USOO863321 OB2

(12) United States Patent (10) Patent No.: US 8,633,210 B2 Charrier et al. (45) Date of Patent: *Jan. 21, 2014

(54) TRIAZOLE COMPOUNDS USEFUL AS 5,710, 158 A 1/1998 Myers et al. PROTEINKNASE INHIBITORS (Continued) (75) Inventors: Jean-Damien Charrier, Wantage (GB); FOREIGN PATENT DOCUMENTS Pan Li, Lexington, MA (US); Ronald Knegtel, Abingdon (GB); Julian DE 2458965 6, 1976 Marian Charles Golec, Faringdon E. 09: k l 3. (GB); David Bebbington, Newbury EP O3O2312 2, 1989 (GB); Hayley Marie Binch, Encinitas, GB 205.2487 1, 1981 CA (US) JP 10-130 150 5, 1998 JP 2000-026421 1, 2000 (73) Assignee: Vertex Pharmaceuticals Incorporated, wo E. gig. Cambridge, MA (US) WO 9322681 11, 1993 (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS This patent is Subject to a terminal dis- Wolff et, al., “Burger's Medicinal Chemistry and Drug Discovery.” claimer. 5th Ed. Part 1, pp.975-977 (1995).* Banker, et. al., (1996), Modern Pharmaceuticals, p. 596.* (21) Appl. No.: 13/094, 183 Ivashchenko,(1980), (12), 1673-7.*et al. Khimiya Geterotsiklicheskikh Soedinenii (22) Filed: Apr. 26, 2011 (Continued) (65) Prior Publication Data Primary Examiner — Jeffrey Murray US 2012/OO71657 A1 Mar. 22, 2012 (74) Attorney, Agent, or Firm — Rory C. Stewart Related U.S. Application Data (57) ABSTRACT (62) Division of application No. 1 1/492.450, filed on Jul. This invention describes novel triazole compounds of for 25, 2006, now Pat. No. 7,951,820, which is a division mula IX: of application No. 09/953,471, filed on Sep. 14, 2001, now Pat. No. 7,115,739. (60) Provisional application No. 60/232,795, filed on Sep. R2 IX 15, 2000, provisional application No. 60/257.887, filed on Dec. 21, 2000, provisional application No. Na 60/286,949, filed on Apr. 27, 2001. us M NH (51) Int. Cl. HN N AOIN 43/54 (2006.01) R. A 6LX3/57 (2006.01) N72 CO7D 40/00 (2006.01) A CO7D 403/00 (2006.01) y 2 CO7D 413/00 (2006.01) R Z CO7D 417/00 (2006.01) CO7D 49/00 (2006.01) (52) U.S. Cl. wherein-- Z'71 is: - -nitrogen or CR 9 and Z,2 is: - -nitrogen or CH, 58 fo - - - - - ificati------s ------h 514/266.23:544/284 provided that at least one of Z' and Z is nitrogen; G is Ring (58) es OSSO Sea C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, See application file for complete search history. wherein said Ring C has one or two ortho substituents inde (56) References Cited p endentlyy selected from —R'; Ring9. D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected U.S. PATENT DOCUMENTS from aryl, heteroaryl, heterocyclyl or carbocyclyl; R and R' 3,133,081 A 5/1964 Lafferty are independently selected from T-R, or R and Rare taken 3,755,322 A 8, 1973 Winter et al. together with their intervening atoms to form a fused ring; R', 3,935,183 A 1/1976 Baron et al. R, and T are as described in the specification. The com 3,998,951 A 12/1976 Harnish et al. pounds are useful as protein inhibitors, especially as 4,051.252 A 9/1977 Mayer et al. 4,493.726 A 1, 1985 Burdeska et al. inhibitors of GSK-3 and Aurora, for treating diseases such as 4,540,698 A 9, 1985 Ishikawa et al. diabetes, , and Alzheimer's disease. 4,711,951 A 12/1987 Axen et al. 5,124,441 A 6, 1992 Carlsson et al. 22 Claims, No Drawings US 8,633,210 B2 Page 2

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Rouse, J. et al., A Novel Kinase Cascade Triggered by Stress and Heat Biscardi, J.S. et al., “c-Src. Receptor Tyrosine Kinases, and Human Shock That Stimulates MAPKAP Kinase-2 and Phosphorylation of Cancer, Adv. Cancer Res., 76, 61 (1999). the Small Heat Shock Proteins, Cell, 78, 1027-1037 (1994). Lynch, S.A. et al., “Increased Expression of the Src Proto-Oncogene Raingeaud, J. et al., MMK3- and MMK6-Regulated Gene Expres in Hairy Cell and a Subgroup of B-Cell Lymphomas'. sion Is Mediated by p38 Mitogen-Activated Protein Kinase Signal Leukemia, 7(9), 1416-1422 (1993). Transduction Pathway, Mol. Cell. Biol., 16, 1247-1255 (1996). Wiener, J.R., “Decreased Src Tyrosine Kinase Activity Inhibits Chen, R.H. et al., “Phosphorylation of the c-Fos transrepression Malignant Human Ovarian Cancer Tumor Growth in a Nude Mouse domain by mitogen-activated protein kinase and 90-kDa ribosomal Model”, Clin. Cancer Res., 5, 2164-2170 (1999). S6 kinase”. Proc. Natl. Acad. Sci. 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Lee, S.J. et al., “Discovery of Potent Cyclic GMP Phosphodiesterase Kazuhiko, N. et al., “Akt/Protein Kinase B Prevents Injury-Induced Inhibitors. 2-Pyridyl- and 2-Imidazolylguinazolines Possessing Motoneuron Death and Accelerates Axonal Regeneration”. J. of Cyclic GMP Phosphodiesterase and Thromboxane Synthesis Inhibi Neuroscience, 2008), 2875-2986 (2000). tory Activities.” J. Med. Chem., 38 (18): 3547-3557 (1995). Molina, T.J. et al., “Profound block in thymocyte development in Medwid, J.B. et al., “Preparation of Triazolo 1.5-cpyrimidines as mice lacking p56lck'. Nature, 357, 161-164 (1992). Potential Antiasthma Agents.” J. Med. Chem. 33, 1230-1241 (1990). Kimura, M. et al., “-dependent Expression and Nezu, Y. et al., “Dimethoxypyrimidines as Novel Herbicides. Part 1. Centrosome Localization of a Third Human Aurora IpIl-related Pro Synthesis and Herbicidal Activity of tein Kinase, AIK3”. J. Biol. Chem., 274(11), 13766-13771 (1997). Dimethoxyphenoxyphenoxypyrimidines and Analogues.” Pestic. IUPAC Compendium of Chemical Terminology on a definition of Sci., 47: 103-113 (1996). “aliphatic compounds' found from http://www.chemSoc.org/ Cohen, P., “Dissection of the Protein Phosphorylation Cascades chembytes/goldbook/index.htm (last visited on Nov. 18, 2007). Involved in Insulin and Growth Factor Action'. Biochem. Soc. Trans. 21, 555-567 (1993). * cited by examiner US 8,633,210 B2 1. 2 TRAZOLE COMPOUNDS USEFUL AS protein has been found to be overexpressed. See Bischoffet PROTEINKNASE INHIBITORS al., EMBO.J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., CROSS REFERENCE TO RELATED 1997, 272, 13766-13771. APPLICATIONS Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of C. and B isoforms that are each This application is a divisional of U.S. application Ser. No. encoded by distinct genes Coghlan et al., Chemistry & Biol 1 1/492,450, now U.S. Pat. No. 7,951,820, filed on Jul. 25, ogy, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion 2006, which is a divisional of U.S. application Ser. No. Genetics Dev., 10, 508-514 (2000). GSK-3 has been impli 09/953,471, now U.S. Pat. No. 7,115,739, filed on Sep. 14, 10 cated in various diseases including diabetes, Alzheimer's dis 2001, which claims priority to U.S. Provisional Patent Appli ease, CNS disorders such as manic depressive disorder and cation 60/232,795 filed Sep.15, 2000, U.S. Provisional Patent neurodegenerative diseases, and cardiomyocyte hypertrophy Application 60/257.887 filed Dec. 21, 2000 and U.S. Provi WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. sional Patent Application 60/286,949 filed Apr. 27, 2001, the (2000) 151, 117. These diseases may be caused by, or result contents of which fare incorporated by reference. 15 in, the abnormal operation of certain cell signaling pathways FIELD OF THE INVENTION in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regu The present invention is in the field of medicinal chemistry latory proteins. These proteins include glycogen synthase and relates to compounds that are protein kinase inhibitors, which is the rate limiting necessary for glycogen compositions containing Such compounds and methods of synthesis, the microtubule associated protein Tau, the gene use. More particularly, this invention relates to compounds transcription factor B-catenin, the translation initiation factor that are inhibitors of GSK-3 and Aurora-2 protein kinases. el F2B, as well as ATP citrate , axin, heat shock factor-1, The invention also relates to methods of treating diseases c-Jun, c-Myc, c-Myb, CREB, and CEPBC. These diverse associated with these protein kinases, such as diabetes, cancer 25 protein targets implicate GSK-3 in many aspects of cellular and Alzheimer's disease. metabolism, proliferation, differentiation and development. In a GSK-3 mediated pathway that is relevant for the treat BACKGROUND OF THE INVENTION ment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this The search for new therapeutic agents has been greatly 30 pathway, GSK-3 is a negative regulator of the insulin-induced aided in recent years by better understanding of the structure signal. Normally, the presence of insulin causes inhibition of of and other biomolecules associated with target GSK-3 mediated phosphorylation and deactivation of glyco diseases. One important class of enzymes that has been the gen synthase. The inhibition of GSK-3 leads to increased Subject of extensive study is the protein kinases. glycogen synthesis and glucose uptake Klein et al., PNAS, Protein kinases mediate intracellular . 35 93, 8455-9 (1996): Cross et al., Biochem. J., 303, 21-26 They do this by effecting a phosphoryltransfer from a nucleo (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); side triphosphate to a protein acceptor that is involved in a Massillon et al., Biochem J. 299, 123-128 (1994). However, signaling pathway. There are a number of kinases and path in a diabetic patient where the insulin response is impaired, ways through which extracellular and other stimuli cause a glycogen synthesis and glucose uptake fail to increase despite variety of cellular responses to occur inside the cell. 40 the presence of relatively high blood levels of insulin. This Examples of such stimuli include environmental and chemi leads to abnormally high blood levels of glucose with acute cal stress signals (e.g. osmotic shock, heat shock, ultraviolet and long term effects that may ultimately result in cardiovas radiation, bacterial endotoxin, H2O), cytokines (e.g. inter cular disease, renal failure and blindness. In such patients, the leukin-1 (IL-1) and tumor necrosis factor C. (TNF-C)), and normal insulin-induced inhibition of GSK-3 fails to occur. It growth factors (e.g. granulocyte macrophage-colony-stimu 45 has also been reported that in patients with type II diabetes, lating factor (GM-CSF), and fibroblast growth factor (FGF). GSK-3 is overexpressed WO 00/38675). Therapeutic inhibi An extracellular stimulus may effect one or more cellular tors of GSK-3 are therefore potentially useful for treating responses related to cell growth, migration, differentiation, diabetic patients suffering from an impaired response to insu secretion of hormones, activation of transcription factors, lin. muscle contraction, glucose metabolism, control of protein 50 GSK-3 activity has also been associated with Alzheimer's synthesis and regulation of cell cycle. disease. This disease is characterized by the well-known Many diseases are associated with abnormal cellular B-amyloid peptide and the formation of intracellular neu responses triggered by protein kinase-mediated events. These rofibrillary tangles. The neurofibrillary tangles contain hyper diseases include autoimmune diseases, inflammatory dis phosphorylated Tau protein where Tau is phosphorylated on eases, neurological and neurodegenerative diseases, cancer, 55 abnormal sites. GSK-3 has been shown to phosphorylate cardiovascular diseases, allergies and asthma, Alzheimer's these abnormal sites in cell and animal models. Furthermore, disease or hormone-related diseases. Accordingly, there has inhibition of GSK-3 has been shown to prevent hyperphos been a substantial effort in medicinal chemistry to find protein phorylation of Tau in cells Lovestone et al., Current Biology kinase inhibitors that are effective as therapeutic agents. 4, 1077-86 (1994); Brownlees et al., Neuroreport 8,3251-55 Aurora-2 is a serine/threonine protein kinase that has been 60 (1997). Therefore, it is believed that GSK-3 activity may implicated in human cancer, Such as colon, breast and other promote generation of the neurofibrillary tangles and the solid tumors. This kinase is believed to be involved in protein progression of Alzheimer's disease. phosphorylation events that regulate the cell cycle. Specifi Another substrate of GSK-3 is 3-catenin which is degra cally, Aurora-2 may play a role in controlling the accurate dated after phosphorylation by GSK-3. Reduced levels of segregation of chromosomes during . Misregulation 65 B-catenin have been reported in Schizophrenic patients and of the cell cycle can lead to cellular proliferation and other have also been associated with other diseases related to abnormalities. In human colon cancer tissue, the aurora-2 increase in neuronal cell death Zhong et al., Nature, 395, US 8,633,210 B2 3 4 698-702 (1998); Takashimaet al., PNAS 90,7789-93 (1993); -continued Pei et al., J. Neuropathol. Exp, 56,70-78 (1997). As a result of the biological importance of GSK-3, there is R. current interest in therapeutically effective GSK-3 inhibitors. n Small molecules that inhibit GSK-3 have recently been N reported WO 99/65897 (Chiron) and WO 00/38675 (Smith 21 Kline Beecham). For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also 10 been targeted for treating the same diseases. However, the various protein kinases often act through different biological R pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful 15 for treating conditions characterized by enhanced p38-C. activity and/or enhanced TGF-B activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake. There is a continued need to find new therapeutic agents to 25 treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive targets for the discovery of new therapeutics due to their important role in cancer, diabe tes, Alzheimer's disease and other diseases. 30 DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein 35 kinase inhibitors, particularly as inhibitors of aurora-2 and GSK-3. These compounds have the general formula I:

40

45 R.

and 50 or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 55 Z' to Zareas described below: Ring A is selected from the group consisting of: G is Ring C or Ring D; 60 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from R', any substitutable non-ortho carbon position on Ring C is independently substituted by R. 65 and two adjacent Substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring US 8,633,210 B2 5 having 0-3 heteroatoms selected from oxygen, Sulfur or nitrogen, said fused ring being optionally Substituted by halo, oxo, or—R; Ring D is a 5-7 membered monocyclic ring or 8-10 membered (R)C(O)O - C(R)=NN(R) - C(R)=N O , bicyclic ring selected from aryl, heteroaryl, heterocyclyl or 5 C(R)N(R)N(R) C(R)N(R)SON(R) , or carbocyclyl, said heteroaryl or heterocyclyl ring having C(R)N(R)CON(R) ; 1-4 ring heteroatoms selected from nitrogen, oxygen or W is C(R)-O-, C(R) S , C(R)SO , sulfur, wherein Ring D is substituted at any substitutable —C(R)SO. , C(R)SON(R) , C(R)-N ring carbon by oxo or —R, and at any substitutable ring (R)-, -CO-, -CO. , —C(R)OC(O) , —C(R) nitrogen by R', provided that when Ring D is a six 10 OC(O)N(R) C(R)N(R)CO C(R)N(R)C membered aryl or heteroaryl ring, -R is hydrogen at each (O)O C(R)=NN(R) C(R)=N O , ortho carbon position of Ring D; C(R)N(R)N(R) C(R)N(R)SON(R) , R" is selected from -halo, —CN, NO, T-V R, phenyl, C(R)N(R)CON(R) , or CONCR) ; 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl each R is independently selected from hydrogen or an ring, or Caliphatic group, said phenyl, heteroaryl, and 15 optionally substituted C. aliphatic group, or two R' heterocyclyl rings each optionally Substituted by up to groups on the same nitrogen atom are taken together with three groups independently selected from halo, oxo, or the nitrogen atom to form a 5-6 membered heterocyclyl or —R, said Caliphatic group optionally substituted with heteroaryl ring; halo, cyano, nitro, or oxygen, or R' and an adjacent Sub each R" is independently selected from hydrogen or an stituent taken together with their intervening atoms form optionally substituted Caliphatic group, or two R7 on the said ring fused to Ring C: same nitrogen are taken together with the nitrogen to form R and Rare independently selected from T-R, or R and R' a 5-8 membered heterocyclyl or heteroaryl ring: are taken together with their intervening atoms to form a each R is independently selected from an optionally substi fused, unsaturated or partially unsaturated, 5-8 membered tuted C, aliphatic group, —OR', SR, COR, ring having 0-3 ring heteroatoms selected from oxygen, 25 —SOR. - N(R), -N(R)N(R) - CN, NO, Sulfur, or nitrogen, wherein any Substitutable carbon on —CON(R), or -COR: and said fused ring formed by RandR is substituted by oxo or R is selected from —R, halo, OR, —C(=O)R, CO.R. T-R, and any substitutable nitrogen on said ring formed by —COCOR, NO, CN, S(O)R, -SOR, -SR, R and R” is substituted by R: -N(R), —CON(R), -SON(R), —OC(=O)R, T is a valence bond or a C alkylidene chain; 30 -N(R)COR, N(R)CO, (optionally substituted C. RandR are independently selected from R,-T-W R. aliphatic), N(R)N(R), -C=NN(R), -C=N- or R and R are taken together with their intervening OR, N(R)CON(R), N(R)SON(R), N(R) atoms to form a fused, 5-8 membered, unsaturated or par SOR, or - OC(=O)N(R). tially unsaturated, ring having 0-3 ring heteroatoms As used herein, the following definitions shall apply unless Selected from nitrogen, oxygen, or Sulfur, wherein each 35 otherwise indicated. The phrase “optionally substituted” is substitutable carbon on said fused ring formed by R and used interchangeably with the phrase “substituted or unsub R is substituted by halo, oxo, —CN, NO, R', or stituted” or with the term “(un)substituted.” Unless otherwise —V-R, and any substitutable nitrogen on said ring indicated, an optionally Substituted group may have a Sub formed by RandR is substituted by R: stituent at each Substitutable position of the group, and each R is selected from —R,-halo. —OR, —C(=O)R, COR, 40 substitution is independent of the other. - COCOR, COCHCOR, NO, CN, S(O)R, The term “aliphatic' as used herein means straight-chain, —S(O).R. —SR, N(R), —CON(R7), -SON(R7), branched or cyclic C-C hydrocarbons which are com –OC(=O)R, N(R)COR, N(R)CO (optionally pletely saturated or which contain one or more units of unsat substituted Caliphatic), N(R)N(R), -C=NN uration but which are not aromatic. For example, suitable (R) -C=N OR, N(R7)CON(R7), N(R7)SON 45 aliphatic groups include Substituted or unsubstituted linear, (R) - N(R)SOR, or - OC(=O)N(R): branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids each R is independently selected from hydrogen oran option thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cy ally substituted group selected from Caliphatic, Co cloalkyl)alkenyl. The terms “alkyl, “alkoxy”, “hydroxy aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero alkyl”, “alkoxyalkyl, and “alkoxycarbonyl', used alone or cyclyl ring having 5-10 ring atoms; 50 as part of a larger moiety includes both straight and branched each R" is independently selected from R", COR". chains containing one to twelve carbon atoms. The terms —CO(Caliphatic), —CON(R), or—SOR", or two “alkenyl and “alkynyl used alone or as part of a larger R" on the same nitrogen are taken together to form a 5-8 moiety shall include both straight and branched chains con membered heterocyclyl or heteroaryl ring: taining two to twelve carbon atoms. The term “cycloalkyl each R is independently selected from —R, halo, OR, 55 used alone or as part of a larger moiety shall include cyclic —C(=O)R, COR, COCOR, NO, CN, -S(O) C-C hydrocarbons which are completely saturated or R, -SOR, SR, N(R) - CONCR), -SON which contain one or more units of unsaturation, but which (R), OC(=O)R, N(R)COR, N(R)CO (option are not aromatic. ally substituted Caliphatic), N(R)N(R), —C=NN The terms “haloalkyl”, “haloalkenyl and “haloalkoxy” (R) -C=N OR, N(R)CON(R), N(R)SON 60 means alkyl, alkenyl oralkoxy, as the case may be, Substituted (R) - N(R)SOR, or - OC(=O)N(R), or R and an with one or more halogen atoms. The term "halogen' means adjacent Substituent taken together with their intervening F, Cl, Br, or I. atoms form said ring fused to Ring C: The term "heteroatom' means nitrogen, oxygen, or Sulfur V is - O -, - S -, -SO , -SO. , N(R)SO , and includes any oxidized form of nitrogen and Sulfur, and the —SON(R)-, - N(R)-, -CO-, -CO. , N(R) 65 quaternized form of any basic nitrogen. Also the term "nitro CO. , N(R)C(O)O N(R)CON(R) , N(R) gen’ includes a substitutable nitrogen of a heterocyclic ring. SON(R) , N(R)N(R) C(O)N(R) OC As an example, in a saturated or partially unsaturated ring US 8,633,210 B2 7 8 having 0-3 heteroatoms selected from oxygen, Sulfur or nitro Zothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, gen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinoli NH (as in pyrrolidinyl) or NR" (as in N-substituted pyrrolidi nyl, indolyl. iSoindolyl, acridinyl, or benzoisoxazolyl. Also nyl). included within the scope of the term "heteroaryl', as it is The terms “carbocycle”, “carbocyclyl', 'carbocyclo', or used herein, is a group in which a heteroatomic ring is fused 'carbocyclic” as used herein means an aliphatic ring system to one or more aromatic or nonaromatic rings where the having three to fourteen members. The terms “carbocycle'. radical or point of attachment is on the heteroaromatic ring. “carbocyclyl”, “carbocyclo', or “carbocyclic” whether satu Examples include tetrahydroquinolinyl, tetrahydroisoquino rated or partially unsaturated, also refers to rings that are linyl, and pyrido 3,4-dpyrimidinyl. The term "heteroaryl optionally substituted. The terms “carbocycle”, “carbocy 10 clyl', 'carbocyclo', or “carbocyclic' also include aliphatic also refers to rings that are optionally substituted. The term rings that are fused to one or more aromatic or nonaromatic "heteroaryl” may be used interchangeably with the term “het rings, such as in a decahydronaphthyl or tetrahydronaphthyl, eroaryl ring or the term "heteroaromatic'. where the radical or point of attachment is on the aliphatic An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the r1ng. 15 like) or heteroaryl (including heteroaralkyl and heteroaryla The term “aryl used alone or as part of a larger moiety as lkoxy and the like) group may contain one or more substitu in “aralkyl”, “aralkoxy’, or “aryloxyalkyl, refers to aromatic ents. Examples of Suitable Substituents on the unsaturated ring groups having five to fourteen members, such as phenyl, carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl benzyl, phenethyl, 1-naphthyl 2-naphthyl, 1-anthracyl and group include a halogen, —R. —OR. —SR, 1.2-methyl 2-anthracyl. The term “aryl also refers to rings that are ene-dioxy, 1.2-ethylenedioxy, protected OH (such as acy optionally substituted. The term “aryl' may be used inter loxy), phenyl (Ph), substituted Ph. —O(Ph), substituted changeably with the term “aryl ring”. “Aryl also includes - O(Ph), -CH(Ph), substituted -CH(Ph), —CHCH fused polycyclic aromatic ring systems in which an aromatic (Ph), substituted —CHCH(Ph), - NO,-CN, N(R), ring is fused to one or more rings. Examples include 1-naph NRC(O)R, NRC(O)N(R), NRCOR, thyl 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included 25 NRNRC(O)R, NRNRC(O)N(R), within the scope of the term “aryl', as it is used herein, is a NRNRCOR, C(O)C(O)R, C(O)CHC(O)R, group in which an aromatic ring is fused to one or more - COR. - C(O)R, C(O)N(R) - OC(O)N(R), non-aromatic rings, such as in an indanyl, phenanthridinyl, or —S(O),R, -SON(R), S(O)R, NRSON(R), tetrahydronaphthyl, where the radical or point of attachment NRSOR, C(=S)N(R), C(-NH) N(R), is on the aromatic ring. 30 -(CH.)NHC(O)R’, -(CH.)NHC(O)CH(V-R)(R): The term “heterocycle”, “heterocyclyl”, or "heterocyclic” wherein R is hydrogen, a substituted or unsubstituted ali as used herein includes non-aromatic ring systems having five phatic group, an unsubstituted heteroaryl or heterocyclic ring, to fourteen members, preferably five to ten, in which one or phenyl (Ph), substituted Ph, O(Ph), substituted O(Ph), more ring carbons, preferably one to four, are each replaced —CH(Ph), or substituted —CH2(Ph); y is 0-6; and V is a by a heteroatom such as N, O, or S. Examples of heterocyclic 35 linker group. Examples of substituents on the aliphatic group rings include 3-1H-benzimidazol-2-one, (1-substituted)-2- or the phenyl ring of R include amino, alkylamino, dialky oxo-benzimidazol-3-yl 2-tetrahydrofuranyl, 3-tetrahydro lamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, furanyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahy dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylami dropyranyl, 1,3-dioxalanyl, 1,3-dithiolanyl, 1,3- nocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbo dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 40 nyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomor An aliphatic group or a non-aromatic heterocyclic ring pholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidi may contain one or more Substituents. Examples of Suitable nyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazi Substituents on the Saturated carbon of analiphatic group or of nyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, a non-aromatic heterocyclic ring include those listed above 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-ph 45 for the unsaturated carbon of an aryl or heteroaryl group and thalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidi the following: =O, =S. =NNHR*, —NN(R*) =N nyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also =NNHC(O)R*, =NNHCO(alkyl), =NNHSO,(alkyl), or included within the scope of the term "heterocyclyl or "het —NR*, where each R* is independently selected from hydro erocyclic', as it is used herein, is a group in which a non gen, an unsubstitutedaliphatic group or a Substitutedaliphatic aromatic heteroatom-containing ring is fused to one or more 50 group. Examples of Substituents on the aliphatic group aromatic or non-aromatic rings, such as in an indolinyl, chro include amino, alkylamino, dialkylamino, aminocarbonyl, manyl, phenanthridinyl, or tetrahydroquinolinyl, where the halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, radical or point of attachment is on the non-aromatic heteroa alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, tom-containing ring. The term "heterocycle”, “heterocyclyl, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, or "heterocyclic” whether saturated or partially unsaturated, 55 hydroxy, haloalkoxy, or haloalkyl. also refers to rings that are optionally Substituted. Suitable Substituents on the nitrogen of a non-aromatic The term "heteroaryl, used alone or as part of a larger heterocyclic ring include —R", N(R'), —C(O)R", moiety as in "heteroaralkyl or "heteroarylalkoxy’, refers to COR", C(O)C(O)R", C(O)CHC(O)R', SOR", heteroaromatic ring groups having five to fourteen members. - SON(R') –C(=S)N(R'), C(=NH) N(R), and Examples of heteroaryl rings include 2-furanyl, 3-furanyl. 60 —NRSOR"; wherein R is hydrogen, an aliphatic group, a N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, substituted aliphatic group, phenyl (Ph), substituted Ph. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, - O(Ph), substituted O(Ph), CH(Ph), substituted CH 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrro (Ph), or an unsubstituted heteroaryl or heterocyclic ring. lyl. 2-pyrrolyl 3-pyrrolyl 2-pyridyl, 3-pyridyl, 4-pyridyl, Examples of substituents on the aliphatic group or the phenyl pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiaz 65 ring include amino, alkylamino, dialkylamino, aminocarbo olyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-tria nyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbo Zolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, ben nyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, US 8,633,210 B2 10 alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, composition thereof. This method is especially useful for hydroxy, haloalkoxy, or haloalkyl. diabetic patients. Another method relates to inhibiting the The term “linker group' or “linker” means an organic production of hyperphosphorylated Tau protein, which is use moiety that connects two parts of a compound. Linkers are ful in halting or slowing the progression of Alzheimer's dis typically comprised of an atom Such as oxygen or Sulfur, a ease. Another method relates to inhibiting the phosphoryla unit such as —NH , —CH2—, —C(O)— —C(O)NH , or tion of B-catenin, which is useful for treating schizophrenia. a chain of atoms, such as an alkylidene chain. The molecular Another aspect of the invention relates to inhibiting GSK-3 mass of a linker is typically in the range of about 14 to 200, activity in a biological sample, which method comprises con preferably in the range of 14 to 96 with a length of up to about tacting the biological sample with a GSK-3 inhibitor of for six atoms. Examples of linkers include a saturated or unsat 10 mula I. urated C. alkylidene chain which is optionally Substituted, Another aspect of this invention relates to a method of and wherein one or two saturated carbons of the chain are inhibiting Aurora-2 activity in a patient, which method com optionally replaced by —C(O)— —C(O)C(O)— prises administering to the patient a compound of formula I or —CONH-, -CONHNH-, -CO. , —OC(O) , a composition comprising said compound. —NHCO - O -, -NHCONH-, - OC(O)NH-, 15 Another aspect of this invention relates to a method of NHNH , NHCO , S—, SO , SO , treating or preventing an Aurora-2-mediated disease with an NH-, -SONH-, or -NHSO, Aurora-2 inhibitor, which method comprises administering to The term “alkylidene chain refers to an optionally substi a patient in need of Such a treatment a therapeutically effec tuted, straight or branched carbon chain that may be fully tive amount of a compound of formula I or a pharmaceutical saturated or have one or more units of unsaturation. The composition thereof. optional substituents are as described above for an aliphatic The term “Aurora-2-mediated condition' or “disease', as group. used herein, means any disease or other deleterious condition A combination of substituents or variables is permissible in which Aurora is known to play a role. The term “Aurora only if Such a combination results in a stable or chemically 2-mediated condition' or “disease' also means those diseases feasible compound. A stable compound or chemically fea 25 or conditions that are alleviated by treatment with an sible compound is one in which the chemical structure is not Aurora-2 inhibitor. Such conditions include, without limita substantially altered when kept at a temperature of 40°C. or tion, cancer. The term "cancer includes, but is not limited to less, in the absence of moisture or other chemically reactive the following cancers: colon and ovarian. conditions, for at least a week. Another aspect of the invention relates to inhibiting Unless otherwise stated, structures depicted herein are also 30 Aurora-2 activity in a biological sample, which method com meant to include all stereochemical forms of the structure; prises contacting the biological sample with the Aurora-2 i.e., the R and S configurations for each asymmetric center. inhibitor of formula I, or a composition thereof. Therefore, single Stereochemical isomers as well as enantio Another aspect of this invention relates to a method of meric and diastereomeric mixtures of the present compounds treating or preventing a CDK-2-mediated diseases with a are within the scope of the invention. Unless otherwise stated, 35 CDK-2 inhibitor, which method comprises administering to a structures depicted herein are also meant to include com patient in need of such a treatment a therapeutically effective pounds which differ only in the presence of one or more amount of a compound of formula I or a pharmaceutical isotopically enriched atoms. For example, compounds having composition thereof. the present structures except for the replacement of a hydro The term “CDK-2-mediated condition' or “disease', as gen by a deuterium or tritium, or the replacement of a carbon 40 used herein, means any disease or other deleterious condition by a C- or 'C-enriched carbon are within the scope of this in which CDK-2 is known to play a role. The term “CDK-2- invention. mediated condition' or “disease” also means those diseases Compounds of formula I or salts thereof may be formu or conditions that are alleviated by treatment with a CDK-2 lated into compositions. In a preferred embodiment, the com inhibitor. Such conditions include, without limitation, cancer, position is a pharmaceutical composition. In one embodi 45 Alzheimer's disease, restenosis, angiogenesis, glomerulone ment, the composition comprises an amount of the protein phritis, cytomegalovirus, HIV, herpes, psoriasis, atheroscle kinase inhibitor effective to inhibit a protein kinase, particu rosis, alopecia, and autoimmune diseases Such as rheumatoid larly GSK-3, in a biological sample or in a patient. In another arthritis. See Fischer, P. M. and Lane, D. P. Current Medici embodiment, compounds of this invention and pharmaceuti nal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, cal compositions thereof, which comprise an amount of the 50 K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, protein kinase inhibitor effective to treat or prevent a GSK 1849 (2000); Fry, D. W. and Garrett, M.D., Current Opinion 3-mediated condition and a pharmaceutically acceptable car in Oncologic, Endocrine & Metabolic Investigational Drugs, rier, adjuvant, or vehicle; may be formulated for administra 2, 40-59 (2000). tion to a patient. Another aspect of the invention relates to inhibiting CDK-2 The term “GSK-3-mediated condition' or “disease', as 55 activity in a biological sample or a patient, which method used herein, means any disease or other deleterious condition comprises administering to the patient a compound of for or state in which GSK-3 is known to play a role. Such diseases mula I or a composition comprising said compound. or conditions include, without limitation, diabetes, Alzhe Another aspect of this invention relates to a method of imer's disease, Huntington's Disease, Parkinson's Disease, treating or preventing an ERK-2-mediated diseases with an AIDS-associated dementia, amyotrophic lateral Sclerosis 60 ERK-2 inhibitor, which method comprises administering to a (AML), multiple sclerosis (MS), schizophrenia, cardio patient in need of such a treatment a therapeutically effective mycete hypertrophy, reperfusion/ischemia, and baldness. amount of a compound of formula I or a pharmaceutical One aspect of this invention relates to a method of enhanc composition thereof. ing glycogen synthesis and/or lowering blood levels of glu The term “ERK-mediated condition', as used herein cose in a patient in need thereof, which method comprises 65 means any disease state or other deleterious condition in administering to the patient a therapeutically effective which ERK is known to play a role. The term “ERK-2- amount of a compound of formula I or a pharmaceutical mediated condition' or “disease” also means those diseases US 8,633,210 B2 11 12 or conditions that are alleviated by treatment with a ERK-2 “disease also means those diseases or conditions that are inhibitor. Such conditions include, without limitation, cancer, alleviated by treatment with a Src inhibitor. Such conditions stroke, diabetes, hepatomegaly, cardiovascular disease include, without limitation, hypercalcemia, osteoporosis, including cardiomegaly, Alzheimer's disease, cystic fibrosis, osteoarthritis, cancer, symptomatic treatment of bone viral disease, autoimmune diseases, atherosclerosis, resteno metastasis, and Paget’s disease. Src protein kinase and its sis, psoriasis, allergic disorders including asthma, inflamma implication in various diseases has been described Soriano, tion, neurological disorders and hormone-related diseases. Cell, 69,551 (1992); Soriano et al., Cell, 64, 693 (1991); The term “cancer includes, but is not limited to the following Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, cancers: breast, ovary, cervix, prostate, testis, genitourinary Drugs of the Future 2000, 25(7), 717. (2000); Talamonti, J. tract, esophagus, larynx, glioblastoma, neuroblastoma, stom 10 Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res. ach, skin, keratoacanthoma, lung, epidermoid carcinoma, 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); large cell carcinoma, Small cell carcinoma, lung adenocarci Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, noma, bone, colon, adenoma, pancreas, adenocarcinoma, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, thyroid, follicular carcinoma, undifferentiated carcinoma, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. papillary carcinoma, seminoma, melanoma, sarcoma, blad 15 Cancer Res., 5, 2164 (1999); Staley, Cell Growth Diff, 8,269 der carcinoma, liver carcinoma and biliary passages, kidney (1997). carcinoma, myeloid disorders, lymphoid disorders, Another aspect of the invention relates to inhibiting Src Hodgkins, hairy cells, buccal cavity and pharynx (oral), lip, activity in a biological sample or a patient, which method tongue, mouth, pharynx, Small intestine, colon-rectum, large comprises administering to the patient a compound of for intestine, rectum, brain and central nervous system, and leu mula I or a composition comprising said compound. kemia. ERK-2 protein kinase and its implication in various The term "pharmaceutically acceptable carrier, adjuvant, diseases has been described Bokemeyer et al. 1996, Kidney or vehicle' refers to a non-toxic carrier, adjuvant, or vehicle Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews that may be administered to a patient, together with a com et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. pound of this invention, and which does not destroy the phar Chem. 270, 18848: Rouse et al., 1994, Cell 78, 1027: 25 macological activity thereof. Raingeaud et al., 1996, Mol. Cell. Biol. 16, 1247; Raingeaud The term “patient' includes human and veterinary sub et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, jects. 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, The term “biological sample', as used herein, includes, 162: Moodie et al., 1993, Science 260, 1658; Frey and Mul without limitation, cell cultures or extracts thereof; prepara der, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J. 30 tions of an enzyme Suitable for in vitro assay, biopsied mate Clin. Invest. 99, 1478: Whelchel et al., 1997, Am. J. Respir: rial obtained from a mammal or extracts thereof, and blood, Cell Mol. Biol. 16,589. saliva, urine, feces, semen, tears, or other body fluids or Another aspect of the invention relates to inhibiting ERK-2 extracts thereof. activity in a biological sample or a patient, which method The amount effective to inhibit protein kinase, for comprises administering to the patient a compound of for 35 example, GSK-3 and Aurora-2, is one that measurably inhib mula I or a composition comprising said compound. its the kinase activity where compared to the activity of the Another aspect of this invention relates to a method of enzyme in the absence of an inhibitor. Any method may be treating or preventing an AKT-mediated diseases with an used to determine inhibition, such as, for example, the Bio AKT inhibitor, which method comprises administering to a logical Testing Examples described below. patient in need of such a treatment a therapeutically effective 40 Pharmaceutically acceptable carriers that may be used in amount of a compound of formula I or a pharmaceutical these pharmaceutical compositions include, but are not lim composition thereof. ited to, ion exchangers, alumina, aluminum Stearate, lecithin, The term 'AKT-mediated condition', as used herein, serum proteins, such as human serum albumin, buffer Sub means any disease state or other deleterious condition in stances such as phosphates, glycine, Sorbic acid, potassium which AKT is known to play a role. The term 'AKT-mediated 45 Sorbate, partial glyceride mixtures of Saturated vegetable condition” or “disease' also means those diseases or condi fatty acids, water, salts or electrolytes, such as protamine tions that are alleviated by treatment with a AKT inhibitor. Sulfate, disodium hydrogen phosphate, potassium hydrogen AKT-mediated diseases or conditions include, but are not phosphate, Sodium chloride, Zinc salts, colloidal silica, mag limited to, proliferative disorders, cancer, and neurodegen nesium trisilicate, polyvinyl pyrrolidone, cellulose-based erative disorders. The association of AKT, also known as 50 Substances, polyethylene glycol, Sodium carboxymethylcel protein kinase B, with various diseases has been described lulose, polyacrylates, waxes, polyethylene-polyoxypropy Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y., et al. lene-block polymers, polyethylene glycol and wool fat. Oncogene, 19 2000; Kazuhiko, N., et al. The Journal of The compositions of the present invention may be admin Neuroscience, 20 2000. istered orally, parenterally, by inhalation spray, topically, rec Another aspect of the invention relates to inhibiting AKT 55 tally, nasally, buccally, vaginally or via an implanted reser activity in a biological sample or a patient, which method voir. The term “parenteral as used herein includes comprises administering to the patient a compound of for Subcutaneous, intravenous, intramuscular, intra-articular, mula I or a composition comprising said compound. intra-synovial, intrasternal, intrathecal, intrahepatic, intrale Another aspect of this invention relates to a method of sional and intracranial injection or infusion techniques. Pref treating or preventing a Src-mediated disease with a Src 60 erably, the compositions are administered orally, intraperito inhibitor, which method comprises administering to a patient neally or intravenously. in need of such a treatmentatherapeutically effective amount Sterile injectable forms of the compositions of this inven of a compound of formula I or a pharmaceutical composition tion may be acqueous or oleaginous Suspension. These Sus thereof. pensions may be formulated according to techniques known The term “Src-mediated condition', as used herein means 65 in the art using Suitable dispersing or wetting agents and any disease state or other deleterious condition in which Src Suspending agents. The sterile injectable preparation may is known to play a role. The term “Src-mediated condition” or also be a sterile injectable solution or Suspension in a non US 8,633,210 B2 13 14 toxic parenterally-acceptable diluent or solvent, for example tive such as benzylalkonium chloride. Alternatively, for oph as a solution in 1,3-butanediol. Among the acceptable thalmic uses, the pharmaceutical compositions may be for vehicles and solvents that may be employed are water, Ring mulated in an ointment such as petrolatum. er's solution and isotonic sodium chloride Solution. In addi The pharmaceutical compositions of this invention may tion, sterile, fixed oils are conventionally employed as a sol- 5 also be administered by nasal aerosol or inhalation. Such Ventor Suspending medium. For this purpose, any bland fixed compositions are prepared according to techniques well oil may be employed including synthetic mono- or di-glyc known in the art of pharmaceutical formulation and may be erides. Fatty acids, such as oleic acid and its glyceride deriva prepared as Solutions in saline, employing benzyl or tives are useful in the preparation of injectables, as are natural other Suitable preservatives, absorption promoters to enhance 10 bioavailability, fluorocarbons, and/or other conventional pharmaceutically-acceptable oils, such as olive oil or castor solubilizing or dispersing agents. oil, especially in their polyoxyethylated versions. These oil In addition to the compounds of this invention, pharma Solutions or Suspensions may also contain a long-chain alco ceutically acceptable derivatives or prodrugs of the com hol diluent or dispersant, such as carboxymethyl cellulose or pounds of this invention may also be employed in composi similar dispersing agents which are commonly used in the tions to treat or prevent the above-identified diseases or formulation of pharmaceutically acceptable dosage forms 15 disorders. including emulsions and Suspensions. Other commonly used A “pharmaceutically acceptable derivative or prodrug’ Surfactants, such as Tweens, Spans and other emulsifying means any pharmaceutically acceptable salt, ester, Salt of an agents or bioavailability enhancers which are commonly used ester or other derivative of a compound of this invention in the manufacture of pharmaceutically acceptable solid, liq which, upon administration to a recipient, is capable of pro uid, or other dosage forms may also be used for the purposes viding, either directly or indirectly, a compound of this inven of formulation. tion or an inhibitorily active metabolite or residue thereof. The pharmaceutical compositions of this invention may be Particularly favored derivatives or prodrugs are those that orally administered in any orally acceptable dosage form increase the bioavailability of the compounds of this inven including, but not limited to, capsules, tablets, aqueous Sus tion when Such compounds are administered to a patient (e.g., pensions or solutions. In the case of tablets for oral use, 25 by allowing an orally administered compound to be more carriers commonly used include lactose and corn starch. readily absorbed into the blood) or which enhance delivery of Lubricating agents, such as magnesium Stearate, are also the parent compound to a biological compartment (e.g., the typically added. For oral administration in a capsule form, brain or lymphatic system) relative to the parent species. useful diluents include lactose and dried cornstarch. When Pharmaceutically acceptable prodrugs of the compounds aqueous Suspensions are required for oral use, the active 30 of this invention include, without limitation, esters, amino ingredient is combined with emulsifying and Suspending acid esters, phosphate esters, metal salts and Sulfonate esters. agents. If desired, certain Sweetening, flavoring or coloring Pharmaceutically acceptable salts of the compounds of this agents may also be added. invention include those derived from pharmaceutically Alternatively, the pharmaceutical compositions of this acceptable inorganic and organic acids and bases. Examples invention may be administered in the form of Suppositories as of suitable acid salts include acetate, adipate, alginate, aspar for rectal administration. These can be prepared by mixing tate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, the agent with a Suitable non-irritating excipient which is camphorate, camphorsulfonate, cyclopentanepropionate, Solid at room temperature but liquid at rectal temperature and digluconate, dodecylsulfate, ethanesulfonate, formate, fuma therefore will melt in the rectum to release the drug. Such rate, glucoheptanoate, glycerophosphate, glycolate, hemisul materials include cocoa butter, beeswax and polyethylene fate, heptanoate, hexanoate, hydrochloride, hydrobromide, glycols. 40 hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, The pharmaceutical compositions of this invention may malonate, methanesulfonate, 2-naphthalenesulfonate, nicoti also be administered topically, especially when the target of nate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phe treatment includes areas or organs readily accessible by topi nylpropionate, phosphate, picrate, pivalate, propionate, Sali cal application, including diseases of the eye, the skin, or the cylate. Succinate, Sulfate, tartrate, thiocyanate, tosylate and lower intestinal tract. Suitable topical formulations are 45 undecanoate. Other acids, such as oxalic, while not in them readily prepared for each of these areas or organs. selves pharmaceutically acceptable, may be employed in the Topical application for the lower intestinal tract can be preparation of salts useful as intermediates in obtaining the effected in a rectal suppository formulation (see above) or in compounds of the invention and their pharmaceutically a Suitable enema formulation. Topically-transdermal patches acceptable acid addition salts. may also be used. 50 Salts derived from appropriate bases include alkali metal For topical applications, the pharmaceutical compositions (e.g., Sodium and potassium), alkaline earth metal (e.g., mag may be formulated in a suitable ointment containing the nesium), ammonium and N' (C. alkyl) salts. This inven active component Suspended or dissolved in one or more tion also envisions the quaternization of any basic nitrogen carriers. Carriers for topical administration of the compounds containing groups of the compounds disclosed herein. Water of this invention include, but are not limited to, mineral oil, or oil-soluble or dispersible products may be obtained by liquid petrolatum, white petrolatum, propylene glycol, poly 55 Such quaternization. oxyethylene, polyoxypropylene compound, emulsifying wax The amount of the protein kinase inhibitor that may be and water. Alternatively, the pharmaceutical compositions combined with the carrier materials to produce a single dos can be formulated in a Suitable lotion or cream containing the age form will vary depending upon the patient treated and the active components suspended or dissolved in one or more particular mode of administration. Preferably, the composi pharmaceutically acceptable carriers. Suitable carriers 60 tions should be formulated so that a dosage of between 0.01 include, but are not limited to, mineral oil, sorbitan 100 mg/kg body weight/day of the inhibitor can be adminis monostearate, polysorbate 60, cetyl esters wax, cetearyl alco tered to a patient receiving these compositions. hol, 2-octyldodecanol, benzyl alcohol and water. It should also be understood that a specific dosage and For ophthalmic use, the pharmaceutical compositions may treatment regimen for any particular patient will depend upon be formulated as micronized suspensions in isotonic, pH 65 a variety of factors, including the activity of the specific adjusted Sterile Saline, or, preferably, as Solutions in isotonic, compound employed, the age, body weight, general health, pH adjusted sterile saline, either with or without a preserva sex, diet, time of administration, rate of excretion, drug com US 8,633,210 B2 15 16 bination, and the judgment of the treating physician and the ring having 0-2 heteroatoms, wherein said R/R' ring is severity of the particular disease being treated. The amount of optionally Substituted. Examples of Ring A Systems are the inhibitor will also depend upon the particular compound shown below by compounds I-A through I-DD, wherein Z' is in the composition. nitrogen or C(R) and Z is nitrogen or C(H). Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent I-A that condition, may be administered together with the inhibi tors of this invention. For example, in the treatment of diabe tes other anti-diabetic agents may be combined with the 10 GSK-3 inhibitors of this invention to treat diabetes. These agents include, without limitation, insulin or insulin ana logues, in injectable or inhalation form, glitaZones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and Sulfonyl ureas. 15 Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, che motherapeutic agents or other anti-proliferative agents such as adriamycin, dexamethasone, Vincristine, cyclophospha mide, fluorouracil, topotecan, taxol. interferons, and plati num derivatives; anti-inflammatory agents such as corticos teroids, TNF blockers, IL-1 RA. azathioprine, cyclophosphamide, and SulfaSalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacroli mus, rapamycin, mycophenolate mofetil, interferons, corti 25 costeroids, cyclophophamide, azathioprine, and Sulfasala Zine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease Such as beta-block 30 ers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticos teroids, anti-leukemic agents, and growth factors; and agents 35 for treating immunodeficiency disorders such as gamma globulin. Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents 40 may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single compo sition. Compounds of this invention may exist in alternative tau tomeric forms, as in tautomers 1 and 2 shown below. Unless 45 otherwise indicated, the representation of either tautomer is meant to include the other.

R2 R2 50 R2 R2 e N N NH M N / 55 1s, Z31 N72 Z| A 2 | A els2 NZ G NZ G 60 1 2 R and R' (at positions Z and Z, respectively) may be taken together to form a fused ring, providing a bicyclic ring 65 system containing Ring A. Preferred R/R' rings include a 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated

US 8,633,210 B2 19 20 -continued -continued X X N1 S72

SC le 2 Zl C. 10

I-T 15 X X N72 ( 2 N Zl R4 X I-AA 25 MN N72Z K 2 N Zl 30 R4 x I-V is O N72

2 Zl

40 X I-CC 45 N72 I-W O %

50 I-DD

55

60 Preferred bicyclic Ring. A systems include I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-I, I-J., I-K, I-L, and I-M, more pref erably I-A, I-B, I-C, I-F, and I-H, and most preferably I-A I-B, and I-H. 65. In the monocyclic Ring A System, preferred R' groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a Caliphatic group Such as methyl, ethyl, US 8,633,210 B2 21 22 cyclopropyl, isopropyl or t-butyl. Preferred R' groups, when (un)Substituted phenyl, hydroxyalkyl, alkoxyalkyl, ami present, include T-R wherein T is a valence bond or a meth nocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, ylene, and R is —R, N(R), or —OR. Examples of pre alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, ferred R' include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, and (N-heterocyclyl)carbonyl. Examples of such preferred ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, R substituents include methyl, cyclopropyl, ethyl, isopropyl. acetamido, optionally Substituted phenyl Such as phenyl or propyl, t-butyl, cyclopentyl, phenyl, COH, COCH, halo-substituted phenyl, and methoxymethyl. CHOH, CHOCH, CHCHCH-OH, CHCHCHOCH, In the bicyclic Ring. A system, the ring formed when R and CHCHCHOCHPh. CHCHCH-NH. Rare taken together may be substituted or unsubstituted. CHCHCH-NHCOOC(CH), CONHCH(CH), Suitable substituents include —R, halo. —OR, —C(=O)R. 10 CONHCHCH-CH CONHCHCHOCH, —COR, COCOR, NO, CN, -S(O)R, -SOR, CONHCHPh, CONH(cyclohexyl), CON(Et), CONCH.) —SR, N(R), —CON(R), -SON(R), —OC(=O) CHPh. CONH(n-CH), CON(Et)CHCHCH R, N(R)COR, N(R)CO, (optionally substituted C. CONHCHCH(CH), CON (n-CH4), CO (3-methoxym aliphatic), (R)N(R), -C=NN(R), -C=N OR, ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), N(R)CON(R), N(R)SON(R), N(R)SOR, or 15 CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- –OC(=O)N(R), wherein R and Rare as defined above. yl), CONHCHCH-OH, CONH, and CO(piperidin-1-yl). A Preferred R/R' ring substituents include -halo, R. —OR, preferred R group is hydrogen. —COR, COR, CONCR), CN, or N(R), wherein R is hydrogen or an optionally substituted Caliphatic An embodiment that is particularly useful for treating group. GSK3-mediated diseases relates to compounds of formula II: RandR may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. II Preferred fused rings include benzo, pyrido, pyrimido, and a R2 partially unsaturated 6-membered carbocyclo ring, wherein 25 R2 said fused ring is optionally Substituted. These are exempli e fied in the following formula I compounds having a pyrazole NH containing bicyclic ring system: S. M HN N

R. 30 n N

2

35 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, 40 pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from —R', any substitutable non-ortho carbon position on Ring C is independently substituted by R. N. Y. and two adjacent Substituents on Ring C are optionally 45 taken together with their intervening atoms to form a fused, le le unsaturated or partially unsaturated, 5-6 membered ring NH, NH, and N / N / having 0-3 heteroatoms selected from oxygen, Sulfur or N N nitrogen, said fused ring being optionally Substituted by halo, oxo, or R: 50 R" is selected from -halo, —CN, NO, T-V R, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Caliphatic group, said phenyl, heteroaryl, and e heterocyclyl rings each optionally Substituted by up to NH. N / three groups independently selected from halo, oxo, or N 55 —R. said Caliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' and an adjacent Sub stituent taken together with their intervening atoms form said ring fused to Ring C: Preferred substituents on the R/Rfused ring include one R and Rare independently selected from T-R, or R and R' or more of the following: -halo, N(R), —Cls alkyl, 60 are taken together with their intervening atoms to form a —C haloalkyl, - NO. —O(C- alkyl). —CO(C- fused, unsaturated or partially unsaturated, 5-8 membered alkyl), —CN, SO(C- alkyl). —SONH, OC(O)NH2, ring having 0-3 ring heteroatoms selected from oxygen, —NHSO(C- alkyl), NHC(O) (C. alkyl). —C(O) Sulfur, or nitrogen, wherein any Substitutable carbon on NH, and —CO(C- alkyl), wherein the (C. alkyl) is most said fused ring formed by RandR is substituted by oxo or preferably methyl. 65 T-R, and any substitutable nitrogen on said ring formed by When the pyrazole ring system is monocyclic, preferred R' R and R” is substituted by R: groups include hydrogen, Caliphatic, alkoxycarbonyl, T is a valence bond or a C alkylidene chain; US 8,633,210 B2 23 24 RandR are independently selected from R,-T-W R. or 8-membered unsaturated or partially unsaturated ring hav or R and R are taken together with their intervening ing 0-2 heteroatoms, wherein said R/R' ring is optionally atoms to form a fused, 5-8 membered, unsaturated or par Substituted. This provides a bicyclic ring system containing a tially unsaturated, ring having 0-3 ring heteroatoms pyrimidine ring. Examples of preferred pyrimidine ring sys Selected from nitrogen, oxygen, or Sulfur, wherein each tems of formula II are the mono- and bicyclic systems shown substitutable carbon on said fused ring formed by R and below. R’ is substituted by halo, oxo. —CN, NO, R', or —V-R, and any substitutable nitrogen on said ring formed by RandR is substituted by R: II-A R is selected from —R, -halo, —OR, —C (=O)R, 10 R2 - COR, COCOR, COCHCOR, NO. —CN, R2 —S(O)R, S(O).R. —SR, N(R) - CONOR7), e NH - SON(R7), OC(=O)R, N(R7)COR, N(R7)CO, S. M (optionally substituted Caliphatic), N(R)N(R), HN N C=NN(R) - C=N OR, N(R7)CON(R7), 15 N(R7)SON(R7), N(R)SOR, or OC(=O)N (R): NN each R is independently selected from hydrogen oran option 2 ally substituted group selected from Caliphatic, Co N aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero cyclyl ring having 5-10 ring atoms; each R" is independently selected from R", COR". —CO (optionally substituted Caliphatic), —CON II-B (R), or -SO.R. or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or 25 heteroaryl ring; na each R is independently selected from —R, halo, OR, —C(=O)R, COR, COCOR, NO, CN, -S(O) R, -SOR, SR, N(R) - CONCR), -SON r 2 (R), OC(=O)R, N(R)COR, N(R)CO, (option 30 N ally substituted Caliphatic), -N(R)N(R) -C=NN (R), C–N OR, N(R)CON(R), N(R)SON (R) - N(R)SOR, or - OC(=O)N(R), or R and an adjacent Substituent taken together with their intervening II-C atoms form said ring fused to Ring C: 35 V is - O -, - S -, -SO , -SO. , N(R)SO , —SON(R)-, - N(R)-, -CO-, -CO. , N(R) CO. , N(R)C(O)O N(R)CON(R) , N(R) X SON(R) , N(R)N(R) C(O)N(R) OC 40 r 2 N (R)C(O)O - C(R)=NN(R) - C(R)—N O , C(R)N(R)N(R) C(R)N(R)SON(R) , or C(R)N(R)CON(R) ; 45 W is C(R)-O , C(R)S , C(R)SO , II-D - C(R)SO. , C(R) SON(R)-, - C(R)-N (R)-, -CO-, -CO. , —C(R)OC(O) , —C(R) OC(O)N(R)-, -C(R)N(R)CO C(R)N(R)C ix. (O)O C(R)=NN(R) , C(R)—N O , 50 C(R)N(R)N(R) C(R)N(R)SON(R) , NN C(R)N(R)CON(R) , or CONCR) ; each R is independently selected from hydrogen, an option R41 4. ally substituted Caliphatic group, or two R' groups on the same nitrogenatom are taken together with the nitrogen 55 atom to form a 5-6 membered heterocyclyl or heteroaryl ring, each R" is independently selected from hydrogen or an II-E optionally substituted Caliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form 60 a 5-8 membered heterocyclyl or heteroaryl ring; and each R is independently selected from an optionally substi tuted Caliphatic group, —OR. —SR, COR. —SOR. - N(R), -N (R)N(R) - CN, NO, CONCR), or COR. 65 When the RandR' groups of formula II are taken together to form a fused ring, preferred R/R' rings include a 5-, 6-, 7 US 8,633,210 B2 25 26 -continued -continued II-F X II-L N21 NN

N N 2 10 II-M II-G X 15 N 21 NN

N N2

II-N

II-H X. 25 N

N N N 2

30 X II-O II-I 35 N21 NN

ls N - N -

40 X II-P 45

50 CC, More preferred pyrimidine ring systems of formula II include II-A, II-B, II-C. II-F, and II-H, most preferably II-A. II-B, and II-H. In the monocyclic pyrimidine ring system of formula II, 55 preferred R' groups include hydrogen, alkyl- or dialky lamino, acetamido, or a Caliphatic group such as methyl, II-K ethyl, cyclopropyl, isopropyl or t-butyl. Preferred R' groups include T-R wherein T is a valence bond or a methylene, and 60 Ris-R, N(R), or -OR. When R is R or -OR, a preferred R is an optionally substituted group selected from Caliphatic, phenyl, or a 5-6 membered heteroaryl or het erocyclyl ring. Examples of preferred R' include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl. 65 t-butyl, alkyl- or dialkylamino, acetamido, optionally Substi tuted phenyl Such as phenyl or halo-substituted phenyl, and methoxymethyl. US 8,633,210 B2 27 28 In the bicyclic pyrimidine ring system of formula II, the ring formed when R and Rare taken together may be sub II-Aa stituted or unsubstituted. Suitable substituents include —R, halo, OR, C(=O)R, COR, COCOR, NO, CN, S(O)R, -SOR, SR, N(R), —CON(R), - SON(R), OC(O)R, N(R)COR, N(R)CO, (op NH tionally substituted aliphatic), N(R)N(R), -C=NN S. M (R) - C=N OR, N(R)CON(R), N(R)SON HN N (R), N(R)SOR, or OC(=O)N(R), wherein R and R" are as defined above. Preferred R/R” ring substituents 10 include -halo, R. —OR, COR, CO.R, CONCR), n N —CN, or N(R), wherein R is an optionally substituted 2 Caliphatic group. N The RandR groups of formula II may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include 15 II-Ba benzo, pyrido, pyrimido, and a partially unsaturated 6-mem bered carbocycloring. These are exemplified in the following formula II compounds having a pyrazole-containing bicyclic ring system: NH S. M HN N NN 25 2 N

R. II-Ha

2 NH 30 R N S/ NH S. M HN N N. Y. 35 le le HC NN NH, NH, and N / N / N N 2 H3C N 40 Particularly preferred are those compounds of formula II-Aa, e II-Ba, or II-Ha wherein ring C is a phenyl ring and R' is halo, NH, methyl, or trifluoromethyl. N / 45 Preferred formula II Ring C groups are phenyl and pyridi N nyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system. Preferred fused rings include a benzo or pyrido Preferred substituents on the R/Rfused ring of formula II ring. Such rings preferably are fused at ortho and meta posi include one or more of the following:-halo, N(R), —Ca 50 tions of Ring C. Examples of preferred bicyclic Ring C sys alkyl, —Chaloalkyl, —NO. —O(Calkyl), —CO(C- tems include naphthyl, quinolinyl and isoquinolinyl. alkyl), —CN, SO(C-alkyl). —SONH, OC(O)NH2, An important feature of the formula II compounds is the R' —NHSO(C. alkyl), NHC(O) (C. alkyl). —C(O) ortho Substituent on Ring C. An ortho position on Ring C or NH, and —CO(C. alkyl), wherein the (C. alkyl) is a Ring D is defined relative to the position where Ring A is straight, branched, or cyclic alkyl group. Preferably, the (Ca attached. Preferred R' groups include -halo, an optionally alkyl) group is methyl. 55 substituted Caliphatic group, phenyl, -COR, OR, When the pyrazole ring system of formula II is monocy —CN, -SOR. - SONH, -N (R), —COR, clic, preferred R groups include hydrogen, a substituted or CONH, NHCOR, OC(O)NH, or NHSO.R. unsubstituted group selected from aryl, heteroaryl, or a C When R' is an optionally substituted Caliphatic group, the aliphatic group. Examples of such preferred R groups most preferred optional Substituents are halogen. Examples include methyl, t-butyl, —CHOCH, cyclopropyl, furanyl. 60 of preferred R' groups include —CF, —Cl, F. —CN, thienyl, and phenyl. A preferred R group is hydrogen. - COCH, OCH, -OH, -CHCH, OCHCH More preferred ring systems of formula II are the follow —CH —CFCH., cyclohexyl, t-butyl, isopropyl, cyclopro ing, which may be substituted as described above, wherein R pyl, -C=CH, —C=C CH - SOCH —SONH2, and Rare taken together with the pyrazole ring to form an - N(CH), -COCH, -CONH, -NHCOCH, OC indazole ring; and R and Rare each methyl, or R and Rare 65 (O)NH, -NHSOCH, and OCF. taken together with the pyrimidine ring to form a quinazoline On Ring C of formula II, preferred R substituents, when or tetrahydroquinazoline ring: present, include -halo, —CN, NO, N(R), optionally US 8,633,210 B2 29 30 Substituted Caliphatic group, —OR, —C(O)R. —COR, with their intervening atoms to forman optionally substituted CONH(R), N(R)COR, -SON(R), and N(R) benzo ring or partially unsaturated 6-membered carbocyclo SO.R. More preferred R substituents include - C1, F, ring: —CN, —CF, -NH2, —NH(Caliphatic), —N(Cali (c) R' is -halo, a Caliphatic group optionally substituted phatic) —O(Caliphatic), Caliphatic, and —CO(C- aliphatic). Examples of such preferred R substituents with halogen, or—CN: include C1, F, CN, CF, NH, NHMe, (d) R and R are taken together with their intervening —NMe2, —OEt, methyl, ethyl, cyclopropyl, isopropyl, t-bu atoms to form a benzo, pyrido, pyrimido or partially unsatur tyl, and —COEt. ated 6-membered carbocycloring optionally substituted with Preferred formula II compounds have one or more, and 10 -halo, -N(R), —C, alkyl, -C, a haloalkyl, - NO, more preferably all, of the features selected from the group —O(C. alkyl). —CO(C. alkyl). —CN. —SO(C- consisting of: alkyl). —SONH2, —OC(O)NH2. —NHSO(C- alkyl). (a) Ring C is a phenyl or pyridinyl ring, optionally Substi —NHC(O)(C. alkyl), —C(O)NH2 or —CO(C. alkyl). tuted by R, wherein when Ring C and two adjacent sub wherein the (C. alkyl) is a straight, branched, or cyclic alkyl stituents thereon form a bicyclic ring system, the bicyclic ring 15 group; and system is selected from a naphthyl, quinolinyl or isoquinoli (e) each R is independently selected from - C1, F. nyl ring: —CN, —CF, -NH2, —NH(Caliphatic), —N(Cali (b)R’ is hydrogen oraliphatic and R is T-R, or R and R' phatic) —O(Caliphatic), Caliphatic, and —CO(C- are taken together with their intervening atoms to form an aliphatic). optionally substituted 5-7 membered unsaturated or partially Representative compounds of formula II are shown below unsaturated ring having 0-2 ring nitrogens; in Table 1. (c) R' is -halo, an optionally substituted Caliphatic group, phenyl, COR, OR, CN, SOR, TABLE 1 - SONH, N(R), COR, CONH NHCOR, –OC(O)NH, or -NHSOR: and 25 I-1 (d) R' is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C aliphatic group, or R and R” are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered 30 carbocycloring. More preferred compounds of formula II have one or more, and more preferably all, of the features selected from the group consisting of (a) Ring C is a phenyl or pyridinyl ring, optionally Substi 35 tuted by R, wherein when Ring C and two adjacent sub stituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; (b) R' is hydrogen or methyl and R is R, N(R), or II-2 —OR, or R and Rare taken together with their intervening 40 atoms to form a 5-7 membered unsaturated or partially unsat urated carbocyclo ring optionally Substituted with —R, halo, —OR, C(=O)R, COR, COCOR, NO, CN, S(O)R, -SOR, SR, N(R), —CON(R), -SON (R), OC(=O)R, N(R)COR, N(R)CO (optionally 45 substituted Caliphatic), N(R)N(R), -C=NN(R), -C=N OR, N(R)CON(R), N(R) SON(R), N(R)SOR, or OC(=O)N(R): (c) R' is -halo, a Chaloaliphatic group, a Caliphatic group, phenyl, or —CN: 50 (d) R' is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, or a Caliphatic group, or R and Rare taken together with their intervening F II-3 atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and 55 (e) each R is independently selected from -halo. —CN, —NO, N(R), optionally substituted C- aliphatic group, —OR, —C(O)R, COR, CONH(R), -N (R) COR, SON(R), or N(R)SOR. Even more preferred compounds of formula II have one or 60 more, and more preferably all, of the features selected from the group consisting of (a) Ring C is a phenyl ring optionally substituted by R: (b) R' is hydrogen or methyl and R is methyl, methoxym ethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an 65 optionally Substituted group selected from 2-pyridyl, 4-py ridyl, piperidinyl, or phenyl, or R and Rare taken together

US 8,633,210 B2 39 40 TABLE 1-continued TABLE 1-continued CH3 II-36 CH3 II-41

NN C 10

15 II-37

II-42

25

II-38 30

35 II-43

40

II-39

45

50

II-40 ss II-44

60 NN OH 2 CH

65 US 8,633,210 B2 41 42 TABLE 1-continued TABLE 1-continued

II-45 CH3 CH3 II-49

10

15

II-46 II-SO

25

30

35

II-47

40

45

50

II-48 II-52 55 HN e

60

65

US 8,633,210 B2 49 50 TABLE 1-continued TABLE 1-continued

FC II-77 CF3 II-81

10 NN C

15

II-78 Br II-82

25

NN CN

30

35 Br II-79 II-83

40

45

50 CF

55

60

65

US 8,633,210 B2 53 54 TABLE 1-continued TABLE 1-continued

II-97 II-93

10

15 OCH

II-94 II-98

25

30

35 II-95 II-99

40

NN C 45

NO 50

II-100 II-96

55

60 NN C

65 US 8,633,210 B2 55 56 TABLE 1-continued TABLE 1-continued

I-101 CH3 II-105

10

NN CF 15 2 N

II-106

F I-102

NH 25 N / 21 NN C HN N

7N1SN 30 N 2 O N

C 35 I-103 II-107

40 e NH S. M HN N

45 NN OCF 2 N

CH3 50

s I-104 O II-108 le 55

e NH N / HN N 60 NN OCF 2 N 65 CH3

US 8,633,210 B2 59 60 TABLE 1-continued TABLE 1-continued

II-117 F F II-121

10 NN Cl

15

II-118 II-122

25

NN Cl

30

35 II-123 II-119

40

45

50

II-124

II-120 55

60

65 US 8,633,210 B2 61 62 TABLE 1-continued TABLE 1-continued

MeOC I-125 F II-129

NH N / HN N 10 N 2 NN Sa 2 N N 15 C

I-126 F II-130

NH 25 N / HN N C O NN

2 30 N

FC

35 I-127 F II-131

40 NH N / HN N

O NN 45 2 N

FC 50

I-128 F II-132

55

NH N / HN N

60 O NN 2 N

65 US 8,633,210 B2 63 64 TABLE 1-continued TABLE 1-continued

CH3 I-133 F II-137

e NH N / HN N

O 10 N 2 N

FC 15

FC

F I-134 F II-138

NH N / HN N 25

O

(SSM 2 N 30

FC FC 35

II-139

40 NH N / HN N

NN 45 KO 4.

FC 50 HN FC

II-140 CH3 I-136 55 e NH N / HN N

60 S

(SSM 2 N

65 FC AcNH FC

US 8,633,210 B2 67 68 TABLE 1-continued TABLE 1-continued

II-149 II-153

NH N / HN N 10 NN CF 2 N

15 NH

ON HN Me

F II-150 II-154

25

N /

30

35

II-151 IL-155

40

NH N / HN N

45 nN. CF HN 2 N

50

F II-152

55 II-156

NH S. M HN N 60 NN CF HN 2 N

65

US 8,633,210 B2 79 80 TABLE 1-continued TABLE 1-continued

F II-197

10 Me AcHN NN C

HNOS N

15

II-198

25

30

II-199 3.5

40

45

50 II-204

55

60 NN C

65

US 8,633,210 B2 83 84 TABLE 1-continued TABLE 1-continued

II-212 F II-216

NH N / HN N 10 21 NN C Sa 2 N N 15

II-217 II-213

NH N / 25 HN N

21 NN C

N 2 30 N N

35

II-218

II-214

40 NH N / HN N

21 NN C 45 21 NN C N N N 2

50

II-215 F II-219

55

NH N / HN N 60 21 NN C 21 NN C

N N N 2 65 US 8,633,210 B2 85 86 TABLE 1-continued TABLE 1-continued

F II-220 II-224

NH N / HN N

10 n N 21 NN Cl 2 N

15 Me

Me

F II-225 II-221 20

NH S. M 25 HN N

n N

2 30 N

Me

Me 35 F II-226 II-222

40 NH S. M HN N

n N 45 1 N

50

II-227 II-223 55 NH N / HN N

60 n N

2 N 2 N 65

US 8,633,210 B2 91 92 TABLE 1-continued TABLE 1-continued

II-248 II-244

10

NN CN

15

II-249

II-245 20

25 NN SON(Me) NN CN

30

OCH

35 II-246

40 NN SON(Me)

45

II-251 50

II-247

55

60

65. In another embodiment, this invention provides a compo sition comprising a compound of formula II and a pharma ceutically acceptable carrier. US 8,633,210 B2 93 94 One aspect of this invention relates to a method of inhibit Another embodiment of this invention relates to com ing GSK-3 activity in a patient, comprising administering to pounds of formula III: the patient a therapeutically effective amount of a composi III tion comprising a compound of formula II. R2 Another aspect relates to a method of treating a disease that R2 is alleviated by treatment with a GSK-3 inhibitor; said e NH method comprising the step of administering to a patient in S. M need of such a treatmentatherapeutically effective amount of HN N a composition comprising a compound of formula II. 10 R. Another aspect relates to a method of enhancing glycogen n N synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a 2 therapeutically effective amount of a composition comprising R N a compound of formula II. This method is especially useful 15 for diabetic patients. or a pharmaceutically acceptable derivative or prodrug Another aspect relates to a method of inhibiting the pro thereof, wherein: duction of hyperphosphorylated Tau protein in a patient in Ring D is a 5-7 membered monocyclic ring or 8-10 membered need thereof, comprising administering to said patient a bicyclic ring selected from aryl, heteroaryl, heterocyclyl or therapeutically effective amount of a composition comprising carbocyclyl, said heteroaryl or heterocyclyl ring having a compound of formula II. This method is especially useful in 1-4 ring heteroatoms selected from nitrogen, oxygen or halting or slowing the progression of Alzheimer's disease. sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R, and at any substitutable ring Another aspect relates to a method of inhibiting the phos nitrogen by R. provided that when Ring D is a six phorylation off-catenin in a patient in need thereof, compris 25 membered arylor heteroaryl ring, -R is hydrogen at each ing administering to said patient a therapeutically effective ortho carbon position of Ring D; amount of a composition comprising a compound of formula R and R” are taken together with their intervening atoms to II. This method is especially useful for treating schizophre form a fused, benzo ring or a 5-8 membered carbocyclo 18. 30 ring, wherein any Substitutable carbon on said fused ring One aspect of this invention relates to a method of inhibit formed by R and R is substituted by oxo or T-R: ing Aurora activity in a patient, comprising administering to T is a Valence bond or a C alkylidene chain; RandR are independently selected from R,-T-W R. the patient a therapeutically effective amount of a composi or R and R are taken together with their intervening tion comprising a compound of formula II. atoms to form a fused, 5-8 membered, unsaturated or par Another aspect relates to a method of treating a disease that 35 tially unsaturated, ring having 0-3 ring heteroatoms is alleviated by treatment with an Aurora inhibitor, said selected from nitrogen, oxygen, or Sulfur, wherein each method comprising the step of administering to a patient in substitutable carbon on said fused ring formed by R and need of such a treatmentatherapeutically effective amount of R’ is substituted by halo, oxo, —CN, NO, R', or a composition comprising a compound of formula II. This —V R', and any substitutable nitrogen on said ring 40 formed by RandR is substituted by R: method is especially useful for treating cancer, Such as colon, R is selected from R, -halo, =O, OR, —C(=O)R, ovarian, and breast cancer. —COR, COCOR, COCHCOR, NO. —CN, One aspect of this invention relates to a method of inhibit —S(O)R, S(O).R. —SR, N(R), —CON(R), ing CDK-2 activity in a patient, comprising administering to - SON(R), OC(=O)R, N(R)COR, N(R)CO, the patient a therapeutically effective amount of a composi 45 (optionally substituted Caliphatic), N(R)N(R). tion comprising a compound of formula II. C=NN(R) -C=N OR, (R)CON(R) - N(R) SON(R), N(R)SOR, or OC(=O)N(R): Another aspect relates to a method of treating a disease that each Ris independently selected from hydrogen oran option is alleviated by treatment with a CDK-2 inhibitor, said ally substituted group selected from Caliphatic, Co method comprising the step of administering to a patient in aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero need of such a treatmentatherapeutically effective amount of 50 cyclyl ring having 5-10 ring atoms; a composition comprising a compound of formula II. This each R is independently selected from R', COR7. method is especially useful for treating cancer, Alzheimer's —CO (optionally substituted Caliphatic), —CON disease, restenosis, angiogenesis, glomerulonephritis, (R), or - SOR", or two R' on the same nitrogen are cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, taken together to form a 5-8 membered heterocyclyl or alopecia, and autoimmune diseases Such as rheumatoid 55 heteroaryl ring; arthritis. each R is independently selected from R, halo, —OR, —C(=O)R, COR, COCOR, NO, CN, S(O) Another method relates to inhibiting GSK-3, Aurora, or R, -SOR. -SR, N(R), —CON(R), -SON CDK-2 activity in a biological sample, which method com (R), OC(=O)R, N(R)COR, N(R)CO, (option prises contacting the biological sample with the GSK-3 or 60 ally substituted Caliphatic), N(R)N(R), C=NN Aurora inhibitor of formula II, or a pharmaceutical composi (R)-C=N OR, (R)CON(R), N(R)SON(R), tion thereof, in an amount effective to inhibit GSK-3, Aurora N(R)SOR, or OC(=O)N(R): or CDK-2. V is - O -, - S -, -SO , SO. , N(R)SO , Each of the aforementioned methods directed to the inhi - SON(R) s N(R) s CO s CO, s N(R) bition of GSK-3, Aurora or CDK-2, or the treatment of a 65 CO N(R)C(O)O N(R)CON(R) N(R) disease alleviated thereby, is preferably carried out with a SON(R) , N(R)N(R) C(O)N(R) OC preferred compound of formula II, as described above. (O)N(R)-, - C(R)-O-, - C(R)S , C(R) US 8,633,210 B2 96 -continued III-B

(R)-, -CO-, -CO, , –C(R)OC(O) , —C(R) OC(O)N(R) C(R)N(R)CO C(R)N(R)C (O)O C(R)=NN(R) , C(R)—N O , 10 C(R)N(R)N(R) C(R)N(R)SON(R) , III-C C(R)N(R)CON(R) , or CONCR) ; each R is independently selected from hydrogen or an optionally substituted Caliphatic group, or two R' 15 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R" is independently selected from hydrogen or an optionally substituted Caliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form III-F a 5-8 membered heterocyclyl or heteroaryl ring. Preferred formula III Ring D monocyclic rings include Substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl 25 rings. When two adjacent Substituents on Ring D are taken together to form a fused ring, the Ring D System is bicyclic. Preferred formula III Ring D bicyclic rings include 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2.3- dihydro-1H-isoindolyl, isoquinolinyl, quinolinyl, and naph 30 thyl. Examples of more preferred bicyclic Ring D systems III-I include naphthyl and isoquinolinyl. Preferred R substituents on Ring D of formula III include X. halo, oxo, CN, NO, N(R), —COR, CONH(R), 35 N(R)COR, -SON(R), N(R)SOR, SR, OR, N72 —C(O)R, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Co aryl, or Caliphatic. 2 More preferred R substituents include -halo. —CN, -oxo, Zl —SR, OR, N(R), —C(O)R, or a substituted or unsub 40 stituted group selected from 5-6 membered heterocyclyl, Preferred substituents on the R/R' fused ring of formula Co aryl, or Caliphatic. Examples of Ring DSubstituents III include —R, oxo, halo, —OR, —C(=O)R. —COR, include —OH, phenyl, methyl, CHOH, CHCH-OH. pyrro —COCOR, NO, CN, -S(O)R, -SOR, -SR, lidinyl, OPh, CF, Cl, Br, F, I, NH, C(O)CH, i-propyl, - N(R), CON(R), —SON(R), OC(=O)R, tert-butyl, SEt, OMe, N(Me), methylene dioxy, and ethylene 45 N(R)COR, N(R)CO (optionally substituted Cali dioxy. phatic), N(R)N(R), C=NN(R), -C=N OR, Preferred rings formed when the R and R' groups of for N(R)CON(R), N(R)SON(R), N(R)SOR, or mula III are taken together to form a fused ring include a 5-, –OC(=O)N(R), wherein R and Rare as defined above. 6-, or 7-membered unsaturated or partially unsaturated car More preferred substituents on the R/R' fused ring include bocyclo ring, wherein any Substitutable carbon on said fused 50 halo, CN, Oxo, Ce alkyl, Calkoxy, (C. alkyl)carbonyl, ring is substituted by oxo or T-R. Examples of preferred (C. alkyl)sulfonyl, mono- or dialkylamino, mono- or bicyclic ring systems are shown below. dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl. Examples of such preferred Substituents include methoxy, methyl, isopropyl, methylsul III-A fonyl, cyano, chloro, pyrrolyl, methoxy, ethoxy, ethylamino, 55 acetyl, and acetamido. Preferred R substituents of formula III include hydrogen, C. aliphatic, alkoxycarbonyl, (un)Substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialky laminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylami 60 noalkyl, phenylaminocarbonyl, and (N-heterocyclyl)carbo nyl. Examples of such preferred R substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclo pentyl, phenyl, COH, COCH, CH-OH, CHOCH, CHCHCH-OH, CHCHCHOCH, CHCHCHOC 65 HPh, CHCHCH-NH, CHCHCH-NHCOOC(CH), CONHCH(CH), CONHCH-CH=CH, CONHCHCHOCH CONHCHPh, CONH(cyclohexyl), US 8,633,210 B2 97 98 CON(Et), CONCH)CHPh, CONH(n-CH), CON(Et) More preferred compounds of formula III have one or CHCHCH, CONHCH-CH(CH), CONCn-CH), more, and more preferably all, of the features selected from CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), the group consisting of CONH(4-tolyl), CONHCH, CO(morpholin-1-yl), CO(4- methylpiperazin-1-yl), CONHCHCH-OH, CONH, and (a) Ring D is an optionally Substituted ring selected from CO(piperidin-1-yl). 5 phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, mor When the R and R groups of formula III are taken pholinyl, 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4-tetrahyd together to form a ring, preferred R/R ring systems con roquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-in taining the pyrazole ring include benzo, pyrido, pyrimido, dolyl, isoquinolinyl, quinolinyl, or naphthyl; 3-oxo-2H-pyridazino, and a partially unsaturated 6-mem (b) R' and R are taken together with their intervening bered carbocyclo ring. Examples of such preferred R/R 10 atoms to form a benzo ring or a 5-7 membered carbocyclo ring systems containing the pyrazole ring include the follow ring optionally substituted with —R, oxo, halo. —OR, 1ng: - C(=O)R, COR, COCOR, NO, CN, -S(O)R, —SOR, SR, N(R), —CON(R), -SON(R), –OC(=O)R, N(R)COR, N(R)CO, (optionally sub 15 stituted Caliphatic), N(R)N(R), -C=NN(R), f N N C=N OR, N(R)CON(R), N(R)SON(R), N | - N(R)SOR, or—OC(=O)N(R); and (c) each R is independently selected from halo, oxo, CN, Y.M . Y.M NO, N(R), COR, CONH(R), N(R)COR, N N —SON(R), N(R)SOR, SR, OR, —C(O)R, or a substituted or unsubstituted group selected from 5-6 mem bered heterocyclyl, Co aryl, or Caliphatic. Even more preferred compounds of formula III have one or N Kl more, and more preferably all, of the features selected from 25 the group consisting of | \, N N (a) R' and R are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated Y./ carbocyclo ring optionally substituted with halo, CN, oxo, N C. alkyl, Ce alkoxy, (C. alkyl)carbonyl, (C. alkyl)sul H 30 fonyl, mono- or dialkylamino, mono- or dialkylaminocarbo nyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered N heteroaryl; | N (b) each R is independently selected from -halo. —CN, N -oxo, SR, OR, N(R), —C(O)R, or a substituted or \ and \ 35 unsubstituted group selected from 5-6 membered heterocy M M clyl, Co-o aryl, or Caliphatic; and N N (c) R is hydrogen and R is selected from R is hydrogen or methyl and R is T-R or R, wherein W is C(R)-O-, - C(R)N(R)-, -CO , CO2 . C(R)OC(O) , - C(R)N(R)CO , or – CONCR)—, and R is an option Preferred substituents on the R/R fused ring of formula 40 ally substituted group selected from Caliphatic or phenyl, III include one or more of the following: -halo, N(R), or R and Rare taken together with their intervening atoms —C alkyl, —C haloalkyl, - NO. —O(C. alkyl). to form a benzo, pyrido, or partially unsaturated 6-membered —CO(C. alkyl). —CN. —SO(C- alkyl). —SONH2, carbocyclo ring optionally substituted with -halo, N(R), —OC(O)NH2. —NHSO(C- alkyl). —NHC(O)(C. —C alkyl, -C haloalkyl, - NO. —O(C. alkyl). alkyl), —C(O)NH, and —CO(Calkyl), wherein the (C. 45 —CO(C. alkyl). —CN, -SO(C- alkyl). —SONH2, alkyl) is a straight, branched, or cyclic alkyl group. Prefer —OC(O)NH, -NHSO(C. alkyl), NHC(O)(C. ably, the (C. alkyl) group is methyl. alkyl), —C(O)NH, or —CO(C. alkyl), wherein the (Ca Preferred formula III compounds have one or more, and alkyl) is a straight, branched, or cyclic alkyl group. more preferably all, of the features selected from the group Representative compounds of formula III are set forth in consisting of: 50 Table 2 below. (a) Ring D is an optionally Substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thie nyl, azepanyl, morpholinyl, 1.2.3,4-tetrahydroisoquinolinyl, TABLE 2 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, III-1 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naph thyl ring; 55 (b) R' and R are taken together with their intervening atoms to form an optionally substituted benzo ring or a 5-7 membered carbocycloring; and (c) R' is hydrogen or methyl and R is T-W-R or R, wherein W is C(R),O C(R)N(R)-, - CO , 60 —CO. , —C(R)OC(O) , C(R)N(R)CO , —C(R)N(R)C(O)O , or – CONCR) , and R is an optionally substituted group selected from Caliphatic or phenyl, or RandR are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, 65 pyrimido, or partially unsaturated 6-membered carbocyclo ring.

US 8,633,210 B2 101 102 TABLE 2-continued TABLE 2-continued

CH3 III-15

C NH III-11 S. M HN N 10 n N

2 N

15 C

III-16 CH3 III-12

e NH S. M HN N 25 NN 2 ENH N 30

C

35

CH3 III-13 III-17 e NH S. M 40 HN N

SN

2 45 N

OEt

OCH 50

III-18

III-14 55

60

C 65 C US 8,633,210 B2 103 104 TABLE 2-continued TABLE 2-continued

CH III-19 CH3 III-23

10

NC CHSO

15 CH

III-24 20 III-20

25

CHO 30 CH

35

III-21 III-25

40

45 HC CHO CH3 Cl CH3

50

III-22 III-26 55

60 CHNH

65 CH US 8,633,210 B2 105 106 TABLE 2-continued TABLE 2-continued

III-27 III-31

10

15

III-32

III-28

25

30 2 C N N 2N

35

III-33 III-29

40

C 45

50

III-34 III-30 55

60

65 US 8,633,210 B2 107 108 TABLE 2-continued TABLE 2-continued

CH3 III-35 CH3 III-39

Y.M HN1 N

NN 10

N

C SEt O 15

III-40 CH3 III-36

Y.M HN N 25 NN

2 C N 30

C

35 III-41

CH III-37

40 Y.M HN N

NN 45 CH N CH CN CH3 o 50

III-42

CH III-38 55

Y.M HN N 60 NN

65 C US 8,633,210 B2 109 110 TABLE 2-continued TABLE 2-continued CH3 III-43 CH3 III-47

Y.M N H NN 10 N O 15 Co III-44 CH3 III-48

Y.M 25 HN N

n N

N 30 Ol Š.

35 III-45 CH3 III-49

40 Y.M HN N

45 n N CH 2 2 N

50

III-46

55 CH3 III-SO

Y.M HN N 60 NN 2 CH N 65

US 8,633,210 B2 115 116 TABLE 2-continued TABLE 2-continued

CH3 III-68 COH III-72

CH N N M HN N

10 NN

N

15 c

III-69 COCH3 III-73

Y.M 25 HN N NN

N 30 c

III-70 35

CHOH III-74

40 / HN1 3.N NN 45 N c 50

III-71

55 CHOCH3 III-75

Y.M HN N 60 NN 2 N 65 US 8,633,210 B2 117 118 TABLE 2-continued TABLE 2-continued OH III-76 NHBoc III-80

10

15

III-81

OCH III-77

25

30

35 III-82 OCH2Ph III-78

40

45

50

OCH III-83 NH2 III-79

55

60

65

US 8,633,210 B2 121 122 TABLE 2-continued TABLE 2-continued

CH3 III-95 CH III-92 O /-/ N N V N CH M 3 HN N 10 NN 2 N 15

O CH III-96

25

O III-93 N 30 N “CHOCH, N M HN N 35 NN III-97 2 O O N 40

45

ch, III-94 50

III-98 O O N-CH3 NH 55 NN

Y.M HN N 60 NN 2 N

65

US 8,633,210 B2 125 126 TABLE 2-continued TABLE 2-continued CH3 III-108 CH3 III-112

Y.M HN N NN 10

Nals N O 15 1X

III-109 CH III-113

Y.M HN N 25 NN

Nals N 30 O)

35 III-110 CH3 III-114

40 Y.M HN1 N NN

45 Nals N

OH

50

III-115 III-111

55

Y.M N H 60 NN

65 CH OH US 8,633,210 B2 127 128 TABLE 2-continued TABLE 2-continued

III-116 III-120

N N M HN N 10 NN

N es 15

III-121 III-117

\ M 25 N HN H

n 30 2 N N

35

COCH III-122 III-118

40

45

50

III-123 III-119

55

60

65 US 8,633,210 B2 129 130 TABLE 2-continued TABLE 2-continued

CH2OH III-124 FC III-128 t M HN N 10 NN

N 15 c

CONH III-125 III-129 F

Y.M 25 HN N SN 30 N c

35 III-126 F III-130

40 Y.M HN N NN 45

N CH3 c 50

III-127 F III-131 F 55

Y.M HN N 60 NN 2 N 65 US 8,633,210 B2 131 132 TABLE 2-continued TABLE 2-continued

III-132 MeO III-136

Y.M HN N 10 NN 2 CF N NN 15 2 N | N III-133 N 2O

Y.M HN N 25 NN

2 CI III-137 N

30

III-134 Cl

35 MeO NN

40 2 N

NN

2 45 N

III-135 50 III-138

FC 55

NN 60 NN 2 N 2

65 US 8,633,210 B2 133 134 TABLE 2-continued TABLE 2-continued III-143 PhO III-139 5 | NN HN N^H

10 NN

Nals N NN 15 2 N III-144

2O N N M C III-140 HN N

NN 25 2 N N

30 III-145 NN 2 \ N 35 N^ HN H NN III-141 40 es--"l S. NH 45 Me HN N III-146 NN

Nals 1s 50 S. NH \—/ HN N

III-142 NN 55 2 N N

Y. Me HN N H 60 n In another embodiment, this invention provides a compo N CH3 sition comprising a compound of formula III and a pharma als ceutically acceptable carrier. N N1 N One aspect of this invention relates to a method of inhibit N/ 65 ing GSK-3 activity in a patient, comprising administering to S. the patient a therapeutically effective amount of a composi tion comprising a compound of formula III. US 8,633,210 B2 135 136 Another aspect relates to a method of treating a disease that Each of the aforementioned methods directed to the inhi is alleviated by treatment with a GSK-3 inhibitor, said method bition of GSK-3, Aurora, CDK-2, or Src, or the treatment of comprising the step of administering to a patient in need of a disease alleviated thereby, is preferably carried out with a Such a treatment a therapeutically effective amount of a com preferred compound of formula III, as described above. position comprising a compound of formula III. Compounds of formula III, wherein R is hydrogen and R' Another aspect relates to a method of enhancing glycogen and Rare taken together with the pyrimidine ring to forman synthesis and/or lowering blood levels of glucose in a patient optionally Substituted quinazoline ring system, are also in need thereof, comprising administering to said patient a inhibitors of ERK-2 and AKT protein kinases. therapeutically effective amount of a composition comprising Accordingly, another method of this invention relates to a a compound of formula III. This method is especially useful 10 method of inhibiting ERK-2 or AKT activity in a patient, for diabetic patients. comprising administering to the patient a therapeutically Another aspect relates to a method of inhibiting the pro effective amount of a composition comprising a compound of duction of hyperphosphorylated Tau protein in a patient in formula III, wherein R is hydrogen and R and R” are taken need thereof, comprising administering to said patient a together with the pyrimidine ring to form an optionally Sub therapeutically effective amount of a composition comprising 15 stituted quinazoline ring system. Another aspect relates to a method of treating a disease that a compound of formula III. This method is especially useful is alleviated by treatment with a ERK-2 or AKT inhibitor, said in halting or slowing the progression of Alzheimer's disease. method comprising the step of administering to a patient in Another aspect relates to a method of inhibiting the phos need of such a treatmentatherapeutically effective amount of phorylation off-catenin in a patient in need thereof, compris a composition comprising a compound of formula III, ing administering to said patient a therapeutically effective wherein R is hydrogen and RandR are taken together with amount of a composition comprising a compound of formula the pyrimidinering to forman optionally Substituted quinaZo III. This method is especially useful for treating schizophre line ring system. This method is especially useful for treating nia. cancer, stroke, hepatomegaly, cardiovascular disease, Alzhe One aspect of this invention relates to a method of inhibit 25 imer's disease, cystic fibrosis, viral disease, autoimmune dis ing Aurora activity in a patient, comprising administering to eases, restenosis, psoriasis, allergic disorders including the patient a therapeutically effective amount of a composi asthma, inflammation, and neurological disorders. tion comprising a compound of formula III. Another embodiment of this invention relates to com Another aspect relates to a method of treating a disease that pounds of formula IV: is alleviated by treatment with an Aurora inhibitor, said 30 method comprising the step of administering to a patient in need of such a treatmentatherapeutically effective amount of IV a composition comprising a compound of formula III. This R2 method is especially useful for treating cancer, Such as colon, R2 ovarian, and breast cancer. 35 e One aspect of this invention relates to a method of inhibit NH ing CDK-2 activity in a patient, comprising administering to S. M the patient a therapeutically effective amount of a composi HN N tion comprising a compound of formula III. R. Another aspect relates to a method of treating a disease that 40 n N is alleviated by treatment with a CDK-2 inhibitor, said 2 method comprising the step of administering to a patient in R N need of such a treatmentatherapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for treating cancer, Alzheimer's 45 disease, restenosis, angiogenesis, glomerulonephritis, or a pharmaceutically acceptable derivative or prodrug cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, thereof, wherein: alopecia, and autoimmune diseases Such as rheumatoid Ring D is a 5-7 membered monocyclic ring or 8-10 membered arthritis. bicyclic ring selected from aryl, heteroaryl, heterocyclyl or One aspect of this invention relates to a method of inhibit 50 carbocyclyl, said heteroaryl or heterocyclyl ring having ing Src activity in a patient, comprising administering to the 1-4 ring heteroatoms selected from nitrogen, oxygen or patient a therapeutically effective amount of a composition sulfur, wherein Ring D is substituted at any substitutable comprising a compound of formula III. ring carbon by oxo or -R, and at any substitutable ring Another aspect relates to a method of treating a disease that nitrogen by R. provided that when Ring D is a six is alleviated by treatment with a Src inhibitor, said method 55 membered arylor heteroaryl ring, -R is hydrogen at each comprising the step of administering to a patient in need of ortho carbon position of Ring D; Such a treatment a therapeutically effective amount of a com R and Rare independently selected from T-R, or R and R' position comprising a compound of formula III. This method are taken together with their intervening atoms to form a is especially useful for treating hypercalcemia, osteoporosis, fused, unsaturated or partially unsaturated, 5-8 membered osteoarthritis, cancer, symptomatic treatment of bone 60 ring having 1-3 ring heteroatoms selected from oxygen, metastasis, and Paget’s disease. Sulfur, or nitrogen, wherein any Substitutable carbon on Another method relates to inhibiting GSK-3, Aurora, said fused ring is optionally and independently substituted CDK-2, or Src activity in a biological sample, which method by T-R, and any substitutable nitrogen on said ring is comprises contacting the biological sample with the GSK-3, substituted by R: Aurora, CDK-2, or Src inhibitor of formula III, or a pharma 65 T is a valence bond or a C alkylidene chain; ceutical composition thereof, in an amount effective to inhibit R° and Rare independently selected from —R,-T-W R. GSK-3, Aurora, CDK-2, or Src. or R and R are taken together with their intervening US 8,633,210 B2 137 138 atoms to form a fused, 5-8 membered, unsaturated or par —SR, OR, N(R), —C(O)R, or a substituted or unsub tially unsaturated, ring containing 0-3 ring heteroatoms stituted group selected from 5-6 membered heterocyclyl, Selected from nitrogen, oxygen, or Sulfur, wherein said Co aryl, or Caliphatic. Examples of Ring DSubstituents fused ring is optionally Substituted by up to three groups include —OH, phenyl, methyl, CH-OH, CH2CH2OH. pyrro independently selected from halo, oxo, —CN, NO, lidinyl, OPh, CF, C=CH, Cl, Br, F, I, NH, C(O)CH, i-pro R', or V R: pyl, tert-butyl, SEt, OMe, N(Me), methylene dioxy, and R is selected from R, -halo, =O. —OR, —C(=O)R, ethylene dioxy. - COR, COCOR, COCHCOR, NO. —CN, When the R and R' groups of formula IV are taken —S(O)R, S(O).R. —SR, N(R), —CON(R), together to form a fused ring, preferred R/R' rings include a - SON(R), OC(=O)R, N(R)COR, N(R)CO, 10 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated (optionally substituted Caliphatic), N(R)N(R), ring having 1-2 heteroatoms. This provides a bicyclic ring C=NN(R) - C=N OR, N(R)CON(R), system containing the pyrimidinering. Examples of preferred N(R)SON(R), N(R)SOR, or OC(=O)N pyrimidine ring systems of formula IV are the mono- and (R): bicyclic systems shown below. each R is independently selected from hydrogen oran option 15 ally substituted group selected from Caliphatic, Co aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero cyclyl ring having 5-10 ring atoms; IV-D each R is independently selected from R', COR7. —CO (optionally substituted Caliphatic), —CON (R), or - SOR", or two R on the same nitrogen are ox taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R is independently selected from —R, halo, OR, —C(=O)R, COR, COCOR, NO, CN, -S(O) N r 2 R, -SOR, SR, N(R) - CON(R), -SON 25 R41 N (R), OC(=O)R, N(R)COR, N(R)CO, (option ally substituted Caliphatic), N(R)N(R), -C=NN (R), -C=N OR, N(R)CON(R), N(R)SON IV-E (R), N(R)SOR, or OC(=O)N(R): V is —O , S: , SO , SO. , N(R)SO , 30 X - SON(R) s N(R) s CO s CO, s N(R) CO N(R)C(O)O N(R)CON(R) , N(R) R SON(R) , N(R)N(R) C(O)N(R) OC NN NN 2 35 N (R)C(O)O - C(R)=NN(R) - C(R)—N O , C(R)N(R)N(R) C(R)N(R)SON(R) , or IV-G C(R)N(R)CON(R) ; W is C(R),O , C(R) S , - C(R)SO. , C(R)SON(R) , 40 ox (R) , —CO , CO: C(R)OC(O) , C(R) OC(O)N(R) C(R)N(R)CO C(R)N(R)C H (O)O C(R)=NN(R) , C(R)—N O , C(R)N(R)N(R) C(R)N(R)SON(R) , r 2 C(R)N(R)CON(R)-, or CONCR) ; 45 Me N each R is independently selected from hydrogen or an optionally substituted Caliphatic group, or two R' IV-H groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and 50 each R" is independently selected from hydrogen or an ox optionally substituted Caliphatic group, or two R' on the M same nitrogen are taken together with the nitrogen to form e NN a 5-8 membered heterocyclyl ring or heteroaryl. 2 Preferred formula IV Ring D monocyclic rings include Me N Substituted and unsubstituted phenyl, pyridinyl, piperidinyl, 55 piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Preferred formula IV Ring D bicyclic rings include IV-J 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoli nyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred Ring D bicyclic rings 60 X include naphthyl and isoquinolinyl. Preferred substituents on Ring D of formula IV include 21 NN halo, oxo, CN, NO, N(R), —COR, CONH(R), Sa 2 N(R)COR, -SON(R), N(R)SOR, SR, OR, N N —C(O)R, or substituted or unsubstituted group selected from 65 5-6 membered heterocyclyl, Co., aryl, or Caliphatic. More preferred R substituents include -halo, CN, -oxo, US 8,633,210 B2 139 140 -continued -continued IV-K

10

IV-L

15

IV-M 25

30

IV-N 35 IV-T

40

45

50

55

IV-V

60

65 US 8,633,210 B2 141 142 -continued -continued X IV-CC

r 2 O N 10

IV-X IV-DD 15

n N 2 N N R4 IV-Y 25 More preferred pyrimidine ring systems of formula IV X include IV-E, IV-G, IV-H, IV-K, IV-L, IV-M, IV-T, and IV-U. s SN In the monocyclic pyrimidine ring system of formula IV. S 30 preferred R' groups include hydrogen, amino, nitro, alkyl- or e 2 dialkylamino, acetamido, or a Caliphatic group Such as N methyl, ethyl, cyclopropyl, isopropyl or t-butyl. Preferred R' groups include T-R wherein T is a valence bond or a meth ylene, and Ris-R, N(R), or -OR. When R is - Ror IV-Z 35 —OR, a preferred R is an optionally substituted group selected from Caliphatic, phenyl, or a 5-6 membered het X eroaryl or heterocyclyl ring. Examples of preferred R' groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, NN 40 cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, aceta K 2 mido, optionally Substituted phenyl Such as phenyl, methox N N yphenyl, trimethoxyphenyl, or halo-substituted phenyl, and R4 methoxymethyl.

45 In the bicyclic pyrimidine ring system of formula IV, the IV-AA ring formed when R and R” are taken together may be sub stituted or unsubstituted. Suitable substituents include —R, X halo, OR, C(=O)R, COR, COCOR, NO, 50 CN, -S(O)R, -SOR, SR, N(R), —CON(R), N n - SON(R), OC(=O)R, N(R)COR, N(R)CO, M N (optionally substituted C- aliphatic), N(R)N(R), K 2 N N C–NN(R), C–N OR, N(R)CON(R) N(R) R4 SON(R) - N(R)SOR, or —OC(=O)N(R), wherein 55 R and Rare as defined above for compounds of formula IV. Preferred R/R' ring substituents include -halo, R. —OR, IV-BB —COR, COR, CONCR), —CN, or N(R), wherein R is a Substituted or unsubstituted Caliphatic group. x 60 The RandR groups of formula IV may be taken together to form a fused ring, thus providing a bicyclic ring system O NN containing a pyrazole ring. Preferred fused rings include 2 benzo, pyrido, pyrimido, and a partially unsaturated 6-mem N 65 bered carbocycloring. These are exemplified in the following formula IV compounds having a pyrazole-containing bicy clic ring system: US 8,633,210 B2 143 144 atoms to form a Substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring. More preferred compounds of formula IV have one or NH N / more, and more preferably all, of the features selected from HN N | N the group consisting of (a) Ring D is an optionally Substituted ring selected from N-1s le phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, mor 10 pholinyl, 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4-tetrahyd roquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-in dolyl, isoquinolinyl, quinolinyl, or naphthyl; N (b) R' is hydrogen or methyl and R is R, N(R), or i N 1\ 15 —OR, or R and R” are taken together with their intervening le e atoms to form a 5-7 membered unsaturated or partially unsat NH, NH, and urated ring having 1-2 ring nitrogens, wherein said ring is S. M S. M N N optionally substituted with —R, halo, oxo, —OR, —C(=O) R, COR, COCOR, NO, CN, -S(O)R, -SOR, —SR, N(R), —CON(R), -SON(R), —OC(=O) R, N(R)COR, N(R)CO (optionally substituted C.

e aliphatic), N(R)N(R) -C=NN(R), -C=N OR, NH. 25 N(R)CON(R), N(R)SON(R), N(R)SOR, or N / N –OC(=O)N(R); and (c) each R is independently selected from halo, oxo, CN, NO, N(R), COR, CONH(R), N(R)COR, 30 - SON(R) - N(R)SOR, SR, OR, —C(O)R, or a Preferred substituents on the R/R fused ring of formula substituted or unsubstituted group selected from 5-6 mem IV include one or more of the following: -halo, N(R), bered heterocyclyl, Co aryl, or Caliphatic. —C alkyl, —C haloalkyl, - NO. —O(C. alkyl). —CO(C. alkyl). —CN, -SO(C- alkyl). —SONH2, Even more preferred compounds of formula IV have one or —OC(O)NH, NHSO(C. alkyl), NHC(O)(C. 35 more, and more preferably all, of the features selected from alkyl), —C(O)NH, and —CO(Calkyl), wherein the (C. the group consisting of alkyl) is a straight, branched, or cyclic alkyl group. Prefer (a) R' and R” are taken together with their intervening ably, the (C. alkyl) group is methyl. atoms to form a 6-membered unsaturated or partially unsat When the pyrazole ring system of formula IV is monocy 40 urated ring having 1-2 ring nitrogens, optionally substituted clic, preferred R groups include hydrogen, a substituted or with halo, CN, oxo, Calkyl, Calkoxy, (C. alkyl)car unsubstituted group selected from aryl, heteroaryl, or a C bonyl, (Calkyl)sulfonyl, mono- or dialkylamino, mono- or aliphatic group. Examples of such preferred R groups dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, include methyl, t-butyl, —CHOCH cyclopropyl, furanyl, or 5-6 membered heteroaryl; thienyl, and phenyl. A preferred R group is hydrogen. 45 (b) each R is independently selected from -halo. —CN, Preferred formula IV compounds have one or more, and -oxo, SR, OR, N(R), —C(O)R, or a substituted or more preferably all, of the features selected from the group unsubstituted group selected from 5-6 membered heterocy consisting of: clyl, Co-o aryl, or Caliphatic; and (a) Ring D is an optionally Substituted ring selected from a 50 phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thie (c) R is hydrogen and R is T-W-R or R, wherein W is nyl, azepanyl, morpholinyl, 1.2.3,4-tetrahydroisoquinolinyl, —C(R)-O , —C(R)-N(R) , —CO , —CO. , 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1,4-isoindolyl, C(R)OC(O) , C(R)N(R)CO , or CONCR) , 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naph and R is an optionally substituted group selected from C. thyl ring; 55 aliphatic orphenyl, or RandR are taken together with their intervening atoms to form a benzo, pyrido, or partially unsat (b)R’ is hydrogenor Caliphatic andR is T-R, or R and urated 6-membered carbocyclo ring optionally substituted Rare taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially with -halo, oxo, N(R), —C. alkyl, -C, a haloalkyl, 60 —NO. —O(C. alkyl). —CO(C. alkyl). —CN, -SO unsaturated ring having 1-2 ring heteroatoms; and (C. alkyl). —SONH2, —OC(O)NH2, NHSO(C- (c) R' is hydrogen or methyl and R is T-W-R or R, alkyl). —NHC(O)(C. alkyl). —C(O)NH, or —CO(C- wherein W is C(R)-O-, - C(R)N(R)-, -CO , alkyl), wherein the (C. alkyl) is a straight, branched, or —CO , C(R)OC(O) , C(R)N(R)CO , cyclic alkyl group. —C(R)N(R)C(O)O , or – CONCR) , and R is an 65 optionally substituted group selected from Caliphatic or Representative compounds of formula IV are set forth in phenyl, or RandR are taken together with their intervening Table 3 below. US 8,633,210 B2 145 146 TABLE 3 TABLE 3-continued

CH3 CH3

10

15 CH3

IV-2

25

MeO

30 MeO C CH OMe

35

IV-3

40

45

CH3 50

55 COMe

60

65 CH US 8,633,210 B2 147 148 TABLE 3-continued TABLE 3-continued

CH IV-13

e NH 10 S. M HN N

NN

15 2 N

IV-10 CF

IV-14

25

30 NN 2 N CH

35 CF IV-11

IV-15

40

45

Cl 50

IV-12

CH3 IV-16 55 e NH S. M HN N

60 n N

H3C 2 O N

65 US 8,633,210 B2 149 150 TABLE 3-continued TABLE 3-continued

CH3 IV-17 IV-21

10

15

CH3

IV.18

IV-22

25

30 MeO

IV-19 35

IV-23 40

45

50

IV-20 55 IV-24

60

65 CF US 8,633,210 B2 151 152 TABLE 3-continued TABLE 3-continued

CH3 IV-25 CH3 IV-29

e NH N / HN N

10 S NN 4N4. N N CH 15

IV-26 2O CH IV-30 e NH N / HN N 25 21 NN

N N N2 30

C

35 CH IV-31 IV-27 e NH N / 40 HN N

NN 2 45 N

CH3

50

IV-32 IV-28 55 e NH N / HN N

60 21 NN N 2 MeO 2 N N

65 US 8,633,210 B2 153 154 TABLE 3-continued disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, CH3 IV-33 alopecia, and autoimmune diseases Such as rheumatoid e arthritis. NH Another method relates to inhibiting GSK-3, Aurora, or N / CDK-2 activity in a biological sample, which method com HN N prises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula IV, or a pharmaceutical compo NN sition thereof, in an amount effective to inhibit GSK-3, 10 Aurora or CDK-2. Each of the aforementioned methods directed to the inhi bition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably carried out with a CH 15 preferred compound of formula IV, as described above. Another embodiment of this invention relates to com In another embodiment, this invention provides a compo pounds of formula V: sition comprising a compound of formula IV and a pharma ceutically acceptable carrier. One aspect of this invention relates to a method of inhibit V ing GSK-3 activity in a patient, comprising administering to R2 R2 the patient a therapeutically effective amount of a composi e tion comprising a compound of formula IV. NH Another aspect relates to a method of treating a disease that S. / is alleviated by treatment with a GSK-3 inhibitor, said method 25 HN N comprising the step of administering to a patient in need of Such a treatment a therapeutically effective amount of a com R N72 position comprising a compound of formula IV. Another aspect relates to a method of enhancing glycogen 2 synthesis and/or lowering blood levels of glucose in a patient 30 R’ Zl in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for diabetic patients. or a pharmaceutically acceptable derivative or prodrug Another aspect relates to a method of inhibiting the pro 35 thereof, wherein: duction of hyperphosphorylated Tau protein in a patient in Z' is N, CR, or CH and Z is N or CH, provided that one of need thereof, comprising administering to said patient a Z" and Z is nitrogen; therapeutically effective amount of a composition comprising G is Ring C or Ring D; a compound of formula IV. This method is especially useful in Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, halting or slowing the progression of Alzheimer's disease. 40 pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Another aspect relates to a method of inhibiting the phos Ring C has one or two ortho substituents independently phorylation off-catenin in a patient in need thereof, compris selected from —R', any substitutable non-ortho carbon ing administering to said patient a therapeutically effective position on Ring C is independently substituted by R. amount of a composition comprising a compound of formula and two adjacent Substituents on Ring C are optionally IV. This method is especially useful for treating schizophre 45 taken together with their intervening atoms to form a fused, nia. unsaturated or partially unsaturated, 5-6 membered ring One aspect of this invention relates to a method of inhibit having 0-3 heteroatoms selected from oxygen, Sulfur or ing Aurora activity in a patient, comprising administering to nitrogen, said fused ring being optionally Substituted by the patient a therapeutically effective amount of a composi halo, oxo, or R: tion comprising a compound of formula IV. 50 Ring D is a 5-7 membered monocyclic ring or 8-10 membered Another aspect relates to a method of treating a disease that bicyclic ring selected from aryl, heteroaryl, heterocyclyl or is alleviated by treatment with an Aurora inhibitor, said carbocyclyl, said heteroaryl or heterocyclyl ring having method comprising the step of administering to a patient in 1-4 ring heteroatoms selected from nitrogen, oxygen or need of such a treatmentatherapeutically effective amount of sulfur, wherein Ring D is substituted at any substitutable a composition comprising a compound of formula IV. This 55 ring carbon by oxo or -R, and at any substitutable ring method is especially useful for treating cancer, Such as colon, nitrogen by R. provided that when Ring D is a six ovarian, and breast cancer. membered arylor heteroaryl ring, -R is hydrogen at each One aspect of this invention relates to a method of inhibit ortho carbon position of Ring D; ing CDK-2 activity in a patient, comprising administering to R" is selected from -halo. —CN, NO, TV R, phenyl, the patient a therapeutically effective amount of a composi 60 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl tion comprising a compound of formula IV. ring, or Caliphatic group, said phenyl, heteroaryl, and Another aspect relates to a method of treating a disease that heterocyclyl rings each optionally Substituted by up to is alleviated by treatment with a CDK-2 inhibitor, said three groups independently selected from halo, oxo, or method comprising the step of administering to a patient in —R. said Caliphatic group optionally substituted with need of such a treatmentatherapeutically effective amount of 65 halo, cyano, nitro, or oxygen, or R' and an adjacent sub a composition comprising a compound of formula IV. This stituent taken together with their intervening atoms form method is especially useful for treating cancer, Alzheimer's said ring fused to Ring C: US 8,633,210 B2 155 156 R and Rare independently selected from T-R, or R and R' same nitrogen are taken together with the nitrogen to form are taken together with their intervening atoms to form a a 5-8 membered heterocyclyl or heteroaryl ring: fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, each R is independently selected from an optionally substi Sulfur, or nitrogen, wherein any Substitutable carbon on tuted C. aliphatic group, —OR. —SR, COR. said fused ring formed by RandR is substituted by oxo or —SOR. - N(R), -N(R)N(R) - CN, NO, T-R, and any substitutable nitrogen on said ring formed by —CON(R), or -COR; and R and R” is substituted by R: R" is selected from halo. —OR, —C(=O)R, —COR, T is a valence bond or a C alkylidene chain; —COCOR, NO, CN, S(O)R, -SOR, SR, RandR are independently selected from R,-T-W R. 10 -N(R), —CON(R), -SON(R), —OC(=O)R, or R and R are taken together with their intervening -N(R)COR, N(R)CO (optionally substituted C. atoms to form a fused, 5-8 membered, unsaturated or par aliphatic), N(R)N(R), -C=NN(R), -C=N- tially unsaturated, ring having 0-3 ring heteroatoms OR, N(R)CON(R), N(R)SON(R), N(R) Selected from nitrogen, oxygen, or Sulfur, wherein each SO.R, —OC(=O)N(R), or an optionally substituted substitutable carbon on said fused ring formed by R and 15 group selected from Caliphatic, Co aryl, a heteroaryl R’ is substituted by halo, oxo, —CN, NO. —R", or ring having 5-10 ring atoms, or a heterocyclyl ring having —V-R, and any substitutable nitrogen on said ring 5-10 ring atoms. formed by RandR is substituted by R: Compounds of formula V may be represented by specify R is selected from —R,-halo. —OR, —C(=O)R, COR, ing Z' and Z as shown below: - COCOR, COCHCOR, NO, CN, S(O)R, —S(O).R. —SR, N(R), —CON(R7), -SON(R7), –OC(=O)R, N(R)COR, N(R)CO (optionally Wa substituted Caliphatic), N(R)N(R), -C=NN R2 (R) -C=N OR, N(R)CON(R7), N(R)SON R2 25 e (R) - N(R)SOR, or - OC(=O)N(R): NH each R is independently selected from hydrogen oran option S. ally substituted group selected from Caliphatic, Co HN N aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero R cyclyl ring having 5-10 ring atoms; N each R is independently selected from R', COR7. 30 —CO (optionally substituted Caliphatic), —CON 2 (R), or - SOR", or two R' on the same nitrogen are R N taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; Vb each R is independently selected from —R, halo, —OR, 35 R2 - C(=O)R, COR, COCOR, NO, CN, S(O) R2 R, -SOR, SR, N(R) - CONCR), -SON e (R), OC(=O)R, N(R)COR, N(R)CO (option NH S- M ally substituted Caliphatic), -N(R)N(R) -C=NN HN N (R), -C=N OR, N(R)CON(R), N(R)SON 40 (R) - N(R)SOR, or - OC(=O)N(R), or Rand an R. adjacent Substituent taken together with their intervening n N atoms form said ring fused to Ring C: V is - O -, - S -, -SO , -SO. , N(R)SO , R 21 - SON(R)-, - N(R) -, -CO-, -CO, , – N(R) 45 , and CO. , N(R)C(O)O N(R)CON(R) , N(R) WC SON(R) , N(R)N(R)-, -C(O)N(R) , OC R2 R2 e 50 NH S. HN N C(R)N(R)CON(R) ; W is C(R)-O-, - C(R) S , —C(R)SO , R NN C(R)SO, C(R) SON(R) -C(R)N(R) , 55 —CO-, -CO. , —C(R)OC(O) , —C(R)OC(O)N 2 (R) C(R)N(R)CO C(R)N(R)C(O)C) , R C(R)=NN(R) , C(R)-N-O C(R)-N Ra (R)N(R) C(R)N(R)SON(R) C(R)-N (R)CON(R) , or CONCR) ; 60 each R is independently selected from hydrogen, an option When the RandR' groups of formula Vare taken together ally substituted Caliphatic group, or two R' groups on to form a fused ring, preferred R/R' rings include a 5-, 6-, 7 the same nitrogenatom are taken together with the nitrogen or 8-membered unsaturated or partially unsaturated ring hav atom to form a 5-6 membered heterocyclyl or heteroaryl ing 0-2 heteroatoms, wherein said R/R' ring is optionally ring, 65 Substituted. This provides a bicyclic ring system containing a each R" is independently selected from hydrogen or an pyridine ring. Examples of preferred bicyclic ring systems of optionally substituted Caliphatic group, or two R' on the formula V are shown below.

US 8,633,210 B2 159 160 -continued -continued Wa-E

15

2O

25 º, 30

35 Wa-K

40

Wb-F 45 50 ZZ 55 Wc-F

60 º, Z

65 US 8,633,210 B2 161 162 -continued -continued Wa-L X Wa-N N r N Nan 2 10 N

15

We-L 25

30

Ra Wa-O 35 Wa-M

40

45

50

55

60

65 US 8,633,210 B2 163 164 -continued bered carbocycloring. These are exemplified in the following Wa-P formula V compounds having a pyrazole-containing bicyclic ox ring system: N

CN r 2 N N NH 10 N/ Wb-P HN R. Y. N72 le X 15 NH 2 N / N R’ Zl N s 21 N| N N1SN le e Vc-P NH, NH, and ax N N 25 N

e NH. 30 S. M N More preferred bicyclic ring systems of formula Vinclude Va-A, Vb-A, Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb-E, Vc-E, Va.-J., Vb-J, Vc-J, Va-K, Vb-K, Vc-K, Va-L, 35 Preferred substituents on the R/Rfused ring of formula V Vb-L, Vc-L, Va-M, Vb-M, and Vc-M, most preferably Va-A, include one or more of the following:-halo, N(R), —Ca Vb-A, Vc-A, Va-B, Vb-B, and Vc-B. alkyl, —Chaloalkyl, - NO. —O(Calkyl). —CO(C- In the monocyclic pyridine ring system of formula V. pre alkyl), —CN, SO(C-alkyl). —SONH, OC(O)NH2. ferred R' groups include hydrogen, alkyl- or dialkylamino, —NHSO(C-alkyl). —NHC(O)(Calkyl). —C(O)NH2, acetamido, or a Caliphatic group such as methyl, ethyl, 40 and —CO(C. alkyl), wherein the (C. alkyl) is a straight, cyclopropyl, isopropyl ort-butyl. Preferred R'groups include branched, or cyclic alkyl group. Preferably, the (C. alkyl) T-R wherein T is a valence bond or a methylene, and R is group is methyl. -R, N(R), or -OR. When R is - R or -OR, a pre When the pyrazolering system is monocyclic, preferred R' ferred R is an optionally Substituted group selected from C. groups include hydrogen, Caliphatic, alkoxycarbonyl, aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocy 45 (un)Substituted phenyl, hydroxyalkyl, alkoxyalkyl, ami clyl ring. Examples of preferred R' include 2-pyridyl, 4-py nocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, ridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-bu alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, tyl, alkyl- or dialkylamino, acetamido, optionally substituted and (N-heterocyclyl)carbonyl. Examples of such preferred phenyl Such as phenyl or halo-substituted phenyl, and meth R substituents include methyl, cyclopropyl ethyl, isopropyl, oxymethyl. 50 propyl, t-butyl, cyclopentyl, phenyl, COH, COCH, In the bicyclic ring system of formula V, the ring formed CHOH, CHOCH, CHCHCH-OH, CHCHCHOCH, when R and R are taken together may be substituted or CHCHCHOCHPh. CHCHCH-NH. unsubstituted. Suitable substituents include—R, halo, —OR, CHCHCH-NHCOOC(CH), CONHCH(CH), —C(=O)R, COR, COCOR, NO, CN, -S(O)R, CONHCHCH-CH CONHCHCHOCH, —SOR, SR, N(R), —CON(R), -SON(R), 55 CONHCHPh, CONH(cyclohexyl), CONOEt), CONCH.) –OC(=O)R, N(R)COR, N(R)CO, (optionally sub CHPh. CONH(n-CH), CON(Et)CHCHCH, stituted Caliphatic), -N(R)N(R), -C=NN(R), CONHCHCH(CH), CONCn-CH4), CO(3-methoxym C–N OR, N(R)CON(R), N(R)SON(R), ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), - N(R)SOR, or - OC(=O)N(R), wherein Rand Rare CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- as defined above. Preferred R/R' ring substituents include 60 -halo, R, OR, COR, COR, CONCR), CN, or yl), CONHCHCH-OH, CONH, and CO(piperidin-1-yl). A —N(R), wherein Risanoptionally substituted Caliphatic preferred R group is hydrogen. group. More preferred ring systems of formula V are the follow The RandR groups of formula V may be taken together ing, which may be substituted as described above, wherein R to form a fused ring, thus providing a bicyclic ring system 65 and Rare taken together with the pyrazole ring to form an containing a pyrazole ring. Preferred fused rings include optionally substituted indazole ring; and R and R are each benzo, pyrido, pyrimido, and a partially unsaturated 6-mem methyl, or R and Rare taken together with the pyridine ring US 8,633,210 B2 165 166 to form an optionally Substituted quinoline, isoquinoline, tet - N(R)COR, -SON(R), and - N(R)SO.R. More pre rahydroquinoline or tetrahydroisoquinoline ring: ferred R substituents include - C1, F, CN, —CF, —NH2, —NH(C. aliphatic), —N(C. aliphatic), —O(C- aliphatic), Caliphatic, and —CO(C- ali W-Aa 5 phatic). Examples of such preferred R substituents include Cl, F, CN, CF, NH, -NHMe, NMe, —OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and —COEt. NH When G is Ring D, preferred formula V. Ring D monocy S. M 10 clic rings include Substituted and unsubstituted phenyl, HN N pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, aZepanyl, and morpholinyl rings. When two adjacent Sub N72 stituents on Ring Dare taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula V Ring D bicy 2 15 clic rings include 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4- Zl tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihy dro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. W-Bal Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl. Preferred substituents on Ring D of formula Vinclude one or more of the following: halo, oxo, CN, NO, N(R), NH COR, CONH(R), N(R)COR, SON(R), S. M - N(R)SOR, -SR, OR, C(O)R, or substituted or HN N unsubstituted group selected from 5-6 membered heterocy 25 clyl, Co aryl, or Caliphatic. More preferred Ring D substituents include -halo, —CN, -oxo, —SR, —OR, N72 - N(R), —C(O)R, or a substituted or unsubstituted group 2 selected from 5-6 membered heterocyclyl, Caryl, or C. Zl aliphatic. Examples of Ring D substituents include —OH, 30 phenyl, methyl, CHOH, CHCH-OH, pyrrolidinyl, OPh. W-Ha. CF, C=CH, Cl, Br, F, I, NH, C(O)CH, i-propyl, tert-butyl, SEt, OMe, N(Me), methylene dioxy, and ethylene dioxy. Preferred formula V compounds have one or more, and more preferably all, of the features selected from the group 35 consisting of: NH S- M (a) Ring C is a phenyl or pyridinyl ring, optionally Substi HN N tuted by R, wherein when Ring C and two adjacent sub stituents thereon form a bicyclic ring system, the bicyclic ring HC 3 N72 system is selected from a naphthyl, quinolinyl or isoquinoli 40 nyl ring, and R' is -halo, an optionally substituted Cali 2 phatic group, phenyl, -COR, OR, —CN, -SO.R. HC Zl - SONH, N(R), COR, CONH, -NHCOR, —OC(O)NH, or NHSO.R. or Ring D is an optionally Substituted ring selected from a phenyl, pyridinyl, piperidi 45 nyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, When G is Ring C, preferred formula V. Ring C groups are 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoli phenyl and pyridinyl. When two adjacent substituents on nyl, 2,3-dihydro-1H-isoindolyl, isoquinolinyl, quinolinyl, or Ring C are taken together to form a fused ring, Ring C is naphthyl ring; contained in a bicyclic ring system. Preferred fused rings (b)R’ is hydrogen or Caliphatic and R” is T-R, or R and include a benzo or pyrido ring. Such rings preferably are 50 Rare taken together with their intervening atoms to form an fused at ortho and meta positions of Ring C. Examples of optionally substituted 5-7 membered unsaturated or partially preferred bicyclic Ring C systems include naphthyl and iso unsaturated ring having 0-2 ring nitrogens; and quinolinyl. Preferred R' groups include -halo, an optionally (c) R is hydrogen and R is hydrogen or a substituted or substituted Caliphatic group, phenyl, -COR, OR, unsubstituted group selected from aryl, heteroaryl, or a C —CN, -SOR. -SONH, -N (R), —COR, 55 aliphatic group, or R and R are taken together with their CONH, -NHCOR, OC(O)NH, or NHSO.R. intervening atoms to form a Substituted or unsubstituted When R' is an optionally substituted Caliphatic group, the benzo, pyrido, pyrimido or partially unsaturated 6-membered most preferred optional Substituents are halogen. Examples carbocycloring. of preferred R' groups include —CF, —Cl, F. —CN, More preferred compounds of formula V have one or more, —COCH, OCH, -OH, -CHCH, OCHCH 60 and more preferably all, of the features selected from the —CH —CFCH., cyclohexyl, t-butyl, isopropyl, cyclopro group consisting of: pyl, —C=CH, —C=C CH, -SOCH —SONH2, (a) Ring C is a phenyl or pyridinyl ring, optionally Substi - N(CH), COCH-CONH NHCOCH, OC(O) tuted by —R, wherein when Ring C and two adjacent sub NH, -NHSOCH, and OCF. stituents thereon form a bicyclic ring system, the bicyclic ring On Ring Cpreferred Rsubstituents, when present, include 65 system is a naphthyl ring, and R' is -halo, a Chaloaliphatic -halo. —CN, NO, N(R), optionally substituted C. group, a Caliphatic group, phenyl, or —CN; or Ring Dis aliphatic group, —OR, —C(O)R, CO.R, CONH(R), an optionally Substituted ring selected from phenyl, pyridi US 8,633,210 B2 167 168 nyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1.2, TABLE 4 3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, iso quinolinyl, quinolinyl, or naphthyl; CH V-1 (b) R' is hydrogen or methyl and R is R, N(R), or —OR, or R and R” are taken together with their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring, said benzo or carbocyclo ring optionally substituted with —R, halo. —OR, —C(=O)R. —COR, COCOR, NO, CN, -S(O)R, -SOR, 10 —SR, N(R), —CON(R), -SON(R), —OC(=O) R, N(R)COR, N(R)CO (optionally substituted C. aliphatic), N(R)N(R) -C=NN(R), -C=N OR, N(R)CON(R), N(R)SON(R), N(R)SOR, or OC(=O)N(R): 15 (c) R is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, or a Caliphatic group, or R and Rare taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, V-2 pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R, wherein each R is independently selected from-halo. —CN, NO, N(R), optionally Substituted Caliphatic group, —OR, —C(O)R. 25 -COR, CONH(R), N(R)COR, -SON(R), or N(R)SO.R. Even more preferred compounds of formula V have one or more, and more preferably all, of the features selected from the group consisting of 30 (a) Ring C is a phenyl or pyridinyl ring, optionally substi tuted by R, wherein when Ring C and two adjacent sub stituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a Caliphatic group optionally substituted with halogen, or —CN; or Ring 35 D is an optionally Substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholi nyl, 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4-tetrahydro quinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 40 (b) R' is hydrogen or methyl and R is methyl, methoxym ethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally Substituted group selected from 2-pyridyl, 4-py ridyl, piperidinyl, or phenyl, or R and Rare taken together with their intervening atoms to form a benzo ring or a 6-mem 45 bered partially unsaturated carbocycloring optionally Substi tuted with halo, CN, Oxo, Ce alkyl, Ce alkoxy, (C. alkyl) carbonyl, (C. alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocar bonyloxy, or 5-6 membered heteroaryl; 50 (c) R' and R are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsatur ated 6-membered carbocycloring optionally substituted with -halo, N(R), —C, alkyl, -C, a haloalkyl, - NO. —O(C. alkyl), —CO(C. alkyl). —CN. —SO(C- 55 alkyl). —SONH, —OC(O)NH, -NHSO(C- alkyl). —NHC(O)(C. alkyl), —C(O)NH2 or —CO(C. alkyl). wherein the (C. alkyl) is a straight, branched, or cyclic alkyl group; and 60 (d) Ring D is substituted by oxo or R, wherein each R is independently selected from —Cl, F. —CN, —CF, —NH, -NH(C. aliphatic). —N(C. aliphatic), —O(C- aliphatic), Caliphatic, and —CO(C- ali phatic). 65 Representative compounds of formula V are set forth in Table 4 below. US 8,633,210 B2 169 170 TABLE 4-continued TABLE 4-continued

10

15

V-10

25

30

35

W-11

40 S. HN

CF 45

50

V-12 55

60

65

US 8,633,210 B2 173 174 TABLE 4-continued TABLE 4-continued

F W-21 F V-25

10

15

V-22 V-26

25 HN

N

2 30 N

FC

35

V-27 V-23

40 NH N / HN N

45

50

V-24 V-28

55

60

65 FC FC

US 8,633,210 B2 181 182 TABLE 4-continued TABLE 4-continued

V-57

10

15

V-58

25

30

35 V-55

40

45

50

V-56 V-60

55

NH N / HN N 60

r2

65

US 8,633,210 B2 185 186 In another embodiment, this invention provides a compo sition comprising a compound of formula V and a pharma VI ceutically acceptable carrier. R2 One aspect of this invention relates to a method of inhibit R2 ing GSK-3 activity in a patient, comprising administering to e NH the patient a therapeutically effective amount of a composi N / tion comprising a compound of formula V. HN N Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of 10 es Such a treatment a therapeutically effective amount of a com - - position comprising a compound of formula V. R N Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient 15 in need thereof, comprising administering to said patient a or a pharmaceutically acceptable derivative or prodrug therapeutically effective amount of a composition comprising thereof, wherein: a compound of formula V. This method is especially useful for G is Ring C or Ring D; diabetic patients. Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, Another aspect relates to a method of inhibiting the pro pyridazinyl, pyridinyl, or 1,2,4-triazinyl ring, wherein said duction of hyperphosphorylated Tau protein in a patient in Ring C has one or two ortho substituents independently need thereof, comprising administering to said patient a selected from —R', any substitutable non-ortho carbon therapeutically effective amount of a composition comprising position on Ring C is independently substituted by R. a compound of formula V. This method is especially useful in and two adjacent Substituents on Ring C are optionally halting or slowing the progression of Alzheimer's disease. 25 taken together with their intervening atoms to form a fused, Another aspect relates to a method of inhibiting the phos phorylation off-catenin in a patient in need thereof, compris unsaturated or partially unsaturated, 5-6 membered ring ing administering to said patient a therapeutically effective having 0-3 heteroatoms selected from oxygen, Sulfur or amount of a composition comprising a compound of formula nitrogen, said fused ring being optionally Substituted by V. This method is especially useful for treating schizophrenia. 30 halo, oxo, or R: One aspect of this invention relates to a method of inhibit Ring D is a 5-7 membered monocyclic ring or 8-10 membered ing Aurora activity in a patient, comprising administering to bicyclic ring selected from aryl, heteroaryl, heterocyclyl or the patient a therapeutically effective amount of a composi carbocyclyl, said heteroaryl or heterocyclyl ring having tion comprising a compound of formula V. 1-4 ring heteroatoms selected from nitrogen, oxygen or Another aspect relates to a method of treating a disease that 35 sulfur, wherein Ring D is substituted at any substitutable is alleviated by treatment with an Aurora inhibitor, said ring carbon by oxo or -R, and at any substitutable ring method comprising the step of administering to a patient in nitrogen by R. provided that when Ring D is a six need of such a treatmentatherapeutically effective amount of membered arylor heteroaryl ring, -R is hydrogen at each a composition comprising a compound of formula V. This ortho carbon position of Ring D; method is especially useful for treating cancer, Such as colon, 40 R" is selected from -halo. —CN, NO, TV R, phenyl, ovarian, and breast cancer. 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl One aspect of this invention relates to a method of inhibit ring, or Caliphatic group, said phenyl, heteroaryl, and ing CDK-2 activity in a patient, comprising administering to heterocyclyl rings each optionally Substituted by up to the patient a therapeutically effective amount of a composi three groups independently selected from halo, oxo, or tion comprising a compound of formula V. 45 —R, said Caliphatic group optionally substituted with Another aspect relates to a method of treating a disease that halo, cyano, nitro, or oxygen, or R' and an adjacent sub is alleviated by treatment with a CDK-2 inhibitor, said stituent taken together with their intervening atoms form method comprising the step of administering to a patient in said ring fused to Ring C: need of such a treatmentatherapeutically effective amount of a composition comprising a compound of formula V. This 50 T is a valence bond or a C alkylidene chain; method is especially useful for treating cancer, Alzheimer's RandR are independently selected from R,-T-W R. disease, restenosis, angiogenesis, glomerulonephritis, or RandR are taken together with their intervening atoms cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, to form a fused, 5-8 membered, unsaturated or partially alopecia, and autoimmune diseases Such as rheumatoid unsaturated, ring having 0-3 ring heteroatoms selected arthritis. 55 from nitrogen, oxygen, or Sulfur, wherein each Substitut Another method relates to inhibiting GSK-3, Aurora, or able carbon on said fused ring formed by R and R is CDK-2 activity in a biological sample, which method com substituted by halo, oxo, —CN, NO, R", or -V. R. prises contacting the biological sample with the GSK-3 or and any substitutable nitrogen on said ring formed by R’ Aurora inhibitor of formula V, or a pharmaceutical composi and R is substituted by R: tion thereof, in an amount effective to inhibit GSK-3, Aurora 60 R is an optionally substituted group selected from Cali or CDK-2. phatic, Co carbocyclyl, Co aryl, a heteroaryl ring hav Each of the aforementioned methods directed to the inhi ing 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring bition of GSK-3, Aurora or CDK-2, or the treatment of a atoms; disease alleviated thereby, is preferably carried out with a each Ris independently selected from hydrogen oran option preferred compound of formula V, as described above. 65 ally substituted group selected from Caliphatic, Co Another embodiment of this invention relates to com aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero pounds of formula VI: cyclyl ring having 5-10 ring atoms; US 8,633,210 B2 187 188 each R" is independently selected from R", COR". —CO (optionally substituted Caliphatic), —CON (R), or—SOR", or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or het eroaryl ring; each R is independently selected from —R, halo, OR, —C(=O)R, COR, COCOR, NO, CN, -S(O) R, -SOR, SR, N(R) - CONCR), -SON (R), OC(=O)R, N(R)COR, N(R)CO (option ally substituted Caliphatic), N(R)N(R), —C=NN 10 (R) -C=N OR, N(R)CON(R), N(R)SON (R) - N(R)SOR, or - OC(=O)N(R), or R and an adjacent Substituent taken together with their intervening N atoms form said ring fused to Ring C: 15 i N 1\ le e NH, NH, and S. M S. M N N

e 25 NH. N / N

30 Preferred substituents on the R/Rfused ring include one or more of the following: -halo, N(R), —C. alkyl, haloalkyl, - NO. —O(C. alkyl). —CO(C. alkyl). (R)CON(R) , or CONCR) ; —CN. —SO(C- alkyl). —SONH, —OC(O)NH2, each R is independently selected from hydrogen, an option 35 —NHSO(C- alkyl), NHC(O) (C. alkyl), —C(O) ally substituted Caliphatic group, or two R' groups on NH, and —CO(C. alkyl), wherein the (C. alkyl) is a the same nitrogenatom are taken together with the nitrogen straight, branched, or cyclic alkyl group. Preferably, the (C. atom to form a 5-6 membered heterocyclyl or heteroaryl alkyl) group is methyl. ring: When the pyrazole ring system is monocyclic, preferred R' 40 groups of formula VI include hydrogen, Caliphatic, each R" is independently selected from hydrogen or an alkoxycarbonyl, (un)Substituted phenyl, hydroxyalkyl, optionally substituted Caliphatic group, or two R7 on the alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbo same nitrogen are taken together with the nitrogen to form nyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, pheny a 5-8 membered heterocyclyl or heteroaryl ring; and laminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of each R is independently selected from an optionally substi 45 such preferred R substituents include methyl, cyclopropyl, tuted Caliphatic group, —OR. —SR, COR. ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, COH, - SOR, - N(R), N(R)N(R), - CN, —NO, COCH, CHOH, CHOCH, CHCHCH-OH, CONCR), or COR. CHCHCHOCH, CHCHCHOCHPh. Preferred R' groups of formula VI include T-R wherein T CHCHCH-NH, CHCHCH-NHCOOC(CH), CONH is a valence bond or a methylene, and R is an optionally 50 CH(CH), CONHCH-CH=CH, CONHCHCHOCH, Substituted group selected from Caliphatic, Cocarbocy CONHCHPh, CONH(cyclohexyl), CONOEt), CONCH.) CHPh. CONH(n-CH), CON(Et))CHCHCH clyl, Co aryl, a heteroaryl ring having 5-10 ring atoms, or a CONHCHCH(CH), CONCn-CH4), CO(3-methoxym heterocyclyl ring having 5-10 ring atoms. A preferred R' ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), group is an optionally Substituted group selected from C. 55 CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- carbocyclyl phenyl, or a 5-6 membered heteroaryl or hetero yl), CONHCHCH-OH, CONH, and CO(piperidin-1-yl). A cyclyl ring. Examples of preferred R' include 2-pyridyl, 4-py preferred R group is hydrogen. ridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl, and When G is Ring C, preferred formula VI Ring C groups are optionally substituted phenyl such as phenyl or halo-substi phenyl and pyridinyl. When two adjacent substituents on tuted phenyl. 60 Ring C are taken together to form a fused ring, Ring C is The RandR groups of formula VI may be taken together contained in a bicyclic ring system. Preferred fused rings to form a fused ring, thus providing a bicyclic ring system include a benzo or pyrido ring. Such rings preferably are containing a pyrazole ring. Preferred fused rings include fused at ortho and meta positions of Ring C. Examples of benzo, pyrido, pyrimido, and a partially unsaturated 6-mem preferred bicyclic Ring C systems include naphthyl and iso bered carbocycloring. These are exemplified in the following 65 quinolinyl. Preferred R' groups include -halo, an optionally formula VI compounds having a pyrazole-containing bicyclic substituted Caliphatic group, phenyl, -COR, OR, ring system: —CN, -SOR. -SONH, -N (R), —COR, US 8,633,210 B2 189 190 CONH NHCOR, OC(O)NH, or NHSO.R. intervening atoms to form a Substituted or unsubstituted When R' is an optionally substituted Caliphatic group, the benzo, pyrido, pyrimido or partially unsaturated 6-membered most preferred optional Substituents are halogen. Examples carbocycloring. of preferred R' groups include —CF, —Cl, F. —CN, More preferred compounds of formula VI have one or —COCH, OCH, -OH, -CHCH, OCHCH more, and more preferably all, of the features selected from —CH, —CFCH., cyclohexyl, t-butyl, isopropyl, cyclopro the group consisting of pyl, —C=CH, —C=C CH, -SOCH —SONH2, - N(CH), COCH-CONH NHCOCH, OC(O) (a) Ring C is a phenyl or pyridinyl ring, optionally Substi NH, -NHSOCH, and OCF. tuted by —R, wherein when Ring C and two adjacent sub 10 stituents thereon form a bicyclic ring system, the bicyclic ring On Ring Cpreferred Rsubstituents, when present, include system is a naphthyl ring, and R' is -halo, a Chaloaliphatic -halo. —CN, NO, N(R), optionally substituted C. group, a Caliphatic group, phenyl, or —CN; or Ring Dis aliphatic group, —OR, —C(O)R, CO.R, CONH(R), an optionally Substituted ring selected from phenyl, pyridi -N(R)COR, -SON(R), and N(R)SO.R. More pre nyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1.2, ferred R substituents include - C1, F, CN, —CF, 15 —NH2, —NH(C. aliphatic), —N(C. aliphatic), 3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, —O(C- aliphatic), Caliphatic, and —CO(C- ali 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, iso phatic). Examples of such preferred R substituents include quinolinyl, quinolinyl, or naphthyl; Cl, F, CN, -CF, NH, -NHMe, NMe, (b) R' is T-R, wherein T is a valence bond or a methylene —OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and and R is an optionally substituted group selected from C. —COEt. aliphatic, C. carbocyclyl, Co aryl, a heteroaryl ring hav When G is Ring D, preferred formula VI Ring D monocy ing 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring clic rings include Substituted and unsubstituted phenyl, atoms; pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, (c) R is hydrogen and R is hydrogen or a substituted or aZepanyl, and morpholinyl rings. When two adjacent Sub 25 unsubstituted group selected from aryl, or a Caliphatic stituents on Ring Dare taken together to form a fused ring, the group, or R and Rare taken together with their intervening Ring D system is bicyclic. Preferred formula VI Ring D atoms to form a Substituted or unsubstituted benzo, pyrido, bicyclic rings include 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3, pyrimido or partially unsaturated 6-membered carbocyclo 4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-di ring; and hydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. 30 (d) Ring D is substituted by oxo or R, wherein each R is Examples of more preferred bicyclic Ring D systems include independently selected from-halo. —CN, NO, N(R), naphthyl and isoquinolinyl. optionally substituted Caliphatic group, —OR, —C(O)R. Preferred substituents on formula VI Ring D include one or COR, CONH(R), N(R)COR, SON(R), or more of the following: halo, oxo, CN, NO, N(R), N(R)SO.R. -COR, CONH(R), N(R)COR, -SON(R), 35 Even more preferred compounds of formula VI have one or -N(R)SOR, -SR, OR, C(O)R, or substituted or more, and more preferably all, of the features selected from unsubstituted group selected from 5-6 membered heterocy the group consisting of clyl, Co aryl, or Caliphatic. More preferred Ring D (a) R' is T-R, wherein T is a valence bond or a methylene substituents include -halo, —CN, -oxo, —SR, —OR, 40 and R is an optionally substituted group selected from Ca —N(R), —C(O)R, or a substituted or unsubstituted group aliphatic, C. carbocyclyl phenyl, or a 5-6 membered het selected from 5-6 membered heterocyclyl, C-aryl, or C. eroaryl or heterocyclyl ring; aliphatic. Examples of Ring D substituents include —OH, (b) Ring C is a phenyl or pyridinyl ring, optionally Substi phenyl, methyl, CH-OH, CH2CH2OH. pyrrolidinyl, OPh. tuted by R, wherein when Ring C and two adjacent sub CF, C=CH, Cl, Br, F, I, NH, C(O)CH, i-propyl, tert-butyl, 45 stituents thereon form a bicyclic ring system, the bicyclic ring SEt, OMe, N(Me), methylene dioxy, and ethylene dioxy. system is a naphthyl ring, and R' is -halo, a Caliphatic Preferred formula VI compounds have one or more, and group optionally Substituted with halogen, or—CN; or Ring more preferably all, of the features selected from the group D is an optionally substituted ring selected from phenyl, consisting of: pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholi (a) Ring C is selected from a phenyl or pyridinyl ring, 50 nyl, 1.2.3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro optionally substituted by R, wherein when Ring Cand two quinolinyl, isoquinolinyl, quinolinyl, or naphthyl; adjacent Substituents thereon form a bicyclic ring system, the (c) R' and R are taken together with their intervening bicyclic ring system is selected from a naphthyl, quinolinyl or atoms to form a benzo, pyrido, pyrimido or partially unsatur isoquinolinyl ring, and R' is -halo, an optionally substituted ated 6-membered carbocycloring optionally substituted with C- aliphatic group, phenyl, -COR, OR, —CN, 55 -halo, -N(R), —C, alkyl, -C, a haloalkyl, - NO, —SOR, -SONH, -N (R), —COR, CONH, —O(C. alkyl). —CO(C. alkyl). —CN. —SO(C- -NHCOR. - OC(O)NH, or -NHSOR: or Ring D is an alkyl). —SONH2, —OC(O)NH2. —NHSO(C. alkyl). optionally Substituted ring selected from a phenyl, pyridinyl, —NHC(O)(C. alkyl), —C(O)NH, or —CO(C. alkyl). piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, mor wherein the (C. alkyl) is a straight, branched, or cyclic alkyl pholinyl, 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4-tetrahyd 60 roquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-in group; and dolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (d) Ring D is substituted by oxo or R, wherein each R is (b) R' is T-R, wherein T is a valence bond or a methylene; independently selected from —Cl, F. —CN, —CF, and —NH2, —NH(C. aliphatic), —N(C. aliphatic), ali (c) R is hydrogen and R is hydrogen or a substituted or 65 phatic), Caliphatic, and —CO(Caliphatic). unsubstituted group selected from aryl, heteroaryl, or a C Another embodiment of this invention relates to com aliphatic group, or R and R are taken together with their pounds of formula VIa: