Method of treating polycystic kidney disease

Abstract

Described herein are methods of treating polycystic kidney disease (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a PPAR-γ modulator wherein the PPAR-γ modulator is a non-activating (non-agonist) modulator of PPAR-γ. The PKD can be autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The PPAR-γ modulator can, for example, be an inverse agonist of PPAR-γ.

Description

[0001]4266.3004 WO METHOD OF TREATING POLYCYSTIC KIDNEY DISEASE RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No.63 / 572,982 5 filed April 2, 2024. The entire contents of the above-referenced application are incorporated by reference herein. BACKGROUND OF THE INVENTION Polycystic Kidney disease (PKD) is a group of kidney diseases associated with 10 bilateral kidney cyst development. There are two forms, autosomal dominant polycystic kidney disease (ADPKD) and a more severe autosomal recessive polycystic kidney disease (ARPKD). ADPKD is associated with mutations in PKD1 (polycystin-1) or PKD2 (polycystin-2). ADPKD is also associated with the formation and progressive enlargement of fluid-filled cysts in the kidneys, and can lead to massive enlargement of the kidneys which 15 can necessitate nephrectomy (Grantham (1997), Trans Am Clin Climatol Assoc. 1997;108:165-70). ARPKD is generally caused by a mutation in ciliary IPT domain containing fibrocystin / polyductin (PKHD1). Many biological pathways are deranged in these diseases including cAMP, Hedgehog, MAPK / EPK and Wnt signaling pathway (Saini et al. (2020), Mol Med 26(1): 128; Reiterova et al. (2022), Int. J. Mol. Sci.2022, 23(6), 3317; 20 Nagao et al. (2012), Curr Mol Pharmacol 5(2):292-300). In addition to the development of cysts, PKD is associated with defects in cilia formation and function. The disease impairs kidney function eventually resulting in end-stage renal disease. Tolvaptan (JYNARQUE®), a vasopressin receptor-2 antagonist, is approved for the treatment of ADPKD and provides largely symptomatic relief by shrinking kidney cysts. 25 Pioglitazone, used in the treatment of type 2 diabetes, has also been described in the literature as a potential treatment for ADPKD and has shown efficacy in several cell and animal models (Saini et al.2020). Additionally, pioglitazone has been described as inhibiting disease progression of polycystic kidney and liver disease in a model of human ARPKD (Yoshihara et al. (2010), Am J Physiol Renal Physiol.300(2): F465–F474). However, human clinical 30 trials to date have been inconclusive (Blazer-Yost et al. (2021), Clinical Kidney Journal 14(7): 1738-1746). Pioglitazone is a potent peroxisome proliferator-activated receptor- gamma (PPAR-γ) agonist and a modest peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist (Nicholls et al. (2012), Diabetes and Vascular Disease Research. 2012;9(2):89-94). Other drugs in the glitazone class (also named thiazolidinediones) without Page 1 of 161 4266.3004 WO PPAR-α activity appear to work less well than pioglitazone. It has been suggested in the literature that PPAR-α agonists might be helpful in the treatment of PKD but this has yet to be confirmed (Lakhia (2021), Curr Opin Nephrol Hypertens.29(4): 432–438). The mode of action of PPAR-^ and PPAR-^ agonists in polycystic kidney disease remains unknown. 5 There remains a need in the art for additional methods of treating PKD. SUMMARY OF THE INVENTION The present invention is at least partially based on the surprising finding that the PPAR-^ inverse agonist, Compound A (a compound of Formula (I) described below), has 10 markedly greater efficacy than pioglitazone in reversing forskolin-stimulated cyst swelling in a mouse cell model of ADPKD. As shown in FIG.1A, Compound A completely reversed forskolin-stimulated cyst swelling. In contrast, pioglitazone only showed a 50% reversal (FIG.1B). The present invention is directed to a method of treating polycystic kidney disease 15 (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a PPAR-^ modulator wherein the PPAR-^ modulator is a non-activating (non- agonist) modulator of PPAR-^. The PPAR-^ modulator can, for example, be an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^. In certain specific aspects, the PPAR-^ modulator is an inverse agonist. Exemplary PPAR-^ modulators include compounds of 20 Formula (I) (shown below), including compounds of Formulae (IA) and (IB) (shown below), and compounds of Formula (II), or pharmaceutically acceptable salts of any of thereof. The PKD can be autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). In additional aspects, the invention is directed to a method of treating polycystic 25 kidney disease (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a compound of Formulae (I), (IA) (IB), or (II), or pharmaceutically acceptable salts of any of thereof. In certain specific aspects, the compound is a compound of Formulae (I), (IA) (IB), or (II) and is an inverse agonist of PPAR-^^^In certain aspects, the compound is a compound of Formula (I), (IA) or (IB) and is an inverse agonist of PPAR- 30 ^^and is also an agonist of PPAR-^^^^n yet other aspects, the compound is a compound of Formula (II), (IIA), (IIB), (IIC) or (IID), and is an inverse agonist of PPAR-^^ In certain additional aspects, the compound is a compound of Formula (II), (IIA), (IIB), (IIC) or (IID) and is an inverse agonist of PPAR-^^and is also an agonist of PPAR-^^ Page 2 of 161 4266.3004 WO Also encompassed is a method treating a ciliopathy or a polycystic disease in a patient in need thereof comprising administering to said patient an effective amount of a PPAR-^ modulator wherein the PPAR-^ modulator is a non-activating (non-agonist) modulator of PPAR-^. The PPAR-^ modulator can, for example, be an inverse agonist of PPAR-^ or a 5 neutral antagonist of PPAR-^. In certain specific aspects, the PPAR-^ modulator is an inverse agonist. Exemplary PPAR-^ modulators include compounds of Formula (I) (shown below), including compounds of Formulae (IA) and (IB) (shown below), and compounds of Formula (II) (including compounds of Formula (IIA), (IIB), (IIC) and (IID), or pharmaceutically acceptable salts of any of thereof. 10 Additionally provided herein are the inventions described in the Enumerated Embodiments section below. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, features and advantages of the invention will be 15 apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. FIG.1A is graph showing the effect of different concentrations (log uM) of 20 Compound A on swelling inhibition (percent change in cyst area) in a mouse cell model of ADPKD. Compound A reduced FSK-induced cyst swelling in a dose dependent manner. FIG.1B is a graph showing the effect of different concentrations (log uM) of pioglitazone on swelling inhibition (percent change in cyst area) in the mouse model of ADPKD. Pioglitazone inhibited FSK-induced cyst swelling to below 50%. 25 FIGs.2A-2D are bar graphs showing the effect of different concentrations of Compound C (“Cmpd C”), pioglitazone (“Pio”), Compound A (“Cmpd A”) and Compound B (“Cmpd B”), respectively, on percent (%) surface area of in vitro cysts. FIGs.2E-2H are bar graphs showing the effect of different concentrations of Compound C (“Cmpd C”), pioglitazone (“Pio”), Compound A (“Cmpd A”) and Compound B 30 (“Cmpd B”), respectively, on the total number of in vitro cysts. DETAILED DESCRIPTION OF THE INVENTION A description of preferred embodiments of the invention follows. Page 3 of 161 4266.3004 WO As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified. For example, the term “a cell” encompasses both a single cell and a combination of two or more cells. "Treating" or "treatment" as used herein covers the treatment of the disease or 5 condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes, for example: preventing or delaying the onset of the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; inhibiting the disease or condition, i.e., arresting its development; relieving the disease or condition, i.e., causing regression of 10 the disease or condition; and / or stabilizing the disease or condition. Treatment includes ameliorating or lessening the severity of symptoms of the disease or condition, and / or inhibition of further progression or worsening of those symptoms. For example, for PKD, treatment can include reduction in the size of cysts (as measured by ultrasound, for example) in kidney as well as other organs including liver, pancreas, spleen, testis and ovary, and / or 15 improvement in renal function or decreased renal injury, and / or slowing of renal injury progression. The improvement in renal function or decreased renal injury can be assessed by measuring a marker of renal function / injury. Such markers include, for example, serum BUN levels, serum creatinine levels, serum cystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels. Treatment can also include reduction in symptoms or other manifestations of 20 the disease including, but not limited to, pain, hypertension, headaches, urinary tract infections, hematuria, kidney stones, vascular abnormalities including intracranial aneurysm and subarachnoid hemorrhage, cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prolapse and aortic regurgitation and / or diverticulosis. An “effective amount” or a “therapeutically effective amount” of a compound or 25 composition described herein refers to an amount of the compound that is sufficient to achieve a specific effect or result, and / or treats the disease or condition and / or the symptoms therefore, for example, alleviating, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. 30 As discussed above, the invention is directed to a method of treating a patient suffering from polycystic kidney disease (PKD), such as ADPKD or ARPKD, comprising administering to said patient an effective amount of a non-activating PPAR-^ modulator. The invention specifically includes methods of treating a patient suffering from PKD comprising Page 4 of 161 4266.3004 WO administering to said patient an effective amount of a PPAR-^ inverse agonist. The invention additionally encompasses a method of treating a patient suffering from ADPKD comprising administering an effective amount of a PPAR-^ inverse agonist . Also included herein, is a method of treating a patient suffering from ARPKD comprising administering an effective 5 amount of a PPAR-^ inverse agonist. Also encompassed is a method of treating a ciliopathy or a polycystic disease in a patient in need thereof comprising administering to said patient an effective amount of a non-activating (non-agonist) modulator of PPAR-^ or an inverse agonist of PPAR-^. Non-limiting examples of PPAR-^ inverse agonists are compounds of Formula (I) and compounds of Formula (II). 10 Peroxisome proliferator active receptors (PPARs) are members of the nuclear hormone receptor superfamily, and comprise several subtypes including PPAR-^, PPAR-^, and PPAR-^. The PPAR-^^subtype is also referred to in the literature and herein as PPARG as well as “PPAR^,” and is the target of the glitazone pharmaceutical agents (including, for example, pioglitazone and rosiglitazone) used in the treatment of type 2 diabetes. PPAR- 15 ^^also regulates osteoblast and osteoclast differentiation. PPAR-^^forms a transcription factor after heterodimerization with retinoid X receptor ^ (RXR^) and binds to peroxisome proliferator response elements (PPRE) on DNA to initiate transcription (Frkic et al. (2018), iScience 5, 69-79; the contents of which are expressly incorporated by reference herein). PPAR-^^is also known as NR1C3 (the gene ID), and PPARG1 and PPARG2 are the two 20 major isoforms of PPARG. Glitazones (also referred to as thiazolidinediones), such as pioglitazone and rosiglitazone, are PPAR-^^receptor agonists. Clinical use of the glitazones has been limited by side effects such as increased risk of bone fracture and bone loss (Stechschulte et al. (2016), PPARG post-translational modifications regulate bone formation and bone resorption, EBioMedicine 10: 174-184). 25 Non-activating PPAR-^^modulators can, for example, block kinase-mediated, such as cdk5-mediated, phosphorylation of PPARG, but are not agonists of the receptor itself. Inverse agonists and neutral antagonists are discussed, for example, in Shah 2011, Differences Between Antagonists and Inverse Agonists, Ro Chi Post Retro Edition 1(3): 16-19 (available at rhochistj.org / RhoChiPost / differences-between-antagonists-and-inverse-30 agonists / #:~:text=In%20conclusion%2C%20inverse%20agonism%20is,pathological%20state s%20of%20receptor%20hyperactivity); the contents of which are expressly incorporated by reference herein. An inverse agonist can bind to the same receptor as an agonist but typically has the opposite effect, for example, an inverse agonist can reduce the basal activity of the Page 5 of 161 4266.3004 WO receptor and may also reduce the effect of a ligand. An “inverse agonist of PPAR-^” is a compound or agent that binds to the same receptor as an agonist of PPAR-^ but reduces the basal activity of the receptor (e.g., at least partially represses basal transcriptional activity) and / or reduces the effect of a ligand. An inverse agonist can be identified using a functional 5 assay, for example, by demonstrating the absence of lipid formation in differentiated 3T3-L1 cells and downregulation of PPARG-driven pro-adipogenic genes, e.g., aP2 and cd36 (Zheng et al. (2018), Structure 26(11): P1431-1439). A neutral antagonist has zero or no activity in the absence of an agonist or inverse agonist but can block the activity of either. A “neutral antagonist of PPAR-^” can inhibit or block the activity of an agonist or inverse agonist but 10 has no activity in the absence of either. Non-activating PPAR-^^modulators exhibit no side effects or reduced side effects as compared with administration of full and partial agonists of PPAR-^. For example, pioglitazone is associated with bone mass reduction, increased risk of fracture, and weight gain (Viscoli et al. (2017), J Clin Endocrinol Metab.2017102(3): 914– 922; Kusnoki et al. (2011), Eur J Pharmacol.668(3): 486-91; the contents of each of which 15 are expressly incorporated by reference herein). In contrast, the inverse agonists, for example, compounds of Formula (I) and compounds of Formula (II), strengthen bone and tend to normalize body weight while maintaining insulin-sensitization and glucose-lowering properties in mouse models. In certain aspects, the PPAR-^^modulator used according to the methods described 20 herein is an inverse agonist of PPAR-^. In yet additional aspects, the PPAR-^^modulator used in the methods of the present invention is a neutral antagonist of PPAR-^. In certain embodiments, the non-activating PPAR-^ modulator, such as a PPAR-^ inverse agonist or neutral antagonist, used to treat PKD is also an agonist of PPAR-^; for example, a modest agonist of PPAR-^ in which the effective potency on PPAR-^ is less than that on PPAR-^. 25 Non-limiting examples of a non-activating PPAR-^ modulator that can be used in the methods described herein include T0070907 (2-Chloro-5-nitro-N-4-pyridinyl-benzamide; LeeLee et al. (2002), J. Biol. Chem.277, 19649-19657; Irwin et al. (2022), JBC 298(11): 102539), JTP-426467 (2-chloro-N-[4-(5-methyl-1,3-benzoxazol-2-yl)phenyl]-5- nitrobenzamide; Nishiu et al. (2006), Diabetes Obes. Metab.8: 58-516), BAY-4931 (CAS 30 No.423150-91-8; Orsi et al. (2022), J. Med. Chem.2022, 65, 21, 14843–1486), BAY-0069 (CAS No.420826-65-9; Id.), BAY-5516 (4-Chloro-N3-(4-(difluoromethoxy)-2- methylphenyl)-6-fluoro-N1-(4-fluorobenzyl)isophthalamide; Orsi et al. Bioorg. Med. Chem. 78: 117130), BAY-5094 (4-Chloro-N1-(3,4-difluorobenzyl)-6-fluoro-N3-(4-(2- Page 6 of 161 4266.3004 WO hydroxypropan-2-yl)-2-methylphenyl)isophthalamide; Id.), and BAY-9683 (Id.), as well as other compounds described in Orsi et al. Bioorg. Med. Chem.78: 117130; the contents of which are expressly incorporated by reference herein. Additional examples are FX-909 and FTX-6746 (Flare Therapeutics, Inc.) as well as compounds described in PCT Application 5 Publication No. WO2022187203 (such as Compounds 1-119 described therein), the contents of which are expressly incorporated by reference herein. Yet additional examples of non- activating PPAR-^ modulators that can be used as described herein are described in US20170121268A1 and US20200179534A1, for example. Exemplary PPAR-^^modulators have also been described in U.S. Pat. Nos.8,957,093, 9,309,227, 9,051,265, 10,016,394, 10 10,744,117, PCT Application Publication Nos. WO2013078233, WO2013078237, and WO2024151519; the contents of each of which are expressly incorporated by reference herein. In certain aspects, the PPAR-^^modulator used in the methods of the present invention can be a compound described in U.S. Pat. Nos.8,957,093, 9,309,227, 9,051,265, and 10,016,394, and PCT Application Publication Nos. WO2013078233, WO2013078237,15 and WO2024151519. The compounds described in these patent publications include non- agonist PPAR-^ modulators, inverse agonists of PPAR-^, and neutral antagonists of PPAR-^. In certain preferred aspects, the PPAR-^ modulator is a compound of Formula (I) (as described, for example, in U.S. Pat. No.10,744,117; the contents of which are expressly incorporated by reference herein): 20 wherein: R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C3-C9)cycloalkyl(C1-C6)alkyl; Y1or Y2are each independently C or N, provided that when Y1or Y2is N, R1or R2, respectively, is absent; 25 R1and R2are independently H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C1-C6)haloalkyl; or R1and R2together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SOq wherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C1- Page 7 of 161 4266.3004 WO C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, oxo, (C1- C6)haloalkyl, nitro, cyano-(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, methylenedioxy, R′O—(C0- C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, aryl, aroyl, or SO2NR′2; 5 R3is optionally mono- or multi-substituted (C1-C6)alkyl, (C1-C6)alkenyl, (C1- C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C1-C6)alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C1-C6)alkyl; wherein if present each substituent on R3is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6- 10 C10)aryl, (C3-C9)cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO2R′, methylenedioxy, OR′, N(R′)2, C(O)N(R′)2, (C1-C6)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl; and provided that group R3N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N1or Y1; 15 wherein each R′ is independently H, (C1-C6) alkyl, (C3-C9)cycloalkyl, (C3- C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q; wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl is optionally mono- or20 independently multi-substituted with (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, halo, oxo, aryl, or aroyl; each of X1-X5is independently N or CH, or is C substituted with an independently selected R4or is C substituted with Z, provided that no more than two of X1-X5are N, and provided that there is no more than one Z group bonded to the ring comprising X1-X5; 25 each R4is independently halo, nitro, (C1-C6)fluoroalkyl, R′—(C0-C6)alkyl, R′O2C— (C0-C6)alkyl, NC—(C0-C6)alkyl, R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)— (C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1- carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N- dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl,30 N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4- oxadiazol-5(4H)-on)-3-yl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, R′S(O)2NHC(O), R′C(O)NHS(O)2, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C1-C6)alkyl or (C3-C9)cycloalkyl-(C0-C6)alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′)2, C-bonded Page 8 of 161 4266.3004 WO tetrazolyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R4is —(C(R″)2)mCO2R′, —(C(R″)2)mCON(R′)2, — (C(R″)2)mCN, —O(C(R″)2)mCO2R′, —O(C(R″)2)mCON(R′)2, or —O(C(R″)2)mCN, wherein m is 1, 2, or 3; 5 R″ is H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C9)cycloalkyl, (C3-C9)cyclo alkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring; Z is a group of formula 10 wherein a wavy line indicates a point of bonding, each of Z1-Z5is independently N or is C substituted with an independently selected H or R4; provided that no more than two of Z1-Z5are N; Y is (C1-C2)alkyl, or sulfur; when Y is (C1-C2)alkyl, R5and R6are independently H or (C1-C4)alkyl or 15 independently each R5and R6together with the carbon atom to which they are bonded form a carbonyl, or, one R5group can further be bonded to X5to form a 4- to 8-membered ring; and, when Y is sulfur, R5and R6are both oxygen; or a pharmaceutically acceptable salt thereof. Compounds of formula (I) are described, for example, U.S. Pat. No.10,744,117, the 20 contents of which are expressly incorporated by reference herein. In various embodiments of practice of a method of the invention, for a compound of formula (I), Y1or Y2can each be C, providing an indole nucleus. R1and R2can be independently H or methyl. In other embodiments, Y1is N and Y2is C, providing a benzimidazole nucleus, or Y1is C and Y2is N, providing an indazole nucleus for the 25 compound of formula (I) used in a method of the invention. More specifically, R3of Formula (I) can be benzyl, α-phenethyl, α-phenpropyl, cycloalkyl or cycloalkylalkyl, any of which can be unsubstituted or substituted, as described herein. Or, R3can be heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which can be unsubstituted or substituted. For instance, R3can be any one of: Page 9 of 161 4266.3004 WO 5 Page 10 of 161 4266.3004 WO wherein a wavy line indicates a point of attachment. 5 In various embodiments for practice of a method of the invention, for a compound of formula (I), YR5R6can be SO2. In other embodiments, Y can be C1-alkyl; and R5and R6can be H, or Y can be C2-alkyl, and R5and R6be H. Further embodiments for practice of a method of the invention comprise the use of an effective dose of a compound of formula (I) wherein R4is —CO2H, —(CH2)mCO2H, —10 O(CH2)mCO2H, —CN, —(CH2)mCN, —O(CH2)mCN, —C(CH3)2CO2H, —C(CH3)2CN, — OC(CH3)2CO2H, —OC(CH3)2CN, —CH(CH3)CO2H, —CH(CH3)CN, —OCH(CH3)CO2H, —OCH(CH3)CN; —CH(CH2CH3)CO2H, —CH(CH2CH3)CN, —OCH(CH2CH3)CO2H, — OCH(CH2CH3)CN; —CH(i-Pr)CO2H, —CH(i-Pr)CN, —OCH(i-Pr)CO2H, —OCH(i-Pr)CN, wherein iPr indicates isopropyl; —CH(t-Bu)CO2H, —CH(t-Bu)CN, —OCH(t-Bu)CO2H, —15 OCH(t-Bu)CN, wherein t-Bu indicates t-butyl; or —(CHR″)mC(═O)N(R″)2, — O(CHR″)mC(═O)N(R″)2, Page 11 of 161 4266.3004 WO wherein a wavy line indicates a point of attachment. In various embodiments for practice of a method of the invention, for the compound 5 of formula (I), no Z group is present on the ring comprising X1-X5, providing a compound of formula (IA), which can be an N-benzyl-indole, an N-benzyl-benzimidazole, or an N-benzyl- indazole, or an analog thereof. More specifically, for practice of a method of the invention, the compound of formula (IA) can be any one of: 10 Page 12 of 161 4266.3004 WO 5 0 Page 13 of 161 4266.3004 WO 5 Page 14 of 161 4266.3004 WO 5 Page 15 of 161 4266.3004 WO 5 Page 16 of 161 4266.3004 WO 5 Page 17 of 161 4266.3004 WO 5 Page 18 of 161 4266.3004 WO 5 Page 19 of 161 4266.3004 WO 5 Page 20 of 161 4266.3004 WO 5 Page 21 of 161 4266.3004 WO 5 Page 22 of 161 4266.3004 WO 5 Page 23 of 161 4266.3004 WO 5 Page 24 of 161 4266.3004 WO 5 Page 25 of 161 4266.3004 WO 5 Page 26 of 161 4266.3004 WO 5 Page 27 of 161 4266.3004 WO 5 Page 28 of 161 4266.3004 WO 5 Page 29 of 161 4266.3004 WO 5 Page 30 of 161 4266.3004 WO 5 Page 31 of 161 4266.3004 WO 5 Page 32 of 161 4266.3004 WO 5 Page 33 of 161 4266.3004 WO 5 Page 34 of 161 4266.3004 WO 5 Page 35 of 161 4266.3004 WO 5 Page 36 of 161 4266.3004 WO 5 , or Page 37 of 161 4266.3004 WO IA-176, or a pharmaceutically acceptable salt of any of thereof. In other embodiments for practice of a method of the invention, for the compound of formula (I), Z can be present, providing a compound of formula (IB). A compound of 5 formula (IB) can be an N-biphenylmethyl-indole, an N-biphenylmethyl-benzimidazole, an N- biphenylmethyl-indazole, or an analog thereof. For instance, in various embodiments, Z1- Z5can all be carbon. In other embodiments, one of two of Z1-Z5can be nitrogen. More specifically, for practice of a method of the invention, the compound of formula (IB) can be any one of: 10 Page 38 of 161 4266.3004 WO 5 Page 39 of 161 4266.3004 WO O OH C F M H O S 5 O O Page 40 of 161 4266.3004 WO 5 Page 41 of 161 4266.3004 WO 5 Page 42 of 161 4266.3004 WO 5 Page 43 of 161 4266.3004 WO 5 Page 44 of 161 4266.3004 WO 5 Page 45 of 161 4266.3004 WO 5 Page 46 of 161 4266.3004 WO 5 - Page 47 of 161 4266.3004 WO 5 Page 48 of 161 4266.3004 WO 5 Page 49 of 161 4266.3004 WO 5 Page 50 of 161 4266.3004 WO 5 Page 51 of 161 4266.3004 WO 5 Page 52 of 161 4266.3004 WO 5 Page 53 of 161 4266.3004 WO 5 Page 54 of 161 4266.3004 WO 5 Page 55 of 161 4266.3004 WO 5 Page 56 of 161 4266.3004 WO 5 Page 57 of 161 4266.3004 WO 5 Page 58 of 161 4266.3004 WO 5 Page 59 of 161 4266.3004 WO 5 Page 60 of 161 4266.3004 WO 5 Page 61 of 161 4266.3004 WO 5 Page 62 of 161 4266.3004 WO 5 Page 63 of 161 4266.3004 WO 5 Page 64 of 161 4266.3004 WO 5 Page 65 of 161 4266.3004 WO 5 Page 66 of 161 4266.3004 WO 5 Page 67 of 161 4266.3004 WO 5 Page 68 of 161 4266.3004 WO 5 Page 69 of 161 4266.3004 WO 5 Page 70 of 161 4266.3004 WO IB-221 5 4266.3004 WO 5 Page 72 of 161 4266.3004 WO 5 Page 73 of 161 4266.3004 WO 5 Page 74 of 161 4266.3004 WO 5 Page 75 of 161 4266.3004 WO 5 Page 76 of 161 4266.3004 WO 5 Page 77 of 161 4266.3004 WO 5 Page 78 of 161 4266.3004 WO 5 Page 79 of 161 4266.3004 WO 5 Page 80 of 161 4266.3004 WO 5 Page 81 of 161 4266.3004 WO 5 Page 82 of 161 4266.3004 WO 5 Page 83 of 161 4266.3004 WO 5 Page 84 of 161 4266.3004 WO 5 Page 85 of 161 4266.3004 WO 5 Page 86 of 161 4266.3004 WO 5 Page 87 of 161 4266.3004 WO 5 Page 88 of 161 4266.3004 WO 5 Page 89 of 161 4266.3004 WO 5 Page 90 of 161 4266.3004 WO 5 Page 91 of 161 4266.3004 WO , or a pharmaceutically acceptable salt thereof. 5 In specific embodiments for practice of a method of the invention, the compound of can be any one of compounds 1A-1 to 1A-176 or IB-1 to IB-360 shown above, and as described in U.S. Pat. No.10,016,394, the contents of which are expressly incorporated by reference herein. The compound can also be a pharmaceutically acceptable salt of any of compounds 1A-1 to 1A-176 or IB-1 to IB-360. 10 In yet additional embodiments, the compound has the formula (I), including Formula (IA) and (IB), and is a partial agonist of PPAR-^. In additional aspects, the compound has the formula (I), including Formula (IA) and (IB), and is a neutral antagonist of PPAR-^^. In yet further embodiments, the compound has the formula (I), for example a compound of Formula (IA) or (IB), and is an inverse agonist of PPAR-^. 15 Specific PPARG modulators of Formula (I) that can be used according to the methods described herein include, for example, IA-48, IA-58, IA-176, IB-1 and IB-2: IA-35 Page 92 of 161 4266.3004 WO 5 Page 93 of 161 4266.3004 WO 5 Page 94 of 161 4266.3004 WO - . 5 In certain additional aspects, the PPAR-^ modulator is a compound of Formula (II) shown below. Compounds of Formula (II) are described, for example, in WO2024151519, the contents of which are expressly incorporated by reference herein. Specifically, compounds of Formula (II) have the chemical structure: 10 (II); or a pharmaceutically acceptable salt or prodrug thereof, wherein: A1’is substituted or unsubstituted carbocyclyl (e.g., C3-C9 carbocyclyl), substituted or unsubstituted heterocyclyl (e.g., 3-9 membered), substituted or unsubstituted aryl (e.g., C6- C10 aryl), or substituted or unsubstituted heteroaryl (e.g., 5-9 membered); 15 A2’is substituted or unsubstituted aryl (e.g., C6-C10 aryl) or substituted or unsubstituted heteroaryl (e.g., 5-9 membered); Page 95 of 161 4266.3004 WO each of L1’, L2’, and L3’is independently a bond or substituted or unsubstituted alkylene (e.g., a substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted C1-C3alkylene); Y’ is C or N; 5 each occurrence of R1’is independently halogen, substituted or unsubstituted alkyl (e.g., C1-C6alkyl), substituted or unsubstituted alkenyl (e.g., C2-C6alkenyl), substituted or unsubstituted alkynyl (e.g., C2-C6alkynyl), substituted or unsubstituted heteroalkyl (e.g., C1- C6 haloalkyl), substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl (e.g., C3-C9carbocyclyl), substituted10 or unsubstituted heterocyclyl (e.g., 3-9 membered), substituted or unsubstituted aryl (e.g., C6- C10 aryl), substituted or unsubstituted heteroaryl (e.g., 5-9 membered), –CN, –ORA, –SCN, – SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, – C(=O)N(RA)2, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, – 15 S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, –OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, – OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, –OS(=O)2SRA, – OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, – SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, –NRAC(=O)RA, –20 NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, – NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, – NRAS(=O)2SRA, –NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, – OSi(RA)3, –OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; 25 R2A’is absent, hydrogen, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), or a nitrogen protecting group, provided that when Y is N, R2Ais absent; R2B’is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted alkenyl (e.g., C2-C6 alkenyl), substituted or unsubstituted alkynyl (e.g., C2-C6alkynyl), substituted or unsubstituted heteroalkyl (e.g., C1-C6heteroalkyl), 30 substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl (e.g., C3-C6 carbocyclyl), substituted or unsubstituted heterocyclyl (e.g, 3- to 9-membered), substituted or unsubstituted aryl (e.g., C6-C10aryl), substituted or unsubstituted heteroaryl (e.g, 5- to 9-membered), –CN, –ORA, –SCN, –SRA, – SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – Page 96 of 161 4266.3004 WO C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, – S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, – OC(=NRA)ORA, –OC(=NRA)SRA, –OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, – 5 OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, –OS(=O)2SRA, – OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, – SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, – 10 NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, – NRAS(=O)2SRA, –NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, – OSi(RA)3, –OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each occurrence of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted alkenyl 15 (e.g., C2-C6 alkenyl), substituted or unsubstituted alkynyl (e.g., C2-C6 alkynyl), substituted or unsubstituted heteroalkyl (e.g., C1-C6heteroalkyl), substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl (e.g, C3- C6 carbocyclyl), substituted or unsubstituted heterocyclyl (e.g., 3- to 9-membered), substituted or unsubstituted aryl (e.g. C6-C10aryl), substituted or unsubstituted heteroaryl 20 (e.g, 5- to 9-membered), a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom(s) to form an substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 25 RB’is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted acyl, or a nitrogen protecting group; and p’ is 0, 1, 2, or 3. In certain aspects, the compound of Formula (II) has the Formula (IIA), Formula (IIB), Formula (IIC) or Formula (IID): 30 Page 97 of 161 4266.3004 WO or a pharmaceutically acceptable salt or prodrug thereof; 5 wherein: each occurrence of R3’is independently halogen, substituted or unsubstituted alkyl (e.g., C1-C6alkyl), substituted or unsubstituted alkenyl (e.g., C2-C6alkenyl), substituted or unsubstituted alkynyl (e.g., C2-C6 alkynyl), substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, 10 substituted or unsubstituted carbocyclyl (e.g, C3-C6carbocyclyl), substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl (e.g. C6-C10 aryl), substituted or unsubstituted heteroaryl (e.g., 5- to 9-membered), –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –15 S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, – OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, – OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, – OS(=O)2RA, –OS(=O)2ORA, –OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, – SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, – 20 SC(=NRA)SRA, –SC(=NRA)N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, – NRAC(=O)N(RA)2, –NRAC(=NRA)RA, –NRAC(=NRA)ORA, –NRAC(=NRA)SRA, – NRAC(=NRA)N(RA)2, –NRAS(=O)RA, –NRAS(=O)ORA, –NRAS(=O)SRA, – NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, –NRAS(=O)2SRA, – Page 98 of 161 4266.3004 WO NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, –OSi(RA)3, – OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; m' is 0, 1, 2, 3, 4, or 5; each occurrence of R4’is independently halogen, substituted or unsubstituted alkyl 5 (e.g., C1-C6 alkyl), substituted or unsubstituted alkenyl (e.g., C2-C6 alkenyl), substituted or unsubstituted alkynyl (e.g., C2-C6alkynyl), substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl (e.g., C3-C6 carbocyclyl), substituted or unsubstituted heterocyclyl (e.g., 3-9 membered), substituted or unsubstituted aryl (e.g., C6-C10aryl),10 substituted or unsubstituted heteroaryl (e.g., 5- to 9-membered), –CN, –ORA, –SCN, –SRA, – SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, –C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, – S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, –S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, –OC(=O)N(RA)2, –OC(=NRA)RA, – 15 OC(=NRA)ORA, –OC(=NRA)SRA, –OC(=NRA)N(RA)2, –OS(=O)RA, –OS(=O)ORA, – OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, –OS(=O)2SRA, – OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –SC(=O)N(RA)2, – SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – 20 NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, – NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, – NRAS(=O)2SRA, –NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, – OSi(RA)3, –OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; and n’ is 0, 1, 2, 3, 4, or 5. 25 More specifically, the compound of formula (II) that can be used in the methods described herein can be any one of the compounds in Table 1 below: Page 99 of 161 4266.3004 WO Table 1 Page 100 of 161 4266.3004 WO Page 101 of 161 4266.3004 WO Page 102 of 161 4266.3004 WO Page 103 of 161 4266.3004 WO Page 104 of 161 4266.3004 WO Page 105 of 161 4266.3004 WO Page 106 of 161 4266.3004 WO Page 107 of 161 4266.3004 WO Page 108 of 161 4266.3004 WO Page 109 of 161 4266.3004 WO Page 110 of 161 4266.3004 WO Page 111 of 161 4266.3004 WO In certain specific aspects, the PPARG modulators of Formula (II) that can be used according to the methods described herein can be selected from: Compound II-8, Compound II-65, Compound II-66, Compound II-67, Compound II-68, Compound II-69, Compound II- 5 72, Compound II-73, Compound II-74, Compound II-80, Compound II-97, Compound II-98, Compound II-99, and Compound II-100. In yet additional embodiments, the compound has the Formula (II), including compounds of Formula (IIA), (IIB), (IIC) and (IID) and is a partial agonist of PPAR-^. In yet further embodiments, the compound has the formula (II), for example, a compound of 10 Formula (IIA), (IIB), (IIC) and (IID), and is an inverse agonist of PPAR-^. The term “about” as used herein, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range. All percent compositions are given as weight-percentages, unless otherwise stated. 15 All average molecular weights of polymers are weight-average molecular weights, unless otherwise specified. As used herein, “individual” (as in the subject of the treatment) or “patient” means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and 20 goats. Non-mammals include, for example, fish and birds. “Acting on” PPAR-^, or “modulating” PPAR-^, can include binding to PPAR- ^^and / or inhibiting the bioactivity of PPAR-^^and / or allosterically regulating the bioactivity of PPAR-^^in vivo. When the term “modulator” is used herein, the term alludes to a compound of the invention, and it is understood that the terms “modulator” and “compound” or 25 “compound of the invention” are synonymous when the context indicates that a compound of the present invention is being referred to. Page 112 of 161 4266.3004 WO In various embodiments, the compounds used in the methods of the invention are not agonists of PPAR-^, i.e., binding of the compound to PPAR-^^does not activate the receptor, as discussed herein. In various embodiments, compounds of the invention bring about inhibition of cdk5-mediated phosphorylation of PPARG while being devoid of classical 5 agonism. Such compounds can also be referred to as “non-agonist PPARG modulatory compounds.” “Substantially” as the term is used herein means completely or almost completely; for example, a composition that is “substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the 10 composition is unaffected by the presence of the trace amount, or a compound is “substantially pure” is there are only negligible traces of impurities present. Phrases such as “under conditions suitable to provide” or “under conditions sufficient to yield” or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant concentrations, and the like, that are 15 within ordinary skill for an experimenter to vary, that provide a useful quantity or yield of a reaction product. It is not necessary that the desired reaction product be the only reaction product or that the starting materials be entirely consumed, provided the desired reaction product can be isolated or otherwise further used. By “chemically feasible” is meant a bonding arrangement or a compound where the 20 generally understood rules of organic structure are not violated; for example, a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, 25 for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein. An “analog” of a chemical structure, as the term is used herein, refers to a chemical structure that preserves substantial similarity with the parent structure, although it may not be readily derived synthetically from the parent structure. A related chemical structure that is 30 readily derived synthetically from a parent chemical structure is referred to as a “derivative.” When a substituent is specified to be an atom or atoms of specified identity, “or a bond”, a configuration is referred to when the substituent is “a bond” that the groups that are Page 113 of 161 4266.3004 WO immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration. All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the 5 present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. 10 As used herein, the terms “stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated herein. A “small molecule” refers to an organic compound, including an organometallic 15 compound, of a molecular weight less than about 2 kDa, that is not a polynucleotide, a polypeptide, a polysaccharide, or a synthetic polymer composed of a plurality of repeating units. As to any of the groups described herein, which contain one or more substituents, it is understood that such groups do not contain any substitution or substitution patterns which are 20 sterically impractical and / or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds. When a group, e.g., an “alkyl” group, is referred to without any limitation on the number of atoms in the group, it is understood that the claim is definite and limited with 25 respect the size of the alkyl group, both by definition; i.e., the size (the number of carbon atoms) possessed by a group such as an alkyl group is a finite number, less than the total number of carbon atoms in the universe and bounded by the understanding of the person of ordinary skill as to the size of the group as being reasonable for a molecular entity; and by functionality, i.e., the size of the group such as the alkyl group is bounded by the functional 30 properties the group bestows on a molecule containing the group such as solubility in aqueous or organic liquid media. Therefore, a claim reciting an “alkyl” or other chemical group or moiety is definite and bounded, as the number of atoms in the group cannot be infinite. Page 114 of 161 4266.3004 WO The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an “isotopically labeled form” of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is 5 indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium (1H), deuterium (2H), or tritium (3H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 11C, 12C, or 14C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13N, 14N, or 15N. A molecule 10 can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 15 14C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14N and 15N, 32S and 34S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the 20 molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic 25 forms are incorporated into precursors as required for use in any particular synthetic route. For example, 14C and 3H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14C and 3H are incorporated into precursor molecules, followed by further elaboration as needed. In general, “substituted” refers to an organic group as defined herein in which one or 30 more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, Page 115 of 161 4266.3004 WO sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents J that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, 5 I, OR′, OC(O)N(R′)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R′, O (oxo), S (thiono), methylenedioxy, ethylenedioxy, N(R′)2, SR′, SOR′, SO2R′, SO2N(R′)2, SO3R′, C(O)R′, C(O)C(O)R′, C(O)CH2C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)2, OC(O)N(R′)2, C(S)N(R′)2, (CH2)0-2N(R′)C(O)R′, (CH2)0-2N(R′)N(R′)2, N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)2, N(R′)SO2R′, N(R′)SO2N(R′)2, N(R′)C(O)OR′, 10 N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)2, N(R′)C(S)N(R′)2, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)2, C(O)N(OR′)R′, or C(═NOR′)R′ wherein R′ can be hydrogen or a carbon- based moiety, and wherein the carbon-based moiety can itself be further substituted; for example, wherein R′ can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, 15 heteroaryl, or heteroarylalkyl or R′ can be independently mono- or multi-substituted with J; or wherein two R′ groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi-substituted with J. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the 20 atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C═O, which can also be written as “CO”, “C(O)”, or “C(═O)”, wherein the C and the O are double bonded. When a carbon atom is substituted with a 25 double-bonded oxygen (═O) group, the oxygen substituent is termed an “oxo” group. When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(═NR) group is termed an “imino” group. When a divalent substituent such as S is double-bonded to a carbon atom, the results C(═S) group is termed a “thiocarbonyl” or “thiono” group. Alternatively, a divalent substituent such as O or S can be connected by two single 30 bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an “oxy” group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system. Page 116 of 161 4266.3004 WO Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR′2)n wherein n is 1, 2, 3, or more, and each R′ is independently selected. C(O) and S(O)2groups can also be bound to one or two heteroatoms, such as nitrogen or oxygen, rather than to a carbon atom. For example, when a C(O) group is bound to one 5 carbon and one nitrogen atom, the resulting group is called an “amide” or “carboxamide.” When a C(O) group is bound to two nitrogen atoms, the functional group is termed a “urea.” When a C(O) is bonded to one oxygen and one nitrogen atom, the resulting group is termed a “carbamate” or “urethane.” When a S(O)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a “sulfonamide.” When a S(O)2 group is bound to two 10 nitrogen atoms, the resulting unit is termed a “sulfamate.” Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, 15 imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles. Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, 20 heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein. By a “ring system” as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or 25 aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By “spirocyclic” is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art. As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically 30 impractical and / or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds. Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some Page 117 of 161 4266.3004 WO embodiments, from 1 to 8 carbon atoms or 1 to 6 carbon atoms. Non-limiting examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, 5 isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n- alkyl and isoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, 10 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, 15 but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, 20 amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments 25 the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N−1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, 30 or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. (Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above. Page 118 of 161 4266.3004 WO Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, — 5 CH═CH(CH3), —CH═C(CH3)2, —C(CH3)═CH2, —C(CH3)═CH(CH3), — C(CH2CH3)═CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to 10 cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, 15 provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined 20 above. Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to —C≡CH, —C≡C(CH3), — 25 C≡C(CH2CH3), —CH2C≡CH, —CH2C≡C(CH3), and —CH2C≡C(CH2CH3) among others. Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 30 about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above. Page 119 of 161 4266.3004 WO Aralkyl or arylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as 5 defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Heterocyclyl groups or the term ‘heterocyclyl’ includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a 10 heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members or 3 to 9 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four hetero atoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one 15 heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring 20 and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, 25 triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl 30 groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above. Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, Page 120 of 161 4266.3004 WO heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl 5 can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, 10 azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those 15 listed above. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, 20 isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,25 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-30 benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- Page 121 of 161 4266.3004 WO dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4- 5 indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2- benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8- benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7- benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-10 dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H- dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11- dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro- 5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H- dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. 15 Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl. 20 Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. The term “alkoxy” refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of 25 branched alkoxy include but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an 30 allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith. Page 122 of 161 4266.3004 WO The terms “halo” or “halogen” or “halide” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine. A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups wherein 5 all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like. A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxy groups 10 wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3- difluoropropoxy, perfluorobutoxy, and the like. The terms “aryloxy” and “arylalkoxy” refer to, respectively, an aryl group bonded to 15 an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. An “acyl” group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, 20 cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of 25 an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” 30 group. An example is a trifluoroacetyl group. The term “amine” includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R—NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as Page 123 of 161 4266.3004 WO dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein. 5 An “amino” group is a substituent of the form —NH2, —NHR, —NR2, —NR3+, wherein each R is independently selected, and protonated forms of each, except for —NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An “alkylamino” group includes a 10 monoalkylamino, dialkylamino, and trialkylamino group. An “ammonium” ion includes the unsubstituted ammonium ion NH4+, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein. 15 The term “amide” (or “amido”) includes C- and N-amide groups, i.e., —C(O)NR2, and —NRC(O)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (—C(O)NH2) and formamide groups (—NHC(O)H). A “carboxamido” group is a group of the formula C(O)NR2, wherein R can be H, alkyl, aryl, etc. 20 The term “urethane” (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups, i.e., —NRC(O)OR and —OC(O)NR2 groups, respectively. The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamide groups, i.e., —SO2NR2and —NRSO2R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (—SO2NH2). An organosulfur structure represented 25 by the formula —S(O)(NR)— is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms. The term “amidine” or “amidino” includes groups of the formula —C(NR)NR2. Typically, an amidino group is —C(NH)NH2. 30 The term “guanidine” or “guanidino” includes groups of the formula — NRC(NR)NR2. Typically, a guanidino group is —NHC(NH)NH2. A “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for Page 124 of 161 4266.3004 WO example sodium, potassium, and the like; with ammonium salts such as NH4+ or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for 5 human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A “zwitterion” is a salt within the meaning herein. The compounds of the present invention may 10 take the form of salts. The term “salts” embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically-acceptable salts.” The term “pharmaceutically-acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the 15 practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic 20 acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 25 benzenesulfonic, pantothenic, trifiuoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates. Suitable pharmaceutically acceptable base addition salts of compounds of the 30 invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples Page 125 of 161 4266.3004 WO of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. All of these salts may be prepared by 5 conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term “pharmaceutically acceptable salts” refers to nontoxic inorganic or organic acid and / or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein. 10 A “hydrate” is a compound that exists in a composition with water molecules. The composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a “hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein. 15 A “solvate” is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric. As the term is used herein a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein. 20 In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully 25 described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of 30 methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described. If a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl group or the number of substituents on a ring, is described as a range, e.g., 0-4, Page 126 of 161 4266.3004 WO what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or 4. In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and / or sub-combinations of the 5 above-listed embodiments. The present invention further embraces the use of isolated compounds of the invention. The expression “isolated compound” refers to a preparation of a compound of the invention, or a mixture of compounds the invention, wherein the isolated compound has been separated from the reagents used, and / or byproducts formed, in the synthesis of the 10 compound or compounds. “Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an “isolated compound” refers to a preparation of a compound of the invention or a mixture of compounds of the invention, which contains the named compound or mixture of compounds of the invention in an amount of at least 10 percent by 15 weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation. 20 The compounds described herein and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC. Within the present invention it is to be understood that a compound of the formula (I) 25 or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings 30 within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric Page 127 of 161 4266.3004 WO forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure. 5 Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like. Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. For example, the equilibrium: 10 is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer. It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or 15 diastereomeric forms or as racemic mixtures. The present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention. The isomers resulting from the presence of a chiral center comprise a pair of non- superimposable isomers that are called “enantiomers.” Single enantiomers of a pure 20 compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking 25 group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated as having an (R) absolute configuration, and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated as having an (S) absolute configuration. In the example in the Scheme below, the Cahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D is oriented away Page 128 of 161 4266.3004 WO from the viewer. The solid wedge indicates that the atom bonded thereby projects toward the viewer out of the plane of the paper, and a dashed wedge indicates that the atom bonded thereby projects away from the viewer out of the plan of the paper, i.e., the plane “of the paper” being defined by atoms A, C, and the chiral carbon atom for the (R) configuration 5 shown below. A carbon atom bearing the A-D atoms as shown above is known as a “chiral” carbon atom, and the position of such a carbon atom in a molecule is termed a “chiral center.” Compounds of the invention may contain more than one chiral center, and the configuration 10 at each chiral center is described in the same fashion. There are various conventions for depicting chiral structures using solid and dashed wedges. For example, for the (R) configuration shown above, the following two depictions are equivalent: 15 The present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization. “Isolated optical isomer” means a compound which has been substantially purified 20 from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight. Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of 25 the invention, or a chiral intermediate thereof, is separated into 99% wt. % pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Page 129 of 161 4266.3004 WO The methods can comprise administration of a pharmaceutical composition comprising a PPAR-^ modulator, such as an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The composition can comprise the compound or a PPAR-^ modulator, 5 such as an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^, alone or in combination with another medicament or active agent. Typical compositions include a PPAR-^ modulator, such as an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^, and a pharmaceutically acceptable excipient which can be a carrier or a diluent. The methods can comprise administration of a pharmaceutical composition 10 comprising a compound of Formula (I), (IA), (IB), or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The composition can comprise the compound of Formula (I) or Formula (II) alone or in combination with another medicament or active agent. Typical compositions include a compound of the Formula (I), (IA), (IB), or (II) and a pharmaceutically acceptable excipient which can be a carrier or a diluent. For 15 example, the compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the 20 active compound. The compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, 25 silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations can be mixed with auxiliary agents which do not 30 deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and / or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired. Page 130 of 161 4266.3004 WO The route of administration can be any route which effectively transports the compound of the invention to the appropriate or desired site of action. If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is 5 used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared 10 with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as 15 described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A 20 unit dosage form for injection can be in ampoules or in multi-dose containers. The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release. 25 Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and / or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as 30 silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). In yet additional aspects, the method comprises further administering an additional therapeutic agent to the patient such as tolvaptan, drugs used for the treatment of Page 131 of 161 4266.3004 WO hypertension including angiotensin-converting enzyme (ACE) inhibitors and angiotensin-2 receptor blockers. The patient can be suffering from or is diagnosed with PKD. In additional aspects, the patient is at risk of PKD. In certain aspects, the patient is an adult. In yet additional aspects, 5 the patient is a child. In yet further aspects, the patient is a male. In additional embodiments, the patient is a female. In certain aspects, the patient has or is diagnosed with PKD, and further suffers from obesity. A patient suffering from obesity has a body mass index 30.0 or higher, or a body mass index of 35 or more, or a body mass index of 40 or more. In certain aspects, the patient 10 suffers from type 2 diabetes. In further embodiments, the patient suffers from obesity and type 2 diabetes. In yet further aspects, the patient has or is diagnosed with PKD, and further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures. In further aspects, the invention is directed to a method of treating a ciliopathy as 15 described herein. Ciliopathies include, for example, conditions associated with mutations that result in abnormal cilial function or formation. Non-limiting examples of ciliopathies that can be treated include, but are not limited to, polycystic kidney disease (PKD), nephronophthisis, Badet-Biedl syndrome, Senior-Loken Syndrome, Joubert’s syndrome, Meckel’s syndrome, and Von Hippel–Lindau Disease (Hildebrandt et al. (2013), N Engl J Med 364(16): 1533- 20 1543; the contents of which are expressly incorporated by reference herein). In yet additional aspects, the invention is directed to treating a polycystic disease as described herein. Non-limiting examples of polycystic diseases include polycystic kidney disease (PKD), polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS) (see, for example, Abdul-Majeed et al., Obstet. 25 Gynecol. Int.2011, Epub 2011; the contents of which are expressly incorporated herein). The PPAR-^ modulators described herein can be effective over a wide dosage range. For example, in the treatment of adult humans, dosages of a compound of Formula (I), (IA), (IB), or (II)from about 0.05 to about 5000 mg, for example, from about 1 to about 2000 mg, or between about 2 and about 2000 mg per day can be used. A typical dosage can be about 10 30 mg to about 1000 mg per day. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which it is administered, the subject to be Page 132 of 161 4266.3004 WO treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Dosage forms (e.g., comprising the PPAR-^ modulator) can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be 5 administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Enumerated Embodiments Embodiment 1: A method of treating polycystic kidney disease (PKD) in a patient in 10 need thereof comprising administering to said patient an effective amount of a PPAR-^ modulator, wherein the PPAR-^ modulator is an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^. Embodiment 2: The method of Embodiment 1 wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD). 15 Embodiment 3: The method of Embodiment 1, wherein the PKD is autosomal recessive polycystic kidney disease (ARPKD). Embodiment 4: The method of any one of Embodiments 1 to 3, wherein the PPAR-^ modulator is an inverse agonist of PPAR-^. Embodiment 5: The method of any one of Embodiments 1 to 4, the PPAR-^ 20 modulator is also an agonist of PPAR-^^^ Embodiment 6: The method of any one of the preceding Embodiments, wherein the PPAR-^ modulator is a compound of Formula (I): wherein: 25 R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C3-C9)cycloalkyl(C1-C6)alkyl; Y1or Y2are each C; Page 133 of 161 4266.3004 WO R1and R2are independently H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C1-C6)haloalkyl; or R1and R2together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SOqwherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C1- 5 C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, oxo, (C1- C6)haloalkyl, nitro, cyano-(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, methylenedioxy, R′O—(C0- C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, aryl, aroyl, or SO2NR′2; R3is optionally mono- or multi-substituted (C1-C6)alkyl, (C1-C6)alkenyl, (C1- 10 C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C1-C6)alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C1-C6)alkyl; wherein if present each substituent on R3is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6- C10)aryl, (C3-C9)cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered 15 mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO2R′, methylenedioxy, OR′, N(R′)2, C(O)N(R′)2, (C1-C6)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl; and provided that group R3N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N1or Y1; wherein each R′ is independently H, (C1-C6) alkyl, (C3-C9)cycloalkyl, (C3- 20 C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q; wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl of R′ is optionally mono- or independently multi-substituted with (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- 25 C6)haloalkoxy, halo, oxo, aryl, or aroyl; each of X1-X5is independently N or CH, or is C substituted with an independently selected R4or is C substituted with Z, provided that no more than two of X1-X5are N, and provided that there is no more than one Z group bonded to the ring comprising X1-X5; each R4is independently halo, nitro, (C1-C6)fluoroalkyl, R′—(C0-C6)alkyl, R′O2C—30 (C0-C6)alkyl, NC—(C0-C6)alkyl), R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)— (C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1- carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N- dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4- Page 134 of 161 4266.3004 WO oxadiazol-5(4H)-on)-3-yl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, R'S(O)2NHC(O), R′C(O)NHS(O)2, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C1-C6)alkyl or (C3-C9)cycloalkyl-(C0-C6)alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′)2, C-bonded 5 tetrazolyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R4is —(C(R″)2)mCO2R′, —(C(R″)2)mCON(R′)2, — (C(R″)2)mCN, —O(C(R″)2)mCO2R′, —O(C(R″)2)mCON(R′)2, or —O(C(R″)2)mCN, wherein m is 1, 2, or 3; R″ is H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C9)cycloalkyl, (C3- 10 C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring; Z is a group of formula , wherein a wavy line indicates a point of bonding, each of Z1-Z5is independently N or is C15 substituted with an independently selected H or R4; provided that no more than two of Z1- Z5are N; Y is (C1-C2)alkyl, or sulfur; when Y is (C1-C2)alkyl, R5and R6are independently H or (C1-C4)alkyl or independently each R5and R6together with the carbon atom to which they are bonded form a carbonyl, or, one R5group can further be bonded to X5to form a 4- to 8- 20 membered ring; and, when Y is sulfur, R1and R6are both oxygen; or a pharmaceutically acceptable salt thereof. Embodiment 7: The method of Embodiment 6, wherein the compound of formula (I) is a compound of formula (IA), wherein the compound of formula (IA) is the compound of 25 formula (I) wherein no Z group is present on the ring comprising X1-X5, or a pharmaceutically acceptable salt thereof. Embodiment 8: The method of Embodiment 7, wherein the compound is selected from IA-1 to IA-176, or is a pharmaceutically acceptable salt thereof. Embodiment 9: The method of Embodiment 6, wherein the compound of formula (I) 30 is a compound of formula (IB), wherein the compound of formula (IB) is a compound of Page 135 of 161 4266.3004 WO formula (I) wherein a Z group is present on the ring comprising X1-X5or a pharmaceutically acceptable salt thereof. Embodiment 10: The method of Embodiment 9, wherein the compound is selected from IB-1 to IB-360, or is a pharmaceutically acceptable salt thereof. 5 Embodiment 11: The method of Embodiment 6, wherein the compound is selected from Compounds IA-35, IA-36, IA-37, IA-38, IA-41, IA-45, IA-46, IA-47, IA-48, IA-58, IA- 59, IA-64, IA-65, IA-176, IB-1, IB-2, IB-73 and IB-74, or a pharmaceutically acceptable salt of any of thereof. Embodiment 12: The method of Embodiment 11, wherein the PPAR-^ modulator is 10 IA-35, or a pharmaceutically acceptable salt thereof. Embodiment 13: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-36, or a pharmaceutically acceptable salt thereof. Embodiment 14: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-37, or a pharmaceutically acceptable salt thereof. 15 Embodiment 15: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-38, or a pharmaceutically acceptable salt thereof. Embodiment 16: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-41, or a pharmaceutically acceptable salt thereof. Embodiment 17: The method of Embodiment 11, wherein the PPAR-^ modulator is 20 IA-45, or a pharmaceutically acceptable salt thereof. Embodiment 18: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-46, or a pharmaceutically acceptable salt thereof. Embodiment 19: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-47, or a pharmaceutically acceptable salt thereof. 25 Embodiment 20: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-48, or a pharmaceutically acceptable salt thereof. Embodiment 21: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-58, or a pharmaceutically acceptable salt thereof. Embodiment 22: The method of Embodiment 11, wherein the PPAR-^ modulator is 30 IA-59, or a pharmaceutically acceptable salt thereof. Embodiment 23: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-64, or a pharmaceutically acceptable salt thereof. Page 136 of 161 4266.3004 WO Embodiment 24: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-65, or a pharmaceutically acceptable salt thereof. Embodiment 25: The method of Embodiment 11, wherein the PPAR-^ modulator is IA-176, or a pharmaceutically acceptable salt thereof. 5 Embodiment 26: The method of Embodiment 11, wherein the PPAR-^ modulator is IB-1, or a pharmaceutically acceptable salt thereof. Embodiment 27: The method of Embodiment 11, wherein the PPAR-^ modulator is IB-2, or a pharmaceutically acceptable salt thereof. Embodiment 28: The method of Embodiment 11, wherein the PPAR-^ modulator is 10 IB-74, or a pharmaceutically acceptable salt thereof. Embodiment 29: The method of any one of the Embodiments 1 to 5, wherein the PPAR-^ modulator is a compound of Formula (II):  (II); 15 or a pharmaceutically acceptable salt or prodrug thereof, wherein: A1’is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; A2’is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each of L1’, L2’, and L3’is independently a bond or substituted or unsubstituted 20 alkylene; Y’ is C or N; each occurrence of R1’is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or 25 unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –CN, –ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, – C(=O)ORA, –C(=O)SRA, –C(=O)N(RA)2, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, – C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, – Page 137 of 161 4266.3004 WO S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, – OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, –OC(=NRA)N(RA)2, – OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, – OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, – 5 SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, – NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, – NRAS(=O)2SRA, –NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, – 10 OSi(RA)3, –OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; R2A’is absent, hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group, provided that when Y is N, R2Ais absent; R2B’is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted 15 heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –CN, – ORA, –SCN, –SRA, –SSRA, –N3, –NO, –N(RA)2, –NO2, –C(=O)RA, –C(=O)ORA, – C(=O)SRA, –C(=O)N(RA)2, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)SRA, – 20 C(=NRA)N(RA)2, –S(=O)RA, –S(=O)ORA, –S(=O)SRA, –S(=O)N(RA)2, –S(=O)2RA, – S(=O)2ORA, –S(=O)2SRA, –S(=O)2N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)SRA, – OC(=O)N(RA)2, –OC(=NRA)RA, –OC(=NRA)ORA, –OC(=NRA)SRA, –OC(=NRA)N(RA)2, – OS(=O)RA, –OS(=O)ORA, –OS(=O)SRA, –OS(=O)N(RA)2, –OS(=O)2RA, –OS(=O)2ORA, – OS(=O)2SRA, –OS(=O)2N(RA)2, –ON(RA)2, –SC(=O)RA, –SC(=O)ORA, –SC(=O)SRA, –25 SC(=O)N(RA)2, –SC(=NRA)RA, –SC(=NRA)ORA, –SC(=NRA)SRA, –SC(=NRA)N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)SRA, –NRAC(=O)N(RA)2, –NRAC(=NRA)RA, – NRAC(=NRA)ORA, –NRAC(=NRA)SRA, –NRAC(=NRA)N(RA)2, –NRAS(=O)RA, – NRAS(=O)ORA, –NRAS(=O)SRA, –NRAS(=O)N(RA)2, –NRAS(=O)2RA, –NRAS(=O)2ORA, – NRAS(=O)2SRA, –NRAS(=O)2N(RA)2, –Si(RA)3, –Si(RA)2ORA, –Si(RA)(ORA)2, –Si(ORA)3, – 30 OSi(RA)3, –OSi(RA)2ORA, –OSi(RA)(ORA)2, –OSi(ORA)3, or –B(ORA)2; each occurrence of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted Page 138 of 161 4266.3004 WO carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together 5 with their intervening atom(s) to form an substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; RB’is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; and p’ is 0, 1, 2, or 3. 10 Embodiment 30: The method of Embodiment 29, wherein the compound has the Formula (IIA), Formula (IIB), Formula (IIC) or Formula (IID), or a pharmaceutically acceptable salt thereof. Embodiment 31: The method of any one of Embodiments 28 and 29, wherein the compound is selected from those shown in Table 1. 15 Embodiment 31A: The method of Embodiment 31, wherein the compound is selected from the group consisting of Compound II-8, Compound II-65, Compound II-66, Compound II-67, Compound II-68, Compound II-69, Compound II-72, Compound II-73, Compound II- 74, Compound II-80, Compound II-97, Compound II-98, Compound II-99, and Compound II-100, or a pharmaceutically acceptable salt thereof. 20 Embodiment 31B: The method Embodiment 31A, wherein the compound is Compound II-8, or a pharmaceutically acceptable salt thereof. Embodiment 31C: The method Embodiment 31A, wherein the compound is Compound II-65, or a pharmaceutically acceptable salt thereof. Embodiment 31D: Embodiment 31A: The method Embodiment 31A, wherein the 25 compound is Compound II-66, or a pharmaceutically acceptable salt thereof. Embodiment 31E: The method Embodiment 31A, wherein the compound is Compound II-67, or a pharmaceutically acceptable salt thereof. Embodiment 31F: The method Embodiment 31A, wherein the compound is Compound II-68, or a pharmaceutically acceptable salt thereof. 30 Embodiment 31G: The method Embodiment 31A, wherein the compound is Compound II-69, or a pharmaceutically acceptable salt thereof. Embodiment 31H: The method Embodiment 31A, wherein the compound is Compound II-72, or a pharmaceutically acceptable salt thereof. Page 139 of 161 4266.3004 WO Embodiment 31I: The method Embodiment 31A, wherein the compound is Compound II-73, or a pharmaceutically acceptable salt thereof. Embodiment 31J: The method Embodiment 31A, wherein the compound is Compound II-74, or a pharmaceutically acceptable salt thereof. 5 Embodiment 31K: The method Embodiment 31A, wherein the compound is Compound II-80, or a pharmaceutically acceptable salt thereof. Embodiment 31L: The method Embodiment 31A, wherein the compound is Compound II-97, or a pharmaceutically acceptable salt thereof. Embodiment 31M: The method Embodiment 31A, wherein the compound is 10 Compound II-98, or a pharmaceutically acceptable salt thereof. Embodiment 31N: The method Embodiment 31A, wherein the compound is Compound II-99, or a pharmaceutically acceptable salt thereof. Embodiment 31O: The method Embodiment 31A, wherein the compound is Compound II-100, or a pharmaceutically acceptable salt thereof. 15 Embodiment 32: The method of any one of Embodiments 28 to 31 and 31A to 31O, wherein the size of one or more kidney cysts as measured by ultrasound is reduced by at least 10% within three months of initiating treatment. Embodiment 33: The method of any one of Embodiments 28 to 31 and 31A to 31O, wherein the treatment results in a reduction in the severity and / or frequency of pain, 20 hypertension, headaches, urinary tract infections, hematuria, kidney stones, aneurysms, and / or diverticulosis. Embodiment 34: The method of any one of Embodiments 28 to 31 and 31A to 31O, wherein the treatment improves at least one marker of renal injury. Embodiment 35: The method of Embodiment 34, wherein the marker is selected from 25 the group consisting of serum BUN levels, serum creatinine levels, serum cystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels. Embodiment 36: The method of any one of Embodiments 28 to 31 and 31A to 31O, wherein the patient further suffers from obesity. Embodiment 37: The method of any one of Embodiments 28 to 31 and 31A to 31O, 30 wherein the patient further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures. Embodiment 38: A method of treating polycystic kidney disease (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a compound having Formula (I), or a pharmaceutically acceptable salt thereof. Page 140 of 161 4266.3004 WO Embodiment 39: The method of Embodiment 38, wherein the compound has the Formula (IA), wherein the compound of formula (IA) is the compound of formula (I) wherein no Z group is present on the ring comprising X1-X5, or a pharmaceutically acceptable salt thereof. 5 Embodiment 40: The method of Embodiment 39, wherein the compound is selected from IA-1 to IA-176, or a pharmaceutically acceptable salt thereof. Embodiment 41: The method of Embodiment 38, wherein the compound has the formula (IB), wherein the compound of formula (IB) is compound of formula (I) wherein a Z group is present on the ring comprising X1-X5or a pharmaceutically acceptable salt thereof. 10 Embodiment 42: The method of Embodiment 41, wherein the compound is selected from IB-1 to IB-360, or a pharmaceutically acceptable salt thereof. Embodiment 43: The method of Embodiment 38, wherein the compound is selected from Compounds IA-35, IA-36, IA-37, IA-38, IA-41, IA-45, IA-46, IA-47, IA-48, IA-58, IA- 59, IA-64, IA-65, IA-176, IB-1, IB-2, IB-73 and IB-74, or a pharmaceutically acceptable salt 15 of any of thereof. Embodiment 44: The method of any one of Embodiments 38 to 43, wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD). Embodiment 45: The method of any one of Embodiments 38 to 43, wherein the PKD is autosomal recessive polycystic kidney disease (ARPKD). 20 Embodiment 46: The method of any one of Embodiments 38 to 43, wherein the size of one or more kidney cysts as measured by ultrasound is reduced by at least 10% within three months of initiating treatment. Embodiment 47: The method of any one of Embodiments 38 to 43, wherein the treatment results in a reduction in the severity and / or frequency of pain, hypertension, 25 headaches, urinary tract infections, hematuria, kidney stones, aneurysms, and / or diverticulosis. Embodiment 48: The method of any one of Embodiments 38 to 43, wherein the treatment improves at least one marker of renal injury. Embodiment 49: The method of any one of Embodiments 38 to 43, wherein the 30 marker is selected from the group consisting of serum BUN levels, serum creatinine levels, serum cystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels. Embodiment 50: The method of any one of Embodiments 38 to 43, wherein the patient further suffers from obesity. Page 141 of 161 4266.3004 WO Embodiment 51: The method of any one of Embodiments 38 to 43, wherein the patient further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures. Embodiment 52: The method of any one of Embodiments 38 to 43, wherein the 5 PPAR-^ modulator is IA-35, or a pharmaceutically acceptable salt thereof. Embodiment 53: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-36, or a pharmaceutically acceptable salt thereof. Embodiment 54: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-37, or a pharmaceutically acceptable salt thereof. 10 Embodiment 55: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-38, or a pharmaceutically acceptable salt thereof. Embodiment 56: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-41, or a pharmaceutically acceptable salt thereof. Embodiment 57: The method of any one of Embodiments 38 to 43, wherein the 15 PPAR-^ modulator is IA-45, or a pharmaceutically acceptable salt thereof. Embodiment 58: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-46, or a pharmaceutically acceptable salt thereof. Embodiment 59: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-47, or a pharmaceutically acceptable salt thereof. 20 Embodiment 60: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-48, or a pharmaceutically acceptable salt thereof. Embodiment 61: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-58, or a pharmaceutically acceptable salt thereof. Embodiment 62: The method of any one of Embodiments 38 to 43, wherein the 25 PPAR-^ modulator is IA-59, or a pharmaceutically acceptable salt thereof. Embodiment 63: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-64, or a pharmaceutically acceptable salt thereof. Embodiment 64: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-65, or a pharmaceutically acceptable salt thereof. 30 Embodiment 65: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IA-176, or a pharmaceutically acceptable salt thereof. Embodiment 66: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IB-1, or a pharmaceutically acceptable salt thereof. Page 142 of 161 4266.3004 WO Embodiment 67: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IB-2, or a pharmaceutically acceptable salt thereof. Embodiment 68: The method of any one of Embodiments 38 to 43, wherein the PPAR-^ modulator is IB-74, or a pharmaceutically acceptable salt thereof. 5 Embodiment 69: A method of treating polycystic kidney disease (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a compound having Formula (II), or a pharmaceutically acceptable salt thereof. Embodiment 70: The method of Embodiment 69, wherein the compound has the Formula (IIA), Formula (IIB), Formula (IIC) or Formula (IID), or a pharmaceutically 10 acceptable salt thereof. Embodiment 71: The method of any one of Embodiments 69 to 70, wherein the compound is selected from the compounds shown in Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 72: The method of any one of Embodiments 69 to 70, wherein the 15 compound is selected from the group consisting of Compound II-8, Compound II-65, Compound II-66, Compound II-67, Compound II-68, Compound II-69, Compound II-72, Compound II-73, Compound II-74, Compound II-80, Compound II-97, Compound II-98, Compound II-99, and Compound II-100. Embodiment 72A: The method Embodiment 72, wherein the compound is Compound 20 II-8, or a pharmaceutically acceptable salt thereof. Embodiment 72B: The method Embodiment 72, wherein the compound is Compound II-65, or a pharmaceutically acceptable salt thereof. Embodiment 72C: Embodiment 31A: The method Embodiment 72, wherein the compound is Compound II-66, or a pharmaceutically acceptable salt thereof. 25 Embodiment 72D: The method Embodiment 72, wherein the compound is Compound II-67, or a pharmaceutically acceptable salt thereof. Embodiment 72E: The method Embodiment 72, wherein the compound is Compound II-68, or a pharmaceutically acceptable salt thereof. Embodiment 72F: The method Embodiment 72, wherein the compound is Compound 30 II-69, or a pharmaceutically acceptable salt thereof. Embodiment 72G: The method Embodiment 72, wherein the compound is Compound II-72, or a pharmaceutically acceptable salt thereof. Page 143 of 161 4266.3004 WO Embodiment 72H: The method Embodiment 72, wherein the compound is Compound II-73, or a pharmaceutically acceptable salt thereof. Embodiment 72I: The method Embodiment 72, wherein the compound is Compound II-74, or a pharmaceutically acceptable salt thereof. 5 Embodiment 72J: The method Embodiment 72, wherein the compound is Compound II-80, or a pharmaceutically acceptable salt thereof. Embodiment 72K: The method Embodiment 72, wherein the compound is Compound II-97, or a pharmaceutically acceptable salt thereof. Embodiment 72L: The method Embodiment 72, wherein the compound is Compound 10 II-98, or a pharmaceutically acceptable salt thereof. Embodiment 72M: The method Embodiment 72, wherein the compound is Compound II-99, or a pharmaceutically acceptable salt thereof. Embodiment 72N: The method Embodiment 72, wherein the compound is Compound II-100, or a pharmaceutically acceptable salt thereof. 15 Embodiment 73: The method of any one of Embodiments 69 to 72 and 72A to 72N, wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD). Embodiment 74: The method of any one of Embodiments 69 to 72 and 72A to 72N, wherein the PKD is autosomal recessive polycystic kidney disease (ARPKD). Embodiment 75: The method of any one of Embodiments 69 to 72 and 72A to 72N, 20 wherein the size of one or more kidney cysts as measured by ultrasound is reduced by at least 10% within three months of initiating treatment. Embodiment 76: The method of any one of Embodiments 69 to 72 and 72A to 72N, wherein the treatment results in a reduction in the severity and / or frequency of pain, hypertension, headaches, urinary tract infections, hematuria, kidney stones, aneurysms, 25 and / or diverticulosis. Embodiment 77: The method of any one of Embodiments 69 to 72 and 72A to 72N, wherein the treatment improves at least one marker of renal injury. Embodiment 78: The method of Embodiment 77, wherein the marker is selected from the group consisting of serum BUN levels, serum creatinine levels, serum cystatin C levels, 30 proteinuria levels, NGAL levels, and Kim-1 levels. Embodiment 79: The method of any one of Embodiments 69 to 72 and 72A to 72N, wherein the patient further suffers from obesity. Page 144 of 161 4266.3004 WO Embodiment 80: The method of any one of Embodiments 69 to 72 and 72A to 72N and 72A to 72N, wherein the patient further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures. Embodiment 81: A method treating a ciliopathy or a polycystic disease in a patient in 5 need thereof comprising administering to said patient an effective amount of a PPAR-^ modulator wherein the PPAR-^ modulator is a non-activating (non-agonist) modulator of PPAR-^. Embodiment 82: The method of Embodiment 81, wherein the patient is suffering from a ciliopathy. 10 Embodiment 83: The method of Embodiment 81, wherein the ciliopathy is selected from the group consisting of polycystic kidney disease (PKD), nephronophthisis, Badet-Biedl syndrome, Senior-Loken Syndrome, Joubert’s syndrome, Meckel’s syndrome, and Von Hippel–Lindau Disease. Embodiment 84: The method of Embodiment 81, wherein the patient is suffering 15 from a polycystic disease. Embodiment 85: The method of Embodiment 84, wherein the polycystic disease is selected from the group consisting of polycystic kidney disease (PKD), polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS). Embodiment 86: The method of any one of Embodiments 81 to 85, wherein the 20 PPAR-^ modulator is an inverse agonist of PPAR-^. Embodiment 87: The method of any one of Embodiment 86, the PPAR-^ modulator is also an agonist of PPAR-^^^^ Embodiment 88: The method of any one of Embodiments 81 to 87, wherein the PPAR-^ modulator is a compound of Formula (I), or a pharmaceutically acceptable salt 25 thereof. Embodiment 89: The method of Embodiment 88, wherein the compound of formula (I) is a compound of formula (IA), wherein the compound of formula (IA) is the compound of formula (I) wherein no Z group is present on the ring comprising X1-X5, or a pharmaceutically acceptable salt thereof. 30 Embodiment 90: The method of Embodiment 89, wherein the compound is selected from IA-1 to IA-176, or is a pharmaceutically acceptable salt thereof. Embodiment 91: The method of Embodiment 88, wherein the compound of formula (I) is a compound of formula (IB), wherein the compound of formula (IB) is a compound of Page 145 of 161 4266.3004 WO formula (I) wherein a Z group is present on the ring comprising X1-X5or a pharmaceutically acceptable salt thereof. Embodiment 92: The method of Embodiment 91, wherein the compound is selected from IB-1 to IB-360, or is a pharmaceutically acceptable salt thereof. 5 Embodiment 93: The method of Embodiment 88, wherein the compound is selected from Compounds IA-35, IA-36, IA-37, IA-38, IA-41, IA-45, IA-46, IA-47, IA-48, IA-58, IA- 59, IA-64, IA-65, IA-176, IB-1, IB-2, IB-73 and IB-74, or a pharmaceutically acceptable salt of any of thereof. Embodiment 94: The method of any one of Embodiments 81 to 87, wherein the 10 PPAR-^ modulator is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Embodiment 95: The method of Embodiment 94, wherein the compound has the Formula (IIA), Formula (IIB), Formula (IIC) or Formula (IID), or a pharmaceutically acceptable salt thereof. 15 Embodiment 96: The method of any one of Embodiments 94 to 95, wherein the compound is selected from the compounds shown in Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 97: The method of any one of Embodiments 94 to 96, wherein the compound is selected from the group consisting of Compound II-8, Compound II-65, 20 Compound II-66, Compound II-67, Compound II-68, Compound II-69, Compound II-72, Compound II-73, Compound II-74, Compound II-80, Compound II-97, Compound II-98, Compound II-99, and Compound II-100. The invention is illustrated by the following examples which are not meant to be limiting in any way. 25 EXAMPLES Example 1: Effect of Compound A in a mouse model of ADPKD Compound A and pioglitazone were tested in an in vitro 3D cyst assay described in Kanhai et al. (2020), Sci Rep.2020 Feb 3;10(1):1672; the contents of which are expressly incorporated by reference herein. Briefly, mouse inner medullary collecting duct Pkd1− / −30 cells (mIMCD3-Pkd1− / −) were cultured in an extracellular matrix-based hydrogel in 384- well plates, and cyst swelling was induced by addition of forskolin, an inducer of cAMP production mediated via adenylyl cyclase. Cells were co-exposed to forskolin (2.5 μM) and Compound A or pioglitazone at increasing concentrations. Page 146 of 161 4266.3004 WO As shown in FIG.1A, Compound A inhibited FSK-induced cyst swelling in a dose- dependent manner. Interestingly, at the lowest concentrations tested, cyst area appeared to increase over that of FSK induction. Compound A completely reversed forskolin-stimulated cyst swelling. In contrast, FIG.1B shows that pioglitazone showed a maximum of only about 5 50% inhibition. Example 2: Effect of compounds on in vitro cyst growth of human ADPKD cells in 3D culture In this study, the effect of Compound A, Compound B, Compound C and pioglitazone 10 was tested on in vitro cyst growth of human ADPKD cells grown within a collagen matrix. Compound A is a compound of Formula (IA) that is an inverse agonist of PPAR-^. Compound B is a compound of Formula (IA) that is a neutral antagonist of PPAR-^. Compound C is a compound of Formula (II) that is an inverse agonist of PPAR-^. Briefly, human ADPKD kidneys were obtained at the time of nephrectomy from the 15 Surgery Department at the University of Kansas Hospital and hospitals that participate in the Tissue Donation Program of the PKD Foundation (Wallace et al. (2019), Methods Cell Biol. 153: 1-23). Surface cysts from ADPKD kidneys were collected, digested in collagenase, and the epithelial cells were grown as a primary culture. Human ADPKD primary cells were seeded within a type I collagen matrix (PureCol: Advanced Biomatrix) and treated with 20 DME / F12 media, containing hydrocortisone (HC), triiodothyronine (T3) and insulin, transferrin, selenium (ITS) supplement, 10 µM forskolin and 25 ng / ml EGF (epidermal growth factor) overnight. The next day, the forskolin (FSK) and EGF concentrations were reduced to either 5 µM and 5 mg / ml, respectively. After cyst initiation (~3 days), forskolin and EGF were removed, and the wells were treated with the experimental conditions (N=6 25 wells per condition). ADPKD cells were seeded within a hanging drop of Matrigel Matrix (reconstituted basement membrane). Matrigel (Corning #354234), is a basement membrane matrix. Cyst growth was monitored for ~5 to 8 days, and after distinct cysts were observed in the control groups, the gels were rinsed in PBS and fixed in 1% formalin in PBS. Images of 30 the cysts at different focal depths were captured using a digital camera attached to the side port of an inverted microscope with a 2x objective. Images at different depths were captured using analysis software Image Pro Premier (Media Cybernetics). Multiple images were Page 147 of 161 4266.3004 WO stitched together and total surface area and the number of all cysts (diameter > 50 um) within each well was determined. The data is shown in FIGs.2A-2H. The results show that Compounds A, B and C inhibit in vivo cyst growth of ADPKD cells stimulated with forskolin. In addition, Compounds A and C showed a dose dependent 5 inhibition of cyst growth and the number of cysts per well at concentrations between 3 to 10 µM, suggesting that these compounds may have therapeutic value in the treatment of ADPKD. In addition, Compounds A and C showed greater inhibition of cyst growth and of the number of cysts than pioglitazone. While this invention has been particularly shown and described with references to 10 preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and 15 patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety. Page 148 of 161

Claims

4266.3004 WO CLAIMS What is claimed is:

1. A method of treating polycystic kidney disease (PKD) in a patient in need thereof 5 comprising administering to said patient an effective amount of a PPAR-^ modulator, wherein the PPAR-^ modulator is an inverse agonist of PPAR-^ or a neutral antagonist of PPAR-^.

2. The method of claim 1, wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD). 10 3. The method of claim 1, wherein the PKD is autosomal recessive polycystic kidney disease (ARPKD).

4. The method of claim 1, wherein the PPAR-^ modulator is an inverse agonist of PPAR-^.

5. The method of any one of the preceding claims, wherein the PPAR-^ modulator is a 15 compound of Formula (I):wherein: R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C3-C9)cycloalkyl(C1-C6)alkyl; Y1or Y2are each C; 20 R1and R2are independently H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C1-C6)haloalkyl; or R1and R2together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SOq wherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, oxo, (C1-25 C6)haloalkyl, nitro, cyano-(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, methylenedioxy, R′O—(C0- C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, aryl, aroyl, or SO2NR′2; Page 149 of 1614266.3004 WO R3is optionally mono- or multi-substituted (C1-C6)alkyl, (C1-C6)alkenyl, (C1- C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C1-C6)alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C1-C6)alkyl; wherein if present each substituent on R3is independently 5 selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6- C10)aryl, (C3-C9)cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO2R′, methylenedioxy, OR′, N(R′)2, C(O)N(R′)2, (C1-C6)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl; and provided that group R3N(R)C(═O)— can be bonded to any one of the four carbon atoms 10 of the phenyl ring not bonded to N1or Y1; wherein each R′ is independently H, (C1-C6) alkyl, (C3-C9)cycloalkyl, (C3- C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q; 15 wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl of R′ is optionally mono- or independently multi-substituted with (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, halo, oxo, aryl, or aroyl; each of X1-X5is independently N or CH, or is C substituted with an independently selected R4or is C substituted with Z, provided that no more than two of X1-X5are N, and 20 provided that there is no more than one Z group bonded to the ring comprising X1-X5; each R4is independently halo, nitro, (C1-C6)fluoroalkyl, R′—(C0-C6)alkyl, R′O2C— (C0-C6)alkyl, NC—(C0-C6)alkyl), R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)— (C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1- carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N- 25 dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4- oxadiazol-5(4H)-on)-3-yl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, R'S(O)2NHC(O), R′C(O)NHS(O)2, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C1-C6)alkyl or (C3-C9)cycloalkyl-(C0-C6)alkyl, wherein any alkyl or cycloalkyl is 30 optionally mono- or independently multi-substituted with R′, OR′, N(R′)2, C-bonded tetrazolyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R4is —(C(R″)2)mCO2R′, —(C(R″)2)mCON(R′)2, — (C(R″)2)mCN, —O(C(R″)2)mCO2R′, —O(C(R″)2)mCON(R′)2, or —O(C(R″)2)mCN, wherein m is 1, 2, or 3; Page 150 of 1614266.3004 WO R″ is H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C9)cycloalkyl, (C3- C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring; Z is a group of formula 5, wherein a wavy line indicates a point of bonding, each of Z1-Z5is independently N or is C substituted with an independently selected H or R4; provided that no more than two of Z1- Z5are N; Y is (C1-C2)alkyl, or sulfur; when Y is (C1-C2)alkyl, R5and R6are independently H or 10 (C1-C4)alkyl or independently each R5and R6together with the carbon atom to which they are bonded form a carbonyl, or, one R5group can further be bonded to X5to form a 4- to 8- membered ring; and, when Y is sulfur, R1and R6are both oxygen; or a pharmaceutically acceptable salt thereof. 15 6. The method of claim 5, wherein the compound of formula (I) is a compound of formula (IA), wherein the compound of formula (IA) is the compound of formula (I) wherein no Z group is present on the ring comprising X1-X5, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the compound is selected from IA-1 to IA-176, or is a pharmaceutically acceptable salt thereof. 20 8. The method of claim 5, wherein the compound of formula (I) is a compound of formula (IB), wherein the compound of formula (IB) is a compound of formula (I) wherein a Z group is present on the ring comprising X1-X5or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the compound is selected from IB-1 to IB-360, or is a pharmaceutically acceptable salt thereof. 25 10. The method of claim 5, wherein the compound is selected from the following compounds or a pharmaceutically acceptable salt of any of thereof:IA-35 Page 151 of 1614266.3004 WO 5Page 152 of 1614266.3004 WO 5IB-1 Page 153 of 1614266.3004 WO.

11. The method of claim 1, wherein the size of one or more kidney cysts as measured by 5 ultrasound is reduced by at least 10% within three months of initiating treatment.

12. The method of claim 1, wherein the treatment results in a reduction in the severity and / or frequency of pain, hypertension, headaches, urinary tract infections, hematuria, kidney stones, aneurysms, and / or diverticulosis.

13. The method of claim 1, wherein the treatment improves at least one marker of renal 10 injury.

14. The method of claim 13, wherein the marker is selected from the group consisting of serum BUN levels, serum creatinine levels, serum cystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels.

15. The method of claim 1, wherein the patient further suffers from obesity. 15 16. The method of claim 1, wherein the patient further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures.

17. A method of treating polycystic kidney disease (PKD) in a patient in need thereof comprising administering to said patient an effective amount of a compound having Formula (I): Page 154 of 1614266.3004 WOwherein: R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C3-C9)cycloalkyl(C1-C6)alkyl; Y1or Y2are each C; 5 R1and R2are independently H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C1-C6)haloalkyl; or R1and R2together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SOqwherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, oxo, (C1-10 C6)haloalkyl, nitro, cyano-(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, methylenedioxy, R′O—(C0- C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, aryl, aroyl, or SO2NR′2; R3is optionally mono- or multi-substituted (C1-C6)alkyl, (C1-C6)alkenyl, (C1- C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (3-9 membered)heterocyclyl, (3-9 15 membered)heterocyclyl(C1-C6)alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C1-C6)alkyl; wherein if present each substituent on R3is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6- C10)aryl, (C3-C9)cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO2R′, 20 methylenedioxy, OR′, N(R′)2, C(O)N(R′)2, (C1-C6)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl; and provided that group R3N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N1or Y1; wherein each R′ is independently H, (C1-C6) alkyl, (C3-C9)cycloalkyl, (C3- C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or wherein two R′ 25 bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q; Page 155 of 1614266.3004 WO wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl of R′ is optionally mono- or independently multi-substituted with (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkoxy, halo, oxo, aryl, or aroyl; each of X1-X5is independently N or CH, or is C substituted with an independently 5 selected R4or is C substituted with Z, provided that no more than two of X1-X5are N, and provided that there is no more than one Z group bonded to the ring comprising X1-X5; each R4is independently halo, nitro, (C1-C6)fluoroalkyl, R′—(C0-C6)alkyl, R′O2C— (C0-C6)alkyl, NC—(C0-C6)alkyl), R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)— (C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1-10 carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N- dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4- oxadiazol-5(4H)-on)-3-yl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, R'S(O)2NHC(O), R′C(O)NHS(O)2, an unsubstituted or substituted aryl, an unsubstituted or substituted 15 heteroaryl, (C1-C6)alkyl or (C3-C9)cycloalkyl-(C0-C6)alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′)2, C-bonded tetrazolyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R4is —(C(R″)2)mCO2R′, —(C(R″)2)mCON(R′)2, — (C(R″)2)mCN, —O(C(R″)2)mCO2R′, —O(C(R″)2)mCON(R′)2, or —O(C(R″)2)mCN, wherein 20 m is 1, 2, or 3; R″ is H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C9)cycloalkyl, (C3- C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring; Z is a group of formula 25, wherein a wavy line indicates a point of bonding, each of Z1-Z5is independently N or is C substituted with an independently selected H or R4; provided that no more than two of Z1- Z5are N; Y is (C1-C2)alkyl, or sulfur; when Y is (C1-C2)alkyl, R5and R6are independently H or 30 (C1-C4)alkyl or independently each R5and R6together with the carbon atom to which they are Page 156 of 1614266.3004 WO bonded form a carbonyl, or, one R5group can further be bonded to X5to form a 4- to 8- membered ring; and, when Y is sulfur, R1and R6are both oxygen; or a pharmaceutically acceptable salt thereof. 5 18 The method of claim 17, wherein the compound has the Formula (IA), wherein the compound of formula (IA) is the compound of formula (I) wherein no Z group is present on the ring comprising X1-X5, or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the compound is selected from IA-1 to IA-176, or a pharmaceutically acceptable salt thereof. 10 20. The method of claim 17, wherein the compound has the formula (IB), wherein the compound of formula (IB) is compound of formula (I) wherein a Z group is present on the ring comprising X1-X5or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the compound is selected from IB-1 to IB-360, or a pharmaceutically acceptable salt thereof. 15 22. The method of claim 17, wherein the compound is selected from the following or a pharmaceutically acceptable salt of any of thereof: 20Page 157 of 1614266.3004 WO 5Page 158 of 1614266.3004 WO 5- . Page 159 of 1614266.3004 WO 23. The method of claim 17, wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD).

24. The method of claim 17, wherein the PKD is autosomal recessive polycystic kidney disease (ARPKD). 5 25. The method of claim 17, wherein the size of one or more kidney cysts as measured by ultrasound is reduced by at least 10% within three months of initiating treatment.

26. The method of claim 17, wherein the treatment results in a reduction in the severity and / or frequency of pain, hypertension, headaches, urinary tract infections, hematuria, kidney stones, aneurysms, and / or diverticulosis. 10 27. The method of claim 17, wherein the treatment improves at least one marker of renal injury.

28. The method of claim 17, wherein the marker is selected from the group consisting of serum BUN levels, serum creatinine levels, serum cystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels. 15 29. The method of claim 17, wherein the patient further suffers from obesity.

30. The method of claim 17, wherein the patient further suffers from osteoporosis, mineral bone disorder, and / or an increased risk of fragility fractures. Page 160 of 161

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