USOO93943 15B2

(12) United States Patent (10) Patent No.: US 9,394,315 B2 Aicher et al. (45) Date of Patent: Jul.19, 2016

(54) TETRAHYDROI18NAPHTHYRIDINE 6,605,634 B2 8, 2003 Zablocki et al. SULFONAMIDE AND RELATED 6,638,960 B2 10/2003 Assmann et al. 6,683,091 B2 1/2004 Asberomet al. COMPOUNDS FOR USEAS AGONSTS OF 6,828,344 B1 12/2004 Seehra et al. RORY AND THE TREATMENT OF DISEASE 7,084, 176 B2 8, 2006 Morie et al. 7,138.401 B2 11/2006 Kasibhatla et al. (71) Applicant: Lycera Corporation, Ann Arbor, MI 7,329,675 B2 2/2008 Cox et al. 7,420,059 B2 9, 2008 O'Connor et al. (US) 7,482.342 B2 1/2009 D’Orchymont et al. 7,569,571 B2 8/2009 Dong et al. (72) Inventors: Thomas D. Aicher, Ann Arbor, MI (US); 7,696,200 B2 4/2010 Ackermann et al. Peter L. Toogood, Ann Arbor, MI (US); 7,713.996 B2 5/2010 Ackermann et al. Xiao Hu, Northville, MI (US) 7,741,495 B2 6, 2010 Liou et al. 7,799,933 B2 9/2010 Ceccarelli et al. (73) Assignee: Lycera Corporation, Ann Arbor, MI 2006,0004000 A1 1/2006 D'Orchymont et al. 2006/010O230 A1 5, 2006 Bischoff et al. (US) 2007/0010537 A1 1/2007 Hamamura et al. 2007/OO 10670 A1 1/2007 Hirata et al. (*) Notice: Subject to any disclaimer, the term of this 2007/0049556 A1 3/2007 Zhang et al. patent is extended or adjusted under 35 2007/0060567 A1 3/2007 Ackermann et al. U.S.C. 154(b) by 0 days. 2007/0154487 A1 7/2007 Littman et al. 2007,019 1603 A1 8/2007 Ackermann et al. 2007/0281922 A1 12/2007 Liu et al. (21) Appl. No.: 14/398,774 2008/0027100 A1 1/2008 McCormick et al. 2008, OO58386 A1 3/2008 Liou et al. (22) PCT Filed: May 8, 2013 2008. O153805 A1 6/2008 Ceccarelli et al. 2009.0075973 A1 3/2009 Newcomet al. (86). PCT No.: PCT/US2O13/04OO85 2009/0247502 A1 10, 2009 Newcom et al. 2009/0275586 A1 11/2009 Govek et al. S371 (c)(1), 2010/0022515 A1 1/2010 Alper et al. (2) Date: Nov. 4, 2014 2010, O130484 A1 5/2010 Ackermann et al. 2010, O234340 A1 9/2010 Schunk et al. 2011/0053915 A1 3/2011 Ivaschenko et al. (87) PCT Pub. No.: WO2013/169864 2011 O112070 A1 5/2011 Baldwin et al. 2011 0118246 A1 5, 2011 Baldwin et al. PCT Pub. Date: Nov. 14, 2013 2011/0178063 A1 7/2011 Baldwin et al. (65) Prior Publication Data 2014f0088094 A1 3/2014 Glicket al. US 2015/O133437 A1 May 14, 2015 FOREIGN PATENT DOCUMENTS EP O882718 A1 12, 1998 Related U.S. Application Data EP 1820515 A1 8, 2007 (60) Provisional application No. 61/644,104, filed on May (Continued) 8, 2012. OTHER PUBLICATIONS (51) Int. Cl. Boger et al., “Regiocontrolled Nucleophilic Addition to Selectively CO7D 49.8/04 (2006.01) Activated p-Quinone Dimines: Alternative Preparation of a Key CO7D 47L/04 (2006.01) Intermediate Employed in the Preparation of the CC-1065 Left-Hand Subunit.” J. Org. Chem., vol. 55, pp. 1379-1390 (1990). C07D 49 I/052 (2006.01) Chang et al., “7-Aroyl-aminoindoline-1-sulfonamides as a Novel (52) U.S. Cl. Class of Potent Antitubulin Agents.” J. Med. Chem... vol. 49, pp. CPC ...... C07D 498/04 (2013.01); C07D 471/04 6656-6659 (2006). (2013.01); C07D 491/052 (2013.01) English Abstract JP6-250441 published 1994 (1 page). (58) Field of Classification Search English Abstract of JP2004307487A published 2004 (2 pages). CPC ...... C07D 498/04: CO7D 471/04 Guimond et al., “Rhodium(III)-Catalyzed Isoquinolone Synthesis: The N-O Bond as a Handle for C N Bond Formation and Catalyst USPC ...... 544/105:514/230.5 Turnover.” J. Am. Chem. Soc., vol. 132, pp. 6908-6909 (2010). See application file for complete search history. (Continued) (56) References Cited Primary Examiner — Kahsay Habte U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Goodwin Procter LLP 5,985,903 A 11/1999 Assmann et al. (57) ABSTRACT 6,020,354 A 2, 2000 Assmann et al. 6,037,367 A 3/2000 Christensen, IV et al. The invention provides tetrahydro 1.8 naphthyridine and 6, 160,001 A 12/2000 Assmann et al. related compounds, pharmaceutical compositions, methods 6,172,092 B1 1/2001 Assmann et al. of promoting RORY activity, increasing the amount of IL-17 6,180,643 B1 1/2001 Zablocki et al. 6,348,032 B1 2/2002 Sperlet al. in a Subject, and treating cancer, bacterial infections, and 6,352,985 B1 3/2002 Yamasaki et al. fungal infections using such tetrahydro 1.8 naphthyridine 6,387,939 B1 5/2002 Assmann et al. and related compounds. 6,440,973 B1 8, 2002 Zablocki et al. 6,534,535 B1 3/2003 Zhu et al. 30 Claims, No Drawings US 9,394,315 B2 Page 2

(56) References Cited WO WO-2011/067364 A1 6, 2011 WO WO-2011,067365 A1 6, 2011 WO WO-2011/067366 A1 6, 2011 FOREIGN PATENT DOCUMENTS WO WO-2011, 109059 A1 9, 2011 WO WO-2012/032O65 A1 3, 2012 EP 2181710 A1 5, 2010 WO WO-2012/032067 A1 3, 2012 JP 6-250441 A 9, 1994 WO WO-2012,037108 A1 3, 2012 JP 200430.7487 A 11, 2004 WO WO-2012/064744 A2 5, 2012 WO WO-92/13856 A1 8, 1992 WO WO-2013, 169588 A1 11, 2013 WO WO-97.01561 A1 1, 1997 WO WO-2013, 169704 A2 11/2013 WO WO-97/.48697 A1 12/1997 WO WO-98.224.57 A1 5.1998 OTHER PUBLICATIONS WO WO-OOf 172O2 A1 3, 2000 WO WO-01 12600 A9 9, 2002 International Search Report and Written Opinion for PCT/US2011/ WO WO-02/100819 A1 12/2002 059788 dated May 23, 2012 (23 pages). WO WO-03/O14075 A2 2, 2003 International Search Report and Written Opinion for PCT/US2013/ WO WO-2004/05683.0 A1 T 2004 040085 dated Oct. 23, 2013 (9 pages). WO WO-2005/028434 A2 3, 2005 International Search Report for PCT/US2013/039422 dated Oct. 11, WOW8 WO-2006W858.87. A 38. 2013 (4 pages). WO WO-2006/057460 A1 6, 2006 synastach Report for PCT/US2013/039839 dated Oct. 18, WO WO-2007/031429 A1 3, 2007 . WO WO-2007/093507 A1 8, 2007 Ishikura et al., An Efficient Synthesis of 3-Heteroarylpyridines via WO WO-2007,1254.05 A2 11, 2007 Diethyl-3-pyridyl)-borane.” Synthesis, pp. 936-938 (1984). WO WO-2008/003703 A1 1, 2008 Jiang et al., “Synthesis and Cytotoxicity Evaluation of Novel WO WO-2008/045664 A2 4/2008 Indolylpyrimidines and Indolylpyrazines as Potential Antitumor WO WO-2008/06274.0 A1 5, 2008 Agents.” Bioorg. Med. Chem... vol. 9, pp. 1149-1154 (2001). WO WO-2008/074692 A1 6, 2008 Liet al., “Chemical Libraries via Sequential C–H Functionalization WO WO-2008/097428 A2 8, 2008 of Phenols.” J. Comb. Chem., vol. 10, pp. 170-174 (2008). WO WO-2009/032667 A1 3, 2009 Liu et al., “1-Sulfonylindazoles as potent and selective 5-HT WO WO-2009/035997 A2 3, 2009 ligands.” Bioorg. Med. Chem. Lett., vol. 19, pp. 2413-2415 (2009). WO WO-2009,077.956 A2 6, 2009 WO WO-2009,147187 A1 12/2009 Murase et al., “A New Concise Synthesis of Arcyriacyanin A and Its WO WO-2009,157196 A1 12/2009 Unique Inhibitory Activity against a Panel of Human Cancer Cell WO WO-2010/017827 A1 2, 2010 Line.” Chem. Pharm. Bull., vol. 48, pp. 81-84 (2000). WO WO-2010/038901 A1 4, 2010 STN Columbus, pp. 1-40, (2011). WO WO-2010.057101 A2 5, 2010 Wang et al., “Synthesis of new carbon-11-labeled 7-aroyl WO WO-2010/0596O2 A2 5, 2010 aminoindoline-1-sulfonamides as potential PET agents for imaging WO WO-2010, 102958 A1 9, 2010 of tubulin polymerization in cancers. J. Label Compd. Radiopharm, WO WO-2010, 117425 A1 10, 2010 vol. 51, pp. 6-11 (2008). WO WO-2010, 125082 A1 11, 2010 Yeh et al., “Practical Cu-catalyzed amination of functionalized WO WO-2011/O19634 A2 2, 2011 heteroaryl halides.” Tetrahedron Letters 47, pp. 601 1-6016 (2006). US 9,394,315 B2 1. 2 TETRAHYDROI18NAPHTHYRIDINE correlated positively with patient survival or slower disease SULFONAMIDE AND RELATED progression in certain cancers. See, for example, Kryczek et COMPOUNDS FOR USEAS AGONSTS OF al. in Blood (2009) Vol 114, 1141-1149; and Sfanos et al. in RORY AND THE TREATMENT OF DISEASE Clinical Cancer Research (2008) vol 14, 3254-3261. Com pounds capable of enhancing RORytactivity are thus contem CROSS REFERENCE TO RELATED plated to provide a therapeutic benefit in the treatment of APPLICATIONS CaCC. Cancer continues to be a significant health problem despite This application is a national stage of International (PCT) the substantial research efforts and scientific advances Patent Application Serial No. PCT/US2013/040085, filed 10 reported in the literature for treating this disease. Some of the May 8, 2013, and published under PCT Article 21(2) in most frequently diagnosed cancers include prostate cancer, English, which claims the benefit of and priority to U.S. breast cancer, and lung cancer. Prostate cancer is the most Provisional Patent Application Ser. No. 61/644,104, filed common form of cancer in men. Breast cancer remains a May 8, 2012, the contents of each of which are hereby incor 15 leading cause of death in women. Current treatment options porated by reference. for these cancers are not effective for all patients and/or can FIELD OF THE INVENTION have substantial adverse side effects. Accordingly, a need exists for improved treatments for The invention provides tetrahydro 1.8 naphthyridine and cancer. The present invention addresses this need and pro related compounds, methods of promoting RORY activity vides other related advantages. and/or increasing the amount of IL-17 in a subject, and thera peutic uses of the tetrahydro 1.8 naphthyridine and related SUMMARY compounds. In particular, the invention provides Sulfona mide-tetrahydro 1.8 naphthyridine and related compounds, The invention provides 1,8-tetrahydro 1.8 naphthyridine methods of using Such compounds to promote RORY activity 25 and related compounds, pharmaceutical compositions, meth and/or increase the amount of IL-17 in a Subject, and treat ods of promoting RORY activity and/or increasing the amount medical conditions in which activation of immune response of IL-17 in a Subject, and methods of treating various medical would be beneficial Such as in cancer and infections. disorders using Such compounds. In particular, one aspect of the invention provides a collection of tetrahydro 1.8naph 30 thyridine and related compounds, Such as a compound repre BACKGROUND OF THE INVENTION sented by Formula I:

Retinoid-related orphan receptors (ROR) are reported to (I) have an important role in numerous biological processes. See, 35 O for example, Dussault et al. in Mech. Dev. (1998) vol. 70. W 147-153; and Andre et al. in EMBO.J. (1998) vol. 17, 3867 N o–, 3877. Scientific investigations relating to each of retinoid related orphan receptors RORO, RORB, and RORY have been described in the literature. See, for example, Hirose et al. in 40 Clyu-k Biochem. Biophys. Res. Commun. (1994) vol. 205, 1976 (R), 1983; Giguere et al. in Genes. Dev. (1994) vol. 8,538-553; Medvedev et al. in Gene (1996) vol. 181, 199-206; Ortiz et al. in Mol. Endocrinol. (1995) vol. 9, 1679-1691; Jetten AM in Curr Drug Targets Inflamm Allergy (2004) vol. 3, 395-412). 45 or a pharmaceutically acceptable salt or Solvate thereof. Continuing research in this field is spurred by the promise of wherein the variables are as defined in the detailed descrip developing new therapeutic agents to treat medical disorders tion. Further description of additional collections of tetrahy associated with retinoid-related orphan receptor activity. dro 1.8 naphthyridine and related compounds, such as For RORY has been reported to be expressed in high concen mulae II-V, are described in the detailed description. tration in various tissues, such as thymus, kidney, liver, 50 Another aspect of the invention provides a method of treat muscle, and certain fat tissue. See, for example, Hirose et al. ing a subject suffering from a medical disorder. The method in Biochem. Biophys. Res. Commun. (1994) vol. 205, 1976 comprises administering to the Subject a therapeutically 1983; Medvedev et al. in Gene (1996) vol. 181, 199-206; effective amount of one or more tetrahydro1.8naphthyri Ortiz et al. in Mol. Endocrinol. (1995) vol. 9, 1679-1691; and dine or related compounds described herein, e.g., a com He et al. in Immunity (1998) vol. 9,797-806. Two isoforms of 55 pound of Formula I, II, III, IV, or V, wherein Formulae I-V are RORY have been identified and are referred to as Y 1 and Y2 as described in the detailed description. A large number of (also referred to as RORyt). See, for example. He et al. in disorders can be treated using the tetrahydro1.8naphthyri Immunity (1998) vol. 9, 797-806. Expression of the y2 iso dine and related compounds described herein. For example, form has been reported to appear in, for example, double the compounds described herein can be used to treat cancer, a positive thymocytes. See, for example. He et al. in Immunity 60 bacterial infection, a fungal infection, or an immune defi (1998) vol. 9, 797-806; and Villey et al. in Eur: J. Immunol. ciency disorder. (1999) vol. 29, 4072-4080. RORyt plays a critical role in Another aspect of the invention provides a method of pro regulating differentiation of Th17 cells, a subset of T helper moting the activity of RORY. The method comprises exposing lymphocytes. See, for example, Ivanov et al. in Cell (2006) a RORY to an effective amount of one or more tetrahydro1, vol. 126, 1121-1133. Th17 cells are important for recruiting 65 8 naphthyridine or related compounds described herein, e.g., tumor-killing cytotoxic CD8+ T cells and natural killer cells a compound of Formula I, II, III, IV, or V. or a pharmaceutical into the tumor microenvironment. The level of Th17 cells composition described herein. US 9,394,315 B2 3 4 Another aspect of the invention provides a method of increasing the amount of IL-17 in a subject. The method comprises administering to a subject an effective amount of one or more tetrahydro 1.8 naphthyridine or related com pounds described herein, e.g., a compound of Formula I, II, 5 III, IV, or V, or a pharmaceutical composition described How X herein, to increase the amount of IL-17 in the subject. The term "cycloalkylene' refers to a diradical of a cycloalkyl DETAILED DESCRIPTION OF THE INVENTION group. Exemplary cycloalkylene groups include 10 The invention provides tetrahydro 1.8 naphthyridine and related compounds, pharmaceutical compositions, methods of promoting RORY activity and/or increasing the amount of IL-17 in a subject, and therapeutic uses of the tetrahydro1, 8 naphthyridine and related compounds. The practice of the 15 present invention employs, unless otherwise indicated, con ventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991 The term “haloalkyl refers to an alkyl group that is sub 1992); "Handbook of experimental immunology' (D. M. stituted with at least one halogen. Exemplary haloalkyl groups include —CHF, —CHF, —CF, —CH2CF, Weir & C. C. Blackwell, eds.): "Current protocols in molecu —CFCF, and the like. lar biology” (F. M. Ausubel et al., eds., 1987, and periodic 25 The term “hydroxyalkyl refers to an alkyl group that is updates); and “Current protocols in immunology” (J. E. Coli Substituted with at least one hydroxyl group. Exemplary gan et al., eds., 1991), each of which is herein incorporated by hydroxyl alkyl groups include —CH2OH. —CH2CH2OH. reference in its entirety. - C(H)(OH)C(OH)H, and the like. Various aspects of the invention are set forth below in The term “aralkyl refers to an alkyl group substituted with sections; however, aspects of the invention described in one 30 an aryl group. Exemplary aralkyl groups include particular section are not to be limited to any particular sec tion. Further, when a variable is not accompanied by a defi nition, the previous definition of the variable controls. Definitions The terms used herein have their ordinary meaning and the 35 meaning of Such terms is independent at each occurrence and thereof. That notwithstanding and except where stated other wise, the following definitions apply throughout the specifi cation and claims. Chemical names, common names, and 40 chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an The term "heteroaralkyl refers to an alkyl group substi ambiguity exists between the structure and the name, the tuted with a heteroaryl group. structure predominates. These definitions apply regardless of 45 The terms “alkenyl and “alkynyl are art-recognized and whether a term is used by itself or in combination with other refer to unsaturated aliphatic groups analogous in length and terms, unless otherwise indicated. Hence, the definition of possible substitution to the alkyls described above, but that “alkyl applies to “alkyl as well as the “alkyl portions of contain at least one double or triple bond respectively. “hydroxyalkyl,” “fluoroalkyl,” “ O-alkyl,” etc. The term “aryl' is art-recognized and refers to a carbocy The term “alkyl is art-recognized, and includes saturated 50 clic aromatic group. Representative aryl groups include phe aliphatic groups, including straight-chain alkyl groups, nyl, naphthyl, anthracenyl, and the like. Unless specified oth branched-chain alkyl groups, cycloalkyl (alicyclic) groups, erwise, the aromatic ring may be substituted at one or more alkyl Substituted cycloalkyl groups, and cycloalkyl Substi ring positions with, for example, halogen, azide, alkyl, tuted alkyl groups. In certain embodiments, a straight chain or aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, 55 amino, nitro, Sulfhydryl, imino, amido, carboxylic acid, branched chain alkyl has about 30 or fewer carbonatoms in its —C(O)alkyl, -COalkyl, carbonyl, carboxyl, alkylthio, sul backbone (e.g., C-C for straight chain, C-C for fonyl, Sulfonamido, Sulfonamide, ketone, aldehyde, ester, branched chain), and alternatively, about 20 or fewer. Like heterocyclyl, aryl or heteroaryl moieties, —CF, —CN, or wise, cycloalkyls have from about 3 to about 10 carbonatoms the like. The term “aryl also includes polycyclic aromatic in their ring structure, and include bicycloalkyls such as 60 ring systems having two or more carbocyclic rings in which where two Saturated carbocyclic rings are fused together. In two or more carbons are common to two adjoining rings (the certain embodiments, the cycloalkyls have about 5, 6 or 7 rings are “fused rings’) wherein all of the fused rings are carbons in the ring structure. Exemplary alkyl groups include aromatic rings, e.g., in a naphthyl group. methyl, ethyl, n-propyl, isopropyl. n-butyl, sec-butyl, isobu The term "heteroaryl is art-recognized and refers to aro tyl, tert-butyl, cyclopropyl, and cyclobutyl. 65 matic groups that include at least one ring heteroatom. In The term “alkylene' refers to a diradical of an alkyl group. certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring Exemplary alkylene groups include —CH2CH2—, heteroatoms. Representative examples of heteroaryl groups US 9,394,315 B2 5 6 include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, wherein R. R. R* and Reach independently representa thiazolyl, triazolyl pyrazolyl pyridinyl, pyrazinyl, pyridazi hydrogen, an alkyl, an alkenyl, -(CH), R', or R' and nyl and pyrimidinyl, and the like. Unless specified otherwise, R", taken together with the Natom to which they are attached the heteroaryl ring may be substituted at one or more ring complete a heterocycle having from 4 to 8 atoms in the ring positions with, for example, halogen, azide, alkyl, aralkyl, structure; R' represents an aryl, a cycloalkyl, a cycloalkenyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, a heterocycle or a polycycle; and m is Zero oran integer in the Sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, range of 1 to 8. In certain embodiments, only one of R or R' —CO-alkyl, carbonyl, carboxyl, alkylthio. Sulfonyl, Sulfona may be a carbonyl, e.g., R. R. and the nitrogen together do mido, Sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl not form an imide. In other embodiments, R and R' (and or heteroaryl moieties, —CF, —CN, or the like. The term 10 optionally R) each independently represent a hydrogen, an "heteroaryl also includes polycyclic aromatic ring systems alkyl, an alkenyl, or -(CH2), R''. having two or more rings in which two or more carbons are The terms “alkoxyl or “alkoxy' are art-recognized and common to two adjoining rings (the rings are “fused rings’) refer to an alkyl group, as defined above, having an oxygen wherein all of the fused rings are heteroaromatic, e.g., in a radical attached thereto. Representative alkoxyl groups naphthyridinyl group. 15 include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The terms ortho, meta and para are art-recognized and refer An “ether is two hydrocarbons covalently linked by an oxy to 1.2-, 1.3- and 1,4-disubstituted benzenes, respectively. For gen. Accordingly, the Substituent of an alkyl that renders that example, the names 1,2-dimethylbenzene and ortho-dimeth alkyl an ether is or resembles an alkoxyl. Such as may be ylbenzene are synonymous. represented by one of—O-alkyl, —O-alkenyl, -O-alkynyl, As used herein, the terms "heterocyclic” and "heterocy and —O-(CH.) R', where m and R'' are described clyl represent, for example, an aromatic or nonaromatic ring above. (e.g., a monocyclic or bicyclic ring) containing one or more The term “oxo' is art-recognized and refers to a “—O' heteroatoms. The heteroatoms can be the same or different Substituent. For example, a cyclopentane Substituted with an from each other. Examples of heteratoms include, but are not oxo group is cyclopentanone. limited to nitrogen, oxygen and Sulfur. Aromatic and nonaro 25 The symbol “ M' indicates a point of attachment. matic heterocyclic rings are well-known in the art. Some The term “substituted” means that one or more hydrogens nonlimiting examples of aromatic heterocyclic rings include, on the atoms of the designated group are replaced with a but are not limited to, pyridine, pyrimidine, indole, purine, selection from the indicated group, provided that the atoms quinoline and isoquinoline. Nonlimiting examples of nonaro normal valencies under the existing circumstances are not matic heterocyclic compounds include, but are not limited to, 30 exceeded, and that the Substitution results in a stable com piperidine, piperazine, morpholine, pyrrolidine and pyrazo pound. Combinations of substituents and/or variables are per lidine. Examples of oxygen containing heterocyclic rings missible only if such combinations result in stable com include, but are not limited to, furan, oxirane, 2H-pyran, pounds. The terms “stable compound or “stable structure' 4H-pyran, 2H-chromene, benzofuran, and 2,3-dihydrobenzo refer to a compound that is sufficiently robust to survive b1,4dioxine. Examples of Sulfur-containing heterocyclic 35 isolation to a useful degree of purity from a reaction mixture, rings include, but are not limited to, thiophene, ben and formulation into an efficacious therapeutic agent. Zothiophene, and parathiazine. Examples of nitrogen contain When any substituent or variable occurs more than one ing rings include, but are not limited to, pyrrole, pyrrolidine, time in any constituent or the compound of the invention, its pyrazole, pyrazolidine, imidazole, imidazoline, imidazoli definition on each occurrence is independent of its definition dine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, 40 at every other occurrence, unless otherwise indicated. indole, purine, benzimidazole, quinoline, isoquinoline, tria It should also be noted that any carbon as well as heteroa Zole, and triazine. Examples of heterocyclic rings containing tom with unsatisfied Valences in the text, schemes, examples two different heteroatoms include, but are not limited to, and tables herein is assumed to have the sufficient number of phenothiazine, morpholine, parathiazine, oxazine, oxazole, hydrogen atom(s) to satisfy the Valences. thiazine, and thiazole. The heterocyclic ring is optionally 45 One or more compounds of the invention may exist in further substituted at one or more ring positions with, for unsolvated as well as solvated forms with pharmaceutically example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, acceptable solvents such as water, ethanol, and the like, and it cycloalkyl, hydroxyl, alkoxyl, amino, nitro, Sulfhydryl, is intended that the invention embrace both solvated and imino, amido, carboxylic acid, —C(O)alkyl, -COalkyl, unsolvated forms. “Solvate” means a physical association of carbonyl, carboxyl, alkylthio. Sulfonyl, Sulfonamido, Sul 50 a compound of this invention with one or more solvent mol fonamide, ketone, aldehyde, ester, heterocyclyl, aryl or het ecules. This physical association involves varying degrees of eroaryl moieties, —CF, —CN, or the like. In certain embodi ionic and covalent bonding, including hydrogen bonding. In ments, the heterocyclyl group is a 3-7 membered ring that, certain instances the solvate will be capable of isolation, for unless specified otherwise, is substituted or unsubstituted. example when one or more solvent molecules are incorpo The term "heterocycloalkyl refers to a saturated hetero 55 rated in the crystal lattice of the crystalline solid. “Solvate cyclyl group having, for example, 3-7 ring atoms. encompasses both solution-phase and isolatable solvates. The terms “amine' and “amino” are art-recognized and Non-limiting examples of Suitable solvates include ethano refer to both unsubstituted and Substituted amines, e.g., a lates, methanolates, and the like. “Hydrate is a solvate moiety that may be represented by the general formulas: wherein the solvent molecule is H.O. 60 Certain compounds contained in compositions of the present invention may exist in particular geometric or Stere R 50 R 50 oisomeric forms. Further, certain compounds described herein may be optically active. The present invention contem \ - R53 plates all Such compounds, including cis- and trans-isomers, Ys, R52 65 R- and S-enantiomers, diastereomers, (D)-isomers, (L)-iso mers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. The US 9,394,315 B2 7 8 compounds may contain one or more stereogenic centers. For As used herein, the term “pharmaceutically acceptable car example, asymmetric carbon atoms may be present in a Sub rier” refers to any of the standard pharmaceutical carriers, stituent Such as an alkyl group. All Such isomers, as well as Such as a phosphate buffered saline Solution, water, emulsions mixtures thereof, are intended to be included in this invention, (e.g., Such as an oil/water or water/oil emulsions), and various Such as, for example, racemic mixtures, single enantiomers, types of wetting agents. The compositions also can include diastereomeric mixtures and individual diastereomers. Addi stabilizers and preservatives. For examples of carriers, stabi tional asymmetric centers may be present depending upon the lizers and adjuvants. (See e.g., Martin, Remington’s Pharma nature of the various substituents on the molecule. Each such ceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. asymmetric center will independently produce two optical 1975). 10 As used herein, the term “pharmaceutically acceptable isomers, and it is intended that all of the possible optical salt” refers to any pharmaceutically acceptable salt (e.g., acid isomers, diastereomers in mixtures, and pure or partially puri or base) of a compound of the present invention which, upon fied compounds are included within the ambit of this inven administration to a subject, is capable of providing a com tion. pound of this invention or an active metabolite or residue Diastereomeric mixtures can be separated into their indi 15 thereof. As is known to those of skill in the art, "salts' of the vidual diastereomers on the basis of their physical chemical compounds of the present invention may be derived from differences by methods known to those skilled in the art, such inorganic or organic acids and bases. Examples of acids as, for example, by chromatography and/or fractional crys include, but are not limited to, hydrochloric, hydrobromic, tallization. Enantiomers can be separated by converting the Sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, gly enantiomeric mixture into a diastereomeric mixture by reac colic, lactic, Salicylic, Succinic, toluene-p-Sulfonic, tartaric, tion with an appropriate optically active compound (e.g., acetic, citric, methanesulfonic, ethanesulfonic, formic, ben chiral auxiliary such as a chiral alcohol or Mosher's acid Zoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, chloride), separating the diastereomers and converting (e.g., and the like. Other acids, such as oxalic, while not in them hydrolyzing) the individual diastereomers to the correspond selves pharmaceutically acceptable, may be employed in the ing pure enantiomers. Alternatively, a particular enantiomer 25 preparation of salts useful as intermediates in obtaining the of a compound of the present invention may be prepared by compounds of the invention and their pharmaceutically asymmetric synthesis. Still further, where the molecule con acceptable acid addition salts. tains a basic functional group (such as amino) or an acidic Examples of bases include, but are not limited to, alkali functional group (such as carboxylic acid) diastereomeric metals (e.g., Sodium) hydroxides, alkaline earth metals (e.g., salts are formed with an appropriate optically-active acid or 30 magnesium), hydroxides, ammonia, and compounds of for base, followed by resolution of the diastereomers thus formed mula NW, wherein W is C alkyl, and the like. by fractional crystallization or chromatographic means Examples of salts include, but are not limited to: acetate, known in the art, and Subsequent recovery of the pure enan adipate, alginate, aspartate, benzoate, benzenesulfonate, tiomers. bisulfate, butyrate, citrate, camphorate, camphorsulfonate, Individual stereoisomers of the compounds of the inven 35 cyclopentanepropionate, digluconate, dodecylsulfate, tion may, for example, be substantially free of other isomers, ethanesulfonate, fumarate, flucoheptanoate, glycerophos or may be admixed, for example, as racemates or with all phate, hemisulfate, heptanoate, hexanoate, hydrochloride, other, or other selected, stereoisomers. Chiral center(s) in a hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lac compound of the present invention can have the S or R con tate, maleate, methanesulfonate, 2-naphthalenesulfonate, figuration as defined by the IUPAC 1974 Recommendations. 40 nicotinate, oxalate, palmoate, pectinate, persulfate, phenyl Further, to the extent a compound described herein may exist propionate, picrate, pivalate, propionate, Succinate, tartrate, as a atropisomer (e.g., Substituted biaryls), all forms of Such thiocyanate, tosylate (also known as toluenesulfonate), unde atropisomer are considered part of this invention. canoate, and the like. Other examples of salts include anions As used herein, the terms “subject' and “patient” are used of the compounds of the present invention compounded with interchangeable and refer to organisms to be treated by the 45 a suitable cation such as Na', NH, and NW (wherein W is methods of the present invention. Such organisms preferably a C alkyl group), and the like. Further examples of salts include, but are not limited to, mammals (e.g., murines, sim include, but are not limited to: ascorbate, borate, nitrate, ians, equines, bovines, porcines, canines, felines, and the phosphate, salicylate, and Sulfate. Further, acids which are like), and most preferably includes humans. generally considered suitable for the formation of pharma The term “ICs is art-recognized and refers to the concen 50 ceutically useful salts from basic pharmaceutical compounds tration of a compound that is required for 50% inhibition of its are discussed, for example, by P. Stahl et al., Camille G. (eds.) target. Handbook of Pharmaceutical Salts. Properties, Selection As used herein, the term “effective amount” refers to the and Use. (2002) Zurich: Wiley-VCH. S. Berge et al., Journal amount of a compound sufficient to effect beneficial or of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, desired results (e.g., a therapeutic, ameliorative, inhibitory or 55 International.J. of Pharmaceutics (1986) 33 201-217: Ander preventative result). An effective amount can be administered son et al., The Practice of Medicinal Chemistry (1996), Aca in one or more administrations, applications or dosages and is demic Press, New York; and in The Orange Book (Food & not intended to be limited to a particular formulation or Drug Administration, Washington, D.C. on their website). administration route. As used herein, the term “treating These disclosures are incorporated herein by reference. includes any effect, e.g., lessening, reducing, modulating, 60 Additional exemplary basic salts include, but are not lim ameliorating or eliminating, that results in the improvement ited to ammonium salts, alkali metal salts such as Sodium, of the condition, disease, disorder, and the like, or ameliorat lithium, and potassium salts, alkaline earth metal salts such as ing a symptom thereof. calcium and magnesium salts, salts with organic bases (for As used herein, the term “pharmaceutical composition' example, organic amines) such as dicyclohexylamines, t-bu refers to the combination of an active agent with a carrier, 65 tylamines, and salts with amino acids such as arginine, lysine inert or active, making the composition especially suitable for and the like. Basic nitrogen-containing groups may be quar diagnostic or therapeutic use in Vivo or ex vivo. ternized with agents such as lower alkylhalides (e.g., methyl, US 9,394,315 B2 10 ethyl, and butyl chlorides, bromides and iodides), dialkyl I. Tetrahydro 1.8 naphthyridine and Related Compounds Sulfates (e.g., dimethyl, diethyl, and dibutyl Sulfates), long One aspect of the invention provides a compound repre chain halides (e.g., decyl, lauryl, and Stearyl chlorides, bro sented by Formula I: mides and iodides), aralkyl halides (e.g., benzyl and phen ethyl bromides), and others. (I) For therapeutic use, salts of the compounds of the present O invention are contemplated as being pharmaceutically W acceptable. However, salts of acids and bases that are non pharmaceutically acceptable may also find use, for example, N O – in the preparation or purification of a pharmaceutically 10 acceptable compound. y-ll-kD. In addition, when a compound of the invention contains (R), both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (Such as, but not limited to, a 15 carboxylic acid) Zwitterions (“inner salts') may be formed. or a pharmaceutically acceptable salt or Solvate thereof; Such acidic and basic salts used within the scope of the wherein: invention are pharmaceutically acceptable (i.e., non-toxic, A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy physiologically acceptable) salts. Such salts of the com cloalkyl; each of which is optionally substituted with 1, 2, or pounds of the invention may be formed, for example, by 3 Substituents independently selected from the group consist reacting a compound of the invention with an amount of acid ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy or base. Such as an equivalent amount, in a medium such as droxyalkyl, Cigalkoxy, Chaloalkoxy, —N(R)(R), one in which the salt precipitates or in an aqueous medium —CO.R. —C(O)R. —CN, C-alkylene-Calkoxy, followed by lyophilization. —Calkylene-N(R)(R), —Calkylene-CO.R. The present invention includes the compounds of the 25 —O Calkylene-N(R)(R), N(R)C(O) Calky invention in all their isolated forms (such as any solvates, lene-N(R)(R), S(O)C, alkyl, -SO.N(R)(R), hydrates, stereoisomers, and tautomers thereof). Further, the - N(R)SO, (Calkyl), C(O)N(R)(R), and - N(R)C invention includes compounds in which one or more of the (O)N(R)(R): atoms may be artificially enriched in a particular isotope X is O—C(R)(R)-C(R)-1-p, —O C(R), C 30 (R)(R) C(R)-up, —O C(R), C(R)(R7)-up, having the same atomic number, but an atomic mass or mass - C(R), C(R)(R)-C(R)-up, —C(O)—C(R) number different from the atomic mass or mass number pre (R)-C(R)-1-p, C(R), N(R) C(R)(R)- dominantly found in nature. The present invention is meant to C(R)-up, —C(R)=N-up, —C(R),C(R)=N-up, include all Suitable isotopic variations of the compounds of -N=C(R)-up, or - N=C(R)C(R)-p; wherein p is a the invention. For example, different isotopic forms of hydro 35 bond to the Sulfonamide ring nitrogen atom in Formula I; gen (H) include protium (H) and deuterium (H). Protium is Y is N(R)(R) or O-aralkyl, wherein said aralkyl is the predominant hydrogenisotope found in nature. Enriching optionally substituted with 1, 2, or 3 substituents indepen for deuterium may afford certain therapeutic advantages, dently selected from the group consisting of halogen, Such as increasing in vivo half-life or reducing dosage hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, Cha requirements, or may provide a compound useful as a stan 40 loalkyl, - N(R)(R), —CN, CO. Calkyl, —C(O)— dard for characterization of biological samples. Isotopically Calkyl, -C(O)N(R)(R), S(O)C-alkyl, -SON enriched compounds can be prepared without undue experi (R)(R), and N(R)SO(C-alkyl); mentation by conventional techniques known to those skilled R" represents independently for each occurrence hydro in the art or by processes analogous to those described in the gen, halogen, or C-alkyl, Schemes and Examples herein using appropriate isotopi 45 R’ is —C(O)-aryl, —C(O)-aralkyl, —C(O)—C(R)- cally-enriched reagents and/or intermediates. cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O)— Throughout the description, where compositions are Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— described as having, including, or comprising specific com Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero ponents, or where processes and methods are described as cycloalkyl; each of which is optionally substituted with 1, 2, having, including, or comprising specific steps, it is contem 50 or 3 Substituents independently selected from the group con plated that, additionally, there are compositions of the present sisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, invention that consist essentially of, or consist of the recited Calkyl, Chaloalkyl, N(R)(R), —CN, CO. components, and that there are processes and methods Calkyl, -C(O) Coalkyl, C(O)N(R)(R), S(O) according to the present invention that consist essentially of Calkyl, -SON(R)(R), and —N(R)SO(C-alkyl); or consist of the recited processing steps. 55 R is hydrogen or C-calkyl; The terms “a” and “an as used herein mean “one or more’ R" and Reach represent independently for each occur and include the plural unless the context is inappropriate. rence hydrogen or C-alkyl: or RandR taken together with The abbreviation “THF is art-recognized and refers to the nitrogen atom to which they are attached form a 3-7 tetrahydrofuran. The abbreviation “DCM is art-recognized membered heterocyclic ring; and refers to dichloromethane. The abbreviation “DMF is 60 R represents independently for each occurrence hydrogen art-recognized and refers to dimethylformamide. The abbre or Calkyl; viation “DMA' is art-recognized and refers to dimethylac R’ is hydrogen, hydroxyl, C-hydroxyalkyl, Coalkyl, etamide. The abbreviation “EDTA is art-recognized and Chaloalkyl, -CO.R. Coalkylene-CO.R. Chy refers to ethylenediaminetetraacetic acid. The abbreviation droxyalkylene-COR, N(R)(R), Calkylene-N(R) “TFA' is art-recognized and refers to trifluoroacetic acid. 65 (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, As a general matter, compositions specifying a percentage Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), are by weight unless otherwise specified. - N(R)CO. Calkyl, or Calkylene-N(R)(C(O)N(R) US 9,394,315 B2 11 12 (R); or R is heterocycloalkyl or C, alkylene-heterocy Calkyl, and Chaloalkyl. In certain other embodiments, cloalkyl, wherein the heterocycloalkyl is optionally substi R’ is C(O)-aryl or —C(O)-aralkyl; each of which is sub tuted with 1, 2, or 3 substituents independently selected from stituted with 2 substituents independently selected from the the group consisting of Oxo, halogen, hydroxyl, Calkyl, group consisting of halogen, hydroxyl, Calkoxy, Cha Chaloalkyl, Chydroxyalkyl, Cigalkoxy, and Cha loalkoxy, Calkyl, and Chaloalkyl, and said substituents loalkoxy; are located at the ortho-positions of the aromatic ring. In R is hydrogen, Calkyl, or—C(O)—Coalkyl: certain other embodiments, R is C(O)-phenyl or —C(O)- R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky benzyl; each of which is optionally substituted with 1, 2, or 3 lene-N(R)(R), or Calkylene-N(R)C(O) Calkyl: Substituents independently selected from the group consist n is 1 or 2; and 10 ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, m and peach represent independently for each occurrence Calkyl, and Chaloalkyl. In certain other embodiments, 0, 1, or 2. R’ is C(O)-phenyl or —C(O)-benzyl; each of which is In certain embodiments, A is aryl or heteroaryl; each of optionally substituted with 1, 2, or 3 substituents indepen which is optionally substituted with 1, 2, or 3 substituents dently selected from the group consisting of halogen, independently selected from the group consisting of halogen, 15 Calkyl, and Chaloalkyl. In certain other embodiments, Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In R’ is represented by: certain other embodiments, A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C-alkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain other embodi ments, A is phenyl optionally substituted with 1, 2, or 3 Substituents independently selected from the group consist ing of halogen, Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain other embodiments, A is phenyl R optionally substituted with 1, 2, or 3 substituents indepen 25 dently selected from the group consisting of halogen and wherein each R' is independently halogen, hydroxyl, Chaloalkyl. In certain embodiments, at least one substitu Calkoxy, Chaloalkoxy, Calkyl, or Chaloalkyl. In ent is attached at the meta-position of the phenyl ring. certain other embodiments, R is represented by: In certain other embodiments, A is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected 30 from the group consisting of halogen, Calkyl, Cha loalkyl, Calkoxy, and Chaloalkoxy. In certain embodiments, A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Calkyl, Cha 35 loalkyl, Calkoxy, and Chaloalkoxy. In certain embodi R ments, A is piperidine or pyrrolidine, each of which is option ally substituted with 1, 2, or 3 substituents independently wherein each R' is independently halogen, Calkyl, or selected from the group consisting of halogen, Calkyl, Chaloalkyl. Chaloalkyl, Calkoxy, and Chaloalkoxy. 40 In certain other embodiments, R is represented by: In certain embodiments, X is —O-C(R)(R)-IC

(R)-p. In certain other embodiments, X is C(R) C (R)(R)-C(R)-y. In certain other embodiments, X is —C(O)—C(R)(R)-C(R)-p. In certain other embodi ments, X is —C(R) N(R)—C(R)(R)—C(R)-up. 45 In certain other embodiments, X is C(R)=N-up. In certain embodiments, Y is N(R)(R). In certain embodiments, Y is —O-aralkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group wherein R" is Calkyl, aryl, or heterocyclyl, each of which consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, 50 is optionally substituted with 1, 2, or 3 substituents indepen Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. dently selected from the group consisting of halogen, Calkyl, -C(O) Coalkyl, -C(O)N(R)(R), S(O) hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, Cha Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl). In loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— certain other embodiments, Y is —O-aralkyl optionally sub Coalkyl, -C(O)N(R)(R), S(O)Cl...alkyl, -SON stituted with 1, 2, or 3 substituents independently selected 55 (R)(R), and N(R)SO,(Calkyl). In certain from the group consisting of halogen, hydroxyl, Calkoxy, embodiments, R" is phenyl optionally substituted with 1, 2, or Chaloalkoxy, C-alkyl, Chaloalkyl, - N(R)(R), 3 Substituents independently selected from the group consist —CN, —CO Cealkyl, and —C(O)—Calkyl. In cer ing of halogen, Coalkyl, and Chaloalkyl. tain other embodiments, Y is —O— benzyl optionally sub In certain embodiments, R is hydrogen. stituted with 1, 2, or 3 substituents independently selected 60 In certain embodiments, R is hydrogen. In certain other from the group consisting of halogen, Calkyl, and Cha embodiments, R is hydroxyl, Chydroxyalkyl, Coalkyl, loalkyl. Chaloalkyl, -CO.R. Cigalkylene-CO.R. Chy In certain embodiments, R' is hydrogen. droxyalkylene-COR, N(R)(R), Calkylene-N(R) In certain embodiments, R is —C(O)-aryl or C(O)- (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, aralkyl; each of which is optionally substituted with 1, 2, or 3 65 Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), Substituents independently selected from the group consist - N(R)CO, C-alkyl, or - N(R)C(O)R. In certain ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, other embodiments, R is C-hydroxyalkyl, C-calkyl, US 9,394,315 B2 13 14 Calkylene-COR. - N(R)(R), Calkylene-N(R) R represents independently for each occurrence hydrogen (R), or Calkylene-N(R)C(O)R’. In certain other embodi or Calkyl; ments, R is C-hydroxyalkyl, methyl, ethyl, or Cisalky R’ is hydrogen, hydroxyl, C-hydroxyalkyl, Cigalkyl, lene-N(H)C(O) Calkyl. Chaloalkyl, -CO.R. Cigalkylene-CO.R. Chy In certain other embodiments, R is heterocycloalkyl or droxyalkylene-COR, N(R)(R), Calkylene-N(R) Calkylene-heterocycloalkyl, wherein the heterocycloalkyl (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, is optionally substituted with 1, 2, or 3 substituents indepen Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), dently selected from the group consisting of oxo, halogen, - N(R)CO, C-alkyl, or Calkylene-N(R)(C(O)N(R) hydroxyl, Ce alkyl, Chaloalkyl, Chydroxyalkyl, (R); or R is heterocycloalkyl or C, alkylene-heterocy Cigalkoxy, and Chaloalkoxy. 10 cloalkyl, wherein the heterocycloalkyl is optionally substi Another aspect of the invention provides a compound rep tuted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, Calkyl, resented by Formula I-A: Chaloalkyl, C-hydroxyalkyl, Cigalkoxy, and Cha loalkoxy; 15 (I-A) R is hydrogen, C-alkyl, or -C(O)—C-alkyl; O R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky W OES lene-N(R)(R), or Calkylene-N(R)C(O)—Calkyl; Y N I and 2 N m and peach represent independently for each occurrence 0, 1, or 2. C The definitions of variables in Formulae I-A above encom pass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a vari or a pharmaceutically acceptable salt or Solvate thereof; able is a single chemical group selected from those chemical wherein: 25 groups set forth above, ii) the definition of a variable is a A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy collection of two or more of the chemical groups selected cloalkyl; each of which is optionally substituted with 1, 2, or from those set forth above, and iii) the compound is defined 3 Substituents independently selected from the group consist by a combination of variables in which the variables are ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy defined by (i) or (ii), e.g., such as where A is aryl, and R is 30 —C(O)-aryl. Further, the definitions of variables A, X, Y, R' droxyalkyl, Cigalkoxy, Chaloalkoxy, N(R)(R), to R. m. and p described in the preceding paragraphs in —CO.R, C(O)R. —CN, C-alkylene-Calkoxy, connection with Formula I are reiterated here for use in asso —Calkylene-N(R)(R), —Calkylene-CO.R. ciation with Formula I-A. —O C-alkylene-N(R)(R), N(R)C(O) Calky Another aspect of the invention provides a compound rep lene-N(R)(R), S(O)C, alkyl, -SO.N(R)(R), 35 -N(R)SO(C-alkyl), C(O)N(R)(R), and - N(R)C resented by Formula II: (O)N(R)(R): X is O—C(R)(R)-IC(R)-1-p, —O C(R) C (R)(R) C(R)-up, —O C(R), C(R)(R)-up, (II) —C(R), C(R)(R)-C(R)-up, —C(O)—C(R) 40 W (R)-C(R)-up, —C(R) N(R)-C(R)(R)-IC OES (R)-up, —C(R)=N-up, —C(R),C(R)=N-up, -N=C Y N l (R)-p, or N=C(R)C(R)- p; wherein p is a bond to the Sulfonamide ring nitrogen atom in Formula I-A; Y is N(R)(R) or O-aralkyl, wherein said aralkyl is 45 COA-4N R7 optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen, hydroxyl, Cigalkoxy, Chaloalkoxy, Coalkyl, Cha or a pharmaceutically acceptable salt or Solvate thereof; loalkyl, - N(R)(R), —CN, CO. Calkyl, —C(O)— wherein: Calkyl, C(O)N(R)(R), S(O)C-alkyl, -SON 50 A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy (R)(R), and N(R)SO,(Calkyl); R' is hydrogen, cloalkyl; each of which is optionally substituted with 1, 2, or halogen, or Coalkyl, 3 Substituents independently selected from the group consist R is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O)— droxyalkyl, Cigalkoxy, Chaloalkoxy, —N(R)(R), Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— 55 —CO.R. —C(O)R. —CN, C-alkylene-Calkoxy, Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero and —Calkylene-N(R)(R): cycloalkyl; each of which is optionally substituted with 1, 2, Y is N(R)(R) or O-aralkyl, wherein said aralkyl is or 3 Substituents independently selected from the group con optionally substituted with 1, 2, or 3 substituents indepen sisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, dently selected from the group consisting of halogen, Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. 60 hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, Cha Coalkyl, -C(O) Coalkyl, -C(O)N(R)(R), S(O), loalkyl, - N(R)(R), —CN, CO. Calkyl, —C(O)— Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl); Calkyl, -C(O)N(R)(R), S(O)C-alkyl, -SON R is hydrogen or Coalkyl; (R)(R), and N(R)SO(C-alkyl); R" and Reach represent independently for each occur R" is hydrogen, halogen, or C-alkyl; rence hydrogen or C-alkyl: or RandR taken together with 65 R’ is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- the nitrogen atom to which they are attached form a 3-7 cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O)— membered heterocyclic ring: Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— US 9,394,315 B2 15 16 Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero tain other embodiments, Y is —O-benzyl optionally substi cycloalkyl; each of which is optionally substituted with 1, 2, tuted with 1, 2, or 3 substituents independently selected from or 3 Substituents independently selected from the group con the group consisting of halogen, Calkyl, and Chaloalkyl. sisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Chaloalkyl, N(R)(R), —CN, CO. In certain embodiments, R' is hydrogen. Calkyl, -C(O) Coalkyl, -C(O)N(R)(R), S(O) In certain embodiments, R is C(O)-aryl or —C(O)- Calkyl, -SON(R)(R), and N(R)SO(C-alkyl); aralkyl; each of which is optionally substituted with 1, 2, or 3 R is hydrogen or C-calkyl; Substituents independently selected from the group consist R and Reach represent independently for each occur ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, rence hydrogen or C-alkyl: or RandR taken together with 10 Calkyl, and Chaloalkyl. In certain other embodiments, the nitrogen atom to which they are attached form a 3-7 R’ is C(O)-aryl or -C(O)-aralkyl; each of which is sub membered heterocyclic ring: stituted with 2 substituents independently selected from the R represents independently for each occurrence hydrogen group consisting of halogen, hydroxyl, Calkoxy, Cha or Calkyl: loalkoxy, Calkyl, and Chaloalkyl, and said Substituents R’ is hydrogen, hydroxyl, C-hydroxyalkyl, C-alkyl, 15 Chaloalkyl, -CO.R. Calkylene-CO.R. Chy are located at the ortho-positions of the aromatic ring. In droxyalkylene-COR, N(R)(R), Calkylene-N(R) certain other embodiments, R is C(O)-phenyl or C(O)- (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, benzyl; each of which is optionally substituted with 1, 2, or 3 Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), Substituents independently selected from the group consist -N(R)CO. Calkyl, or Calkylene-N(R)(C(O)N(R) ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, (R); or R7 is heterocycloalkyl or Calkylene-heterocy Calkyl, and Chaloalkyl. In certain other embodiments, cloalkyl, wherein the heterocycloalkyl is optionally substi R’ is C(O)-phenyl or —C(O)-benzyl; each of which is tuted with 1, 2, or 3 substituents independently selected from optionally substituted with 1, 2, or 3 substituents indepen the group consisting of Oxo, halogen, hydroxyl, Calkyl, dently selected from the group consisting of halogen, Chaloalkyl, Chydroxyalkyl, Cigalkoxy, and Cha 25 Calkyl, and Chaloalkyl. In certain other embodiments, loalkoxy; R’ is represented by: R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky lene-N(R)(R), or Calkylene-N(R)C(O)—Calkyl; and m and peach represent independently for each occurrence 30 0, 1, or 2. In certain embodiments, A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, R Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In 35 certain other embodiments, A is aryl optionally substituted wherein each R' is independently halogen, hydroxyl, with 1, 2, or 3 substituents independently selected from the Calkoxy, Chaloalkoxy, Calkyl, or Chaloalkyl. In group consisting of halogen, C-alkyl, Chaloalkyl, certain other embodiments, R is represented by: Calkoxy, and Chaloalkoxy. In certain other embodi ments, A is phenyl optionally substituted with 1, 2, or 3 40 Substituents independently selected from the group consist ing of halogen, Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen and 45 Chaloalkyl. In certain embodiments, at least one substitu R ent is attached at the meta-position of the phenyl ring. In certain other embodiments, A is heterocycloalkyl wherein each R' is independently halogen, Calkyl, or optionally substituted with 1, 2, or 3 substituents indepen Chaloalkyl. dently selected from the group consisting of halogen, 50 Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In In certain embodiments, R is represented by: certain embodiments, A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. 55 In certain embodiments, Y is N(R)(R). In certain embodiments, Y is —O-aralkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. 60 wherein R" is Calkyl, aryl, or heterocyclyl, each of which Coalkyl, -C(O) Coalkyl, -C(O)N(R)(R), S(O), is optionally substituted with 1, 2, or 3 substituents indepen Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl). In dently selected from the group consisting of halogen, certain other embodiments, Y is —O-aralkyl optionally sub hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Cha stituted with 1, 2, or 3 substituents independently selected loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— from the group consisting of halogen, hydroxyl, Calkoxy, 65 Calkyl, -C(O)N(R)(R), S(O)C-alkyl, -SON Chaloalkoxy, C-alkyl, Chaloalkyl, - N(R)(R), (R)(R), and N(R)SO(C-alkyl). In certain —CN, —CO Cealkyl, and —C(O)—Calkyl. In cer embodiments, R" is phenyl optionally substituted with 1, 2, or US 9,394,315 B2 17 18 3 Substituents independently selected from the group consist hydroxyl, C-alkyl, Chaloalkyl, Calkoxy, and Cha ing of halogen, Calkyl, and Chaloalkyl. loalkoxy. In certain other embodiments, A is aryl optionally In certain embodiments, R is hydrogen. substituted with 1, 2, or 3 substituents independently selected In certain embodiments, R is hydrogen. In certain other from the group consisting of halogen, Calkyl, Cha embodiments, R is hydroxyl, Chydroxyalkyl, C-alkyl, loalkyl, Calkoxy, and Chaloalkoxy. In certain other Chaloalkyl, -CO.R, C-alkylene-CO.R. Cahy embodiments, A is phenyl optionally substituted with 1, 2, or droxyalkylene-COR, N(R)(R), Calkylene-N(R) 3 Substituents independently selected from the group consist (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R. ing of halogen, C-alkyl, Chaloalkyl, Cigalkoxy, and Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), Chaloalkoxy. In certain other embodiments, A is phenyl -N(R)CO, C-alkyl, or - N(R)C(O)R. In certain 10 optionally substituted with 1, 2, or 3 substituents indepen other embodiments, R is C-hydroxyalkyl, C-alkyl, C dently selected from the group consisting of halogen and alkylene-CO.R. Calkylene-N(R)(R), or Calkylene Chaloalkyl. In certain embodiments, at least one substitu N(R)C(O)R. In certain other embodiments, R is Chy ent is attached at the meta-position of the phenyl ring. droxyalkyl, methyl, ethyl, or C-alkylene-N(H)C(O)— In certain other embodiments, A is heterocycloalkyl Calkyl. 15 optionally substituted with 1, 2, or 3 substituents indepen Another aspect of the invention provides a compound rep dently selected from the group consisting of halogen, resented by Formula II-A: Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain embodiments, A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents O (II-A) independently selected from the group consisting of halogen, \ Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. f o In certain embodiments, R is represented by: R2 -N N D 25 A 21 O R7

or a pharmaceutically acceptable salt or Solvate thereof; 30 R wherein: A is aryl, heteroaryl, or heterocycloalkyl; each of which is wherein each R is independently fluoro, chloro, or Cha optionally substituted with 1, 2, or 3 substituents indepen loalkyl. dently selected from the group consisting of halogen, In certain embodiments, R is hydrogen. In certain other hydroxyl, Calkyl, Chaloalkyl, Calkoxy, and Cha 35 embodiments, R is C-hydroxyalkyl, C-alkyl, Cha loalkoxy; R' is hydrogen; loalkyl, -CO.R., Calkylene-COR, Chydroxyalky R is —C(O)-phenyl substituted with 2 substituents inde lene-COR, N(R)(R), Calkylene-N(R)(R), Chy pendently selected from the group consisting of halogen, droxyalkylene-N(R)(R), N(R)C(O)R’, Calkylene-N Calkyl, and Chaloalkyl, wherein the Substituents are (R)C(O)R’, Calkylene-C(O)N(R)(R), N(R)CO located at the ortho positions of the phenyl ring; 40 Calkyl, or N(R)C(O)R’. In certain other embodiments, R is hydrogen; R’ is C-hydroxyalkyl, C-alkyl, C. alkylene-CO.R. R and Reach represent independently for each occur Calkylene-N(R)(R), or Calkylene-N(R)C(O)R. In rence hydrogen or C-alkyl: or RandR taken together with certain other embodiments, R is Chydroxyalkyl, methyl, the nitrogen atom to which they are attached form a 3-7 ethyl, or Calkylene-N(H)C(O) Calkyl. membered heterocyclic ring: 45 Another aspect of the invention provides a compound rep R represents independently for each occurrence hydrogen resented by Formula III: or Calkyl; R’ is hydrogen, hydroxyl, C-hydroxyalkyl, C-alkyl, Chaloalkyl, -CO.R. Calkylene-CO.R. Chy (III) droxyalkylene-COR, N(R)(R), Calkylene-N(R) 50 (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), -N(R)CO. Calkyl, or Calkylene-N(R)(C(O)N(R) (R); or R7 is heterocycloalkyl or Calkylene-heterocy cloalkyl, wherein the heterocycloalkyl is optionally substi 55 tuted with 1, 2, or 3 substituents independently selected from the group consisting of Oxo, halogen, hydroxyl, Calkyl, Chaloalkyl, Chydroxyalkyl, Cigalkoxy, and Cha loalkoxy; or a pharmaceutically acceptable salt or Solvate thereof; R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky 60 wherein: lene-N(R)(R), or Calkylene-N(R)C(O)—Calkyl; A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy and cloalkyl; each of which is optionally substituted with 1, 2, or m and peach represent independently for each occurrence 3 Substituents independently selected from the group consist 0, 1, or 2. ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy In certain embodiments, A is aryl or heteroaryl; each of 65 droxyalkyl, Cigalkoxy, Chaloalkoxy, —N(R)(R), which is optionally substituted with 1, 2, or 3 substituents —CO.R. —C(O)R. —CN, C-alkylene-Calkoxy, independently selected from the group consisting of halogen, and Calkylene-N(R)(R): US 9,394,315 B2 19 20 Y is N(R)(R) or O-aralkyl, wherein said aralkyl is Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. optionally substituted with 1, 2, or 3 substituents indepen Coalkyl, -C(O) Coalkyl, C(O)N(R)(R), S(O), dently selected from the group consisting of halogen, Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl). In hydroxyl, Cigalkoxy, Chaloalkoxy, Coalkyl, Cha certain other embodiments, Y is —O-aralkyl optionally sub loalkyl, - N(R)(R), —CN, CO. Calkyl, —C(O)— 5 stituted with 1, 2, or 3 substituents independently selected Calkyl, C(O)N(R)(R), S(O)C-alkyl, -SON from the group consisting of halogen, hydroxyl, Calkoxy, (R)(R), and N(R)SO(C-alkyl); Chaloalkoxy, Calkyl, Chaloalkyl, -N(R)(R), R" is hydrogen, halogen, or C-alkyl: —CN, —CO Cealkyl, and —C(O)—Calkyl. In cer R’ is —C(O)-aryl, —C(O)-aralkyl, —C(O)—C(R)- tain other embodiments, Y is —O-benzyl optionally substi cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O) - 10 tuted with 1, 2, or 3 substituents independently selected from Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— the group consisting of halogen, Calkyl, and Chaloalkyl. Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero In certain embodiments, R' is hydrogen. cycloalkyl; each of which is optionally substituted with 1, 2, In certain embodiments, R is C(O)-aryl or -C(O)- or 3 Substituents independently selected from the group con aralkyl; each of which is optionally substituted with 1, 2, or 3 sisting of halogen, hydroxyl, Cigalkoxy, Chaloalkoxy, is Substituents independently selected from the group consist Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, Coalkyl, -C(O) Calkyl, C(O)N(R)(R), S(O), Calkyl, and Chaloalkyl. In certain other embodiments, Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl); R’ is C(O)-aryl or -C(O)-aralkyl; each of which is sub R is hydrogen or Coalkyl; stituted with 2 substituents independently selected from the R" and Reach represent independently for each occur group consisting of halogen, hydroxyl, Calkoxy, Cha rence hydrogen or Calkyl: or RandR taken together with loalkoxy, Calkyl, and Chaloalkyl, and said Substituents the nitrogen atom to which they are attached form a 3-7 are located at the ortho-positions of the aromatic ring. In membered heterocyclic ring: certain other embodiments, R is C(O)-phenyl or C(O)- R represents independently for each occurrence hydrogen benzyl; each of which is optionally substituted with 1, 2, or 3 or C1-alkyl Substituents independently selected from the group consist R" is hydrogen, hydroxyl, Chydroxyalkyl, Calkyl, 25 ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, Chaloalkyl, -CO.R. Calkylene-CO.R. Chy Calkyl, and Chaloalkyl. In certain other embodiments, droxyalkylene-COR. - N(R)(R), Calkylene-N(R) R’ is C(O)-phenyl or —C(O)-benzyl; each of which is (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R. optionally substituted with 1, 2, or 3 substituents indepen Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), dently selected from the group consisting of halogen, - N(R)CO, C-alkyl, or Calkylene-N(R)(C(O)N(R) 30 (R); or R is heterocycloalkyl or C, alkylene-heterocy Calkyl, and Chaloalkyl. In certain other embodiments, cloalkyl, wherein the heterocycloalkyl is optionally substi R’ is represented by: tuted with 1, 2, or 3 substituents independently selected from the group consisting of Oxo, halogen, hydroxyl, Calkyl, Chaloalkyl, Chydroxyalkyl, Cigalkoxy, and Cha loalkoxy; 35 R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky lene-N(R)(R), or Calkylene-N(R)C(O)—Calkyl; and m and peach represent independently for each occurrence R 0, 1, or 2. 40 In certain embodiments, A is aryl or heteroaryl; each of wherein each R' is independently halogen, hydroxyl, which is optionally substituted with 1, 2, or 3 substituents Calkoxy, Chaloalkoxy, Calkyl, or Chaloalkyl. In independently selected from the group consisting of halogen, certain other embodiments, R is represented by: Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In certain other embodiments, A is aryl optionally substituted 45 with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain other embodi ments, A is phenyl optionally substituted with 1, 2, or 3 Substituents independently selected from the group consist- 50 ing of halogen, Calkyl, Chaloalkyl, Calkoxy, and R Chaloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents indepen wherein each R' is independently halogen, Calkyl, or dently selected from the group consisting of halogen and Chaloalkyl. Chaloalkyl. In certain embodiments, at least one substitu ent is attached at the meta-position of the phenyl ring. 55 In certain embodiments, R is represented by: In certain other embodiments, A is heterocycloalkyl optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen, Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In certain embodiments, A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In certain embodiments, Y is N(R)(R). In certain wherein R" is Calkyl, aryl, or heterocyclyl, each of which embodiments, Y is —O-aralkyl optionally substituted with 1, 65 is optionally substituted with 1, 2, or 3 substituents indepen 2, or 3 substituents independently selected from the group dently selected from the group consisting of halogen, consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, Cha US 9,394,315 B2 21 22 loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— In certain embodiments, A is aryl or heteroaryl; each of Coalkyl, C(O)N(R)(R), S(O)Cl...alkyl, -SON which is optionally substituted with 1, 2, or 3 substituents (R)(R), and N(R)SO(C-alkyl). In certain independently selected from the group consisting of halogen, embodiments, R" is phenyl optionally substituted with 1, 2, or hydroxyl, C-alkyl, Chaloalkyl, Calkoxy, and Cha 3 Substituents independently selected from the group consist loalkoxy. In certain other embodiments, A is aryl optionally ing of halogen, Coalkyl, and Chaloalkyl. substituted with 1, 2, or 3 substituents independently selected In certain embodiments, R is hydrogen. from the group consisting of halogen, Calkyl, Cha In certain embodiments, R is hydrogen. In certain other loalkyl, Calkoxy, and Chaloalkoxy. In certain other embodiments R is hydroxyl, C-hydroxyalkyl, C-alkyl, embodiments, A is phenyl optionally substituted with 1, 2, or Chaloalkyl, -CO.R. Calkylene-CO.R. Chy 10 3 Substituents independently selected from the group consist droxyalkylene-COR, N(R)(R), Calkylene-N(R) ing of halogen, C-alkyl, Chaloalkyl, Cigalkoxy, and (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, Chaloalkoxy. In certain other embodiments, A is phenyl Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), optionally substituted with 1, 2, or 3 substituents indepen -N(R)CO. Calkyl, or - N(R)C(O)R. In certain dently selected from the group consisting of halogen and other embodiments, R is C-hydroxyalkyl, Cigalkyl, C. 15 Chaloalkyl. In certain embodiments, at least one substitu alkylene-COR. - N(R)(R), Calkylene-N(R)(R), or ent is attached at the meta-position of the phenyl ring. Calkylene-N(R)C(O)R’. In certain other embodiments, In certain other embodiments, A is heterocycloalkyl R’ is Chydroxyalkyl, methyl, ethyl, or C-alkylene-N(H) optionally substituted with 1, 2, or 3 substituents indepen C(O)—Calkyl. dently selected from the group consisting of halogen, Another aspect of the invention provides a compound rep Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In resented by Formula III-A: certain embodiments, A is piperidine or pyrrolidine, each of which is optionally substituted with 1, 2, or 3 substituents (III-A) independently selected from the group consisting of halogen, O Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. OES 25 In certain embodiments, R is represented by: l N N

R2 CO4. 21 7 R1 R 30 or a pharmaceutically acceptable salt or solvate thereof; wherein: R A is aryl, heteroaryl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents indepen 35 wherein each R is independently fluoro, chloro, or Cha dently selected from the group consisting of halogen, loalkyl. hydroxyl, Coalkyl, Chaloalkyl, Calkoxy, and Cha In certain embodiments, R is hydrogen. In certain other loalkoxy; embodiments, R is C-hydroxyalkyl, C-alkyl, Cha R" is hydrogen; loalkyl, -CO.R., Calkylene-CO.R, Chydroxyalky R’ is —C(O)-phenyl substituted with 2 substituents inde 40 lene-COR, N(R)(R), Calkylene-N(R)(R), Chy pendently selected from the group consisting of halogen, droxyalkylene-N(R)(R), N(R)C(O)R’, Calkylene-N Calkyl, and Chaloalkyl, wherein the substituents are (R)C(O)R’, Calkylene-C(O)N(R)(R), N(R)CO located at the ortho positions of the phenyl ring; Calkyl, or N(R)C(O)R’. In certain other embodiments, R is hydrogen; R’ is Chydroxyalkyl, C-alkyl, C. alkylene-CO.R. R and Reach represent independently for each occur 45 Calkylene-N(R)(R), or Calkylene-N(R)C(O)R. In rence hydrogen or C-alkyl: or RandR taken together with certain other embodiments, R is C-hydroxyalkyl, methyl, the nitrogen atom to which they are attached form a 3-7 ethyl, or Calkylene-N(H)C(O)—Calkyl. membered heterocyclic ring: Another aspect of the invention provides a compound rep R represents independently for each occurrence hydrogen resented by Formula IV: or Calkyl, 50 R’ is hydrogen, hydroxyl, C-hydroxyalkyl, C-alkyl, Chaloalkyl, -CO.R, C-alkylene-CO.R. Chy (IV) droxyalkylene-COR, N(R)(R), Calkylene-N(R) W (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, OES Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), 55 -N(R)CO, C-alkyl, or Calkylene-N(R)(C(O)N(R) Y N l (R); or R is heterocycloalkyl or C, alkylene-heterocy n cloalkyl, wherein the heterocycloalkyl is optionally substi A. 21 R7 tuted with 1, 2, or 3 substituents independently selected from RI the group consisting of Oxo, halogen, hydroxyl, Calkyl, 60 Chaloalkyl, Chydroxyalkyl, Calkoxy, and Cha O loalkoxy; R is hydrogen, Calkyl, Chydroxyalkyl, Calky or a pharmaceutically acceptable salt or Solvate thereof; lene-N(R)(R), or Calkylene-N(R)C(O) Coalkyl: wherein: and 65 A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy m and peach represent independently for each occurrence cloalkyl; each of which is optionally substituted with 1, 2, or 0, 1, or 2. 3 Substituents independently selected from the group consist US 9,394,315 B2 23 24 ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy Coalkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In droxyalkyl, Cigalkoxy, Chaloalkoxy, —N(R)(R), certain embodiments, A is piperidine or pyrrolidine, each of —CO.R. —C(O)R. —CN, —Calkylene-Calkoxy, which is optionally substituted with 1, 2, or 3 substituents and Calkylene-N(R)(R): independently selected from the group consisting of halogen, Y is N(R)(R) or O-aralkyl, wherein said aralkyl is Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. optionally substituted with 1, 2, or 3 substituents indepen In certain embodiments, Y is N(R)(R). In certain dently selected from the group consisting of halogen, embodiments, Y is —O-aralkyl optionally substituted with 1, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Cha 2, or 3 substituents independently selected from the group loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, C(O)N(R)(R), S(O)C-alkyl, -SON 10 Calkyl, Chaloalkyl, N(R)(R), —CN, CO. (R)(R), and N(R)SO(C-alkyl); Calkyl, -C(O) Coalkyl, C(O)N(R)(R), S(O) R" is hydrogen, halogen, or C-alkyl: Calkyl, -SON(R)(R), and —N(R)SO(C-alkyl). In R is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- certain other embodiments, Y is —O-aralkyl optionally sub cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O)— 15 stituted with 1, 2, or 3 substituents independently selected Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— from the group consisting of halogen, hydroxyl, Calkoxy, Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero Chaloalkoxy, C-alkyl, Chaloalkyl, - N(R)(R), cycloalkyl; each of which is optionally substituted with 1, 2, —CN, —CO Cealkyl, and —C(O)—Calkyl. In cer or 3 Substituents independently selected from the group con sisting of halogen, hydroxyl, Calkoxy, C. haloalkoxy, tain other embodiments, Y is —O-benzyl optionally substi Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. tuted with 1, 2, or 3 substituents independently selected from Calkyl, -C(O) Coalkyl, -C(O)N(R)(R), S(O) the group consisting of halogen, Calkyl, and Chaloalkyl. Calkyl, -SON(R)(R), and N(R)SO(C-alkyl); In certain embodiments, R' is hydrogen. R is hydrogen or C-calkyl; In certain embodiments, R is C(O)-aryl or -C(O)- R and Reach represent independently for each occur 25 aralkyl; each of which is optionally substituted with 1, 2, or 3 rence hydrogen or C-alkyl: or RandR taken together with Substituents independently selected from the group consist the nitrogen atom to which they are attached form a 3-7 ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, membered heterocyclic ring: Calkyl, and Chaloalkyl. In certain other embodiments, R represents independently for each occurrence hydrogen R’ is C(O)-aryl or —C(O)-aralkyl; each of which is sub or Calkyl, 30 stituted with 2 substituents independently selected from the R’ is hydrogen, hydroxyl, C-hydroxyalkyl, C-alkyl, group consisting of halogen, hydroxyl, Calkoxy, Cha Chaloalkyl, -CO.R., Calkylene-CO.R. Chy loalkoxy, Calkyl, and Chaloalkyl, and said Substituents droxyalkylene-COR, N(R)(R), Calkylene-N(R) are located at the ortho-positions of the aromatic ring. In (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, certain other embodiments, R is C(O)-phenyl or —C(O)- Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), 35 benzyl; each of which is optionally substituted with 1, 2, or 3 -N(R)CO, C-alkyl, or Calkylene-N(R)(C(O)N(R) Substituents independently selected from the group consist (R); or R7 is heterocycloalkyl or Calkylene-heterocy ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, cloalkyl, wherein the heterocycloalkyl is optionally substi Calkyl, and Chaloalkyl. In certain other embodiments, tuted with 1, 2, or 3 substituents independently selected from R’ is C(O)-phenyl or —C(O)-benzyl; each of which is the group consisting of Oxo, halogen, hydroxyl, Calkyl, 40 optionally substituted with 1, 2, or 3 substituents indepen Chaloalkyl, Chydroxyalkyl, Cigalkoxy, and Cha dently selected from the group consisting of halogen, loalkoxy; Calkyl, and Chaloalkyl. In certain other embodiments, R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky R’ is represented by: lene-N(R)(R), or Calkylene-N(R)C(O)—Calkyl; 45 and m and peach represent independently for each occurrence 0, 1, or 2. In certain embodiments, A is aryl or heteroaryl; each of which is optionally substituted with 1, 2, or 3 substituents 50 independently selected from the group consisting of halogen, R Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In certain other embodiments, A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the wherein each R' is independently halogen, hydroxyl, group consisting of halogen, C-alkyl, Chaloalkyl, 55 Calkoxy, Chaloalkoxy, Calkyl, or Chaloalkyl. In Calkoxy, and Chaloalkoxy. In certain other embodi certain other embodiments, R is represented by: ments, A is phenyl optionally substituted with 1, 2, or 3 Substituents independently selected from the group consist ing of halogen, Coalkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain other embodiments, A is phenyl 60 optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen and Chaloalkyl. In certain embodiments, at least one substitu ent is attached at the meta-position of the phenyl ring. R In certain other embodiments, A is heterocycloalkyl 65 optionally substituted with 1, 2, or 3 substituents indepen wherein each R' is independently halogen, Calkyl, or dently selected from the group consisting of halogen, Chaloalkyl. US 9,394,315 B2 25 26 In certain embodiments, R is represented by: hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, Cha loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— Coalkyl, -C(O)N(R)(R), S(O)Cl...alkyl, -SON

(R)(R), and N(R)SO(C-alkyl); R" is hydrogen, halogen, or C-alkyl; R’ is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- cycloalkyl, -C(O)—C(R)-heterocyclyl, -C(O)— Cisalkyl, —C(O)—Calkylene-Calkoxyl. —C(O)— 10 Calkylene-cycloalkyl, or —C(O)—Calkylene-hetero cycloalkyl; each of which is optionally substituted with 1, 2, wherein R" is Calkyl, aryl, or heterocyclyl, each of which or 3 Substituents independently selected from the group con is optionally substituted with 1, 2, or 3 substituents indepen sisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, dently selected from the group consisting of halogen, 15 Calkyl, Chaloalkyl, N(R)(R), —CN, CO. hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Cha Coalkyl, -C(O) Coalkyl, C(O)N(R)(R), S(O), loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— Calkyl, -SO.N(R)(R), and N(R)SO,(Calkyl); Calkyl, C(O)N(R)(R), S(O)C-alkyl, -SON R is hydrogen or C-calkyl; (R)(R), and - N(R)SO(C-alkyl). In certain R" and Reach represent independently for each occur embodiments, R" is phenyl optionally substituted with 1, 2, or rence hydrogen or Calkyl: or RandR taken together with 3 Substituents independently selected from the group consist the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring; ing of halogen, Coalkyl, and Chaloalkyl. R represents independently for each occurrence hydrogen In certain embodiments, R is hydrogen. or Calkyl; and In certain embodiments, R is hydrogen. In certain other 25 m and peach represent independently for each occurrence embodiments R is hydroxyl, Chydroxyalkyl, C-alkyl, 0, 1, or 2. Chaloalkyl, -CO.R. Calkylene-CO.R. Chy In certain embodiments, A is aryl or heteroaryl; each of droxyalkylene-COR, N(R)(R), Calkylene-N(R) which is optionally substituted with 1, 2, or 3 substituents (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, 30 independently selected from the group consisting of halogen, Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In - N(R)CO, C-alkyl, or - N(R)C(O)R. In certain certain other embodiments, A is aryl optionally substituted other embodiments, R is Chydroxyalkyl, C-alkyl, with 1, 2, or 3 substituents independently selected from the Calkylene-COR. - N(R)(R), Calkylene-N(R) group consisting of halogen, C-alkyl, Chaloalkyl, (R), or C-alkylene-N(R)C(O)R. In certain other embodi 35 Calkoxy, and Chaloalkoxy. In certain other embodi ments, R is C-shydroxyalkyl, methyl ethyl, or Cisalky ments, A is phenyl optionally substituted with 1, 2, or 3 lene-N(H)C(O)—Calkyl. Substituents independently selected from the group consist Another aspect of the invention provides a compound of Formula V: ing of halogen, C-alkyl, Chaloalkyl, Cigalkoxy, and 40 Chaloalkoxy. In certain other embodiments, A is phenyl optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen and (V) Chaloalkyl. In certain embodiments, at least one substitu O 45 ent is attached at the meta-position of the phenyl ring. OES In certain other embodiments, A is heterocycloalkyl Y N optionally substituted with 1, 2, or 3 substituents indepen n N dently selected from the group consisting of halogen, Y Coalkyl, Chaloalkyl, Cigalkoxy, and Chaloalkoxy. In 50 certain embodiments, A is piperidine or pyrrolidine, each of 44N4 which is optionally substituted with 1, 2, or 3 substituents RI R6 independently selected from the group consisting of halogen, Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. In certain embodiments, Y is N(R)(R). In certain or a pharmaceutically acceptable salt or Solvate thereof; 55 embodiments, Y is —O-aralkyl optionally substituted with 1, wherein: 2, or 3 substituents independently selected from the group A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, cloalkyl; each of which is optionally substituted with 1, 2, or Calkyl, Chaloalkyl, - N(R)(R), —CN, CO. 3 Substituents independently selected from the group consist Calkyl, -C(O) Coalkyl, C(O)N(R)(R), S(O) ing of halogen, hydroxyl, Calkyl, Chaloalkyl, Chy 60 Calkyl, -SON(R)(R), and —N(R)SO(C-alkyl). In droxyalkyl, Cigalkoxy, Chaloalkoxy, N(R)(R), certain other embodiments, Y is —O-aralkyl optionally sub —CO.R. —C(O)R. —CN, C-alkylene-Calkoxy, stituted with 1, 2, or 3 substituents independently selected and Calkylene-N(R)(R): from the group consisting of halogen, hydroxyl, Calkoxy, Y is N(R)(R) or O-aralkyl, wherein said aralkyl is 65 Chaloalkoxy, Calkyl, Chaloalkyl, -N(R)(R), optionally substituted with 1, 2, or 3 substituents indepen —CN, —CO Cealkyl, and —C(O)—Calkyl. In cer dently selected from the group consisting of halogen, tain other embodiments, Y is —O-benzyl optionally substi US 9,394,315 B2 27 28 tuted with 1, 2, or 3 substituents independently selected from (R)(R), and - N(R)SO(C-alkyl). In certain the group consisting of halogen, Calkyl, and Chaloalkyl. embodiments, R" is phenyl optionally substituted with 1, 2, or In certain embodiments, R' is hydrogen. 3 Substituents independently selected from the group consist In certain embodiments, R is —C(O)-aryl or C(O)- ing of halogen, Calkyl, and Chaloalkyl. aralkyl; each of which is optionally substituted with 1, 2, or 3 In certain embodiments, R is hydrogen. Substituents independently selected from the group consist In certain embodiments, R is hydrogen. In certain other ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, embodiments R is hydroxyl, Chydroxyalkyl, Coalkyl, Calkyl, and Chaloalkyl. In certain other embodiments, Chaloalkyl, -CO.R. Cigalkylene-CO.R. Chy R’ is C(O)-aryl or C(O)-aralkyl; each of which is sub 10 droxyalkylene-COR, N(R)(R), Calkylene-N(R) stituted with 2 substituents independently selected from the (R), Chydroxyalkylene-N(R)(R), N(R)C(O)R’, group consisting of halogen, hydroxyl, Calkoxy, Cha Calkylene-N(R)C(O)R. Calkylene-C(O)N(R)(R), loalkoxy, Calkyl, and Chaloalkyl, and said Substituents - N(R)CO, C-alkyl, or - N(R)C(O)R. In certain are located at the ortho-positions of the aromatic ring. In other embodiments, R is C-hydroxyalkyl, C-alkyl, C 15 alkylene-COR, N(R)(R), Calkylene-N(R)(R), or certain other embodiments, R is C(O)-phenyl or C(O)- Calkylene-N(R)C(O)R. In certain other embodiments, benzyl; each of which is optionally substituted with 1, 2, or 3 R’ is Chydroxyalkyl, methyl, ethyl, or C-alkylene-N(H) Substituents independently selected from the group consist C(O)—C alkyl. ing of halogen, hydroxyl, Calkoxy, Chaloalkoxy, The definitions of variables in Formulae I through V above Calkyl, and Chaloalkyl. In certain other embodiments, encompass multiple chemical groups. The application con R’ is C(O)-phenyl or C(O)-benzyl; each of which is templates embodiments where, for example, i) the definition optionally substituted with 1, 2, or 3 substituents indepen of a variable is a single chemical group selected from those dently selected from the group consisting of halogen, chemical groups set forth above, ii) the definition is a collec Calkyl, and Chaloalkyl. In certain other embodiments, 25 tion of two or more of the chemical groups selected from R’ is represented by: those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). 30 In certain other embodiments, the compound is one of the compounds listed in Tables 1-3 below or a pharmaceutically acceptable salt thereof.

TABLE 1 R 35 OE fi EO wherein each R' is independently halogen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, or Chaloalkyl. In Y N N certain other embodiments, R is represented by: 40 s O R 21

No Y Z.

45 I-1 C F

R H wherein each R' is independently halogen, Calkyl, or Chaloalkyl. y In certain embodiments, R is represented by: 50 CF O

I-2 F C

H 55

CF. O I-3 CF 60 wherein R" is Calkyl, aryl, or heterocyclyl, each of which H is optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen, CF. O hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Cha 65 loalkyl, - N(R)(R), —CN, -CO, C-alkyl, -C(O)— Calkyl, C(O)N(R)(R), S(O)C-alkyl, -SON US 9,394,315 B2 29 30 TABLE 1-continued TABLE 1-continued

Z Z o==o OE i EO Y. N N Y N N N n 2 21 10 No Y Z. No. Y Z.

I-4 C F I-11 H 15

F O

I-12 I-5 F C

y 25 F O H C

I-6 C 30 I-13 CF CF H y H

C O 35 I-14

40

I-15 F I-8 21 C 45 NS | ay F O O 50

I-9 E I-16 C 55 y C O

60 C I-17

65 US 9,394,315 B2 31 32 TABLE 1-continued TABLE 1-continued Z Z OE i EO O i O Y N N N N n n 21 21 10 No. Y Z. No. Z.

I-18 F

I-26

I-19 C O 25 I-27 / O Na C 30 Orr 2 I-28 21 F

35 O Na2 I-21 C

I-29 y 40 CF. O S. I-22 45

I-30

CF. O 50

I-23

I-31

55

C O

60 I-32 I-24

65 US 9,394,315 B2 33 34 TABLE 1-continued TABLE 1-continued

Z

O i FO OE N Y N n 21 10 No. No. Y I-33 I-41 C 15 y C I-34 c

25 I-42 C CF I-35 C y 30 C

I-36

35 I-43 C

I-37 C I y 40 C

45 I-38

50 CF I-39 S. 55

CF

60 I-40

65 -- CF

US 9,394,315 B2 39 40 TABLE 2-continued

opo

No. Y I-15 opo N \ N

C O O D I-16 opo N

O D CCF O I-17 opo l N O H CC F 3 O D

I-18 opo C F 3 N

O H FYSN Y C O D II-19 opo N F

O H O D

II-20 opo N C

C O O D II-21 -opio N

CCF O O D US 9,394,315 B2 41 42 TABLE 2-continued Z

OESEO

No.

II-22 C

II-23 21J D II-24

opo C D S>N

II-26

II-27

II-28

US 9,394,315 B2 45 46 TABLE 2-continued Z

OESEO Y GI)N N

N N A B No. Y Z. I-35 F copo CF Hy NN N y F O 21 N V C(O)CH

TABLE 3 25 TABLE 3-continued

No. Compound No. Compound

III-1 C III-4 C 30

35 YX Y. Yi YC N - N N - s O s O C O 2 1.O H 1.

40

III-2 C III-5 C

45 E OE i EO H O i EO NH N N N N N n 50 O 2 OH O 2 o1 "1 OH O '', 1.

55 III-6 C III-3 C

60 OESEO

H 1. H 65 O US 9,394,315 B2 48 TABLE 3-continued TABLE 3-continued

No. Compound No. Compound

5 III-12 III-7 C Cl

F 10 OESEO E OESEO H H E N N N N N N n s OH C O 2 O '',1.OH 15 21 O '1

III-13 III-8 C C 2O E OE i EO C OESEO N N N 25 H N N N

O s OH F 4fn1 C O s w OH 2 o1 “1 30

III-9 OMe III-14 s

N 35 C OESEO E OESEO H H N N N N N N n 40 C O s OH O OH 2 O '1 F 4fn1-1

III-15 III-10 C 45

N E O E C OESEO N N N 50 H N N N O 21 O 1. OH s C O 2 O '',1. OH 55 III-11 C III-16

N 60 E OESE C OESEO H N N l H N N N

O 4N1 - 65 C O 21s w OH US 9,394,315 B2 49 TABLE 3-continued TABLE 3-continued

No. Compound No. Compound III-17 C III-22 C

C OESEO C 10 OESEO H H N N N N N N n n OH C O C O 2 O '',1. 21 O '1 15 O O

III-18 C III-23 C

No C C OESEO OESEO H H N N N N N N 25

C O s OH s 2 O '1 C O 2 O '1. N

III-19 30 III-24 C H H

N C C 35 OESEO OESEO H H N N N N N N s D C O 21 Y w N O s O H C O 2 O 'w '1 OH 40

III-2S C III-20

OH 45 N 1. C C OESEO OESEO H H N N N N N N 50 s C O s t OH C O N 2 O '1 21 O '1N

III-21 55 w III-26 Cl

N C OESEO H N N N

C O s t OH 2 O '1 65 US 9,394,315 B2

TABLE 3-continued TABLE 3-continued

No. Compound No. Compound

III-27 C 5 III-31 C

C OESEO 10 C H OESEO N N N H n N N N O n

C O 2 isk C O O 15 21 O '1N 1.

III-32 C III-28 C 2O

C C OESEO OESEO 25 H H N N N N N N O n

N C O 2 ... -OH C O 21 ...'1 -N N o1 "1 30 O III-33 C

35 E OESEO III-29 C H N N N O n N O

40 O 21 isk C OESE O H N N N III-34 C

C O 45 21 O '1N N

OESEO O H N N N 50 9 lun III-30 C 55 III-35 C

C O=S=

EO C ON '1 y r OH

US 9,394,315 B2 55 56 TABLE 3-continued TABLE 3-continued No. Compound No. Compound III-S1 C

III-46 C

C OESEO C 10 2 N o==oN r C S Out'1. C O 15 S. 'N O 1. III-52

III-47 C N C O i EO O N N C 2 25 C N O '',1 O N o==oN O sN 30 Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The schemes III-48 C are given for the purpose of illustrating the invention, and are not intended to limit the scope or spirit of the invention. 35 Starting materials shown in the schemes can be obtained from commercial sources or be prepared based on procedures described in the literature. o==o The synthetic route illustrated in Scheme 1 is a general N method for preparing amide-substituted 5,6,7,8-tetrahydro1, 40 8 naphthyridine compounds. Reaction of diaminopyridine A with a mixture of an acid and Substituted dimethylaminoac rolein B provides amino-1.8-naphthyridine C. Alternatively, amino-1.8-naphthyridine C can be prepared by reacting III-49 diaminopyridine A with 1,3-dicarbonyl compound B1 (See, 45 for example, Reichart et al. in Tet. Lett. 1977, 24, 2087-90; Eva, E. et al. J. Het. Chem. 1976, 13, 841-844, and Bernstein etal.J. Amer: Chem. Soc. 1947, 69, 1151-1158) or substituted Vinamidinium salt B2 (See, for example, Norma et al. in Synthesis 2001, 9, 1351-1355). 50 Reaction of amino-1,8-naphthyridine C with an acylating reagent (e.g., an acid chloride) provides amido-1.8-naphthy ridine D. Reduction of amido-1.8-naphthyridine D by hydro genation provides amido-tetrahydro-1,8-naphthyridine E. which can be reacted with a sulphonyl chloride or sulfamoyl 55 chloride to provide the final sulfonamide-tetrahydro-1.8- III-SO C naphthyridine F. The reaction procedures in Scheme 1 are contemplated to be amenable to preparing a wide variety of amide-substituted tetrahydro 1.8 naphthyridine compounds having different 60 substituents at the R through R positions. For example, numerous Substituted 2,6-diaminopyridines are known in the literature and/or are commercially available. Furthermore, if a functional group that is part of the R-R group would not beamenable to a reaction condition described in Scheme 1, it 65 is contemplated that the functional group can first be pro tected using standard protecting group chemistry and strate gies, and then the protecting group is removed after complet US 9,394,315 B2 57 58 ing the desired synthetic transformation. See, for example, carbamate (Bhagwanthet al. in J. Org Chem. 2009, 74, 4634 Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic 4637) followed by deprotection; (3) Pd-mediated addition of Synthesis, 2" ed.: Wiley: New York, 1991, for further hexamethyldisilazide (Stefko et al. in J. Org. Chem. 2011, 76, description of protecting chemistry and strategies. In certain other embodiments, a functional group in Substituent R 6619-6635), and (4) Pd-mediated addition of diphenylmetha through R in tetrahydro1.8 naphthyridine F can converted nimine followed by deprotection with acid (Grasa et al. in J. to another functional group using standard functional group Org. Chem. 2001, 66,7729-7737). Reaction of amine F with manipulation procedures known in the art. See, for example, an acid chloride provides amide G. It is understood that an “Comprehensive Organic Synthesis” (B.M. Trost & I. Flem acid (RCOH) and amide-coupling reagent can be used in ing, eds., 1991-1992) lieu of the acid chloride in the step used to produce amide G.

SCHEME 1.

"N's NH2

R- 2 HN2 N N RY A n n RCOCI R 21N 2 RY RY O RY N RIII 1. iii R RI N N N or O or RK C RIV RIV O RY ii. N B R 1N B1 B2 H H H R N N N RY R N N N RY N n1 N H2, Pd/C N n RSOCI J. R- MeOH A. R- e 2 2 RY 2 RY RIII RIII D E RH o==o R Di? N N RY O 21 RIV

RIII F RandR' to R' may be, for example, hydrogen or a substituent, such as methyl; and RandR' may be, for example, a cyclic group, such as phenyl.

Scheme 2 illustrates a general method for preparing amido dihydro-2H-pyrido|3.2-b1,4loxazines. Alkylation of nitro- SCHEME 2. hydroxy-pyridine A with a 2-haloester provides pyridinyl W ether B. Conversion of nitro-hydroxy-pyridine A to pyridinyl R ether B can also be carried out by Mitsunobu alkylation of a Br N NO ORT 2-hydroxyester. Next, reductive cyclization of pyridinyl ether 55 N n X B affords 4H-pyrido3.2-b 14oxazine-3-one C. Reduction R- 21 O of the amide using, for example, a hydride (e.g., aborane or OH Hs lithium aluminum hydride) provides dihydro-2H-pyrido3.2- A b1,4-oxazine D. Treatment of oxazine D with a sulphonyl 60 B N NO chloride or sulfamoyl chloride provides sulfonamido-bromo- Y n RY dihydro-2H-pyrido3.2-b1,4oxazine E. R-4- reduction Bromo-dihydro-2H-pyrido 3.2-b1,4-oxazine E can be 2 O OR St"- converted to amino-dihydro-2H-pyrido 3.2-b1,4-oxazine F using procedures known in the art, Such as (1) Ullmann 65 O CuSO mediated addition of ammonia (Hauser et al. in J. Org. B Chem. 1950, 15, 1224-1232); (2) Pd-mediated addition of a US 9,394,315 B2 59 60 -continued by reaction with an alkylating agent(s), aldehyde (reductive H Br N N O alkylations), acyl halide, Sulphonyl chloride, isocyanate, and N n the like) to afford the compound I. R- H 2 O RIV C H Br N N SCHEME 3. N1 n D RSOCI HN N NH2 R 10 N n t 21 O RIV R- ZnCH2C(H)(N(H)(Boc))COR D RH 4\ A OE i EO 15 HN N NH2 Br N N RN1 - N NHBOc intramolecular N n cyclication R 21 COOR VI --> 2 O RIV B H E HN N N O RII N n R- s O i EO 21 "NHBoc HN N N RC(O)Cl 25 C Bn R H H CC21 O l RY O N N N O F r N H RH R 30 O 2 '' 'NHBoc OESEO D R N N Bn H H 35 O N N N O COA 2 O RIV r N R-SOCI O R- 21 G “NHBoc R may be, for example, hydrogen or a substituent, such as methyl; Rabd R" may be, for example, a cyclic group, such as phenyl; E Rand R' may be, for example, a substituent, such as methyl; and 40 RH X is a leaving group, such as halogen, Bn OESEO H 1. selective O N s N deprotection -e- Reacting halo-amino-pyridine A with a Negishi reagent 45 (formed from a 2-((tert-butoxycarbonyl)amino)-3-iodopro O CO2 '' 'NHBoc 2. R-C(O)Cl panoate) provides amino acid B. Then, intramolecular cyclization of amino acid B promoted by heat or a base F provides dihydro-1,8-naphthyridin-2(1H)-one C. Reacting RH 50 dihydro-1,8-naphthyridin-2(1H)-one C with benzylchloro OESEO formate affords bis-carbamate D. Selective reduction of the H amide group in bis-carbamate D using borane or lithium R N N N aluminum hydride provides tetrahydro-1,8-naphthyridine E. R Reaction of tetrahydro-1,8-naphthyridine E with a sulphonyl 55 O CO21 '' 'NHBoc chloride or sulfamoyl chloride provides sulfonamide F. Next, the benzylcarbamate protecting group is removed from Sul G fonamide F to provide an amino-tetrahydro-1,8-naphthyri Rii dine (not shown) that can be subjected to amide coupling OESEO 60 conditions using a carboxylic acid and an amide coupling H agent to provide amido-tetrahydro-1,8-naphthyridine G. The R N N N remaining Boc protecting group on amido-tetrahydro-1.8- R naphthyridine G can be removed by treatment with acid to rO CO21 * ''NH, provide amino-tetrahydro-1,8-naphthyridine H. It is under 65 stood that the amino group on amino-tetrahydro-1,5-naph H thyridine H can be converted to other functional groups (e.g., US 9,394,315 B2 61 62 -continued -continued RII RII

OESEO OE i EO H 5 Br N N RY R. N N N N r R- RVII R 2 '1 CC4fn1 DC N. 10 E RVII RH I O i EO R may be, for example, hydrogen or a substituent, such as methyl; Rand R" may be, for example, a cyclic group, such as phenyl; RT-R'Hare substituents, such as methyl; and 15 Xis, for example, halogen, R O R-C(O)Cl 2 ODC RY Scheme 4 illustrates an alternative general method for pre F paring amido-dihydro-2H-pyrido3.2-b1,4oxazines. Alky RH lation of hydroxy-pyridine A with 2-halo-alkanone B affords OESEO pyridinyl ether C. Exhaustive reduction (e.g., using Raney Nickel) with in situ intramolecular cyclization provides s N N RY bromo-dihydro-2H-pyrido 3.2-boxazine D. Reaction of R oxazine D with a sulphonyl chloride or sulfamoyl chloride 25 y DC provides bromo-sulfonamido-dihydro-2H-pyrido3.2-box O CC RY G azine E. Bromo-sulfonamido-dihydro-2H-pyrido3.2-box Rand R" may be, for example, a cyclic group, such as phenyl; and azine E can be converted to amine Fusing procedures known R. R', and R may be, for example, hydrogen or a substituent, such as methyl. in the art, such as (1) Ullmann CuSO mediated addition of 30 ammonia (Hauser et al. in J. Org. Chem. 1950, 15, 1224 1232); (2) Pd-mediated addition of a carbamate (Bhagwanth Scheme 5 illustrates another general procedure for prepar et al. in J. Org Chem. 2009, 74, 4634-4637) followed by ing amido-tetrahydro-1.8-naphthyridines with a hydroxyl or alkoxyl group at the 6-position. Reacting halo-amino-pyri deprotection; (3) Pd-mediated addition of hexamethyldisi 35 lazide (Stefko et al. in J. Org. Chem. 2011, 76, 6619-6635), dine A with a Negishi reagent (formed from a 2-alkoxy-3- and (4) Pd-mediated addition of diphenylmethanimine fol iodopropanoate) provides pyridinyl ester B. Then, intramo lowed by deprotection with acid (Grasa et al. in J. Org. Chem. lecular cyclization of pyridinyl ester B promoted by heat or a 2001, 66, 7729-7737). Reaction of amine F with an acid base provides dihydro-1,8-naphthyridin-2(1H)-one C. React chloride provides amide G. It is understood that an acid 40 ing dihydro-1,8-naphthyridin-2(1H)-one C with benzylchlo (R'COH) and amide-coupling reagent can be used in lieu of roformate affords bis-carbamate D. Selective reduction of the the acid chloride in the step used to produce amide G. amide group in bis-carbamate D using borane or lithium aluminum hydride provides tetrahydro-1,8-naphthyridine E. 45 Reaction of tetrahydro-1,8-naphthyridine E with a sulphonyl SCHEME 4. chloride or sulfamoyl chloride provides sulfonamide F. Next, O the benzylcarbamate protecting group is removed from Sul Br N NO fonamide F to provide an amino-tetrahydro-1,8-naphthyri n X -- R -> dine (not shown) that can be subjected to amide coupling R conditions using a carboxylic acid and an amide coupling 21 OH RY agent to provide amido-tetrahydro-1,8-naphthyridine G. To A B the extent a hydroxy-tetrahydro-1,8-naphthyridine is desired, NO Br N variable R may be a trialkylsilyl group, which may be N n RY 55 removed by reacting amido-tetrahydro-1,8-naphthyridine G R- reduction with a silyl group deprotecting agent, such as tetrabutylam monium fluoride. 2 O1. R -e-cyclication O C 60 SCHEME5. H Br N N R HN N NH2 N n N n t RSOCI2 R -- R- 21 ZnCHC(H)(OR")COR 21 O RIV 65 X A US 9,394,315 B2 63 64 -continued -continued HN s NH2 RH l? ORY intellarcyclication OESEO 2 COOR VI --> 5 R N l B n HN N O R 2 N n O 2 'ORIV e -3- Ne 10 G VORY R may be, for example, hydrogen or a substituent, such as methyl; C RandR" may be, for example, a cyclic group, such as phenyl; Bn R" is a hydroxyl protecting group or alkyl; N O R is a substituent, such as methyl; and X may be, for example, halogen, r N n H 15 !, R 2 'ORIV Scheme 6 illustrates another general procedure for prepar B D ing aralkyloxy-tetrahydro-1,8-naphthyridine compounds. l H H 2O Reaction of aralkvloXV-aminopvridiney py A with a mixture of an O N N N acid and substituted dimethylaminoacrolein B provides 1.8- l R-SOCI naphthyridine C. Alternatively, 1.8-naphthyridine C can be * R- 21 DFV prepared by reacting aralkyloxy-aminopyridine with 1,3-di OR carbonyl compound B1 (See, for example, Reichart et al. in E RH 25 Tet. Lett. 1977, 24, 2087-90; Eva, E. etal.J. Het. Chem. 1976, 13, 841-844, and Bernstein et al. J. Amer: Chem. Soc. 1947, o==o 69, 1151-1158) or substituted vinamidinium salt B2 (See, for O N N 1. deprotection example, Norma et al. in Synthesis 2001, 9, 1351-1355). n --2. R-C(O)Cl 30 ReductionAt of 1.8-naphthyridine C by hydrogenation (e.g., O R- 21 using H with Pd/C in methanol) provides tetrahydro-1.8- 'ORIV naphthyridine D, which can be reacted with a sulphonyl chlo F ride or sulfamoyl chloride to provide the final aralkyloxy sulfonamide-tetrahydro-1,8-naphthyridine E.

SCHEME 6. RVIII O N NH2 R ? 21 R H --O N N RY A acid Ns-sR- H 2 21 RW -e-

RIII O RY RIII RIV 1. C R N O s N or RY O RIV O RY RIII B B1 1N B2

RH O i EO H N RY REO N N RY -es-RSOCI NR RIV 21 RIV RIII RIII E RandR"-R may be, for example, hydrogen or a substituent, such as methyl; R" may be, for example, a cyclic group, such as phenyl; and is aralkyl, such as benzyl. US 9,394,315 B2 65 66 Scheme 7 illustrates an alternative general procedure for noma, or cancer of the central nervous system tissue. In preparing aralkyloxy-dihydro-2H-pyrido3.2-b 14ox certain other embodiments, the cancer is colon cancer, Small azines. Ullman coupling of an alcohol (R' OH) with bro cell lung cancer, non-small cell lung cancer, renal cancer, mide A provides aralkyloxy-dihydro-2H-pyrido3.2-b1.4 ovarian cancer, renal cancer, or melanoma. oxazine B. Additional exemplary cancers include fibrosarcoma, myX osarcoma, liposarcoma, chondrosarcoma, osteogenic sar coma, chordoma, angiosarcoma, endotheliosarcoma, lym SCHEME 7. phangiosarcoma, lymphangioendotheliosarcoma, Ewings tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell RH 10 carcinoma, basal cell carcinoma, adenocarcinoma, Sweat O EO gland carcinoma, sebaceous gland carcinoma, papillary car cinoma, papillary adenocarcinomas, cystadenocarcinoma, Br N N RY medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, R 15 seminoma, embryonal carcinoma, Wilms tumor, epithelial CC2 ODC RIV RH-OH carcinoma, glioma, astrocytoma, medulloblastoma, and A hemangioblastoma. RH In certain embodiments, the caner is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain OESEO metastase, glioblastoma multiforms, glioblastoma, brain RTI- O N l RY stem glioma, poor prognosis malignant brain tumor, malig N n nant glioma, anaplastic astrocytoma, anaplastic oligodendro R glioma, neuroendocrine tumor, rectal adeno carcinoma, 21 O RIV Dukes C & D colorectal cancer, unresectable colorectal car 25 B cinoma, metastatic hepatocellular carcinoma, Kaposi's sar R,R, and R may be, for example, hydrogen or a substituent, such as methyl; coma, karotype acute myeloblastic leukemia, Hodgkin’s R" may be, for example, a cyclic group, such as phenyl; and lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell RH is aralkyl, such as benzyl, lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, meta 30 static melanoma, localized melanoma, malignant mesothe II. Therapeutic Applications of Tetrahydro 1.8 naphthyridine lioma, malignant pleural effusion mesothelioma syndrome, and Related Compounds peritoneal carcinoma, papillary serous carcinoma, gyneco It is contemplated that the tetrahydro 1.8 naphthyridine logic sarcoma, Soft tissue sarcoma, Scelroderma, cutaneous and related compounds described herein, such as a compound vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, of Formula I, II, III, IV, or V, provide therapeutic benefits to 35 fibrodysplasia ossificans progressive, hormone refractory Subjects suffering from a cancer, bacterial infection, fungal prostate cancer, resected high-risk Soft tissue sarcoma, infection, or immune deficiency disorder. Accordingly, one unrescectable hepatocellular carcinoma, Waidenstrom's aspect of the invention provides a method of treating a disor macroglobulinemia, Smoldering myeloma, indolent der selected from the group consisting of cancer, bacterial myeloma, fallopian tube cancer, androgen independent pros infection, fungal infection, and immune deficiency disorder. 40 tate cancer, androgen dependent stage IV non-metastatic The method comprises administering a therapeutically effec prostate cancer, hormone-insensitive prostate cancer, chemo tive amount of a tetrahydro 1.8 naphthyridine or related com therapy-insensitive prostate cancer, papillary thyroid carci pound described herein, such as a compound of Formula I, II, noma, follicular thyroid carcinoma, medullary thyroid carci III, IV, or V, to a subject in need thereof to ameliorate a noma, or leiomyoma. symptom of the disorder, wherein Formula I, II, III, IV, and V 45 In certain embodiments, the disorder is a bacterial infec areas described above. In certain embodiments, the particular tion. The bacterial infection can be characterized according to compound of Formula I, II, III, IV, or V is a compound defined classifications known in the art. For example, in certain by one of the embodiments described above. embodiments, the bacterial infection is a gram-positive bac In certain embodiments, the disorder is cancer. In certain terial infection, Such as a gram-positive cocci bacterial infec embodiments, the cancer is a solid tumor or leukemia. In 50 tion or a gram-positive bacilli bacterial infection. In other certain other embodiments, the cancer is colon cancer, pan embodiments, the bacterial infection is a gram-negative bac creatic cancer, breast cancer, ovarian cancer, prostate cancer, terial infection, Such as a gram-negative coccibacterial infec squamous cell carcinoma, basal cell carcinoma, adenocarci tion or a gram-negative bacillibacterial infection. The bacte noma, Sweat gland carcinoma, sebaceous gland carcinoma, rial infection can also be characterized according to whether lung cancer, leukemia, bladder cancer, stomach cancer, cer 55 it is caused by anaerobic or aerobic bacteria. Accordingly, in Vical cancer, testicular cancer, skin cancer, rectal cancer, thy certain embodiments, the bacterial infection is an anaerobic roid cancer, kidney cancer, uterus cancer, espophagus cancer, bacterial infection. In certain other embodiments, the bacte liver cancer, an acoustic neuroma, oligodendroglioma, men rial infection is an aerobic bacterial infection. ingioma, neuroblastoma, or retinoblastoma. In certain other A variety of bacteria are contemplated to be susceptible to embodiments, the cancer is Small cell lung cancer, non-Small 60 the tetrahydro 1.8 naphthyridine compounds. Representa cell lung cancer, melanoma, cancer of the central nervous tive bacteria include Staphylococci species, e.g., S. aureus, system tissue, brain cancer, Hodgkin’s lymphoma, non Enterococci species, e.g., E. faecalis and E. faecium, Strep Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutane tococci species, e.g., S. pyogenes and S. pneumoniae, ous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In Escherichia species, e.g., E. coli, including enterotoxigenic, certain other embodiments, the cancer is breast cancer, colon 65 enteropathogenic, enteroinvasive, enterohemorrhagic and cancer, Small-cell lung cancer, non-small cell lung cancer, enteroaggregative E. coli strains: Haemophilus species, e.g., prostate cancer, renal cancer, ovarian cancer, leukemia, mela H. influenza, and Moraxella species, e.g., M. catarrhalis. US 9,394,315 B2 67 68 Other examples include Mycobacteria species, e.g., M. tuber purposes the biochemical reactions carried out by each organ culosis, M. avian-intracellulare, M. kansasii, M. bovis, M. ism. The MicroScan WalkAway can also be used to determine africanum, M. genavense, M. leprae, M. xenopi, M. Simiae, a preliminary MIC, which may be confirmed using the M. Scrofulaceum, M. malmoense, M. cellatum, M. abscessus, method described below. M. chelonae, M. Szulgai, M. gordonae, M. haemophilum, M. Frozen stock cultures may be used as the initial source of fortuni and M. marinum, Corynebacteria species, e.g., C. organisms for performing microbroth dilution minimum inhi diphtheriae, Vibrio species, e.g., V. cholerae, Campylobacter bition concentration (MIC) testing. Stock cultures are passed species, e.g., C. jejuni; Helicobacter species, e.g., H. pylori; on their standard growth medium for at least 1 growth cycle Pseudomonas species, e.g., P. aeruginosa, Legionella spe (18-24 hours) prior to their use. Most bacteria may be pre cies, e.g., L. pneumophila, Treponema species, e.g., T. palli 10 pared directly from agar plates in 10 mL aliquots of the dum, Borrelia species, e.g., B. burgdorferi; Listeria species, appropriate broth medium. Bacterial cultures are adjusted to e.g., L. monocytogenes, Bacillus species, e.g., B. cereus, Bor the opacity of a 0.5 McFarland Standard (optical density datella species, e.g., B. pertussis, Clostridium species, e.g., value of 0.28-0.33 on a Perkin-Elmer Lambda EZ150 Spec C. perfingens, C. tetani, C. difficile and C. botulinum, Neis trophotometer, Wellesley, Mass., set at a wavelength of 600 seria species, e.g., N. meningitidis and N. gomorrhoeae, 15 nm). The adjusted cultures are then diluted 400 fold (0.25 mL Chlamydia species, e.g., C. psittaci, C. pneumoniae and C. inoculum+100 mL broth) in growth media to produce a start trachomatis, Rickettsia species, e.g., R. rickettsii and R. ing Suspension of approximately 5x105 colony forming units prowazeki, Shigella species, e.g., S. Sonnei, Salmonella spe (CFU)/mL. Most bacterial strains may be tested in cation cies, e.g., S. typhimurium, Yersinia species, e.g., Y. entero adjusted Mueller Hinton Broth (CAMHB). colitica and Y. pseudotuberculosis, Klebsiella species, e.g., Test compounds (“drugs) are solubilized in a solvent suit K. pneumoniae, Mycoplasma species, e.g., M. pneumoniae: able for the assay, such as DMSO. Drug stock solutions may and Trypanosoma brucei. In certain embodiments, the com be prepared on the day of testing. Microbroth dilution stock pounds described herein are used to treat a subject suffering plates may be prepared in two dilution series, 64 to 0.06 ug from a bacterial infection selected from the group consisting drug/mL and 0.25 to 0.00025ug drug/mL. For the high con of S. aureus, E. faecalis, E. faecium, S. pyogenes, S. pneumo 25 centration series, 200LL of stock solution (2 mg/mL) is added nia, and P aeruginosa. to duplicate rows of a 96-well microtiter plate. This is used as The antibacterial activity of compounds described herein the first well in the dilution series. Serial two-fold decremen may be evaluated using assays known in the art, Such as the tal dilutions are made using a BioMek FX robot (Beckman microbroth dilution minimum inhibition concentration Coulter Inc., Fullerton, Calif.) with 10 of the remaining 11 (MIC) assay, as further described in National Committee for 30 wells, each of which will contain 100 uL of the appropriate Clinical Laboratory Standards. Performance Standards for solvent/diluent. Row 12 contains solvent/diluent only and Antimicrobial Susceptibility Testing: Fourteenth Informa serves as the control. For the first well of the low concentra tional Supplement. NCCLS document M100-S14 ISBN tion series, 200LL of an 8 g/mL stock are added to duplicate 1-56238-516-X}. This assay may be used to determine the rows of a 96-well plate. Serial two-fold dilutions are made as minimum concentration of a compound necessary to prevent 35 described above. visible bacterial growth in a solution. In general, the drug to Daughter 96-well plates may be spotted (3.2 LL/well) from be tested is serially diluted into wells, and aliquots of liquid the stock plates listed above using the BioMek FX robot and bacterial culture are added. This mixture is incubated under used immediately or frozen at -70° C. until use. Aerobic appropriate conditions, and then tested for growth of the organisms are inoculated (100 uL Volumes) into the thawed bacteria. Compounds with low or no antibiotic activity (a high 40 plates using the BioMek FX robot. The inoculated plates are MIC) will allow growth at high concentrations of compound, be placed in Stacks and covered with an empty plate. These while compounds with high antibiotic activity will allow plates are then incubated for 16 to 24 hours in ambient atmo bacterial growth only at lower concentrations (a low MIC). sphere according to CLSI guidelines (National Committee The assay uses stock bacterial culture conditions appropri for Clinical Laboratory Standards, Methods for Dilution, ate for the chosen strain of bacteria. Stock cultures from the 45 Antimicrobial Tests for Bacteria that Grow Aerobically: permanent stock culture collection can be stored as frozen Approved Standard-Sixth Edition. NCCLS document suspensions at -70° C. Cultures may be suspended in 10% M7-A6 (ISBN 1-56238-486-4}). skim milk (BD) prior to snap freezing in dry ice/ethanol and After inoculation and incubation, the degree of bacterial then placed in a -70° C. freezer. Cultures may be maintained growth can be estimated visually with the aid of a Test Read on Tryptic Soy Agar containing 5% Sheep Blood at room 50 ing Mirror (Dynex Technologies 220 16) in a darkened room temperature (20°C.), and each culture may be recovered from with a single light shining directly through the top of the frozen form and transferred an additional time before MIC microbroth tray. The MIC is the lowest concentration of drug testing. Fresh plates are inoculated the day before testing, that prevents macroscopically visible growth under the con incubated overnight, and checked to confirm purity and iden ditions of the test. tity. 55 In certain embodiments, the disorder is a fungal infection. The identity and purity of the cultures recovered from the Exemplary fungi that may be treated include, for example, stock culture can be confirmed to rule out the possibility of Acremonium, Absidia (e.g., Absidia corymbifera). Alterna contamination. The identity of the Strains may be confirmed ria, Aspergillus (e.g., Aspergillus clavatus, Aspergillus fia by standard microbiological methods (See, e.g., Murray et al., vus, Aspergillus filmigatus, Aspergillus nidulans, Aspergillus Manual of Clinical Microbiology, Eighth Edition. ASM Press 60 niger; Aspergillus terreus, and Aspergillus versicolor), Aure {ISBN 1-55581-255-4}). In general, cultures are streaked Obasidium, Basidiobolus, Blastomyces (e.g., Blastomyces onto appropriate agar plates for visualization of purity, dermatitidis), Candida (e.g., Candida albicans, Candida gla expected colony morphology, and hemolytic patterns. Gram brata, Candida guilliermondii, Candida kefir, Candida stains can also be utilized. The identities are confirmed using krusei, Candida lusitaniae, Candida parapsilosis, Candida a MicroScan WalkAway 40 SI Instrument (Dade Behring, 65 pseudotropicalis, Candida Stellatoidea, Candida tropicalis, West Sacramento, Calif.). This device utilizes an automated Candida utilis, Candida lipolytica, Candida famata and Can incubator, reader, and computer to assess for identification dida rugosa), Cephalosporium, Chaetonium, Chrysospo US 9,394,315 B2 69 70 rium, Cladosporium (e.g., Cladosporium carrioni and Cla amount of IL-17 in a subject. The method comprises admin dosporium trichloides), Coccidioides (e.g., Coccidioides istering to a subject an effective amount of a tetrahydro 1.8 immitis), Conidiobolus, Coprinus, Corynespora, Cryptococ naphthyridine or related compound described herein, Such as cus (e.g., Cryptococcus neoformans), Curvularia, Cunning a compound of Formula I, II, III, IV, or V, to increase the hamella (e.g., Cunninghamella elegans), Exophiala (e.g., amount of IL-17 in the subject, wherein Formula I, II, III, IV. Exophiala dermatitidis and Exophiala spinifera), Epidermo and V are as described above. In certain embodiments, the phyton (e.g., Epidermophyton floccosum), Fonsecaea (e.g., particular compound of Formula I, II, III, IV, or V is the Fonsecaea pedrosoi), Fusarium (e.g., Fusarium Solani), compound defined by one of the embodiments described Geotrichum (e.g., Geotrichum candiddum and Geotrichum above. clavatum), Hendersonula, Histoplasma, Leptosphaeria, 10 Loboa, Madurella, Malassezia (e.g., Malassezia furfur), In certain embodiments, the Subject is a human. In certain Microsporum (e.g., Microsporum canis and Microsporum embodiments, administering the compound increases the gypseum), Mycocentrospora, Mucor, Neotestudina, Paecilo amount of IL-17 produced by Th-17 cells in the subject. A myces, Paracoccidioides (e.g., Paracoccidioides brasilien change in the amount of IL-17 produced by, for example, sis), Penicillium (e.g., Penicillium marneffei), Phialophora, 15 Th-17 cells can be measured using procedures described in Pneumocystis (e.g., Pneumocystis carinii), Pseudallescheria the literature, such as an ELISA assay or intracellular staining (e.g., Pseudalescheria boydii), Rhinosporidium, Rhizomu assay. cor, Rhizopus (e.g., Rhizopus microsporus var. rhizopodifor Further, it is contemplated that tetrahydro 1.8 naphthyri mis and Rhizopus Oryzae), Saccharomyces (e.g., Saccharo dine and related compounds described herein, Such as a com myces cerevisiae), Scopulariopsis, Sporothrix (e.g., pound of Formula I, II, III, IV, or V, may increase the synthesis Sporothrix schenckii), Trichophyton (e.g., Trichophyton men of IL-17 in a subject. Accordingly, another aspect of the tagrophytes and Trichophyton rubrum), TrichospOron (e.g., invention provides a method of increasing the synthesis of TrichospOron asahi, TrichospOron beigelii and TrichospOron IL-17 in a subject. The method comprises administering to a cutaneum), and Wangiella. Subject an effective amount of a compound described herein, In certain embodiments, the disorder is an immune defi 25 e.g., a compound of Formula I, II, III, IV, or V, to increase the ciency disorder. Exemplary immune deficiency disorders synthesis of IL-17 in the subject, wherein Formula I, II, III, include, for example, a human immunodeficiency viral infec IV, and Vareas described above. In certain embodiments, the tion, a patient with a deficient immune system due to chemo particular compound of Formula I, II, III, IV, or V is a com therapy, or a patient recovering from Surgery who has a defi pound defined by one of the embodiments described above. cient immune system. 30 The description above describes multiple embodiments In certain embodiments, the Subject is a human. providing definitions for variables used herein. The applica Another aspect of the invention provides for the use of a tion specifically contemplates all combinations of such vari compound described herein (Such as a compound of Formula ables, e.g., particular combinations of the definitions set forth I, II, III, IV, or V) in the manufacture of a medicament. In for variables A and X. certain embodiments, the medicament is for treating a disor 35 III. Combination Therapy der described herein, such as cancer. Another aspect of the invention provides for combination Another aspect of the invention provides for the use of a therapy. Tetrahydro 1.8 naphthyridine and related com compound described herein (Such as a compound of Formula pounds (e.g., a compound of Formula I, II, III, IV, or V) or I, II, III, IV, or V) for treating a medical disorder, such a their pharmaceutically acceptable salts may be used in com medical disorder described herein (e.g., cancer). 40 bination with additional therapeutic agents to treat medical Further, it is contemplated that tetrahydro1.8naphthyri disorders, such as a cancer, bacterial infection, fungal infec dine and related compounds described herein, such as a com tion, and immune deficiency disorder. pound of Formula I, II, III, IV, or V. can promote the activity Exemplary therapeutic agents that may be used as part of a of RORY. Accordingly, another aspect of the invention pro combination therapy in treating cancer, include, for example, vides a method of promoting the activity of RORY. The 45 mitomycin, tretinoin, ribomustin, gemcitabine, Vincristine, method comprises exposing a RORY to an effective amount of etoposide, cladribine, mitobronitol, methotrexate, doxorubi a tetrahydro 1.8 naphthyridine or related compound cin, carboquone, pentostatin, nitracrine, Zinostatin, described herein, such as a compound of Formula I, II, III, IV. cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, or V, to promote RORY activity, wherein Formula I, II, III, IV. fotemustine, thymalfasin, Sobuzoxane, nedaplatin, cytara and V are as described above. In certain embodiments, the 50 bine, bicalutamide, Vinorelbine, Vesnarinone, aminoglute particular compound of Formula I, II, III, IV, or V is the thimide, amsacrine, proglumide, elliptinium acetate, ket compound defined by one of the embodiments described anserin, doxifluridine, etretinate, isotretinoin, Streptozocin, above. Promoting the activity of RORY means to increase the nimustine, Vindesine, flutamide, drogenil, butocin, carmofur, activity of RORY. In certain embodiments, exposing a RORY razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfa to an effective amount of a tetrahydro 1.8 naphthyridine or 55 mide, prednimustine, picibanil, levamisole, teniposide, related compound described herein (such as a compound of improSulfan, enocitabine, lisuride, oxymetholone, tamox Formula I, II, III, IV, or V) results in an increase in RORY ifen, progesterone, mepitioStane, epitiostanol, formestane, activity of at least 5%, 10%, 20%, or 50% relative to the interferon-alpha, interferon-2 alpha, interferon-beta, inter activity of RORY under substantially the same conditions but feron-gamma, colony stimulating factor-1, colony Stimulat without the presence of the tetrahydro 1.8 naphthyridine or 60 ing factor-2, denileukin diftitox, interleukin-2, and leutiniz related compound. ing hormone releasing factor. Further, it is contemplated that tetrahydro1.8naphthyri Exemplary therapeutic agents that may be used as part of a dine and related compounds described herein, such as a com combination therapy in treating a bacterial infection, include, pound of Formula I, II, III, IV, or V. can increase the amount for example, amoxicillin, azithromycin, cefazolin, ceftriax of interleukin-17 (IL-17) in a subject. IL-17 is a cytokine that 65 one, cefuroxime, cephalexin, ciprofloxacin, clindamycin, affects numerous biological functions. Accordingly, another doxycycline, levofloxacin, lineZolid, metronidazole, moxi aspect of the invention provides a method of increasing the floxacin, and penicillin. US 9,394,315 B2 71 72 Exemplary therapeutic agents that may be used as part of a monotherapy for treating the disorder. In certain embodi combination therapy in treating a fungal infection, include, ments, the tetrahydro 1.8 naphthyridine or related compound for example, 2-phenylphenol; 8-hydroxyquinoline Sulphate: (e.g., a compound of any one of Formula I, II, III, IV, or V) and acilbenzolar-S-methyl; aldimorph; amidoflumet, ampropyl the additional therapeutic agent(s) are present in the same fos; ampropylfos-potassium; andoprim; anilazine; azacona composition, which is Suitable for oral administration. Zole; azoxystrobin; benalaxyl; benodanil; benomyl; benthia In certain embodiments, the tetrahydro 1.8 naphthyridine valicarb-isopropyl; benzamacril; benzamacril-isobutyl: orrelated compound (e.g., a compound of any one of Formula bilanafos; binapacryl; biphenyl; bitertanol; blasticidin-S; I, II, III, IV, or V) and the additional therapeutic agent(s) may bromuconazole; butylamine; calcium polysulphide; capsi act additively or synergistically. A synergistic combination mycin; captafol; captan; carbendazim; carboxin; carpropa 10 mid; carvone; chinomethionat, chlobenthiazone; chlorfena may allow the use of lower dosages of one or more agents Zole; chloroneb; chlorothalonil; chlozolinate; clozylacon; and/or less frequent administration of one or more agents of a cyaZofamid; cyflufenamid; cymoxanil; cyproconazole; combination therapy. A lower dosage or less frequent admin cyprodinil; cyprofuram; Dagger G; debacarb; dichlofluanid; istration of one or more agents may lower toxicity of the dichlone; dichlorophen; diclocymet; diclomeZine; dicloran; 15 therapy without reducing the efficacy of the therapy. diethofencarb; difenoconazole; diflumetorim; dimethirimol; Another aspect of this invention is a kit comprising athera dimethomorph; dimoxystrobin; diniconazole; diniconazole peutically effective amount of the tetrahydro 1.8 naphthyri M; dinocap: diphenylamine; dipyrithione; ditalimfos; dine or related compound (e.g., a compound of any one of dithianon; dodine; draZOXolon; edifenphos; epoxiconazole; Formula I, II, III, IV, or V), a pharmaceutically acceptable ethaboxam, ethirimol; etridiazole; famoxadone; fenamidone; carrier, vehicle or diluent, and optionally at least one addi fenapanil; fenarimol; fenbuconazole; fenfuram; fenhexamid; tional therapeutic agent listed above. fenitropan; fenoxanil; fempiclonil; fempropidin; fempropi IV. Pharmaceutical Compositions and Dosing Considerations morph; ferbam; fluazinam; flubenzimine; fludioxonil; flume As indicated above, the invention provides pharmaceutical tover; flumorph; fluoromide; fluoxastrobin: fluguinconazole; compositions, which comprise a therapeutically-effective flurprimidol; flusilazole; flusulphamide, hexaconazole; 25 amount of one or more of the compounds described above, hymexazole; imazalil; imibenconazole; iminoctadine triac formulated together with one or more pharmaceutically etate; iminoctadine tris(albesil); iodocarb; ipconazole; acceptable carriers (additives) and/or diluents. The pharma iprobenfos; iprodione; iprovalicarb; irumamycin; isoprothi ceutical compositions may be specially formulated for olane; isovaledione; kasugamycin; kresoxim-methyl, oxy administration in Solid or liquid form, including those fenthiin; paclobutrazole; pefurazoate; penconazole; pencycu 30 adapted for the following: (1) oral administration, for ron; phosdiphen; phthalide; picoxystrobin; piperalin; example, drenches (aqueous or non-aqueous solutions or Sus polyoxins; polyoxorim; probenazole; prochloraz: procymi pensions), tablets, e.g., those targeted for buccal, Sublingual, done; propamocarb; propanosine-sodium; propiconazole; and systemic absorption, boluses, powders, granules, pastes propineb; produinazid; prothioconazole; pyraclostrobin; for application to the tongue; (2) parenteral administration, pyrazophos; pyrifenox, pyrimethanil; pyroquilon; pyroxyfur, 35 for example, by Subcutaneous, intramuscular, intravenous or pyrrollenitrine; tetraconazole; thiabendazole; thicyofen; thi epidural injection as, for example, a sterile Solution or Sus fluZamide; thiophanate-methyl; thiram, tioxymid; tricycla pension, or Sustained-release formulation; (3) topical appli Zole; tridemorph; trifloxystrobin; triflumizole; triforine; triti cation, for example, as a cream, ointment, or a controlled conazole; uniconazole; validamycin A; VincloZolin; Zineb; release patch or spray applied to the skin; (4) intravaginally or Ziram; and Zoxamide. 40 intrarectally, for example, as a pessary, cream or foam; (5) The amount of tetrahydro 1.8 naphthyridine or related sublingually; (6) ocularly; (7) transdermally; or (8) nasally. compound (e.g., a compound of Formula I, II, III, IV, or V) The phrase “therapeutically-effective amount’ as used and additional therapeutic agent and the relative timing of herein means that amount of a compound, material, or com administration may be selected in order to achieve a desired position comprising a compound of the present invention combined therapeutic effect. For example, when administer 45 which is effective for producing some desired therapeutic ing a combination therapy to a patient in need of such admin effect in at least a sub-population of cells in an animal at a istration, the therapeutic agents in the combination, or a phar reasonable benefit/risk ratio applicable to any medical treat maceutical composition or compositions comprising the ment. therapeutic agents, may be administered in any order Such as, The phrase “pharmaceutically acceptable' is employed for example, sequentially, concurrently, together, simulta 50 herein to refer to those compounds, materials, compositions, neously and the like. Further, for example, a tetrahydro 1.8 and/or dosage forms which are, within the scope of Sound naphthyridine or related compound (e.g., a compound of any medical judgment, Suitable for use in contact with the tissues one of Formula I, II, III, IV, or V) may be administered during of human beings and animals without excessive toxicity, irri a time when the additional therapeutic agent(s) exerts its tation, allergic response, or other problem or complication, prophylactic or therapeutic effect, or vice versa. 55 commensurate with a reasonable benefit/risk ratio. The doses and dosage regimen of the active ingredients Wetting agents, emulsifiers and lubricants, such as Sodium used in the combination therapy may be determined by an lauryl Sulfate and magnesium Stearate, as well as coloring attending clinician. In certain embodiments, the tetrahydro1, agents, release agents, coating agents, Sweetening, flavoring 8 naphthyridine or related compound (e.g., a compound of and perfuming agents, preservatives and antioxidants can any one of Formula I, II, III, IV, or V) and the additional 60 also be present in the compositions. therapeutic agent(s) are administered in doses commonly Examples of pharmaceutically-acceptable antioxidants employed when Such agents are used as monotherapy for include: (1) water soluble antioxidants, such as ascorbic acid, treating the disorder. In other embodiments, the tetrahydro1, cysteine hydrochloride, Sodium bisulfate, sodium met 8 naphthyridine or related compound (e.g., a compound of abisulfite, sodium sulfite and the like; (2) oil-soluble antioxi any one of Formula I, II, III, IV, or V) and the additional 65 dants, such as ascorbyl palmitate, butylated hydroxyanisole therapeutic agent(s) are administered in doses lower than the (BHA), butylated hydroxytoluene (BHT), lecithin, propyl doses commonly employed when such agents are used as gallate, alpha-tocopherol, and the like; and (3) metal chelat US 9,394,315 B2 73 74 ing agents, such as citric acid, ethylenediamine tetraacetic Stearic acid, and mixtures thereof: (10) coloring agents; and acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the (11) controlled release agents such as crospovidone or ethyl like. cellulose. In the case of capsules, tablets and pills, the phar Formulations of the present invention include those suit maceutical compositions may also comprise buffering able for oral, nasal, topical (including buccal and Sublingual), agents. Solid compositions of a similar type may also be rectal, vaginal and/or parenteral administration. The formu employed as fillers in Soft and hard-shelled gelatin capsules lations may conveniently be presented in unit dosage form using Such excipients as lactose or milk Sugars, as well as high and may be prepared by any methods well known in the art of molecular weight polyethylene glycols and the like. pharmacy. The amount of active ingredient which can be A tablet may be made by compression or molding, option combined with a carrier material to produce a single dosage 10 ally with one or more accessory ingredients. Compressed form will vary depending upon the host being treated, the tablets may be prepared using binder (for example, gelatin or particular mode of administration. The amount of active hydroxypropylmethyl cellulose), lubricant, inert diluent, pre ingredient which can be combined with a carrier material to servative, disintegrant (for example, sodium starch glycolate produce a single dosage form will generally be that amount of or cross-linked sodium carboxymethyl cellulose), Surface the compound which produces a therapeutic effect. Gener 15 active or dispersing agent. Molded tablets may be made by ally, out of one hundred percent, this amount will range from molding in a suitable machine a mixture of the powdered about 0.1 percent to about ninety-nine percent of active ingre compound moistened with an inert liquid diluent. dient, preferably from about 5 percent to about 70 percent, The tablets, and other solid dosage forms of the pharma most preferably from about 10 percent to about 30 percent. ceutical compositions of the present invention, such as drag In certain embodiments, a formulation of the present inven ees, capsules, pills and granules, may optionally be scored or tion comprises an excipient selected from the group consist prepared with coatings and shells, such as enteric coatings ing of cyclodextrins, celluloses, liposomes, micelle forming and other coatings well known in the pharmaceutical-formu agents, e.g., bile acids, and polymeric carriers, e.g., polyesters lating art. They may also be formulated so as to provide slow and polyanhydrides; and a compound of the present inven or controlled release of the active ingredient therein using, for tion. In certain embodiments, an aforementioned formulation 25 example, hydroxypropylmethyl cellulose in varying propor renders orally bioavailable a compound of the present inven tions to provide the desired release profile, other polymer tion. matrices, liposomes and/or microspheres. They may be for Methods of preparing these formulations or compositions mulated for rapid release, e.g., freeze-dried. They may be include the step of bringing into association a compound of sterilized by, for example, filtration through a bacteria-retain the present invention with the carrier and, optionally, one or 30 ing filter, or by incorporating sterilizing agents in the form of more accessory ingredients. In general, the formulations are sterile solid compositions which can be dissolved in sterile prepared by uniformly and intimately bringing into associa water, or some other sterile injectable medium immediately tion a compound of the present invention with liquid carriers, before use. These compositions may also optionally contain or finely divided solid carriers, or both, and then, if necessary, opacifying agents and may be of a composition that they shaping the product. 35 release the active ingredient(s) only, or preferentially, in a Formulations of the invention suitable for oral administra certain portion of the gastrointestinal tract, optionally, in a tion may be in the form of capsules, cachets, pills, tablets, delayed manner. Examples of embedding compositions lozenges (using a flavored basis, usually Sucrose and acacia or which can be used include polymeric Substances and waxes. tragacanth), powders, granules, or as a solution or a suspen The active ingredient can also be in micro-encapsulated form, sion in an aqueous or non-aqueous liquid, or as an oil-in 40 if appropriate, with one or more of the above-described water or water-in-oil liquid emulsion, or as an elixir or syrup, excipients. or as pastilles (using an inert base. Such as gelatin and glyc Liquid dosage forms for oral administration of the com erin, or Sucrose and acacia) and/or as mouth washes and the pounds of the invention include pharmaceutically acceptable like, each containing a predetermined amount of a compound emulsions, microemulsions, Solutions, Suspensions, syrups of the present invention as an active ingredient. A compound 45 and elixirs. In addition to the active ingredient, the liquid of the present invention may also be administered as a bolus, dosage forms may contain inert diluents commonly used in electuary or paste. the art, such as, for example, water or other solvents, solubi In solid dosage forms of the invention for oral administra lizing agents and emulsifiers. Such as ethyl alcohol, isopropyl tion (capsules, tablets, pills, dragees, powders, granules, alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl trouches and the like), the active ingredient is mixed with one 50 benzoate, propylene glycol, 1,3-butylene glycol, oils (in par or more pharmaceutically-acceptable carriers, such as ticular, cottonseed, groundnut, corn, germ, olive, castor and Sodium citrate or dicalcium phosphate, and/or any of the sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene following: (1) fillers or extenders, such as starches, lactose, glycols and fatty acid esters of Sorbitan, and mixtures thereof Sucrose, glucose, mannitol, and/or silicic acid; (2) binders, Besides inert diluents, the oral compositions can also Such as, for example, carboxymethylcellulose, alginates, 55 include adjuvants such as wetting agents, emulsifying and gelatin, polyvinyl pyrrolidone, Sucrose and/or acacia; (3) Suspending agents, Sweetening, flavoring, coloring, perfum humectants, such as glycerol; (4) disintegrating agents, such ing and preservative agents. as agar-agar, calcium carbonate, potato or tapioca starch, Suspensions, in addition to the active compounds, may alginic acid, certain silicates, and sodium carbonate; (5) Solu contain Suspending agents as, for example, ethoxylated isos tion retarding agents. Such as paraffin; (6) absorption accel 60 tearyl alcohols, polyoxyethylene Sorbitol and Sorbitan esters, erators, such as quaternary ammonium compounds and Sur microcrystalline cellulose, aluminum metahydroxide, bento factants, such as poloxamer and Sodium lauryl Sulfate; (7) nite, agar-agar and tragacanth, and mixtures thereof wetting agents. Such as, for example, cetyl alcohol, glycerol Formulations of the pharmaceutical compositions of the monostearate, and non-ionic Surfactants; (8) absorbents. Such invention for rectal or vaginal administration may be pre as kaolin and bentonite clay; (9) lubricants, such as talc, 65 sented as a Suppository, which may be prepared by mixing calcium Stearate, magnesium Stearate, Solid polyethylene gly one or more compounds of the invention with one or more cols, sodium lauryl Sulfate, Zinc stearate, Sodium Stearate, Suitable nonirritating excipients or carriers comprising, for US 9,394,315 B2 75 76 example, cocoa butter, polyethylene glycol, a Suppository persing agents. Prevention of the action of microorganisms wax or a salicylate, and which is solid at room temperature, upon the Subject compounds may be ensured by the inclusion but liquid at body temperature and, therefore, will melt in the of various antibacterial and antifungal agents, for example, rectum or vaginal cavity and release the active compound. paraben, chlorobutanol, phenol sorbic acid, and the like. It Formulations of the present invention which are suitable may also be desirable to include isotonic agents. Such as for vaginal administration also include pessaries, tampons, Sugars, sodium chloride, and the like into the compositions. In creams, gels, pastes, foams or spray formulations containing addition, prolonged absorption of the injectable pharmaceu Such carriers as are known in the art to be appropriate. tical form may be brought about by the inclusion of agents Dosage forms for the topical or transdermal administration 10 which delay absorption Such as aluminum monostearate and of a compound of this invention include powders, sprays, gelatin. ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under In some cases, in order to prolong the effect of a drug, it is sterile conditions with a pharmaceutically-acceptable carrier, desirable to slow the absorption of the drug from subcutane and with any preservatives, buffers, or propellants which may 15 ous or intramuscular injection. This may be accomplished by be required. the use of a liquid Suspension of crystalline or amorphous The ointments, pastes, creams and gels may contain, in material having poor water solubility. The rate of absorption addition to an active compound of this invention, excipients, of the drug then depends upon its rate of dissolution which, in Such as animal and vegetable fats, oils, waxes, paraffins, turn, may depend upon crystal size and crystalline form. starch, tragacanth, cellulose derivatives, polyethylene gly Alternatively, delayed absorption of a parenterally-adminis cols, silicones, bentonites, silicic acid, talc and Zinc oxide, or tered drug form is accomplished by dissolving or Suspending mixtures thereof the drug in an oil vehicle. Powders and sprays can contain, in addition to a compound Injectable depot forms are made by forming microencap of this invention, excipients such as lactose, talc, silicic acid, 25 Sule matrices of the Subject compounds in biodegradable aluminum hydroxide, calcium silicates and polyamide pow polymers such as polylactide-polyglycolide. Depending on der, or mixtures of these Substances. Sprays can additionally the ratio of drug to polymer, and the nature of the particular contain customary propellants, such as chlorofluorohydro polymer employed, the rate of drug release can be controlled. carbons and Volatile unsubstituted hydrocarbons, such as 30 Examples of other biodegradable polymers include poly butane and propane. (orthoesters) and poly(anhydrides). Depot injectable formu Transdermal patches have the added advantage of provid lations are also prepared by entrapping the drug in liposomes ing controlled delivery of a compound of the present inven or microemulsions which are compatible with body tissue. tion to the body. Such dosage forms can be made by dissolv When the compounds of the present invention are admin ing or dispersing the compound in the proper medium. 35 istered as pharmaceuticals, to humans and animals, they can Absorption enhancers can also be used to increase the flux of be given perse or as a pharmaceutical composition contain the compound across the skin. The rate of such flux can be ing, for example, 0.1 to 99% (more preferably, 10 to 30%) of controlled by either providing a rate controlling membrane or active ingredient in combination with a pharmaceutically dispersing the compound in a polymer matrix or gel. 40 acceptable carrier. Ophthalmic formulations, eye ointments, powders, solu The preparations of the present invention may be given tions and the like, are also contemplated as being within the orally, parenterally, topically, or rectally. They are of course Scope of this invention. given in forms suitable for each administration route. For Pharmaceutical compositions of this invention suitable for example, they are administered in tablets or capsule form, by parenteral administration comprise one or more compounds 45 injection, inhalation, eye lotion, ointment, Suppository, etc. of the invention in combination with one or more pharmaceu administration by injection, infusion or inhalation; topical by tically-acceptable sterile isotonic aqueous or nonaqueous lotion or ointment; and rectal by Suppositories. Oral admin Solutions, dispersions, Suspensions or emulsions, or sterile istrations are preferred. powders which may be reconstituted into sterile injectable The phrases “parenteral administration” and “adminis 50 tered parenterally as used herein means modes of adminis Solutions or dispersions just prior to use, which may contain tration other than enteral and topical administration, usually Sugars, alcohols, antioxidants, buffers, bacteriostats, solutes by injection, and includes, without limitation, intravenous, which render the formulation isotonic with the blood of the intramuscular, intraarterial, intrathecal, intracapsular, intended recipient or Suspending or thickening agents. intraorbital, intracardiac, intradermal, intraperitoneal, tran Examples of Suitable aqueous and nonaqueous carriers 55 stracheal, Subcutaneous, Subcuticular, intraarticulare, Sub which may be employed in the pharmaceutical compositions capsular, Subarachnoid, intraspinal and intrasternal injection of the invention include water, ethanol, polyols (such as glyc and infusion. erol, propylene glycol, polyethylene glycol, and the like), and The phrases “systemic administration.” “administered sys Suitable mixtures thereof, vegetable oils, such as olive oil, and temically.” “peripheral administration” and “administered injectable organic esters, such as ethyl oleate. Proper fluidity 60 peripherally as used herein mean the administration of a compound, drug or other material other than directly into the can be maintained, for example, by the use of coating mate central nervous system, such that it enters the patient’s system rials, such as lecithin, by the maintenance of the required and, thus, is Subject to metabolism and other like processes, particle size in the case of dispersions, and by the use of for example, Subcutaneous administration. Surfactants. 65 These compounds may be administered to humans and These compositions may also contain adjuvants such as other animals for therapy by any suitable route of adminis preservatives, wetting agents, emulsifying agents and dis tration, including orally, nasally, as by, for example, a spray, US 9,394,315 B2 77 78 rectally, intravaginally, parenterally, intracisternally and topi certain aspects and embodiments of the present invention, and cally, as by powders, ointments or drops, including buccally are not intended to limit the invention. and Sublingually. Regardless of the route of administration selected, the Example 1 compounds of the present invention, which may be used in a Suitable hydrated form, and/or the pharmaceutical composi tions of the present invention, are formulated into pharma Synthesis of 2,6-Difluoro-N-(8-(4-fluorobenzene ceutically-acceptable dosage forms by conventional methods sulfonyl)-5,6,7,8-tetrahydro 1.8 naphthyridin-2-yl) known to those of skill in the art. benzamide (1) Actual dosage levels of the active ingredients in the phar 10 maceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular F patient, composition, and mode of administration, without being toxic to the patient. 15 The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide F thereof, the route of administration, the time of administra OESEO tion, the rate of excretion or metabolism of the particular H compound being employed, the rate and extent of absorption, N N N the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound F O 21s employed, the age, sex, weight, condition, general health and 25 prior medical history of the patient being treated, and like factors well known in the medical arts. The title compound was prepared according to the proce A physician or veterinarian having ordinary skill in the art dures described below. can readily determine and prescribe the effective amount of 30 the pharmaceutical composition required. For example, the Part I Synthesis of 1.8-Naphthyridin-2-ylamine physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage 35 HN N NH2 until the desired effect is achieved. N In general, a suitable daily dose of a compound of the 21 1. N N4S4 O invention will be that amount of the compound which is the PPA, 120° C. lowest dose effective to produce a therapeutic effect. Such an HN N N effective dose will generally depend upon the factors 40 N n described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at 21N 21 about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent 45 Pyridine-2,6-diamine (0.30g, 2.8 mmol), 3-dimethylami (e.g., as sensitizing agents), the effective amount may be less noacrolein (90%, 0.30g, 2.8 mmol), and polyphosphoric acid than when the agent is used alone. (PPA) (2.7 mL) were combined and the reaction mixture was If desired, the effective daily dose of the active compound heated to 120° C. for 10 hours. Then, the reaction mixture was may be administered as two, three, four, five, six or more poured on ice water and neutralized with Solid sodium car Sub-doses administered separately at appropriate intervals 50 bonate. The resulting aqueous mixture was extracted three throughout the day, optionally, in unit dosage forms. Pre times with ethyl acetate and the combined organic extracts ferred dosing is one administration per day. were washed with brine, concentrated, and purified by col The invention further provides a unit dosage form (such as umn chromatography (EtOAC/hexanes) to give 1.8-naph a tablet or capsule) comprising a tetrahydro 1.8 naphthyri thyridin-2-ylamine Yield 85 mg (21%). LCMS (ESI): calc. dine or related compound described herein (such as a com 55 CH-N=145; obs. M+H=146. pound of any one of Formulae I-V or a specific compound described herein, such as in Tables 1-3) in a therapeutically Part II—Synthesis of effective amount for the treatment of an immune or inflam 2,6-Difluoro-N-1.8 naphthyridin-2-ylbenzamide matory disorder, such as one of the particular immune disor 60 ders or inflammatory disorders described herein.

EXAMPLES HN N N n n ArC(O)Cl The invention now being generally described, will be more 65 -- readily understood by reference to the following examples, 21 21 Pyridine, DMF which are included merely for purposes of illustration of US 9,394,315 B2 79 80 -continued -continued F F

H C N Nn Nn 5 F O 2 2 F OESEO H 1,8-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was 10 N N N dissolved in dichloromethane (2 mL) and pyridine (0.10 mL. N 1.2 mmol). 2,6-Difluorobenzoyl chloride (0.068 mL, 0.76 F O mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture 15 was diluted with ethyl acetate and washed with water fol 2,6-Difluoro-N-(5,6,7,8-tetrahydro 1.8 naphthyridin-2- lowed by brine. The resulting organic solution was purified by yl)benzamide (30 mg, 0.10 mmol) was dissolved in dichlo column chromatography (EtOAC/hexanes) to give 2,6-dif romethane (0.3 mL) and pyridine (0.025 mL, 0.31 mmol). luoro-N-1.8 naphthyridin-2-ylbenzamide. Yield 35 mg 4-Fluorobenzenesulfonyl chloride (23 mg, 0.12 mmol) was (21%). LCMS (ESI): calc. CHFNO=285; obs. then added and the reaction mixture was stirred at room M+H=286. temperature for 12 hours. Next, the reaction mixture was washed with 1M HCl(aq), sat’d NaHCO(aq), and brine. The Part III Synthesis of 2,6-Difluoro-N-(5,6,7,8-tet resulting organic Solution was concentrated, dissolved in rahydro 1.8 naphthyridin-2-yl)benzamide DMSO, and purified by HPLC to give 2,6-difluoro-N-(8-(4- 25 fluorobenzenesulfonyl)-5,6,7,8-tetrahydro 1.8 naphthyri din-2-yl)benzamide. "H NMR 250 MHz CDC1 & 8.13 (bs, 1H), 8.03 (dd, J=7.9, 4.3 Hz, 2H), 7.83 (d. J=7.9 Hz, 1H), 7.48 F (p, J=6.5 Hz, 1H), 7.38 (d. J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 30 2H), 7.06 (t, J=7.8 Hz, 2H), 4.07 (dd, J=5.8, 4.3 Hz, 2H), 2.76 H H, HCI, Pd/C N. N. N. -> (t, J=6.5 Hz, 2H), 2.06 (p, J-5.8 Hz, 2H). LCMS (ESI): calc. Crs EtOH CHFNOS=447; obs. M+H=448. r) Example 2 F 35

H Synthesis of 2,6-Dichloro-N-4-(toluene-3-sulfonyl)- N. N. N. 3,4-dihydro-2H-pyrido3.2-b 14oxazin-6-yl)-ben Zamide (2) F O 2 40

2,6-Difluoro-N-1.8 naphthyridin-2-ylbenzamide (35 mg. 0.12 mmol) and 10% Pd/C (15 mg) were suspended in ethanol (5 mL). Concentrated HCl (0.02 mL, 0.24 mmol) was then 45 added and the reaction mixture was stirred under hydrogen (1 C atmosphere) for three hours. Next, the reaction mixture was OESEO filtered through Celite and concentrated to give 2,6-difluoro H N N N N-(5,6,7,8-tetrahydro 1.8 naphthyridin-2-yl)benzamide. 50 Yield 33 mg (95%). LCMS (ESI): calc. CHFNO=289; obs. M+H=290. C O CC2 OD Part IV—Synthesis of 2,6-Difluoro-N-(8-(4-fluo robenzenesulfonyl)-5,6,7,8-tetrahydro 1.8 naphthyri 55 din-2-yl)benzamide Part I Synthesis of (6-Bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester 60 F

N. N. N. / Br N-N: O n / No -e- 65 DMSO r) pyridine, CH2Cl2 Crs21 So O US 9,394,315 B2 81 82 -continued -continued Br N NO H n Br N N O

2 r’s 5 COr21 O

6-Bromo-2-nitropyridin-3-ol (10.8 g. 49.1 mmol) was dis (2-Amino-6-bromopyridin-3-yloxy)acetic acid methyl solved in dimethylsulfoxide (DMSO) (30 mL). Potassium 10 ester (4.0 g, 15 mmol) was dissolved in MeCH (40 mL). carbonate (13.6 g. 98.6 mmol) and bromoacetic acid methyl KCO (3.0 g, 22 mmol) was added and the reaction was ester (7.0 mL, 74 mmol) were added and the reaction mixture stirred at 70° C. for 1 hour. Then, the solvent was removed was stirred at 60° C. for two hours. Then, the reaction mixture under reduced pressure and the resulting slurry was Sus was cooled to room temperature and neutralized with 1N pended in dichloromethane (DCM) and washed with HO HCl(aq). The aqueous solution was extracted twice with ethyl 15 and then brine. The organic layer was dried (Na2SO) and the acetate, and the combined organic extracts were washed with product was precipitated from DCM/EtO to give 6-bromo brine. The product was purified by column chromatography 4H-pyrido 3.2-b1,4-oxazin-3-one. Yield 1.9 g (8.3 mmol. (SiO, EtOAc/hexanes) to afford (6-bromo-2-nitropyridin-3- 55%). LCMS (ESI): calc. CHBrNO=228, 230; obs. M+H=229, 231. yloxy)acetic acid methyl ester. Yield 10.9 g (37.5 mmol. 2O 76%). LCMS (ESI): calc. CHBrNO=290,292; obs. Low ionization. Part IV Synthesis of 6-Bromo-3,4-dihydro-2H-pyrido 3.2-b1,4-oxazine Part II—Synthesis of (2-Amino-6-bromopyridin-3-yloxy)acetic acid 25 methyl ester H Br N N O BH, DMS complex Br N NO -- n 30 2n r THF Fe, conc HCI O H 4N~ N MeOH Br N N O Br N NH2 35 CC21 O D s 2 r O N O 40 6-Bromo-4H-pyrido 3.2-b1,4-oxazin-3-one (1.35 g, 5.89 mmol) was dissolved in THF (40 mL). Boranedimeth (6-Bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester ylsulphide complex (2.0 M in THF, 5.89 mL, 11.79 mmol) (10.9 g, 37.5 mmol) was dissolved in methanol (90 mL). was added and the resulting mixture heated to 70° C. under Concentrated HCl (10 mL) was then added followed by iron nitrogen for 15 minutes. Next, the reaction mixture was (6.4g, 110 mmol). The reaction mixture was stirred at 60°C. 45 cooled to room temperature, quenched with methanol (~5 for 1 hour. Then, the reaction mixture was cooled to room mL), and then dried under vacuum to obtain a white solid. The temperature and neutralized with solid sodium bicarbonate. crude material was dissolved indichloromethane and washed The insoluble iron salts were removed by centrifugation. with H2O. The aqueous phase was discarded and the organic Silica gel was then added to the Supernatant and the solvents phase was dried under vacuum to give 6-bromo-3,4-dihydro were removed under reduced pressure. The resulting crude 50 2H-pyrido3.2-b1,4-oxazine. Yield: 1.1 g (87%). LCMS material was purified by column chromatography (SiO, (ESI): calc. CHBrNO=214, 216; obs. M+H=215, 217. EtOAc/hexanes) to give (2-amino-6-bromopyridin-3-yloxy) acetic acid methyl ester. Yield 4.0 g (15 mmol, 40%). LCMS Part V Synthesis of 6-Bromo-4-(toluene-3-sulfo (ESI): calc. CHBrNO=260, 262: obs. M+H=261,263. 55 nyl)-3,4-dihydro-2H-pyrido 3.2-b1,4-oxazine Part III Synthesis of 6-Bromo-4H-pyrido 3.2-b1,4-oxazine-3-one

60 H Br N NH2 Br N N O n K2CO3 -- Her -e- pyridine MeOH N r 21 O OESEO

65 C US 9,394,315 B2 83 84 -continued Part VII—Synthesis of 2,6-Dichloro-N-4-(toluene 3-sulfonyl)-3,4-dihydro-2H-pyrido3.2-b 14ox azin-6-yl-benzamide

Br N o==oN

CC2 O D C OESEO -- HN N N -- C 6-Bromo-3,4-dihydro-2H-pyrido3.2-b 14oxazine (1.0 15 g, 4.65 mmol) and m-tolylsulfonyl chloride were dissolved in C O pyridine (10 mL). The resulting mixture was stirred at 80°C. CC2 O D for one hour. An additional portion of m-tolylsulfonyl chlo ride (0.98g, 5.12 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. Next, excess solvent was removed under vacuum, and the resulting oil was triturated C with water to obtain a tan solid, which was collected by OESEO vacuum filtration and washed with water and diethyl ether to 25 R. N. give 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido 3.2-b 14oxazine. Yield 1.3 g (76%). LCMS (ESI): calc. C O CO21 O CHBrNOS=368,370; obs. M+H=369,371. 30 4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido3.2-b1, Part VI Synthesis of 4-(Toluene-3-sulfonyl)-3,4- 4oxazin-6-ylamine (20 mg, 0.065 mmol) was dissolved in dihydro-2H-pyrido3.2-b1,4-oxazin-6-ylamine p-dioxane (0.400 mL) and water (0.100 mL), followed by 35 2,6-dichlorobenzoyl chloride (21 uL, 0.098 mmol) and NaHCO (11 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 15 hours, concentrated under vacuum, and purified by HPLC to give 2,6-dichloro-N-4- 40 (toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido3.2-b 14ox azin-6-yl)-benzamide. LCMS (ESI): calc. CH, o==oC. o==oC. ClNOS=477; obs. M+H=478. Br N N HN N N 45 CO21N, CO21N, Example 3

50 Synthesis of 2-Phenyl-N-4-(toluene-3-sulfonyl)-3,4- 6-Bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido dihydro-2H-pyrido3.2-b1,4-oxazin-6-yl)-propi 3.2-b 14oxazine (300 mg. 0.81 mmol) was dissolved in onamide (3) p-dioxane (10 mL), followed by benzophenone imine (409

LL, 2.44 mmol), Sodium tert-butoxide (207 mg, 2.15 mmol), 55 XantPhos (70 mg, 0.12 mmol), and finally Pd(dba), (74 mg. 0.08 mmol). The resulting mixture was heated to 100° C. for 2.5 hours. Then, the reaction mixture was concentrated under vacuum and partitioned in a mixture of ethyl acetate and 60 water. The aqueous phase was discarded, and the organic o==o O phase was concentrated and purified by flash chromatography HN N N -- Hip (12 g silica column, 0-60% EtOAc/Hexane) to give 4-(tolu ene-3-sulfonyl)-3,4-dihydro-2H-pyrido 3.2-b1,4-oxazin 65 CC D OH 6-ylamine Yield 80 mg (32%). LCMS (ESI): calc. 4N CHNOS=305; obs. M+H=306. US 9,394,315 B2 85 86 -continued loxy-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido3.2-b 1.4 oxazine. LCMS (ESI): calc. CHNOS-396; obs. M-H=397. Example 5 Synthesis of 6-(2,6-Dichlorobenzyloxy)-4-m-tolyl sulfonyl)-3,4-dihydro-2H-pyrido3.2-b 14oxazine (5) 10

4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido3.2-b1, 4-oxazin-6-ylamine (20 mg, 0.065 mmol) was dissolved in 15 N-methylpyrrolidinone (0.5 mL), followed by (d.1)-2-phenyl C propionic acid (30 uL, 0.11 mmol), HATU (45 mg, 0.12 OESEO mmol), and diisopropyl ethylamine (23 uL, 0.13 mmol). The Br N N reaction mixture was stirred at room temperature for 18 -- C. -e- hours. Then, the reaction mixture was then purified by HPLC s D C to give 2-phenyl-N-4-(toluene-3-sulfonyl)-3,4-dihydro-2H CC pyrido 3.2-b1,4-oxazin-6-yl)-propionamide. LCMS (ESI): calc. CHNOS=437; obs. M+H=438. 25 Example 4 C

O N o==oN Synthesis of 6-(Benzyloxy)-4-m-tolylsulfonyl)-3,4- 30 dihydro-2H-pyrido3.2-b1,4oxazine (4) C CC4N D

35 To 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-py rido 3.2-b1,4oxazine (50 mg, 140 mmol) in 2,6-dichlo robenzyl alcohol (400 uL) was added CuI (15 mg, 79 mmol), 1,10-phenanthroline (15 mg, 83 mmol), and CsCO (70 mg. OESEO 210 mmol). The resulting mixture was heated to 130°C. for 2 40 hours. Next, the reaction mixture was cooled to room tem Br N l -- OH perature and quenched with a small amount of water, then extracted with ethyl acetate. The aqueous phase was dis CO carded and the organic phase was concentrated under reduced CC 45 pressure. The resulting residue was purified by HPLC to give 6-(2,6-dichloro-benzyloxy)-4-(toluene-3-sulfonyl)-3,4-di hydro-2H-pyrido3.2b 14oxazine. LCMS (ESI): calc. CH.ClNOS=464; obs. M+H=465.

O i EO 50 Example 6 O N N Synthesis of 6-(1-Phenylethoxy)-4-m-tolylsulfonyl)- 3,4-dihydro-2H-pyrido3.2-b 14oxazine (6)

CC4\, D 55

To 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-py rido 3.2-b1,4oxazine (50 mg, 140 mmol) in benzyl alcohol (400 uL) was added CuI (15 mg, 79 mmol), 1,10-phenanthro 60 line (15 mg, 83 mmol), and CsCO (70 mg, 210 mmol). The resulting mixture was heated to 130° C. for 2 hours. Next, the o==o reaction mixture was cooled to room temperature and Br N N -- OH --> quenched with a small amount of water, then extracted with ethyl acetate. The aqueous phase was discarded and the 65 organic phase concentrated under reduced pressure. The CC21 O D resulting residue was purified by HPLC to afford 6-benzy US 9,394,315 B2 87 88 -continued ECso values for test compounds were calculated from the quotient of the fluorescence signal at 665 nm divided by the fluorescence signal at 615 nm using GraphPad Prism soft Wa. Part III Results Compounds 1-6 from the above Examples were tested. Compounds 1-5 were determined to have an ECs less than or O N l equal 15uM. No promotion of RORY activity was detected for compound 6 during the assay measuring ECso values less 10 than or equal to 20 uM. CO21 O INCORPORATION BY REFERENCE To 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-py The entire disclosure of each of the patent documents and rido 3.2-b1,4oxazine (50 mg, 140 mmol) in (d.1)-1-phe 15 scientific articles referred to herein is incorporated by refer nylethanol (400 uL) was added CuI (15 mg, 79 mmol), 1,10 ence for all purposes. phenanthroline (15 mg, 83 mmol), and CsCO (70 mg, 210 mmol). The resulting mixture was heated to 130° C. for 2 EQUIVALENTS hours. Next, the reaction mixture was cooled to room tem perature and quenched with a small amount of water, then The invention may be embodied in other specific forms extracted with ethyl acetate. The aqueous phase was dis without departing from the spirit or essential characteristics carded and the organic phase was concentrated under reduced thereof. The foregoing embodiments are therefore to be con pressure. The resulting residue was purified by HPLC to give sidered in all respects illustrative rather than limiting the 6-(1-phenyl-ethoxy)-4-(toluene-3-sulfonyl)-3,4-dihydro invention described herein. Scope of the invention is thus 25 indicated by the appended claims rather than by the foregoing 2H-pyrido3.2-b 14oxazine. LCMS(ESI): calc. description, and all changes that come within the meaning CHNOS=410; obs. M+H=411. and range of equivalency of the claims are intended to be embraced therein. Example 7 We claim: Biological Assays for RORY Activity 30 1. A compound represented by Formula I:

Exemplary compounds from the above Examples were (I) tested for ability to increase RORY activity using a RORy V Ligand Binding Domain (LBD) TR-FRET Assay. Assay pro 35 cedures and results are described below. N O -, Part I Procedures for RORY-Ligand Binding Domain TR-FRET Assay y-ll-kD. 40 Recombinant, HIS-tagged RORY-LBD was expressed in SF9 cells using a baculovirus expression system. Cells were or a pharmaceutically acceptable salt or Solvate thereof; lysed and the lysate was used as a source for RORY-LBD for wherein: the assay. A 1:80 dilution of RORY-LBD lysate in assay buffer A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy (25 mM HEPES pH 7.0, 100 mM NaCl, 0.01% Tween, 0.1% 45 cloalkyl; each of which is optionally substituted with 1, BSA) was prepared and 5 uL was added to each well (RORy 2, or 3 substituents independently selected from the LBD final concentration ~3 nM). Control wells received group consisting of halogen, hydroxyl, Calkyl, lysate from SF9 cells not expressing RORY-LBD. Chaloalkyl, Cohydroxyalkyl, C-galkoxy, Cha Compounds to be tested were diluted to 100x final test loalkoxy, N(R)(R), —COR, C(O)R. —CN, concentration in DMSO and further diluted to 4x final test 50 —C, alkylene-Calkoxy, —Calkylene-N(R)(R), concentration using assay buffer to provide the test com —C, alkylene-CO.R. —O C-alkylene-N(R) pound mixture. An aliquot (5 LL) of the test compound mix (R), N(R)C(O) Coalkylene-N(R)(R), S(O), ture was added to each well. Calkyl, -SON(R)(R), N(R)SO(C-alkyl). A 4x stock of biotinylated-LXXLL peptide from SRC1-2 C(O)N(R)(R), and N(R)C(O)N(R)(R): 55 X is -O-C(R)(R)-C(R)-p or - O C(R). C (Biotin-CPSSHSSLTERHKILHRLLOEGSPS) was pre (R)(R)—p; wherein p is a bond to the sulfonamide pared in assay buffer and a 5 uL aliquot added to each well ring nitrogen atom in Formula I; (450 nM final concentration). A 4x solution of europium Y is N(R)(R) or O-aralkyl, wherein said aralkyl is tagged anti-HIS antibody (2 nM final concentration) and APC optionally substituted with 1, 2, or 3 substituents inde conjugated Streptavidin (60nM final concentration) were pre 60 pendently selected from the group consisting of halo pared and a 5 uL aliquot added to each well. gen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, The final assay mixture was incubated for 4 hours to over Chaloalkyl, - N(R)(R), —CN, CO, C-alkyl, night, and the fluorescence signal was measured on an Envi C(O) Coalkyl, -C(O)N(R)(R), S(O), sion plate reader: (Excitation filter 340 nm; APC emis Calkyl, -SON(R)(R), and - N(R)SO, sion=665 nm.; Europium emission=615 nmi; dichroic 65 (Cigalkyl); mirror-D400/D630; delay time=100 us, integration R" represents independently for each occurrence hydro time=200 us). gen, halogen, or Coalkyl, US 9,394,315 B2 89 90 R is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- 9. The compound of claim 1, wherein Y is —O-benzyl cycloalkyl, —C(O)—C(R)-heterocyclyl, optionally substituted with 1, 2, or 3 substituents indepen —C(O)—Calkyl, —C(O)—Calkylene dently selected from the group consisting of halogen, Calkoxyl. —C(O)—Calkylene-cycloalkyl, or Calkyl, and Chaloalkyl. 10. The compound of claim 6, wherein R7 is hydrogen. —C(O)—Calkylene-heterocycloalkyl; each of which 11. The compound of claim 6, wherein R is Chydroxy is optionally substituted with 1, 2, or 3 substituents inde alkyl, methyl, ethyl, or Calkylene-N(H)C(O)—Calkyl. pendently selected from the group consisting of halo 12. The compound of claim 1, wherein the compound is gen, hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, represented by Formula II: Chaloalkyl, N(R)(R), —CN, CO. Calkyl, 10 - C(O) Calkyl, -C(O)N(R)(R), —S(O), Calkyl, -SON(R)(R), and - N(R)SO, (II) (C1-alkyl); V R is hydrogen or C-calkyl; OES R and Reach represent independently for each occur 15 rence hydrogen or C-alkyl; or RandR taken together Y N with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring: 2 7 R represents independently for each occurrence hydrogen COA O R or Calkyl; R’ is hydrogen, hydroxyl, C-hydroxyalkyl, C-alkyl, Chaloalkyl, -CO.R. Calkylene-CO.R. Chy or a pharmaceutically acceptable salt or Solvate thereof; droxyalkylene-CO.R. N(R)(R), Calkylene-N wherein: (R)(R), Chydroxyalkylene-N(R)(R), -N(R)C 25 A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocy (O)R. Calkylene-N(R)C(O)R’, Calkylene-C(O) cloalkyl; each of which is optionally substituted with 1, N(R)(R), N(R)CO. Calkyl, or Calkylene-N 2, or 3 substituents independently selected from the (R)(C(O)N(R)(R); or R7 is heterocycloalkyl or group consisting of halogen, hydroxyl, Calkyl, Calkylene-heterocycloalkyl, wherein the heterocy Chaloalkyl, Cohydroxyalkyl, C-galkoxy, Cha cloalkyl is optionally substituted with 1, 2, or 3 substitu 30 loalkoxy, N(R)(R), —COR. - C(O)R. —CN, ents independently selected from the group consisting of —C, alkylene-Calkoxy, and —C, alkylene-N(R) oXo, halogen, hydroxyl, Calkyl, Chaloalkyl, (R): Cohydroxyalkyl, Calkoxy, and Chaloalkoxy; Y is N(R)(R) or O-aralkyl, wherein said aralkyl is optionally substituted with 1, 2, or 3 substituents inde R is hydrogen, Calkyl, or—C(O)—Coalkyl: 35 pendently selected from the group consisting of halo R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky gen, hydroxyl, Cigalkoxy, Chaloalkoxy, C-alkyl, lene-N(R)(R), O Calkylene-N(R)C(O)— Chaloalkyl, N(R)(R), —CN, CO. Calkyl, Coalkyl, C(O) Coalkyl, C(O)N(R)(R), S(O), n is 1 or 2; and Calkyl, -SON(R)(R), and - N(R)SO, m and peach represent independently for each occurrence 40 (Cigalkyl); 0, 1, or 2. R" is hydrogen, halogen, or Calkyl; 2. The compound of claim 1, wherein A is phenyl option R’ is —C(O)-aryl, -C(O)-aralkyl, -C(O)—C(R)- ally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Calkyl, cycloalkyl, -C(O)-IC(R)-heterocyclyl, -C(O)— Chaloalkyl, Calkoxy, and Chaloalkoxy. 45 Cisalkyl, —C(O)—Calkylene-Calkoxyl, 3. The compound of claim 1, wherein A is heteroaryl —C(O)—Calkylene-cycloalkyl, or —C(O)— optionally substituted with 1, 2, or 3 substituents indepen Calkylene-heterocycloalkyl; each of which is option dently selected from the group consisting of halogen, ally substituted with 1, 2, or 3 substituents indepen Calkyl, Chaloalkyl, Calkoxy, and Chaloalkoxy. dently selected from the group consisting of halogen, 4. The compound of claim 1, wherein X is O—C(R) 50 hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, (R)—C(R), p. Chaloalkyl, - N(R)(R), —CN, CO, C-alkyl, 5. The compound of claim 1, wherein Y is N(R)(R). —C(O)—C, alkyl, -C(O)N(R)(R), S(O), 6. The compound of claim 5, wherein R is C(O)-arylor Calkyl, -SON(R)(R), and - N(R)SO, —C(O)-aralkyl; each of which is optionally substituted with (Cigalkyl); 1, 2, or 3 substituents independently selected from the group 55 consisting of halogen, hydroxyl, Calkoxy, Chaloalkoxy, R is hydrogen or C-calkyl; Calkyl, and Chaloalkyl. R" and Reach represent independently for each occur 7. The compound of claim 5, wherein R is —C(O)-phenyl rence hydrogen or Calkyl; or —C(O)-benzyl; each of which is optionally substituted or RandR taken together with the nitrogen atom to which with 1, 2, or 3 substituents independently selected from the 60 they are attached form a 3-7 membered heterocyclic ring: group consisting of halogen, Calkyl, and Chaloalkyl. R represents independently for each occurrence hydrogen 8. The compound of claim 1, wherein Y is —O-aralkyl or Calkyl; optionally substituted with 1, 2, or 3 substituents indepen R’ is hydrogen, hydroxyl, C-hydroxyalkyl, Coalkyl, dently selected from the group consisting of halogen, Chaloalkyl, -CO.R. Calkylene-CO.R. Chy hydroxyl, Cigalkoxy, Chaloalkoxy, Calkyl, Cha 65 droxyalkylene-COR. - N(R)(R), Calkylene-N loalkyl, - N(R)(R), —CN, CO. Calkyl, and (R)(R), Chydroxyalkylene-N(R)(R), -N(R)C —C(O)—Calkyl. (O)R. Calkylene-N(R)C(O)R’, Calkylene-C(O) US 9,394,315 B2 91 92 N(R)(R), N(R)CO, C-alkyl, or C-alkylene-N wherein each R' is independently halogen, Calkyl, or (R)(C(O)N(R)(R); or R7 is heterocycloalkyl or Chaloalkyl. Calkylene-heterocycloalkyl, wherein the heterocy 19. The compound of claim 15, wherein R is represented cloalkyl is optionally substituted with 1, 2, or 3 substitu by: ents independently selected from the group consisting of 5 oxo, halogen, hydroxyl, Calkyl, Chaloalkyl,

Chydroxyalkyl, Calkoxy, and Chaloalkoxy: R is hydrogen, C-alkyl, C-hydroxyalkyl, C-alky lene-N(R)(R), O Calkylene-N(R)C(O)— Coalkyl, and 10 m and peach represent independently for each occurrence 0, 1, or 2. 13. The compound of claim 12, wherein A is aryl optionally substituted with 1, 2, or 3 substituents independently selected wherein R" is Calkyl, aryl, or heterocyclyl, each of from the group consisting of halogen, Calkyl, Cha 15 which is optionally substituted with 1, 2, or 3 substitu loalkyl, Calkoxy, and Chaloalkoxy. ents independently selected from the group consisting of 14. The compound of claim 12, wherein A is phenyl option halogen, hydroxyl, Calkoxy, Chaloalkoxy, ally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Calkyl, Calkyl, Chaloalkyl, N(R)(R), —CN, Chaloalkyl, Calkoxy, and Chaloalkoxy. —CO, C-alkyl, -C(O) Calkyl, -C(O)N(R) 15. The compound of claim 12, wherein Y is N(R)(R). (R), S(O)Calkyl, -SO.N(R)(R), and—N(R4) 16. The compound of claim 15, wherein R is —C(O)-aryl SO(C-alkyl). or —C(O)-aralkyl; each of which is optionally substituted 20. The compound of claim 12, wherein Y is —O-aralkyl with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, Calkoxy, Cha 25 optionally substituted with 1, 2, or 3 substituents indepen loalkoxy, Calkyl, and Chaloalkyl. dently selected from the group consisting of halogen, 17. The compound of claim 15, wherein R is —C(O)- hydroxyl, Calkoxy, Chaloalkoxy, Calkyl, Cha phenyl or C(O)-benzyl; each of which is optionally substi loalkyl, - N(R)(R), —CN, CO. Calkyl, and tuted with 1, 2, or 3 substituents independently selected from 30 —C(O)—Calkyl. the group consisting of halogen, Calkyl, and Chaloalkyl. 21. The compound of claim 12, wherein Y is —O-benzyl 18. The compound claim 15, wherein R is represented by: optionally substituted with 1, 2, or 3 substituents indepen dently selected from the group consisting of halogen, 35 Calkyl, and Chaloalkyl. O R 22. The compound of claim 16, wherein R is hydrogen. 23. The compound of claim 16, wherein R7 is Chydroxy alkyl, Calkyl, Calkylene-CO.R. Calkylene-N(R) 40 (R), or Calkylene-N(R)C(O)R’. R 24. A compound in Table 2A or 3A below, or a pharma ceutically acceptable salt thereof: TABLE 2A

No. Y

II-11 C y CF O US 9,394,315 B2 93 94 TABLE 2A-continued

O Y B--opoO

No. Y

II-12 F

H

II-13 F Hy

II-14 C y

II-15 C opo N y N C O OD

II-16 C Hy

II-17 F

H N N N N 2 OH

II-18 F opo H N N

y 2n O DOH US 9,394,315 B2 95 96 TABLE 2A-continued

O Y B--opoO N

No. Y II-19 opo

F O opo AA - aC N N

C O II-21 opo N YX Y. Y. YC

CF O D II-22 J.

C O C O F.

II-23

F OF II-24

YYX Y. Y. W.C

F O

opo s C D

US 9,394,315 B2 100 TABLE 3A-continued TABLE 3A-continued

No. Compound No. Compound

III-11 Cl III-16

N C OESEO 10 OESEO H N Ns N N Ns N O 2 O '1 OH Cl O 2 O '1 OH 15

III-17 Cl III-12 C

Cl OSEO E OESEO H N N N N N N n n 25 Cl O 2 O '1 2 o1 1 OH O

30 III-13 III-18 C No Cl 35 OESEO CI H ESEO N N N H N N N s Cl O 2 O '1 OH s 40 Cl O 2 o1 ".“1 OH III-19 III-14 w H H 45

N N CI Cl OSEO OSEO H H N N N 50 N N N

Cl O s '' OH s 2 O '',1. Cl O 2 O '1 OH

III-15 55 III-20 so 'r, OH N 60 N1 “1 CI C OESEO OESEO H H N N N N N N

s 65 s CI O 21 '',-OH CI O 2 O '1. OH US 9,394,315 B2 102 TABLE 3A-continued TABLE 3A-continued

No. Compound No. Compound

5 III-21 III-26 C w

N 10 C C OESEO OESEO H H N N. N N N n n O C O OH 15 COJ4n-1- N 2 O '1 O III-22 C

2O

C III-29 C OESE R. N. N OH 25 C C O OESEO H N N. 30 C O III-23 C CO4N1", ~. 35 O

40 III-30 C C O 4\, O

C III-24 C OESEO 45 H N N.

C C OESE COJ H 50 O CC ''',-- N N N n O O C O 21 O p o N 55 III-31 C III-2S C

C 60 H OSFO N N N H N N N C O CO21 O ''',1N N 1 C O 2s N 65 US 9,394,315 B2 103 104 TABLE 3A-continued TABLE 3A-continued

No. Compound No. Compound III-32 III-52

N C OE i EO O N N 2

C N O '1

15 III-48 25. A pharmaceutical composition comprising a com pound of claim 1 and a pharmaceutically acceptable carrier. 26. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to treat the disorder, wherein the cancer is selected from the group C * OH consisting of colon cancer, pancreatic cancer, breast cancer, N O '1 25 ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, Sweat gland carci III-49 noma, Sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney can or 30 cer, uterus cancer, espophagus cancer, liver cancer, an acous tic neuroma, oligodendroglioma, meningioma, neuroblas toma, and retinoblastoma. 27. The method of claim 26, wherein the disorder is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, pros 35 tate cancer, Squamous cell carcinoma, basal cell carcinoma, C N O '.1. OH adenocarcinoma, Sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal III-S1 C cancer, thyroid cancer, kidney cancer, uterus cancer, espopha gus cancer, liver cancer, an acoustic neuroma, oligodendro 40 glioma, meningioma, neuroblastoma, or retinoblastoma. C 28. A method of increasing the amount of IL-17 in a sub OF i FO ject, comprising administering to a Subject an effective amount of a compound of claim 1 to increase the amount of O N N IL-17 in the subject. 2 45 29. The method of claim 26, wherein the subject is a human. N O '1 30. A method of promoting the activity of RORY, compris ing exposing a RORY to an effective amount of a compound of claim 1 to promote the activity of said RORY. k k k k k