USOO9260425B2

(12) United States Patent (10) Patent No.: US 9.260,425 B2 D0 et al. (45) Date of Patent: Feb. 16, 2016

(54) PYRAZOLO3,4-CIPYRIDINE COMPOUNDS WO 2006/042102 A2 4/2006 AND METHODS OF USE WO 2010/022081 A1 2, 2010 WO 2012 O78777 A1 6, 2012 (75) Inventors: Steven Do, San Jose, CA (US); Huiyong Hu, San Mateo, CA (US); Aleksandr OTHER PUBLICATIONS Kolesnikov, San Francisco, CA (US); Dong et al., “QSAR study of Akt protein kinase B (PKB) inhibitors Wendy Lee, San Ramon, CA (US); using support vector machine” Eur J Med Chem. 44(10):4090-7 Vickie H. Tsui, San Francisco, CA (US); (2009). Xiaojing Wang, Foster City, CA (US); Muddassar et al., “Elucidation of binding mode and three dimen Zhaoyang Wen, San Francisco, CA (US) sional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors' J Mol Model. 15(2): 183-92 (73) Assignee: Genetech, Inc., South San Francisco, (Feb. 2009). CA (US) Ohi et al., CAS Registry, Database Accession No. 2003:972059. “Preparation of pyrazole derivatives as JNK inhibitors'. (*) Notice: Subject to any disclaimer, the term of this PCT ISR and Written Opinion of the ISA for PCT/EP2012/065643. patent is extended or adjusted under 35 Wang et al., “Discovery of novel pyrazolo 1.5-alpyrimidines as U.S.C. 154(b) by 0 days. potent pan-Pim inhibitors by structure- and property-based drug design” Bioorg Med Chem Lett. 23(11):3149-53 (Jun. 2013). (21) Appl. No.: 13/571,595 Zhu et al., “Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt' Bioorg Med Chem. 15(6):2441 (22) Filed: Aug. 10, 2012 52 (2007). (65) Prior Publication Data * cited by examiner US 2013/OO3990.6 A1 Feb. 14, 2013 Primary Examiner — Samira Jean-Louis Related U.S. Application Data (74) Attorney, Agent, or Firm — Tony W. Peng (60) Provisional application No. 61/522,857, filed on Aug. 12, 2011. (57) ABSTRACT (51) Int. C. Pyrazolo 3,4-cpyridine compounds of Formula I, including CO7D 47L/04 (2006.01) Stereoisomers, geometric isomers, tautomers, and pharma CO7D 23/00 (2006.01) ceutically acceptable salts thereof, wherein R' and Rare as (52) U.S. C. defined herein, are useful for inhibiting Pim kinase, and for CPC ...... C07D 471/04 (2013.01); C07D 231/00 treating disorders such as cancer mediated by Pim kinase. (2013.01) Methods of using compounds of Formula I for invitro, in situ, (58) Field of Classification Search and in vivo diagnosis, prevention or treatment of Such disor CPC ...... C07D 471/04: CO7D 231/00 ders in mammalian cells, or associated pathological condi See application file for complete search history. tions, are disclosed. (56) References Cited U.S. PATENT DOCUMENTS R2 R! 5,604.240 A 2f1997 Chambers et al. N N 7,429,609 B2 9, 2008 Ohi et al. 2005/02O8582 A1* 9/2005 Ohi et al...... 435.7.1 Na2NN N H FOREIGN PATENT DOCUMENTS

EP 1510516 A1 3, 2005 WO 02/14317 A2 2, 2002 WO 02/20013 A2 3, 2002 14 Claims, No Drawings US 9,260,425 B2 1. 2 PYRAZOLO3.4-CIPYRIDINE COMPOUNDS Macdonald et al. (2006) Cell Biol vol. 7 pp. 1: Aho et al. AND METHODS OF USE (2004) FEBS Letters vol. 571 (1-3) pp. 43-9:Tamburini et al. (2009) Blood vol. 114 (8) pp. 1618-27). Pim kinase may CROSS REFERENCE TO RELATED affect cell survival since phosphorylation of Bad increases APPLICATIONS Bcl-2 activity and therefore promotes cell survival. Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases This non-provisional application filed under 37 CFRS1.53 causes depression of eIF4E, promoting mRNA translation (b), claims the benefit under 35 USC S119(e) of U.S. Provi and cellular growth. In addition, Pim-1 has been recognized sional Application Ser. No. 61/522,857 filed on 12 Aug. 2011, to promote cell cycle progression through phosphorylation of which is incorporated by reference in its entirety. 10 CDC25A, p21, and Cdc25C (Mochizuki et al. (1999) J Biol Chemvol. 274 (26) pp. 18659-66; Bachmann et al. (2006) Int FIELD OF THE INVENTION J BiochemCell Biol vol.38 (3) pp. 430-43; Wang et al. (2002) The invention relates generally to pyrazolo 3,4-cpyridine Biochim Biophys Acta vol. 1593 (1) pp. 45-55. compounds for treating disorders mediated by Pim kinase 15 Pim kinases show Synergy in transgenic mouse models (Pim-1, Pim-2, and/or Pim-3) inhibitors, thus useful as cancer with c-Myc-driven and Akt-driven tumors (Verbeek et al. therapeutics. The invention also relates to compositions, (1991) Mol Cell Biol vol. 11 (2) pp. 1176-9: Allen et al. more specifically pharmaceutical compositions comprising Oncogene (1997) Vol. 15 (10) pp. 1133-41; Hammerman et these compounds and methods of using the same, either alone al. (2005) Blood vol. 105 (11) pp. 4477-83). Pim Kinases are or in combination, to treat various forms of cancer and hyper involved in transforming activity of oncogenes identified in proliferative disorders, as well as methods of using the com acute myeloid leukemia (AML) including Flt3-ITD, BCR pounds for in vitro, in situ, and in vivo diagnosis or treatment abl, and Tel-Jak2. Expression of these oncogenes in BaF3 of mammalian cells, or associated pathological conditions. cells results in upregulation of Pim-1 and Pim-2 expression, resulting in IL-3 independent growth, and Subsequent Pim BACKGROUND OF THE INVENTION 25 inhibition results in apoptosis and cell growth arrest (Adam et Pim kinases are family of three highly-related serine and al. (2006) Cancer Research vol. 66 (7) pp. 3828-35). Pim threonine protein kinases encoded by the genes Pim-1, Pim-2, overexpression and dysregulation has also been noted as a and Pim-3. The gene names are derived from the phrase frequent event in many hematopoietic cancers, including leu Proviral Insertion, Moloney, frequent integration sites for 30 kemias and lymphoma (Amson et al. (1989) Proc Natl Acad murine moloney virus wherein the insertions lead to overex Sci USA vol. 86 (22) pp. 8857-61); Cohen et al. (2004) Leuk pression of Pim kinases and either denovo T-cell lymphomas, Lymphoma vol. 45 (5) pp. 951-5; Hittmann et al. (2006) or dramatic acceleration of tumorigenesis in a transgenic Leukemia vol. 20 (10) pp. 1774-82) as well as multiple Myc-driven lymphoma model (Cuypers et al. (1984) Cell, myeloma (Claudio et al. (2002) Blood vol. 100 (6) pp. 2175 vol.37 (1) pp. 141-50; Selten et al. (1985) EMBO.J. vol.4 (7) 35 86. Pim 1 has been shown to be overexpressed and correlated pp. 1793-8; van der Lugt et al. (1995) EMBO J. vol. 14 (11) to prostate cancer progression (Cibull et al. (2006) J Clin pp. 2536-44: Mikkers et al. (2002) Nature Genetics, vol. 32 Pathol vol. 59 (3) pp. 285-8: Dhanasekaran et al. (2001) (1) pp. 153-9; van Lohuizen et al. (1991) Cell, vol. 65 (5) pp. Nature vol. 412 (6849) pp. 822-6). Pim 1 expression increases 737-52). These experiments reveal synergy with the onco in mouse models with disease progression (Kim et al. (2002) gene c-Myc, and Suggest that inhibition of the Pim kinases 40 Proc Natl AcadSci USA vol. 99 (5) pp. 2884-9). Pim-1 has may have therapeutic benefit. been reported to be the most highly overexpressed mRNA in Mouse genetics Suggests that antagonizing Pim kinases the Subset of human prostate tumor samples which have a may have an acceptable safety profile; a Pim 1-/-: Pim-2-/-, c-Myc-driven genesignature (Ellwood-Yen et al. (2003) Can Pim-3-/- mouse knockout is viable although slightly smaller cer Cell vol. 4 (3) pp. 223-38). Pim-3 has been also been than wild type littermates (Mikkers et al. (2004) Mol Cell 45 Biol vol. 24 (13) pp. 6104-154). The three genes give rise to shown to be overexpressed and to have a functional role in six protein isoforms including a protein kinase domain, and pancreatic cancer and hepatocellular carcinoma (Li et al. apparently without recognizable regulatory domains. All six (2006) Cancer Research vol. 66 (13) pp. 6741-7: Fujii et al. isoforms are constitutively active protein kinases that do not (2005) Int J. Cancer, vol. 114 (2) pp. 209-18). require post-translational modification for activity, thus Pim 50 Beyond oncology therapeutic and diagnostic applications, kinases are regulated primarily at the transcriptional level Pim kinases could play an important role in normal immune (Qianet al. (2005) J Biol Chem, vol. 280 (7) pp. 6130-7). Pim system function and Pim inhibition could be therapeutic for a kinase expression is highly inducible by cytokines and number of different immunologic pathologies including growth factors receptors and Pims are direct transcriptional targets of the Stat proteins, including Stat3 and Stats. Pim-1, 55 inflammation, autoimmune conditions, allergy, and immune for example, is required for the 130-mediated Stat3 prolifera Suppression for organ transplantation (Aho et al. Expression tion signal (Aksoy et al. (2007) Stem Cells, vol. 25 (12) pp. of human Pim family genes is selectively up-regulated by 2996-3004; Hirano et al. (2000) Oncogene vol. 19 (21) pp. cytokines promoting T helper type 1, but not Thelper type 2, 2548-56; Shirogane et al. (1999) Immunity vol. 11 (6) pp. cell differentiation. Immunology (2005) vol. 116 (1) pp. 709-19). 60 82-8). Pim kinases function in cellular proliferation and survival pathways parallel to the PI3k/Akt/mTOR signaling axis (Hammerman et al. (2005) Blood vol. 105 (11) pp. 4477-83). SUMMARY OF THE INVENTION Indeed, several of the phosphorylation targets of the PI3kaxis including Bad and elF4E-BP1 are cell growth and apoptosis 65 The invention relates to pyrazolo 3,4-cpyridine com regulators and are also phosphorylation targets of the Pim pounds for treating disorders mediated by Pim kinase (Pim-1, kinases (Fox et al. (2003) Genes Dev vol. 17 (15) pp. 1841-54; Pim-2, and/or Pim-3) inhibitors Formula I compounds. US 9,260,425 B2 3 4 Formula I compounds have the structure: scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials N described. In the event that one or more of the incorporated \ literature, patents, and similar materials differs from or con N 2 N/ tradicts this application, including but not limited to defined H terms, term usage, described techniques, or the like, this 10 application controls. and Stereoisomers, geometric isomers, tautomers, and DEFINITIONS pharmaceutically acceptable salts thereof. The various sub stituents, including R' and Rare as defined herein. The term “alkyl as used herein refers to a saturated linear One aspect of the invention is a pharmaceutical composi 15 or branched-chain monovalent hydrocarbon radical of one to tion comprised of a Formula I compound and a pharmaceu twelve carbonatoms (C-C), wherein the alkyl radical may tically acceptable carrier, glidant, diluent, or excipient. The be optionally substituted independently with one or more pharmaceutical composition may further comprise a second substituents described below. In another embodiment, an chemotherapeutic agent. alkyl radical is one to eight carbon atoms (C-Cs), or one to Another aspect of the invention is a process for making a six carbonatoms (C-C). Examples of alkyl groups include, pharmaceutical composition which comprises combining a but are not limited to, methyl (Me, —CH), ethyl (Et, Formula I compound with a pharmaceutically acceptable car —CH2CH), 1-propyl (n-Pr, n-propyl. —CH2CH2CH), rier. 2-propyl (i-Pr. i-propyl, -CH(CH)), 1-butyl (n-Bu, n-bu The invention includes a method of treating a disease or tyl, —CH2CH2CHCH), 2-methyl-1-propyl (i-Bu, i-butyl, disorder which method comprises administering a therapeu 25 —CH-CH(CH)), 2-butyl (s-Bu, s-butyl, —CH(CH) tically effective amount of a Formula I compound to a patient CHCH), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH)), with a disease or disorder selected from cancer, immune 1-pentyl (n-pentyl, —CH2CH2CH2CHCH), 2-pentyl disorders, cardiovascular disease, viral infection, inflamma (—CH(CH)CHCHCH), 3-pentyl ( CH(CHCH)), tion, metabolism/endocrine function disorders and neuro 2-methyl-2-butyl ( C(CH) CHCH), 3-methyl-2-butyl logical disorders, and mediated by Pim kinase. The method 30 (-CH(CH)CH(CH)), 3-methyl-1-butyl ( CHCHCH includes further administering an additional therapeutic agent (CH)), 2-methyl-1-butyl ( CHCH(CH)CHCH), selected from a chemotherapeutic agent, an anti-inflamma 1-hexyl ( CHCHCHCHCHCH), 2-hexyl ( CH tory agent, an immunomodulatory agent, a neurotropic factor, (CH)CHCHCHCH), 3-hexyl (-CH(CHCH.) an agent for treating cardiovascular disease, an agent for (CHCHCH)), 2-methyl-2-pentyl (—C(CH) treating liver disease, an anti-viral agent, an agent for treating 35 CHCHCH), 3-methyl-2-pentyl ( CH(CH)CH(CH) blood disorders, an agent for treating diabetes, and an agent CHCH), 4-methyl-2-pentyl ( CH(CH)CH-CH(CH)), for treating immunodeficiency disorders. 3-methyl-3-pentyl ( C(CH)(CHCH)), 2-methyl-3-pen The invention includes a kit for treating a condition medi tyl ( CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl ( C ated by Pim kinase, comprising: a) a first pharmaceutical (CH)-CH(CH)), 3.3-dimethyl-2-butyl ( CH(CH)C composition comprising a Formula I compound; and b) 40 (CH), 1-heptyl, 1-octyl, and the like. instructions for use. The term “alkylene' as used herein refers to a saturated The invention includes a Formula I compound for use as a linear or branched-chain divalent hydrocarbon radical of one medicament, and for use in treating a disease or disorder to twelve carbon atoms (C-C), wherein the alkylene radi selected from cancer, immune disorders, cardiovascular dis cal may be optionally substituted independently with one or ease, viral infection, inflammation, metabolism/endocrine 45 more substituents described below. In another embodiment, function disorders and neurological disorders, and mediated an alkylene radical is one to eight carbon atoms (C-Cs), or by Pim kinase. one to six carbon atoms (C-C). Examples of alkylene The invention includes use of a Formula I compound in the groups include, but are not limited to, methylene (-CH ), manufacture of a medicament for the treatment of cancer, ethylene (—CHCH ), propylene (—CH2CH2CH2—). immune disorders, cardiovascular disease, viral infection, 50 and the like. inflammation, metabolism/endocrine function disorders and The term “alkenyl refers to linear or branched-chain neurological disorders, and where the medicament mediates monovalent hydrocarbon radical of two to eight carbonatoms Pim kinase. (C-C) with at least one site of unsaturation, i.e., a carbon The invention includes methods of making a Formula I carbon, sp double bond, wherein the alkenyl radical may be compound. 55 optionally substituted independently with one or more sub stituents described herein, and includes radicals having “cis' DETAILED DESCRIPTION OF EXEMPLARY and “trans' orientations, or alternatively, “E” and “Z” orien EMBODIMENTS tations. Examples include, but are not limited to, ethylenyl or vinyl ( CH=CH-), allyl ( CH-CH=CH-), and the like. Reference will now be made in detail to certain embodi 60 The term “alkenylene' refers to linear or branched-chain ments of the invention, examples of which are illustrated in divalent hydrocarbon radical of two to eight carbon atoms the accompanying structures and formulas. While the inven (C-C) with at least one site of unsaturation, i.e., a carbon tion will be described in conjunction with the enumerated carbon, sp' double bond, wherein the alkenylene radical may embodiments, it will be understood that they are not intended be optionally and independently substituted with one or more to limit the invention to those embodiments. On the contrary, 65 Substituents described herein, and includes radicals having the invention is intended to cover all alternatives, modifica “cis' and “trans' orientations, or alternatively, “E” and “Z” tions, and equivalents which may be included within the orientations. Examples include, but are not limited to, ethyl US 9,260,425 B2 5 6 enylene O vinylene (-CH=CH-), allyl about 20 ring atoms in which at least one ring atom is a ( CH-CH=CH ), and the like. heteroatom selected from nitrogen, oxygen, phosphorus and The term “alkynyl refers to a linear or branched monova Sulfur, the remaining ring atoms being C, where one or more lent hydrocarbon radical of two to eight carbonatoms (C-Cs) ring atoms is optionally substituted independently with one or with at least one site of unsaturation, i.e., a carbon-carbon, sp more substituents described below. A heterocycle may be a triple bond, wherein the alkynyl radical may be optionally monocycle having 3 to 7 ring members (2 to 6 carbon atoms substituted independently with one or more substituents and 1 to 4 heteroatoms selected from N, O, P, and S) or a described herein. Examples include, but are not limited to, bicycle having 7 to 10 ring members (4 to 9 carbon atoms and ethynyl ( C=CH), propynyl (propargyl, —CHC=CH), 1 to 6 heteroatoms selected from N, O, P, and S), for example: and the like. 10 a bicyclo4.5, 5.5, 5.6, or 6.6 system. Heterocycles are The term “alkynylene' refers to a linear or branched diva described in Paquette, Leo A.: “Principles of Modern Hetero lent hydrocarbon radical of two to eight carbonatoms (C-Cs) cyclic Chemistry” (W. A. Benjamin, New York, 1968), par with at least one site of unsaturation, i.e., a carbon-carbon, sp ticularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of triple bond, wherein the alkynylene radical may be optionally Heterocyclic Compounds. A series of Monographs” (John substituted independently with one or more substituents 15 Wiley & Sons, New York, 1950 to present), in particular described herein. Examples include, but are not limited to, Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) ethynylene (-C=C- ), propynylene (propargylene, 82:5566. “Heterocyclyl also includes radicals where hetero —CH2C=C ), and the like. cycle radicals arefused with a saturated, partially unsaturated The terms “carbocycle”, “carbocyclyl', 'carbocyclic ring ring, or aromatic carbocyclic or heterocyclic ring. Examples and “cycloalkyl refer to a monovalent non-aromatic, Satu of heterocyclic rings include, but are not limited to, morpho rated or partially unsaturated ring having 3 to 12 carbonatoms lin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, (C-C) as a monocyclic ring or 7 to 12 carbon atoms as a piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, be arranged, for example, as a bicyclo4.5, 5.5, 5.6 or octahydropyrido 1,2-alpyrazin-2-yl, 1,4-diazepan-1-yl, 6.6 system, and bicyclic carbocycles having 9 or 10 ring 25 pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahy atoms can be arranged as a bicyclo5.6 or 6.6 system, or as drothienyl, tetrahydropyranyl, dihydropyranyl, tetrahy bridged systems such as bicyclo[2.2.1]heptane, bicyclo drothiopyranyl, piperidino, morpholino, thiomorpholino, 2.2.2]octane and bicyclo3.2.2]nonane. Spiro moieties are thioxanyl, piperazinyl, homopiperazinyl, aZetidinyl, oxeta also included within the scope of this definition. Examples of nyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl. monocyclic carbocycles include, but are not limited to, cyclo 30 oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrroli propyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclo nyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1.3-diox pent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1- olanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclo imidazolidinyl, 3-azabicyco3.1.0 hexanyl, 3-azabicyclo decyl cycloundecyl cyclododecyl, and the like. Carbocyclyl 35 4.1.0 heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl groups are optionally Substituted independently with one or quinolizinyl and N-pyridyl ureas. Spiro moieties are also more substituents described herein. included within the scope of this definition. Examples of a Aryl means a monovalent aromatic hydrocarbon radical heterocyclic group wherein 2 ring atoms are substituted with of 6-20 carbon atoms (C-C) derived by the removal of one oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thio hydrogen atom from a single carbon atom of a parent aro 40 morpholinyl. The heterocycle groups herein are optionally matic ring system. Some aryl groups are represented in the substituted independently with one or more substituents exemplary structures as 'Ar. Aryl includes bicyclic radicals described herein. comprising an aromatic ring fused to a Saturated, partially The term "heteroaryl' refers to a monovalent aromatic unsaturated ring, or aromatic carbocyclic ring. Typical aryl radical of 5-, 6-, or 7-membered rings, and includes fused ring groups include, but are not limited to, radicals derived from 45 systems (at least one of which is aromatic) of 5-20 atoms, benzene (phenyl), Substituted benzenes, naphthalene, containing one or more heteroatoms independently selected anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphtha from nitrogen, oxygen, and Sulfur. Examples of heteroaryl lene, 1.2.3,4-tetrahydronaphthyl, and the like. Aryl groups groups are pyridinyl (including, for example, 2-hydroxypy are optionally substituted independently with one or more ridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (includ substituents described herein. 50 ing, for example, 4-hydroxypyrimidinyl), pyrazolyl, triaz Arylene' means a divalent aromatic hydrocarbon radical olyl pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, of 6-20 carbon atoms (C-C) derived by the removal of two thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl pyrrolyl, hydrogenatom from a two carbonatoms of a parent aromatic quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, ring system. Some arylene groups are represented in the benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indoliz exemplary structures as 'Ar. Arylene includes bicyclic radi 55 inyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridi cals comprising an aromatic ring fused to a Saturated, par nyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, tially unsaturated ring, or aromatic carbocyclic ring. Typical furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, arylenegroups include, but are not limited to, radicals derived benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, from benzene (phenylene), Substituted benzenes, naphtha and furopyridinyl. Heteroaryl groups are optionally Substi lene, anthracene, biphenylene, indenylene, indanylene, 1.2- 60 tuted independently with one or more substituents described dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the herein. like. Arylene groups are optionally Substituted with one or The heterocycle or heteroaryl groups may be carbon (car more substituents described herein. bon-linked), or nitrogen (nitrogen-linked) bonded where The terms "heterocycle.” “heterocyclyl and "heterocyclic Such is possible. By way of example and not limitation, car ring are used interchangeably herein and refer to a saturated 65 bon bonded heterocycles or heteroaryls are bonded at posi or a partially unsaturated (i.e., having one or more double tion 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a and/or triple bonds within the ring) carbocyclic radical of 3 to pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, US 9,260,425 B2 7 8 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahy cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, drofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, as well as head and neck cancer. position 2, 4, or 5 of an oxazole, imidazole or thiazole, posi A “chemotherapeutic agent' is a chemical compound use tion 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, posi ful in the treatment of cancer, regardless of mechanism of tion 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, action. Classes of chemotherapeutic agents include, but are position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, not limited to: alkylating agents, antimetabolites, spindle poi 5, 6, 7, or 8 of an isoquinoline. son plant alkaloids, cytotoxic/antitumor antibiotics, topoi By way of example and not limitation, nitrogen bonded Somerase inhibitors, antibodies, photosensitizers, and kinase heterocycles or heteroaryls are bonded at position 1 of an inhibitors. Chemotherapeutic agents include compounds aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyr 10 used in “targeted therapy' and conventional chemotherapy. roline, imidazole, imidazolidine, 2-imidazoline, 3-imidazo Examples of chemotherapeutic agents include: erlotinib line, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperi (TARCEVAR), Genentech/OSI Pharm.), docetaxel (TAXO dine, piperazine, indole, indoline, 1H-indazole, position 2 of TERE(R), Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, a isoindole, or isoindoline, position 4 of a morpholine, and CAS No. 51-21-8), gemcitabine (GEMZARR, Lilly), position 9 of a carbazole, or 3-carboline. 15 PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis The terms “treat' and “treatment” refer to both therapeutic diamine, dichloroplatinum(II), CAS No. 15663-27-1), carbo treatment and prophylactic or preventative measures, wherein platin (CAS No. 41575-94-4), paclitaxel (TAXOL(R), Bristol the object is to prevent or slow down (lessen) an undesired Myers Squibb Oncology, Princeton, N.J.), trastuzumab physiological change or disorder, Such as the development or (HERCEPTINR), Genentech), temozolomide (4-methyl-5- spread of cancer. For purposes of this invention, beneficial or oxo-2,3,4,6,8-pentazabicyclo4.3.0nona-2.7.9-triene-9-car desired clinical results include, but are not limited to, allevia boxamide, CAS No. 85622-93-1, TEMODARR, tion of symptoms, diminishment of extent of disease, stabi TEMODAL(R), Schering Plough), tamoxifen ((Z)-2-[4-(1,2- lized (i.e., not worsening) state of disease, delay or slowing of diphenylbut-1-enyl)phenoxy-N,N-dimethylethanamine, disease progression, amelioration or palliation of the disease NOLVADEXR, ISTUBALR, VALODEX(R), and doxorubi state, and remission (whether partial or total), whether detect 25 cin (ADRIAMYCINR), Akti-1/2, HPPD, and rapamycin. able or undetectable. “Treatment can also mean prolonging More examples of chemotherapeutic agents include: Oxali Survival as compared to expected Survival if not receiving platin (ELOXATINR, Sanofi), bortezomib (VELCADE(R), treatment. Those in need of treatment include those already Millennium Pharm.), sutent (SUNITINIB(R, SU11248, with the condition or disorder as well as those prone to have Pfizer), letrozole (FEMARAR), Novartis), imatinib mesylate the condition or disorder or those in which the condition or 30 (GLEEVECR), Novartis), XL-518 (Mek inhibitor, Exelixis, disorder is to be prevented. WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, The phrase “therapeutically effective amount’ means an Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, amount of a compound of the present invention that (i) treats Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, or prevents the particular disease, condition, or disorder, (ii) Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK attenuates, ameliorates, or eliminates one or more symptoms 35 222584 (Novartis), fulvestrant (FASLODEXR, AstraZen of the particular disease, condition, or disorder, or (iii) pre eca), leucovorin (folinic acid), rapamycin (sirolimus, RAPA vents or delays the onset of one or more symptoms of the MUNE(R), Wyeth), everolimus (AFINITORR, Novartis), particular disease, condition, or disorder described herein. In lapatinib (TYKERBR, GSK572016, Glaxo Smith Kline), the case of cancer, the therapeutically effective amount of the lonafarnib (SARASARTM, SCH 66336, Schering Plough), drug may reduce the number of cancer cells; reduce the tumor 40 Sorafenib (NEXAVARR, BAY43-9006, Bayer Labs), gefi size; inhibit (i.e., slow to Some extent and preferably stop) tinib (IRESSAR), AstraZeneca), irinotecan (CAMP cancer cell infiltration into peripheral organs; inhibit (i.e., TOSARR), CPT-11, Pfizer), tipifarnib (ZARNESTRATM, slow to some extent and preferably stop) tumor metastasis; Johnson & Johnson), ABRAXANETM (Cremophor-free), inhibit, to Some extent, tumor growth; and/or relieve to some albumin-engineered nanoparticle formulations of paclitaxel extent one or more of the symptoms associated with the 45 (American Pharmaceutical Partners, Schaumberg, II), Van cancer. To the extent the drug may prevent growth and/or kill detanib (rINN, ZD6474, ZACTIMAR), AstraZeneca), chlo existing cancer cells, it may be cytostatic and/or cytotoxic. ranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsiroli For cancer therapy, efficacy can be measured, for example, by mus (TORISEL(R), Wyeth), pazopanib (GlaxoSmithKline), assessing the time to disease progression (TTP) and/or deter canfosfamide (TELCYTAR, Telik), abiraterone (ZYTIGAR), mining the response rate (RR). 50 Johnson & Johnson), thiotepa and cyclosphosphamide (CY The terms “cancer refers to or describe the physiological TOXANR, NEOSAR(R); alkyl sulfonates such as busulfan, condition in mammals that is typically characterized by improSulfan and piposulfan; aziridines Such as benzodopa, unregulated cell growth. A “tumor comprises one or more carboquone, meturedopa, and uredopa; ethylenimines and cancerous cells. Examples of cancer include, but are not methylamelamines including altretamine, triethylen limited to, carcinoma, lymphoma, blastoma, Sarcoma, and 55 emelamine, triethylenephosphoramide, triethylenethiophos leukemia or lymphoid malignancies. More particular phoramide and trimethylomelamine; acetogenins (especially examples of such cancers include squamous cell cancer (e.g., bullatacin and bullatacinone); a camptothecin (including the epithelial squamous cell cancer), lung cancer including synthetic analog topotecan); bryostatin: cally statin: CC-1065 Small-cell lung cancer, non-Small cell lung cancer (including its adoZelesin, carZelesin and bizelesin synthetic (NSCLC), adenocarcinoma of the lung and squamous car 60 analogs); cryptophycins (particularly cryptophycin 1 and cinoma of the lung, cancer of the peritoneum, hepatocellular cryptophycin 8); dolastatin; duocarmycin (including the Syn cancer, gastric or stomach cancer including gastrointestinal thetic analogs, KW-2189 and CB1-TM1); eleutherobin: pan cancer, pancreatic cancer, glioblastoma, cervical cancer, ova cratistatin; a sarcodictyin; spongistatin: nitrogen mustards rian cancer, liver cancer, bladder cancer, hepatoma, breast Such as chlorambucil, chlornaphazine, chlorophosphamide, cancer, colon cancer, rectal cancer, colorectal cancer, 65 estramustine, ifosfamide, mechlorethamine, mechlore endometrial or uterine carcinoma, salivary gland carcinoma, thamine oxide hydrochloride, melphalan, novembichin, kidney or renal cancer, prostate cancer, Vulval cancer, thyroid phenesterine, prednimustine, trofosfamide, uracil mustard; US 9,260,425 B2 10 nitrosoureas such as carmustine, chlorozotocin, fotemustine, acetate), AROMASINR) (exemestane; Pfizer), formestanie, lomustine, nimustine, and ranimnustine; antibiotics such as fadrozole, RIVISORR) (vorozole), FEMARAR (letrozole; the enediyne antibiotics (e.g., calicheamicin, calicheamicin Novartis), and ARIMIDEXOR (anastrozole; AstraZeneca); gammall, calicheamicin omegal (Angew Chem. Intl. Ed. (iii) anti-androgens such as flutamide, nilutamide, bicaluta Engl. (1994) 33:183-186); dynemicin, dynemicin A; bispho mide, leuprolide, and goserelin; as well as troxacitabine (a sphonates, such as clodronate; an esperamicin; as well as 1,3-dioxolane nucleoside cytosine analog); (iv) protein neocarzinostatin chromophore and related chromoprotein kinase inhibitors such as MEK inhibitors (WO 2007/ enediyne antibiotic chromophores), aclacinomysins, actino 044515); (v) lipid kinase inhibitors; (vi) antisense oligonucle mycin, authramycin, azaserine, bleomycins, cactinomycin, otides, particularly those which inhibit expression of genes in carabicin, caminomycin, carzinophilin, chromomycinis, dac 10 signaling pathways implicated in aberrant cell proliferation, tinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-nor leucine, morpholino-doxorubicin, cyanomorpholino-doXo for example, PKC-alpha, Raf and H-Ras, such as oblimersen rubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), (GENASENSE(R), Genta Inc.); (vii) ribozymes such as VEGF epirubicin, esorubicin, idarubicin, nemorubicin, marcello expression inhibitors (e.g., ANGIOZYME(R) and HER2 mycin, mitomycins such as mitomycin C, mycophenolic 15 expression inhibitors; (viii) vaccines such as gene therapy acid, nogalamycin, olivomycins, peplomycin, porfiromycin, vaccines, for example, ALLOVECTINR, LEUVECTINR, puromycin, quelamycin, rodorubicin, Streptonigrin, Strepto and VAXID(R); PROLEUKINR rIL-2: topoisomerase 1 Zocin, tubercidin, ubenimex, Zinostatin, Zorubicin; anti-me inhibitors such as LURTOTECANR); ABARELIX(R) rmRH; tabolites such as methotrexate and 5-fluorouracil (5-FU); (ix) anti-angiogenic agents such as bevacizumab (AVAS folic acid analogs such as denopterin, methotrexate, pterop TINR, Genentech); and pharmaceutically acceptable salts, terin, trimetrexate; purine analogs such as fludarabine, 6-mer acids and derivatives of any of the above. captopurine, thiamiprine, thioguanine; pyrimidine analogs Also included in the definition of “chemotherapeutic Such as ancitabine, azacitidine, 6-azauridine, carmofur, cyt agent” are therapeutic antibodies such as alemtuzumab arabine, dideoxyuridine, doxifluridine, enocitabine, floxuri (Campath), bevacizumab (AVASTINR), Genentech); cetux dine; androgens Such as calusterone, dromostanolone propi 25 imab (ERBITUX(R), Imclone); panitumumab (VECTIBIX(R), onate, epitiostanol, mepitioStane, testolactone; anti-adrenals Amgen), rituximab (RITUXANR, Genentech/Biogen Idec), Such as aminoglutethimide, mitotane, triloStane; folic acid pertuzumab (OMNITARGTM,2C4, Genentech), trastuzumab replenisher such as frolinic acid; aceglatone; aldophospha (HERCEPTINR), Genentech), tositumomab (Bexxar, mide glycoside; aminolevulinic acid; eniluracil; amsacrine; Corixia), and the antibody drug conjugate, gemtuzumab ozo bestrabucil; bisantrene; ediatraxate; defofamine; demecol 30 gamicin (MYLOTARG(R), Wyeth). cine; diaziquone; elformithine; elliptinium acetate; an Humanized monoclonal antibodies with therapeutic poten epothilone: etoglucid: gallium nitrate; hydroxyurea; lentinan; tial as chemotherapeutic agents in combination with the PI3K lonidainine; maytansinoids such as maytansine and ansami inhibitors of the invention include: alemtuzumab, apoli tocins; mitoguaZone; mitoxantrone; mopidanmol; nitraerine; Zumab, aselizumab, atlizumab, bapineuZumab, bevaci pentostatin: phenamet, pirarubicin; losoxantrone; podophyl 35 Zumab, bivatuZumab mertansine, cantuzumab mertansine, linic acid; 2-ethylhydrazide; procarbazine; PSKR polysac cedelizumab, certolizumab pegol, cidfusituzumab, cidtu charide complex (JHS Natural Products, Eugene, Oreg.); Zumab, daclizumab, eculizumab, efalizumab, epratuZumab, razoxane, rhizoxin; sizofuran; Spirogermanium; tenuaZonic erlizumab, felvizumab, fontolizumab, gemtuzumab ozo acid; triaziquone; 2.2.2"-trichlorotriethylamine; trichoth gamicin, inotuZumab ozogamicin, ipilimumab, labetuZumab, ecenes (especially T-2 toxin, Verracurin A, roridin A and 40 lintuZumab, matuZumab, mepolizumab, motavizumab, anguidine); urethan; vindesine; dacarbazine; mannomustine; motovizumab, natalizumab, nimotuZumab, noloVizumab, mitobronitol; mitolactol; pipobroman, gacytosine; arabino numavizumab, ocrelizumab, omalizumab, palivizumab, pas side (Ara-C); cyclophosphamide; thiotepa, 6-thioguanine; colizumab, pectfusituzumab, pectuZumab, pertuZumab, pex mercaptopurine; methotrexate; platinum analogs such as cis elizumab, ralivizumab, ranibizumab, reslivizumab, resli platin and carboplatin: vinblastine: etoposide (VP-16); ifos 45 Zumab, resy Vizumab, rovelizumab, ruplizumab, famide: mitoxantrone; Vincristine; vinorelbine (NAVEL SibrotuZumab, Siplizumab, SontuZumab, tacatuZumab tetraX BINE(R); novantrone; teniposide; ediatrexate; daunomycin; etan, tadocizumab, talizumab, tefibazumab, tocilizumab, aminopterin; capecitabine (XELODAR), Roche); ibandr toralizumab, trastuzumab, tucotuZumab celmoleukin, onate; CPT-11: topoisomerase inhibitor RFS 2000; difluo tucusituzumab, umavizumab, urtoxazumab, and visilizumab. romethylornithine (DMFO); retinoids such as retinoic acid; 50 A “metabolite' is a product produced through metabolism and pharmaceutically acceptable salts, acids and derivatives in the body of a specified compound or salt thereof. Metabo of any of the above. lites of a compound may be identified using routine tech Examples of chemotherapeutic agents also include: dex niques known in the art and their activities determined using amethasone, thioTEPA, doxorubicin, Vincristine, rituximab, tests Such as those described herein. Such products may result cyclophosphamide, prednisone, melphalan, lenalidomide, 55 for example from the oxidation, reduction, hydrolysis, ami bortezomib, rapamycin, and cytarabine. dation, deamidation, esterification, deesterification, enzy Also included in the definition of “chemotherapeutic matic cleavage, and the like, of the administered compound. agent” are: (i) anti-hormonal agents that act to regulate or Accordingly, the invention includes metabolites of com inhibit hormone action on tumors such as anti-estrogens and pounds of the invention, including compounds produced by a selective estrogen receptor modulators (SERMs), including, 60 process comprising contacting a Formula I compound of this for example, tamoxifen (including NOLVADEXOR); tamox invention with a mammal for a period of time sufficient to ifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, yield a metabolic product thereof. trioxifene, keoxifene, LY 1 17018, onapristone, and FAR The term “package insert” is used to refer to instructions ESTONR) (toremifine citrate); (ii) aromatase inhibitors that customarily included in commercial packages of therapeutic inhibit the enzyme aromatase, which regulates estrogen pro 65 products, that contain information about the indications, duction in the adrenal glands, such as, for example, 4(5)- usage, dosage, administration, contraindications and/or imidazoles, aminoglutethimide, MEGASER) (megestrol warnings concerning the use of Such therapeutic products. US 9,260,425 B2 11 12 The term "chiral refers to molecules which have the prop The counterion may be any organic or inorganic moiety that erty of non-Superimposability of the mirror image partner, stabilizes the charge on the parent compound. Furthermore, a while the term “achiral” refers to molecules which are super pharmaceutically acceptable salt may have more than one imposable on their mirror image partner. charged atom in its structure. Instances where multiple The term “stereoisomers' refers to compounds which have 5 charged atoms are part of the pharmaceutically acceptable identical chemical constitution, but differ with regard to the salt can have multiple counter ions. Hence, a pharmaceuti arrangement of the atoms or groups in space. cally acceptable salt can have one or more charged atoms “Diastereomer' refers to a stereoisomer with two or more and/or one or more counter ion. centers of chirality and whose molecules are not mirror If the compound of the invention is a base, the desired images of one another. Diastereomers have different physical 10 pharmaceutically acceptable salt may be prepared by any properties, e.g. melting points, boiling points, spectral prop suitable method available in the art, for example, treatment of erties, and reactivities. Mixtures of diastereomers may sepa the free base with an inorganic acid, such as hydrochloric rate under high resolution analytical procedures such as elec acid, hydrobromic acid, Sulfuric acid, nitric acid, methane trophoresis and chromatography. Sulfonic acid, phosphoric acid and the like, or with an organic "Enantiomers' refer to two stereoisomers of a compound 15 acid, such as acetic acid, trifluoroacetic acid, maleic acid, which are non-Superimposable mirror images of one another. Succinic acid, mandelic acid, fumaric acid, malonic acid, Stereochemical definitions and conventions used herein pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyra generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of nosidyl acid, Such as glucuronic acid or galacturonic acid, an Chemical Terms (1984) McGraw-Hill Book Company, New alpha hydroxy acid, Such as citric acid or tartaric acid, an York; and Eliel, E. and Wilen, S., “Stereochemistry of 20 amino acid, such as aspartic acid or glutamic acid, an aro Organic Compounds”, John Wiley & Sons, Inc., New York, matic acid, such as benzoic acid or cinnamic acid, a Sulfonic 1994. The compounds of the invention may contain asym acid, Such as p-toluenesulfonic acid or ethanesulfonic acid, or metric or chiral centers, and therefore exist in different stere the like. oisomeric forms. It is intended that all stereoisomeric forms If the compound of the invention is an acid, the desired of the compounds of the invention, including but not limited 25 pharmaceutically acceptable salt may be prepared by any to, diastereomers, enantiomers and atropisomers, as well as suitable method, for example, treatment of the free acid with mixtures thereof Such as racemic mixtures, form part of the an inorganic or organic base. Such as an amine (primary, present invention. Many organic compounds existin optically secondary or tertiary), an alkali metal hydroxide or alkaline active forms, i.e., they have the ability to rotate the plane of earth metal hydroxide, or the like. Illustrative examples of plane-polarized light. In describing an optically active com- 30 Suitable salts include, but are not limited to, organic salts pound, the prefixes D and L, or Rand S. are used to denote the derived from amino acids, such as glycine and arginine, absolute configuration of the molecule about its chiral ammonia, primary, secondary, and tertiary amines, and cyclic center(s). The prefixes d and 1 or (+) and (-) are employed to amines, such as piperidine, morpholine and piperazine, and designate the sign of rotation of plane-polarized light by the inorganic salts derived from Sodium, calcium, potassium, compound, with (-) or 1 meaning that the compound is 35 magnesium, manganese, iron, copper, Zinc, aluminum and levorotatory. A compound prefixed with (+) or d is dextroro lithium. tatory. For a given chemical structure, these Stereoisomers are The phrase “pharmaceutically acceptable' indicates that identical except that they are mirror images of one another. A the Substance or composition must be compatible chemically specific stereoisomer may also be referred to as an enanti and/or toxicologically, with the other ingredients comprising omer, and a mixture of Such isomers is often called an enan- 40 a formulation, and/or the mammal being treated therewith. tiomeric mixture. A 50:50 mixture of enantiomers is referred A “solvate” refers to an association or complex of one or to as a racemic mixture or a racemate, which may occur where more solvent molecules and a compound of the invention. there has been no stereoselection or stereospecificity in a Examples of solvents that form solvates include, but are not chemical reaction or process. The terms “racemic mixture' limited to, water, isopropanol, ethanol, methanol, DMSO, and “racemate” refer to an equimolar mixture of two enan- 45 ethylacetate, acetic acid, and ethanolamine. tiomeric species, devoid of optical activity. The terms “compound of this invention, and “compounds The term “tautomer' or “tautomeric form' refers to struc of the present invention' and “compounds of Formula I tural isomers of different energies which are interconvertible include compounds of Formulas I and stereoisomers, geomet via a low energy barrier. For example, proton tautomers (also ric isomers, tautomers, Solvates, metabolites, and pharmaceu known as prototropic tautomers) include interconversions via 50 tically acceptable salts and prodrugs thereof. migration of a proton, Such as keto-enol and imine-enamine Any formula or structure given herein, including Formula isomerizations. Valence tautomers include interconversions I compounds, is also intended to represent hydrates, Solvates, by reorganization of some of the bonding electrons. and polymorphs of Such compounds, and mixtures thereof. The phrase “pharmaceutically acceptable salt as used Any formula or structure given herein, including Formula herein, refers to pharmaceutically acceptable organic or inor- 55 I compounds, is also intended to represent unlabeled forms as ganic salts of a compound of the invention. Exemplary salts well as isotopically labeled forms of the compounds. Isoto include, but are not limited, to Sulfate, citrate, acetate, oxalate, pically labeled compounds have structures depicted by the chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid formulas given herein except that one or more atoms are phosphate, isonicotinate, lactate, salicylate, acid citrate, tar replaced by an atom having a selected atomic mass or mass trate, oleate, tannate, pantothenate, bitartrate, ascorbate, suc- 60 number. Examples of isotopes that can be incorporated into cinate, maleate, gentisinate, fumarate, gluconate, glucur compounds of the invention include isotopes of hydrogen, onate, Saccharate, formate, benzoate, glutamate, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlo methanesulfonate “mesylate”, ethanesulfonate, benzene rine, such as, but not limited to 2H (deuterium, D), 3H (tri Sulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methyl tium), 11C, 13C, 14C, 15N, 18F, 31P, 32P. 35S, 36C1, and ene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceutically 65 125I. Various isotopically labeled compounds of the present acceptable salt may involve the inclusion of another molecule invention, for example those into which radioactive isotopes Such as an acetate ion, a Succinate ion or other counter ion. such as 3H, 13C, and 14C are incorporated. Such isotopically US 9,260,425 B2 13 14 labelled compounds may be useful in metabolic studies, reac Co heterocyclyl), —(C-C heteroaryl)-(C-Co tion kinetic studies, detection or imaging techniques, such as heteroaryl), —(C-C heteroaryl)-(C-C heterocyclyl). positron emission tomography (PET) or single-photon emis —(C-Coheteroaryl)-(C-Coheterocyclyl)-(C-Cohetero sion computed tomography (SPECT) including drug or Sub cyclyl), —(C-Coheteroaryl)-NR—(C-Coheterocyclyl), strate tissue distribution assays, or in radioactive treatment of 5 —(C-C heteroaryl)-(C-C alkylene)-(C-C heterocy patients. Deuterium labelled or substituted therapeutic com clyl), -(C-Co heteroaryl)-NR—(C-C2 alkylene)-(C2 pounds of the invention may have improved DMPK (drug Coheterocyclyl), and —(C-Coheteroaryl)-NR—(C-C2 metabolism and pharmacokinetics) properties, relating to dis alkylene)-(C-Coheteroaryl); tribution, metabolism, and excretion (ADME). Substitution R is independently selected from H and C-C alkyl with heavier isotopes such as deuterium may afford certain 10 optionally substituted with F. C1, CN, —COH, -COCH, therapeutic advantages resulting from greater metabolic sta —COCH, —COC(CH), COCH(OH)CH, bility, for example increased in vivo half-life or reduced dos - CONH – CONHCH – CONCCH) - NO, NH, age requirements. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds - NHCH, -N(CH), -NHCOCH, N(CH)COCH, 15 NHS(O)CH, NHCHCH-NH, of this invention and prodrugs thereof can generally be pre - NHCHCHCH-NH. - NHCHCHCHCH-NH. pared by carrying out the procedures disclosed in the schemes - N(CH)C(CH),CONH, N(CH)CHCHS(O)CH, or in the examples and preparations described below by sub –O, - OH, —OCH, –OCHCHOCH, stituting a readily available isotopically labeled reagent for a —OCHCH-NH —S(O)N(CH), —SCH, and —S(O) non-isotopically labeled reagent. Further, substitution with CH: heavier isotopes, particularly deuterium (i.e., 2H or D) may where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, het afford certain therapeutic advantages resulting from greater erocyclyl, aryl, and heteroaryl are optionally substituted with metabolic stability, for example increased in vivo half-life or one or more groups independently selected from F, Cl, Br, I, reduced dosage requirements oran improvement in therapeu tic index. It is understood that deuterium in this context is —CH, —CHCH. —CH(CH), —CHCH(CH), 25 —CH-NH2, - CH-NHCH, —CHN(CH), regarded as a Substituent in the compound of the formula (I). - CHCH-NH. - CHCHCH-NH2, The concentration of such a heavier isotope, specifically deu - CHCHCHCH-NH. - CH-CH(CH)NH, terium, may be defined by an isotopic enrichment factor. In -CHCONH, -CHOH, -CHCH-OH, -C(CH),OH, the compounds of this invention any atom not specifically —CH(OH)CH(CH), —C(CH),CHOH, -CHC(CH), designated as a particular isotope is meant to represent any OH, -CHCHSOCH, CN, CF, -COH, stable isotope of that atom. Unless otherwise stated, when a 30 - COCH, COCH, -COC(CH), COCH(OH) position is designated specifically as “H” or “hydrogen, the CH, CONH – CONHCH-CONCCH), C(CH), position is understood to have hydrogen at its natural abun CONH, NO, NH, -NHCH, N(CH), -NH dance isotopic composition. Accordingly, in the compounds COCH, - N(CH)COCH, —NHS(O)CH, of this invention any atom specifically designated as a deute NHCHCH-NH. - NHCHCHCH-NH. rium (D) is meant to represent deuterium. 35 NHCHCHCHCH-NH, -N(CH)C(CH),CONH, Pyrazolo 3,4-cPyridine Compounds - N(CH)CHCHS(O)CH, —O, -OH, - OCH, The present invention provides pyrazolo 3,4-cpyridine –OCHCHOCH, OCHCH-NH, -S(O)N(CH), compounds of Formula I, and pharmaceutical formulations —SCH, —CHOCH. —S(O)CH cyclopropyl, cyclobu thereof, which are potentially useful in the treatment of dis tyl, cyclopentyl, cyclohexyl, cycloheptyl, aZetidinyl, azepa eases, conditions and/or disorders modulated by Pim kinases. 40 nyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperi Formula I compounds have the structure: din-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino. Exemplary embodiments of Formula I compounds include R2 45 wherein R' is C-C heteroaryl. R Exemplary embodiments of Formula I compounds include N y wherein R' is selected from the structures: Na2NN H F 50 and Stereoisomers, geometric isomers, tautomers, or phar maceutically acceptable salts thereof, wherein: rs rs s R" is selected from –CN, -CHCN, -CHCONH, Na2 Na2 Na2 CONH CONHCH, CONCH), NHCONH, 55 C-C carbocyclyl, C-C heterocyclyl, C-C heteroaryl, —(C-Co heteroaryl)-(C-Co heteroaryl), —(C-C het eroaryl)-(C-Co heterocyclyl), —(C-Co heteroaryl)-O- s rs (C-Co heterocyclyl), —(C-Co heteroaryl)-O-(C-C2 Na2 Né alkylene)-(C-C heterocyclyl), —(C-C heteroaryl)- 60 NR—(C-Co heterocyclyl), and —(C-Co heteroaryl)- NR—(C-C2 alkylene)-(C-Coheterocyclyl); \ \ N R is selected from C-C alkyl, C-C carbocyclyl, N N C-Coheterocyclyl, C-Coheteroaryl, Co-Co aryl, —(C- N Co aryl)-(C-C heterocyclyl), —(C-C alkylene)-(C- 65 Co heterocyclyl), —(C-C alkylene)-NR(C-Cohetero cyclyl), —(C-C2 alkylene)-NR—(C-C2 alkylene)-(C2 US 9,260,425 B2 15 16 -continued (R), (R), (R), fy\ | ANN | \ry leN le le

(R), (R), N \ \ 10 fy rty Y N le (R) ) le

15 R3X R3X N N -H(R'), NJ- H(R)

(R') R4 pi (R), 25 A ) X) - " - (R), (R) (R) 30 N1s N ky o-C) O 2 Na2 le *4. 35 R (R), (R), F N n^. N \\ An Na2 N 40

where the wavy line indicates the site of attachment; and 45 R" is selected from F, Cl, Br, I, —CH, CHCH-CH (CH), —CHCH(CH), —CH-NH. —CH-NHCH —CHN(CH), —CHCH-NH, CHCHCH-NH2, - CHCHCHCH-NH. - CH-CH(CH)NH, -CHCONH, -CHOH, -CHCH-OH, -C(CH),OH, 50 —CH(OH)CH(CH), C(CH),CHOH, -CHC(CH), OH, -CHCHSOCH, CN, CF, -COH, - COCH, COCH, -COC(CH), COCH(OH) CH-CONH – CONHCH – CONCCH), C(CH), CONH, -NO, NH, -NHCH, N(CH), -NH where the wavy line indicates the site of attachment. 55 COCH, - N(CH)COCH, —NHS(O)CH, NHCHCH-NH, NHCHCHCH-NH. Exemplary embodiments of Formula I compounds include - NHCHCHCHCH-NH - N(CH)C(CH)CONH2, wherein R' is selected from CN, -CHCN, - N(CH)CHCHS(O)CH, —O, -OH, - OCH, -CHCONH, -CONH – CONHCH, -CON(CH), –OCHCHOCH, OCHCH-NH, -S(O)N(CH), and -NHCONH. 60 —SCH, —CHOCH. —S(O)CH cyclopropyl, cyclobu Exemplary embodiments of Formula I compounds include tyl, cyclopentyl, cyclohexyl, cycloheptyl, aZetidinyl, azepa wherein R is C-Coheteroaryl. nyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperi din-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), Exemplary embodiments of Formula I compounds include morpholinomethyl, and morpholino; and wherein R is —(C-Coheteroaryl)-(C-Coheterocyclyl). 65 n is 0, 1, or 2. Exemplary embodiments of Formula I compounds include Exemplary embodiments of Formula I compounds include wherein R is selected from the structures: compounds having the structure of Formula Ia: US 9,260,425 B2 17 18 –OCHCHOCH, OCHCH-NH, -S(O)N(CH), 4 Ia —SCH, and —S(O)CH; and (R) n is 0, 1, or 2. 2xa Exemplary embodiments of Formula I compounds include r R2 compounds having the structure of Formula Ic: Nin N \

Ic N 2 NM H 10 where R is selected from F, Cl, Br, I, —CH, —CHCH —CH(CH), —CH-CH(CH), —CH-NH2, —CH-NHCH, CHN(CH), —CHCH-NH2, —CHCHCH-NH, CHCHCHCH-NH, -CHCH (CH)NH, -CHCONH, CHOH, -CHCH-OH, 15 —C(CH),OH, -CH(OH)CH(CH), C(CH) CH-OH, —CHC(CH)OH, -CH2CHSOCH, —CN, —CF, —COH, -COCH, COCH, COC(CH), —COCH (OH)CH – CONH – CONHCH, -CON(CH), where R is selected from F, Cl, Br, I, —CH, CHCHs. —C(CH)CONH, NO, NH, -NHCH, -N —CH(CH), —CHCH(CH), —CH-NH. (CH), -NHCOCH, -N(CH)COCH, -NHS(O)CH, - CH-NHCH, —CHN(CH), - CHCH-NH. NHCHCH-NH. —NHCHCHCH-NH. —CHCHCH-NH, CHCHCHCH-NH, -CHCH -NHCHCHCHCH-NH, -N(CH)C(CH),CONH, (CH)NH, -CHCONH, CHOH, -CHCH-OH, - N(CH)CHCHS(O)CH, —O, -OH, - OCH, —C(CH),OH, -CH(OH)CH(CH), C(CH) CH-OH, –OCHCHOCH, OCHCH-NH, -S(O)N(CH), 25 —CHC(CH)OH, -CH2CHSOCH, —CN, —CF, —SCH, —CHOCH —S(O)CH cyclopropyl, cyclobu —COH,-COCH, COCH, —COC(CH), —COCH tyl, cyclopentyl, cyclohexyl, cycloheptyl, aZetidinyl, azepa (OH)CH, -CONH – CONHCH, -CON(CH), nyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperi —C(CH),CONH, -NO, NH, -NHCH, -N din-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), (CH), -NHCOCH, N(CH)COCH, -NHS(O)CH, 30 NHCHCH-NH, NHCHCHCH-NH. morpholinomethyl, and morpholino; and - NHCHCHCHCH-NH - N(CH)C(CH)CONH2, n is 0, 1, or 2. N(CH)CHCHS(O)CH =O, —OH, OCH, Exemplary embodiments of Formula I compounds include –OCHCHOCH, OCHCH-NH, -S(O)N(CH), compounds having the structure of Formula Ib: —SCH, —CHOCH, -S(O)CH, cyclopropyl, cyclobu tyl, cyclopentyl, cyclohexyl, cycloheptyl, aZetidinyl, azepa 35 nyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperi Ib din-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), R3 V morpholinomethyl, and morpholino; and N n is 0, 1, or 2. 40 Biological Evaluation & R2 Determination of the Pim kinase activity of a Formula I N compound is possible by a number of direct and indirect y detection methods. Certain exemplary compounds described N 21 N herein were assayed for their Pim kinase binding activity, H 45 including isoforms Pim-1, Pim-2, and Pim-3, (Example 901) and in vitro activity against tumor cells (Example 902). Cer where R is selected from H, C-C carbocyclyl, and tain exemplary compounds of the invention had Pim binding C-C alkyl where carbocyclyl and alkyl are optionally sub activity ICso values less than about 1 micromolar (LLM). Cer stituted with F, C1, CN, -COH, -COCH, -COCH, tain compounds of the invention had tumor cell-based activity —COC(CH), COCH(OH)CH – CONH – CON 50 ECso values less than about 1 micromolar (LLM). HCH, -CON(CH), NO, NH, -NHCH, Exemplary Formula I compounds in Table 1 were made, - N(CH), -NHCOCH, N(CH)COCH, -NHS(O), characterized, and tested for inhibition of Pim kinase accord CH, NHCHCH-NH, -NHCHCHCH-NH. ing to the methods of this invention, and have the following —NHCHCHCHCH-NH - N(CH)C(CH)CONH2, structures and corresponding names (ChemBioDraw Ultra, - N(CH)CHCHS(O)CH =O, -OH, - OCH, Version 11.0, CambridgeSoft Corp., Cambridge Mass.). TABLE 1.

Pim-1 No. Structure Name Ki (Lm) 101 21 3-methyl-5-(pyridin-3-yl)- O.19 1H-pyrazolo34-cpyridine Nan 21 \

N N N N H