USOO7473691B2

(12) United States Patent (10) Patent No.: US 7473,691 B2 Davies et al. (45) Date of Patent: Jan. 6, 2009

(54) PYRAZOLE COMPOUNDS USEFUL AS 6,579,983 B1* 6/2003 Batchelor et al...... 544,330 PROTEINKNASE INHIBITORS 6,589,958 B1 7, 2003 Frietze 6,593,326 B1 7/2003 Bradbury et al. 6,610,677 B2 8, 2003 Davies et al. (75) Inventors: Robert Davies, Somerville, MA (US); 6,613,776 B2 9/2003 Knegteletal. Pan Li, Lexington, MA (US) 6,638,926 B2 10/2003 Davies et al. 6,642,227 B2 11/2003 Cao et al. (73) Assignee: Vertex Pharmaceuticals Incorporated, 6,653,300 B2 11/2003 Bebbington et al. Cambridge, MA (US) 6,653,301 B2 11/2003 Bebbington et al. 6,656,939 B2 12/2003 Bebbington et al. (*) Notice: Subject to any disclaimer, the term of this 6,660,731 B2 12/2003 Bebbington et al. patent is extended or adjusted under 35 6,664.247 B2 12/2003 Bebbington et al. U.S.C. 154(b) by 159 days. 6,696.452 B2 2/2004 Davies et al. 6,727,251 B2 4/2004 Bebbington et al. (21) Appl. No.: 09/952,875 6,743,791 B2 6/2004 Cao et al. (22) Filed: Sep. 14, 2001 (Continued) FOREIGN PATENT DOCUMENTS (65) Prior Publication Data US 2003/OO64982 A1 Apr. 3, 2003 EP O136976 A2 4f1985 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 60/286,949, filed on Apr. 27, 2001, provisional application No. 60/257.887, Alonso, M. et al., “GSK-3 Inhibitors: Discoveries and Develoments', filed on Dec. 21, 2000, provisional application No. Current Medicinal Chemistry, 11, 755-763 (2004). 60/232,795, filed on Sep. 15, 2000. (Continued) (51) Int. Cl. Primary Examiner James O. Wilson A6 IK3I/496 (2006.01) Assistant Examiner Tamthom N. Truong A6 IK3I/506 (2006.01) (74) Attorney, Agent, or Firm Jennifer G. Che CO7D 40/4 (2006.01) CO7D 403/2 (2006.01) (57) ABSTRACT A61 K3 1/541 (2006.01) CO7D 413/14 (2006.01) This invention describes novel protein inhibitors of CO7D 417/14 (2006.01) formula VII: (52) U.S. Cl...... 514/252.19; 514/275; 544/295; 544/328; 544/331 VII (58) Field of Classification Search ...... 514/235.8, 514/241, 252.19, 275; 544/111-114, 122, 544/180, 297, 331, 295,328; 540/598 See application file for complete search history. HN N (56) References Cited

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Hendriksen, E.J. et al., “Modulation of muscle insulin resistance by Dimethoxyphenoxyphenoxypyrimidines and Analogues.”s Pestic. selective inhibition of GSK-3 in Zucker diabetic fatty rats.” Am. J. Sci., 47: 103-113 (1996). Physiol. Endocrinol. Metab., 284: E892-E900 (2003). Gnecco, D. et al., “An Improved Preparation of 1-Methyl-4-Cyano Okafor, C.O., “Studies in the Heterocyclic Series, X. 1.3.9- 4-phenylpiperidine'. Org. Prep. Proced. Int., 18 (4), 478-480 (1996). Triazaphenothiazine Ring System, a New Phenothiazine Ring.” J. Fedorynski, M. et al., “Synthesis of 1-Arycyclopropanecarbonitriles Org. Chem., 40(19): 2753-2755 (1975). under Phase-transfer Catalytic Conditions'. Org. Prep. Proceed. Int., Jambhekar, S.S., "Biopharmaceutical Properties of Drug Sub 27(3), 355-359 (1995). stances” in Principles of Medicinal Chemistry, 4th ed., 12-24. (1995). Suzuki, S. et al., “Application of electrogenerated triphenylmethyl Layzer, R.B., "Section Five - Degenerative Diseases of the Nervous anion as a base for alkylation of arylacetic esters and arylacetonitriles System” in Cecil Textbook of Medicine, 20th ed., 2: 2050-2057 and isomerization of allylbenzenes', Can. J. Chem., 72(2): 357-361 (1996). (1994). Lee, S.J. et al., “Discovery of Potent Cyclic GMP Phosphodiesterase Prasad, G. et al., "18-Crown-6 as a catalyst in the dialkylation of Inhibitors. 2-Pyridyl- and 2- Imidazolylcquinazolines Possessing o-nitrophenacyl derivatives”. J. Org. Chem. 25, 7188-7199 (1991). Cyclic GMP Phosphodiesterase and Thromboxane Synthesis Inhibi Moss, R.A. et al., "Conversion of Obstinate Nitriles to Amindines tory Activities.” J. Med. Chem., 38 (18): 3547-3557 (1995). by Garigipati's Reaction'. Tetrahedron Lett., 36(48), 8761-8764 Medwid, J.B. et al., “Preparation of Triazolo 1.5-cpyrimidines as (1995). Potential Antiasthma Agents.” J. Med. Chem. 33, 1230-1241 (1990). Garigipati, R.S., “An efficient conversion of nitriles to amidines”. Nezu, Y. et al., “Dimethoxypyrimidines as Novel Herbicides. Tetrahedron Lett., 31(14), 1969-1972 (1990). Part 1. Synthesis and Herbicidal Activity of * cited by examiner US 7,473,691 B2 1. 2 PYRAZOLE COMPOUNDS USEFUL AS encoded by distinct genes Coghlan et al., Chemistry & Biol PROTEINKNASE INHIBITORS ogy, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10,508-514 (2000). GSK-3 has been impli CROSS REFERENCE TO RELATED cated in various diseases including diabetes, Alzheimer's dis APPLICATIONS ease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy This application claims priority to U.S. Provisional Patent WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. Application 60/232,795 filed Sep.15, 2000, U.S. Provisional (2000) 151, 117. These diseases may be caused by, or result Patent Application 60/257.887 filed Dec. 21, 2000 and U.S. in, the abnormal operation of certain cell signaling pathways Provisional Patent Application 60/286,949 filed Apr. 27, 10 in which GSK-3 plays a role. GSK-3 has been found to 2001, the contents of which are incorporated herein by refer phosphorylate and modulate the activity of a number of regu CCC. latory proteins. These proteins include glycogen synthase which is the rate limiting necessary for glycogen FIELD OF THE INVENTION synthesis, the microtubule associated protein Tau, the gene 15 transcription factor B-catenin, the translation initiation factor The present invention is in the field of medicinal chemistry elF2B, as well as ATP citrate , axin, heat shock factor-1, and relates to compounds that are protein kinase inhibitors, c-Jun, c-Myc, c-Myb, CREB, and CEPBC. These diverse compositions containing Such compounds and methods of protein targets implicate GSK-3 in many aspects of cellular use. More particularly, this invention relates to compounds metabolism, proliferation, differentiation and development. that are inhibitors of GSK-3 and Aurora-2 protein kinases. In a GSK-3 mediated pathway that is relevant for the treat The invention also relates to methods of treating diseases ment of type II diabetes, insulin-induced signaling leads to associated with these protein kinases, such as diabetes, cancer cellular glucose uptake and glycogen synthesis. Along this and Alzheimer's disease. pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of BACKGROUND OF THE INVENTION 25 GSK-3 mediated phosphorylation and deactivation of glyco gen synthase. The inhibition of GSK-3 leads to increased The search for new therapeutic agents has been greatly glycogen synthesis and glucose uptake Klein et al., PNAS, aided in recent years by better understanding of the structure 93, 8455-9 (1996): Cross et al., Biochem. J., 303, 21-26 of and other biomolecules associated with target (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); diseases. One important class of enzymes that has been the 30 Massillon et al., Biochem J. 299, 123-128 (1994). However, Subject of extensive study is the protein kinases. in a diabetic patient where the insulin response is impaired, Protein kinases mediate intracellular . glycogen synthesis and glucoseuptake fail to increase despite They do this by effecting a phosphoryl extracellular and other the presence of relatively high blood levels of insulin. This stimuli cause a variety of cellular responses to occur inside leads to abnormally high blood levels of glucose with acute the cell. Examples of such stimuli include environmental and 35 and long term effects that may ultimately result in cardiovas chemical stress signals (e.g. osmotic shock, heat shock, ultra cular disease, renal failure and blindness. In such patients, the violet radiation, bacterial endotoxin, HO), cytokines (e.g. normal insulin-induced inhibition of GSK-3 fails to occur. It interleukin-1 (IL-1) and tumor necrosis factor C. (TNF-C.)), has also been reported that in patients with type II diabetes, and growth factors (e.g. granulocyte macrophage-colony GSK-3 is overexpressed WO 00/38675). Therapeutic inhibi stimulating factor (GM-CSF), and fibroblast growth factor 40 tors of GSK-3 are therefore potentially useful for treating (FGF). An extracellular stimulus may effect one or more diabetic patients suffering from an impaired response to insu cellular responses related to cell growth, migration, differen lin. tiation, secretion of hormones, activation of transcription fac GSK-3 activity has also been associated with Alzheimer's tors, muscle contraction, glucose metabolism, control of pro disease. This disease is characterized by the well-known tein synthesis and regulation of cell cycle. 45 B-amyloid peptide and the formation of intracellular neu Many diseases are associated with abnormal cellular rofibrillary tangles. The neurofibrillary tangles contain hyper responses triggered by protein kinase-mediated events. These phosphorylated Tau protein where Tau is phosphorylated on diseases include autoimmune diseases, inflammatory dis abnormal sites. GSK-3 has been shown to phosphorylate eases, neurological and neurodegenerative diseases, cancer, these abnormal sites in cell and animal models. Furthermore, cardiovascular diseases, allergies and asthma, Alzheimer's 50 inhibition of GSK-3 has been shown to prevent hyperphos disease or hormone-related diseases. Accordingly, there has phorylation of Tau in cells Lovestone et al., Current Biology been a substantial effort in medicinal chemistry to find protein 4, 1077-86 (1994); Brownlees et al., Neuroreport 8,3251-55 kinase inhibitors that are effective as therapeutic agents. (1997). Therefore, it is believed that GSK-3 activity may Aurora-2 is a serine/threonine protein kinase that has been promote generation of the neurofibrillary tangles and the implicated in human cancer, Such as colon, breast and other 55 progression of Alzheimer's disease. solid tumors. This kinase is believed to be involved in protein Another substrate of GSK-3 is 3-catenin which is degra phosphorylation events that regulate the cell cycle. Specifi dated after phosphorylation by GSK-3. Reduced levels of cally, Aurora-2 may play a role in controlling the accurate B-catenin have been reported in Schizophrenic patients and segregation of chromosomes during . Misregulation have also been associated with other diseases related to of the cell cycle can lead to cellular proliferation and other 60 increase in neuronal cell death Zhong et al., Nature, 395, abnormalities. In human colon cancer tissue, the aurora-2 698-702 (1998); Takashima et al., PNAS,90,7789-93 (1993); protein has been found to be overexpressed. See Bischoffet Pei et al., J. Neuropathol. Exp. 56, 70-78 (1997). al., EMBO.J., 1998, 17, 3052-3065; Schumacher et al., J. Cell As a result of the biological importance of GSK-3, there is Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem. current interest in therapeutically effective GSK-3 inhbitors. 1997, 272, 13766-13771. 65 Small molecules that inhibit GSK-3 have recently been Glycogen synthase kinase-3 (GSK-3) is a serine/threonine reported WO99/65897 (Chiron) and WO 00/38675 (Smith protein kinase comprised of C. and B isoforms that are each Kline Beecham). US 7,473,691 B2 3 4 For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also -continued been targeted for treating the same diseases. However, the various protein kinases often act through different biological 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 for treating conditions characterized by enhanced p38-C. activity and/or enhanced TGF-B activity. While p38 activity 10 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 15 glucose uptake. There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive targets for the discovery of 2O new therapeutics due to their important role in cancer, diabe tes, Alzheimer's disease and other diseases.

DESCRIPTION OF THE INVENTION 25 It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of aurora-2 and GSK-3. These compounds have the general formula I: 30

35

40

and

45 or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z' to Z are as described below: Ring A is selected from the group consisting of: 50

G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, 55 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 r position on Ring C is independently substituted by R. Ry N1s s and two adjacent Substituents on Ring C are optionally 60 taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring RX having 0-3 heteroatoms selected from oxygen, Sulfur or r nitrogen, said fused ring being optionally Substituted by Ry 21 s halo, oxo, or R: 65 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having US 7,473,691 B2 5 6 1-4 ring heteroatoms selected from nitrogen, oxygen or O—, C(R)—NN(R) , C(R)=N O , sulfur, wherein Ring D is substituted at any substitutable C(R), N(R)N(R) - C(R)N(R)SON(R) , or ring carbon by oxo or —R, and at any substitutable ring C(R)N(R)CON(R) ; nitrogen by R', provided that when Ring D is a six W is C(R)-O-, -C(R)S , —C(R) SO = C(R) membered arylor heteroaryl ring, -R is hydrogen at each 5 SO. , —C(R)SON(R)-, - C(R)N(R)- ortho carbon position of Ring D; —CO-, -CO. , —C(R)OC(O) , —C(R)OC(O)N R" is selected from -halo, —CN, NO, T-V R, phenyl, (R) C(R)N(R)CO C(R)N(R)C(O)O , 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl C(R)=NN(R) C(R)=N-O-, - C(R)-N ring, or Caliphatic group, said phenyl, heteroaryl, and (R)N(R) C(R)N(R)SON(R) C(R)-N heterocyclyl rings each optionally Substituted by up to 10 (R)CON(R) , or CONCR) ; three groups independently selected from halo, oxo, or each R is independently selected from hydrogen or an —R, said Caliphatic group optionally substituted with optionally substituted C. aliphatic group, or two R' halo, cyano, nitro, or oxygen, or R' and an adjacent Sub groups on the same nitrogen atom are taken together with stituent taken together with their intervening atoms form the nitrogen atom to form a 5-6 membered heterocyclyl or said ring fused to Ring C: 15 heteroaryl ring; R and Rare independently selected from T-R, or R and R' each R" is independently selected from hydrogen or an are taken together with their intervening atoms to form a optionally substituted Caliphatic group, or two R7 on the fused, unsaturated or partially unsaturated, 5-8 membered same nitrogen are taken together with the nitrogen to form ring having 0-3 ring heteroatoms selected from oxygen, a 5-8 membered heterocyclyl or heteroaryl ring: Sulfur, or nitrogen, wherein any Substitutable carbon on each R is independently selected from an optionally substi said fused ring formed by RandR is substituted by oxo or tuted C, aliphatic group, —OR', SR, COR, T-R, and any substitutable nitrogen on said ring formed by —SOR, N(R), -N(R)N(R) - CN, NO, R and R” is substituted by R: —CON(R), or -COR; and T is a valence bond or a C alkylidene chain; 25 R is selected from —R, halo, OR, —C(=O)R, CO.R. R° and Rare independently selected from —R,-T-W-R, or —COCOR, NO, CN, S(O)R, -SOR, -SR, R and Rare taken together with their intervening atoms -N(R), —CON(R), -SON(R), —OC(=O)R, to form a fused, 5-8 membered, unsaturated or partially -N(R)COR, N(R)CO (optionally substituted C. unsaturated, ring having 0-3 ring heteroatoms selected aliphatic), N(R)N(R), -C=NN(R), -C=N- from nitrogen, oxygen, or Sulfur, wherein each Substitut 30 OR, N(R)CON(R), N(R)SON(R), N(R) able carbon on said fused ring formed by R and R is SOR, or - OC(=O)N(R). substituted by halo, oxo, CN, NO, R', or As used herein, the following definitions shall apply unless —V R', and any substitutable nitrogen on said ring otherwise indicated. The phrase “optionally substituted” is formed by RandR is substituted by R: used interchangeably with the phrase “substituted or unsub R is selected from R,-halo, OR, —C(=O)R, CO.R. 35 stituted” or with the term “(un)substituted.” Unless otherwise —COCOR, COCHCOR, NO, CN, -S(O)R, indicated, an optionally Substituted group may have a Sub —S(O).R. —SR, N(R), —CON(R), -SON(R), stituent at each Substitutable position of the group, and each –OC(=O)R, N(R7)COR, N(R7)CO, (optionally substitution is independent of the other. substituted C- aliphatic), N(R)N(R), -C= The term “aliphatic' as used herein means straight-chain, NN(R), -C=N OR, NOR7)CON(R), N(R7) 40 branched or cyclic C-C2 hydrocarbons which are com SON(R7), N(R)SOR, or OC(=O)N(R7); pletely saturated or which contain one or more units of unsat each R is independently selected from hydrogen oran option uration but which are not aromatic. For example, suitable ally substituted group selected from Caliphatic, Co aliphatic groups include Substituted or unsubstituted linear, aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids cyclyl ring having 5-10 ring atoms; 45 thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cy each R" is independently selected from R", COR". cloalkyl)alkenyl. The terms “alkyl, “alkoxy”, “hydroxy —CO(Caliphatic), —CON(R), or—SOR", or two alkyl”, “alkoxyalkyl, and “alkoxycarbonyl', used alone or R" on the same nitrogen are taken together to form a 5-8 as part of a larger moiety includes both straight and branched membered heterocyclyl or heteroaryl ring: 50 chains containing one to twelve carbon atoms. The terms each R is independently selected from —R, halo, —OR, “alkenyl and “alkynyl used alone or as part of a larger - C(=O)R, COR, COCOR, NO, CN, S(O) moiety shall include both straight and branched chains con R, -SOR. -SR, N(R), —CON(R), -SO, taining two to twelve carbon atoms. The term “cycloalkyl N(R), OC(=O)R, N(R)COR, N(R)CO (op used alone or as part of a larger moiety shall include cyclic tionally substituted C- aliphatic), N(R)N(R), 55 C-C hydrocarbons which are completely saturated or C=NN(R) - C=N OR, N(R)CON(R), which contain one or more units of unsaturation, but which N(R)SON(R), N(R)SOR, or OC(=O) are not aromatic. N(R), or R and an adjacent substituent taken together The terms “haloalkyl”, “haloalkenyl and “haloalkoxy” with their intervening atoms form said ring fused to Ring means alkyl, alkenyl oralkoxy, as the case may be, Substituted C; 60 with one or more halogen atoms. The term "halogen' means V is - O -, - S -, -SO , SO. , N(R)SO , F, Cl, Br, or I. —SON(R)-, - N(R)-, -CO-, -CO. , N(R) The term "heteroatom' means nitrogen, oxygen, or Sulfur CO. , N(R)C(O)O N(R)CON(R) , N(R) and includes any oxidized form of nitrogen and Sulfur, and the SON(R) , N(R)N(R) C(O)N(R) OC quaternized form of any basic nitrogen. Also the term "nitro (O)N(R)-, - C(R)-O-, - C(R)S , C(R) 65 gen’ includes a substitutable nitrogen of a heterocyclic ring. SO-, - C(R)SO. , —C(R)SON(R)-, - C(R) As an example, in a saturated or partially unsaturated ring N(R) C(R)N(R)C(O) C(R)N(R)C(O) having 0-3 heteroatoms selected from oxygen, Sulfur or nitro US 7,473,691 B2 7 8 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-dipyrimidinyl. The term "heteroaryl optionally substituted. The terms “carbocycle”, “carbocy also refers to rings that are optionally substituted. The term clyl', 'carbocyclo', or “carbocyclic' also include aliphatic 10 "heteroaryl” may be used interchangeably with the term “het rings that are fused to one or more aromatic or nonaromatic eroaryl ring or the term "heteroaromatic'. rings, such as in a decahydronaphthyl or tetrahydronaphthyl, An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the where the radical or point of attachment is on the aliphatic like) or heteroaryl (including heteroaralkyl and heteroaryla r1ng. lkoxy and the like) group may contain one or more substitu The term “aryl used alone or as part of a larger moiety as 15 ents. Examples of Suitable Substituents on the unsaturated in “aralkyl”, “aralkoxy’, or “aryloxyalkyl, refers to aromatic carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl ring groups having five to fourteen members, such as phenyl, group include a halogen, —R. —OR. —SR, 1.2-methyl benzyl, phenethyl, 1-naphthyl 2-naphthyl, 1-anthracyl and ene-dioxy, 1.2-ethylenedioxy, protected OH (such as acy 2-anthracyl. The term “aryl also refers to rings that are loxy), phenyl (Ph), substituted Ph. —O(Ph), substituted optionally substituted. The term “aryl' may be used inter - O(Ph), -CH(Ph), substituted -CH(Ph), —CHCH changeably with the term “aryl ring”. “Aryl also includes (Ph), substituted —CHCH(Ph), - NO, CN, N(R), fused polycyclic aromatic ring systems in which an aromatic NRC(O)Ro, NRC(O)N(R), NRCOR, ring is fused to one or more rings. Examples include 1-naph NRNRC(O)Ro, NRNRC(O)N(R), thyl 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included NRNRCOR, C(O)C(O)R, C(O)CHC(O)R, within the scope of the term “aryl', as it is used herein, is a 25 - COR. - C(O)R, C(O)N(R) - OC(O)N(R), group in which an aromatic ring is fused to one or more —S(O).R., -SON(R) - S(O)R°, - NRSON(R), non-aromatic rings, such as in an indanyl, phenanthridinyl, or NRSOR, C(=S)N(R), C(-NH) N(R), tetrahydronaphthyl, where the radical or point of attachment -(CH.)NHC(O)R°, -(CH.)NHC(O)CH(V-R)(R): is on the aromatic ring. wherein R is hydrogen, a substituted or unsubstituted ali The term “heterocycle”, “heterocyclyl”, or "heterocyclic” 30 phatic group, an unsubstituted heteroaryl or heterocyclic ring, as used herein includes non-aromatic ring systems having five phenyl (Ph), substituted Ph, O(Ph), substituted O(Ph), to fourteen members, preferably five to ten, in which one or - CH(Ph), or substituted -CH(Ph); y is 0-6; and V is a more ring carbons, preferably one to four, are each replaced linker group. Examples of substituents on the aliphatic group by a heteroatom such as N, O, or S. Examples of heterocyclic or the phenyl ring of R include amino, alkylamino, dialky rings include 3-1H-benzimidazol-2-one, (1-substituted)-2- 35 lamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, oxo-benzimidazol-3-yl 2-tetrahydrofuranyl, 3-tetrahydro dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylami furanyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahy nocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbo dropyranyl, 1,3-dioxalanyl, 1,3-dithiolanyl, 1,3- nyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, An aliphatic group or a non-aromatic heterocyclic ring 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomor 40 may contain one or more Substituents. Examples of Suitable pholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidi Substituents on the Saturated carbon of analiphatic group or of nyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazi a non-aromatic heterocyclic ring include those listed above nyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, for the unsaturated carbon of an arylor heteroaryl group and 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-ph the following: =O, =S, =NNHR*, =NN(R*) =N , thalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidi 45 =NNHC(O)R*, =NNHCO(alkyl). =NNHSO,(alkyl), or nyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also =NR*, where each R* is independently selected from included within the scope of the term "heterocyclyl or "het hydrogen, an unsubstituted aliphatic group or a Substituted erocyclic', as it is used herein, is a group in which a non aliphatic group. Examples of Substituents on the aliphatic aromatic heteroatom-containing ring is fused to one or more group include amino, alkylamino, dialkylamino, aminocar aromatic or non-aromatic rings, such as in an indolinyl, chro 50 bonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocar manyl, phenanthridinyl, or tetrahydroquinolinyl, where the bonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, radical or point of attachment is on the non-aromatic heteroa alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, tom-containing ring. The term "heterocycle”, “heterocyclyl, hydroxy, haloalkoxy, or haloalkyl. or "heterocyclic” whether saturated or partially unsaturated, Suitable Substituents on the nitrogen of a non-aromatic also refers to rings that are optionally Substituted. 55 heterocyclic ring include —R", N(R'), —C(O)R", The term "heteroaryl, used alone or as part of a larger COR", C(O)C(O)R", C(O)CHC(O)R', SOR", moiety as in "heteroaralkyl or "heteroarylalkoxy’, refers to - SON(R') –C(=S)N(R'), C(=NH) N(R'), and heteroaromatic ring groups having five to fourteen members. —NRSOR"; wherein R is hydrogen, an aliphatic group, a Examples of heteroaryl rings include 2-furanyl, 3-furanyl. substituted aliphatic group, phenyl (Ph), substituted Ph. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 60 - O(Ph), substituted O(Ph), CH(Ph), substituted CH 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, (Ph), or an unsubstituted heteroaryl or heterocyclic ring. 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrro Examples of substituents on the aliphatic group or the phenyl lyl. 2-pyrrolyl 3-pyrrolyl 2-pyridyl, 3-pyridyl, 4-pyridyl, ring include amino, alkylamino, dialkylamino, aminocarbo 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thia nyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbo Zolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-tria 65 nyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, Zolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, ben alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, Zothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, hydroxy, haloalkoxy, or haloalkyl. US 7,473,691 B2 9 10 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 5 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 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 10 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-, 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, 15 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 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 25 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 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. 30 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, 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 35 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 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. 40 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 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 45 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 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 50 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 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 55 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 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. 60 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 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 65 mediated condition' or “disease” also means those diseases composition thereof. This method is especially useful for or conditions that are alleviated by treatment with a ERK-2 diabetic patients. Another method relates to inhibiting the inhibitor. Such conditions include, without limitation, cancer, US 7,473,691 B2 11 12 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. 5 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 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 10 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 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, 15 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: macological activity thereof. Raingeaudet al., 1996, Mol. Cell Biol. 16, 1247; Raingeaudet The term “patient' includes human and veterinary sub al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 25 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, JClin. tions of an enzyme Suitable for in vitro assay, biopsied mate Invest. 99, 1478: Whelchel et al., 1997, Am. J. Respir: Cell rial obtained from a mammal or extracts thereof, and blood, Mol. Biol. 16, 589. 30 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 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 35 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 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. 40 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 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. 45 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 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. 50 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 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 55 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 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 60 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 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 65 also be a sterile injectable solution or Suspension in a non “disease also means those diseases or conditions that are toxic parenterally-acceptable diluent or solvent, for example alleviated by treatment with a Src inhibitor. Such conditions as a solution in 1,3-butanediol. Among the acceptable US 7,473,691 B2 13 14 vehicles and solvents that may be employed are water, Ring tive such as benzylalkonium chloride. Alternatively, for oph er's solution and isotonic sodium chloride Solution. In addi thalmic uses, the pharmaceutical compositions may be for tion, sterile, fixed oils are conventionally employed as a sol mulated in an ointment such as petrolatum. Ventor Suspending medium. For this purpose, any bland fixed The pharmaceutical compositions of this invention may oil may be employed including synthetic mono- or di-glyc- 5 also be administered by nasal aerosol or inhalation. Such erides. Fatty acids, such as oleic acid and its glyceride deriva compositions are prepared according to techniques well tives are useful in the preparation of injectables, as are natural known in the art of pharmaceutical formulation and may be pharmaceutically-acceptable oils, such as olive oil or castor prepared as Solutions in saline, employing benzyl or oil, especially in their polyoxyethylated versions. These oil other Suitable preservatives, absorption promoters to enhance Solutions or Suspensions may also contain a long-chain alco- 10 bioavailability, fluorocarbons, and/or other conventional hol diluent or dispersant, such as carboxymethyl cellulose or solubilizing or dispersing agents. similar dispersing agents which are commonly used in the In addition to the compounds of this invention, pharma formulation of pharmaceutically acceptable dosage forms ceutically acceptable derivatives or prodrugs of the com including emulsions and Suspensions. Other commonly used pounds of this invention may also be employed in composi Surfactants, such as Tweens, Spans and other emulsifying 15 tions to treat or prevent the above-identified diseases or agents or bioavailability enhancers which are commonly used disorders. in the manufacture of pharmaceutically acceptable solid, liq A “pharmaceutically acceptable derivative or prodrug’ uid, or other dosage forms may also be used for the purposes means any pharmaceutically acceptable salt, ester, Salt of an of formulation. ester or other derivative of a compound of this invention The pharmaceutical compositions of this invention may be 20 which, upon administration to a recipient, is capable of pro orally administered in any orally acceptable dosage form viding, either directly or indirectly, a compound of this inven including, but not limited to, capsules, tablets, aqueous Sus tion or an inhibitorily active metabolite or residue thereof. pensions or solutions. In the case of tablets for oral use, Particularly favored derivatives or prodrugs are those that carriers commonly used include lactose and corn starch. increase the bioavailability of the compounds of this inven Lubricating agents, such as magnesium Stearate, are also 25 tion when Such compounds are administered to a patient (e.g., typically added. For oral administration in a capsule form, by allowing an orally administered compound to be more useful diluents include lactose and dried cornstarch. When readily absorbed into the blood) or which enhance delivery of aqueous Suspensions are required for oral use, the active the parent compound to a biological compartment (e.g., the ingredient is combined with emulsifying and Suspending brain or lymphatic system) relative to the parent species. agents. If desired, certain Sweetening, flavoring or coloring 30 Pharmaceutically acceptable prodrugs of the compounds agents may also be added. of this invention include, without limitation, esters, amino Alternatively, the pharmaceutical compositions of this acid esters, phosphate esters, metal salts and sulfonate esters. invention may be administered in the form of Suppositories Pharmaceutically acceptable salts of the compounds of this for rectal administration. These can be prepared by mixing invention include those derived from pharmaceutically the agent with a Suitable non-irritating excipient which is 35 acceptable inorganic and organic acids and bases. Examples Solid at room temperature but liquid at rectal temperature and of suitable acid salts include acetate, adipate, alginate, aspar therefore will melt in the rectum to release the drug. Such tate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, materials include cocoa butter, beeswax and polyethylene camphorate, camphorsulfonate, cyclopentanepropionate, glycols. digluconate, dodecylsulfate, ethanesulfonate, formate, fuma The pharmaceutical compositions of this invention may 40 rate, glucoheptanoate, glycerophosphate, glycolate, hemisul also be administered topically, especially when the target of fate, heptanoate, hexanoate, hydrochloride, hydrobromide, treatment includes areas or organs readily accessible by topi hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, cal application, including diseases of the eye, the skin, or the malonate, methanesulfonate, 2-naphthalenesulfonate, nico lower intestinal tract. Suitable topical formulations are tina, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phe readily prepared for each of these areas or organs. 45 nylpropionate, phosphate, picrate, pivalate, propionate, Sali Topical application for the lower intestinal tract can be cylate. Succinate, Sulfate, tartrate, thiocyanate, tosylate and effected in a rectal suppository formulation (see above) or in undecanoate. Other acids, such as oxalic, while not in them a Suitable enema formulation. Topically-transdermal patches selves pharmaceutically acceptable, may be employed in the may also be used. preparation of salts useful as intermediates in obtaining the For topical applications, the pharmaceutical compositions 50 compounds of the invention and their pharmaceutically may be formulated in a suitable ointment containing the acceptable acid addition salts. active component Suspended or dissolved in one or more Salts derived from appropriate bases include alkali metal carriers. Carriers for topical administration of the compounds (e.g., Sodium and potassium), alkaline earth metal (e.g., mag of this invention include, but are not limited to, mineral oil, nesium), ammonium and N(Calkyl) salts. This invention liquid petrolatum, white petrolatum, propylene glycol, poly- 55 also envisions the quaternization of any basic nitrogen-con oxyethylene, polyoxypropylene compound, emulsifying wax taining groups of the compounds disclosed herein. Water or and water. Alternatively, the pharmaceutical compositions oil-soluble or dispersible products may be obtained by such can be formulated in a Suitable lotion or cream containing the quaternization. active components suspended or dissolved in one or more The amount of the protein kinase inhibitor that may be pharmaceutically acceptable carriers. Suitable carriers 60 combined with the carrier materials to produce a single dos include, but are not limited to, mineral oil, sorbitan age form will vary depending upon the patient treated and the monostearate, polysorbate 60, cetyl esters wax, cetearyl alco particular mode of administration. Preferably, the composi hol, 2-octyldodecanol, benzyl alcohol and water. tions should be formulated so that a dosage of between 0.01 For ophthalmic use, the pharmaceutical compositions may 100 mg/kg body weight/day of the inhibitor can be adminis be formulated as micronized suspensions in isotonic, pH 65 tered to a patient receiving these compositions. adjusted Sterile Saline, or, preferably, as Solutions in isotonic, It should also be understood that a specific dosage and pH adjusted sterile saline, either with or without a preserva treatment regimen for any particular patient will depend upon US 7,473,691 B2 15 16 a variety of factors, including the activity of the specific R’ and R' (at positions Z and Z, respectively) may be compound employed, the age, body weight, general health, taken together to form a fused ring, providing a bicyclic ring sex, diet, time of administration, rate of excretion, drug com system containing Ring A. Preferred R/R' rings include a 5-, bination, and the judgment of the treating physician and the 6-, 7-, or 8-membered unsaturated or partially unsaturated severity of the particular disease being treated. The amount of 5 ring having 0-2 heteroatoms, wherein said R/R' ring is the inhibitor will also depend upon the particular compound optionally Substituted. Examples of Ring A Systems are in the composition. shown below by compounds I-A through I-DD, wherein Z' is Depending upon the particular protein kinase-mediated nitrogen or C(R) and Z is nitrogen or C(H). condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent 10 that condition, may be administered together with the inhibi tors of this invention. For example, in the treatment of diabe I-A tes other anti-diabetic agents may be combined with the GSK-3 inhibitors of this invention to treat diabetes. These agents include, without limitation, insulin or insulin ana 15 logues, in injectable or inhalation form, glitaZones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and Sulfonyl ureas. 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, 25 cyclophosphamide, and SulfaSalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacroli mus, rapamycin, mycophenolate mofetil, interferons, corti costeroids, cyclophophamide, azathioprine, and Sulfasala Zine; neurotrophic factors such as acetylcholinesterase 30 inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease Such as beta-block ers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as 35 corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticos teroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. 40 N72 Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the 45 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 otherwise indicated, the representation of either tautomer is 50 meant to include the other.

R2 R2 R2. R2 55 e N N NH I-E

HN N^H s–- HN N/ Z3 1s Z2 Z3 1. Z2 60 A A PlelsZl G Al-lsZl G

65

US 7,473,691 B2 21 22

-continued -continued I-DD N1\ | N X le e NH NH H N / N / N N72 N N O and 2 10 Zl Preferred substituents on the R/R fused ring include one or more of the following: -halo, N(R), —Cls alkyl, —Cs haloalkyl, - NO. —O(C- alkyl). —CO(C- Preferred bicyclic Ring A systems include I-A, I-B, I-C, 15 alkyl), —CN, SO(C- alkyl). —SONH, OC(O)NH2. I-D, I-E, I-F, I-G, I-H, I-I, I-J., I-K, I-L, and I-M, more pref —NHSO(C- alkyl). —NHC(O)(C. alkyl). —C(O)NH2, erably I-A, I-B, I-C, I-F, and I-H, and most preferably I-A and —CO(C- alkyl), wherein the (C. alkyl) is most pref erably methyl. I-B, and I-H. When the pyrazolering system is monocyclic, preferred R' In the monocyclic Ring A System, preferred R groups, groups include hydrogen, Caliphatic, alkoxycarbonyl, when present, include hydrogen, alkyl- or dialkylamino, (un)Substituted phenyl, hydroxyalkyl, alkoxyalkyl, ami acetamido, or a Caliphatic group Such as methyl, ethyl, nocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, cyclopropyl, isopropyl or t-butyl. Preferred R' groups, when alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, present, include T-R wherein T is a valence bond or a meth and (N-heterocyclyl)carbonyl. Examples of such preferred ylene, and R is —R, N(R), or —OR. Examples of pre 25 R substituents include methyl, cyclopropyl ethyl, isopropyl, ferred R' include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, propyl, t-butyl, cyclopentyl, phenyl, COH, COCH, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, CHOH, CHOCH, CHCHCH-OH, CHCHCHOCH, acetamido, optionally Substituted phenyl Such as phenyl or CHCHCHOCHPh. CHCHCH-NH. halo-substituted phenyl, and methoxymethyl. CHCHCH-NHCOOC(CH), CONHCH(CH), CONHCHCH-CH CONHCHCHOCH, In the bicyclic Ring. A system, the ring formed when R and 30 CONHCHPh, CONH(cyclohexyl), CON(Et), CONCH.) R" are taken together may be substituted or unsubstituted. CHPh. CONH(n-CH), CON(Et)CHCHCH, Suitable substituents include —R, halo. —OR, —C(=O)R. CONHCHCH(CH), CONCn-CH4), CO(3-methoxym —COR, COCOR, NO, CN, -S(O)R, -SOR, ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), —SR, N(R), —CON(R), -SON(R), —OC(=O) 35 CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- R, N(R)COR, N(R)CO(optionally substituted C. yl), CONHCHCH-OH, CONH, and CO(piperidin-1-yl). A aliphatic), N(R)N(R) -C=NN(R), -C=N OR, preferred R group is hydrogen. N(R)CON(R), N(R)SON(R), N(R)SOR, or An embodiment that is particularly useful for treating –OC(=O)N(R), wherein R and Rare as defined above. GSK3-mediated diseases relates to compounds of formula II: Preferred R/R' ring substituents include -halo, R. —OR, 40 —COR, COR, CONCR), CN, or N(R), wherein II R is hydrogen or an optionally substituted Caliphatic R2 group. R2 e RandR may be taken together to form a fused ring, thus 45 NH providing a bicyclic ring system containing a pyrazole ring. S. M Preferred fused rings include benzo, pyrido, pyrimido, and a HN N partially unsaturated 6-membered carbocyclo ring, wherein RX said fused ring is optionally Substituted. These are exempli n N 50 fied in the following formula I compounds having a pyrazole 2 containing bicyclic ring system: Ry N

55 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said S. NH Ring C has one or two ortho substituents independently HN N | N N i N 60 selected from R', any substitutable non-ortho carbon position on Ring C is independently substituted by R. Z3 1. Z2 le le and two adjacent Substituents on Ring C are optionally NH NH taken together with their intervening atoms to form a fused, 7N,2 s SN unsaturated or partially unsaturated, 5-6 membered ring 65 having 0-3 heteroatoms selected from oxygen, Sulfur or nitrogen, said fused ring being optionally Substituted by halo, oxo, or R: US 7,473,691 B2 23 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 (R)CON(R) , or CONCR) ; heterocyclyl rings each optionally Substituted by up to each R is independently selected from hydrogen, an option three groups independently selected from halo, oxo, or 5 ally substituted Caliphatic group, or two R' groups on —R, said Caliphatic group optionally substituted with the same nitrogenatom are taken together with the nitrogen halo, cyano, nitro, or oxygen, or R' and an adjacent Sub atom to form a 5-6 membered heterocyclyl or heteroaryl stituent taken together with their intervening atoms form ring: said ring fused to Ring C: each R" is independently selected from hydrogen or an R and Rare independently selected from T-R, or R and R' 10 optionally substituted Caliphatic group, or two R7 on the are taken together with their intervening atoms to form a same nitrogen are taken together with the nitrogen to form fused, unsaturated or partially unsaturated, 5-8 membered a 5-8 membered heterocyclyl or heteroaryl ring; and 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 15 —SOR. - N(R) - N(R)N(R) - CN, NO, T-R, and any substitutable nitrogen on said ring formed by CON(R), or COR. R and R” is substituted by R: When the RandR' groups of formula II are taken together T is a valence bond or a C alkylidene chain; to form a fused ring, preferred R/R' rings include a 5-, 6-, 7 R° and Rare 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 25 —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, COR, - COCOR, COCHCOR, NO, CN, S(O)R, —S(O).R. —SR, N(R), —CON(R7), -SON(R7), 30 –OC(=O)R, N(R)COR, N(R)CO (optionally substituted C, aliphatic), N(R)N(R), -C=NN (R), -C=N OR, N(R7)CON(R7), N(R7)SON (R) - N(R)SOR, or - OC(=O)N(R): each R is independently selected from hydrogen oran option 35 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; each R" is independently selected from R", COR". II-B —CO,(optionally substituted C- aliphatic), —CON 40 (R), or -SO.R. or two R' on the same nitrogen are 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) 45 R, SOR, SR, N(R), —CON(R), -SO, N(R), OC(=O)R, N(R)COR, N(R)CO,(op tionally substituted C- aliphatic), N(R)N(R), II-C C=NN(R) -C=N OR, N(R)CON(R), N(R)SON(R), N(R)SOR, or OC(=O) 50 N(R), or R and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is - O -, - S -, -SO , SO. , N(R)SO , —SON(R)-, - N(R)-, -CO-, -CO. , N(R) 55 CO. , N(R)C(O)O N(R)CON(R) , N(R) SON(R) , N(R)N(R) C(O)N(R) OC (O)N(R)-, - C(R)-O-, - C(R)S , C(R) II-D SO-, - C(R)SO. , —C(R)SON(R)-, - C(R) N(R) C(R)N(R)C(O) C(R)N(R)C(O) 60 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) ; W is C(R)-O-, -C(R).S. , C(R) SO = C(R) SO. , —C(R)SON(R)-, - C(R)N(R) , 65 - CO-, -CO. , —C(R)OC(O) –C(R)OC(O)N (R) C(R)N(R)CO C(R)N(R)C(O)C) , US 7,473,691 B2 25 26

-continued -continued II-E sy II-K 21 NN

N 2 10 N N

II-L

II-F 15 ax N 21 n N

S N 2

II-M

II-G 25 N 21 NN

N N 2 30 ax II-N 35 N II-H

40 II-O

45

II-I

50 II-P

55

60 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. 65. In the monocyclic pyrimidine ring system of formula II, preferred R groups include hydrogen, alkyl- or dialky lamino, acetamido, or a Caliphatic group Such as methyl, US 7,473,691 B2 27 28 ethyl, cyclopropyl, isopropyl or t-butyl. Preferred R' groups More preferred ring systems of formula II are the follow include T-R wherein T is a valence bond or a methylene, and ing, which may be substituted as described above, wherein R Ris-R, N(R), or -OR. When R is R or -OR, a and Rare taken together with the pyrazole ring to form an preferred R is an optionally substituted group selected from indazole ring; and RandR'' are each methyl, or R and Rare Caliphatic, phenyl, or a 5-6 membered heteroaryl or het 5 taken together with the pyrimidine ring to form a quinazoline erocyclyl ring. Examples of preferred R' include 2-pyridyl, or tetrahydroquinazoline ring: 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl. t-butyl, alkyl- or dialkylamino, acetamido, optionally Substi tuted phenyl Such as phenyl or halo-substituted phenyl, and II-Aa methoxymethyl. 10 In the bicyclic pyrimidine ring system of formula II, the ring formed when R and Rare taken together may be sub stituted or unsubstituted. Suitable substituents include —R, NH halo, OR, C(=O)R, COR, COCOR, NO, S. M CN, S(O)R, -SOR, SR, N(R), —CON(R), 15 HN N - SON(R), OC(=O)R, N(R)COR, N(R)CO, (optionally substituted C aliphatic), N(R)N(R), n N C=NN(R), -C=N OR, N(R)CON(R), N(R)SON(R), N(R)SOR, or OC(=O)N(R), 2 wherein RandR are as defined above. Preferred R/R” ring N substituents include -halo, —R, —OR, —COR, —COR, II-Ba —CON(R), —CN, or N(R), wherein R is an optionally Substituted Caliphatic group. The RandR groups of formula II may be taken together 25 to form a fused ring, thus providing a bicyclic ring system NH containing a pyrazole ring. Preferred fused rings include S. M benzo, pyrido, pyrimido, and a partially unsaturated 6-mem HN N bered carbocycloring. These are exemplified in the following formula II compounds having a pyrazole-containing bicyclic ring system: 30 SN 2 N

II-Ha 35

NH N / HN N NH |Y N S. M HN N RX n N le le 40 NH NH H3C N / N / n N N N Ry N s 1so 2 \ 45 H3C N le NH Particularly preferred are those compounds of formula II-Aa, S M II-Ba, or II-Ha wherein ring C is a phenyl ring and R' is halo, N N 50 methyl, or trifluoromethyl. Preferred formula II Ring C groups are phenyl and pyridi nyl. When two adjacent substituents on Ring C are taken Preferred substituents on the R/Rfused ring of formula II together to form a fused ring, Ring C is contained in a bicyclic include one or more of the following:-halo, N(R), —Ca 55 ring system. Preferred fused rings include a benzo or pyrido alkyl, —Chaloalkyl, —NO. —O(Calkyl), —CO(C- ring. Such rings preferably are fused at ortho and meta posi alkyl), —CN, SO(C-alkyl). —SONH, OC(O)NH2, tions of Ring C. Examples of preferred bicyclic Ring C sys —NHSO(C-alkyl), NHC(O)(Calkyl), C(O)NH2. tems include naphthyl, quinolinyl and isoquinolinyl. and —CO(C. alkyl), wherein the (C. alkyl) is a straight, An important feature of the formula II compounds is the R' branched, or cyclic alkyl group. Preferably, the (C. alkyl) 60 ortho Substituent on Ring C. An ortho position on Ring C or group is methyl. Ring D is defined relative to the position where Ring A is When the pyrazole ring system of formula II is monocy attached. Preferred R' groups include -halo, an optionally clic, preferred R groups include hydrogen, a substituted or substituted Caliphatic group, phenyl, -COR, OR, unsubstituted group selected from aryl, heteroaryl, or a C —CN, -SOR. -SONH, -N (R), —COR, aliphatic group. Examples of such preferred R groups 65 CONH, NHCOR, OC(O)NH, or NHSO.R. include methyl, t-butyl, —CHOCH cyclopropyl, furanyl, When R' is an optionally substituted Caliphatic group, the thienyl, and phenyl. A preferred R group is hydrogen. most preferred optional Substituents are halogen. Examples US 7,473,691 B2 29 30 of preferred R' groups include —CF, —Cl, F. —CN, group, —OR, —C(O)R, COR, CONH(R), -N (R) —COCH, OCH, -OH, -CHCH, OCHCH COR, SON(R), or N(R)SOR. —CH, —CFCH., cyclohexyl, t-butyl, isopropyl, cyclopro Even more preferred compounds of formula II have one or pyl, —C=CH, —C=C CH, -SOCH —SONH2, - N(CH), -COCH – CONH, -NHCOCH, OC more, and more preferably all, of the features selected from (O)NH, -NHSOCH, and OCF. the group consisting of On Ring C of formula II, preferred R substituents, when (a) Ring C is a phenyl ring optionally substituted by R: present, include -halo, —CN, NO, N(R), optionally (b) R' is hydrogen or methyl and R' is methyl, methoxym Substituted Caliphatic group, —OR, —C(O)R. —COR, ethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an CONH(R), N(R)COR, SON(R), and N(R) 10 optionally Substituted group selected from 2-pyridyl, 4-py SO.R. More preferred R substituents include - C1, F, ridyl, piperidinyl, or phenyl, or R and R” are taken together —CN. —CF, -NH2, —NH(Caliphatic), —N(Cali with their intervening atoms to forman optionally substituted phatic) —O(Caliphatic), Caliphatic, and —CO(C- benzo ring or partially unsaturated 6-membered carbocyclo aliphatic). Examples of such preferred R substituents ring: include C1, F, CN, CF, NH, NHMe, 15 —NMe2, —OEt, methyl, ethyl, cyclopropyl, isopropyl, t-bu (c) R' is -halo, a Caliphatic group optionally substituted tyl, and —COEt. with halogen, or—CN: Preferred formula II compounds have one or more, and (d) R and R are taken together with their intervening more preferably all, of the features selected from the group atoms to form a benzo, pyrido, pyrimido or partially unsatur consisting of: ated 6-membered carbocycloring optionally substituted with (a) Ring C is a phenyl or pyridinyl ring, optionally Substi -halo, N(R), —C. alkyl, -C, a haloalkyl, - NO. tuted by R, wherein when Ring C and two adjacent sub —O(C. alkyl). —CO(C. alkyl). —CN. —SO(C- stituents thereon form a bicyclic ring system, the bicyclic ring alkyl). —SONH2, —OC(O)NH2. —NHSO(C. alkyl). system is selected from a naphthyl, quinolinyl or isoquinoli —NHC(O)(C. alkyl), —C(O)NH2 or —CO(C. alkyl). nyl ring: 25 wherein the (C. alkyl) is a straight, branched, or cyclic alkyl (b)R’ is hydrogen or Caliphatic and R” is T-R, or R and group; and Rare taken together with their intervening atoms to form an (e) each R is independently selected from - C1, F, optionally substituted 5-7 membered unsaturated or partially —CN. —CF, -NH2, —NH(Caliphatic), —N(Cali unsaturated ring having 0-2 ring nitrogens; phatic) —O(Caliphatic), Caliphatic, and —CO(C- (c) R' is -halo, an optionally substituted Caliphatic 30 group, phenyl, COR, OR, CN, SOR, aliphatic). - SONH, N(R), COR, CONH, -NHCOR, Representative compounds of formula II are shown below –OC(O)NH, or -NHSOR: and in Table 1. (d) R' is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 35 TABLE 1 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 carbocycloring. More preferred compounds of formula II have one or more, 40 and more preferably all, of the features selected from the group consisting of (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 45 system is a naphthyl ring; (b) R' is hydrogen or methyl and R is R, N(R), or —OR, or R and R” are taken together with their intervening II-1 atoms to form a 5-7 membered unsaturated or partially unsat 50 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 substituted Caliphatic), N(R)N(R), -C=NN(R), C–N OR, N(R)CON(R), N(R)SON(R), 55 N(R)SOR, or OC(=O)N(R): (c) R' is -halo, a Chaloaliphatic group, a Caliphatic group, phenyl, or —CN: (d) R is hydrogen and R is hydrogen or a substituted or 60 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, pyrimido or partially unsaturated 6-membered carbocyclo ring; and 65 II-2 (e) each R is independently selected from -halo. —CN, —NO, N(R), optionally substituted C- aliphatic

US 7,473,691 B2 39 40

TABLE 1-continued TABLE 1-continued

F CH3

2 NH S. M HN N

10 NN OCH3 NN Cl 2

15 c OCH3

II-35 II-31 20 CH3

2 NH S. / HN N 25 NN Cl NN C 2 N 30

Cl II-36

II-32 35

40

45

II-37 II-33 50

55

60

II-34 65 II-38

US 7,473,691 B2 43 44

TABLE 1-continued TABLE 1-continued

10

15

II-47

II-SO

25

30

35

40 II-48 HN e

45

50

II-52

55

60

II-49 65 II-53

US 7,473,691 B2 53 54

TABLE 1-continued TABLE 1-continued

CF3 F

10

15

II-84 II-81

25

Br

30

35 NN Br

40

II-82 II-85

45

50

55

60

II-83 65 II-86

US 7,473,691 B2 57 58

TABLE 1-continued TABLE 1-continued

10

15

N II-97 II-94 20

25

F. F

30 NH S. M HN N

NN C 35 2 N

40 NO II-98

II-95

45

F 50 F

NH Sl M HN N 55

NN C 2 N 60

NH2

II-96 65 II-99 US 7,473,691 B2 59 60

TABLE 1-continued TABLE 1-continued CH

| N N H3C 2

10

15

CH

I-103 II-100

25

30

CH 35

I-104 N CF3 2 N 40

II-101 45

HC 50 F II-105

NH 55 S. M HN N

7N1SN 60 21 NN CI N 2 O N

Cl 65 II-102 I-106 US 7,473,691 B2 61 62

TABLE 1-continued TABLE 1-continued

NH 10 N / HN N 21 NN C

NN CF 15 2 N

II-107

25

30

NH S. / HN N I-111 35 21 NN CF3 Sn 2 N N

40

II-108 NN C 45

50 F I-112 F

NH 55 S. M HN N

21 NN CF3 N 2 60 N N

65 II-109 I-113

US 7,473,691 B2 65 66

TABLE 1-continued TABLE 1-continued

NH 10 N / HN N

n CF 15 2 N

II-121 I-124

25

MeOC 30

NH S. M HN N

35 NN CF 2 N

40

II-122 I-125 45

50

NH N / 55 HN N

NN CF Cl 2 N 60

II-123 65 I-126 US 7,473,691 B2 67 68

TABLE 1-continued TABLE 1-continued

NH S. M 10 HN N

N 2 NN N 2 N N

FC FC

IL-127 20 I-130

25

F. F

30 NH S. M HN N

35

40

II-128 I-131

45

50

55

60

FC

65 I-132

US 7,473,691 B2 75 76

TABLE 1-continued TABLE 1-continued

Me

e NH S. M HN N 10 n CF HN 2 N

15 NH

I-156 HN

II-153

25

F

30 NH S. M HN N

N21 NN CF 35 lsN N2

40

II-154 I-157

45

50

NH 55 S. M HN N

N21 NN CF3

60 ls 2 HN N N

IL-155 65 I-158 US 7,473,691 B2 77 78

TABLE 1-continued TABLE 1-continued

NH S. / HN N 10

NN CF3 2 N 15

O

I-162

HN

II-159

25

F 30

NH S. M I-163 HN N 35 N21 NN CF

MeOls N N 2 40

II-160 45

50 I-164

NH 55 S. M HN N

N21 NN CF3 60

EtS

65 II-161

US 7,473,691 B2 85 86

TABLE 1-continued TABLE 1-continued

NH S. M 10 HN N AcNH NN 2 15 N N

Cbz1 Nu CF II-190

II-187

25

MeSONH

30 NH S. M HN N

NN II-191 35 2 N N MeO.S1 - CF 40

II-188 NH2

45

II-192 50

NH S. M HN N 55 NN 2 N N 60

CH-1 Nu CF:

II-189 65 II-193

US 7,473,691 B2 89 90

TABLE 1-continued TABLE 1-continued

NH S. M 10 HN N

Me NN C

2 15 N

II-201

II-204

25

NH N / HN N 30

n HN N 35 NN 4. 21N 5 40 N

45 II-205

F 50

NH N / NH HN N HN N/ 55 n N NN % 21N 60 N

65 US 7,473,691 B2 91 92

TABLE 1-continued TABLE 1-continued

F

10

15

II-210

25

CH3

30 M

4.NNHN 35

40

II-211 II-208

45

50

55

60

II-209 65 II-212

US 7,473,691 B2 95 96

TABLE 1-continued TABLE 1-continued

NH 10 S. M HN N

21 NN CI 15 N N N2

II-223 II-220

25

30

NH S. M HN N

35

40

II-221 II-224

45

50

55

60

65 II-222 II-225

US 7,473,691 B2 101 102

TABLE 1-continued TABLE 1-continued

10

Cl

II-238 II-241

25

35

40 Cl

II-242 II-239 45

50

55

60

II-240 65 II-243 US 7,473,691 B2 103 104

TABLE 1-continued TABLE 1-continued F

NH N / 10 HN N

NN SONH2 NN CN 2 N 15

II-247

II-244

NH S. M 25 HN N

NN SONH2 2 30 N

II-248 NN CN 35

NH OCH 40 S. M HN N

II-245 NN SON(Me) 45 2 N

II-249 50 F

55 NH S. M HN N

60 NN SON(Me) 2

65 II-246 US 7,473,691 B2 105 106 method comprising the step of administering to a patient in TABLE 1-continued need of such a treatmentatherapeutically effective amount of a composition comprising a compound of formula II. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases Such as rheumatoid NH arthritis. S. M HN N Another method relates to inhibiting GSK-3, Aurora, or 10 CDK-2 activity in a biological sample, which method com HC prises contacting the biological sample with the GSK-3 or NN CF Aurora inhibitor of formula II, or a pharmaceutical composi tion thereof, in an amount effective to inhibit GSK-3, Aurora 2 or CDK-2. N 15 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 preferred compound of formula II, as described above. Another embodiment of this invention relates to com In another embodiment, this invention provides a compo pounds of formula III: sition comprising a compound of formula II and a pharma ceutically acceptable carrier. III One aspect of this invention relates to a method of inhibit R2 ing GSK-3 activity in a patient, comprising administering to 25 R2 the patient a therapeutically effective amount of a composi e tion comprising a compound of formula II. NH Another aspect relates to a method of treating a disease that S. M is alleviated by treatment with a GSK-3 inhibitor, said method HN N comprising the step of administering to a patient in need of 30 RX Such a treatment a therapeutically effective amount of a com n N position comprising a compound of formula II. Another aspect relates to a method of enhancing glycogen 2 synthesis and/or lowering blood levels of glucose in a patient Ry N in need thereof, comprising administering to said patient a 35 therapeutically effective amount of a composition comprising a compound of formula II. This method is especially useful or a pharmaceutically acceptable derivative or prodrug for diabetic patients. thereof, wherein: Another aspect relates to a method of inhibiting the pro Ring D is a 5-7 membered monocyclic ring or 8-10 membered duction of hyperphosphorylated Tau protein in a patient in 40 bicyclic ring selected from aryl, heteroaryl, heterocyclyl or need thereof, comprising administering to said patient a carbocyclyl, said heteroaryl or heterocyclyl ring having therapeutically effective amount of a composition comprising 1-4 ring heteroatoms selected from nitrogen, oxygen or a compound of formula II. This method is especially useful in sulfur, wherein Ring D is substituted at any substitutable halting or slowing the progression of Alzheimer's disease. ring carbon by oxo or -R and at any substitutable ring Another aspect relates to a method of inhibiting the phos 45 phorylation off-catenin in a patient in need thereof, compris nitrogen by —R' provided that when Ring D is a six ing administering to said patient a therapeutically effective membered arylor heteroaryl ring, -R is hydrogen at each amount of a composition comprising a compound of formula ortho carbon position of Ring D; II. This method is especially useful for treating schizophre R and Rare taken together with their intervening atoms to form a fused, benzo ring or a 5-8 membered carbocyclo nia. 50 One aspect of this invention relates to a method of inhibit ring, wherein any Substitutable carbon on said fused ring ing Aurora activity in a patient, comprising administering to formed by R and R” is substituted by oxo or T-R: the patient a therapeutically effective amount of a composi T is a valence bond or a C alkylidene chain; tion comprising a compound of formula II. RandR are independently selected from R,-T-W R. Another aspect relates to a method of treating a disease that 55 or R and R are taken together with their intervening is alleviated by treatment with an Aurora inhibitor, said atoms to form a fused, 5-8 membered, unsaturated or par method comprising the step of administering to a patient in tially unsaturated, ring having 0-3 ring heteroatoms need of such a treatmentatherapeutically effective amount of selected from nitrogen, oxygen, or Sulfur, wherein each a composition comprising a compound of formula II. This substitutable carbon on said fused ring formed by R and method is especially useful for treating cancer, Such as colon, 60 R’ is substituted by halo, oxo. —CN, NO, R', or ovarian, and breast cancer. —V R', and any substitutable nitrogen on said ring One aspect of this invention relates to a method of inhibit formed by RandR is substituted by R: ing CDK-2 activity in a patient, comprising administering to R is selected from R, -halo, =O. —OR, —C(=O)R, the patient a therapeutically effective amount of a composi —COR, COCOR, COCHCOR, NO. —CN, tion comprising a compound of formula II. 65 —S(O)R, S(O).R. —SR, N(R), —CON(R), Another aspect relates to a method of treating a disease that - SON(R), OC(=O)R, N(R)COR, N(R)CO, is alleviated by treatment with a CDK-2 inhibitor, said (optionally substituted Caliphatic), N(R)N(R), US 7,473,691 B2 107 108 C=NN(R), C–N OR, N(R)CON(R), lidinyl, OPh, CF, C=CH, Cl, Br, F, I, NH, C(O)CH, i-pro N(R)SON(R), N(R)SOR, or - OC(=O) pyl, tert-butyl, SEt, OMe, N(Me), methylene dioxy, and N(R): ethylene dioxy. each R is independently selected from hydrogen oran option Preferred rings formed when the R and R' groups of for ally substituted group selected from Caliphatic, Co mula III are taken together to form a fused ring include a 5-, aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero 6-, or 7-membered unsaturated or partially unsaturated car cyclyl ring having 5-10 ring atoms; bocyclo ring, wherein any Substitutable carbon on said fused each R is independently selected from R', COR7. ring is substituted by oxo or T-R. Examples of preferred —CO (optionally substituted Caliphatic), —CON bicyclic ring systems are shown below. (R), or - SOR", or two R on the same nitrogen are 10 taken together to form a 5-8 membered heterocyclyl or III-A heteroaryl ring; R2 each R is independently selected from —R, halo, —OR, R2 - C(=O)R, COR, COCOR, NO, CN, S(O) e R, -SOR. -SR, N(R), —CON(R), -SO, 15 NH N(R), OC(=O)R, N(R)COR, N(R)CO (op S. M tionally substituted C- aliphatic), N(R)N(R), HN N C=NN(R) - C=N OR, N(R)CON(R), N(R)SON(R), N(R)SOR, or OC(=O)N NN (R): 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) III-B SON(R) , N(R)N(R) C(O)N(R) OC (O)N(R)-, - C(R)-O-, - C(R) S , C(R), 25 SO-, - C(R)SO. , —C(R)SON(R) -, - C(R) N(R) C(R)N(R)C(O) , C(R)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) ; 30 W is C(R)-O-, -C(R) S – C(R) SO = C(R) SO. , —C(R)SON(R)-, - C(R)N(R) , —CO-, -CO. , —C(R)OC(O) , —C(R)OC(O)N III-C (R) C(R)N(R)CO C(R)N(R)C(O)C) , C(R)=NN(R) , C(R)-N-O C(R)-N 35 (R)N(R) C(R)N(R)SON(R) C(R)-N (R)CON(R) , or CONCR) ; each R is independently selected from hydrogen or an optionally substituted Caliphatic group, or two R' groups on the same nitrogen atom are taken together with 40 the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and III-F each R" is independently selected from hydrogen or an optionally substituted Caliphatic group, or two R' on the 45 same nitrogen are taken together with the nitrogen to form 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 50 rings. When two adjacent Substituents on Ring D are taken together to form a fused ring, the Ring D System is bicyclic. III-I Preferred formula III Ring D bicyclic rings include 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2.3- dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinoli 55 nyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D Systems include naphthyl and isoquinolinyl. Preferred R substituents on Ring D of formula III include halo, oxo, CN, NO, N(R) - COR, CONH(R), N(R)COR, SON(R), N(R)SOR, SR, OR, 60 —C(O)R, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Co aryl, or Caliphatic. More preferred R substituents include -halo. —CN, -oxo, Preferred substituents on the R/R' fused ring of formula —SR, OR, N(R), —C(O)R, or a substituted or unsub III include —R, oxo, halo, —OR, —C(=O)R. —COR, stituted group selected from 5-6 membered heterocyclyl, 65 - COCOR, NO, CN, -S(O)R, -SOR, SR, Co aryl, or Caliphatic. Examples of Ring DSubstituents - N(R) - CONCR), -SON(R) - OC(=O)R, include —OH, phenyl, methyl, CH-OH, CH2CH2OH. pyrro - N(R)COR, N(R)CO,(optionally substituted Cali US 7,473,691 B2 109 110 phatic), N(R)N(R), -C=NN(R), -C=N OR, —CO (C. alkyl). —CN. —SO(C. alkyl). —SONH2, N(R)CON(R), N(R)SON(R), N(R)SOR, or —OC(O)NH, -NHSO(C. alkyl), NHC(O)(C. –OC(=O)N(R), wherein R and Rare as defined above. alkyl), —C(O)NH2, and—CO(C-alkyl), wherein the (Ca More preferred substituents on the R/R' fused ring include alkyl) is a straight, branched, or cyclic alkyl group. Prefer halo, CN, Oxo, Ce alkyl, Calkoxy, (C. alkyl)carbonyl, ably, the (C. alkyl) group is methyl. (C. alkyl)sulfonyl, mono- or dialkylamino, mono- or Preferred formula III compounds have one or more, and dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, more preferably all, of the features selected from the group or 5-6 membered heteroaryl. Examples of such preferred consisting of: Substituents include methoxy, methyl, isopropyl, methylsul (a) Ring D is an optionally Substituted ring selected from a fonyl, cyano, chloro, pyrrolyl, methoxy, ethoxy, ethylamino, 10 phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thie acetyl, and acetamido. nyl, azepanyl, morpholinyl, 1.2.3,4-tetrahydroisoquinolinyl, Preferred R substituents of formula III include hydrogen, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, C. aliphatic, alkoxycarbonyl, (un)Substituted phenyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naph hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialky thyl ring; laminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylami 15 (b) R' and R” are taken together with their intervening noalkyl, phenylaminocarbonyl, and (N-heterocyclyl)carbo atoms to form an optionally substituted benzo ring or a 5-7 nyl. Examples of such preferred R substituents include membered carbocycloring; and methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclo (c) R is hydrogen or methyl and R is T-W-R or R, pentyl, phenyl, COH, COCH, CHOH, CHOCH, wherein W is C(R)-O-, - C(R)N(R)-, -CO , CHCHCH-OH, CHCHCHOCH, —CO , C(R)OC(O) , C(R)N(R)CO , CHCHCHOCHPh. CHCHCH-NH. - C(R)N(R)C(O)O , or -CONCR) , and R is an CHCHCH-NHCOOC(CH), CONHCH(CH), optionally substituted group selected from Caliphatic or CONHCH-CH=CH, CONHCHCHOCH, phenyl, or RandR are taken together with their intervening CONHCHPh, CONH(cyclohexyl), CONOEt), CONCH.) atoms to form a substituted or unsubstituted benzo, pyrido, CHPh. CONH(n-CH), CON(Et)CHCHCH 25 pyrimido, or partially unsaturated 6-membered carbocyclo CONHCHCH(CH), CONCn-CH), CO(3-methoxym r1ng. ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), More preferred compounds of formula III have one or CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- more, and more preferably all, of the features selected from yl), CONHCHCH-OH, CONH2, and CO(piperidin-1-yl). the group consisting of When the R and R groups of formula III are taken 30 (a) Ring D is an optionally Substituted ring selected from together to form a ring, preferred R/R ring systems con phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, mor taining the pyrazole ring include benzo, pyrido, pyrimido, pholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahyd 3-oxo-2H-pyridazino, and a partially unsaturated 6-mem roquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-in bered carbocyclo ring. Examples of such preferred R/R dolyl, isoquinolinyl, quinolinyl, or naphthyl; ring systems containing the pyrazole ring include the follow 35 (b) R' and R are taken together with their intervening 1ng: atoms to form a benzo ring or a 5-7 membered carbocyclo ring optionally substituted with —R, oxo, halo. —OR, - C(=O)R, COR, COCOR, NO, CN, -S(O)R, —SOR, SR, N(R), —CON(R), -SON(R), N1 N. 40 –OC(=O)R, N(R)COR, N(R)CO,(optionally sub stituted 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); and (c) each R is independently selected from halo, oxo, CN, 45 NO, N(R), COR, CONH(R), N(R)COR, —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 more, and more preferably all, of the features selected from the group consisting of (a) R' and R are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, 55 C. alkyl, Ce alkoxy, (C. alkyl)carbonyl, (C. alkyl)sul fonyl, mono- or dialkylamino, mono- or dialkylaminocarbo nyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; (b) each R is independently selected from -halo. —CN, 60 -oxo, SR, OR, N(R), —C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocy clyl, Co-o aryl, or Caliphatic; and (c) R is hydrogen and R is selected from R is hydrogen or methyl and R is T-W R or R, wherein W is C(R) Preferred substituents on the R/R fused ring of formula 65 O-, - C(R)N(R)-, -CO-, -CO. , —C(R)OC III include one or more of the following: -halo, N(R), (O) = C(R)N(R)CO , or -CON(R)—, and R is an —C alkyl, —C haloalkyl, - NO. —O(C. alkyl). optionally substituted group selected from Caliphatic or US 7,473,691 B2 111 112 phenyl, or RandR are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated TABLE 2-continued 6-membered carbocyclo ring optionally substituted with -halo, N(R), —C, alkyl, -C, a haloalkyl, - NO. —O(C. alkyl), —CO(C. alkyl). —CN. —SO(C- alkyl). —SONH, —OC(O)NH, -NHSO(C- alkyl). —NHC(O)(C. alkyl), —C(O)NH, or —CO(C. alkyl). wherein the (C. alkyl) is a straight, branched, or cyclic alkyl group. 10 CHO Representative compounds of formula III are set forth in Table 2 below.

TABLE 2 15

III-4

25

30 III-1 C

III-5 35

40

45 AcNH

C III-2 III-6 50

55

C N 60

C

III-3 65 III-7 US 7,473,691 B2 113 114

TABLE 2-continued TABLE 2-continued

CH3 CH3

10

ENH

15 C

III-8 III-12

25

30

III-9 OCH

III-13 35

40

45

C III-10

III-14 50

55

60

C

III-11 65 III-15 US 7,473,691 B2 115 116

TABLE 2-continued TABLE 2-continued

CH CH

10

NC N

15

CH

III-19 III-16

25

30 CHO N CH3

III-20 35

OEt

40

III-17

CHO N 45

C

III-21

50

55

CHNH 60 C

CH

III-18 65 III-22 US 7,473,691 B2 117 118

TABLE 2-continued TABLE 2-continued

10

CHSO; N

15

III-23

III-27

25

30 CI

III-24 III-28 35

40

C

45 CH3 N

III-25 50

55

60

65 III-30

US 7,473,691 B2 121 122

TABLE 2-continued TABLE 2-continued CH CH

Y.M HN N 10 NN

2 O

SEt 15 N X O III-39 III-43

20 CH

Y.M HN N 25 NN 2 N 30 NMe2 III-40 III-44 35 CH3

Y./ 40 HN N NN 2 OMe CH3 45 N CH3 CH III-45 III-41 50

55 Y.M HN N NN 60 2 Cl N

Cl Cl 65 III-42 III-46

US 7,473,691 B2 139 140

TABLE 2-continued TABLE 2-continued

CH3 NC

HN YN 10 NN

es N 15 N 3.

III-103 III-107

CH3 N M HN N 25 NN

N1. N 30

III-104 III-108 35 CH3 Y. 40 HN N NN 2 N N 45

III-109 III-105 50 CH3 NC

Y,M 55 HN N NN als NN N N 60 Nals N

OH

III-106 65 III-110 US 7,473,691 B2 141 142

TABLE 2-continued TABLE 2-continued

Y.M

HN1 N 10 NN

N1. N 15 as CH3 III-111 CO 20 CH III-115

Y.M HN N 25 NN

N1. N 1)O 30 III-112 35 N es 40 Qy

III-116 45

50 III-113

55

60

OH 65 III-114 III-117 US 7,473,691 B2 143 144

TABLE 2-continued TABLE 2-continued

5 COCH3

Y.M NY. HN N HN H 10 NN n N

N1. N N1. N 15

III-118 III-122

O

Y.M N O) HN N 25 N HN N NN 2. n N 4. N 30 2 N N

III-119 35 III-123

CHOH \ 40 Y. HN N N^ HN H n N NN 2 45 N N 2 N N OH

III-12O 50 III-124

CONH N 55 N | MN N N HN N HN H n NN 2 4.Pl N 60 N 2. N

65 III-121 III-125 US 7,473,691 B2 145 146

TABLE 2-continued TABLE 2-continued CONH

Y.M HN N

NN 10

Nals N

CH3 15

III-126

F F

III-130

Y,M HN1 N 25 n 2 N 30

III-127

FC 35

Y.M 40 HN1 N

n III-131 45 2 N

III-128 50

F

55 Y.M HN1 N

NN 60 2

65 III-129 III-132 US 7,473,691 B2 147 148

TABLE 2-continued TABLE 2-continued

MeO

10

15 n N

2 N

III-133

III-136

25

C

MeO

30

C

35

n N

2 40 N

III-134

III-137 45

50 FC

55

60

65 III-13S III-138 US 7,473,691 B2 149 150

TABLE 2-continued TABLE 2-continued

PhO

Y.M HN N 10 NN s-KCH3 N 15 S.

III-142

Y,M III-139 HN N 25 NN

C Nals N

30

III-143

35

40

45

III-140 III-144

50 \ / 55 HN N

n N als Me 60 N r O esN N

Me 65 III-141 III-145 US 7,473,691 B2 151 152 One aspect of this invention relates to a method of inhibit TABLE 2-continued ing CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composi tion comprising a compound of formula III. Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatmentatherapeutically effective amount of 10 a composition comprising a compound of formula III. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, 15 alopecia, and autoimmune diseases Such as rheumatoid arthritis. One aspect of this invention relates to a method of inhibit ing Src activity in a patient, comprising administering to the III-146 patient a therapeutically effective amount of a composition comprising a compound of formula III. Another aspect relates to a method of treating a disease that In another embodiment, this invention provides a compo is alleviated by treatment with a Src inhibitor, said method sition comprising a compound of formula III and a pharma comprising the step of administering to a patient in need of ceutically acceptable carrier. 25 Such a treatment a therapeutically effective amount of a com One aspect of this invention relates to a method of inhibit position comprising a compound of formula III. This method ing GSK-3 activity in a patient, comprising administering to is especially useful for treating hypercalcemia, osteoporosis, the patient a therapeutically effective amount of a composi osteoarthritis, cancer, symptomatic treatment of bone tion comprising a compound of formula III. 30 Another aspect relates to a method of treating a disease that metastasis, and Paget’s disease. is alleviated by treatment with a GSK-3 inhibitor, said method Another method relates to inhibiting GSK-3, Aurora, comprising the step of administering to a patient in need of CDK-2, or Src activity in a biological sample, which method Such a treatment a therapeutically effective amount of a com comprises contacting the biological sample with the GSK-3, position comprising a compound of formula III. 35 Aurora, CDK-2, or Src inhibitor of formula III, or a pharma Another aspect relates to a method of enhancing glycogen ceutical composition thereof, in an amount effective to inhibit synthesis and/or lowering blood levels of glucose in a patient GSK-3, Aurora, CDK-2, or Src. in need thereof, comprising administering to said patient a Each of the aforementioned methods directed to the inhi therapeutically effective amount of a composition comprising bition of GSK-3, Aurora, CDK-2, or Src, or the treatment of a compound of formula III. This method is especially useful 40 a disease alleviated thereby, is preferably carried out with a for diabetic patients. preferred compound of formula III, as described above. Another aspect relates to a method of inhibiting the pro Compounds of formula III, wherein R is hydrogen and R' duction of hyperphosphorylated Tau protein in a patient in and Rare taken together with the pyrimidine ring to forman need thereof, comprising administering to said patient a 45 optionally Substituted quinazoline ring system, are also therapeutically effective amount of a composition comprising inhibitors of ERK-2 and AKT protein kinases. a compound of formula III. This method is especially useful Accordingly, another method of this invention relates to a in halting or slowing the progression of Alzheimer's disease. method of inhibiting ERK-2 or AKT activity in a patient, Another aspect relates to a method of inhibiting the phos 50 comprising administering to the patient a therapeutically phorylation off-catenin in a patient in need thereof, compris effective amount of a composition comprising a compound of ing administering to said patient a therapeutically effective formula III, wherein R is hydrogen and R and R” are taken amount of a composition comprising a compound of formula together with the pyrimidine ring to form an optionally Sub III. This method is especially useful for treating schizophre stituted quinazoline ring system. nia. 55 Another aspect relates to a method of treating a disease that One aspect of this invention relates to a method of inhibit is alleviated by treatment with a ERK-2 or AKT inhibitor, said ing Aurora activity in a patient, comprising administering to method comprising the step of administering to a patient in the patient a therapeutically effective amount of a composi need of such a treatmentatherapeutically effective amount of tion comprising a compound of formula III. a composition comprising a compound of formula III, Another aspect relates to a method of treating a disease that 60 wherein R is hydrogen and RandR are taken together with is alleviated by treatment with an Aurora inhibitor, said the pyrimidinering to forman optionally Substituted quinaZo method comprising the step of administering to a patient in line ring system. This method is especially useful for treating need of such a treatmentatherapeutically effective amount of cancer, stroke, hepatomegaly, cardiovascular disease, Alzhe a composition comprising a compound of formula III. This 65 imer's disease, cystic fibrosis, viral disease, autoimmune dis method is especially useful for treating cancer, Such as colon, eases, restenosis, psoriasis, allergic disorders including ovarian, and breast cancer. asthma, inflammation, and neurological disorders. US 7,473,691 B2 153 154 Another embodiment of this invention relates to com tionally substituted C- aliphatic), N(R)N(R), pounds of formula IV: C=NN(R) -C=N-OR, N(R)CON(R), N(R)SON(R), N(R)SOR, or OC(=O)N (R): IV 5 R2 V is - O -, - S -, -SO , -SO. , N(R)SO , R2 —SON(R)-, - N(R) ,-CO-, -CO. , N(R) e NH CO N(R)C(O)O N(R)CON(R) N(R) S. M SON(R) , N(R)N(R) -, -C(O)N(R)-, - OC HN N 10 (O)N(R)-, - C(R)-O-, - C(R)S , C(R) RX SO-, - C(R)SO. , C(R)SON(R)-, - C(R) n N N(R) C(R)N(R)C(O) , C(R)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 15 C(R)N(R)CON(R) ; W is C(R)-O-, -C(R)S , —C(R) SO = C(R) or a pharmaceutically acceptable derivative or prodrug SO, , –C(R)SON(R)-, - C(R)N(R)- thereof, wherein: —CO-, -CO. , C(R)OC(O) –C(R)OC(O)N Ring D is a 5-7 membered monocyclic ring or 8-10 membered (R) C(R)N(R)CO C(R)N(R)C(O)O , bicyclic ring selected from aryl, heteroaryl, heterocyclyl or C(R)=NN(R) C(R)=N. O. , C(R)-N carbocyclyl, said heteroaryl or heterocyclyl ring having (R)N(R) , C(R)N(R)SON(R) C(R)-N 1-4 ring heteroatoms selected from nitrogen, oxygen or (R)CON(R) , or CONCR) ; sulfur, wherein Ring D is substituted at any substitutable each R is independently selected from hydrogen or an ring carbon by oxo or —R, and at any substitutable ring 25 optionally substituted C. aliphatic group, or two R' nitrogen by R", provided that when Ring D is a six groups on the same nitrogen atom are taken together with membered aryl or heteroaryl ring, -R is hydrogen at each the nitrogen atom to form a 5-6 membered heterocyclyl or ortho carbon position of Ring D; heteroaryl ring; and R and Rare independently selected from T-R, or R and R' 30 are taken together with their intervening atoms to form a each R" is independently selected from hydrogen or an fused, unsaturated or partially unsaturated, 5-8 membered optionally substituted Caliphatic group, or two R7 on the ring having 1-3 ring heteroatoms selected from oxygen, same nitrogen are taken together with the nitrogen to form Sulfur, or nitrogen, wherein any Substitutable carbon on a 5-8 membered heterocyclyl ring or heteroaryl. said fused ring is optionally and independently substituted 35 Preferred formula IV Ring D monocyclic rings include by T-R, and any substitutable nitrogen on said ring is Substituted and unsubstituted phenyl, pyridinyl, piperidinyl, substituted by R: piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl T is a valence bond or a C alkylidene chain; R° and Rare independently selected from —R,-T-W R. rings. Preferred formula IV Ring D bicyclic rings include or R and R are taken together with their intervening 40 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoli atoms to form a fused, 5-8 membered, unsaturated or par nyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, iso tially unsaturated, ring containing 0-3 ring heteroatoms quinolinyl, quinolinyl, and naphthyl. Examples of more pre Selected from nitrogen, oxygen, or Sulfur, wherein said ferred Ring D bicyclic rings include naphthyl and fused ring is optionally Substituted by up to three groups isoquinolinyl. independently selected from halo, oxo. —CN, NO, 45 R', or V R: Preferred substituents on Ring D of formula IV include R iS selected from —R, -halo, =O. —OR, —C(=O)R, halo, oxo, CN, NO, N(R), —COR, CONH(R), - COR, COCOR, COCHCOR, NO. —CN, N(R)COR, SON(R), N(R)SOR, SR, OR, —S(O)R, S(O).R. —SR, N(R), —CON(R), —C(O)R, or substituted or unsubstituted group selected from - SON(R), OC(=O)R, N(R)COR, N(R)CO, 50 (optionally substituted Caliphatic), N(R)N(R), 5-6 membered heterocyclyl, Co aryl, or Caliphatic. C=NN(R) - C=N OR, N(R)CON(R), More preferred R substituents include -halo, —CN, -oxo, N(R)SON(R), N(R)SOR, or OC(=O)N —SR, OR, N(R), —C(O)R, or a substituted or unsub (R): stituted group selected from 5-6 membered heterocyclyl, each R is independently selected from hydrogen oran option 55 Caryl, or Caliphatic. Examples of Ring D substituents ally substituted group selected from Caliphatic, Co include —OH, phenyl, methyl, CHOH, CHCH-OH. pyrro aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero lidinyl, OPh, CF, C=CH, Cl, Br, F, I, NH, C(O)CH, i-pro cyclyl ring having 5-10 ring atoms; pyl, tert-butyl, SEt, OMe, N(Me), methylene dioxy, and each R" is independently selected from R", COR". ethylene dioxy. —CO(optionally substituted C- aliphatic), —CON 60 (R), or - SOR", or two R on the same nitrogen are When the R and R' groups of formula IV are taken taken together to form a 5-8 membered heterocyclyl or together to form a fused ring, preferred R/R' rings include a heteroaryl ring; 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated each R is independently selected from —R, halo, OR, ring having 1-2 heteroatoms. This provides a bicyclic ring - C(=O)R, COR, COCOR, NO, CN, S(O) 65 system containing the pyrimidinering. Examples of preferred R, -SOR, SR, N(R), —CON(R), -SO, pyrimidine ring systems of formula IV are the mono- and N(R), OC(=O)R, N(R)COR, N(R)CO, (op bicyclic systems shown below.

US 7,473,691 B2 157 158

-continued -continued

10

IW-S 15

Iv. T 25

30

35 IV-AA

40

45 IV-V IV-BB

50

55

IV-CC

60

65 US 7,473,691 B2 159 160

-continued IV-DD -continued N1\ | N le e NH NH N / N / N N 10 and

More preferred pyrimidine ring systems of formula IV Preferred substituents on the R/R fused ring of formula include IV-E, IV-G, IV-H, IV.-J., IV-K, IV-L, IV-M, IV-T, and 15 IV include one or more of the following: -halo, N(R), IV-U. —C alkyl, —C haloalkyl, - NO. —O(C. alkyl). In the monocyclic pyrimidine ring system of formula IV. —CO (C. alkyl). —CN. —SO(C. alkyl). —SONH2, preferred RX groups include hydrogen, amino, nitro, alkyl- or —OC(O)NH, -NHSO(C. alkyl), NHC(O)(C. dialkylamino, acetamido, or a Caliphatic group Such as alkyl), —C(O)NH2, and—CO(C-alkyl), wherein the (Ca methyl, ethyl, cyclopropyl, isopropyl or t-butyl. Preferred R' alkyl) is a straight, branched, or cyclic alkyl group. Prefer groups include T-R wherein T is a valence bond or a meth ably, the (C. alkyl) group is methyl. ylene, and R is R, N(R), or -OR. When Ris-R or When the pyrazole ring system of formula IV is monocy —OR, a preferred R is an optionally substituted group clic, preferred R groups include hydrogen, a substituted or selected from Caliphatic, phenyl, or a 5-6 membered het 25 unsubstituted group selected from aryl, heteroaryl, or a C eroaryl or heterocyclyl ring. Examples of preferred Rygroups aliphatic group. Examples of such preferred R groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, include methyl, t-butyl, —CHOCH cyclopropyl, furanyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, aceta thienyl, and phenyl. A preferred R group is hydrogen. mido, optionally Substituted phenyl Such as phenyl, methox Preferred formula IV compounds have one or more, and yphenyl, trimethoxyphenyl, or halo-substituted phenyl, and 30 more preferably all, of the features selected from the group methoxymethyl. consisting of: In the bicyclic pyrimidine ring system of formula IV, the (a) Ring D is an optionally substituted ring selected from a ring formed when RX and Ry are taken together may be phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thie substituted or unsubstituted. Suitable substituents include nyl, azepanyl, morpholinyl, 1.2.3,4-tetrahydroisoquinolinyl, -R, halo, OR, C(=O)R, COR, COCOR, NO, 35 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, CN, -S(O)R, -SOR, -SR, N(R), —CON(R), 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naph - SON(R), OC(=O)R, N(R)COR, N(R)CO, (optionally substituted C- aliphatic), N(R)N(R), thyl ring; C=NN(R), -C=N OR, N(R)CON(R), (b)R’ is hydrogen or Caliphatic and R is T-R or R and N(R)SON(R), N(R)SOR, or OC(=O)N(R), 40 Rare taken together with their intervening atoms to form an wherein R and R are as defined above for compounds of optionally substituted 5-7 membered unsaturated or partially formula IV. Preferred R/R' ring substituents include -halo, unsaturated ring having 1-2 ring heteroatoms; and R, OR, COR, COR, CONCR), —CN, or (c) R' is hydrogen or methyl and R is T-W-R or R, —N(R), wherein R is a substituted or unsubstituted C. wherein W is C(R)-O-, - C(R)N(R)-, -CO , aliphatic group. 45 —CO , C(R)OC(O) , C(R)N(R)CO , The RandR groups of formula IV may be taken together - C(R)N(R)C(O)O , or -CONCR) , and R is an to form a fused ring, thus providing a bicyclic ring system optionally substituted group selected from Caliphatic or containing a pyrazole ring. Preferred fused rings include phenyl, or RandR are taken together with their intervening benzo, pyrido, pyrimido, and a partially unsaturated 6-mem atoms to form a Substituted or unsubstituted benzo, pyrido, bered carbocycloring. These are exemplified in the following 50 pyrimido, or partially unsaturated 6-membered carbocyclo formula IV compounds having a pyrazole-containing bicy r1ng. clic ring system: More preferred compounds of formula IV have one or more, and more preferably all, of the features selected from the group consisting of (a) Ring D is an optionally Substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, mor pholinyl, 1.2.3,4-tetrahydroisoquinolinyl, 1.2.3,4-tetrahyd roquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-in S. NH dolyl, isoquinolinyl, quinolinyl, or naphthyl; HN N | N N i N 60 (b) R' is hydrogen or methyl and R is R, N(R), or —OR, or R and R” are taken together with their intervening RX n N le le atoms to form a 5-7 membered unsaturated or partially unsat NH NH urated ring having 1-2 ring nitrogens, wherein said ring is Ry N 65 optionally substituted with —R, halo, oxo, —OR, —C(=O) 1so s s R, COR, COCOR, NO, CN, -S(O)R, -SOR, —SR, N(R), —CON(R), -SON(R), —OC(=O) US 7,473,691 B2 161 162 R, N(R)COR, N(R)CO(optionally substituted C. aliphatic), N(R)N(R) -C=NN(R), -C=N OR, TABLE 3-continued N(R)CON(R), N(R)SON(R), N(R)SOR, or –OC(=O)N(R); and CH3 (c) each R is independently selected from halo, oxo, CN, e N, N(R), CO.R, CONH(R), N(R)COR, NH S. M —SON(R) - N(R)SOR, SR, OR, C(O)R, or a HN N substituted or unsubstituted group selected from 5-6 mem 10 bered heterocyclyl, Co aryl, or Caliphatic. n Even more preferred compounds of formula IV have one or more, and more preferably all, of the features selected from MeO 2 the group consisting of N 15 (a) R' and R” are taken together with their intervening MeO C atoms to form a 6-membered unsaturated or partially unsat urated ring having 1-2 ring nitrogens, optionally substituted OMe with halo, CN, Oxo, Ce alkyl, Calkoxy, (C. alkyl)car IV-2 bonyl, (Calkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, CH3 or 5-6 membered heteroaryl; e (b) each R is independently selected from -halo, —CN, NH S. M -oxo, SR, OR, N(R), —C(O)R, or a substituted or HN N unsubstituted group selected from 5-6 membered heterocy 25 clyl, Co aryl, or Caliphatic; and AcNH NN (c) R' is hydrogen and R is T-W R or R, wherein W is —C(R)-O , —C(R)N(R) , —CO , —CO , 2 C(R)OC(O) C(R)N(R)CO , or CONCR) , 30 S N and R is an optionally substituted group selected from C. aliphatic or phenyl, or RandR are taken together with their intervening atoms to form a benzo, pyrido, or partially unsat IV-3 urated 6-membered carbocyclo ring optionally substituted 35 CH3 with -halo, Oxo, N(R), —C, alkyl, -Cia haloalkyl, e —NO. —O(C. alkyl). —CO(C. alkyl). —CN, -SO NH (C. alkyl). —SONH —OC(O)NH, NHSO(C- S. M HN N alkyl), NHC(O)(C. alkyl). —C(O)NH, or —CO(C- 40 alkyl), wherein the (C. alkyl) is a straight, branched, or cyclic alkyl group. Representative compounds of formula IV are set forth in r N1. N Table 3 below. 45

TABLE 3 CH3

IV-4 CH3 50 CH3

e NH S. M HN N 55 ON r Nals N 60 CH IV-1 US 7,473,691 B2 163 164

TABLE 3-continued TABLE 3-continued

CH3

10

15 CH

IV-6 CH

IV-10

25

30

CH

IV-7 35 COMe

40

IV-11

45

IV-8 50

55

60

65 IV-12

US 7,473,691 B2 167 168

TABLE 3-continued TABLE 3-continued

CH3 CH3

10

CF 15

IV-20 IV-24

25

30 CH

CH3 IV-25

IV-21 35

40

MeO 2 45

IV-26 IV-22 50

55

60

CH3

IV-23 65 IV-27 US 7,473,691 B2 169 170

TABLE 3-continued TABLE 3-continued

NH S. M HN N 10 NN MeO 2 N 15

IV-32 IV-28

CH3

e NH S. M 25 HN N S NN

N 2 30 N 21 CH3

N-N IV-33

IV-29 35 In another embodiment, this invention provides a compo sition comprising a compound of formula IV and a pharma CH ceutically acceptable carrier. One aspect of this invention relates to a method of inhibit e ing GSK-3 activity in a patient, comprising administering to NH 40 S. M the patient a therapeutically effective amount of a composi HN N tion comprising a compound of formula IV. Another aspect relates to a method of treating a disease that 21 NN is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of N 2 45 Such a treatment a therapeutically effective amount of a com N N position comprising a compound of formula IV. Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient 50 in need thereof, comprising administering to said patient a IV-30 therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful CH3 for diabetic patients. Another aspect relates to a method of inhibiting the pro e NH 55 duction of hyperphosphorylated Tau protein in a patient in S. M need thereof, comprising administering to said patient a HN N therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful in 21 NN halting or slowing the progression of Alzheimer's disease. 60 Another aspect relates to a method of inhibiting the phos N 2 phorylation off-catenin in a patient in need thereof, compris N N ing administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating schizophre 65 18. IV-31 One aspect of this invention relates to a method of inhibit ing Aurora activity in a patient, comprising administering to US 7,473,691 B2 171 172 the patient a therapeutically effective amount of a composi Ring D is a 5-7 membered monocyclic ring or 8-10 membered tion comprising a compound of formula IV. bicyclic ring selected from aryl, heteroaryl, heterocyclyl or Another aspect relates to a method of treating a disease that carbocyclyl, said heteroaryl or heterocyclyl ring having is alleviated by treatment with an Aurora inhibitor, said 1-4 ring heteroatoms selected from nitrogen, oxygen or method comprising the step of administering to a patient in 5 sulfur, wherein Ring D is substituted at any substitutable need of such a treatmentatherapeutically effective amount of ring carbon by oxo or -R, and at any substitutable ring a composition comprising a compound of formula IV. This nitrogen by R. provided that when Ring D is a six method is especially useful for treating cancer, Such as colon, membered arylor heteroaryl ring, -R is hydrogen at each ovarian, and breast cancer. ortho carbon position of Ring D; One aspect of this invention relates to a method of inhibit 10 R" is selected from -halo, —CN, NO, T-V R, phenyl, ing CDK-2 activity in a patient, comprising administering to 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl the patient a therapeutically effective amount of a composi ring, or Caliphatic group, said phenyl, heteroaryl, and tion comprising a compound of formula IV. heterocyclyl rings each optionally Substituted by up to Another aspect relates to a method of treating a disease that three groups independently selected from halo, oxo, or is alleviated by treatment with a CDK-2 inhibitor, said 15 —R. said Caliphatic group optionally substituted with method comprising the step of administering to a patient in halo, cyano, nitro, or oxygen, or R' and an adjacent Sub need of such a treatmentatherapeutically effective amount of stituent taken together with their intervening atoms form a composition comprising a compound of formula IV. This said ring fused to Ring C: method is especially useful for treating cancer, Alzheimer's R and Rare independently selected from T-R, or R and R' disease, restenosis, angiogenesis, glomerulonephritis, are taken together with their intervening atoms to form a cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, fused, unsaturated or partially unsaturated, 5-8 membered alopecia, and autoimmune diseases Such as rheumatoid ring having 0-3 ring heteroatoms selected from oxygen, arthritis. Sulfur, or nitrogen, wherein any Substitutable carbon on Another method relates to inhibiting GSK-3, Aurora, or said fused ring formed by RandR is substituted by oxo or CDK-2 activity in a biological sample, which method com 25 T-R, and any substitutable nitrogen on said ring formed by prises contacting the biological sample with the GSK-3 or R and R” is substituted by R: Aurora inhibitor of formula IV, or a pharmaceutical compo T is a valence bond or a C alkylidene chain; sition thereof, in an amount effective to inhibit GSK-3, R° and Rare independently selected from —R,-T-W R. Aurora or CDK-2. or R and R are taken together with their intervening Each of the aforementioned methods directed to the inhi 30 atoms to form a fused, 5-8 membered, unsaturated or par bition of GSK-3, Aurora or CDK-2, or the treatment of a tially unsaturated, ring having 0-3 ring heteroatoms disease alleviated thereby, is preferably carried out with a selected from nitrogen, oxygen, or sulfur, wherein each preferred compound of formula IV, as described above. substitutable carbon on said fused ring formed by R and Another embodiment of this invention relates to com R’ is substituted by halo, oxo, —CN, NO, R', or 35 —V-R, and any substitutable nitrogen on said ring pounds of formula V: formed by RandR is substituted by R: R is selected from-R,-halo, —OR, —C(=O)R, CO.R. V —COCOR, COCHCOR, NO, CN, -S(O)R, R2 —S(O).R.—SR, N(R), CONCR), -SON(R), R2. 40 –OC(=O)R, N(R7)COR, N(R7)CO,(optionally e substituted Caliphatic), N(R)N(R), -C=NN NH (R), -C=N OR, N(R7)CON(R7), N(R7)SON N / (R) - N(R)SOR, or—OC(=O)N(R): HN N each Ris independently selected from hydrogen oran option RX 45 ally substituted group selected from Caliphatic, Co N72 aryl, a heteroaryl ring having 5-10 ring atoms, or a hetero cyclyl ring having 5-10 ring atoms; 2 Ry Zl each R" is independently selected from R", COR". —CO (optionally substituted Caliphatic), —CON 50 (R), or - SOR", or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or or a pharmaceutically acceptable derivative or prodrug heteroaryl ring; thereof, wherein: each R is independently selected from R, halo, —OR, Z' is N, CR, or CH and Z is N or CH, provided that one of —C(=O)R, COR, COCOR, NO, CN, S(O) Z" and Z is nitrogen; 55 R, -SOR. -SR, N(R), —CON(R), -SON G is Ring C or Ring D; (R), —OC(=O)R, N(R)COR, N(R)CO,(option Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, ally substituted Caliphatic), N(R)N(R), -C=NN pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said (R) -C=N OR, N(R)CON(R), N(R)SON Ring C has one or two ortho substituents independently (R) - N(R)SOR, or - OC(=O)N(R), or Rand an selected from R', any substitutable non-ortho carbon 60 adjacent Substituent taken together with their intervening position on Ring C is independently substituted by R. atoms form said ring fused to Ring C: and two adjacent Substituents on Ring C are optionally V is —O— —S— —SO— —SO , —N(R)SO , taken together with their intervening atoms to form a fused, —SON(R)-, - N(R) ,-CO-, -CO, , – N(R) unsaturated or partially unsaturated, 5-6 membered ring CO N(R)C(O)O N(R)CON(R) N(R) having 0-3 heteroatoms selected from oxygen, Sulfur or 65 SON(R) , N(R)N(R) C(O)N(R) OC nitrogen, said fused ring being optionally Substituted by (O)N(R)-, - C(R),O C(R)S C(R) halo, oxo, or—R; SO , —C(R)SO. , —C(R)SO.N(R) , US 7,473,691 B2 173 174 C(R)N(R) C(R)N(R)C(O) C(R)-N (R)C(O)O - C(R)=NN(R) - C(R)—N O , -continued WC C(R)N(R)N(R) C(R)N(R)SON(R) , or R 2 C(R)N(R)CON(R) ; R2 W is C(R)-O-, -C(R).S. , C(R) SO = C(R) e NH. SO. , —C(R)SON(R)-, - C(R)N(R) , S- M —CO-, -CO. , —C(R)OC(O) , —C(R)OC(O)N HN N (R) , C(R)N(R)CO C(R)N(R)C(O)O , RX n C(R)=NN(R) , C(R)-N-O C(R)-N 10 N (R)N(R) C(R)N(R)SON(R) C(R)-N (R)CON(R) , or CONCR) ; Ry 2 each R is independently selected from hydrogen, an option ally substituted Caliphatic group, or two R' groups on Ra the same nitrogenatom are taken together with the nitrogen 15 atom to form a 5-6 membered heterocyclyl or heteroaryl ring: When the RandR' groups of formula Vare taken together to form a fused ring, preferred R/R' rings include a 5-, 6-, 7 each R" is independently selected from hydrogen or an or 8-membered unsaturated or partially unsaturated ring hav optionally substituted Caliphatic group, or two R7 on the ing 0-2 heteroatoms, wherein said R/R' ring is optionally same nitrogen are taken together with the nitrogen to form Substituted. This provides a bicyclic ring system containing a a 5-8 membered heterocyclyl or heteroaryl ring: pyridine ring. Examples of preferred bicyclic ring systems of each R is independently selected from an optionally substi formula V are shown below. tuted Caliphatic group, —OR. —SR, COR. 25 - SOR. - N(R) - N(R)N(R) - CN, NO, Wa-A —CON(R), or -COR; and R2 R2 R" is selected from halo. —OR, —C(=O)R. —COR, e - COCOR, NO. —CN, -S(O)R, -SOR, SR, 30 NH - N(R), —CON(R), -SON(R), —OC(=O)R, S. M N(R)COR, N(R)CO(optionally substituted C. HN N aliphatic), N(R)N(R), -C=NN(R), -C=N- OR, N(R)CON(R), N(R)SON(R), N(R) 35 SOR, —OC(=O)N(R), or an optionally substituted r2 group selected from Caliphatic, Cao aryl, a heteroaryl N ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms. Wb-A Compounds of formula V may be represented by specify ing Z' and Z as shown below: 40 X

Wa R2 r21 R2 45 e NH, We-A S. M HN N 50 HN RX N

2 Ry N r2 Vb 55 Ra R2 Wa-B e NH, and S. M HN N 60 R NN

Ry 21 65 US 7,473,691 B2 175 176

-continued -continued

15

Wa-E 25 Wa-C

30

35

40

45

50

55

Wa-D

60

65 US 7,473,691 B2 177 178

-continued -continued

10

We-K 15

Ra

25 Wa-L

30

35

40

45

We-L

50

55

Wa-K Wa-M

60

65 US 7,473,691 B2 179 180

-continued -continued Wb-O

HN HN

2 N N N 21 n N

S 21 10 lsN 21

WC-O

15 X X N 2 n N 2. NN ls N 2

N 21 Ra Wa-P Ra

25 Wa-N X N X 2 N N 2 30 N N

Vb-P Nr’s N 4.

35 X N

N N 2 40 Vc-P

45 C D 50 Ra (S^ More preferred bicyclic ring systems of formula Vinclude NS 2 Va-A, Vb-A, Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, 55 Va-E, Vb-E, Vc-E, Va.-J., Vb-J, Vc-J, Va-K, Vb-K, Vc-K, Va-L, Ra Vb-L, Vc-L, Va-M, Vb-M, and Vc-M, most preferably Va-A, Wa-O Vb-A, Vc-A, Va-B, Vb-B, and Vc-B. In the monocyclic pyridine ring system of formula V. pre ferred RX groups include hydrogen, alkyl- or dialkylamino, x 60 acetamido, or a Caliphatic group Such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R' groups include N21 N T-R wherein T is a valence bond or a methylene, and R is -R, N(R), or -OR. When R is - R or -OR, a pre ferred R is an optionally Substituted group selected from C. ls-- 65 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocy clyl ring. Examples of preferred R' include 2-pyridyl, 4-py ridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-bu US 7,473,691 B2 181 182 tyl, alkyl- or dialkylamino, acetamido, optionally substituted CHPh. CONH(n-CH), CON(Et)CHCHCH phenyl Such as phenyl or halo-substituted phenyl, and meth CONHCHCH(CH), CONCn-CH), CO(3-methoxym oxymethyl. ethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), In the bicyclic ring system of formula V, the ring formed CONHCH, CO(morpholin-1-yl), CO(4-methylpiperazin-1- when R and R are taken together may be substituted or 5 yl), CONHCHCH-OH, CONH, and CO(piperidin-1-yl). A unsubstituted. Suitable substituents include—R, halo, —OR, preferred R group is hydrogen. —C(=O)R, COR, COCOR, NO, CN, -S(O)R, More preferred ring systems of formula V are the follow —SOR, SR, N(R), —CON(R), -SON(R), ing, which may be substituted as described above, wherein R –OC(=O)R, N(R)COR, N(R)CO(optionally sub and Rare taken together with the pyrazole ring to form an stituted Caliphatic), -N(R)N(R), -C=NN(R), 10 optionally substituted indazole ring; and R and R” are each C–N OR, N(R)CON(R), N(R)SON(R), methyl, or R and Rare taken together with the pyridine ring -N(R)SOR, or - OC(=O)N(R), wherein R and Rare to form an optionally Substituted quinoline, isoquinoline, tet as defined above. Preferred R/R' ring substituents include rahydroquinoline or tetrahydroisoquinoline ring: -halo, R, OR, COR, COR, CONCR), CN, or —N(R) wherein Risan optionally substituted Caliphatic 15 group. The RandR groups of formula V may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-mem bered carbocycloring. These are exemplified in the following formula V compounds having a pyrazole-containing bicyclic ring system:

25

W-Bal

N / 30 HN N | N i N RX N72 le e

S. NH S. NH 35 Ry % N N N 40 le e W-Ha. NH NH N / N / N N

45 Preferred substituents on the R/Rfused ring of formula V include one or more of the following:-halo, N(R), —Ca alkyl, —Chaloalkyl, - NO. —O(Calkyl). —CO(C- alkyl), —CN, SO(C-alkyl). —SONH, OC(O)NH2, 50 —NHSO(C-alkyl), NHC(O)(Calkyl), C(O)NH2. and —CO(C. alkyl), wherein the (C. alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C. alkyl) group is methyl. When the pyrazole ring system is monocyclic, preferred R' 55 When G is Ring C, preferred formula V. Ring C groups are groups include hydrogen, Caliphatic, alkoxycarbonyl, phenyl and pyridinyl. When two adjacent substituents on (un)Substituted phenyl, hydroxyalkyl, alkoxyalkyl, ami Ring C are taken together to form a fused ring, Ring C is nocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, contained in a bicyclic ring system. Preferred fused rings alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, include a benzo or pyrido ring. Such rings preferably are and (N-heterocyclyl)carbonyl. Examples of such preferred 60 fused at ortho and meta positions of Ring C. Examples of R substituents include methyl, cyclopropyl, ethyl, isopropyl. preferred bicyclic Ring C systems include naphthyl and iso propyl, t-butyl, cyclopentyl, phenyl, COH, COCH, quinolinyl. Preferred R' groups include -halo, an optionally CHOH, CHOCH, CHCHCH-OH, CHCHCHOCH, substituted Caliphatic group, phenyl, -COR, OR, CHCHCHOCHPh. CHCHCH-NH2, —CN, -SOR. -SONH, -N (R), —COR, CHCHCH-NHCOOC(CH), CONHCH(CH), 65 CONH, NHCOR, OC(O)NH, or NHSO.R. CONHCH-CH=CH, CONHCHCHOCH, When R' is an optionally substituted Caliphatic group, the CONHCHPh, CONH(cyclohexyl), CONOEt), CONCH.) most preferred optional Substituents are halogen. Examples US 7,473,691 B2 183 184 of preferred R' groups include —CF, —Cl, F. —CN, intervening atoms to form a Substituted or unsubstituted —COCH, OCH, -OH, -CHCH, OCHCH benzo, pyrido, pyrimido or partially unsaturated 6-membered —CH, —CFCH., cyclohexyl, t-butyl, isopropyl, cyclopro carbocycloring. pyl, —C=CH, —C=C CH, -SOCH —SONH2, More preferred compounds of formula V have one or more, - N(CH), -COCH, -CONH, -NHCOCH, OC and more preferably all, of the features selected from the (O)NH, -NHSOCH, and OCF. group consisting of: On Ring Cpreferred Rsubstituents, when present, include (a) Ring C is a phenyl or pyridinyl ring, optionally Substi tuted by —R, wherein when Ring C and two adjacent sub -halo, —CN, NO, N(R), optionally substituted C stituents thereon form a bicyclic ring system, the bicyclic ring aliphatic group, —OR, —C(O)R, COR, CONHCR), 10 system is a naphthyl ring, and R' is -halo, a Chaloaliphatic -N(R)COR, -SON(R), and N(R)SO.R. More pre group, a Caliphatic group, phenyl, or —CN; or Ring Dis ferred R substituents include - C1, F. —CN, —CF, an optionally Substituted ring selected from phenyl, pyridi —NH, -NH(C. aliphatic). —N(C. aliphatic), nyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1.2, —O(C- aliphatic), Caliphatic, and —CO(C- ali 3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, phatic). Examples of such preferred R substituents include 15 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, iso Cl, F, CN, -CF, NH, -NHMe, NMe, quinolinyl, quinolinyl, or naphthyl; —OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and (b) R' is hydrogen or methyl and R is R, N(R), or —COEt. —OR, or R and R” are taken together with their intervening When G is Ring D, preferred formula V Ring D monocy atoms to form a benzo ring or a 5-7 membered partially clic rings include Substituted and unsubstituted phenyl, unsaturated carbocyclo ring, said benzo or carbocyclo ring pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, optionally substituted with —R, halo. —OR, —C(=O)R. aZepanyl, and morpholinyl rings. When two adjacent Sub —COR, COCOR, NO, CN, -S(O)R, -SOR, stituents on Ring Dare taken together to form a fused ring, the —SR, N(R), —CON(R), -SON(R), —OC(=O) Ring D system is bicyclic. Preferred formula V Ring D bicy R, N(R)COR, N(R)CO,(optionally substituted C. clic rings include 1.2.3.4—tetrahydroisoquinolinyl, 1.2.3,4- 25 aliphatic), N(R)N(R) -C=NN(R), -C=N OR, tetrahydroquinolinyl, 2.3—dihydro-1H-isoindolyl, 2,3-dihy N(R)CON(R), N(R)SON(R), N(R)SOR, or dro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. OC(=O)N(R): Examples of more preferred bicyclic Ring D systems include (c) R is hydrogen and R is hydrogen or a substituted or naphthyl and isoquinolinyl. unsubstituted group selected from aryl, or a Caliphatic Preferred substituents on Ring D of formula Vinclude one 30 group, or R and Rare taken together with their intervening or more of the following: halo, oxo, CN, NO. —N(R), atoms to form a Substituted or unsubstituted benzo, pyrido, COR, CONH(R), N(R)COR, SON(R), pyrimido or partially unsaturated 6-membered carbocyclo -N(R)SOR, -SR, OR, C(O)R, or substituted or ring; and unsubstituted group selected from 5-6 membered heterocy (d) Ring D is substituted by oxo or R, wherein each R is clyl, Co aryl, or Caliphatic. More preferred Ring D 35 independently selected from-halo. —CN, NO, N(R), substituents include -halo, —CN, -oxo, —SR, —OR, optionally Substituted Caliphatic group, —OR, —C(O)R. —N(R), —C(O)R, or a substituted or unsubstituted group COR, CONH(R), N(R)COR, -SON(R), or selected from 5-6 membered heterocyclyl, C-aryl, or C. N(R)SO.R. aliphatic. Examples of Ring D substituents include —OH, Even more preferred compounds of formula V have one or phenyl, methyl, CH-OH, CH2CH2OH. pyrrolidinyl, OPh. 40 more, and more preferably all, of the features selected from CF, CO=CH, Cl, Br, F, I, NH, C(O)CH, i-propyl, tert the group consisting of butyl, SEt, OMe, N(Me), methylene dioxy, and ethylene (a) Ring C is a phenyl or pyridinyl ring, optionally Substi dioxy. tuted by R, wherein when Ring C and two adjacent sub Preferred formula V compounds have one or more, and stituents thereon form a bicyclic ring system, the bicyclic ring more preferably all, of the features selected from the group 45 system is a naphthyl ring, and R' is -halo, a Caliphatic consisting of: group optionally Substituted with halogen, or—CN; or Ring (a) Ring C is a phenyl or pyridinyl ring, optionally Substi D is an optionally substituted ring selected from phenyl, tuted by R, wherein when Ring C and two adjacent sub pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholi stituents thereon form a bicyclic ring system, the bicyclic ring nyl, 1.2.3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro system is selected from a naphthyl, quinolinyl or isoquinoli 50 quinolinyl, isoquinolinyl, quinolinyl, or naphthyl; nyl ring, and R' is -halo, an optionally substituted Cali (b) R' is hydrogen or methyl and R' is methyl, methoxym phatic group, phenyl, -COR, OR, CN, -SO.R. ethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an - SONH, N(R), COR, CONH, -NHCOR, optionally Substituted group selected from 2-pyridyl, 4-py —OC(O)NH, or NHSOR: or Ring D is an optionally 55 ridyl, piperidinyl, or phenyl, or R and R” are taken together Substituted ring selected from a phenyl, pyridinyl, piperidi with their intervening atoms to form a benzo ring or a 6-mem nyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, bered partially unsaturated carbocyclo ring optionally Substi 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoli tuted with halo, CN, oxo, Calkyl, Calkoxy, (C. alkyl) nyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, iso carbonyl, (C. alkyl)sulfonyl, mono- or dialkylamino, quinolinyl, quinolinyl, or naphthyl ring; 60 mono- or dialkylaminocarbonyl, mono- or dialkylaminocar (b)R’ is hydrogenor Caliphatic andR is T-R, or R and bonyloxy, or 5-6 membered heteroaryl; Rare taken together with their intervening atoms to form an (c) R' and R are taken together with their intervening optionally substituted 5-7 membered unsaturated or partially atoms to form a benzo, pyrido, pyrimido or partially unsatur unsaturated ring having 0-2 ring nitrogens; and ated 6-membered carbocycloring optionally substituted with (c) R is hydrogen and R is hydrogen or a substituted or 65 -halo, N(R), —C. alkyl, -C, a haloalkyl, - NO. unsubstituted group selected from aryl, heteroaryl, or a C —O(C. alkyl). —CO(C. alkyl). —CN. —SO(C- aliphatic group, or R and R are taken together with their alkyl). —SONH2, —OC(O)NH2. —NHSO(C. alkyl). US 7,473,691 B2 185 186 —NHC(O)(C. alkyl), —C(O)NH2 or —CO(C. alkyl). wherein the (C. alkyl) is a straight, branched, or cyclic alkyl TABLE 4-continued group; and (d) Ring D is substituted by oxo or R, wherein each R is CH3 independently selected from —Cl, F. —CN, —CF, —NH2, —NH(C. aliphatic), —N(C. aliphatic), —O(C- aliphatic), Caliphatic, and —CO(C- ali phatic). Representative compounds of formula V are set forth in 10 Table 4 below.

TABLE 4

15 CH

e NH S. M HN N 2O NN 2 25

V-1 30

V-5

35 | N N le NH S. M 40 HN N

r 2 45 N

W6 50

55

60

65 V-7 US 7,473,691 B2 187 188

TABLE 4-continued TABLE 4-continued

10

15

CH

25

30

35 CH3

40

45

V-13 50

55

60

FC

V-10 65 V-14