, nap esters or prodrugs thereof, are administered orally, nasally, sylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phos transdermally, pulmonary, inhalationally, buccally, Sublin phoric, polygalacturonic, propionic, salicyclic, Stearic, Sub gually, intraperintoneally, Subcutaneously, intramuscularly, acetic, succinic, Sulfamic, Sulfanilic, Sulfuric, tannic, tartaric, 55 intravenously, rectally, intrapleurally, intrathecally and toluene Sulfonic, and the commonly occurring amine acids, parenterally. In one embodiment, the compound is adminis e.g., glycine, alanine, phenylalanine, arginine, etc. tered orally. One skilled in the art will recognize the advan Other examples of pharmaceutically acceptable salts tages of certain routes of administration. include hexanoic acid, cyclopentane propionic acid, pyruvic The dosage regimen utilizing the compounds is selected in acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin 60 accordance with a variety of factors including type, species, namic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene age, weight, sex and medical condition of the patient; the Sulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, severity of the condition to be treated; the route of adminis 4-methylbicyclo-2.2.2-oct-2-ene-1-carboxylic acid, 3-phe tration; the renal and hepatic function of the patient; and the nylpropionic acid, trimethylacetic acid, tertiary butylacetic particular compound or salt thereof employed. An ordinarily acid, muconic acid, and the like. The present invention also 65 skilled physician or veterinarian can readily determine and encompasses salts formed when an acidic proton present in prescribe the effective amount of the drug required to prevent, the parent compound either is replaced by a metalion, e.g., an counter or arrest the progress of the condition. US 8,263,610 B2 169 170 Techniques for formulation and administration of the dis- -continued closed compounds of the invention can be found in Reming- N-N ton: the Science and Practice of Pharmacy, 19" edition, W Mack Publishing Co., Easton, Pa. (1995). In an embodiment, 21NN the compounds described herein, and the pharmaceutically 5 acceptable salts thereof, are used in pharmaceutical prepara- N N tions in combination with a pharmaceutically acceptable car- R.-- rier or diluent. Suitable pharmaceutically acceptable carriers 2 include inert solid fillers or diluents and sterile aqueous or organic Solutions. The compounds will be present in Such 10 pharmaceutical compositions in amounts Sufficient to pro vide the desired dosage amount in the range described herein. All percentages and ratios used herein, unless otherwise Example 1 or Compound 1 (Table 1) indicated, are by weight. Other features and advantages of the 15 present invention are apparent from the different examples. Synthesis of 7-(3,4-dichlorophenyl)-6,7-dihydro-3H The provided examples illustrate different components and benzof pyrazolo 3,4-cisoquinoline methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present disclosure the skilled artisan can identify and employ 20 other components and methodology useful for practicing the N-NH present invention.

5. Examples 25 General Procedure A: Compounds of the present invention can be conveniently prepared by the general procedure illus trated below: 30

C N DMF-DMA R.-- -- 35 C 100° C., 24h Step 1. Synthesis of (E)-4-(3,4-dichlorophenyl)-2-(dim R ethylamino)methylene)-3,4-dihydronaphthalen-1 (2H)-one. 4. The mixture of 4-(3,4-dichlorophenyl)-3,4-dihydronaphtha len-1 (2H)-one (10.0 g, 34.5 mmol) in 1,1-dimethoxy-N,N- dimethylmethanamine (80 mL) was heated at 110°C. for 24 W \ hours. The excess 1,1-dimethoxy-N,N-dimethylmetha N namine was removed under reduced pressure. The residue 45 was dried on high vacuum to afford the yellowish desired product (11.5 g, 97%). The compound was used in Step-2 without any further purification. 1. Step 2. Synthesis of 7-(3,4-dichlorophenyl)-3-(4-meth N - 21 NN No oxybenzyl)-6,7-dihydro-3H-benzof pyrazolo 3,4-c iso (i) Hunig's Base, CH3COOH 50 quinoline. To the mixture of (E)-4-(3,4-dichlorophenyl)-2- 21 110° C. 1 h ((dimethylamino)methylene)-3,4-dihydronaphthalen-1 (ii) microwave, 220° C., 90 min (2H)-one (0.20 g, 0.58 mmol) and 1-(4-methoxybenzyl)-1H pyrazol-5-amine hydrochloride (0.14 g. 0.58 mmol) was added glacial acetic acid (5 mL) and Hunig's Base (0.4 mL). 55 The mixture was heated at 110°C. for 1 hour, then transferred to microwave vial and heated at 220° C. for 90 minutes. The Ns / reaction mixture was evaporated and dissolved in dichlo W N O romethane (100 mL), washed with water (30 mL), brine (30 21 NN CFCOOH mL), dried over sodium Sulfate and concentrated to dryness. Mew 60 The crude was purified by flash column chromatography 170° C., 90 min (SiO, 10% EtOAc inhexane) to give the pure desired product S1S as a brown solid (0.15g. 53%). M.p.=76-78° C.; H NMR R; it (CDC1,400 MHz) 89.53 (d. J=8 Hz, 1H), 8.32 (s, 1H), 8.02 21 (s, 1H), 7.54 (t, J=6.8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.35-7.26 65 (m, 4H), 7.06 (d. J=8 Hz, 1H), 6.96 (d. J=8 HZ, 1H), 6.843 (d. R J=7.2 Hz, 2H), 4.28 (t, J=8 Hz, 1H), 4.17 (s. 2H), 3.77 (s.3H), 3.29-3.26 (m, 2H); LCMS: 486 IM+1.

US 8,263,610 B2 175 176 The compound, 6,9-dihydro-5H-pyrazolo 3.4-k1.8 7.11 (s, 1H), 6.76 (d. J=2.4 Hz, 2H), 3.89 (s.3H), 3.84 (s.3H), phenanthroline was prepared using 6,7-dihydroquinolin-8 2.95-2.82 (m, 4H); LCMS M+H: 282. (5H)-one as described in the 3 step general procedure A. The Example 13 crude product was purified using reverse phase HPLC to give the desired product as a yellow solid (0.027 g., 0.12 mmol). Synthesis of 10-bromo-6,7-dihydro-3H-benzof M.p.=263-265° C.; H NMR (DMSO-d) 400 MHz 8: 13.67 pyrazolo 3,4-cisoquinoline (s, 1H), 8.61 (dd, J=1.5, 4.7 Hz, 1H), 8.10 (d. J=3.2 Hz, 2H), 7.73 (d. J–7.4 Hz, 1H), 7.35 (dd, J=2.7, 7.4 Hz, 1H), 2.97 (ddt, J=3.0, 7.2, 9.2 Hz, 4H), LCMS M+H: 223. Elemental Analysis calculated for CHN: % C, 70.76, 96 H, 4.54% 10 N-NH N, 25.21. Found CHN 0.08 (CFCOH):% C, 68.21, 9% H, 4.36, 96 N, 23.66. Br Example 11 15

Synthesis of 9-methoxy-6,7-dihydro-3H-benzof pyrazolo 3,4-cisoquinoline The compound, 10-bromo-6,7-dihydro-3H-benzof pyra Zolo3.4-cisoquinoline was prepared using 7-bromo-3,4-di hydronaphthalen-1 (2H)-one as described in the 3 step general procedure A. The crude product was purified using reverse N-NH phase HPLC to give the desired product as a yellow solid (0.032g, 0.11 mmol). H NMR (DMSO-d)400 MHz 8:9.55 21 NN 25 (s, 1H), 8.59 (d. J=1.0 Hz, 1H), 8.35 (dd, J=1.2, 2.4 Hz, 1H), 7.71 (dd, J=2.3.4.2 Hz, 1H), 7.43 (d. J=7.9 Hz, 1H), 6.90-6.65 S. (m. 1H), 2.95-2.82 (m, 4H); LCMS M+H: 299. Example 14 No 30 Synthesis of 10-nitro-6,7-dihydro-3H-benzof pyra Zolo3.4-cisoquino line The compound, 9-methoxy-6,7-dihydro-3H-benzof pyrazolo 3,4-cisoquinoline was prepared using 6-methoxy N-NH 3,4-dihydronaphthalen-1 (2H)-one as described in the 3 step 35 general procedure A. The crude product was purified using 21 N reverse phase HPLC to give the desired product as a yellow solid (0.022 g, 0.088 mmol). H NMR (DMSO-d) 400 MHz ON N 8:9.30 (dd, J=1.5, 4.7 Hz, 1H), 8.48 (s, 1H), 8.25 (d. J=2.4 Hz, 1H), 7.12-6.92 (m, 2H), 6.90-6.68 (m, 2H), 3.84 (s, 3H), 40 2.95-2.82 (m, 4H); LCMS M+H: 252. The compound, 10-nitroo-6,7-dihydro-3H-benzof pyra Example 12 Zolo3.4-cisoquinoline was prepared using 7-nitro-3,4-dihy dronaphthalen-1 (2H)-one as described in the 3 step general 45 procedure A. The desired product was obtained as a yellow Synthesis of 9,10-dimethoxy-6,7-dihydro-3H-benzo solid (0.036 g). M.p.=214-217° C. "H NMR (CDC1) 400 fpyrazolo 3,4-cisoquinoline MHz & 10.43 (d. J=2.0 Hz, 1H), 8.49 (s, 1H), 8.32 (dd, J–2.6 and 8.4 Hz, 1H), 8.28 (d. J=2.4 Hz, 1H), 6.84 (d. J=2.4 Hz, 1H), 3.15-3.12 (m, 2H), 3.08-3.03 (m, 2H); LCMS M+H: 50 267. Example 15 Synthesis of 6,7-dihydro-3H-pyrazolo 4.3-a3.7 21 NN phenanthrolin-9(8H)-one -O S 55

No

60 The compound, 9,10-dimethoxy-6,7-dihydro-3H-benzof pyrazolo 3,4-cisoquinoline was prepared using 6.7- dimethoxy-3,4-dihydronaphthalen-1 (2H)-one as described in the 3 step general procedure A. The crude product was purified using reverse phase HPLC to give the desired product 65 as a yellow solid (0.072g, 0.26 mmol). H NMR (DMSO-d) 400MHz 8:9.10 (s, 1H), 8.51 (s, 1H), 8.31 (d. J–2.4 Hz, 1H), US 8,263,610 B2 177 178 The compound, 6,7-dihydro-3H-pyrazolo 4.3-a3.7 LCMS M+H: 377; Elemental analysis (%): C, 63.59; H, phenanthrolin-9(8H)-one was prepared using 2-methoxy-7, 4.10: N, 10.98. Calcd for CHBrN: C, 63.85; H, 3.75; N, 8-dihydroquinolin-5(6H)-one as described in the 3 step gen 11.17. eral procedure A. The desired product was obtained as a yellow solid (0.005 g). Mp=290-296° C.; H NMR (DMSO Example 17 de, 400 MHz) 8: 12.46 (brs, 1H), 9.27 (d. J=9.8 Hz, 1H), 8.42 (s, 1H), 8.23 (d. J=2.8 Hz, 1H), 6.68 (d. J=2.4 Hz, 1H), 6.40 Synthesis of 1-bromo-7-(2-chlorophenyl)-6,7-dihy (d. J=9.8 Hz, 1H), 2.92 (m, 4H); LC/MS M+H: 239. dro-3H-benzof pyrazolo 3,4-c isoquinoline General Procedure B: Compounds of the present invention can be conveniently prepared by the general procedure illus 10 trated below: N-NH

Example 16 Br 15 Synthesis of 1-bromo-7-phenyl-6,7-dihydro-3H benzof pyrazolo 3,4-cisoquinoline

N-NH

21 NN 25 The compound, 1-bromo-7-(2-chlorophenyl)-6,7-dihy N NBS, CH2Cl2 Her dro-3H-benzof pyrazolo 3,4-cisoquinoline was prepared RT, 16 h using 7-(2-chlorophenyl)-6,7-dihydro-3H-benzof pyrazolo 3,4-cisoquinoline as described in general procedure B. The desired product was obtained as solid. Mp=180-182°C.; H NMR (CDC1) 400 MHz 8:9.47 (d. J=1.2 Hz, 1H), 8.38 (s. 1H), 8.22 (s, 1H), 7.43-7.57 (m, 3H), 7.26 (s, 1H), 7.02-7.19 (m,3H), 6.81 (dd. 1H, J=7.8, 1.6 Hz), 4.87 (t, 1H, J=6.6 Hz), 35 3.29-3.43 (m, 2H); LC/MS M+H: 410. Example 18 Synthesis of tert-butyl 4-(4-(7-(2-chlorophenyl)-6,7- dihydro-3H-benzof pyrazolo 3,4-c isoquinolin-1- 40 yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

45

50

To a solution of 7-phenyl-6,7-dihydro-3H-benzof pyra Zolo3.4-c isoquinoline (0.018 g., 0.060 mmol) in dichlo romethane (2 mL) was added N-bromosuccinimide (0.011 g, 55 0.063 mmol). The reaction was stirred at room temperature for 16 hours followed by addition of water (2 mL) and dichlo romethane (3 mL). The organic layer was separated, dried using NaSO, filtered and concentrated under reduced pres 60 Sure. The crude product was purified using flash column chromatography (SiO, 10% EtOAc in hexane) to give the pure desired product, 1-bromo-7-phenyl-6,7-dihydro-3H To a solution of 1-bromo-7-(2-chloro-phenyl)-6,7-dihy benzof pyrazolo 3,4-c isoquinoline as a yellow solid (0.010 dro-3H-2,3,4-triaza-cyclopentacphenanthrene (0.119 g, g, 4.4%). M.p.-176-178° C.; H NMR (DMSO-de, 400 MHz) 65 0.29 mmol) in toluene (3 mL) and EtOH (1.5 mL) was added 89.36 (m, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 7.56 (m, 2H), 4-4-(4.4.5.5-tetramethyl-1,3,2dioxaborolan-2-yl)-pyra 7.30-7.15 (m, 6H), 4.73 (t, J=7.2 Hz, 1H), 3.42 (m, 2H): Zol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester-N- US 8,263,610 B2 179 180 acetyl-1-bronic acid (0.110g, 0.29 mmol) followed by aque General Procedure C: Compounds of the present invention ous solution of NaCO (0.18 g, 1.74 mmol) in water (1.74 can be conveniently prepared by the general procedure illus mL) and 1,1-bis(di-t-butylphosphino) ferrocene palladium trated below: dichloride (BDTBPF PdC, CASH 95408-45-0, 15 mg). The reaction was then purged with nitrogen and heated at 90° C. for 16 hours. On completion of the reaction, EtOAc (30 O mL) and water (20 mL) was added to the reaction mixture. The organic layer was separated, washed with brine (2x20 N DMF-DMA mL) and concentrated under reduced pressure to give the o He 10 Ri 100° C., 24h crude product. The crude product was purified by flash col 2 umn chromatography (SiO, 33% EtOAc in hexane) to give Step-1 the desired product,4--4-7-(2-chloro-phenyl)-6,7-dihydro 3H-2,3,4-triaza-cyclopentacphenanthren-1-yl-pyrazol-1- R y1}-piperidine-1-carboxylic acid tert-butyl ester (0.088 g. 15 52%), as an orange solid. M.p.=139-141° C.; 400 MHz H HN1 (N1 \, NMR (DMSO-d) 8: 9.52-9.47 (, 1H), 8.6 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.62-7.5 (m, 3H), 7.32-7.25 O (m. 1H), 7.22-7.15 (m, 1H), 7.06-7.02 (m, 1H), 6.96-6.92 (m, 1H), 4.82 (t, J=8 Hz, 1H), 4.48-4.38 (1H), 4.1-4.0 (m, 2H), N 21 N1 No 3.48-332 (m, 2H), 2.92 (brs, 2H), 2.1-2.0 (m, 2H), 1.88-1.76 R-H 2 2 CFCOOH (m. 2H), 1.42 (s, 9H); LCMS M+H: 581.6. 100° C., 24h R Step-2 Example 19 25 Synthesis of 7-(2-chlorophenyl)-1-(1-piperidin-4-yl 1H-pyrazol-4-yl)-6,7-dihydro-3H-benzof pyrazolo W -YC) O / 3,4-cisoquinoline 21 h CFCOOH 30 S1S 100° C., 6 h R-i Step-3 2

35 R N-NH 21 NN 40 N1S 2

45 R

Example 20 To a solution of 4-4-7-(2-chloro-phenyl)-6,7-dihydro 50 3H-2,3,4-triaza-cyclopentacphenanthren-1-yl-pyrazol-1- y1}-piperidine-1-carboxylic acid tert-butyl ester (0.068 g. Synthesis of 3,6,7,8-tetrahydrobenzo 6,7cyclohepta 0.117 mmol) in dichloromethane (5 mL) was added 4M HCl 1.2-dpyrazolo 3,4-bipyridine (g) in dioxane (0.3 mL). The reaction was shaken overnight at room temperature. A lot of orange solid were formed. On 55 completion, toluene (1 mL) was added and the solvent removed under reduced pressure. The crude product was puri fied using reverse phase HPLC to give the desired product, 7-(2-chloro-phenyl)-1-(1-piperidin-4-yl-1H-pyrazol-4-yl)- 6,7-dihydro-3H-2,3,4-triaza-cyclopentacphenanthrene 60 TFA salt, as an orange solid (0.042 g. 60%). MpD225°C.; H NMR (DMSO-d) 400 MHz 8:9.46 (d. J=7.43, 1H), 8.61 (s, 1H), 8.5 (brs, 2H), 8.25 (s, 1H), 8.04 (s, 1H), 7.48-7.58 (m, 3H), 7.14-7.25 (m, 2H), 6.90-7.02 (m, 2H), 4.79 (brs, 1H), 65 3.30-3.41 (m, 2H), 3.03-3.13 (m, 2H), 2.10-2.18 (m, 4H); LC/MS M+H: 481. US 8,263,610 B2 181 182 Step 1 2H), 5.69 (s. 2H), 3.76 (s.3H), 2.59 (q, J=6.0 Hz, 4H), 2.21 (quintet, J=7.2 Hz, 2H); LCMS M+H: 356. Synthesis of (E)-6-((dimethylamino)methylene)-6.7, 8.9-tetrahydro-5H-benzo.7 annulen-5-one Step 3

Synthesis of 3,6,7,8-tetrahydrobenzo 6,7cyclohepta 1.2-dpyrazolo 3,4-bipyridine

10

15

A solution of 6,7,8,9-tetrahydro-5H-benzo.7 annulen-5- one (1.0 g. 6.24 mmol) in 1,1-dimethoxy-N,N-dimethyl methanamine (2.5 mL) was heated at 100° C. for 24 hours. On completion of the reaction, the solvent was removed under reduced pressure. The oily residue was triturated with n-hex A solution of 3-(4-methoxybenzyl)-3,6,7,8-tetrahy ane (2x50 mL) to give the desired pure product, (E)-6-(dim drobenzo 6,7cyclohepta 1,2-dipyrazolo 3,4-bipyridine (2.0 ethylamino)methylene)-6,7,8,9-tetrahydro-5H-benzo 7an nulen-5-one (1.1 g, 82%) as a brown solid. "H NMR (CDCls, 25 g, 5.63 mmol) in trifluoroacetic acid (10 mL) was heated at 400 MHz): 8 7.75 (s, 1H), 7.62 (d. J=6.2 Hz, 1H), 7.34-7.25 100° C. for 6 hours. On completion of the reaction, the solvent (m. 2H), 7.09 (d. J=6.4 Hz, 1H), 3.11 (s, 6H), 2.75 (t, J=6.8 removed under reduced pressure. The residue was dissolved Hz, 2H), 2.35 (t, J=6.4 Hz, 2H), 1.83 (quintet, J=6.8 Hz, 2H). in water (20 mL) and then it was basified to pH=10 using LCMS M+H: 216. ammonium hydroxide. The aqueous layer was extracted with 30 10% methanol in dichloromethane (2x100 mL). The organic Step 2 extracts were combined, dried using sodium sulfate and con centrated under reduced pressure. The crude product was purified using flash column chromatography (SiO, gradient Synthesis of 3-(4-methoxybenzyl)-3,6,7,8-tetrahy 35 100% dichloromethane to 2% methanol in dichloromethane) drobenzo 6,7cyclohepta 1,2-dipyrazolo 3,4-bipyri to give the pure desired product (0.9 g, 68%) as off-colored dine solid. "H NMR (DMSO-de, 400 MHz): 8 13.58 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.44-7.36 (m, 40 3H), 7.32 (t, J=8.0 Hz, 1H), 2.60-2.38 (m, 4H), 2.15 (quintet, 3H); LCMS M+H: 236.

Example 21 45 Synthesis of 3,6-dihydrochromeno4,3-dipyrazolo 3,4-bipyridine

50 N-NH

To a mixture of 6,7,8,9-tetrahydro-5H-benzo.7 annulen-5- 55 one (8.5 g., 39.5 mmol) and 1-(4-methoxybenzyl)-1H-pyra Zol-5-amine (8.2 g 44.47 mmol) was added trifluoroacetic acid (4.25 mL, 54.3 mmol). The reaction mixture was heated at 100° C. for 24 hours. On completion of the reaction, the 60 Solvent was removed under reduced pressure and the crude The compound, 3,6-dihydrochromeno4,3-dipyrazolo.3, product was purified by flash column chromatography (SiO, 4-bipyridine was prepared using chroman-4-one as described gradient from 5% EtOAc in hexanes to 30% EtOAc in hex in the 3 step general procedure C. The desired product was anes) to give the desired product (4.2 g, 30%) as an off obtained as a yellow solid (0.230 g, 50%). "H NMR (DMSO colored solid. "H NMR (CDC1, 400 MHz) 8: 7.97 (s, 1H), 65 de, 400MHz): 8 13.66(s, 1H), 8.21 (d. J=7.6 Hz, 1H), 8.14 (s, 7.85 (s, 1H), 7.79 (d. J=7.2 Hz, 1H), 7.46-7.44 (m, 1H), 7.38 1H), 8.11 (s, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, (d. J=7.6 Hz, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 6.84 (d. J=7.6 Hz, 1H), 7.03 (d. J=8 Hz, 1H), 5.34 (s. 2H); LCMS M+H: 224. US 8,263,610 B2 183 184 Example 22 12.84 (bs, 1H), 8.40 (s, 1H), 8.14 (s. 2H), 7.49-7.60 (m, 3H), 4.07 (q, J=7.2 Hz, 1H), 1.61 (d. J=7.2 Hz, 1H); LCMS Synthesis of 3,6-dihydropyrazolo 3,4-bithio M+H: 222. chromeno 4.3-dipyridine Example 25 N-NH Synthesis of 3,7-dihydroisothiochromeno4.3-d pyrazolo 3,4-bipyridine 21 NN N 10 N-NH

S NY The compound 3,6-dihydropyrazolo 3,4-bithiochromeno 15 4,3-dipyridine was prepared using thiochroman-4-one as S described in the 3 step general procedure C. The desired product was obtained as a yellow colored solid (0.400 g, The compound, 3,7-dihydroisothiochromeno4.3-dipyra 30%). H NMR (CDC1,400 MHz): & 10.55 (s, 1H), 8.43 (d. Zolo3.4-bipyridine was prepared using isothiochroman-4- J=6.8 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 741-7.25 (m, 3H), one as described in the 3 step general procedure C. The 4.07 (s. 2H); LCMS M+H: 240. desired product was obtained as a yellow colored solid (0.500 g, 75%). H NMR (CDC1, 400 MHz): 8 13.70 (1H, s), Example 23 8.27-8.24 (m, 2H), 8.07 (s, 1H), 7.48-7.39 (m, 3H), 4.05 (s, 2H); LCMS M+H: 240. Synthesis of 7-methyl-6,7-dihydro-3H-benzof pyra 25 Example 26 Zolo3.4-cisoquinoline Synthesis of 6,7-dihydro-3H-1 benzoxepino 5,4-d pyrazolo 3,4-bipyridine N-NH 30 21 NN N 35

The compound, 7-methyl-6,7-dihydro-3H-benzof pyra The compound, 6,7-dihydro-3H-1 benzoxepino 5,4-d Zolo3.4-cisoquinoline was prepared using 4-methyl-3,4-di 40 pyrazolo 3,4-bipyridine was prepared using 3,4-dihy hydronaphthalen-1 (2H)-one as described in the 3 step general procedure C. The desired product was obtained as a yellow drobenzo boxepin-5(2H)-one as described in the 3 step gen colored solid (0.230 g, 70%). "H NMR (DMSO-d 400 eral procedure C. The desired product was obtained as a MHz): 8 13.53 (s, 1H), 8.30 (dd, J=8.8, 4.0 Hz, 1H), 8.05 (s, yellow colored solid (0.150 g, 75%). "H NMR (DMSO-d 2H), 7.34-7.42 (m,3H), 3.09-3.18 (m, 2H), 2.83 (dd, J=12.0, 45 400 MHz): 8 13.65 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.77 (d. 5.6 Hz, 1H), 1.17 (s) and 1.15 (s), 3H; LCMS M+H: 236. J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.16 (d. J=8.0 Hz, 1H), 4.49 (t, J=6.0 Hz, 2H)), 2.89 (t, J=5.6 Example 24 Hz, 2H); LCMS M+H: 238. Example 27 50 Synthesis of 6-methyl-3,6-dihydroindeno1,2-d Synthesis of 6-phenyl-3,6-dihydrochromeno4.3-d pyrazolo 3,4-bipyridine pyrazolo 3,4-bipyridine N-NH W 55 21 NN N

60

The compound, 6-methyl-3,6-dihydroindeno1,2-dipyra Zolo3.4-bipyridine was prepared using 3-methyl-2,3-dihy dro-1H-inden-1-one as described in the 3 step general proce 65 dure C. The desired product was obtained as a yellow colored solid (0.400 g, 41%). H NMR (DMSO-de, 400 MHz): 8 US 8,263,610 B2 185 186 The compound, 6-phenyl-3,6-dihydrochromeno 4.3-d Example 30 pyrazolo 3,4-bipyridine was prepared using 2-phenylchro man-4-one as described in the 3 step general procedure C. The Synthesis of N-(6,7-dihydro-3H-benzof pyrazolo.3, desired product was obtained as a yellow colored solid (0.142 4-cisoquinolin-9-yl)acetamide g, 66%). "H NMR (DMSO-de, 400 MHz): 8 13.72 (s, 1H), 8.22 (t, J=7.6 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.44-7.30 (m, 6H), 7.14 (t, J=7.2 Hz, 1H), 7.06 (d. J=7.6 Hz, 1H), 6.62 (s, 1H); LCMS M+H: 300. 10 AcO, Pyridine Example 28 He RT, 3 h Synthesis of HN Step-1 O 3,6-dihydroindeno1,2-dipyrazolo 3,4-bipyridine 15

O General Procedure C He N-NH - H N-NH W 1. 25 - The compound, 3,6-dihydroindeno1,2-dipyrazolo 3,4-b 30 pyridine was prepared using 2,3-dihydro-1H-inden-1-one as Step 1 described in the 3 step general procedure C. The desired product was obtained as a solid (0.5 g, 79%). H NMR Synthesis of N-(5-oxo-5,6,7,8-tetrahydronaphthalen 2-yl)acetamide (CDOD, 400 MHz): 88.30 (s, 1H), 8.15-8.10 (m, 1H), 8.05 35 (s, 1H), 7.79-7.70 (m. 1H), 7.52-748 (m, 2H), 4.00 (s. 2H): To a solution of 6-amino-3,4-dihydronaphthalen-1 (2H)- LCMS M+H: 208. one (0.5 g, 3.1 mmol) in pyridine (5 mL) was added acetic anhydride (0.38 g, 3.7 mmol). The solution was stirred at Example 29 room temperature for 3 hours. The reaction was then diluted 40 with dichloromethane (50 mL). The organic layer was sepa rated, washed with 2M HCl (2x25 mL), brine (50 mL), dried Synthesis of 3,6,7,8-tetrahydropyrazolo 4.3':5,6 using sodium sulfate and concentrated under reduced pres pyrido 3,4-d1 benzazepine sure. The crude was product was obtained as an off colored solid (0.5 g. 79%) and used in the next reaction without any 45 further purification. "H NMR (CDC1, 400 MHz): 8 8.94 (d.

J=8.0 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.20 (d. J=8.0 Hz, 1H0, 2.96 (t, J–6.2 Hz, 2H), 2.62 (quintet, J=6.0Hz, 2H), 2.12 (s, 3H), 2.11 (t, J=6.0 Hz, 2H); LCMS M+H: 204. 50 Step 2 Synthesis of N-(6,7-dihydro-3H-benzof pyrazolo.3, 4-cisoquinolin-9-yl)acetamide 55

N-NH

The compound, 3,6,7,8-tetrahydropyrazolo 4',3':5,6py 60 rido3,4-d1 benzazepine was prepared using 3,4-dihydro 1H-benzoblazepin-5(2H)-one as described in the 3 step gen eral procedure C. The desired product was obtained as a solid (0.022g, 19%). Mp.=215-217°C., H NMR (DMSO-de, 400 ul MHz): 8 8.05 (s, 1H), 7.9 (s, 1H), 7.8-7.72 (m, 1H), 6.8-6.7 65 N (m. 2H), 7.2-7.12 (m, 2H), 5.78-5.7 (m, 2H), 3.6-3.52 (m, 2H); LCMS M+H: 237. US 8,263,610 B2 187 188 The compound, N-(6,7-dihydro-3H-benzof pyrazolo.3, 8.00 (s. 2H), 7.70 (s, 1H), 6.90 (s, 1H), 3.09 (t, J=6.2 Hz, 2H), 4-cisoquinolin-9-yl)acetamide was prepared using N-(5- 2.96 (t, J=6.2 Hz, 2H); LCMS M+H: 212. oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide aS described in the 3 step general procedure C. The desired Example 32 product was obtained as a yellow colored solid (0.25 g, 99%). 5 H NMR (CDC1,400 MHz): 8 13.46 (s, 1H), 10.08 (s, 1H), Synthesis of 6,7-dihydro-3H-pyrazolo 3,4-c thieno 8.20 (d. J=8.0 Hz, 1H), 8.05 (s, 1H), 5.00 (s, 1H), 7.66 (d. 3.2-fisoquinoline J=8.0 Hz, 1H), 7.60 (s, 1H), 3.00 (t, J=6.0 Hz, 2H), 2.84 (t, N-NH

J=6.0 Hz, 1H). 2.05 (s.3H); LCMS M+H: 279. 10 General Procedure D: Compounds of the present invention can be conveniently prepared by the general procedure illus trated below:

Example 31 15 The compound, 6,7-dihydro-3H-pyrazolo 3,4-c thieno3, Synthesis of 6,7-dihydro-3H-furo3.2-fpyrazolo.3, 2-fisoquinoline was prepared using 6,7-dihydrobenzob 4-cisoquinoline thiophen-4(5H)-one as described in the 3 step general proce dure D. The desired product was obtained as a yellow colored solid (0.130 g, 55%). H NMR (DMSO-de, 400 MHz): 8 13.45 (s, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.60 (d. J–4.8 Hz, 1H), 7.44 (d. J=4.8 Hz, 1H), 3.12 (t, J=6.8 Hz, 2H), 3.03 (t, 25 J=7 Hz, 2H); LCMS M+H: 228. Bredreck's Reagent, Toluene 100° C., 4 days Example 33 Synthesis of 3H-spirochromeno4.3-dpyrazolo 3,4- 30 bipyridine-6,4'-piperidine N-NH 21 NN General Procedure C 35 He N

NH 40 The compound, 3H-spirochromeno4.3-dpyrazolo 3,4- bipyridine-6,4'-piperidine was prepared using tert-butyl 4-oxospirochroman-2,4'-piperidine-1'-carboxylate aS 45 described in the 3 step general procedure D. The desired product was obtained as a solid (0.015 g, 42%). H NMR (CDC1, 400 MHz): 8 8.057 (s, 1H), 8.05 (s, 1H), 7.88 (dd, J=8.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.078 (d. J=8.0 Hz, 1H), 6.90 (d. J=8.0 Hz), 5.94 (s, 1H), 3.59 (d. J–3.2 Hz, 2H), 50 2.95 (t, J=5.2 Hz, 2H), 2.10-2.00 (m, 4H); LCMS M+H: Step 1: Synthesis of (E)-5-(dimethylamino)methylene)-6, 293. 7-dihydrobenzofuran-4(5H)-one. A solution of 6,7-dihy drobenzofuran-4(5H)-one (1.0 g, 7.3 mmol) and Bredreck’s Example 34 reagent (1.53 g, 8.81 mmol) in toluene (10 mL) was heated at 100° C. for 4 days. On completion of the reaction, the solvent 55 Synthesis of 6,7-dihydro-3H-benzof pyrazolo 3,4-c. was removed under reduced pressure to give the desired prod isoquinolin-8-ol uct as a brown oil (0.6 g., 43%). The crude product was used in the next step without any further purification. LCMS M+H: 192. Step 2: Synthesis of 6,7-dihydro-3H-furo3.2-fpyrazolo 60 3,4-c isoquinoline. The compound, 6,7-dihydro-3H-furo3, TBDMS-Cl, Imidazole 2-fpyrazolo 3,4-cisoquinoline was prepared using (E)-5- He ((dimethylamino)methylene)-6,7-dihydrobenzofuran-4 RT, 16h (5H)-one as described in the general procedure C (Steps 2 and 65 Step 1 3). The desired product was obtained as a yellow colored solid OH (0.035 g, 55%). "H NMR (CDC1,400 MHz): 8 13.4 (s, 1H), US 8,263,610 B2 189 -continued -continued O

General Procedure D n N DMF-DMA He -- Reflux, 16h 2 1. N S Step-3 OTBDMS

(SNN HN \{ X- OCH CFCOOH, 100° C., 16 h Step-4 15 / OH Step-1: Synthesis of 5-(tert-butyldimethylsilyloxy)-3,4- dihydronaphthalen-1 (2H)-one. To a solution of 5-hydroxy-3, Y 4-dihydronaphthalen-1 (2H)-one (0.5g, 3.08 mmol) in DMF (5 mL) was added Imidazole (0.527 g, 7.74 mmol) and tert butyldimethylsilyl chloride (0.581 g, 3.8 mmol). The reaction r mixture was stirred at room temperature for 16 hours. Ice N-se cooled water (50 mL) was then added and the reaction mix 25 ture extracted with EtOAc (3x50 mL). The organic extracts Step 1: Synthesis of 2-((dimethylamino)methylene)cyclo were combined, washed with 2NNaOH (2x30 mL), water (50 mL), dried using sodium sulfate and concentrated under hexane-1,3-dione. A mixture of cyclohexane-1,3-dione (10g, reduced pressure to give (0.6 g. 70%) of the desired productas 89 mmol) and DMF-dimethylacetal (21.2 mL, 178 mmol) an oil. The crude product was used in the next step without 30 was stirred at room temperature for 16 hours. On completion further purification. "H NMR (CDC1, 400 MHz): 8 7.96 (d. of the reaction, the reaction mixture was concentrated under J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.96 (d. J=8.0 Hz, 1H), reduced pressure and the residue triturated with hexane (50 2.87 (t, J=6.0 Hz, 2H), 2.61 (t, J=6.2 Hz, 2H), 2.14 (quintet, J=6.0 Hz, 2H), 1.04 (s.9H), 0.14 (s, 6H); LCMS (M+H): 277. mL) to give the desired product as a solid. "H NMR (CDC1, Step 2: Synthesis of 6,7-dihydro-3H-benzof pyrazolo.3, 400 MHz): 88.0 (s, 1H), 3.35 (s, 3H), 3.14 (s, 3H), 2.41 (t, 4-cisoquinolin-8-ol. The compound, 6,7-dihydro-3H-benzo 35 J=6.2 Hz, 4H), 1.92 (quintet, J=6.2 Hz, 2H). LCMS M+H: fpyrazolo 3,4-cisoquinolin-8-ol was prepared using 168. 5-(tert-butyldimethylsilyloxy)-3,4-dihydronaphthalen-1 Step 2: Synthesis of 2-(methylthio)-7,8-dihydroquinazo (2H)-one as described in the 3 step general procedure D. The lin-5(6H)-one. To a solution of 2-(dimethylamino)methyl desired product was obtained as a solid (0.2g,37%). "HNMR 40 ene)cyclohexane-1,3-dione (0.5g, 2.9 mmol) in DMF (2 mL) (DMSO-de, 400 MHz): 8 13.50 (s, 1H), 9.48 (s, 1H), 8.10 (s, was added sodium acetate (0.39 g, 4.7 mmol) and methyl 2H), 7.82 (d. J=8 Hz, 1H), 7.22 (t, J=8 Hz, 1H), 6.90 (d. J=8 carbamimidothioate (0.9 g, 3.5 mmol). The reaction mixture HZ, 1H), 3.16-2.94 (m, 2H), 2.90-2.82 (m, 2H); LCMS was heated at 100° C. for 5 hours. On completion of the M+H: 238. reaction, the reaction mixture was diluted with dichlo Example 35 45 romethane (30 mL). The organic layer was separated and washed with water (2x30 mL). The solvent was then removed Synthesis of 3-(4-methoxybenzyl)-9-(methylsulfa under reduced pressure and the residue dissolved in EtOAc nyl)-6,7-dihydro-3H-pyrazolo4".3',5,6]pyrido4.3-f (50 mL) and washed with water (2x30 mL). The organic layer quinazoline was dried using Sodium sulfate and concentrated under 50 reduced pressure to give the desired product (0.5g, 86%) as a solid. "H NMR (CDC1,400 MHz): 88.94 (s, 1H), 3.01 (t, J=6 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.58 (s, 3H), 2.14 (quintet, J=6.2 Hz, 2H), LCSM M+H: 195. DMF-DMA He Step 3: Synthesis of (E)-6-((dimethylamino)methylene)-2- RT, 16 h 55 (methylthio)-7,8-dihydroquinazolin-5(6H)-one. To a solu Step-1 tion of 2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1.0 mmol) in toluene (3 mL) was added DMFDMA (0.2 mL, 1.5 mmol). The reaction mixture was then refluxed for 16 -N NH 60 hours. The reaction mixture was then cooled to room tem perature and concentrated under reduced pressure. The crude 's-N- Nulls compound was purified by flash column chromatography Ns NH2 (SiO, gradient from 100% dichloromethane to 2% methanol NaOAc, DMF 100° C., 5 h in dichloromethane) to give the pure desired product (0.15g. 65 60%) as a solid. "H NMR (CDC1,400 MHz): 8 9.0 (s, 1H), Step-2 7.72 (s, 1H), 3.18 (s, 6H), 2.98 (t, J=6.0Hz, 2H), 2.92 (t, J–6.0 Hz, 2H), 2.60 (s.3H); LCMS M+H: 250. US 8,263,610 B2 191 192 Step 4: Synthesis of 3-(4-methoxybenzyl)-9-(methylsulfa solved in ethylacetate (200 mL) and washed with water (2x20 nyl)-6,7-dihydro-3H-pyrazolo4".3':5,6pyrido4.3-f mL), dried using anhydrous sodium sulfate, filtered and con quinazoline. To a mixture of (E)-6-(dimethylamino)methyl centrated under reduced pressure to give the desired product, ene)-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (8 g. 3-(4-methoxybenzyl)-9-(methylsulfonyl)-6,7-dihydro-3H 32 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine pyrazolo4".3':5,6pyrido4.3-fcquinazoline (1.5 g., 77%) as a (7.2g, 35 mmol) was added trifluoroacetic acid (3 mL). The tan solid. LCMS M+H: 422. The compound was used with reaction mixture was heated at 100° C. for 16 hours. The out any further purification. reaction was cooled to room temperature and diluted with a General Procedure E: Compounds of the present invention 1:1 mixture of methanol and isopropanol (40 mL). The mix can be conveniently prepared by the general procedure illus ture was stirred for 30 minutes and filtered. The solid obtained trated below: was then further purified using flash column chromatography 10 (SiO, gradient from 100% chloroform to 2% EtOAc in chlo Synthesis of N-substituted 6,7-dihydro-3H-pyrazolo roform) to give the desired product (3.0g, 24%) as a yellow 4.3':5,6pyrido4.3-fcuinazolin-9-amines solid. "H NMR (CDC1, 400 MHz): 89.52 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.40 (d. J=8.0 Hz, 2H), 6.82 (d. J=8.0 Hz, 2H), 5.64 (s. 2H), 3.78 (s.3H), 3.16 (t, J=6.0 Hz, 2H), 3.10 (t, 15 J=6.2 Hz, 2H), 2.65 (s.3H); LCMS M+H: 390. Example 36 W O O / (i) R1,R2,NH Synthesis of 3-(4-methoxybenzyl)-9-(methylsulfo DMSO, 100° C. 1 h --- nyl)-6,7-dihydro-3H-pyrazolo.4.3':5,6pyrido4.3-f (i) CF3COOH, quinazoline 60° C., 17 h

25 WNs. O / Oxone(R), 21 h MeOH, H2O RT, 18 h 30 N1 N S

Ns N 2

35 N-- Step 1: To a 0.5M solution of sulfone (0.1 mL, 50 mole) in / DMSO was added a 0.5M solution of amine (0.1 mL, 50 21 NN mole) in DMSO. The reaction mixture was heated at 100° C. for 1 hour. The reaction was then concentrated under reduced 40 pressure to give an oily residue, which was used in Step 2 N1 N N without any further purification. Step 2: To the oily residue obtained from step (i) was added 2 trifluoroacetic acid (1 mL). The reaction mixture was then SN/ \, shaken at 60° C. for 17 hours. The reaction was then concen 45 trated under reduced pressure. The crude product was purified To a suspension of 3-(4-methoxybenzyl)-9-(methylsulfa using reverse phase HPLC to give the desired product as a nyl)-6,7-dihydro-3H-pyrazolo4".3':5,6pyrido4.3-f solid. quinazoline (1.9 g, 4.8 mmol) in 2:1 mixture of methanol water (100 mL) was added potassium monopersulfate triple Examples 37-67 salt (OxoneR, 9.2g, 15 mmol) and the suspension stirred for 50 18 hours. On completion of the reaction, the mixture was Compounds in Table 3 are synthesized by using general concentrated under reduced pressure. The residue was dis procedure E as described herein. TABLE 3

LCMS Structure IUPAC Name M+H

N-(2-morpholin-4-ylethyl)-6,7- 352 dihydro-3H pyrazolo4',3':5,6pyrido4,3- figuinazolin-9-amine