USOO9481692B2
(12) United States Patent (10) Patent No.: US 9.481,692 B2 Jones et al. (45) Date of Patent: *Nov. 1, 2016
(54) HETEROCYCLIC MODULATORS OF HIF 31/5377 (2013.01); A61K 3.1/541 (2013.01); ACTIVITY FOR TREATMENT OF DISEASE A61K 45/06 (2013.01); C07D 405/14 (2013.01); C07D 413/04 (2013.01); C07D (71) Applicant: Board of Regents, University of Texas 413/14 (2013.01); C07D 417/04 (2013.01); System, Austin, TX (US) C07D 417/14 (2013.01); C07D 471/04 (2013.01) (72) Inventors: Philip Jones, Houston, TX (US); (58) Field of Classification Search Maria Emilia DiFrancesco, Houston, CPC ...... CO7D 413/14: A61K 31/454 TX (US); Alessia Petrocchi, Houston, See application file for complete search history. TX (US); Christopher L. Carroll, (56) References Cited Houston, TX (US); Joe Marszalek, Houston, TX (US); Barbara Czako, U.S. PATENT DOCUMENTS Houston, TX (US); Ryan Johnson, 6.300.344 B1 10, 2001 Taniguchianiguchi et allal. E. R SS Jay Theroff, 8,470,811 B2 6/2013 Härter et al. ouston, TX (US) 2004/0058964 A1 3/2004 Devadas et al. 2006/0269942 A1 11, 2006 Kolb et al. (73) Assignee: Board of Regents, The University of 2007/0105900 A1 5/2007 Berdini et al. Texas System, Austin, TX (US) 2010.0063104 A1 3/2010 Nakai et al. 2010/0249085 A1 9/2010 Boyer (*)c Notice:- r Subject to any distic the t 2011/031293.02011/030.1122 A1 12/2011 Haerter et al. patent 1s extended or adjusted under 2012/002895.0 A1 2/2012 Haerter et al. U.S.C. 154(b) by 0 days. 2013/0196964 A1 8/2013 Harter et al. Thishi patent is subjectsubi to a terminalinal dis-di 2014/00664242014/0057914 A1 3/20142/2014 Jones et al. claimer. 2014/OO73634 A1 3/2014 Jones et al. 20140329797 A1 11/2014 Herter et al. (21) Appl. No.: 14/645,591 2015,0239876 A1 8/2015 Jones et al. (22) Filed: Mar. 12, 2015 FOREIGN PATENT DOCUMENTS
O O EP 2768826 A1 8, 2014 (65) Prior Publication Data WO 97O3973 A1 2, 1997 US 2015/O252O58 A1 Sep. 10, 2015 WO WOOO16760 A2, 3, 2000 WO OO27394 A1 5.2000 O O WO WOO306823.0 A1 8, 2003 Related U.S. Application Data WO WO2005OO2576 A2 1, 2005 (63) Continuation of application No. 13/974.258, filed on WO WO2005O18557 A2 3, 2005 Aug. 23, 2013, now Pat. No. 9,018,380. (Continued) (60) gyal application No. 61/743,131, filed on Aug. OTHER PUBLICATIONS Harter Met al., “Inhibition of Hypoxia-Induced Gene Transcription (51) Int. Cl. by Substituted Pyrazolyl Oxadiazoles: Initial Lead Generation and CO7D 413/14 (2006.01) Structure—Activity Relationships' ChemMedChem 9(1):61-6, A6 IK 3L/454 (2006.01) Nov. 27, 2013. CO7D 53/04 (2006.01) Ellinghaus Pet al., "BAY 87/2243, a highly potent and selective CO7D 413/04 (2006.01) inhibitor of hypoxia-induced gene activation has antitumor activi CO7D 417/4 2006.O1 ties by inhibition of mitochondrial complex I.” Cancer Medicine CO7D 417/04 30: 8: Gatta,2(5): 611-24, A. et Aug. al., 20,“Synthesis 2013. of imidazo 1.2-cpyrazolo4.3- A6 IK 45/06 (2006.01) elpyrimidines, 1-2pyrazolo4.3-e 1,2,4-triazolo 1.5-c pyrimidines A6 IK 3/496 (2006.01) and 1,2,4-triazolo5.1-ipurines as adenosine A2 receptor antago CO7D 47L/04 (2006.01) nists.” Eur, J. Med Chern, 1993, vol. 28, pp. 569-576. A6 IK 3/42.45 (2006.01) WO2014031936A3, International Search Report, May 22, 2015. A6 IK 3/437 (2006.01) US20140.066424 Notice of Allowance, Jan. 9, 2015. A6 IK 3/4439 (2006.01) (Continued) A6 IK 3L/4545 (2006.01) A 6LX 3/59 (2006.01) Primary Examiner — Robert Havlin A 6LX 3/5.377 (2006.01) (74) Attorney, Agent, or Firm — Dennis A. Bennett; A6 IK 3/54 (2006.01) Cynthia Hathaway CO7D 405/4 (2006.01) (57) ABSTRACT (52) U.S. Cl. CPC C07D 513/04 (2013.01); A6IK3I/4245 The present invention relates to compounds and methods (2013.01); A61K 31/437 (2013.01); A61 K which may be useful as inhibitors of HIF pathway activity 31/4439 (2013.01); A61K 31/454 (2013.01); for the treatment or prevention of cancer and other hypoxia A6 IK3I/4545 (2013.01); A61K 31/496 mediated diseases. (2013.01); A61 K3I/519 (2013.01); A61 K 10 Claims, 11 Drawing Sheets US 9,481,692 B2 Page 2
(56) References Cited Institute, U.S. Pat. No. 9,115,120. Notice of Allowance, Apr. 17. 2015. Jones, Philip et al., Heterocyclic modulators of HIF activity for FOREIGN PATENT DOCUMENTS treatment of disease, Univ. Texas MD Anderson Cancer Center WO 2006O70198 A1 T 2006 Institute, WO 201403.1936 A2. International Preliminary Report on WO 2005.116736 A1 11, 2006 Patentability, publication date, Feb. 24, 2015. WO 2008145243 A2 4/2008 Jones, Philip et al., Heterocyclic modulators of HIF activity for WO 2008.005457 A2 10, 2008 treatment of disease, Univ. Texas MD Anderson Cancer Center WO 2008141731 A2 11/2008 Institute, WO 201403.1933A2. International Preliminary Report on WO WO2010O39248 A1 4/2010 Patentability, publication date, Feb. 24, 2015. WO 2010054762 A1 5, 2010 Jones, Philip et al., Heterocyclic modulators of HIF activity for WO 2010054763 A1 5, 2010 treatment of disease, Univ. Texas MD Anderson Cancer Center WO 2010054764 A1 5, 2010 Institute, WO 2014031928A1. International Preliminary Report on WO 2011141325 A1 11, 2011 Patentability, publication date, Feb. 24, 2015. WO 2011141326 A1 11, 2011 Kalluraya et al., Studies on arylthiophene heterocycles. Part 1. WO WO2O13057101 A1 4/2013 Synthesis and biological activity of Some 2-aryl/arylarnino-4-5-(p- WO 2014031928 A1 2, 2014 WO 201403.1936 A1 2, 2014 nitrophenyl)-2-thienyl) thiazoles, Oriental Journal of Chemistry WO WO2O15130790 A2 9, 2015 (1996), 12(2), 141-144, CAS Accession No. 748862. WO WO2O15130790 A3 12/2015 Nakai Hisao et al., Preparation of nitrogen-containing heterocyclic compounds as p38 MAP kinase inhibitors, STN record of WO2007040208, Acc No. 2007:410206, DN 146:421971, 2007. OTHER PUBLICATIONS Coqueron PY et al., Iterative oxazole assembly via alpha chloroglycinates: total synthesis of (-)- muscoride A., Angew Chem WO2014031933A3 International Search Report, May 22, 2014. Int Ed Engl. Mar. 28, 2003:42(12)14 11-1414. WO2014031936A3 International Search Report, May 22, 2014. Jones, Philip et al., Salts of heterocyclic modulators of hifactivity WO2014031928A3 International Search Report, May 22, 2014. for treatment of disease, Univ. Texas MD Anderson Cancer Center U.S. Appl. No. 14/800.307, filed Jul. 15, 2015, Jones, Philip et al. Institute, US 20150239876A1. Non-final rejection, Feb. 5, 2016. Jones, Philip et al., Heterocyclic modulators of HIF activity for Jones, Philip et al., Heterocyclic modulators of HIF activity for treatment of disease, Univ. Texas MD Anderson Cancer Center treatment of disease, Univ. Texas MD Anderson Cancer Center Institute, U.S. Pat. No. 9,018,380, Corrected Notice of Allowance, Institute, US 20140073634A1, Non-final rejection, Mar. 31, 2015. Mar. 3, 2015. Jones, Philip et al., Heterocyclic modulators of HIF activity for Jones, Philip et al., Heterocyclic modulators of HIF activity for treatment of disease, Univ. Texas MD Anderson Cancer Center treatment of disease, Univ. Texas MD Anderson Cancer Center Institute, US 20140073634A1, Final rejection, Oct. 22, 2015. U.S. Patent Nov. 1, 2016 Sheet 1 of 11 US 9,481,692 B2
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3. s US 9,481,692 B2 1. 2 HETEROCYCLIC MODULATORS OF HIF pathway and its downstream effector pathways, but do so in ACTIVITY FOR TREATMENT OF DISEASE the presence of oxygen creating a “pseudohypoxic' state. These subsets of tumors become dependent on the HIF This application is a continuation of U.S. application Ser. pathway for their continued growth. An example of a No. 13/974.258, filed Aug. 23, 2013, which claims the genetically driven HIF tumor indication is renal cell carci benefit of priority of U.S. provisional application No. noma (RCC), in which the tumor suppressor VHL is inac 61/743,131 filed Aug. 24, 2012, the disclosures of which are tivated by mutation, deletion or promoter hypermethylation expressly incorporated by reference as if written herein in in 70% of tumors (Kim and Kaelin, 2004). VHL inactivation their entireties. results in HIFC. stabilization that is independent of oxygen Disclosed herein are new heterocyclic compounds, com 10 concentration. In another example, tumors where either positions and their application as a pharmaceutical for the fumarate hydratase (FH) or a subunit in the succinate treatment of disease. Methods to inhibit HIF pathway activ dehydrogenase (SDH) complex is inactivated, HIFC. accu ity through the degradation of the HIFC. protein subunits in mulation occurs due to inhibition of PHDs by succinate and a human or animal Subject are also provided for the treat fumarate (Bardella et al., 2011; Gill, 2012; Isaacs et al., ment of diseases mediated by HIF pathway activity. 15 2005; Pollard et al., 2005). The lack of HIFC. hydroxylation The heterodimeric HIF transcription factor is composed prevents VHL mediated degradation. of a stable HIF1B (aka ARNT) and an oxygen regulatable In other tumors, the Pi3K pathway is frequently mutated HIFC. subunit (HIF1C. or EPAS1 (aka HIF2C)(Semenza, (ie., PTEN loss, AKT, PIK3CA, TSC1/2, LKB1 and others) 2012b). Under normal physiological conditions, the capacity ultimately leading to an increase in the activity of mamma of the cell to degrade the HIFC. subunits exceeds the amount lian target of rapaycin (mTOR), which results in an increase of HIFC. protein that is being synthesized. The HIFC. subunit in HIFC. protein translation to the point where it overwhelms is regulated by hydroxylation at two key proline residues (ie. the degradation pathway. Therefore, in tumors with active Pro' and Pro in HIF1C) by a family of proline hydroxy Pi3K pathway, HIF pathway activity is frequently increased lases (PHD1, PHD2 and PHD3), that utilize C-ketoglutarate (Wouters and Koritzinsky, 2008). Taken together, in tumors and oxygen as Substrates to generate hydroxylated HIFC. 25 where the HIF pathway is driven by specific genetic succinate and CO (Kaelin and Ratcliffe, 2008). Hydroxy changes, therapeutic interventions that inactivate the HIF lation of HIFC. makes it a substrate for the VHL ubiquitin pathway in genetically driven HIF dependent tumors may ligase complex, which promotes HIFC. polyubiquitination, provide Substantial therapeutic benefit as monotherapy or as thus targeting HIFC. for proteosomal degradation. This pro part of a combination therapy. cess is very rapid at normal oxygen levels, with a <5 minute 30 In addition to the activitation of HIF through genetic half-life of HIFC. protein, thus enabling rapid regulation of alterations, HIF is also activated in hypoxia that results from the complex and HIF activity in response to changes in the tumor outgrowing the vasculature as well as a result of oxygen levels (Maxwell et al., 1999). therapeutic intervention. HIF mediated survival of cells in Frequently in disease, the HIF pathway is activated by hypoxia is a major contributor to resistance to therapies, lack either reduced oxygen levels or genetic alterations that 35 of durable response and the foundation of residual disease. increase the amount of stabilized HIFC. subunit (Semenza, When tumor cells become hypoxic, several HIF dependent 2012a). Increased HIFC. levels occur through several mecha mechanisms prolong the Survival of the cells in the harsh nisms that include increased in HIFC. subunit mRNA expres nutrient and oxygen deprived environment. These include Sion, HIFC protein translation, or through a decrease in genomic instability to promote adaptation (Klein and Glazer, HIFC. protein degradation. Increased HIF leads to several 40 2010; Koi and Boland, 2011), metabolic reprogramming, biological pathways being activated through HIF mediated induction of autophagy to recycle energy (MaZure and transcription of genes that promote stem cell maintenance, Pouyssegur, 2010), secretion of pro-angiogenic factors to metabolic reprogamming, endothelial to mesenchymal tran promote neovascularization and cessation of pro-growth sition (EMT), Survival, proliferation, migration, pH regula pathways. Severe hypoxia mediates innate resistance to tion and angiogenesis. 45 radiotherapy and chemotherapy, which require oxygen and A Substantial body of preclinical experimentation and proliferation, respectively, as part of their mechanisms of clinical evidence has implicated HIF as an important thera action. Alternatively, resistance can be adaptive as in the peutic target that is essential for the maintenance of a Subset case of anti-angiogenic therapies, such as anti-VEGF thera of tumors and a potential major contributor to therapeutic pies, that create hypoxic niches due to the destruction of the resistance and residual disease (Kaelin, 2011; Kaelin and 50 vasculature, which creates more intratumoral hypoxia thus Ratcliffe, 2008: Li et al., 2005: Semenza, 2012a: Semenza, activating HIF and promoting its milieu of procancerous 2012b). In numerous clinical studies, tumor hypoxia has pathways. Multiple reports in a mouse models of cancer been reported to correlate with poor prognosis and incom show that treatment with an anti-VEGF therapy promoted plete response to current therapeutic agents, including vari metastasis, most likely through HIF mediated activation of ous chemotherapies as well as radiotherapy (Harada et al., 55 tumor cell migration/invasion (Ebos et al., 2009; Paez-Ribes 2012: Rohwer and Cramer, 2011; Wilson and Hay, 2011). et al., 2009). Hypoxia has also been proposed to promote This is most likely due to HIF regulation of procancerous genomic alteration by increasing DNA damage, including mechanisms, including increased proliferation, activation of impairment of mismatch repair, nucleotide excision repair, Survival pathways Such as autophagy, enhanced glycolysis double Strand break repair and homologous recombination as part of a metabolic reprogramming shift away from 60 repair. The introduction of point mutations, frameshifts, oxidative phosphorylation, increased migration/invasion insertions, deletions, amplifications and translocations give promoting metastasis, maintenance of pluripotent “stem rise to tumor heterogeneity and evolution that provide the cell' population and stimulation of angiogenesis through the genetic alterations that enable adaptive resistance of tumors. synthesis and secretion of pro-angiogenic growth factors. In most tumor types, inhibition of the HIF pathway The loss of any of several tumor suppressors (i.e. VHL, 65 activity will senstitize tumors to standard of care therapies SDH, FH, TSC and others) and/or dysregulation of several Such as anti-angiogenic therapies, radiotherapies, chemo oncogenic pathways (i.e. RAS and Pi3K) activate the HIF therapies and targeted therapies by either improving the US 9,481,692 B2 3 4 perfusion of drug and oxygen throughout the tumor via -continued normalization of vascular function (Carmeliet and Jain, R23 2011; Chauhan et al., 2012) and by directly targeting the resistent HIF activated tumor cells to inhibit HIF mediated : N1 NN **, and * NN N : Survival pathways. V V In addition to cancer, inactivation of HIF pathway activate NR NRN would be beneficial for conditions where activation of HIF promotes the disease state through aberrant Survival or through promotion of neovascularization. These include traumatic shock, pulmonary arterial hypertension, obstruc 10 D is selected from the group consisting of alkyl, het tive sleep apnea, cardiovascular diseases such as cardiac eroalkyl, alkoxy, alkylthio, carbonyl, alkylcarbonyl, car arrhythmia and heart failure, diseases that involve neoan giogenesis such as ocular macular degeneration and rheu boxyl, oxy, thio. Sulfinyl, Sulfonyl, Sulfonamido, amino, matoid arthritis, sepsis and inflammation and diseases of the amido, alkylamino, and heteroaryl, any of which can be lung and kidney where fibrosis occurs due HIF mediated optionally substituted with one or more substituents selected EMT (Arjamaa et al., 2009; Semenza, 2012a: Westra et al., 15 from the group consisting of hydrogen, deuterium, halogen, 2010). alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, To date, numerous Small molecules have been reported acyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, that downregulate the HIF pathway via several direct and cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and Oxo, any indirect mechanisms which target various HIF intervention of which may be optionally substituted; points (Jones and Harris, 2012; Poon et al., 2009; Semenza, E is selected from the group consisting of aryl and 2012b). These include reducing HIFC. mRNA, reducing HIFC. protein translation, reducing reactive oxygen species heteroaryl; (ROS), increasing HIFC. degradation, disrupting HIFO/ G is selected from the group consisting of Saturated 3- to 7-membered cycloalkyl and saturated 3- to 7-membered HIF1B dimerization or the HIFC. interaction with p300, a heterocycloalkyl: co-factor for HIF translation. Genetic and pharmacological 25 inhibition of the HIF pathway utilizing RNAi, genetic abla R is selected from the group consisting of —Y-alkyl tion or via small molecule inhibitors have been reported to N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, reduce the growth of tumors in preclinical models clearly alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, establishing that the HIF pathway performs a critical func aminoalkyl, acyl, carboxylalkyl, carbonyl, carboxyl, cyano, tion in tumor growth and maintenance (Onnis et al., 2009). 30 hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio. Promoting HIFC. degradation as part of a therapeutic inter thiolalkyl, mercaptyl, thiol, Sulfonate, Sulfonamido, alkyl vention regime would be highly beneficial to patients. Sulfonyl, amino, amido, alkylamino, dialkylamino, carbam Herein we describe a series of selective small molecule ate, nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, inhibitors of HIF pathway activity that promote VHL and cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, PHD mediated degradation of HIF. Novel compounds and pharmaceutical compositions, cer 35 tain of which have been found to inhibit HIF pathway activity have been discovered, together with methods of R37 synthesizing and using the compounds including methods S-N for the treatment of HIF pathway-mediated diseases in a O Y, 38 patient by administering the compounds. 40 In certain embodiments of the present invention, com pounds have structural Formula I: cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbo (R)-A-Y-B-D-E-(Rs), (I) nyl, heteroarylcarbonyl, cycloalkylalkyl, arylalkyl, hetero or a salt thereof, wherein: cycloalkylalkyl, heterocycloalkylcarbonylalkyl, and het n is 0, 1, or 2: 45 eroarylalkyl, any of which can be optionally substituted with p is 0, 1, or 2: one or more Substituents selected from the group consisting q is 0, 1, 2, 3, or 4: of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, u is 0, 1, or 2: haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, amido A is selected from the group consisting of aryl and alkyl, acyl, carbonyl, carboxyl, carboxylalkyl, alkylcarbo heteroaryl; 50 nyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl, amino B is selected from the group consisting of alkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, Oxo, alkylthio, thiol, R23 R23 acylthio. Sulfonamido, alkylsulfonyl, amino, amido, car 55 bamate, alkylamino, dialkylamino, alkylaminoalkyl, dialky : *, N : , ; * , laminoalkyl, nitro, trisubstituted silyl, trisubstituted siloxy, NN N NN1 N n N N cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylhetero o o NR cycloalkyl, any of which may be optionally Substituted; R is selected from the group consisting of hydrogen, R23 R23 R23 R23 R23 60 deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, het R23 eroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acyl, car : * , : N * , bonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, N1N N1 Y haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oXo, alkylthio, mercaptyl, thiol, haloalkylthio, perhaloalky 65 lthio, cyanoalkylthio, haloalkylsulfonyl, alkylsulfonyl, R23 R23 alkoxyalkylsulfonyl, cyanoalkylsulfonyl, Sulfonate, Sulfona mido, amino, amido, alkylamino, dialkylamino, carbamate, US 9,481,692 B2 5 6 nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, amino, amido, alkylamino, dialkylamino, carbamate, nitro, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalky cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and het loxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, eroarylalkyl, trisubstituted silyl, -SFs —(C(R)(Rs.)) - cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and het O-alkyl, -(C(R)(Rs.) O-cycloalkyl, -S(O)-alkyl, eroarylalkyl, any of which may be optionally substituted; —S(O)-cycloalkyl, cycloalkylthio. —CF, —OCF, —(C each R is independently selected from the group con (R)(R)). OCF, saturated heterocycloalkyloxy, -(C sisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, (Rs)(Rs.) O-saturated heterocycloalkyl, -(C(Rs.) perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, (R-2)), Saturated heterocycloalkyl, saturated carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, heterocycloalkylthio. —S(O)-saturated heterocycloalkyl, 10 perhaloalkoxy, oxo, alkylthio, amino, alkylamino, dialky —(C(R)(Rs.)), OCFs, lamino, nitro, cycloalkyl, aryl, and heteroaryl, any of which may be optionally substituted; R1, R32, Ras, Ra, and Rs are independently selected R31 R31 R31 R31 from the group consisting of hydrogen, deuterium, alkyl, 15 and perfluoroalkyl, any of which can be optionally substi tuted; R32 F, HolR32 HorsR32 R32 CF, Rs is selected from the group consisting of hydrogen, R3 R33 R3 R33 R3 R33 deuterium, alkyl, perfluoroalkyl, cycloalkyl, and Saturated heterocycloalkyl, any of which can be optionally substi OH, H OR3s, F, tuted; R32 R34 R32 R34 R32 R34 R, and Rs are independently selected from the group consisting of alkyl and perfluoroalkyl, or R-7 and Rs, taken together, form a heterocyloalkyl, any of which can be optionally substituted; 25 Y is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylthio, carbonyl, alkylcar bonyl, carboxyl, oxy, thio, Sulfinyl, Sulfonyl, Sulfonamido, amino, amido, alkylamino, and carbamate, any of which can be optionally substituted with one or more substituents 30 selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio. amino, alkylamino, dialkylamino, and cycloalkyl, any of 35 which may be optionally substituted; and Y is selected from the group consisting of a bond, carbonyl, alkylcarbonyl, carboxyl, oxy, thio. Sulfinyl, Sulfo nyl, Sulfonamido, amino, amido, alkylamino, and carbam ate, any of which can be optionally substituted with one or 40 more Substituents selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car bonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, per haloalkoxy, Oxo, alkylthio, mercaptyl, thiol, Sulfonate, Sul 45 fonamido, amino, amido, alkylamino, dialkylamino, carbamate, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and het eroarylalkyl, any of which may be optionally substituted. Certain compounds disclosed herein may possess useful HIF pathway inhibiting activity, and may be used in the treatment or prophylaxis of a disease or condition in which any of which may be optionally substituted; the HIF pathway plays an active role. Thus, in broad aspect, Ra and Rs are independently selected from the group certain embodiments also provide pharmaceutical composi consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, 55 tions comprising one or more compounds disclosed herein haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car together with a pharmaceutically acceptable carrier, as well bonyl, carboxyl, alkoxy, haloalkoxy, perhaloalkoxy, alkyl as methods of making and using the compounds and com Sulfonyl, Sulfonamido, amido, cycloalkyl, aryl, heterocy positions. Certain embodiments provide methods for inhib cloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, iting the HIF pathway. Other embodiments provide methods heterocycloalkylalkyl, and heteroarylalkyl, or R and Rs. 60 for treating a HIF pathway-mediated disorder in a patient in taken together, form a heterocyloalkyl or heteroaryl, any of need of Such treatment, comprising administering to said which can be optionally substituted with one or more patient a therapeutically effective amount of a compound or Substituents selected from the group consisting of hydrogen, composition according to the present invention. Also pro deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, per vided is the use of certain compounds disclosed herein for haloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, car 65 use in the manufacture of a medicament for the treatment of boxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, a disease or condition ameliorated by the inhibition of the oxo, alkylthio, mercaptyl, thiol, Sulfonate, Sulfonamido, HIF pathway. US 9,481,692 B2 7 8 In certain embodiments, -continued if A is phenyl, B is not R23 : N1 NN **, and * NYN :
: N :::::: 5 o \ o
R23 R23 R23
Q2 Q3 10 D is selected from the group consisting of amido, 5-mem wherein Q and Q are freely Substituted; bered heteroaryl, and 6-membered heteroaryl, any of which can be optionally substituted with one or more substituents if A is phenyl or pyridyl, Y is CH, B is selected from the group consisting of hydrogen, deuterium, 15 halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, cyano, hydroxy, alkoxy, haloalkoxy, : N :::::: : :::::: : :::::: perhaloalkoxy, cycloalkyl, aryl, heterocycloalkyl, het N eroaryl, and oxo, any of which may be optionally Substi N1 N s^-" is s tuted; o )=x o E is selected from the group consisting of phenyl, 5-mem. Q1 Q1 Q1 bered heteroaryl, 6-membered heteroaryl, and 9-membered bicyclic heteroaryl; Ra and Rs are independently selected from the group and Q is methyl, ethyl, or trifluoromethyl, then D is not consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car 25 bonyl, carboxyl, alkoxy, haloalkoxy, perhaloalkoxy, alkyl Sulfonyl, Sulfonamido, amido, cycloalkyl, aryl, heterocy it. e iii., ii e ##, cloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, N y1 Y- heterocycloalkylalkyl, and heteroarylalkyl, or R and Rs. O-N O taken together, form a heterocyloalkyl or heteroaryl, any of 30 which can be optionally substituted with one or more it. 21 f ##, # y Ny- ##, deuterium,Substituents halogen,selected fromalkyl, the haloalkyl,group consisting perhaloalkyl, of hydrogen, het O-N N - O eroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, it. N iii., ii ##, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio. Ny-N Ny-N 35 mercaptyl,dialkylamino, thiol, carbamate, Sulfonamido, and cycloalkyl, amino, amido, any of alkylamino, which may O N-O be optionally substituted; it. N Oy1 ##, if Oy1 ##, deuterium,R is selected halogen, from alkyl, the grouphaloalkyl, consisting perhaloalkyl, of hydrogen, het \ f \ f 0 eroalkyl, hydroxyalkyl, cyano, hydroxy, alkoxy, haloalkoxy, N-N N perhaloalkoxy, alkylthio, amino, alkylamino, dialkylamino, it. O ##, or fi ##; cycloalkyl, aryl, and heteroaryl; Y is alkyl, which can be optionally substituted with one Y1 (1 or more substituents selected from the group consisting of N N 45 hydrogen, deuterium, alkyl, cycloalkyl, and halogen; and Y is selected from the group consisting of a bond, carbonyl, alkylcarbonyl, carboxyl, oxy, thio. Sulfinyl, Sulfo and nyl, Sulfonamido, amino, amido, alkylamino, and carbam wherein * represents the point of attachment to Y and ** ate, any of which can be optionally substituted with one or represents the point of attachment to D, and it represents the 50 more substituents selected from the group consisting of point of attachment to B and iiii represents the point of hydrogen, deuterium, halogen, alkyl, haloalkyl, perha attachment to E. loalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, OXo, In further embodiments, alkylthio, mercaptyl, thiol, Sulfonamido, amino, amido, A is selected from the group consisting of aryland mono- 55 alkylamino, dialkylamino, carbamate, and cycloalkyl, any of or bicyclic heteroaryl; which may be optionally substituted. B is selected from the group consisting of In further embodiments, B is 60 "n/ N * 8. ^^-" --" RNr 65 R23 US 9,481,692 B2 9 10 In further embodiments, D is selected from the group namido, alkylsulfonyl, amino, amido, alkylamino, dialky consisting of —C(=O)NR—, 5-membered heteroaryl, lamino, nitro, heterocycloalkyl, heterocycloalkyloxy, and 6-membered heteroaryl; E is selected from the group consisting of phenyl, pyrimi dine, 1,3-benzodioxol, indole, and 1-benzofuran; R37 R is selected from the group consisting of —Y-alkyl S-N N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, amino O Y, 38 alkyl, acyl, carboxylalkyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio. 10 heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbo thiolalkyl, Sulfonamido, alkylsulfonyl, amino, amido, alky nyl, any of which can be optionally substituted with one or more Substituents selected from the group consisting of lamino, dialkylamino, nitro, cycloalkyl, aryl, heterocy hydrogen, deuterium, halogen, alkyl, alkenyl, amidoalkyl, cloalkyl, heteroaryl, cycloalkyloxy, aryloxy, heterocy acyl, carboxylalkyl, hydroxyalkylcarbonyl, alkynylcarbo cloalkyloxy, heteroaryloxy, 15 nyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, oxo, Sulfonamido, alkylsulfonyl, amino, amido, carbamate, dialkylamino, dialkylaminoalkyl, O| /7R trisubstituted siloxy, cycloalkyl, heterocycloalkyl, alkylhet S-N erocycloalkyl, any of which may be optionally substituted; R is selected from the group consisting of hydrogen, O Y.38 deuterium, alkyl, and cycloalkyl, any of which may be optionally Substituted; and cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbo each R is independently selected from the group con sisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl, nyl, and heterocycloalkylcarbonylalkyl, any of which can be perhaloalkyl, cyano, Saturated 3- to 6-membered cycloalkyl, optionally substituted with one or more substituents selected 25 4- to 6-membered heterocycloalkyl, and 5- to 6-membered from the group consisting of hydrogen, deuterium, halogen, heteroaryl. alkyl, alkenyl, alkynyl, amidoalkyl, acyl, carboxylalkyl, In further embodiments of the present invention, n is 1; p alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl, is 1; and R is selected from the group consisting of alkyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcar haloalkyl, perhaloalkyl, hydroxy, and cyclopropyl. bonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, het 30 In certain embodiments, disclosed herein are compounds eroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, having structural Formula II hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, thiol, acyl thio. Sulfonamido, alkylsulfonyl, amino, amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl, dialkylamino (II) alkyl, trisubstituted silyl, trisubstituted siloxy, cycloalkyl, 35 aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl, any of which may be optionally substituted; R is selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, het 40 eroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialky lamino, acyl, carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio, haloalkylthio, perhaloalkyl or a salt thereof, wherein: thio, cyanoalkylthio, alkylsulfonyl, alkoxyalkylsulfonyl, 45 X, X, and Xs are independently selected from the group cyanoalkylsulfonyl, haloalkylsulfonyl, Sulfonamido, alkyl consisting of CRI, N, O, and S, and wherein X2, X, and Sulfonamido, amino, alkylamino, dialkylamino, amido, Xs, taken together, form a 5-membered heteroaryl; cycloalkyl, aryl, heterocycloalkyl, heteroaryl perhaloalkyl Z and Z are independently selected from the group consisting of N, NR, C=O, and CR; cycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl, Z is selected from the group consisting of N, NR, heterocycloalkylcarbonyl, and heterocycloalkylalkyl, any of 50 C—O, and CR; which can be optionally substituted; R is selected from the group consisting of —Y-alkyl R is selected from the group consisting of hydrogen, N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, deuterium, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, amino hydroxyalkyl, cycloalkyl, aryl, heterocycloalkyl, and het alkyl, acyl, carboxylalkyl, carbonyl, carboxyl, carbonyl, eroaryl, any of which may be optionally substituted; 55 cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, OXo, Y is —CH2—, and alkylthio, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, Y is selected from the group consisting of a bond, amino, amido, alkylamino, dialkylamino, nitro, cycloalkyl, carbonyl, amino, and alkylamino. aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy, In further embodiments, heterocycloalkyloxy, heteroaryloxy, A is selected from the group consisting of phenyl, 5-mem 60 bered heteroaryl, and 6-membered heteroaryl; E is phenyl: O R R is selected from the group consisting of —Y-alkyl | /7 N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, S-N haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car 65 O Y. 38 boxylalkyl, carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, OXO, thiolalkyl, Sulfonyl, Sulfo US 9,481,692 B2 11 12 cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbo nyl, and heterocycloalkylcarbonylalkyl, any of which can be O R optionally substituted with one or more substituents selected | /7 from the group consisting of hydrogen, deuterium, halogen, S-N alkyl, alkenyl, alkynyl, amidoalkyl, acyl, carboxylalkyl, O Y. 38s alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcar heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbo bonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, het nyl, any of which can be optionally substituted with one or eroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, more Substituents selected from the group consisting of hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, thiol, acyl 10 hydrogen, deuterium, halogen, alkyl, alkenyl, amidoalkyl, thio. Sulfonamido, alkylsulfonyl, amino, amido, carbamate, acyl, carboxylalkyl, hydroxyalkylcarbonyl, alkynylcarbo alkylamino, dialkylamino, alkylaminoalkyl, dialkylamino nyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, alkyl, trisubstituted silyl, trisubstituted siloxy, cycloalkyl, cyano, hydroxy, alkoxy, oxo, Sulfonamido, alkylsulfonyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl, 15 amino, amido, carbamate, dialkylamino, dialkylaminoalkyl, any of which may be optionally substituted; trisubstituted siloxy, cycloalkyl, heterocycloalkyl, alkylhet R. R. and Ra are independently selected from the erocycloalkyl, any of which may be optionally substituted; group consisting of hydrogen, deuterium, halogen, alkyl, R2, R1, and R1a are hydrogen; haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, R. R7, Rio, and Ro are hydrogen; perhaloalkoxy, alkylthio, amino, and saturated 3- to 7-mem R is selected from the group consisting of null, hydro bered cycloalkyl, any of which may be optionally substi gen, deuterium, halogen, and alkyl, and tuted; R is selected from the group consisting of hydrogen, R. Rio, and Ro are independently selected from the deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, group consisting of hydrogen, deuterium, halogen, alkyl, and saturated 3- to 6-membered cycloalkyl. haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, 25 In further embodiments, perhaloalkoxy, alkylthio, amino, and cycloalkyl, any of R is selected from the group consisting of hydrogen, which may be optionally substituted; deuterium, fluorine, bromine, cyano, methyl, isopropyl. R7 and Rs are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxy 30 alkyl, aminoalkyl, dialkylamino, acyl, carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perha loalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio. haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfo nyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsul 35 fonyl, Sulfonamido, alkylsulfonamido, amino, alkylamino, ethylene, dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, het eroaryl perhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl, and heterocy 40 cloalkylalkyl, any of which can be optionally substituted; R is selected from the group consisting of null, hydro als gen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, het eroalkyl, hydroxyalkyl, cyano, hydroxy, alkoxy, haloalkoxy, trifluoromethyl, bromomethyl, hydroxymethyl, difluo perhaloalkoxy, alkylthio, amino, alkylamino, and dialky 45 romethoxy, methoxy, ethoxy, isopropoxy, hydroxy, nitro, lamino; and acetyl, carboxyl, -COCH, R is selected from the group consisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, saturated 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl. 50 In further embodiments, two of X2, X, and Xs are N, and one of X2, X, and Xs A -/- is O; or one of X, X and X is N., one of X, X, and X is O. and one of X, X, and Xs is CH; and 55 —SOCH - SOCHCH, SOCH2CHCH. —SONH2, R is selected from the group consisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to 6-membered cycloalkyl. In further embodiments, at least one of Z or Z is CR; 60 R is selected from the group consisting of —Y-alkyl N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car boxylalkyl, carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, OXO, thiolalkyl, Sulfonyl, Sulfo 65 namido, alkylsulfonyl, amino, amido, alkylamino, dialky lamino, nitro, heterocycloalkyl, heterocycloalkyloxy,
US 9,481,692 B2 15 16 -continued -continued / \ - O O - 1. O
10 - N-(O s - s Y.
A O F F ~k. F, Šs F F - s O s 15 OH
25 C) s -(-), O) -O-O-OX
O O O 35 -Oc. vs. A w N
N O N - N- SR; s O
s s NH2 Null O - 4. and /. O O \
Rs is selected from the group consisting of hydrogen, S (SO deuterium, halogen, methyl, isopropyl, tert-butyl, cyclopro pyl, cyclohexyl, acetyl, hydroxymethyl, methoxymethyl, 55 methoxy, isopropoxy, methylamino, dimethylamino, meth trifluoromethyl, trifluoromethylthio, difluoromethoxy, and ylthio, cyanomethyl, cyanomethylthio, cyano. —SOCH, trifluoromethoxy; —SOCH(CH), —SOCHCH(CH), R is selected from the group consisting of hydrogen, —SONHCHCHCH, -SOCHF, -SOCF, go deuterium, methyl, acetyl,
2 s OH, and 65 A-lis HO , - O s US 9,481,692 B2 17 18 -continued -continued ''N- O -O-o-O-is and N O, N s N. s R is selected from the group consisting of hydrogen, O-OX deuterium, methyl, ethyl, 3-pyridyl, and cyclopropyl. 10 / \,, In further embodiments, R is selected from the group consisting of hydrogen, halogen, cyano, methyl, isopropyl. 15 / \ / \ N - s / \, OH ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy, hydroxy, carboxyl, —COCH, —SOCH, -SONH, 25 an- s v-'s s 30
O O S-NH OH v- i? Y N OH, s 35 O O O O i? Y-? X S-NH O- S-NH NH2 s s 40 O O / N / - Y - s O O 45 | Cr?y
50
55 / ( /- s
s 60 O /-( -O-O--O- 65 US 9,481,692 B2 19 20 -continued Ra Rao, and Rao are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, and Saturated 3- to 7-mem bered cycloalkyl, any of which may be optionally substi tuted; and Rs is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, 10 alkylthio, haloalkylthio, and perhaloalkylthio. In further embodiments, R is selected from the group consisting of
15
NH OH, O O \ / OH V / s 25
a N/ \ O/ , N/ \N-, O O / -O--I s -Q/\, s 30 o, NH2, NH,/ and N/ : O O O \ / Y . and 35 R is methyl. / \ . . In further embodiments, two of X2, X, and Xs are N, and O one of X, X, and Xs is O. In further embodiments, one of X, X and X is N; one of X2, X, and Xs is O; and one of X2, X, and X is CH. 40 In certain embodiments, disclosed herein are compounds having structural Formula III:
(III) 45 - \c
50
or a salt thereof, wherein: 55 X and X are N and X is O, X and Xs are N and X is O; X and Xs are N and X is O: X is CH, X is N, and Xs is O; or X is CH, X is O, and X is N: Z is selected from the group consisting of N and CR; R is selected from the group consisting of heterocy 60 cloalkyl, alkoxyalkoxy, alkylsulfonylalkoxy, heterocy cloalkyloxy, heterocycloalkylcarbonyl, alkoxyalkylamido, O--(| \, heterocycloalkylsulfonyl, alkoxyalkylsulfonamido, wherein said heterocycloalkyl, heterocycloalkyloxy, heterocy cloalkylcarbonyl, and heterocycloalkylsulfonyl can be 65 In further embodiments. Rs is selected from the group optionally substituted with one or more substituents selected consisting of isopropyl, tert-butyl, -CF, —OCF, from the group consisting hydrogen, alkyl, and oxo; —OCHF, and —SCF. US 9,481,692 B2 21 22 In further embodiments, R is selected from the group cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalky consisting of loxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,
5 O| /7R S-N
O Y. 38
10 cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbo O s nyl, and heterocycloalkylcarbonylalkyl, any of which can be O optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, N S- N alkyl, alkenyl, alkynyl, amidoalkyl, acyl, carboxylalkyl, O)---OJ. : S 15 alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl, /\, aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcar O bonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, het eroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, / \, . - Y - hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, Oxo, thiol, acyl O thio. Sulfonamido, alkylsulfonyl, amino, amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl, dialkylamino alkyl, trisubstituted silyl, trisubstituted siloxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl, 25 any of which may be optionally substituted; R is selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, cycloalkyl, aryl, heterocycloalkyl, and het eroaryl; 30 R. R. and Ra are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, and Saturated 3- to 7-mem 35 bered cycloalkyl, any of which may be optionally substi tuted; R. Rio, and Ro are independently selected from the R. R. R. R. 7, and Rio are hydrogen; and group consisting of hydrogen, deuterium, halogen, alkyl, Rs is selected from the group consisting of isopropyl. haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, tert-butyl, -CF, —OCF, —OCHF, and —SCF. 40 perhaloalkoxy, alkylthio, amino, and cycloalkyl, any of In certain embodiments, disclosed herein are compounds which may be optionally substituted; having structural Formula IV: R, and Rs are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxy alkyl, aminoalkyl, dialkylamino, acyl, carbonyl, carboxyl, R14 R23 cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perha R13 loalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio. r )- R11 R16 haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfo Zin N nyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsul Sz 50 fonyl, Sulfonamido, alkylsulfonamido, amino, alkylamino, dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, het eroaryl perhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl, and heterocy cloalkylalkyl, any of which can be optionally substituted; 55 and R is selected from the group consisting of hydrogen, or a salt thereof, wherein: deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, Z and Z are independently selected from the group saturated 3- to 6-membered cycloalkyl, 4- to 6-membered consisting of N, NR, C=O, and CR; heterocycloalkyl, and 5- to 6-membered heteroaryl. Z is selected from the group consisting of N, NR, 60 In further embodiments, R is hydrogen. C=O, and CR: R is selected from the group consisting of In further embodiments, —Y-alkyl-N(R)Rs, hydrogen, deuterium, halogen, alkyl, at least one of Z or Z is CR; alkenyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, R is selected from the group consisting of —Y-alkyl aminoalkyl, acyl, carboxylalkyl, carbonyl, carboxyl, carbo N(R)Rs, hydrogen, deuterium, halogen, alkyl, alkenyl, nyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, 65 haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, car oxo, alkylthio, thiolalkyl, Sulfonyl, Sulfonamido, alkylsul boxylalkyl, carboxyl, carbonyl, cyano, hydroxy, alkoxy, fonyl, amino, amido, alkylamino, dialkylamino, nitro, haloalkoxy, perhaloalkoxy, Oxo, thiolalkyl, Sulfonyl, Sulfo US 9,481,692 B2 23 24 namido, alkylsulfonyl, amino, amido, alkylamino, dialky- -continued lamino, nitro, heterocycloalkyl, heterocycloalkyloxy, H S-N S-NH O V / Rs. 5 O O s | \ O O (5 R38, | / \ S-N OH, S-NH OH, heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbo O O nyl, any of which can be optionally substituted with one or more Substituents selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, amidoalkyl, S-NH O-, S-NH NH2, acyl, carboxylalkyl, hydroxyalkylcarbonyl, alkynylcarbo- is nyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, O cyano, hydroxy, alkoxy, oxo, Sulfonamido, alkylsulfonyl, O O amino, amido, carbamate, dialkylamino, dialkylaminoalkyl, O O trisubstituted siloxy, cycloalkyl, heterocycloalkyl, alkylhet- -N: O- -N erocycloalkyl, any of which may be optionally substituted; s s R is selected from the group consisting of hydrogen, O S O deuterium, alkyl, and cycloalkyl; -r O R2, R1, and Ra are hydrogen; O O R. R.17, Rio, and R2 are hydrogen; and 25 / N / V R is selected from the group consisting of hydrogen, i-N O. -N N-, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, O O and saturated 3- to 6-membered cycloalkyl. In further embodiments, N N N-- R is selected from the group consisting of hydrogen, 30 V / deuterium, fluorine, bromine, cyano, methyl, isopropyl. O N --. 35 \ / | \
amino, methylamino, dimethylamino,
40 ethylene, / \ als 45 7 trifluoromethyl, bromomethyl, hydroxymethyl, difluo -O- -O- romethoxy, methoxy, ethoxy, isopropoxy, hydroxy, nitro, 50 M V acetyl, carboxyl, -COCH, N CN, N. O.
A- SH, A- S s 55 OX s NS S1 N sa'S 1 OM \,O \ / O O A \ / SEOM NH O , s —SOCH —SOCHCH, SOCH2CHCH. —SONH, 60
O O / \ N N -N H S-N S-N 65 SO H s \ 3 || \ N N I s O s O s US 9,481,692 B2 25 26 -continued -continued
O s O O-S s / \ 7 10 O i- - 1. O
O / \ p- / 15 O HN - s O C C
25 - . OH
O
30 N 21 N
O O O 35 21 OS s NM /O .
O
40
45
50
55 - 4. and N
60 Rs is selected from the group consisting of hydrogen, deuterium, halogen, methyl, isopropyl, tert-butyl, cyclopro pyl, cyclohexyl, acetyl, hydroxymethyl, methoxymethyl, methoxy, isopropoxy, methylamino, dimethylamino, meth 65 ylthio, cyanomethyl, cyanomethylthio, cyano. —SOCH, —SOCH(CH), —SOCHCH(CH), - SONHCHCHCH, -SOCHF, -SOCF, US 9,481,692 B2 28
O O v-1 v- and N-1
10 O
and R is selected from the group consisting of hydrogen, Y, Y deuterium, methyl, ethyl, 3-pyridyl, and cyclopropyl. In further embodiments of the present invention, R is selected from the group consisting of hydrogen, halogen, cyano, methyl, isopropyl.
A-AXO O 2O w‘s N. :H- 1 \, : Y (\ O O 25 -N O \= ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy, hydroxy, carboxyl, -COCH, O / \ 30 —SOCH, -SONH2, g1N- N. NN s N O
O S-NH | \ | \ -O-O-O O s O s O S-NH s -N OH,
OR V / Oin
O O 45 S-NH OH, S-NH O-, O K. O| \ K -O-O-O O
HO s O. s / /.\ 55 / \ xO s H O, trifluoromethyl, trifluoromethylthio, difluoromethoxy, and trifluoromethoxy; 65 R is selected from the group consisting of hydrogen, deuterium, methyl, acetyl, amino, methylamino, dimethylamino, US 9,481,692 B2 29 30 -continued O / OHO-HC 5 s -O-OX-O 10 II v 15 O )— O >
OH,
25 IS/\/ H / / H/ )/ 30 /St. " SAS/ " A (\
35 and R is methyl. In further embodiments, R is hydrogen. In certain embodiments, disclosed herein are compounds having structural Formula V: 40
(V)
R 21 45 )- H ^s-X Né N R39 O
50 K R18
or a salt thereof, wherein: Z2 is selected from the group consisting of N and CR; R is selected from the group consisting of heterocy 55 cloalkyl, alkoxyalkoxy, alkylsulfonylalkoxy, heterocy cloalkyloxy, heterocycloalkylcarbonyl, alkoxyalkylamido, heterocycloalkylsulfonyl, alkoxyalkylsulfonamido, wherein said heterocycloalkyl, heterocycloalkyloxy, heterocy cloalkylcarbonyl, and heterocycloalkylsulfonyl can be 60 optionally substituted with one or more substituents selected from the group consisting hydrogen, alkyl, and oxo; Ra Rao, and Rao are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, 65 perhaloalkoxy, alkylthio, amino, and Saturated 3- to 7-mem bered cycloalkyl, any of which may be optionally substi tuted; and US 9,481,692 B2 31 32 Rs is selected from the group consisting of alkyl, -continued haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, O alkylthio, haloalkylthio, and perhaloalkylthio. In further embodiments, R is selected from the group 5 O)---OJ. : S consisting of /\, O
- N- - O 10 i? Y- - Y O- -O-( -O 15
O-- s 2O /\, O
, and -/ Y- - Y | - 25 O O O R. R. R. R7, and Ro are hydrogen; and Rs is selected from the group consisting of isopropyl. tert-butyl, —CF —OCF. —OCHF, and —SCF. '^ In further embodiments, disclosed herein is a compound selected from the group consisting of Examples 1 to 163, or / -- X C. a salt thereof. O In further embodiments, disclosed herein is a pharmaceu N O S-N tical composition comprising a compound as disclosed H/ \ / | O 35 herein together with a pharmaceutically acceptable carrier. O s O s In further embodiments, disclosed herein is a method of O / O - treatment of a HIF pathway-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof. Hi?I \- H \ /N , a In further embodiments, said disease is cancer. O In further embodiments, said cancer is selected from the / \ group consisting of colon cancer, breast cancer, ovarian S-N N- N OH, cancer, lung cancer, prostrate cancer, cancers of the oral | \ / cavity and pharynx (lip, tongue, mouth, larynx, pharynx), 45 esophagus, stomach, Small intestine, large intestine, colon, rectum, liver and biliary passages; pancreas, bone, connec tive tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, 50 and other components of the central and peripheral nervous systems, as well as associated structures Such as the menin In further embodiments. Rs is selected from the group ges; cancers of the thyroid and other endocrine glands; consisting of isopropyl, tert-butyl, -CF, —OCF, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple —OCHF, and —SCF. myeloma, hematopoietic malignancies including leukemias In further embodiments, 55 (Chronic Lymphocytic Leukemia (CLL), Acute Lympho cytic Leukemia (ALL)) and lymphomas including lympho R is selected from the group consisting of cytic, granulocytic and monocytic; adrenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondro 60 sarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosar -O-\ / : - \ /O coma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genito urinary tract cancers, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, O s hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyo sarcoma, leukemias, liposarcoma, lymphatic system cancer, US 9,481,692 B2 33 34 lymphomas, lymphangiosarcoma, lymphangioendothe In further embodiments, said compounds which may be liosarcoma, medullary thyroid carcinoma, medulloblastoma, used as a medicament include the compounds of Formula I, meningioma mesothelioma, myelomas, myxosarcoma neu II, III, IV, and V, optionally including any further limitation roblastoma, neurofibrosarcoma, oligodendroglioma, osteo to the scope of said Formulas as defined above. In further genic sarcoma, epithelial ovarian cancer, papillary carci embodiments, said compounds may be selected from the noma, papillary adenocarcinomas, paraganglioma, group consisting of Examples 1 to 163, or a salt thereof. parathyroid tumours, pheochromocytoma, pinealoma, plas In certain embodiments, the disclosed are compounds for macytomas, retinoblastoma, rhabdomyosarcoma, sebaceous use in the treatment of a HIF pathway-mediated disease. gland carcinoma, seminoma, skin cancers, melanoma, Small In further embodiments, said compounds which may be cell lung carcinoma, non-Small cell lung carcinoma, 10 used in the treatment of a HIF pathway-mediated disease squamous cell carcinoma, Sweat gland carcinoma, Syn include the compounds of Formula I, II, III, IV, and V. ovioma, thyroid cancer, uveal melanoma, and Wilm's tumor. optionally including any further limitation to the scope of In further embodiments, disclosed herein is a method of said Formulas as defined above. In further embodiments, treatment of a disease caused by abnormal cell proliferation 15 said compounds may be selected from the group consisting comprising the administration of a therapeutically effective of Examples 1 to 163, or a salt thereof. amount of a compound as disclosed herein to a patient in In further embodiments, said disease is cancer. need thereof. In further embodiments, said cancer is selected from the In further embodiments, disclosed herein is a method of group consisting of colon cancer, breast cancer, ovarian treatment of a HIF pathway-mediated disease comprising cancer, lung cancer, prostrate cancer, cancers of the oral the administration of cavity and pharynx (lip, tongue, mouth, larynx, pharynx), a. a therapeutically effective amount of a compound as esophagus, stomach, Small intestine, large intestine, colon, disclosed herein; and rectum, liver and biliary passages; pancreas, bone, connec b. another therapeutic agent. tive tissue, skin, cervix, uterus, corpus endometrium, testis, In further embodiments, disclosed herein is a method for 25 bladder, kidney and other urinary tissues, including renal achieving an effect in a patient comprising the administra cell carcinoma (RCC); cancers of the eye, brain, spinal cord, tion of a therapeutically effective amount of a compound as and other components of the central and peripheral nervous disclosed herein to a patient, wherein the effect is selected systems, as well as associated structures Such as the menin from the group consisting of preventing or reducing resis ges; cancers of the thyroid and other endocrine glands; tance to radiotherapy and chemotherapy, preventing or 30 Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple reducing tumor invasion and tumor metastasis, and prevent ing or reducing angiogenesis. myeloma, hematopoietic malignancies including leukemias In certain embodiments, the compositions and methods (Chronic Lymphocytic Leukemia (CLL), Acute Lympho disclosed herein may be used to inhibit HIF pathway activ cytic Leukemia (ALL)) and lymphomas including lympho ity, to downregulate HIF-1C. (which is induced by hypoxia 35 cytic, granulocytic and monocytic; adrenocarcinoma, or genetic alterations, as well as in various disease states, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic e.g. in persons with certain genetic backgrounds), by astrocytoma, basal cell carcinoma, blastoglioma, chondro increasing HIF-1C. degradation, decreasing HIF heterodimer sarcoma, choriocarcinoma, chordoma, craniopharyngioma, formation, increasing HIF-1C, prolyl hydroxylation, and/or cutaneous melanoma, cystadenocarcinoma, endotheliosar to reduce transcription of hypoxia response element (HRE) 40 coma, embryonal carcinoma, ependymoma, Ewing's tumor, downstream elements. epithelial carcinoma, fibrosarcoma, gastric cancer, genito In certain embodiments, the compositions and methods urinary tract cancers, glioblastoma multiforme, head and disclosed herein may be used to reduce tumor growth, to neck cancer, hemangioblastoma, hepatocellular carcinoma, inhibit neoangiogenesis (e.g., by downregulating VEGF), to hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyo normalize tumor vasculature, to enhance radiotherapy and 45 sarcoma, leukemias, liposarcoma, lymphatic system cancer, chemotherapy, to prevent metastasis, to reduce tumor stem lymphomas, lymphangiosarcoma, lymphangioendothe cell numbers, and to prevent induction of anaerobic cellular liosarcoma, medullary thyroid carcinoma, medulloblastoma, metabolism. meningioma mesothelioma, myelomas, myxosarcoma neu In certain embodiments, the compositions and methods roblastoma, neurofibrosarcoma, oligodendroglioma, osteo disclosed herein may be used to treat HIF-deregulated 50 genic sarcoma, epithelial ovarian cancer, papillary carci diseases with an inflammatory component, Such as cancers, noma, papillary adenocarcinomas, paraganglioma, stroke, and rheumatoid arthritis. parathyroid tumours, pheochromocytoma, pinealoma, plas In certain embodiments, the compositions and methods macytomas, retinoblastoma, rhabdomyosarcoma, sebaceous disclosed herein may be used to treat HIF-deregulated gland carcinoma, seminoma, skin cancers, melanoma, Small diseases cardiovascular diseases such as cardiac arrhythmia 55 cell lung carcinoma, non-Small cell lung carcinoma, and heart failure. squamous cell carcinoma, Sweat gland carcinoma, Syn In certain embodiments, the compositions and methods ovioma, thyroid cancer, uveal melanoma, and Wilm's tumor. disclosed herein are useful for preventing or reducing resis In certain embodiments, disclosed herein are compounds tance to radiotherapy and chemotherapy. for use in the treatment of a disease caused by abnormal cell In certain embodiments, the compositions and methods 60 proliferation. disclosed herein are useful for preventing or reducing tumor In certain embodiments, disclosed herein are compounds invasion and tumor metastasis. for use in the treatment of HIF-deregulated diseases with an In certain embodiments, the compositions and methods inflammatory component, such as cancers, stroke, and rheu disclosed herein are useful for preventing or reducing angio matoid arthritis. genesis and disorders related to angiogenesis. 65 In certain embodiments, disclosed herein are compounds In certain embodiments, the compounds disclosed herein for use in the treatment of HIF-deregulated cardiovascular may be used as a medicament. diseases such as cardiac arrhythmia and heart failure. US 9,481,692 B2 35 36 In certain embodiments, disclosed herein are compounds Unless otherwise defined, all technical and scientific for use in the treatment of preventing or reducing resistance terms used herein have the same meaning as commonly to radiotherapy and chemotherapy. understood by one of ordinary skill in the art to which this In certain embodiments, disclosed herein are compounds invention belongs. When a conflict occurs, the meaning for use in the prevention or reduction of tumor invasion and ascribed herein controls. tumor metastasis. When ranges of values are disclosed, and the notation In certain embodiments, disclosed herein are compounds “from n1 . . . to n2 is used, where n1 and n2 are the for use in the prevention or reduction of angiogenesis and numbers, then unless otherwise specified, this notation is disorders related to angiogenesis. intended to include the numbers themselves and the range 10 between them. This range may be integral or continuous In further embodiments, said compounds which may be between and including the end values. By way of example, used in the treatment of a disease caused by abnormal cell the range “from 2 to 6 carbons' is intended to include two, proliferation, HIF-deregulated diseases with an inflamma three, four, five, and six carbons, since carbons come in tory component, such as cancers, stroke, and rheumatoid integer units. Compare, by way of example, the range “from arthritis, HIF-deregulated cardiovascular diseases such as 15 1 to 3 uM (micromolar), which is intended to include 1 uM, cardiac arrhythmia and heart failure, for use in preventing or 3 LM, and everything in between to any number of signifi reducing resistance to radiotherapy and chemotherapy, pre cant figures (e.g., 1.255 uM, 2.1 uM, 2.9999 uM, etc.). vention or reduction of tumor invasion and tumor metasta The term “about,’ as used herein, is intended to qualify sis, or prevention or reduction of angiogenesis and disorders the numerical values which it modifies, denoting such a related to angiogenesis include the compounds of Formula I, value as variable within a margin of error. When no par II, III, IV, and V, optionally including any further limitation ticular margin of error. Such as a standard deviation to a to the scope of said Formulas as defined above. In further mean value given in a chart or table of data, is recited, the embodiments, said compounds may be selected from the term “about should be understood to mean that range which group consisting of Examples 1 to 163, or a salt thereof. would encompass the recited value and the range which 25 would be included by rounding up or down to that figure as BRIEF DESCRIPTION OF THE DRAWINGS well, taking into account significant figures. The term “acyl, as used herein, alone or in combination, FIG. 1 Compounds of this invention inhibit the growth refers to a carbonyl attached to an alkenyl, alkyl, aryl, of diffuse large B-cell lymphoma TMD8 cells as shown by cycloalkyl, heteroaryl, heterocycle, or any other moiety reduced number of viable cells following treatment with 30 were the atom attached to the carbonyl is carbon. An Example 80. “acetyl group refers to a —C(O)CH group. An “alkylcar FIG. 2 Compounds of this invention inhibit the growth bonyl' or "alkanoyl group refers to an alkyl group attached of neuroblastoma NB-1 cells as shown by reduced number to the parent molecular moiety through a carbonyl group. of viable cells following treatment with Examples 2 (FIG. Examples of Such groups include methylcarbonyl and eth 2A) and 80 (FIG. 2B). 35 ylcarbonyl. Examples of acyl groups include formyl. FIG. 3 Compounds of this invention inhibit the growth alkanoyl and aroyl. of glioblastoma Gli56 cells as shown by reduced number of The term “alkenyl, as used herein, alone or in combina viable cells following treatment with Example 80. tion, refers to a straight-chain or branched-chain hydrocar FIG. 4 Compounds of this invention inhibit the growth bon radical having one or more double bonds and containing of glioblastoma D423 cells as shown by reduced number of 40 from 2 to 20 carbon atoms. In certain embodiments, said viable cells following treatment with Examples 2 (FIG. 4A) alkenyl will comprise from 2 to 6 carbon atoms. The term and 80 (FIG. 4B). “alkenylene' refers to a carbon-carbon double bond system FIG. 5 Compounds of this invention inhibit the growth attached at two or more positions such as ethenylene of NB-1 xenografts in vivo, daily oral treatment with 10 (—CH=CH-),(—C::C ). Examples of suitable alkenyl mg/kg of Example 80 reduces the tumor growth. 45 radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4- FIG. 6 Compounds of this invention inhibit the growth butadienyl and the like. Unless otherwise specified, the term of H460 xenografts in vivo, daily oral treatment with 150 “alkenyl may include “alkenylene' groups. mg/kg of Example 2 reduces the tumor growth. The term “alkoxy, as used herein, alone or in combina FIG. 7 Compounds of this invention reduce the level of tion, refers to an alkyl ether radical, wherein the term alkyl hypoxia in H460 xenografts, daily oral treatment with 150 50 is as defined below. Examples of suitable alkyl ether radicals mg/kg of Example 2 reduce the level of hypoxia as measure include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, by hypoxyprobe. iso-butoxy, sec-butoxy, tert-butoxy, and the like. FIG. 8 Compounds of this invention reduce the level of The term “alkyl, as used herein, alone or in combination, the HIF regulated gene carbonic anhydrase IX in H460 refers to a straight-chain or branched-chain alkyl radical Xenografts, daily oral treatment with 150 mg/kg of Example 55 containing from 1 to 20 carbon atoms. In certain embodi 2 reduce the level of CAIX as shown by IHC. ments, said alkyl will comprise from 1 to 10 carbon atoms. FIG. 9 Compounds of this invention inhibit the growth In further embodiments, said alkyl will comprise from 1 to of leukemia OCI-AML3 cells as shown by reduced number 6 carbon atoms. Alkyl groups may be optionally Substituted of viable cells following treatment with Example 80. as defined herein. Examples of alkyl radicals include methyl, FIG. 10 Compounds of this invention reduce disease 60 ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, tert burden in human leukemia model, daily oral treatment with butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The 10 mg/kg of Example 80 reduces disease burden in OCI term “alkylene,” as used herein, alone or in combination, AML3 models in NSG mice as measured by IVIS imaging. refers to a saturated aliphatic group derived from a straight FIG. 11—Compounds of this invention prolong the sur or branched chain saturated hydrocarbon attached at two or vival in human leukemia model, daily oral treatment with 10 65 more positions, such as methylene (-CH2—). Unless oth mg/kg of Example 80 extends survival in OCI-AML3 mod erwise specified, the term “alkyl may include “alkylene’ els in NSG mice. groups. US 9,481,692 B2 37 38 The term “alkylamino,” as used herein, alone or in The term “arylalkyl or “aralkyl, as used herein, alone or combination, refers to an alkyl group attached to the parent in combination, refers to an aryl group attached to the parent molecular moiety through an amino group. Suitable alky molecular moiety through an alkyl group. lamino groups may be mono- or dialkylated, forming groups The term “arylalkynyl or “aralkynyl, as used herein, such as, for example, N-methylamino, N-ethylamino, N.N- alone or in combination, refers to an aryl group attached to dimethylamino, N,N-ethylmethylamino and the like. the parent molecular moiety through an alkynyl group. The term “alkylidene, as used herein, alone or in com The term “arylalkanoyl or “aralkanoyl or “aroyl, as bination, refers to an alkenyl group in which one carbon used herein, alone or in combination, refers to an acyl radical atom of the carbon-carbon double bond belongs to the derived from an aryl-substituted alkanecarboxylic acid such 10 as benzoyl, napthoyl phenylacetyl, 3-phenylpropionyl (hy moiety to which the alkenyl group is attached. drocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlo The term “alkylthio.” as used herein, alone or in combi rohydrocinnamoyl, and the like. nation, refers to an alkylthioether (R—S ) radical wherein The term aryloxy as used herein, alone or in combination, the term alkyl is as defined above and wherein the sulfur refers to an aryl group attached to the parent molecular may be singly or doubly oxidized. Examples of suitable 15 moiety through an oxy. alkylthioether radicals include methylthio, ethylthio, n-pro The terms “benzo' and “benz, as used herein, alone or in pylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butyl combination, refer to the divalent radical CH= derived thio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the from benzene. Examples include benzothiophene and ben like. Zimidazole. The term “alkynyl, as used herein, alone or in combi The term “carbamate,” as used herein, alone or in com nation, refers to a straight-chain or branched chain hydro bination, refers to an ester of carbamic acid ( NHCOO—) carbon radical having one or more triple bonds and contain which may be attached to the parent molecular moiety from ing from 2 to 20 carbon atoms. In certain embodiments, said either the nitrogen or acid end, and which may be optionally alkynyl comprises from 2 to 6 carbon atoms. In further substituted as defined herein. embodiments, said alkynyl comprises from 2 to 4 carbon 25 The term "O-carbamyl” as used herein, alone or in atoms. The term “alkynylene' refers to a carbon-carbon combination, refers to a —OC(O)NRR', group-with R and triple bond attached at two positions such as ethynylene R" as defined herein. (—C:::C , —C-C ). Examples of alkynyl radicals The term “N-carbamyl” as used herein, alone or in include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, combination, refers to a ROC(O)NR' group, with R and R' butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, 30 as defined herein. The term “carbonyl, as used herein, when alone includes and the like. Unless otherwise specified, the term “alkynyl” formyl C(O)H and in combination is a —C(O)—group. may include “alkynylene' groups. The term "carboxyl or “carboxy, as used herein, refers The terms "amido” and “carbamoyl,” as used herein, to —C(O)OH or the corresponding "carboxylate' anion, alone or in combination, refer to an amino group as 35 Such as is in a carboxylic acid salt. An "O-carboxy' group described below attached to the parent molecular moiety refers to a RC(O)O— group, where R is as defined herein. through a carbonyl group, or vice versa. The term A“C-carboxy” group refers to a —C(O)OR groups where R “C-amido” as used herein, alone or in combination, refers to is as defined herein. a —C(O)N(RR) group with RandR' as defined herein or as The term "cyano.” as used herein, alone or in combina defined by the specifically enumerated “R” groups desig 40 tion, refers to —CN. nated. The term "N-amido” as used herein, alone or in The term “cycloalkyl, or, alternatively, “carbocycle, as combination, refers to a RC(O)N(R')—group, with R and R' used herein, alone or in combination, refers to a Saturated or as defined herein or as defined by the specifically enumer partially Saturated monocyclic, bicyclic or tricyclic alkyl ated “R” groups designated. The term “acylamino” as used group wherein each cyclic moiety contains from 3 to 12 herein, alone or in combination, embraces an acyl group 45 carbon atom ring members and which may optionally be a attached to the parent moiety through an amino group. An benzo fused ring system which is optionally Substituted as example of an “acylamino' group is acetylamino (CHC(O) defined herein. In certain embodiments, said cycloalkyl will NH ). comprise from 5 to 7 carbon atoms. Examples of such item “amino.” as used herein, alone or in combina cycloalkyl groups include cyclopropyl, cyclobutyl, cyclo tion, refers to —NRR", wherein R and R' are independently 50 pentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl. selected from the group consisting of hydrogen, alkyl, acyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamanty1 and heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocy the like. “Bicyclic” and “tricyclic” as used herein are cloalkyl, any of which may themselves be optionally sub intended to include both fused ring systems, such as deca stituted. Additionally, R and R' may combine to form hydronaphthalene, octahydronaphthalene as well as the mul heterocycloalkyl, either of which may be optionally substi 55 ticyclic (multicentered) saturated or partially unsaturated tuted. type, including spiro-ring fused systems. The bicyclic and The term “aryl, as used herein, alone or in combination, tricyclic types of isomer are exemplified in general by, means a carbocyclic aromatic system containing one, two or bicyclol, 1.1 pentane, camphor, adamantane, bicyclo3.2.1 three rings wherein such polycyclic ring systems are fused octane, and 4.4.1-bicyclononane. together. The term “aryl” embraces aromatic groups such as 60 The term “ester,” as used herein, alone or in combination, phenyl, naphthyl, anthracenyl, and phenanthryl. refers to a carboxy group bridging two moieties linked at The term “arylalkenyl or “aralkenyl, as used herein, carbon atoms. alone or in combination, refers to an aryl group attached to The term “ether,” as used herein, alone or in combination, the parent molecular moiety through an alkenyl group. refers to an oxy group bridging two moieties linked at The term “arylalkoxy' or “aralkoxy, as used herein, 65 carbon atoms. alone or in combination, refers to an aryl group attached to The term “halo,” or “halogen, as used herein, alone or in the parent molecular moiety through an alkoxy group. combination, refers to fluorine, chlorine, bromine, or iodine. US 9,481,692 B2 39 40 The term “haloalkoxy, as used herein, alone or in com further embodiments, said hetercycloalkyl will comprise bination, refers to a haloalkyl group attached to the parent from 1 to 2 heteroatoms as ring members. In certain embodi molecular moiety through an oxygen atom. ments, said hetercycloalkyl will comprise from 3 to 8 ring The term “haloalkyl, as used herein, alone or in combi members in each ring. In further embodiments, said heter nation, refers to an alkyl radical having the meaning as cycloalkyl will comprise from 3 to 7 ring members in each defined above wherein one or more hydrogens are replaced ring. In yet further embodiments, said hetercycloalkyl will with a halogen. Specifically embraced are monohaloalkyl, comprise from 5 to 6 ring members in each ring. “Hetero dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl cycloalkyl and "heterocycle” are intended to include sul radical, for one example, may have an iodo, bromo, chloro fones, cyclic sulfonamides, sulfoxides, N-oxides of tertiary or fluoro atom within the radical. Dihalo and polyhaloalkyl 10 nitrogen ring members, and carbocyclic fused, benzo fused, radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of and spiro-ring fused ring systems; additionally, both terms haloalkyl radicals include fluoromethyl, difluoromethyl, tri also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle fluoromethyl, chloromethyl, dichloromethyl, trichlorom group. Examples of heterocycle groups include aziridinyl, ethyl, pentafluoroethyl, heptafluoropropyl, difluorochlorom 15 ethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl. azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihy dichloroethyl and dichloropropyl. "Haloalkylene' refers to a droisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, haloalkyl group attached at two or more positions. Examples dihydro1.3oxazolo 4,5-b]pyridinyl, benzothiazolyl, dihy include fluoromethylene ( CFH ), difluoromethylene droindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl. (—CF ), chloromethylene (—CHCl ) and the like. 1,3-dioxolanyl. iSoindolinyl, morpholinyl, piperazinyl, pyr The term "heteroalkyl, as used herein, alone or in rolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, combination, refers to a stable straight or branched chain, or isothiazolidine, and the like. The heterocycle groups may be cyclic hydrocarbon radical, or combinations thereof, fully optionally substituted unless specifically prohibited. saturated or containing from 1 to 3 degrees of unsaturation, The term “hydrogen, as used herein, refers to both consisting of the stated number of carbon atoms and from 25 protium (H) and deuterium (H). This definition extends to one to three heteroatoms selected from the group consisting hydrogen atoms which appear in chemical structural draw of O, N, and S, and wherein the nitrogen and sulfur atoms ings disclosed herein, including at sites where hydrogen may optionally be oxidized and the nitrogen heteroatom may atoms are not explicitly shown. For example, a chemical structure disclosed herein may include an ethyl group rep optionally be quaternized. The heteroatom(s) O, N and S resented as may be placed at any interior position of the heteroalkyl 30 group. Up to two heteroatoms may be consecutive. Such as, for example, -CH NH OCH. The term "heteroaryl, as used herein, alone or in com bination, refers to a 3 to 15 membered unsaturated hetero monocyclic ring, or a fused monocyclic, bicyclic, or tricy 35 clic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the which includes five hydrogen atoms which are not explicitly group consisting of O, S, and N. In certain embodiments, drawn, any of which can be protium (H) or deuterium (H). said heteroaryl will comprise from 5 to 7 carbon atoms. The This definition also extends to hydrogen atoms which form term also embraces fused polycyclic groups wherein het 40 a part of a named chemical substituent disclosed herein. For erocyclic rings are fused with aryl rings, wherein heteroaryl example, a generic chemical structure disclosed herein may rings are fused with other heteroaryl rings, wherein het recite an aryl group, which encompasses specific embodi eroaryl rings are fused with heterocycloalkyl rings, or ments such as a phenyl group, which comprises five hydro wherein heteroaryl rings are fused with cycloalkyl rings. gen atoms, any of which can be protium (H) or deuterium Examples of heteroaryl groups include pyrrolyl pyrrolinyl, 45 (H). imidazolyl pyrazolyl pyridyl, pyrimidinyl, pyrazinyl, The term “deuterium enrichment” refers to the percentage pyridazinyl, triazolyl pyranyl, furyl, thienyl, oxazolyl, isox of incorporation of deuterium at a given position in a azolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, molecule in the place of hydrogen. For example, deuterium indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, enrichment of 1% at a given position means that 1% of isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotri 50 molecules in a given sample contain deuterium at the azolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzo specified position. Because the naturally occurring distribu Xadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, tion of deuterium is about 0.0156%, deuterium enrichment benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetra at any position in a compound synthesized using non hydroquinolinyl, tetraZolopyridazinyl, tetrahydroisoquinoli enriched starting materials is about 0.0156%. The deuterium nyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the 55 enrichment can be determined using conventional analytical like. Exemplary tricyclic heterocyclic groups include carba methods known to one of ordinary skill in the art, including Zolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridi mass spectrometry and nuclear magnetic resonance spec nyl, phenanthridinyl, Xanthenyl and the like. troscopy. The terms "heterocycloalkyl and, interchangeably, “het In certain embodiments, compounds disclosed herein are erocycle,” as used herein, alone or in combination, each 60 enriched with deuterium. Carbon-hydrogen bond strength is refer to a saturated, partially unsaturated, or fully unsatu directly proportional to the absolute value of the ground rated monocyclic, bicyclic, or tricyclic heterocyclic group state vibrational energy of the bond. This vibrational energy containing at least one heteroatom as a ring member, depends on the mass of the atoms that form the bond, and wherein each said heteroatom may be independently increases as the mass of one or both of the atoms making the selected from the group consisting of nitrogen, oxygen, and 65 bond increases. Since deuterium (D) has twice the mass of sulfur In certain embodiments, said hetercycloalkyl will protium (H), a C-D bond is stronger than the corresponding comprise from 1 to 4 heteroatoms as ring members. In C H bond. If a C-H bond is broken during a rate US 9,481,692 B2 41 42 determining step in a chemical reaction (i.e. the step with the members, comprising between them one to four heteroatoms highest transition state energy), then Substituting a deute selected from the group consisting of O, S, and N. rium for that protium will cause a decrease in the reaction The term “lower cycloalkyl, as used herein, alone or in rate, including cases where a C-H bond is broken during combination, means a monocyclic cycloalkyl having metabolism of a compound disclosed herein. This phenom between three and six ring members. Lower cycloalkyls may enon is known as the Deuterium Kinetic Isotope Effect be unsaturated. Examples of lower cycloalkyl include cyclo (DKIE). The magnitude of the DKIE can be expressed as the propyl, cyclobutyl, cyclopentyl, and cyclohexyl. ratio between the rates of a given reaction in which a C "H The term “lower heterocycloalkyl, as used herein, alone bond is broken, and the same reaction where deuterium is or in combination, means a monocyclic heterocycloalkyl substituted for protium. The DKIE can range from about 1 10 having between three and six ring members, of which (no isotope effect) to very large numbers. Such as 50 or more. between one and four may be heteroatoms selected from the The deuteration approach has the potential to slow the group consisting of O, S, and N. Examples of lower hetero metabolism of the compounds disclosed herein. Various cycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidi deuteration patterns can be used to (a) reduce or eliminate nyl, piperidinyl, piperazinyl, and morpholinyl. Lower het unwanted metabolites, (b) increase the half-life of the parent 15 erocycloalkyls may be unsaturated. drug, (c) decrease the number of doses needed to achieve a The term “lower amino,” as used herein, alone or in desired effect, (d) decrease the amount of a dose needed to combination, refers to —NRR", wherein R and R' are inde achieve a desired effect, (e) increase the formation of active pendently selected from the group consisting of hydrogen, metabolites, if any are formed, (f) decrease the production of lower alkyl, and lower heteroalkyl, any of which may be deleterious metabolites in specific tissues, and/or (g) create optionally substituted. Additionally, the R and R' of a lower a more effective drug and/or a safer drug for polypharmacy, amino group may combine to form a five- or six-membered whether the polypharmacy be intentional or not. Deuterium heterocycloalkyl, either of which may be optionally substi can be introduced into a compound as disclosed herein by tuted. synthetic techniques that employ deuterated reagents, The term “mercaptyl” as used herein, alone or in combi whereby incorporation rates are pre-determined; and/or by 25 nation, refers to an RS - group, where R is as defined exchange techniques, wherein incorporation rates are deter herein. mined by equilibrium conditions, and may be highly vari The term "nitro, as used herein, alone or in combination, able depending on the reaction conditions. Synthetic tech refers to NO. niques where deuterium is directly and specifically inserted The terms “oxy' or “oxa, as used herein, alone or in by a deuterated reagent of known isotopic content, can yield 30 combination, refer to —O—. high deuterium abundance, but can be limited by the chem The term “oxo, as used herein, alone or in combination, istry required. Exchange techniques, on the other hand, may refers to —O. yield lower deuterium incorporation, often with the isotope The term “perhaloalkoxy' refers to an alkoxy group being distributed over many sites on the molecule. where all of the hydrogen atoms are replaced by halogen The term “hydrazinyl as used herein, alone or in com 35 atOmS. bination, refers to two amino groups joined by a single bond, The term “perhaloalkyl as used herein, alone or in i.e., —N-N-. combination, refers to an alkyl group where all of the The term “hydroxy, as used herein, alone or in combi hydrogen atoms are replaced by halogen atoms. nation, refers to —OH. The terms "sulfonate,” “sulfonic acid,” and “sulfonic,” as The term “hydroxyalkyl, as used herein, alone or in 40 used herein, alone or in combination, refer the SOH combination, refers to a hydroxy group attached to the group and its anion as the Sulfonic acid is used in Salt parent molecular moiety through an alkyl group. formation. The term “imino,” as used herein, alone or in combina The term “sulfanyl, as used herein, alone or in combi tion, refers to —N—. nation, refers to —S—. The term “iminohydroxy, as used herein, alone or in 45 The term "sulfinyl, as used herein, alone or in combi combination, refers to —N(OH) and —N O—. nation, refers to —S(O)—. The phrase “in the main chain” refers to the longest The term “sulfonyl, as used herein, alone or in combi contiguous or adjacent chain of carbon atoms starting at the nation, refers to —S(O) -. point of attachment of a group to the compounds of any one The term “N-sulfonamido” refers to a RS(=O)NR'— of the formulas disclosed herein. 50 group with R and R' as defined herein. The term "isocyanato” refers to a —NCO group. The term “S-sulfonamido” refers to a S(=O)NRR', The term “isothiocyanato” refers to a —NCS group. group, with R and R' as defined herein. The phrase “linear chain of atoms’ refers to the longest The terms “thia” and “thio.” as used herein, alone or in straight chain of atoms independently selected from carbon, combination, refer to a —S— group or an ether wherein the nitrogen, oxygen and Sulfur. 55 oxygen is replaced with sulfur. The oxidized derivatives of The term “lower,” as used herein, alone or in a combi the thio group, namely sulfinyl and Sulfonyl, are included in nation, where not otherwise specifically defined, means the definition of thia and thio. containing from 1 to and including 6 carbon atoms. The term “thiol, as used herein, alone or in combination, The term “lower aryl, as used herein, alone or in com refers to an —SH group. bination, means phenyl or naphthyl, either of which may be 60 The term “thiocarbonyl, as used herein, when alone optionally substituted as provided. includes thioformyl —C(S)H and in combination is a The term “lower heteroaryl, as used herein, alone or in —C(S)— group. combination, means either 1) monocyclic heteroaryl com The term “N-thiocarbamyl” refers to an ROC(S)NR' prising five or six ring members, of which between one and group, with R and R' as defined herein. four said members may be heteroatoms selected from the 65 The term “O-thiocarbamyl” refers to a OC(S)NRR', group consisting of O, S, and N, or 2) bicyclic heteroaryl, group with R and R' as defined herein. wherein each of the fused rings comprises five or six ring The term “thiocyanato’ refers to a CNS group. US 9,481,692 B2 43 44 The term "trihalomethanesulfonamido” refers to a XCS Substituent, or term (e.g. aryl, heterocycle, R, etc.) occur (O)NR— group with X is a halogen and R as defined more than one time in a formula or generic structure, its herein. definition at each occurrence is independent of the definition The term “trihalomethanesulfonyl refers to a XCS at every other occurrence. Those of skill in the art will (O) - group where X is a halogen. further recognize that certain groups may be attached to a The term “trihalomethoxy' refers to a XCO— group parent molecule or may occupy a position in a chain of where X is a halogen. elements from either end as written. Thus, by way of The term “trisubstituted silyl, as used herein, alone or in example only, an unsymmetrical group Such as —C(O)N combination, refers to a silicone group Substituted at its three (R)— may be attached to the parent moiety at either the free valences with groups as listed herein under the defini 10 tion of substituted amino. Examples include trimethysilyl, carbon or the nitrogen. tert-butyldimethylsilyl, triphenylsilyl and the like. Asymmetric centers exist in the compounds disclosed Any definition herein may be used in combination with herein. These centers are designated by the symbols “R” or any other definition to describe a composite structural group. “S. depending on the configuration of Substituents around the chiral carbon atom. It should be understood that the By convention, the trailing element of any Such definition is 15 that which attaches to the parent moiety. For example, the invention encompasses all stereochemical isomeric forms, composite group alkylamido would represent an alkyl group including diastereomeric, enantiomeric, and epimeric forms, attached to the parent molecule through an amido group, and as well as d-isomers and 1-isomers, and mixtures thereof. the term alkoxyalkyl would represent an alkoxy group Individual stereoisomers of compounds can be prepared attached to the parent molecule through an alkyl group. synthetically from commercially available starting materials When a group is defined to be “null.” what is meant is that which contain chiral centers or by preparation of mixtures of said group is absent. enantiomeric products followed by separation Such as con The term “optionally substituted” means the anteceding version to a mixture of diastereomers followed by separation group may be substituted or unsubstituted. When substi or recrystallization, chromatographic techniques, direct tuted, the substituents of an “optionally substituted’ group 25 separation of enantiomers on chiral chromatographic col may include, without limitation, one or more Substituents umns, or any other appropriate method known in the art. independently selected from the following groups or a Starting compounds of particular Stereochemistry are either particular designated set of groups, alone or in combination: commercially available or can be made and resolved by lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, techniques known in the art. Additionally, the compounds lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, 30 lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, disclosed herein may exist as geometric isomers. The pres lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, ary ent invention includes all cis, trans, syn, anti, entgegen (E), loxy, lower alkoxy, lower haloalkoxy, Oxo, lower acyloxy, and Zusammen (Z) isomers as well as the appropriate carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyes mixtures thereof. Additionally, compounds may exist as ter, lower carboxamido, cyano, hydrogen, halogen, hydroxy, 35 tautomers; all tautomeric isomers are provided by this amino, lower alkylamino, arylamino, amido, nitro, thiol, invention. Additionally, the compounds disclosed herein can lower alkylthio, lower haloalkylthio, lower perhaloalkylthio. exist in unsolvated as well as Solvated forms with pharma arylthio, sulfonate, sulfonic acid, trisubstituted silyl N, SH, ceutically acceptable solvents such as water, ethanol, and the SCH, C(O)CH, COCH CO.H. pyridinyl, thiophene, like. In general, the Solvated forms are considered equivalent furanyl, lower carbamate, and lower urea. Two substituents 40 to the unsolvated forms. may be joined together to form a fused five-, six-, or The term “bond refers to a covalent linkage between two seven-membered carbocyclic or heterocyclic ring consisting atoms, or two moieties when the atoms joined by the bond of Zero to three heteroatoms, for example forming methyl are considered to be part of larger Substructure. A bond may enedioxy or ethylenedioxy. An optionally Substituted group be single, double, or triple unless otherwise specified. A may be unsubstituted (e.g., —CH2CH), fully substituted 45 dashed line between two atoms in a drawing of a molecule (e.g., —CFCF), monosubstituted (e.g., —CH2CHF) or indicates that an additional bond may be present or absent at substituted at a level anywhere in-between fully substituted that position. When a group in a chemical formula is and monosubstituted (e.g., —CHCF). Where substituents designated to be “a bond.” the group reduces to a linkage are recited without qualification as to substitution, both between the groups to which it is linked in the formula. By Substituted and unsubstituted forms are encompassed. 50 way of example, in Formula I, when Y is a bond, it becomes Where a substituent is qualified as “substituted,” the substi a direct link between A and -alkyl-N(R)Rs, forming Rs (R) tuted form is specifically intended. Additionally, different N-alkyl-A-Y. —(B-(R2),)-D-E-(Rs). sets of optional Substituents to a particular moiety may be As used herein, the term "modulate” means to increase or defined as needed; in these cases, the optional Substitution decrease the activity of a target or the amount of a Substance. will be as defined, often immediately following the phrase, 55 As used herein, the term “increase' or the related terms “optionally substituted with.” “increased,' 'enhance' or "enhanced’ refers to a statisti The term R or the term R', appearing by itself and without cally significant increase, and the terms “decreased.' 'Sup a number designation, unless otherwise defined, refers to a pressed,” or “inhibited' to a statistically significant decrease. moiety selected from the group consisting of hydrogen, For the avoidance of doubt, an increase generally refers to alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and hetero 60 at least a 10% increase in a given parameter, and can cycloalkyl, any of which may be optionally Substituted. encompass at least a 20% increase, 30% increase, 40% Such R and R' groups should be understood to be optionally increase, 50% increase, 60% increase, 70% increase, 80% substituted as defined herein. Whether an R group has a increase, 90% increase, 95% increase, 97% increase, 99% or number designation or not, every R group, including R, R even a 100% increase over the control, baseline, or prior and R' where n=(1, 2, 3, ... n), every substituent, and every 65 in-time value. Inhibition generally refers to at least a 10% term should be understood to be independent of every other decrease in a given parameter, and can encompass at least a in terms of selection from a group. Should any variable, 20% decrease, 30% decrease, 40% decrease, 50% decrease, US 9,481,692 B2 45 46 60% decrease, 70% decrease, 80% decrease, 90% decrease, chemical or biochemical methods in an ex vivo environ 95% decrease, 97% decrease, 99% or even a 100% decrease ment. For example, prodrugs can be slowly converted to a over the control value. compound when placed in a transdermal patch reservoir The term “disease' as used herein is intended to be with a suitable enzyme or chemical reagent. Prodrugs are generally synonymous, and is used interchangeably with, the often useful because, in some situations, they may be easier terms “disorder and “condition' (as in medical condition), to administer than the compound, or parent drug. They may, in that all reflect an abnormal condition of the human or for instance, be bioavailable by oral administration whereas animal body or of one of its parts that impairs normal the parent drug is not. The prodrug may also have improved functioning, is typically manifested by distinguishing signs solubility in pharmaceutical compositions over the parent and symptoms, and causes the human or animal to have a 10 drug. A wide variety of prodrug derivatives are known in the reduced duration or quality of life. art, Such as those that rely on hydrolytic cleavage or oxida The term “combination therapy” means the administra tive activation of the prodrug. An example, without limita tion of two or more therapeutic agents to treat a therapeutic tion, of a prodrug would be a compound which is adminis condition or disorder described in the present disclosure. tered as an ester (the “prodrug), but then is metabolically Such administration encompasses co-administration of these 15 hydrolyzed to the carboxylic acid, the active entity. Addi therapeutic agents in a Substantially simultaneous manner, tional examples include peptidyl derivatives of a compound Such as in a single formulation (e.g., a capsule or injection) and N-oxides of amines or heterocyclic groups such as having a fixed ratio of active ingredients or in multiple, pyridine. separate dosage forms for each active ingredient. In addi The term “metabolite' refers to a compound produced tion, such administration also encompasses use of each type through biological transformation of a compound following of therapeutic agent in a sequential manner. In either case, administration to a subject. In order to eliminate foreign the treatment regimen will provide beneficial effects of the Substances Such as therapeutic agents, the animal body drug combination in treating the conditions or disorders expresses various enzymes, such as the cytochrome Paso described herein. enzymes (CYPs), esterases, proteases, reductases, dehydro The phrase “therapeutically effective' is intended to 25 genases, and monoamine oxidases, to react with and convert qualify the amount of active ingredients used in the treat these foreign substances to more polar intermediates or ment of a disease or disorder. This amount will achieve the metabolites for renal excretion. Such metabolic reactions goal of reducing or eliminating the said disease or disorder. frequently involve the oxidation of a carbon-hydrogen The term “therapeutically acceptable' refers to those (C-H) bond to either a carbon-oxygen (C–O) or a carbon compounds (or salts, polymorphs, prodrugs, tautomers, 30 carbon (C-C)-bond, N-oxidation, or covalent bonding of a Zwitterionic forms, etc.) which are suitable for use in contact polar molecule or functional group (such as Sulfate, glu with the tissues of patients without undue toxicity, irritation, curonic acid, glutathione, or glycine, to the therapeutic and allergic response, are commensurate with a reasonable agent. The resultant metabolites may be stable or unstable benefit/risk ratio, and are effective for their intended use. under physiological conditions, and can have substantially As used herein, reference to “treatment of a patient is 35 different pharmacokinetic, pharmacodynamic, and acute and intended to include prophylaxis. long-term toxicity profiles relative to the parent compounds. In the present invention, the term “radiation” means Certain compounds disclosed herein may, after administra ionizing radiation comprising particles or photons that have tion to a subject result in formation of metabolites, which in Sufficient energy or can produce Sufficient energy via nuclear Some cases have biological activity as HIF pathway modu interactions to produce ionization (gain or loss of electrons). 40 lators or activity against other biological systems. In certain An exemplary and preferred ionizing radiation is an X-ra embodiments, metabolites of the compounds disclosed diation. Means for delivering X-radiation to a target tissue or herein include N-oxides, particularly N-oxides of heterocy cell are well known in the art. The amount of ionizing clic groups such as pyridine. In further embodiments, radiation needed in a given cell generally depends on the metabolites of compounds disclosed herein may themselves nature of that cell. Means for determining an effective 45 have substantial activity as HIF pathway inhibitors. amount of radiation are well known in the art. Used herein, The compounds disclosed herein can exist as therapeuti the term “an effective dose of ionizing radiation means a cally acceptable salts. Suitable acid addition salts include dose of ionizing radiation that produces an increase in cell those formed with both organic and inorganic acids, and will damage or death. normally be pharmaceutically acceptable. However, salts of The term “radiation therapy” refers to the use of electro 50 non-pharmaceutically acceptable salts may be of utility in magnetic or particulate radiation in the treatment of neopla the preparation and purification of the compound in ques sia and includes the use of ionizing and non-ionizing radia tion. Basic addition salts may also be formed and be tion. pharmaceutically acceptable. Representative acid addition As used herein, the term "patient’ means all mammals salts include acetate, adipate, alginate, L-ascorbate, aspar including humans. Examples of patients include humans, 55 tate, benzoate, benzenesulfonate (besylate), bisulfate, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, butyrate, camphorate, camphorsulfonate, citrate, diglucon the patient is a human. ate, formate, fumarate, gentisate, glutarate, glycerophos The term “prodrug” refers to a compound that is made phate, glycolate, hemisulfate, heptanoate, hexanoate, hippu more active in vivo. Certain compounds disclosed herein rate, hydrochloride, hydrobromide, hydroiodide, may also exist as prodrugs, as described in Hydrolysis in 60 2-hydroxyethan sulfonate (isethionate), lactate, maleate, Drug and Prodrug Metabolism: Chemistry, Biochemistry, malonate, DL-mandelate, mesitylenesulfonate, methanesul and Enzymology (Testa, Bernard and Mayer, Joachim M. fonate, naphthylenesulfonate, nicotinate, 2-naphthalenesul Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the fonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpro compounds described herein are structurally modified forms prionate, phosphonate, picrate, pivalate, propionate, of the compound that readily undergo chemical changes 65 pyroglutamate. Succinate, Sulfonate, tartrate, L-tartrate, under physiological conditions to provide the compound. trichloroacetate, trifluoroacetate, phosphate, glutamate, Additionally, prodrugs can be converted to the compound by bicarbonate, para-toluenesulfonate (p-tosylate), and unde US 9,481,692 B2 47 48 canoate. Also, basic groups in the compounds disclosed manufacturing), and dissolution rates (an important factor in herein can be quaternized with methyl, ethyl, propyl, and bioavailability). Differences in stability can result from butyl chlorides, bromides, and iodides; dimethyl, diethyl, changes in chemical reactivity (e.g. differential oxidation, dibutyl, and diamyl Sulfates; decyl, lauryl, myristyl, and Such that a dosage form discolors more rapidly when com steryl chlorides, bromides, and iodides; and benzyl and prised of one polymorph than when comprised of another phenethyl bromides. For a more complete discussion of the polymorph) or mechanical changes (e.g. tablets crumble on preparation and selection of salts, refer to Pharmaceutical storage as a kinetically favored polymorph converts to Salts: Properties, Selection, and Use (Stahl, P. Heinrich. thermodynamically more stable polymorph) or both (e.g., Wiley-VCHA, Zurich, Switzerland, 2002). tablets of one polymorph are more susceptible to breakdown The term “therapeutically acceptable salt, as used herein, 10 at high humidity). As a result of solubility/dissolution dif represents salts or Zwitterionic forms of the compounds ferences, in the extreme case, some polymorphic transitions disclosed herein which are water or oil-soluble or dispersible may result in lack of potency or, at the other extreme, and therapeutically acceptable as defined herein. The salts toxicity. In addition, the physical properties of the crystal can be prepared during the final isolation and purification of may be important in processing, for example, one poly the compounds or separately by reacting the appropriate 15 morph might be more likely to form solvates or might be compound in the form of the free base with a suitable acid. difficult to filter and wash free of impurities (i.e., particle Examples of acids which can be employed to form thera shape and size distribution might be different between peutically acceptable addition salts include inorganic acids polymorphs). Such as hydrochloric, hydrobromic, Sulfuric, and phos Polymorphs of a molecule can be obtained by a number phoric, and organic acids such as oxalic, maleic. Succinic, of methods, as known in the art. Such methods include, but and citric. Salts can also be formed by coordination of the are not limited to, melt recrystallization, melt cooling, compounds with an alkali metal or alkaline earth ion. Solvent recrystallization, desolvation, rapid evaporation, Basic addition salts can be prepared during the final rapid cooling, slow cooling, vapor diffusion and Sublima isolation and purification of the compounds, often by react tion. ing a carboxy group with a suitable base Such as the 25 While it may be possible for the compounds and prodrugs hydroxide, carbonate, or bicarbonate of a metal cation or disclosed herein to be administered as the raw chemical, it with ammonia or an organic primary, secondary, or tertiary is also possible to present them as a pharmaceutical formu amine. The cations of therapeutically acceptable salts lation. Accordingly, provided herein are pharmaceutical include lithium, Sodium (e.g., NaOH), potassium (e.g., formulations which comprise one or more of certain com KOH), calcium (including Ca(OH)), magnesium (including 30 pounds and prodrugs disclosed herein, or one or more Mg(OH) and magnesium acetate), Zinc, (including pharmaceutically acceptable salts, esters, amides, or Solvates Zn(OH) and zinc acetate) and aluminum, as well as non thereof, together with one or more pharmaceutically accept toxic quaternary amine cations such as ammonium, tetram able carriers thereof and optionally one or more other ethylammonium, tetraethylammonium, methylamine, dim therapeutic ingredients. The carrier(s) must be “acceptable' ethylamine, trimethylamine, triethylamine, diethylamine, 35 in the sense of being compatible with the other ingredients ethylamine, tributylamine, pyridine, N,N-dimethylaniline, of the formulation and not deleterious to the recipient N-methylpiperidine, N-methylmorpholine, dicyclohexylam thereof. Proper formulation is dependent upon the route of ine, procaine, dibenzylamine, N,N-dibenzylphenethylam administration chosen. Any of the well-known techniques, ine, 1-ephenamine, and N,N'-dibenzylethylenediamine. carriers, and excipients may be used as Suitable and as Other representative organic amines useful for the formation 40 understood in the art; e.g., in Remington’s Pharmaceutical of base addition salts include ethylenediamine, etha Sciences. The pharmaceutical compositions disclosed herein nolamine, diethanolamine, piperidine, piperazine, choline may be manufactured in any manner known in the art, e.g., hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrroli by means of conventional mixing, dissolving, granulating, done, imidazole, n-methyl-d-glucamine, N, N'-dibenzyleth dragee-making, levigating, emulsifying, encapsulating, ylenediamine, N, N'-diethylethanolamine, N, N'-dimethyl 45 entrapping or compression processes. ethanolamine, triethanolamine, and tromethamine. Basic The formulations include those suitable for oral, parent amino acids such as 1-glycine and 1-arginine, and amino eral (including Subcutaneous, intradermal, intramuscular, acids which may be Zwitterionic at neutral pH, such as intravenous, intraarticular, and intramedullary), intraperito betaine (N.N.N-trimethylglycine) are also contemplated. neal, transmucosal, transdermal, intranasal, rectal and topi Salts disclosed herein may combine in 1:1 molar ratios, 50 cal (including dermal, buccal, Sublingual and intraocular) and in fact this is often how they are initially synthesized. administration although the most Suitable route may depend However, it will be recognized by one of skill in the art that upon for example the condition and disorder of the recipient. the stoichiometry of one ion in a salt to the other may be The formulations may conveniently be presented in unit otherwise. Salts shown herein may be, for the sake of dosage form and may be prepared by any of the methods convenience in notation, shown in a 1:1 ratio; all possible 55 well known in the art of pharmacy. Typically, these methods Stoichiometric arrangements are encompassed by the scope include the step of bringing into association a compound of of the present invention. the Subject invention or a pharmaceutically acceptable salt, The terms, “polymorphs” and “polymorphic forms and ester, amide, prodrug or solvate thereof (“active ingredient') related terms herein refer to crystal forms of the same with the carrier which constitutes one or more accessory molecule, and different polymorphs may have different 60 ingredients. In general, the formulations are prepared by physical properties such as, for example, melting tempera uniformly and intimately bringing into association the active tures, heats of fusion, Solubilities, dissolution rates and/or ingredient with liquid carriers or finely divided solid carriers vibrational spectra as a result of the arrangement or confor or both and then, if necessary, shaping the product into the mation of the molecules in the crystal lattice. The differences desired formulation. in physical properties exhibited by polymorphs affect phar 65 Formulations of the compounds and prodrugs disclosed maceutical parameters such as storage stability, compress herein Suitable for oral administration may be presented as ibility and density (important in formulation and product discrete units such as capsules, cachets or tablets each US 9,481,692 B2 49 50 containing a predetermined amount of the active ingredient; contain Suitable stabilizers or agents which increase the as a powder or granules; as a solution or a Suspension in an solubility of the compounds and prodrugs to allow for the aqueous liquid or a non-aqueous liquid; or as an oil-in-water preparation of highly concentrated solutions. liquid emulsion or a water-in-oil liquid emulsion. The active In addition to the formulations described previously, a ingredient may also be presented as a bolus, electuary or 5 compound or prodrug as disclosed herein may also be paste. formulated as a depot preparation. Such long acting formu Pharmaceutical preparations which can be used orally lations may be administered by implantation (for example include tablets, push-fit capsules made of gelatin, as well as Subcutaneously or intramuscularly) or by intramuscular soft, sealed capsules made of gelatin and a plasticizer, Such injection. Thus, for example, the compounds and prodrugs as glycerol or Sorbitol. Tablets may be made by compression 10 may be formulated with suitable polymeric or hydrophobic or molding, optionally with one or more accessory ingredi materials (for example as an emulsion in an acceptable oil) ents. Compressed tablets may be prepared by compressing or ion exchange resins, or as sparingly soluble derivatives, in a suitable machine the active ingredient in a free-flowing for example, as a sparingly soluble salt. form Such as a powder or granules, optionally mixed with For buccal or Sublingual administration, the compositions binders, inert diluents, or lubricating, Surface active or 15 may take the form of tablets, lozenges, pastilles, or gels dispersing agents. Molded tablets may be made by molding formulated in conventional manner. Such compositions may in a Suitable machine a mixture of the powdered compound comprise the active ingredient in a flavored basis Such as moistened with an inert liquid diluent. The tablets may Sucrose and acacia or tragacanth. optionally be coated or scored and may be formulated so as The compounds and prodrugs may also be formulated in to provide slow or controlled release of the active ingredient rectal compositions such as Suppositories or retention therein. All formulations for oral administration should be in enemas, e.g., containing conventional Suppository bases dosages suitable for Such administration. The push-fit cap Such as cocoa butter, polyethylene glycol, or other glycer Sules can contain the active ingredients in admixture with ides. filler such as lactose, binders such as starches, and/or Certain compounds and prodrugs disclosed herein may be lubricants such as talc or magnesium Stearate and, option 25 administered topically, that is by non-systemic administra ally, stabilizers. In soft capsules, the active compounds and tion. This includes the application of a compound disclosed prodrugs may be dissolved or Suspended in Suitable liquids, herein externally to the epidermis or the buccal cavity and Such as fatty oils, liquid paraffin, or liquid polyethylene the instillation of Such a compound into the ear, eye and glycols. In addition, stabilizers may be added. Dragee cores nose. Such that the compound does not significantly enter the are provided with Suitable coatings. For this purpose, con 30 blood stream. In contrast, Systemic administration refers to centrated Sugar Solutions may be used, which may option oral, intravenous, intraperitoneal and intramuscular admin ally contain gum arabic, talc, polyvinyl pyrrollidone, car istration. bopol gel, polyethylene glycol, and/or titanium dioxide, Formulations suitable for topical administration include lacquer Solutions, and Suitable organic solvents or solvent liquid or semi-liquid preparations Suitable for penetration mixtures. Dyestuffs or pigments may be added to the tablets 35 through the skin to the site of inflammation Such as gels, or dragee coatings for identification or to characterize dif liniments, lotions, creams, ointments or pastes, and drops ferent combinations of active compound doses. suitable for administration to the eye, ear or nose. The active The compounds and prodrugs may be formulated for ingredient for topical administration may comprise, for parenteral administration by injection, e.g., by bolus injec example, from 0.001% to 10% w/w (by weight) of the tion or continuous infusion. Formulations for injection may 40 formulation. In certain embodiments, the active ingredient be presented in unit dosage form, e.g., in ampoules or in may comprise as much as 10% w/w. In other embodiments, multi-dose containers, with an added preservative. The it may comprise less than 5% w/w. In certain embodiments, compositions may take Such forms as Suspensions, Solutions the active ingredient may comprise from 2% w/w to 5% or emulsions in oily or aqueous vehicles, and may contain w/w. In other embodiments, it may comprise from 0.1% to formulatory agents such as Suspending, stabilizing and/or 45 1% w/w of the formulation. dispersing agents. The formulations may be presented in For administration by inhalation, compounds and prod unit-dose or multi-dose containers, for example sealed rugs may be conveniently delivered from an insufflator, ampoules and vials, and may be stored in powder form or in nebulizer pressurized packs or other convenient means of a freeze-dried (lyophilized) condition requiring only the delivering an aerosol spray. Pressurized packs may comprise addition of the sterile liquid carrier, for example, saline or 50 a suitable propellant such as dichlorodifluoromethane, sterile pyrogen-free water, immediately prior to use. Extem trichlorofluoromethane, dichlorotetrafluoroethane, carbon poraneous injection solutions and Suspensions may be pre dioxide or other Suitable gas. In the case of a pressurized pared from sterile powders, granules and tablets of the kind aerosol, the dosage unit may be determined by providing a previously described. valve to deliver a metered amount. Alternatively, for admin Formulations for parenteral administration include aque 55 istration by inhalation or insufllation, the compounds and ous and non-aqueous (oily) sterile injection solutions of the prodrugs disclosed herein may take the form of a dry powder active compounds and prodrugs which may contain antioxi composition, for example a powder mix of the compound dants, buffers, bacteriostats and solutes which render the and a Suitable powder base such as lactose or starch. The formulation isotonic with the blood of the intended recipi powder composition may be presented in unit dosage form, ent; and aqueous and non-aqueous sterile Suspensions which 60 in for example, capsules, cartridges, gelatin or blister packs may include Suspending agents and thickening agents. Suit from which the powder may be administered with the aid of able lipophilic solvents or vehicles include fatty oils such as an inhalator or insufflator. sesame oil, or synthetic fatty acid esters, such as ethyl oleate Intranasal delivery, in particular, may be useful for deliv or triglycerides, or liposomes. Aqueous injection Suspen ering compounds to the CNS. It had been shown that sions may contain Substances which increase the Viscosity of 65 intranasal drug administration is a noninvasive method of the Suspension, such as sodium carboxymethyl cellulose, bypassing the blood-brain barrier (BBB) to deliver neuro Sorbitol, or dextran. Optionally, the Suspension may also trophins and other therapeutic agents to the brain and spinal US 9,481,692 B2 51 52 cord. Delivery from the nose to the CNS occurs within regimen) that also has therapeutic benefit. By way of minutes along both the olfactory and trigeminal neural example only, in a treatment for cancer involving adminis pathways. Intranasal delivery occurs by an extracellular tration of one of the compounds described herein, increased route and does not require that drugs bind to any receptor or therapeutic benefit may result by also providing the patient undergo axonal transport. Intranasal delivery also targets the with another therapeutic agent for cancer. In any case, nasal associated lymphatic tissues (NALT) and deep cervical regardless of the disease, disorder or condition being treated, lymph nodes. In addition, intranasally administered thera the overall benefit experienced by the patient may simply be peutics are observed at high levels in the blood vessel walls additive of the two therapeutic agents or the patient may and perivascular spaces of the cerebrovasculature. Using experience a synergistic benefit. this intranasal method in animal models, researchers have 10 The compounds disclosed herein, including compounds Successfully reduced stroke damage, reversed Alzheimer's of Formula I, are also useful as chemo- and radio-sensitizers neurodegeneration, reduced anxiety, improved memory, for cancer treatment. They are useful for the treatment of stimulated cerebral neurogenesis, and treated brain tumors. mammals who have previously undergone or are presently In humans, intranasal insulin has been shown to improve undergoing or will be undergoing treatment for cancer. Such memory in normal adults and patients with Alzheimer's 15 other treatments include chemotherapy, radiation therapy, disease. Hanson L R and Frey W H, 2nd, J Neuroimmune Surgery or immunotherapy, Such as cancer vaccines. Pharmacol. 2007 March; 2(1):81-6. Epub 2006 Sep. 15. The instant compounds are particularly useful in combi Preferred unit dosage formulations are those containing nation with therapeutic, anti-cancer and/or radiotherapeutic an effective dose, as herein below recited, or an appropriate agents. Thus, the present invention provides a combination fraction thereof, of the active ingredient. of the presently compounds of Formula I with therapeutic, It should be understood that in addition to the ingredients anti-cancer and/or radiotherapeutic agents for simultaneous, particularly mentioned above, the formulations described separate or sequential administration. The compounds of above may include other agents conventional in the art this invention and the other anticancer agent can act addi having regard to the type of formulation in question, for tively or synergistically. A synergistic combination of the example those Suitable for oral administration may include 25 present compounds and another anticancer agent might flavoring agents. allow the use of lower dosages of one or both of these agents Compounds and prodrugs may be administered orally or and/or less frequent dosages of one or both of the instant via injection at a dose of from 0.1 to 500 mg/kg per day. The compounds and other anticancer agents and/or to administer dose range for adult humans is generally from 5 mg to 2 the agents less frequently can reduce any toxicity associated g/day. Tablets or other forms of presentation provided in 30 with the administration of the agents to a subject without discrete units may conveniently contain an amount of one or reducing the efficacy of the agents in the treatment of cancer. more compound or prodrug which is effective at such dosage In addition, a synergistic effect might result in the improved or as a multiple of the same, for instance, units containing 5 efficacy of these agents in the treatment of cancer and/or the mg to 500 mg, usually around 10 mg to 200 mg. reduction of any adverse or unwanted side effects associated The amount of active ingredient that may be combined 35 with the use of either agent alone. with the carrier materials to produce a single dosage form The therapeutic agent, anti-cancer agent and/or radiation will vary depending upon the host treated and the particular therapy can be administered according to therapeutic pro mode of administration. tocols well known in the art. It will be apparent to those The compounds and prodrugs can be administered in skilled in the art that the administration of the therapeutic various modes, e.g. orally, topically, or by injection. The 40 agent, anti-cancer agent and/or radiation therapy can be precise amount of compound administered to a patient will varied depending on the disease being treated and the known be the responsibility of the attendant physician. The specific effects of the anti-cancer agent and/or radiation therapy on dose level for any particular patient will depend upon a that disease. Also, in accordance with the knowledge of the variety of factors including the activity of the specific skilled clinician, the therapeutic protocols (e.g., dosage compound employed, the age, body weight, general health, 45 amounts and times of administration) can be varied in view sex, diets, time of administration, route of administration, of the observed effects of the administered therapeutic rate of excretion, drug combination, the precise disorder agents (i.e., anti-neoplastic agent or radiation) on the patient, being treated, and the severity of the indication or condition and in view of the observed responses of the disease to the being treated. Also, the route of administration may vary administered therapeutic agents, and observed adverse depending on the condition and its severity. 50 affects. In certain instances, it may be appropriate to administer at Dosage ranges for X-rays range from daily doses of 50 to least one of the compounds and prodrugs described herein 200 roentgens for prolonged periods of time (3 to 4 weeks), (or a pharmaceutically acceptable salt or ester thereof) in to single doses of 2000 to 6000 roentgens. Dosage ranges for combination with another therapeutic agent. By way of radioisotopes vary widely, and depend on the half-life of the example only, if one of the side effects experienced by a 55 isotope, the strength and type of radiation emitted, and the patient upon receiving one of the compounds herein for the uptake by the neoplastic cells. treatment of cancer is nausea, then it may be appropriate to Any suitable means for delivering radiation to a tissue administer an antiemetic agent in combination. Or, by way may be employed in the present invention. Common means of example only, the therapeutic effectiveness of one of the of delivering radiation to a tissue is by an ionizing radiation compounds described herein may be enhanced by adminis 60 source external to the body being treated. Alternative meth tration of an adjuvant (i.e., by itself the adjuvant may only ods for delivering radiation to a tissue include, for example, have minimal therapeutic benefit, but in combination with first delivering in vivo a radiolabeled antibody that immu another therapeutic agent, the overall therapeutic benefit to noreacts with an antigen of the tumor, followed by deliver the patient is enhanced). Or, by way of example only, the ing in vivo an effective amount of the radio labeled antibody benefit of experienced by a patient may be increased by 65 to the tumor. In addition, radioisotopes may be used to administering one of the compounds described herein with deliver ionizing radiation to a tissue or cell. Additionally, the another therapeutic agent (which also includes a therapeutic radiation may be delivered by means of a radiomimetic US 9,481,692 B2 53 54 agent. As used herein a “radiomimetic agent' is a chemo eran) etc.); alkyl sulfonates like Busulfan Myleran, therapeutic agent, for example melphalan, that causes the nitrosoureas (e.g., Carmustine or BCNU (bis-chloroethylni same type of cellular damage as radiation therapy, but trosourea), fotemustine Lomustine, and Semustine, Strepto without the application of radiation. Zocin etc.), and other alkylating agents (e.g., Dacarbazine, In one embodiment, the compounds of formula I can be procarbazine ethylenimine/methylmelamine, thriethylen administered in combination with one or more agent emelamine (TEM), triethylene thiophosphoramide (thio selected from aromatase inhibitors, anti-estrogens, anti-pro tepa), hexamethylmelamine (HMM, altretamine), and Mito gesterons, anti-androgens, or gonadorelin agonists, anti cycin, uramustine etc.) including Temozolomide (brand inflammatory agents, antihistamines, anti-cancer agent, names Temodar and Temodal and Temcad), altretamine (also inhibitors of angiogenesis, topoisomerase 1 and 2 inhibitors, 10 hexalen) and mitomycin; microtubule active agents, alkylating agents, antineoplastic, 3) noncovalent DNA-binding agents antitumor antibiot antimetabolite, dacarbazine (DTIC), platinum containing ics, including nucleic acid inhibitors (e.g., Dactinomycin compound, lipid or protein kinase targeting agents, protein Actinomycin D1, etc.), anthracyclines (e.g., Daunorubicin or lipid phosphatase targeting agents, anti-angiogenic Daunomycin, and Cerubidine. Doxorubicin Adrianycin, agents, agents that induce cell differentiation, bradykinin 1 15 epirubicin (Ellence), and Idarubicin Idamycin, valrubicin receptor and angiotensin II antagonists, cyclooxygenase (Valstar) etc.), anthracenediones (e.g., anthracycline ana inhibitors, heparanase inhibitors, lymphokines or cytokine logues, such as, Mitoxantrone, etc.), bleomycins (Blenox inhibitors, bisphosphanates, rapamycin derivatives, anti ane), etc., amsacrine and plicamycin (Mithramycin), dac apoptotic pathway inhibitors, apoptotic pathway agonists, tinomycin, mitomycin C: PPAR agonists, HSP90 inhibitor, smoothened antagonist, 4) antimetabolites, including, antifolates (e.g., Methotrex inhibitors of Ras isoforms, telomerase inhibitors, protease ate, Folex, aminopterin, pemetrexed, raltitrexed and Mexate, inhibitors, metalloproteinase inhibitors, aminopeptidase trimetrexate etc.), purine antimetabolites (e.g., 6-Mercap inhibitors, imununomodulators, therapeutic antibody and a topurine 6-MP. Purinethol, cladribine, 6-Thioguanine protein kinase inhibitor, e.g., a tyrosine kinase or serine/ 6-TG. clofarabine (Clolar, Evoltra), Azathioprine, Acyclo threonine kinase inhibitor. 25 vir, Fludarabine or fludarabine phosphate (Fludara) Ganci In another embodiment is provided a combination of a clovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine compound of formula I and an anti-cancer agent for simul CdA, and 2'-Deoxycoformycin Pentostatin, etc.), pyrimi taneous, separate or sequential administration. dine antagonists (e.g., fluoropyrimidines e.g., 5-fluorouracil Examples of cancer agents or chemotherapeutic agents for (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine). use in combination with the compounds as disclosed herein 30 capecitabine Carmofur or HCFU (1-hexylcarbamoyl-5-fluo can be found in Cancer Principles and Practice of Oncology rouracil), tegafur etc.), gemcitabine (Gemzar), and cytosine by V. T. Devita and S. Hellman (editors), 6th edition (Feb. arabinosides (e.g., Cytarabine, or cytosine arabinoside, 15, 2001), Lippincott Williams & Wilkins Publishers, and Cytosar ara-C and Fludarabine, 5-azacytidine, 2,2'-difluo WO 2006/061638. A person of ordinary skill in the art would rodeoxycytidine etc.) and hydroxyurea (Hydrea and Droxia, be able to discern which combinations of agents would be 35 hydroxycarbamide), plus lonidamine; useful based on the particular characteristics of the drugs 5) enzymes, including, L-asparaginase and derivatives and the cancer involved. Classes of Such agents include the Such as pegaspargase (Oncaspar), and RNASe A: following: estrogen receptor modulators, androgen receptor 7) hormones and antagonists, Examples of hormones and modulators, retinoid receptor modulators, cytotoxic/cyto hormonal analogues believed to be useful in the treatment of static agents, antiproliferative agents, prenyl-protein trans 40 neoplasms include, but are not limited to antiestrogens and ferase inhibitors, HMG-CoA reductase inhibitors and other selective estrogen receptor modulators (SERMs), such as angiogenesis inhibitors, HIV protease inhibitors, reverse tamoxifen, toremifene, raloxifene, iodoxyfene, droloxifene, transcriptase inhibitors, inhibitors of cell proliferation and 4-hydroxytamoxifen, trioxifene, keOXifene, onapristone; Survival signaling, bisphosphonates, aromatase inhibitors, anti-androgens. Such as enZalutamide (Xtandi(R), flutamide, siRNA therapeutics, Y-secretase inhibitors, agents that inter 45 nilutamide, bicalutamide, leuprolide, and goserelin, and fere with receptor tyrosine kinases (RTKs), agents that cyproterone acetate; adrenocorticosteroids Such as pred interfere with cell cycle checkpoints, PARP inhibitors, nisone and prednisolone; aminoglutethimide, finasteride and HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90 other aromatase inhibitors such as anastrozole, letrazole, inhibitors, CYP17 inhibitors, 3rd generation AR antagonists, Vorazole, exemestane, formestanie, and fadrozole; Estrogen JAK inhibitors e.g. Ruxolitinib (trade name Jakafi, and BTK 50 Receptor Downregulators (EROs) including Faslodex or kinase inhibitors. fulvestrant, progestrins such as megestrol acetate, Sa-reduc Anticancer agents suitable for use in the combination tase inhibitors such as finasteride and dutasteride; and therapy with compounds as disclosed herein include, but are gonadotropin-releasing hormones (GnRH) and analogues not limited to: thereof. Such as Leutinizing Hormone-releasing Hormone 1) alkaloids and natural product drugs, including, micro 55 (LHRH) agonists and antagonists such as goserelin lupro tubule inhibitors (e.g., Vincristine, Vinblastine, and Vin lide, leuprorelin and buserelin. desine, and vinorelbine etc.), microtubule stabilizers (e.g., 8) platinum compounds (e.g., Cisplatin and Carboplatin, Paclitaxel Taxoll, and Docetaxel, Taxotere, etc.), and chro oxaliplatin, Triplatin tetranitrate (rINN; also known as matin function inhibitors, including, topoisomerase inhibi BBR3464), eptaplatin, lobaplatin, nedaplatin, or satraplatin tors, such as, epipodophyllotoxins (e.g., Etoposide VP-161, 60 etc.); and Teniposide IVM-261, etc.), and agents that target topoi 9) retinoids such as bexarotene (Targretin). Somerase I (e.g., Camptothecin, topotecan (Hycamtin) and 10) proteasome inhibitors such as bortezomib and carfil Irinotecan CPT-11, rubitecan (Orathecin) etc.); zomib (Kyprolis(R). 2) covalent DNA-binding agents alkylating agents. 11) anti-mitotics in addition to diterpenoids and Vinca including, nitrogen mustards (e.g., Mechloretharnine, chlo 65 alkaloids include polo-like kinase (PLK) inhibitors, mitotic rmethine, Chlorambucil, Cyclophosphamide, estramustine kinesin spindle protein (KSP) inhibitors including (Emcyt, Estracit), ifosfamide, Ifosphamide, melphalan (Alk SB-743921 and MK-833 and CenpE inhibitors. US 9,481,692 B2 55 56 12) monoclonal antibodies, including cancer immuno B7-H3 monoclonal antibodies such as MGA271, anti-B7 therapy monoclonal antibodies and humanized monoclonal H4 monoclonal antibodies, and anti-TIM3 monoclonal antibodies. For example: antibodies; 12-a) cancer immunotherapy monoclonal antibodies 18) hematopoietic growth factors; include agents selected from the group consisting of Tras 19) agents that induce tumor cell differentiation (e.g., tuzumab (HerceptinR), an example of an anti-erbB2 anti tretinoin (all trans retinoic acid) (brand names Aberela, body inhibitor of growth factor function; cetuximab (Er Airol, Renova, Atralin, Retin-A, Avita, Retacnyl, Refissa, or bituxTM, C225), an example of an anti-erbB1 antibody Stieva-A)); inhibitor of growth factor function; bevacizumab (Avas 20) gene therapy techniques; Such as gene therapy vac tin R), an example of a monoclonal antibody directed against 10 cines, for example, ALLOVECTINR, LEUVECTINR, and VEGFR: rituximab, alemtuzumab, gemtuzumab, panitu VAXIDR; mumab, to situmomab, pertuzumab. 21) antisense therapy techniques; 12-b) humanized monoclonal antibodies with therapeutic 22) tumor vaccines; include Avicine(R); oregovomab (Ova potential as chemotherapeutic agents in combination RexR); Theratope(R) (STn-KLH); Melanoma Vaccines: include: alemtuzumab, apolizumab, aselizumab, atlizumab, 15 G1-4000 series (GI-4014, G1-4015, and G1-4016), which are bapineuZumab, bevacizumab, bivatuZumab mertansine, can directed to five mutations in the Ras protein; GlioVax-1; tuZumab mertansine, cedelizumab, certolizumab pegol, cid MelaVax: Advexin(R) or INGN-201: Sig/E7/LAMP-1, fusituzumab, cidtuZumab, daclizumab, eculizumab, efali encoding HPV-16 E7; MAGE-3 Vaccine or M3TK; HER Zumab, epratuZumab, erlizumab, felvizumab, fontolizumab, 2VAX; ACTIVE, which stimulates T-cells specific for gemtuzumab ozogamicin, inotuZumab ozogamicin, ipilim tumors; GM-CSF cancer vaccine; and Listeria onocyto umab, labetuZumab, lintuZumab, matuZumab, mepolizumab, genes-based vaccines; motavizumab, motovizumab, natalizumab, nimotuZumab, 23) therapies directed against tumor metastases (e.g., nolovizumab, numavizumab, ocrelizumab, omalizumab, Batimistat, etc.); palivizumab, pascolizumab, pectfusituzumab, pectuZumab, 24) inhibitors of angiogenesis. Receptor kinase angiogen pertuzumab (PerjetaR), pexelizumab, ralivizumab, ranibi 25 esis inhibitors may also find use in the present invention. Zumab, reslivizumab, reslizumab, resy Vizumab, roVeli Inhibitors of angiogenesis related to VEGFR and TIE-2. Zumab, ruplizumab, SibrotuZumab, Siplizumab, Sontuzumab, Other inhibitors may be used in combination with the tacatuZumab tetraxetan, tadocizumab, talizumab, tefiba compounds of the invention. For example, anti-VEGF anti Zumab, tocilizumab, toralizumab, trastuzumab, tucotu bodies, which do not recognize VEGFR (the receptor tyro Zumab celmoleukin, tucusituzumab, umavizumab, urtoxa 30 sine kinase), but bind to the ligand; Small molecule inhibi Zumab, and visilizumab; tors of integrin (alphav beta3) that inhibit angiogenesis; 13) monoclonal antibodies conjugated with anticancer endostatin and angiostatin (non-RT) may also prove useful drugs, toxins, and/or radionuclides, etc. gemtuzumab ozo in combination with the compounds of the invention. One gamicin (MYLOTARG), trastuzumab emtansine (T-DM1)/ example of a VEGFR antibody is bevacizumab (AvastinR). ado-trastuzumab emtansine (KadcylaR); 35 Other anti-angiogenic compounds include acitretin, fenre 14) biological response modifiers (e.g., interferons e.g., tinide, thalidomide, Zoledronic acid, angiostatin, aplidine, IFN-alpha., etc. and interleukins e.g., IL-2, etc., denileu cilengtide, combretastatin A-4, endostatin, halofluginone, kin diftitox (Ontak), G-CSF, GM-CSF: etc.); rebimastat, removab, Lenalidomid (Revlimid), squalamine, 15) adoptive immunotherapy. Immunotherapeutic regi Vitaxin, and pomalidomide (Pomalyst(R): mens include ex-Vivo and in-vivo approaches to increasing 40 25) signal transduction pathway inhibitors. Signal trans immunogenicity of patient tumor cells Such as transfection duction pathway inhibitors are those inhibitors which block with cytokines (eg. IL-2 or aldesleukin, IL-4, GMCFS), as or inhibit a chemical process which evokes an intracellular well as IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, change. As used herein these changes include, but are not IL-11, IL-12, and active biological variants approaches to limited to, cell proliferation or differentiation or survival. increase T-cell activity, approaches with transfected immune 45 Signal transduction pathway inhibitors useful in the present cells and approaches with antiidiotypic antibodies; invention include, but are not limited to, inhibitors of 16) immunosuppressant selected from the group consist receptor tyrosine kinases, non-receptor tyrosine kinases, ing of fingolimod, cyclosporine A, Azathioprine, dexam SH2/SH3 domain blockers, serine/threonine kinases, phos ethasone, tacrolimus, sirolimus, pimecrolimus, mycopheno phatidyl inositoi-3-OH kinases, myoinositol signaling, and late salts, everolimus, basiliximab, daclizumab, anti 50 Ras oncogenes. Signal transduction pathway inhibitors may thymocyte globulin, anti-lymphocyte globulin, and be employed in combination with the compounds of the tofacitinib. Agents capable of enhancing antitumor immune invention; responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) 26) kinase inhibitors, including tyrosine kinases, serine/ antibodies such as Ipilimumab (MDX-010 or MDX-101, threonine kinases, kinases involved in the IGF-1 R signaling Yervoy) and tremelimumab, and other agents capable of 55 axis, PI3k/AKT/mTOR pathway inhibitors, and SH2/SH3 blocking CTLA4: domain blockers. Examples of relevant kinases include: 17) immune modulators, for use in conjunction with the 26-a) tyrosine kinases. Several protein tyrosine kinases compound as disclosed herein include stauroSprine and catalyze the phosphorylation of specific tyrosine residues in macrocyclic analogs thereof, including UCN-01, CEP-701 various proteins involved in the regulation of cell growth. and midostaurin; squalamine; DA-9601, alemtuzumab; 60 Such protein tyrosine kinases can be broadly classified as interferons (e.g. IFN-O, IFN-b etc.); altretamine receptor or non-receptor kinases. Receptor tyrosine kinase (HexalenR); SU 101 or leflunomide; imidazoquinolines inhibitors which may be combined with the compounds of Such as residuimod, imiquimod, anti-PD-1 human monoclo the invention include those involved in the regulation of cell nal antibodies MDX-1106 (also known as BMS-936558), growth, which receptor tyrosine kinases are sometimes MK3475, CT-011, and AMP-224, anti-PD-L1 monoclonal 65 referred to as “growth factor receptors.” Examples of growth antibodies such as MDX-1105, anti-OX40 monoclonal anti factor receptor inhibitors, include but are not limited to bodies, and LAG3 fusion proteins such as IMP321g, anti inhibitors of insulin growth factor receptors (IGF-1 R, IR US 9,481,692 B2 57 58 and IRR); epidermal growth factor family receptors (EGFR, 26-d) PI3k/AKT/mTOR pathway inhibitors, including ErbB2, and ErbB4); platelet derived growth factor receptors GDC-0941, XL-147, GSK690693 and temsirolimus, (PDGFRs), vascular endothelial growth factor receptors SF-1126 (PI3K inhibitor), BEZ-235 (PI3K inhibitor): (VEGFRs), tyrosine kinase with immunoglobulin-like and 26-e) SH2/SH3 domain blockers. SH2/SH3 domain epidermal growth factor homology domains (TIE-2), mac blockers are agents that disrupt SH2 or SH3 domain binding rophage colony stimulating factor (c-FMS), c-KIT, cMET, in a variety of enzymes or adaptor proteins including, but not fibroblast growth factor receptors (FGFRs), hepatocyte limited to, PI3-K p85 subunit, Src family kinases, adaptor growth factor receptors (HGFRs), Trk receptors (TrkA, molecules (She, Crk, Nck, Grb2) and Ras-GAP Examples of TrkB, and TrkC), ephrin (Eph) receptors, the RET protoon Src inhibitors include, but are not limited to, dasatinib and cogene, and Human Epidermal Growth Factor Receptor 2 10 (HER-2). Examples of small molecule inhibitors of epider BMS-354825 (J. Med. Chern. (2004) 47 6658-6661); mal growth factor receptors include but are not limited to 27) inhibitors of Ras oncogenes. Inhibitors of Ras onco gefitinib, lapatinib (Tykerb(R), erlotinib (TarcevaR), afatinib gene may also be useful in combination with the compounds (GilotrifR), TomtovokR, and TovokR), and .lmatinib of the present invention. Such inhibitors include, but are not (Gleevec R) is one example of a PDGFR inhibitor. Examples 15 limited to, inhibitors of farnesyltransferase, geranyl-geranyl of VEGFR inhibitors include pazopanib (VotrientTM), Van transferase, and CAAX proteases as well as anti-sense detanib (ZD6474), AZD2171, vatalanib (PTK-787), Axi oligonucleotides, ribozymes and immunotherapy. Such tinib (AG013736: InlytaR), dovitinib (CHIR-258), cabozan inhibitors have been shown to block Ras activation in cells tinib (CometridR), Sunitinib, and Sorafenib. Protein Kinase containing mutant Ras, thereby acting as antiproliferative C (PKC) inhibitors, such as ruboxistaurin, AEB071 agents. (Sotrastaurin) LY-3 17615 and perifosine. Examples of small 28) Raf/MEK/ERK pathway modulators. The Raf/MEK/ molecule inhibitors of multiple tyrosine kinases include but ERK pathway is critical for cell survival, growth, prolifera are not limited to bosutinib (BosulifR) and. Other kinase tion and tumorigenesis. Li, Nanxin, et al. "B-Raf kinase inhibitors include but are not limited to BIBF-1120, dasat inhibitors for cancer treatment. Current Opinion in Inves inib (sprycel), pelitinib, nilotinib, and lestaurtinib (CEP 25 tigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinases 701). Tyrosine kinases that are not transmembrane growth exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the factor receptor kinases are termed non-receptor, or intracel three isoforms, studies have shown that B-Raf functions as lular tyrosine kinases. Inhibitors of non-receptor tyrosine the primary MEK activator. B-Raf is one of the most kinases are sometimes referred to as “anti-metastatic agents' frequently mutated genes in human cancers. B-Raf kinase and are useful in the present invention. Targets or potential 30 represents an excellent target for anticancer therapy based targets of anti-metastatic agents, include, but are not limited on preclinical target validation, epidemiology and drugabil to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr ity. Small molecule inhibitors of B-Rafare being developed Abl), FAK (focal adhesion kinase) and Bruton's tyrosine for anticancer therapy. Examples of small molecule inhibi kinase (BTK). Examples of small molecule inhibitors of tors of B-Raf include but are not limited to dabrafenib Bcr-Abl include but are not limited to ponatinib (IclusigR). 35 (TafinlarR). Nexavar(R) (Sorafenib tosylate) is a multikinase Non-receptor kinases and agents, which inhibit non-receptor inhibitor, which includes inhibition of B-Raf, and is tyrosine kinase function, are described in Sinha, S. and approved for the treatment of patients with advanced renal Corey, S.J., J. Hematother. Stem Cell Res. (1999) 8 465-80; cell carcinoma and unresectable hepatocellular carcinoma. and Bolen, J. B. and Brugge, J. S., Annu. Rev. of Immunol. Other Raf inhibitors have also been disclosed or have (1997) 15371-404; 40 entered clinical trials, for example GSK-21 18436, RAF-265, 26-b) serine/threonine kinases. Inhibitors of serine/threo vemurafenib (Zelboraf, PLX-4032), PLX3603 and XL-281. nine kinases may also be used in combination with the Examples of small molecule inhibitors of MEK include but compounds of the invention in any of the compositions and are not limited to trametinib (Mekinist(R), Other MEK methods described above. Examples of serine/threonine inhibitors include ARRY-886 (AZD6244); kinase inhibitors that may also be used in combination with 45 29) Cell cycle signaling inhibitors, including inhibitors of a compound of the present invention include, but are not cyclindependent kinases (CDKs) are also useful in combi limited to, polo-like kinase inhibitors (Pik family e.g., Plk1. nation with the compounds of the invention in the compo Plk2, and Plk3), which play critical roles in regulating sitions and methods described above. Examples of cyclin processes in the cell cycle including the entry into and the dependent kinases, including CDK2, CDK4, and CDK6 and exit from mitosis: MAP kinase cascade blockers, which 50 inhibitors for the same are described in, for instance, Rosa include other Ras/Raf kinase inhibitors, mitogen or extra nia G. R. et al., Exp. Opin. Ther. Patents (2000) 10 215-230; cellular regulated kinases (MEKS), and extracellular regu 30) Inhibitors of phosphatidyl inositoi-3-OH kinase family lated kinases (ERKs); Aurora kinase inhibitors (including members including blockers of P13-kinase, ATM, DNA-PK, inhibitors of Aurora A and Aurora B); protein kinase C and Ku may also be useful in combination with the present (PKC) family member blockers, including inhibitors of PKC 55 invention; Subtypes (alpha, beta, gamma, epsilon, mu, lambda, iota, 31) Antagonists of smoothened receptor (SMO) may also Zeta); inhibitors of kappa-B (lkB) kinase family (IKK-alpha, be useful in combination with the present invention. IKK-beta); PKB/Akt kinase family inhibitors; and inhibitors Examples of antagonists of Smoothened receptor include but of TGF-beta receptor kinases. Examples of Plk inhibitors are are not limited to vismodegib (Erivedge(R): described in PCT Publication No. WOO4/O14899 and 60 32) Inhibitors of protein translation may also be useful in WO07/03036; combination with the present invention. Examples of inhibi 26-c) kinases involved in the IGF-1 R signaling axis. tors of protein translation include but are not limited to Inhibitors of kinases involved in the IGF-1 R signaling axis omacetaxine mepesuccinate (SynriboR); and may also be useful in combination with the compounds of 33) anti-cancer agents with other mechanisms of action the present invention. Such inhibitors include but are not 65 including miltefosine (Impavido and Miltex), masoprocol, limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and mitoguaZone, alitretinoin, mitotane, arsenic trioxide, cele 14.3.3 signaling inhibitors; coxib, and anagrelide. US 9,481,692 B2 59 60 Compounds disclosed herein may also be employed in dromostanolone propionate (Masterone Injection(R): conjunction with anti-emetic agents to treat nausea or Elliott’s B Solution (Elliott’s B Solution(R); epirubicin (El emesis, including acute, delayed, late-phase, and anticipa lence(R); Epoetin alfa (EpogenR); erlotinib (Tarceva(R): tory emesis, which may result from the use of a compound estramustine (EmcytR): etoposide phosphate (Etopo as disclosed herein, alone or with radiation therapy. For the 5 phos(R): etoposide, VP-16 (Vepesider); exemestane (Aroma prevention or treatment of emesis, a compound as disclosed sin(R); Filgrastim (NeupogenR); floxuridine (intraarterial) herein may be used in conjunction with other anti-emetic (FUDRR); fludarabine (Fludara(R); fluorouracil, 5-FU agents, especially neurokinin-1 receptor antagonists, 5HT3 (Adrucil(R); flutamide (Eulexin R), fulvestrant (Faslodex(R): receptor antagonists, such as ondansetron, granisetron, tro gefitinib (IressaR); gemcitabine (Gemzar(R); gemtuzumab pisetron, and Zatisetron, GABAB receptor agonists, such as 10 oZogamicin (MylotargR); goserelin acetate (Zoladex baclofen, a corticosteroid such as Decadron (dexametha sone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten Implant(R); goserelin acetate (Zoladex(R); histrelin acetate or others such as disclosed in U.S. Pat. Nos. 2,789,118, (Histrelin Implant(R); hydroxyurea (Hydrea(R); Ibritu 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3.996,359, momab Tiuxetan (Zevalin R); idarubicin (Idamycin R); ifos 3,928,326 and 3,749,712, an antidopaminergic, such as the 15 famide (IFEXCR); imatinib mesylate (GleevecR): interferon phenothiazines (for example prochlorperazine, flu alfa 2a (Roferon AR); Interferon alfa-2b (Intron AR): ipi phenazine, thioridazine and mesoridazine), metoclopramide limumab (Yervoy(R), irinotecan (Camptosar R); lapatinib or dronabinol. In another embodiment, conjunctive therapy (TYKERB(R), lenalidomide (Revlimid(R); letrozole (Fe with an anti-emesis agent selected from a neurokinin-1 mara(R); leucovorin (WellcovorinR), LeucovorinR); Leupro receptor antagonist, a 5HT3 receptor antagonist and a cor lide Acetate (Eligard R); levamisole (ErgamisolR); lomus ticosteroid is disclosed for the treatment or prevention of tine, CCNU (CeeBUR); meclorethamine, nitrogen mustard emesis that may result upon administration of the instant (MustargenR); megestrol acetate (Megace(R); melphalan, compounds. L-PAM (Alkeran R); mercaptopurine, 6-MP (PurinetholR): A compound as disclosed herein may also be administered mesna (MesneXOR); mesna (Mesnex Tabs(R); methotrexate with an agent useful in the treatment of anemia. Such an 25 (MethotrexateR); methoxsalen (Uvadex(R); mitomycin C anemia treatment agent is, for example, a continuous eyth (Mutamycin R); mitotane (Lysodren(R); mitoxantrone (No ropoiesis receptor activator (Such as epoetin alfa). Vantrone(R); nandrolone phenpropionate (Durabolin-50R): A compound as disclosed herein may also be administered nelarabine (Arranon(R); Nofetumomab (Verluma(R): with an agent useful in the treatment of neutropenia. Such a Oprelvekin (Neumega(R); oxaliplatin (EloxatinR); pacli neutropenia treatment agent is, for example, a hematopoietic 30 taxel (PaxeneR); paclitaxel (Taxol.R.); paclitaxel protein growth factor which regulates the production and function of bound particles (Abraxane(R); palifermin (Kepivance(R): neutrophils such as a human granulocyte colony stimulating panitumumab (VECTIBIX(R), pamidronate (Aredia(R): factor, (G-CSF). Examples of a G-CSF include filgrastim. PaZopanib (Votrient(R), pegademase (Adagen (Pegademase A compound as disclosed herein may also be useful for Bovine)(R); pegaspargase (Oncaspar R); Pegfilgrastim (Neu treating or preventing cancer in combination with siRNA 35 lastaR); pemetrexed disodium (AlimtaR); pentostatin (Ni therapeutics. pent(R); pertuzumab (OMNITARG(R), 2C4), pipobroman A compound as disclosed herein may also be useful for (Vercyte?R); plicamycin, mithramycin (Mithracinr); treating cancer in combination with the following therapeu porfimer sodium (PhotofrinR); procarbazine (Matulane(R): tic agents: abarelix (Plenaxis Depot(R); aldesleukin (Pro quinacrine (Atabrine(R); Rapamycin (Sirolimus, RAPA kine(R); Aldesleukin (Proleukin R); Alemtuzumabb (Cam 40 MUNE(R).), Rasburicase (Elitek(R); Rituximab (Rituxan R): path(R); alitretinoin (PanretinR); allopurinol (ZyloprimR): rubitecan (Orathecin), ruxolitinib (JakafiR); sargramostim altretamine (HexalenR); amifostine (Ethyol(R); anastrozole (Leukine(R); Sargramostim (Prokine(R); Sorafenib (Nexa (ArimideX(R); arsenic trioxide (TrisenoX(R); asparaginase var(R); streptozocin (Zanosar R); Sunitinib maleate (Elspar R); Axitinib (Inly taR); azacitidine (VidazaR); beva (Sutent(R); talc (Sclerosol(R); tamoxifen (Nolvadex(R): cuzimab (AvastinR); bexarotene capsules (TargretinR): 45 temozolomide (Temodar R); temsirolimus (Torisel(R); teni bexarotene gel (TargretinR); bicalutamide (Casodex(R), poside, VM-26 (VumonR); testolactone (TeslacR); thiogua bleomycin (Blenoxane(R); bortezomib (VelcadeR); busulfan nine, 6-TG (Thioguanine(R); thiotepa (Thioplex(R); topote intravenous (BusulfeXR); busulfan oral (Myleran R); calus can (Hycamtin R); toremifene (Fareston(R); Tositumomab terone (Methosarb(R); capecitabine (Xeloda(R); carboplatin (BexxarR); Tositumomab/I-131 to situmomab (Bexxar R): (ParaplatinR); carmustine (BCNUR), BiCNUR); carmustine 50 Trastuzumab (HerceptinR); tretinoin, ATRA (VesanoidR): (GliadelR); carmustine with Polifeprosan 20 Implant (Glia Uracil Mustard (Uracil Mustard Capsules.(R); valrubicin del WaferR); celecoxib (Celebrex(R); cetuximab (Erbitux(R): (Valstar R); vandetanib (ZACTIMAR), vemurafenib (Zelbo chlorambucil (Leukeran R); cisplatin (PlatinolR); cladribine rafR), vinblastine (Velban R); Vincristine (OncovinR): (Leustatin R, 2-CdAR); clofarabine (ClolarR); cyclophos vinorelbine (Navelbine(R); vorinostat (ZollinzaR); Zoledro phamide (Cytoxan R, Neosar(R); cyclophosphamide (Cy 55 nate (ZometaR), nilotinib (TasignaR); and dasatinib (Spry toxan Injection(R); cyclophosphamide (Cytoxan Tablet(R): cel(R). ARRY-886 (Mek inhibitor, AZD6244), SF-1126 cytarabine (Cytosar-UR); cytarabine liposomal (Depo (PI3K inhibitor), BEZ-235 (PI3K inhibitor), XL-147 (PI3K CytR); dacarbazine (DTIC-Dome(R); dactinomycin, actino inhibitor), PTK787/ZK 222584, crizotinib (XalkoriR), and mycin D (CosmegenR); Darbepoetin alfa (AranespR); dasa vemurafenib (ZelborafR). tinib (Sprycel(R); daunorubicin liposomal (DanuoXome(R): 60 In any case, the multiple therapeutic agents (at least one daunorubicin, daunomycin (DaunorubicinR); daunorubicin, of which is a compound disclosed herein) may be adminis daunomycin (Cerubidine(R); Denileukin diftitox (OntakR): tered in any order or even simultaneously. If simultaneously, dexrazoxane (Zinecard(R); docetaxel (TaxotereR): doxoru the multiple therapeutic agents may be provided in a single, bicin (Adriamycin PFSR); doxorubicin (Adriamycin R, unified form, or in multiple forms (by way of example only, Rubex.R.); doxorubicin (Adriamycin PFS Injection(R); doxo 65 either as a single pill or as two separate pills). One of the rubicin liposomal (Doxil R): doxorubicin liposomal therapeutic agents may be given in multiple doses, or both (Doxil (R); dromostanolone propionate (Dromostanolone(R): may be given as multiple doses. If not simultaneous, the US 9,481,692 B2 61 62 timing between the multiple doses may be any duration of skin cancers, melanoma, Small cell lung carcinoma, non time ranging from a few minutes to four weeks. Small cell lung carcinoma, squamous cell carcinoma, Sweat Thus, in another aspect, certain embodiments provide gland carcinoma, synovioma, thyroid cancer, uveal mela methods for treating disorders and symptoms relating cancer noma, and Wilm's tumor. in a human or animal Subject in need of Such treatment 5 In certain embodiments, the compositions and methods comprising administering to said subject an amount of a disclosed herein are useful for preventing or reducing tumor compound disclosed herein effective to reduce or prevent invasion and tumor metastasis. In certain embodiments, the compositions and methods said disorder in the Subject, in combination with at least one disclosed herein are useful for preventing or reducing angio additional agent for the treatment of said disorder that is genesis and disorders related to angiogenesis. Besides being known in the art. In a related aspect, certain embodiments 10 useful for human treatment, certain compounds and formu provide therapeutic compositions comprising at least one lations disclosed herein may also be useful for veterinary compound disclosed herein in combination with one or more treatment of companion animals, exotic animals and farm additional agents for the treatment of disorders and Symp animals, including mammals, rodents, and the like. More toms relating to cancer. preferred animals include horses, dogs, and cats. The compounds, compositions, and methods disclosed 15 herein are useful for the treatment of disease. In certain LIST OF ABBREVIATIONS embodiments, the diseases is one of dysregulated cellular proliferation, including cancer. The cancer may be hormone CHC1-chloroform; i-PrCH-isopropanol: HO-water; dependent or hormone-resistant, such as in the case of breast DCM-dichloromethane; NaSO sodium sulfate; cancers. In certain embodiments, the cancer is a solid tumor. MgSO magnesium sulfate; EtOAc-ethyl acetate; In other embodiments, the cancer is a lymphoma or leuke EtOH-ethanol: EtO-diethyl ether: THF-tetrahydrofuran: mia. In certain embodiments, the cancer is and a drug NMP=N-Methyl-2-pyrrollidone; NaOH sodium hydroxide: resistant phenotype of a cancer disclosed herein or known in MeOH=methanol: CDC1-deuterated chloroform; the art. Tumor invasion, tumor growth, tumor metastasis, HCl–hydrochloric acid; MeCN=acetonitrile; and angiogenesis may also be treated using the compositions 25 CsCO=cesium carbonate; DMF-N,N-dimethylforma mide: CDOD-deuterated methanol; DMSO-di-deuterated and methods disclosed herein. Precancerous neoplasias are dimethyl Sulfoxide; DMSO-dimethyl sulfoxide; also treated using the compositions and methods disclosed TFA=trifluoroacetic acid; AcOH-acetic acid; herein. HBr hydrobromic acid; HCOOH=formic acid; Cancers to be treated by the methods disclosed herein KCO potassium carbonate; DBU=1,8-diazabicyclo include colon cancer, breast cancer, ovarian cancer, lung 30 5.4.0]undec-7-ene; NaHCO=Sodium hydrogen carbonate; cancer and prostrate cancer; cancers of the oral cavity and KCN-potassium cyanide; TEA=EtN=triethylamine: pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, DMAP=4-dimethylaminopyridine: stomach, Small intestine, large intestine, colon, rectum, liver NHOH.HCl–hydroxylammonium chloride; DIEA-N,N-di and biliary passages; pancreas, bone, connective tissue, skin, isopropylethylamine; LiOH=lithium hydroxide: cervix, uterus, corpus endometrium, testis, bladder, kidney 35 NHHCO ammonium hydrogen carbonate; and other urinary tissues, including renal cell carcinoma NH-OH-ammonium hydroxide. KPO potassium phos (RCC); cancers of the eye, brain, spinal cord, and other phate tribasic; NaOtBu=sodium t-butoxide: CuBr copper components of the central and peripheral nervous systems, (II) bromide: CuCl2 copper (II) chloride; CuCN as well as associated structures such as the meninges; and (LiCl)=Copper(I) cyanide di(lithium chloride) complex; thyroid and other endocrine glands. The term “cancer also 40 EDC.HCl=1-Ethyl-3-(3-dimethylaminopropyl)carbodiim encompasses cancers that do not necessarily form Solid ide hydrochloride; HOBT=1-hydroxybenzotriazole; tumors, including Hodgkin’s disease, non-Hodgkin’s lym PyBop=(Benzotriazol-1-yloxy)tripyrrolidinophosphonium phomas, multiple myeloma and hematopoietic malignancies hexafluorophosphate: LiCl=lithium chloride; NaI-sodium including leukemias (Chronic Lymphocytic Leukemia iodide; NaBr-sodium bromide: N-nitrogen; Ar-argon; (CLL), Acute Lymphocytic Leukemia (ALL)) and lympho 45 MnO=manganese dioxide; HATU-2-(1H-7-AZabenzotri mas including lymphocytic, granulocytic and monocytic. azol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophos phate methanaminium; BH-THF=borane tetrahydrofuran Additional types of cancers which may be treated using the complex solution; POCl phosphorus oxychloride: compounds and methods of the invention include, but are AcO-acetic anhydride: NH-NH.HO-hydrazine hydrate; not limited to, adrenocarcinoma, angiosarcoma, astrocy NaBH sodium borohydride; NaBHCN=sodium cyano toma, acoustic neuroma, anaplastic astrocytoma, basal cell 50 borohydride; n-Bulli-n-butyllithium; CHI-methyl iodide: carcinoma, blastoglioma, chondrosarcoma, choriocarci CS carbon disulfide; AIBN-azobisisobutyronitrile; noma, chordoma, craniopharyngioma, cutaneous melanoma, KF potassium fluoride; BuSnH=tributyltin hydride: cystadenocarcinoma, endotheliosarcoma, embryonal carci RuPhos-2-Dicyclohexylphosphino-2,6'-diisopropoxybi noma, ependymoma, Ewings tumor, epithelial carcinoma, phenyl; XPhos-2-Dicyclohexylphosphino-2',4',6'-triisopro fibrosarcoma, gastric cancer, genitourinary tract cancers, 55 pylbiphenyl; and Pd(dba)-tris(dibenzylideneacetone)di glioblastoma multiforme, head and neck cancer, hemangio palladium(0); Pd(Ph) tetrakis(triphenylphosphine) blastoma, hepatocellular carcinoma, hepatoma, Kaposi's palladium(0): NCS-N-chlorosuccinimide; DEAD-diethyl sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, aZodicarboxylate; OsO-osmium tetraoxide; DIBAL-H-di liposarcoma, lymphatic system cancer, lymphomas, lymp iso-butyl aluminium hydride; t-BuOH-tert-butanol: hangiosarcoma, lymphangioendotheliosarcoma, medullary 60 Py-pyridine: NaOMe-sodium methoxide: prep thyroid carcinoma, medulloblastoma, meningioma mesothe HPLC preparative high-performance liquid chromatogra lioma, myelomas, myxosarcoma neuroblastoma, neurofibro phy. sarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarci General Methods for Preparing Compounds nomas, paraganglioma, parathyroid tumours, pheochromo 65 cytoma, pinealoma, plasmacytomas, retinoblastoma, rhab The following schemes can be used to practice the present domyosarcoma, sebaceous gland carcinoma, seminoma, invention. Additional structural groups, including but not US 9,481,692 B2 63 64 limited to those defined elsewhere in the specification and hydroxide in a solvent such as Xylene and the mixture stirred not shown in the compounds described in the schemes can at 170° C. for 36 h to yield the 1,2,4-triazole directly. incorporated to give various compounds disclosed herein, or Alkylation of the triazole with an appropriately substituted intermediate compounds which can, after further manipula benzyl halide, or heterocyclic methyl halide, or equivalent tion using techniques known in the art, be converted to synthon yields a mixture of regioisomers. This transforma compounds of the present invention. For example, in ceratin tion can be achieved using reagents such CSCO or KCO embodiments the A, B, D, and E rings in the structures in a polar solvent like DMF or DMSO, or KCO, in the described in the schemes can be substituted with various presence of NaI in THF. These transformations can be groups as defined herein. accomplished at RT, although with some Substrates it may be
SCHEME 1 HO NH-NH2-H2O O Y. Pyridine, CHCl3 - N. EtOH OEt / O°() C. to reflux O N reflux, O/N C O S. NH2 N O OEt NH HC O OS HNHN ONN ul R Ethane-1,2-diol R NH 100 N 180° C., 3 hrs M 100 2 HNHN N Her O N 1.5 eq THF, NaOH HN Reflux
HCI
R100 NH2 NaOH Xylene, |70° C., 36 hrs O?iyN- N KO NN R100 s N
ls"I)S. N (,MN He-O.CsCO3 -- DMF
M N O le N
55 One route for preparation of compounds of the present necessary to use elevated temperatures and/or microwave invention is depicted in Scheme 1. Ethyl 2-chloro-2-oxoac irradiation to drive the reaction to completion. The regioi etate can be condensed with a hydroxyamidine, and cyclized Somer can be separated at this stage, or later in the synthetic in refluxing pyridine to form a 1,2,4-oxadiazole. The result sequence by chromographic methods such as column chro ing ester can be treated with hydrazine hydrate in refluxing 60 matography or HPLC to yield compounds of this invention. ethanol to give the corresponding hydrazide. This can in turn In a related manner, other heterocyclic carboxylic acids be condensed with a substituted amidine in refluxing solvent can be transformed to the corresponding hydrazide, for such as THF to yield an intermediate, which after a solvent instance as depicted in Scheme 2 by coupling with Boc switch to ethane-1,2-diol and refluxing the reaction for hydrazide, using a coupling reagent Such as HATU in the several hours the desired 1,2,4-triazole can be prepared. 65 presence of a base like KCO in a solvent like DCM. Alternatively, the hydrazide can be mixed with the amidine Thereafter the Boc group can be removed using acid Such as hydrochloride Salt in the presence of a base Such as sodium TFA in a solvent such as DCM. The resulting hydrazides can US 9,481,692 B2 65 66 be coupled as described above with a substituted amidine to 2-(2-amino-1,1'-biphenyl)palladium(II) in the presence of yield the corresponding 1,2,4-triazole, and alkylated as a base Such as NaOtBu in THF at 65° C. for 2 h. Alterna described in Scheme 1 above to yield the desired compound tively, a catalyst system comprising of X-Phos, Pd(dba) of this invention. These compounds can be further manipu and N',N'-dimethylethane-1,2-diamine in the presence of a lated synthetically as described hereafter. base Such as CsCO and be used for the transformation in
SCHEME 2 Boc NH2 HO GD) HN-NH GD) HN-NH GD) IN={ HCI BocNHNH2 TFADCM R101 O K2CO3 O O NaOH HATU, DCM GD THF Reflux
N usy-G) 1G) -- R101 Cs2CO3, DMF X-G) R101 N
Compounds of the invention bearing 2-halopyridines, 35 a solvent such as dioxane. The reaction being conducted by Such as 2-chloropyridine, or heterocycles bearing a similarly microwave irradiation at 120° C. for 1 h. In addition, this reactive halogen Substituents, for instance 2-chloropyrimi transformation can be conducted using a catalytic system dines or 2-chlorothiazoles, can be displaced with a variety of comprising of X-Phos and Pd(dba) in the presence of a nucleophiles, such as primary and secondary amines 40 base Such as CsCO in a solvent such as toluene, by heating Scheme 3. For example, by refluxing an excess of the at 140° C. for 18 h. amine at 120° C. overnight, using a solvent such as DMSO if required.
45 SCHEME3 SCHEME 4
C 50 DIPEA -e- DMSO, 120° C. On
RHP 55 THF 659 C. 2h
60 Alternatively, these heterocyclic halides or aromatic halides can be cross coupled with amines using palladium catalysis, using methods known to those trained in the art Scheme 4. For example, aromatic bromides can be coupled using a catalyst system comprising of dicyclohexyl(2,6'- 65 diisopropoxy-1, 1'-biphenyl-2-yl)phosphine and chloro-(2- dicyclohexylphosphino-2,6'-diisopropoxy-1,1'-biphenyl) US 9,481,692 B2
-continued -continued R104 v NH Rool H Br Y R105 HN1 NaBHCN, SOr Pd(dba)3, XPhos, CsCO3, N-NG- GB)–GD)-GE) -EtOH, RT - dioxane, MW at 120° C., 2h O 10 R1091N N toluene, 140°C., 18 h S-Gro-O-O 15 Alternatively, compounds of the present invention con taining a primary or a secondary amine can be further Furthermore, these heterocyclic halides or aromatic manipulated by reaction with a carboxylic acid in the halides can be cross coupled with Stannanes or boronates presence of coupling agents like EDCI or HATU, a carbox using palladium catalysis, applying methods known to those ylic acid chloride, or a sulfonyl chloride in the presence of trained in the art Scheme 5. For example, aromatic bro a base Such as triethylamine in a Suitable solvent, for mides can be coupled with alkenyl Stannanes using a catalyst example DCM, as depicted in Scheme 7. system comprising of tetrakis(triphenylphosphine)palla dium(0) in the presence of a base Such as KCO in a solvent 25 Such as dioxane, conducting the reaction thermally at 110° SCHEME 7 C. for 12 h.
-e- 30 DCM, RT SCHEME5 N Y R106 Qr OR R108 R110COCl, EtN 21 Sn(Bu)3 Hs DCM, 0° C. R107 35 Br Y K2CO3. (Ph3P)4Pd SOr Dioxane 110° C., 12h R 106 40 R108 21 "O-O-O Or'O-O-O R107
45 Compounds of the present invention can be further RSOCl, Et3N manipulated using synthetic transformation known to those DCM, 0° C. trained in the art to yield alternative compounds also cov ered within the scope of this invention. For instance, as is depicted in Scheme 6, compounds bearing a protected amine 50 can be deprotected using synthetic transformations known to those trained in the art, for example a Cbz-protecting group can be removed using HBr in AcOH/HO at temperatures around 40°C. The resulting primary or secondary amine can undergo a reductive amination reaction to yield higher 55 Substituted amines, for instance by reacting the amine with an aldehyde in the presence of a reducing agent such as NaBH(CN) in a alcoholic solvent. 60 Another route for the preparation of compounds of the SCHEME 6 present invention is depicted in Scheme 8. Starting from Cbz 48% HBr, compounds of the invention bearing a carboxylic ester, these 1. AcOH can readily be transformed into amides. For example, a 65 mixture of the ester can be reacted with the desired amine in S-Gr’O-O-O He! the presence of 1,2,4-triazole and DBU, and heated to 70-100° C. overnight. US 9,481,692 B2 70 An additional route to prepare the compounds of this SCHEME 8 invention is described in Scheme 10. Compounds bearing an R112 alkenyl group can be further manipulated by oxidative v transformations. For example, they can undergo di-hydroxy NH / lation by applying methods known to those trained in the art, MeOC Y R113 including using a catalytic amount of OsO4 in the presence Or Her1,2,4-triazole of N-methylmorpholine-oxide in a suitable solvent such as DBU tet-butanol. Alternatively, the double bond can be converted 70-100° C. into the corresponding epoxide by a Suitable oxidizing O 10 reagent, for example 3-chloro-benzoperoxy acid, and the R112 Y epoxide species could in turn be further functionalized by reaction with a suitable nucleophilic reagent Such an amine R113 Scheme 10. 15 Compounds of the invention bearing a phenol moiety can be further manipulated by reaction with a variety of alky SCHEME 10 lating reagents such as alkyl-, benzyl- or allyl-halides, in the R115 OsO4, presence of a base Such as KCO or CsCO in a Suitable R117 NMMO solvent like DMF, occasionally heating the reaction if nec 4ny, Y tBuOH essary Scheme 9a). In addition, if Such transformations are carried out with compounds of the invention bearing 2-hy R116 droxypyridines, the products of N-alkylation can be HO R115 obtained as well as the products of O-alkylation. An addi tional way to functionalize the compounds of this invention 25 bearing a phenol moiety is described in Scheme 9b, and consists in reacting a Suitable alcohol in the presence of an aZodicarboxylate reagent, like diethyl azodicarboxylate R115 mCPBA, (DEAD) and a phosphine, for example PhP according to DCM the methodology described by Mistunobu et al. (Synthesis 30 1981, 1-28) or any modification thereof known to those R117 21 sor E D E trained in the art. R16 R18 w
SCHEME 9 35 O R115 NH R >-y Y R119 Scheme 9a 7 SO E D E Hs R114-Halide, R116 HO Y K2CO3 HO R115 --e- 40 Or DMF -- -Y1 Rs.1 R116 R119 45 HO Y R114-Halide, K2CO3 --- A DMF Furthermore, compounds described in this invention bear N ing an unsubstituted aniline group can be further manipu lated by methods known to those skilled in the art and R1" Y 50 14 | A 8. d converted into compounds bearing a Sulfonamide moiety, as N depicted in Scheme 11. For example, treatment of unsub stituted anilines with sodium nitrite in the presence of s Y Suitable acidifing reagents, such as acetic acid and hydro chloric acid, followed by treatment with sulfur dioxide in the A 55 1. presence of a suitable inorganic salt such as CuCl2, results R114 in the formation of the corresponding sulfonyl chloride. The Scheme 9b latter could then be further progressed to a sulfonamide by R114-OH, reaction with an amine in the presence of a base such as HO Y DEAD 60 pyridine, in a suitable solvent, for example DCM. Or -e-PhO, THF SCHEME 11 HN NaNO, HCl, AcOH O'G-G-G CuCl2, SO2, H2O US 9,481,692 B2 71 72 -continued as DCM or other methods known to those trained in the art. V / Pyr DCM Fictionalization on the periphery of the molecule can then be Y. Y " " - undertaken if required using methods described above and below. The nitrile can then be transformed into the hydroxy v cror R121NH amidine through treatment with hydroxylamine hydrochlo / ride in the presence of a tertiary amine base, in a alcohol R120 O O Solvent at elevated temperature. Coupling with a carboxylic acids, using coupling reagents such as carbonyl diimidazole \/ in a solvent like DCM leads to a cyclization precursor which 10 can be dehydrated to compounds of this invention at elevated temperature, such as heating at 135°C. in a solvent like DMF. Another route for the preparation of compounds of the present invention is depicted in Scheme 12, where in 1.3, 15 4-oxadiazoles can be prepared using synthetic procedures SCHEME 13 known to those trained in the art. Starting from a suitable 1. X6 triazole carboxylic acid ester, this can be alkylated to give Hy - COEt NH the desired substituted benzyl triazole, or heteromethyltri Xo Xs MeOH5O C. azole. This synthetic sequence may give regioisomers which can be separated at various points along the synthetic sequence using chromaographical techniques. In turn, the resulting ester product is reacted with hydrazine hydrate in Orn an alcoholic solvent to give the corresponding hydrazide. X6 KCO This can be coupled with an appropriately substituted ben 25 Hy 5 s CONH2 2-3 Zoic or heterocyclic acid using reagents such as phosphorous Xo Xs THF, 50° C., o/n oxychloride at elevated temperatures to synthesize the desired 1,3,4-oxadiazoles of this invention. As described O above these can be transformed into other compounds TFAA, Et3N described in this invention using protocols described above 30 4's NH and below. W i 2 DCM, 0° C. to RT Xo Xs
SCHEME 12 N 35 X6 26 NH-OH-HCl, DIPEA Orn OryN si HeEtOH, 80° C., 2h Hy26 s s COEt KCO2-3 40 Xo Xs THF, 50° C., 18 h X6 N -OH O-coil 1. 0 X i). CDI, DCM, RT to 45° C. Ory coE N2H4H2O, EtsN 1. Her Xo Xs MeOH, rt, of n N. S NH, ii). DMF, 135° C. O 45 W. CO2H
X6 NH2 He N1 X6 N H POCl, 100° C., 2.5 h N 1. 3is & N 50 o, Xs N-O
Compounds described in this invention containing a thi azole ring can be prepared by those skilled in the art Another route for the preparation of compounds of the 55 according to a synthetic route like the one described in present invention is depicted in Scheme 13 for targeting Scheme 14. A suitable alpha-bromo acetophenone can be isomeric oxadiazoles. Substituted triazole esters are con converted to a thiazole 2-carboxylate by reaction with an verted to the corresponding primary amides, for instance by amino-2-thioxoacetate heating at reflux in a solvent such as using methanolic ammonia Solution at elevated temperature. EtOH. The thiazole 2-carboxylate can then be progressed to These amides are alkylated with suitable functionalized 60 the corresponding hydrazide by stirring in a suitable solvent, alkyl halides and tosylates, for example using a base Such as such as MeOH, in the presence of hydrazine hydrate. CsCO or KCO in a solvent such as DMF or THF to yield Reaction with a suitable amidine followed by thermal cycl isomeric N-substituted triazoles which can be separated ization, for example in a high boiling solvent such as using chromographic techniques such as column chroma ethylene glycol, can be used to access a thiazole-containing tography on silica. The primary amide can then be dehy 65 tricyclic intermediate. The latter can in turn be alkylated as drated to the corresponding nitrile, for example by using previously described in Scheme 1, and substituent A could trifluoroacetic anhydride and triethylamine in a solvent such be further manipulated as described in Schemes 3 to 11. US 9,481,692 B2 74 glycol or THF affords the desired oxazole-containing tricy SCHEME 14 clic intermediate. The latter can in turn be alkylated as previously described in Scheme 1, and substituent A could S be further manipulated as described in Schemes 3 to 11. OEt HN O SCHEME 15 O Br EtOH, 80° C. 1) O 10 OEt C Y-O NH-NH2-H2O, O S. MeOH EtO N Her O NH2 EtN, DCM 2) POCl3, heating O 15 NH N N NH-NH2-H2O, S N us HCI EtOH EO O e H s ) O R 22 NH 2 N NaOH, THF, heating HN O O NH N N l HCI R123 NH2 H SS. y O NH O He / N Ethylene glycol, 180° C. / He 25 HN O
R22 H N O THF, heat 30 / -e- N Orn HN N N KCO O M NS 2 3 NH HN R123 y 35 R122 N X-OO OriK2CO3 HN es 40 y R123
45
R122 50
Additionally, compounds described in this invention con taining an oxazole ring can be prepared by those skilled in the art according to a synthetic route like the one described 55 in Scheme 15. A Suitable alpha-amino acetophenone can be R123 acylated with a 2-chloro-2-oxo-acetate in the presence of a base Such as triethylamine in a solvent Such as including Compounds described in the present invention that con DCM, NMP, MeCN. The resulting alpha-ketoamide product tain an isoxazole ring can be prepared in a regiospecific can then be cyclized to the corresponding oxazole-2-car 60 manner by synthetic routes such those described in Scheme boxylate by heating in the presence of a condensing agent 16. In one case (Scheme 16a) a suitable benzaldehyde can be Such as POCl, and the resulting product can in turn be converted in the corresponding chloro-oxime by condensa converted to the carbohydrazide by stirring in a solvent such tion with hydroxalamine in a solvent such as MeCH at as MeCH or EtOH in the presence of hydrazine hydrate. In elevated temperature, followed by treatment with a suitable analogous manner to the synthetic route previously 65 chlorinating agent, for example N-chlorosuccinimide, in a described in Scheme 14, reaction with a suitable amidine solvent such as DMF. Thermal cycloaddition with methyl followed by condensation in a solvent such as ethylene propiolate in the presence of a suitable base, for example US 9,481,692 B2 75 triethylamine, in a solvent Such as toluene gives the isox -continued azole-5-carboxylate intermediates. Functional group SCHEME 16b manipulations similar to those described in Schemes 14 and O 15 can be used to progress the latter intermediates to the OEt EtO fully functionalized isoxazole derivatives described here in, O and substituent A could be further manipulated as described O in Schemes 3 to 11. In a similar fashion, isoxazole-3- -- carboxylate intermediates can be prepared by condensation NaOMe, MeOH of a suitable acetophenone with an oxalate in the presence of O O a strong base, such as NaOMe in MeCH, followed by 10 cyclization of the derived diketo ester in the presence of oM NH2 OH hydroxylamine Scheme 16b. Functional group manipula MeOH, heat tions previously described in Schemes 14 and 15 can then be O employed to access the fully functionalized isomeric isox 15 azole intermediates, substituent A could be further manipu N -O NH-NHoHO2 2L lov, lated as described in Schemes 3 to 11. MeO / HipEtOH
SCHEME 16: O NH SCHEME 16a O N-O 1) us HCI 1) NH-OH, MeOH, heat R124 NH2 Her NH 7 -e- H 2) NCS, DMF 25 HN 2) THF, base, heat O N -OH E-COMe, EtN -e- Toluene C 30 N-O Ori / N / KCO2-v-3 O-1 N NH-NH2-H2O, HN N --- EtOH MeO S. Her )- 35 R 124 O N-O NH O- N 1) HCI R124 NH2 NH S. -e- 40 HN 2) THF, base, heat O
O-1 N Gr Br 45 HN1 NN S. - KCOS -
R 124 50 The invention is further illustrated by the following examples, which may be made my methods known in the art and/or as shown below. Additionally, these compounds may 55 be commercially available. Intermediate A R124 Ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiaz N ole-5-carboxylate ON O-1 Y 60 N S. N )- 65 R124 OCF OEt US 9,481,692 B2 77 78 Step 1 3-(4-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5- carbohydrazide O To the solution of ethyl 3-(4-(trifluoromethoxy)phenyl)- OEt 5 1,2,4-oxadiazole-5-carboxylate (13.6 g., 45.0 mmol) in C EtOH (200 mL), NH-NH.HO (80%, 14 mL, 225 mmol) O was added. The reaction mixture was stirred at RT overnight. HO The desired compound precipitated from the reaction mix V Pyridine, CHCl3 ture, filtered and washed with EtOH (50 mL) to afford N O°C. to reflux 10 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbo hydrazide as a light yellow solid (9.7 g, 75%). MS (ES+) FCO -() {NH2 CHFNO requires: 288. found: 289 M+H". O-1 N Step 2
s O OCF O NH HC OEt H2NHN NN N NH2 N -> To a solution of (E)-N'-hydroxy-4-(trifluoromethoxy)ben O 1.5 eq Zimidamide (3.0 g, 13.6 mmol) and pyridine (1.6 g. 20.4 THF, NaOH mmol) in CHCl (20 mL), ethyl 2-chloro-2-oxoacetate (2.2 OCF Reflux g, 16.4 mmol) was added slowly at 0°C. The mixture was O stirred at reflux for 3 h, and then concentrated to give the 25 O h Ethane-1,2-diol crude product, which was purified by silica gel column N 180° C., 3 hrs chromatography (Petroleum ether:EtOAc=10:1) to give X- HNHN N -- ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5- HN carboxylate as a white solid (4.5 g, 82%). MS (ES+) OCF CHFNO requires: 302. found: 303M+H". 30 N- N OS N Intermediate B NN2 QN
5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluo 35 OCF romethoxy)phenyl)-1,2,4-oxadiazole
5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluo 40 romethoxy)phenyl)-1,2,4-oxadiazole To a solution of 3-(4-(trifluoromethoxy)phenyl)-1,2,4- NNX-Cl oxadiazole-5-carbohydrazide (9.7 g. 33.7 mmol) and ace 45 timidamide hydrochloride (4.8 g. 50.5 mmol) in dry THF (300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The OCF mixture was refluxed overnight. The solution was cooled, concentrated and ethane-1,2-diol (100 mL) was added. The Step 1 resulting mixture was heated at 180° C. for 3 h, cooled to RT, 50 diluted with HO (800 mL), and extracted with EtOAc (3x400 mL). The combined organic layers were washed with HO (300 mL) and brine (100 mL), dried over NaSO, EO O NN NH-NH2-H2O filtered, and concentrated under reduced pressure to afford EtOH the crude solid product, which was treated with EtOAc (150 N reflux, O/N 55 N He mL). The resulting suspension was stirred at RT for 15 min, O and then filtered to afford 4.8 g of the pure desired com pound. The remaining filtrate was concentrated and purified OCF by silica gel column chromatography (Petroleum ether: O EtOAc=1:1) to afford 1.4 g of another batch of 5-(5-methyl H2NHN Q NN 60 1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2, N 4-oxadiazole as a white solid-overall 6.2 g, yield 59%. MS O (ES+) CHFNO requires: 311. found: 312 M+H". The invention is further illustrated by the following OCF 65 examples, which may be made my methods known in the art and/or as shown below. Additionally, these compounds may be commercially available. US 9,481,692 B2 79 80 EXAMPLE 1. 5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluo romethoxy)phenyl)-1,2,4-oxadiazole 4-(4-((5-Methyl-3-(3-(4-(trifluoromethoxy)phenyl)- To a solution of N'-hydroxy-4-(trifluoromethoxy)benz 1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl) 5 imidamide (1.3 g, 5.1 mmol) and 5-methyl-1H-1,2,4-triaz pyridin-2-yl)piperazin-1-ium trifluoroacetate ole-3-carboxylic acid (650 mg, 5.1 mmol) in DMF (15 mL), EDC.HCl (980 mg, 5.1 mmol) and HOBT (690 mg, 5.1 mmol) were added at RT. The mixture was stirred at RT for 1 h, and then heated to 140°C. for 3 h. The resulting mixture was cooled, diluted with HO (20 mL) and extracted with 10 EtOAc (4x40 mL). The combined organic layers were washed with HO (10 mL) and brine (10 mL), dried over Na2SO, filtered and concentrated under reduced pressure, and the residue was purified by Combiflash reverse phase chromatography (50%-60% MeCN/HO containing 0.01% 15 trifluoroacetic acid) to give 5-(5-methyl-1H-1,2,4-triazol-3- OCF yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (590 mg, 37%). MS (ES+) CHFNO, requires: 311. found: 312|M+H". Step 2
N C O F.
CsCO3 DMF
OCF
Step 1 Benzyl 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy) phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl) 45 methyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4- (trifluoromethoxy)phenyl)-1,2,4-oxadiazole (311 mg, 1.0 mmol) and benzyl 4-(4-(chloromethyl)pyridin-2-yl)pipera OH 50 Zine-1-carboxylate (690 mg, 2.0 mmol) in DMF (15 mL), CsCO, (820 mg, 2.5 mmol) was added at RT. The mixture was stirred at RT overnight, then diluted with HO (50 mL), NH2 EDCL, HOBT DMF and extracted with EtOAc (3x50 mL). The combined N-OH RT to 140° C. 55 organic layers were washed with HO (20 mL) and brine (20 N He mL), dried over NaSO filtered and concentrated under reduced pressure, and the residue was purified by Silica gel FCO column chromatography (Petroleum ether:EtOAc=1:2) to give benzyl 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phe o-N 60 nyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl) pyridin-2-yl)piperazine-1-carboxylate (350 mg, 56%) as a yellow oil and benzyl 4-(4-((3-methyl-5-(3-(4-(trifluo romethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol 65 1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate as a white solid (50 mg, 8%). MS (ES+) CoH,FNO requires: 620. found: 621 M+H".
US 9,481,692 B2 83 84 5-(5-Methyl-1-((2-(4-methylpiperazin-1-yl)pyridin mixture was stirred at RT for 3 h, then filtered to give the 4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluo crude tert-butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecar romethoxy)phenyl)-1,2,4-oxadiazole boxylate as a white solid (300 mg.93%), which was directly used for next step without further purification. MS (ES+) The mixture of 4-(4-((5-methyl-3-(3-(4-(trifluo C.H.N.O. requires: 302. found: 247 M+H-56". romethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol Step 2 1-yl)methyl)pyridin-2-yl)piperazin-1-ium trifluoroacetate (100 mg, 0.2 mmol), formaldehyde (0.5 mL, 6.0 mmol. 38% in HO) and paraformaldehyde (100 mg, 3.3 mmol) in EtOH 10 Bes (1 mL) was stirred at RT, then treated with NaBHCN (63 HN-NH mg, 1.0 mmol) in one portion. The mixture was stirred at RT TFADCM for 3 h, and then concentrated under reduced pressure to give -e- the crude product, which was purified by pre-HPLC (Mobile O O phase: A-10 mM NHHCO/HO, B=MeCN; Gradient: B=60%-95% in 18 min: Column: XBridge C18, 5 um, 30 15 mmx 150 mm) to afford 5-(5-methyl-1-((2-(4-methylpiper azin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4- (trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid HN-N f \ (45 mg, 45%). MS (ES+) CHFNO requires: 500. found: 501 M+H"; "H NMR (500 MHz, DMSO-d) & 8.22 (d. J=8.3 Hz, 2H), 8.08 (d. J=5.3 Hz, 1H), 7.60 (d. J=8.2 Hz, 2H), 6.77 (s, 1H), 6.42 (d. J=5.3 Hz, 1H), 5.50 (s. 2H), 3.50-3.48 (m, 4H), 2.58 (s.3H), 2.41-2.32 (m, 4H), 2.20 (s, 3H). 25 5-Phenylfuran-2-carbohydrazide EXAMPLE 3 To a solution of tert-butyl 2-(5-phenylfuran-2-carbonyl) 1-Methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)- hydrazinecarboxylate (300 mg, 1 mmol) in DCM (10 mL), 1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine TFA (4.85 g, 50 mmol) was added dropwise. The mixture 30 was stirred at RT overnight, then concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether:TEA=50:50:1) to afford 5-phenyl furan-2-carbohydrazide as a light yellow solid (150 mg. 74%). MS (ES+) CHNO, requires: 202. found: 203 35 M+H". Step 3
40 HN in- oHC O Her Step 1 O NaOH THF Reflux 45 HO / BocNHNH HN1 N O -- O K2CO3 HATU, DCM )- Boc HN-NH 5-Methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole O O To a suspension of 5-phenylfuran-2-carbohydrazide (100 mg, 0.5 mmol) and acetamidine hydrochloride (141 mg, 1.49 mmol) in THF (20 mL), NaOH (59 mg, 1.49 mmol) was added. The mixture was refluxed overnight, cooled, then 60 treated with HO (30 ml) and extracted with EtOAc (3x20 tert-Butyl mL). The combined organic layers were washed with HO 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate (1x10 mL) and brine (1x10 mL), dried over NaSO, filtered, concentrated under reduced pressure and purified by To a stirred suspension of 5-phenylfuran-2-carboxylic silica gel column chromatography (EtOAc:Petroleum acid (200 mg, 1.06 mmol), tert-butyl hydrazinecarboxylate 65 ether=1:1) to afford 5-methyl-3-(5-phenylfuran-2-yl)-1H-1, (140 mg, 1.06 mmol) and KCO (440 mg, 3.19 mmol) in 2,4-triazole as a white solid (15 mg, 13%). MS (ES+) DCM (20 mL), HATU (404 mg, 1.06 mmol) was added. The CHNO requires: 225. found: 226. M--H".
US 9,481,692 B2 89 90 Step 1 methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-ox adiazole (88 mg, 57%) as an off-white powder. MS(ES+) CHCINO requires: 352 found: 353 M+H". NH What is claimed is: 1. The compound O WN us NH- Cl- 5 NaOH O () O HN-NH Xylene, 170° C., 36 h W1. 10 S& N N NN Or, HN1 y-g N-O COO us N O F 15 DN,F -
or a salt thereof. 2. A pharmaceutical composition comprising the com 2-(5-Methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4- 2O pound oxadiazole To a solution of 5-phenyl-1,3,4-oxadiazole-2-carbohy drazide (400 mg, 1.96 mmol) and acetamidine hydrochloride (573 mg, 6.07 mmol) in xylene (20 mL) NaOH (243 mg, 25 6.07 mmol) was added. The mixture was stirred at 170° C. for 36 h, and then the reaction was cooled to RT, washed with HO (20 mL), extracted with 4:1 CHCli-PrCH (5x50 mL), dried with MgSO and concentrated. The crude prod F F Cr' Nels uct was purified on a Biotage pre-packed silica gel column 30 DN, (MeOH:DCM 2% to 20% MeOH) to afford 2-(5-methyl 1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (100 mg, or a salt thereof, together with a pharmaceutically acceptable 22%) as a white powder. MS(ES+) CHNO requires: 227 carrier. found: 228 M+H". 3. A method of treatment of cancer comprising the admin Step 2 35 istration of a therapeutically effective amount of compound
a NN O W1V N C 40 -N NNN Or, HN V / C N-O s CO us O Cs2CO3, NaI F N DMF, rt, o?n F Cr' {l 45 DN,
C N - N. NN N or a salt thereof, to a patient in need thereof. 4. The method as recited in claim 3 wherein said cancer N S. O is selected from the group consisting of colon cancer, breast o)2 Ny-g 50 cancer, ovarian cancer, lung cancer, prostrate cancer, can cers of the oral cavity and pharynx, esophagus, stomach, Small intestine, large intestine, colon, rectum, liver and biliary passages; pancreas, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney 2-(1-((2-Chloropyridin-4-yl)methyl)-5-methyl-1H-1, 55 and other urinary tissues; cancers of the eye, brain, spinal 2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole cord, and meninges; cancers of the thyroid and other endo crine glands; Hodgkin’s disease, non-Hodgkin’s lympho To a solution of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5- mas, multiple myeloma, leukemias and lymphomas; adre phenyl-1,3,4-oxadiazole (1.00 mg, 0.44 mmol) in DMF (3 nocarcinoma, angiosarcoma, astrocytoma, acoustic mL) CsCO (430 mg, 1.32 mmol), NaI (78 mg 0.52 mmol) 60 neuroma, anaplastic astrocytoma, basal cell carcinoma, blas and 2-chloro-4-(chloromethyl)pyridine (78 mg, 0.48 mmol) toglioma, chondrosarcoma, choriocarcinoma, chordoma, were added. The reaction was allowed to stir overnight at RT craniopharyngioma, cutaneous melanoma, cystadenocarci and then diluted with HO (10 mL), extracted with EtOAc noma, endotheliosarcoma, embryonal carcinoma, (3x10 mL), 4:1 CHCli-ProH (5x10 mL), dried with ependymoma, Ewings tumor, epithelial carcinoma, fibro MgSO and concentrated. The crude product was purified on 65 sarcoma, gastric cancer, genitourinary tract cancers, glio a Biotage pre-packed silica gel column (EtOAc: Hexane 12% blastoma multiforme, head and neck cancer, hemangioblas to 100% EtOAc) to afford 2-(1-((2-chloropyridin-4-yl) toma, hepatocellular carcinoma, hepatoma, Kaposi's US 9,481,692 B2 91 92 sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lymphomas, lymp hangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothe lioma, myelomas, myxosarcoma neuroblastoma, neurofibro sarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarci nomas, paraganglioma, parathyroid tumours, pheochromo cytoma, pinealoma, plasmacytomas, retinoblastoma, rhab domyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, Small cell lung carcinoma, non Small cell lung carcinoma, squamous cell carcinoma, Sweat gland carcinoma, synovioma, thyroid cancer, uveal mela or a salt thereof, to a patient in need thereof. noma, and Wilm's tumor. 9. The method as recited in claim 1, additionally com 5. The method as recited in claim 4 wherein said cancer prising the administration of another therapeutic agent. 15 is chosen from leukemia, lymphoma, neuroblastoma, and 10. A method for achieving an effect in a patient com glioblastoma. prising the administration of a therapeutically effective 6. The method as recited in claim 4 wherein said cancer is diffuse large B-cell lymphoma. amount of a compound as recited in claim 1 to a patient, 7. The method as recited in claim 4 wherein said cancer wherein the effect is selected from the group consisting of is leukemia. preventing or reducing resistance to radiotherapy and che 8. A method of treatment of acute myelogenous leukemia motherapy, preventing or reducing tumor invasion and comprising the administration of a therapeutically effective tumor metastasis, and preventing or reducing angiogenesis. amount of the compound k k k k k