WO2019084476A1 - Fibroblast growth factor 23 antagonists and related compositions and methods - Google Patents

Abstract

This disclosure relates to small molecule inhibitors of Fibroblast growth factor 23 (FGF-23) and related compositions and methods of treatment.

Description

FIBROBLAST GROWTH FACTOR 23

ANTAGONISTS AND RELATED COMPOSITIONS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Serial No. 62/577,351 , filed October 26, 2017, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This disclosure relates to small molecule inhibitors of Fibroblast growth factor 23 (FGF-23) and related compositions and methods of treatment.

BACKGROUND

There has recently been substantial interest in fibroblast growth factors (FGFs), their biological activity, and their association with certain diseases. Fibroblast growth factor 23 (FGF-23), a 251-amino acid protein, is of particular interest. Currently available data appears to suggest that FGF-23 is either directly or indirectly involved in the regulation of phosphate homeostasis. Moreover, FGF-23 appears to be associated with certain renal phosphate wasting disorders leading to hypophosphatemia, which are among the more significant causes of defective mineralization of bone and growth plate development. For example, patients with autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder, carry one of several FGF-23 mutations that make the protein resistant to proteolytic cleavage. Additionally, other hereditary hypophosphatemic disorders, such as X- linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR) are also caused by elevated circulating FGF-23. Also, tumors that cause oncogenic osteomalacia (OOM) have been shown to overexpress FGF-23 mRNA, which is likely attributable to the elevated concentrations of FGF-23 in the blood that consequently causes renal phosphate wasting in this group of patients. In addition to phosphate wasting, elevations of FGF-23 suppress the renal production of 1 ,25 dihydroxy vitamin D3. High circulating levels of FGF-23 also lead to cardiovascular diseases and abnormalities of innate immune responses. FGF-23 is a potential target for reducing cardiovascular and infectious complications associated with elevated FGF-23 in chronic kidney diseases.

An FGF-23 specific human monoclonal antibody, KRN23, is being developed to block FGF-23 actions. Clinical trials have shown efficacy of KRN23 to raise serum phosphate and improve rickets in XLH. (Carpenter, T. O., et al. J. Clin. Invest. 2014; 124(4): 1587-97.) This antibody has a long half-life, and to avoid toxicity, a low affinity anti-FGF-23 antibody was selected for clinical development, because high affinity FGF-23 blocking antibodies had detrimental effects in pre-clinical studies. The partial efficacy and long duration of action limit the clinical utility of KRN23.

There is therefore a clear unmet need to develop drugs to treat disorders of FGF-23 excess.

SUMMARY

Provided herein are compounds that inhibit FGF-23. These compounds are useful for the treatment of renal phosphate wasting disorders, and are particularly useful for the treatment of chronic kidney disorder.

Accordingly, in one aspect, provided herein is a compound having the structure of Formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein:

ring W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine; X is OH, halogen, an optionally substituted alkyl, or an optionally substituted amine; Y is H, an optionally substituted alkyl, or halogen; and

R is an optionally substituted alkene, an optionally substituted aryl, or an optionally substituted alkyl.

In another aspect, the present disclosure provides a method for treating a disorder associated with Fibroblast growth factor-23 (FGF-23) excess in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof. In an additional aspect, the present disclosure provides a method for treating chronic kidney disease in a subject in need thereof, comprising administering to the selected subject an effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the A) molecular structure of Zinc13407541 (MD-3); B) dose-dependent inhibition by MD-3 of FGFR/a-KL-dependent Elk1-GAL luciferase activity in HEK-293 cells; C-D) MD-3 blocks FGF-23 effects on FGF-23-dependent Npt2a and Cyp24a1 expression in renal tubule cells; E-F) increases of serum phosphate and 1 ,25(OH)2D levels by

administration of MD-3 to wild-type mice. G) MD-3 blocks FGF-23 induced TNF-a expression in RAW 264.7 macrophages. Values (mean ± SD, n=3-5) with the different superscript.

Fig. 2 shows the retrosynthetic analysis of MD-3.

Fig. 3 shows a comparison of FGF-23 antagonist properties of 14 exemplary compounds. Values (mean ± SD, n=3-5) with the different superscript are significantly different at P<0.05.

Fig. 4 shows exemplary MD-3 analogues.

Fig. 5 shows MD-3 Pharmacokinetics in mice (n = 3) following IV administration of a single dose (1 mg/kg). Data represent mean ± SD.

Fig. 6 shows a comparison of FGF-23 antagonist properties of MD-3 along with some Exemplary MD-3 analogues. Values (mean ± SD, n=3-5) with the different superscript are significantly different at P<0.05.

Fig. 7 shows a comparison of FGF-23 antagonist properties of MD-3 along with new

Exemplary MD-3 analogues.

Fig. 8 shows the synthetic scheme that is the basis for the production of all aldehyde intermediates and oxime analogues of MD-3.

Fig. 9 shows aliphatic core aldehyde synthons for MD-3 and analogue preparation. Fig. 10 shows aromatic core aldehyde synthons for MD-3 analogue preparation. DETAILED DESCRIPTION

Fibroblast growth factor-23 (FGF-23) is a bone-derived phosphaturic and vitamin D (1 ,25D) regulating hormone. (Xiao, Z., et al. Sci. Signal. 2016;9(455):ra1 13.; Han, X., et al. FEBS Lett. 2016;590(1 ):53-67.; Quarles, L. D. Nat. Rev. Endocrinol. 2012;8(5):276-86.; Urakawa, I., et al. Nature. 2006;444(7120):770-4.) FGF-23 production by mature Obs/Ocys (Liu, S., et al. J. Biol. Chem. 2003;278(39):37419-26.; Quarles, L. D. J. Clin. Invest.

2003; 1 12(5):642-6..) in bone creates several FGF-23 endocrine networks, including: an FGF-23 vitamin D counter-regulatory loop, where 1 ,25D stimulates FGF-23 transcription in bone and FGF23 suppresses 1 ,25D production by the kidney through activation of FGFR3 and FGFR4 (Quarles, L. D. J. Clin. Invest. 2003; 1 12(5):642-6.; Quarles, L. D. J. Clin. Invest. 2008; 1 18(12):3820-8.); a calcium-FGF23 endocrine loop, involving calcium regulation of FGF-23 in bone and FGF-23 stimulation of distal tubule calcium reabsorption through FGFR1 (Andrukhova, O., et al. EMBO J. 2014;33(3):229-46. ; Han, X., et al. PLoS One. 2016; 1 1 (2):e0147845.); and a bone mineralization/kidney axis, where FGF-23 is regulated by extracellular matrix mineralization to coordinate renal phosphate handling (Quarles, L. D. Nat. Rev. Endocrinol. 2012. PubMed PMID: 22249518.).

Excess FGF-23 is the cause of hereditary hypophosphatemic disorders in humans and their mouse homologues (Han, X., et al. FEBS Lett. 2016;590(1 ):53-67; Liu, S., et al. J. Biol. Chem. 2003;278(39):37419-26; Martin, A., et al. Faseb. J. 201 1. doi: fj.10-177816 [pii].; Quarles, L. D. Am. J. Physiol. Endocrinol. Metab. 2003;285(1 ):E1-9. ; Mackenzie, N. C, et al. PLoS One. 2012;7(2):e32177.; Han, X., et al. J. Biol. Chem. 2015;290(16): 10447-59.; Liu, S., et al. Am. J. Physiol. Endocrinol. Metab. 2006;291 (1 ):E38-49.; Liu, S., et al. Am. J.

Physiol. Endocrinol. Metab. 2008;295(2):E254-61.; Wang, X., et al. PLoS Genetics.

2012;8(5):e1002708. ; Martin, A., et al. FASEB J. 201 1 ;25(8):2551-62.; Xiao, Z., et al. PLoS One. 2014;9(8):e104154.; Zhang, Q., et al. Bone Research. 2016;4: 1601 1.), including X- linked hypophosphatemic rickets (XLH)/Hyp mice, caused by inactivating mutations of Phex (Liu, S., et al. Am. J. Physiol. Endocrinol. Metab. 2006;291 (1 ):E38-49.; Liu, S., et al. Am. J. Physiol. Endocrinol. Metab. 2008;295(2):E254-61.; Feng, J. Q., et al. Nat. Genet.

2006;38(1 1 ): 1310-5.), autosomal recessive hypophosphatemic rickets 1 (ARHR1 ), caused by inactivating mutations of Dmp1 (Liu, S., et al. Am. J. Physiol. Endocrinol. Metab.

2008;295(2):E254-61.; Feng, et al.), ARHR2, caused by inactivating mutations in Enppl (Mackenzie, et al.; Liu, S., et al. Am. J. Physiol. Endocrinol. Metab. 2006;291 (1 ):E38-49.; Liu, S., et al. Am. J. Physiol. Endocrinol. Metab. 2008;295(2):E254-61 .; Wang, et al.; Martin, A., et al. FASEB J. 201 1 ;25(8):2551 -62.), and Raine Syndrome (RNS), caused by inactivation mutations in FAM20C (Whyte, M. P., et al. J. Bone Miner. Res. 2016. doi:

10.1002/jbmr.3034.; Oya, K., et al. Histochemistry and Cell Biology. 2016. doi:

10.1007/s00418-016-1490-z.). These distinct mutations impair bone mineralization and increase in FGF-23 gene transcription in Obs/Ocys through both common and distinct pathways. These rare acquired and hereditary disorders caused by primary increase in FGF-23 are the diseases for which an FGF-23 antagonist needs to be developed. An intriguing but less certain population for inhibiting FGF-23 is patients with secondary elevations of FGF-23 in the setting of chronic kidney disease. FGF-23 is elevated in chronic kidney disease (CKD) (Weber, T. J., et al. J. Bone Miner. Res. 2003; 18(7): 1227-34.), and suppresses 1 ,25D as an initial adaptive response to minimize phosphate absorption in CKD (Qharles, L. D. J. Clin. Invest. 2003; 1 12(5):642-6.; Quarles, L. D. Exp. Cell. Res.

2012;318(9): 1040-8.).

Chronic elevations of FGF-23 in CKD, however, are maladaptive and linked to increased morbidity and mortality (Gutierrez, O. M. , et al. N. Engl. J. Med. 2008;359(6):584- 92.), cardiovascular disease (Gutierrez, O. M., et al. N. Engl. J. Med. 2008;359(6):584-92; Gutierrez, O. M., et al. Circulation. 2009; 1 19(19):2545-52.; Isakova, T., et al. JAMA.

201 1 ;305(23):2432-9.; Hsu, H. J., et al. Am. J. Med. Sci. 2009;337(2): 1 16-22.; Jean, G., et al. Nephrol. Dial. Transplant. 2009;24(3):948-55.), and inflammation (Munoz Mendoza, J., et al. Clin. J. Am. Soc. Nephrol. 2012;7(7): 1 155-62.; Hanks, L. J., et al. PLoS One.

2015; 10(3):e0122885.). Preclinical studies in CKD models show that inhibiting FGF-23 with a blocking antibody increased mortality (Shalhoub, V., et al. J. Clin. Invest.

2012; 122(7):2543-53.). A critical barrier to treating disorders caused by FGF-23 excess is the absence of a safe and effective way to inhibit FGF-23 activation of FGFRs/a-Klotho signaling. Receptor tyrosine kinases inhibitors are non-specific, and block not only FGF-23, but also other FGF ligands, making them unsuitable for treatment of disorders of FGF-23 excess.

Compounds of the Invention

Provided herein are compounds that inhibit FGF-23. These compounds are useful for the treatment of renal phosphate wasting disorders, and are particularly useful for the treatment of chronic kidney disorder. Thus, in one aspect, provided herein is a compound having the structure of Formula

(I):

(I) or a pharmaceutically acceptable salt thereof, wherein:

ring W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine; X is OH, halogen, an optionally substituted alkyl, or an optionally substituted amine;

Y is H, an optionally substituted alkyl, or halogen; and

R is an optionally substituted alkene, an optionally substituted aryl, or an optionally substituted alkyl.

In some embodiments of Formula (I), X is OH, or halogen;

Y is H, or halogen; and

R is an alkyl, a heterocycle, an aromatic group, a heteroaromatic group, an alkene optionally substituted with a cycloalkyi, or an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyi, halogen, amide, amine, or haloalkyl.

In specific embodiments of Formula (I), X is OH;

Y is H; and

R is an alkene substituted with an unsubstituted phenyl ring or a phenyl ring substituted with methoxy, methyl, thiomethyl, difluoro or tert-butyl.

In an additional embodiment of Formula (I), X is OH;

Y is H; and

R is a heterocyclic group, or a phenyl group optionally substituted with thiomethyl, methoxy, amine or fluoro.

In a particular embodiment of Formula (I), X is OH;

Y is H; and R is an alkene substituted with a phenyl ring optionally substituted with alkyl, alkoxy, thioalkyi, halogen, amide, amine, or haloalkyl.

In certain embodiments of Formula (I), W is a 4-8 member cycloalkene ring, thiophene, phenyl, or pyridine;

X is OH;

Y is H; and

R is selected from the group consisting of a C Ce alkyl optionally substituted with cycloalkyl, aryl, or heterocycle;

an aryl or heterocycle, optionally, independently for each occurrence, substituted one, two, or three times with hydroxyl, Ci-Ce alkyl, CrCe alkoxy, CrCe thioalkyi, halogen, NH₂, N(H)Ci-C₆ alkyl, N(Ci-C₆ alkyl)₂, thiol, nitrile, -C(0)R', heterocycle, or cycloalkyl; or an alkene optionally substituted with a 4-8 membered cycloalkyl ring, a 4-8 membered cycloalkene ring, a heterocycle, phenyl, or benzyl, wherein the cycloalkyl, cycloalkene, heterocycle, phenyl, or benzyl group is optionally, independently for each occurrence, substituted one, two, or three times with hydroxyl, Ci-Ce alkyl, halogen, d-Ce alkoxy, NH₂, N(H)CrC₆ alkyl, N(Ci-C₆ alkyl)₂, CrC₆ thioalkyi, thiol, nitrile, C(0)R', trifluoromethyl, heterocycle, or cycloalkyl;

wherein R' is C C₆ alkyl, 0-C C₆ alkyl, NH₂, N(H)C C₆ alkyl, N(Ci-C₆ alkyl)₂, or H, wherein the Ci-Ce alkyl of R' is optionally substituted with OH or O-C1-3 alkyl.

In an additional embodiment, R is a Ci-Ce alkyl optionally substituted with phenyl; phenyl or benzodioxole, optionally, independently for each occurrence, substituted one or two times with CrCe alkyl, CrCe alkoxy, C Ce thioalkyi, NH₂, N(H)Ci-C6 alkyl, N(Ci- C₆ alkyl)₂, or -C(0)R'; or

an alkene optionally substituted with phenyl or benzyl, wherein the phenyl or benzyl group is optionally, independently for each occurrence, substituted one or two times with d- Ce alkyl, halogen, alkoxy, or trifluoromethyl;

wherein R' is Ci-C₆ alkyl, 0-Ci-C₆ alkyl, NH₂, N(H)Ci-C₆ alkyl, N(Ci-C₆ alkyl)₂, or H, wherein the CrCe alkyl of R' is optionally substituted with OH or O-C1-3 alkyl.

In certain embodiments of Formula (I), W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine;

X is OH;

Y is H; and

Ar is a five or six-mem bered aromatic or five or six-membered heteroaromatic ring;

Ri is a CrCe alkyl, hydrogen, halogen, hydroxy, C Ce alkoxy, NH2, N(H)Ci-C6 alkyl, N(Ci-C6 alkyl)2, CrCe thioalkyl, thiol, nitrile, ketone, aldehyde, heterocycle, or cycloalkyl;

W is a Ci-Ce alkyl, hydrogen, halogen , hydroxy, Ci-Ce alkoxy, ketone, aldehyde, NH2, N(H)Ci-C₆ alkyl, N(C C₆ alkyl)₂, or nitrile;

R₂ is H, Ci-C₆ alkyl, aryl, halogen, hydroxy, Ci-C₆ alkoxy, NH₂, N(H)C C₆ alkyl, N(d- Ce alkyl)2, heterocycle, ketone, aldehyde, or nitrile.

In certain particular embodiments, Ar is phenyl, pyridine, furan, or thiophene.

In certain embodiments of Formula (I), W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine;

X is OH ;

Y is H ; and

R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyl;

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl; or

a phenyl group optionally substituted with thiomethyl, methoxy, amine, or fluoro. In an embodiment, the compound of Formula (I) has the structure of Formula (I I):

(II)

or a pharmaceutically acceptable salt thereof, wherein:

X is OH, halogen, an optionally substituted alkyl, or an optionally substituted amine;

Y is H, an optionally substituted alkyl, or halogen; and

R is an optionally substituted alkene, an optionally substituted aryl, or an optionally substituted alkyl;

n is 0, 1 , 2, 3, or 4.

In some embodiments of Formula (II), X is OH or halogen;

Y is H or halogen;

R is an alkyl, a heterocycle, an aromatic group, a heteroaromatic group, an alkene optionally substituted with a cycloalkyi, or an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyi, halogen, amide, amine, or haloalkyl; and

n is 1.

In certain embodiments of Formula (II), X is OH;

Y is H;

n is 1 or 2; and

R is selected from the group consisting of a C Ce alkyl optionally substituted with cycloalkyi, aryl, or heterocycle;

an aryl or heterocycle, optionally, independently for each occurrence, substituted one, two, or three times with hydroxyl, Ci-Ce alkyl, CrCe alkoxy, CrCe thioalkyi, halogen, NH₂, N(H)Ci-C₆ alkyl, N(C C₆ alkyl)₂, thiol, nitrile, -C(0)R', heterocycle, or cycloalkyi; or an alkene optionally substituted with a 4-8 membered cycloalkyi ring, a 4-8 membered cycloalkene ring, a heterocycle, phenyl, or benzyl, wherein the cycloalkyi, cycloalkene, heterocycle, phenyl, or benzyl group is optionally, independently for each occurrence, substituted one, two, or three times with hydroxyl, Ci-Ce alkyl, halogen, C Ce alkoxy, NH₂, N(H)CrC₆ alkyl, N(Ci-C₆ alkyl)₂, CrC₆ thioalkyi, thiol, nitrile, C(0)R', trifluoromethyl, heterocycle, or cycloalkyi;

wherein R' is Ci-C₆ alkyl, 0-Ci-C₆ alkyl, NH₂, N(H)Ci-C₆ alkyl, N(Ci-C₆ alkyl)₂, or H, wherein the Ci-Ce alkyl of R' is optionally substituted with OH or O-C1-3 alkyl.

In an additional embodiment, R is a Ci-Ce alkyl optionally substituted with phenyl; phenyl or benzodioxole, optionally, independently for each occurrence, substituted one or two times with CrCe alkyl, CrCe alkoxy, C Ce thioalkyi, NH₂, N(H)Ci-C6 alkyl, N(Ci- C₆ alkyl)₂, or -C(0)R'; or an alkene optionally substituted with phenyl or benzyl, wherein the phenyl or benzyl group is optionally, independently for each occurrence, substituted one or two times with Ci- Ce alkyl, halogen, alkoxy, or trifluoromethyl;

wherein R' is Ci-C₆ alkyl, 0-Ci-C₆ alkyl, NH₂, N(H)Ci-C₆ alkyl, N(CrC₆ alkyl)₂, or H, wherein the d-Ce alkyl of R' is optionally substituted with OH or O-C1-3 alkyl.

In certain embodiments of Formula (II), X is OH;

Y is H;

R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyi; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl; and

n is 0, 1 , 2, 3, or 4.

In certain embodiments, the compound of Formula (I) is selected from the following compo

or a pharmaceutically acceptable salt thereof, wherein:

X is OH, halogen, an optionally substituted alkyl, or an optionally substituted amine;

Y is H, an optionally substituted alkyl, or halogen; and

R is an optionally substituted alkene, an optionally substituted aryl, or an optionally substituted alkyl.

In some embodiments of these compounds, X is OH or halogen;

Y is H or halogen;

R is an alkyl, a heterocycle, an aromatic group, a heteroaromatic group, an alkene optionally substituted with a cycloalkyi, or an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl.

In some embodiments of these compounds, X is OH;

Y is H; and

R is an alkyl; a heterocycle; an aryl; a heteroaryl; an alkene optionally substituted with a cycloalkyi; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl.

In an additional embodiment, the compound of Formula (I) is selected from the following compounds:

or a pharmaceutically acceptable salt thereof, wherein:

X is OH, halogen, an optionally substituted alkyl, or an optionally substituted amine;

Y is H, an optionally substituted alkyl, or halogen; and

R is an optionally substituted alkene, an optionally substituted aryl, or an optionally substituted alkyl.

In some embodiments, X is OH or halogen;

Y is H or halogen;

R is an alkyl, a heterocycle, an aromatic group, a heteroaromatic group, an alkene optionally substituted with a cycloalkyi, or an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl.

In some embodiments of these compounds, X is OH;

Y is H; and

R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyi; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl.

In certain embodiments, R is selected from the group consisting of:

wherein:

Ar is an optionally substituted five or six-membered aromatic or five or six-membered heteroaromatic ring;

Ri is an alkyl, hydrogen, halogen, hydoxy, alkoxy, amine, thioalkyl, thiol, nitrile, ketone, aldehyde, heterocyde, or cycloalkyl;

W is an alkyl, hydrogen, halogen, hydoxy, alkoxy, ketone, aldehyde, amine, or nitrile;

F¾ is H, alkyl, aryl, halogen, hydoxy, alkoxy, amine, heterocyde, ketone, aldehyde, or nitrile.

In some particular embodiments of these R definitions, Ar is phenyl; and Ri is hydrogen, methoxy, thiomethyl, methyl, tert-butyl or amide.

In some additional embodiments, Ar is heteroaryl; Ri is hydrogen, methoxy, thiomethyl, methyl, tert-butyl or amide.

In an embodiment, the compound of Formula (I) is selected from the structure of Formula (I II):

or a pharmaceutically acceptable salt thereof, wherein: X is OH , halogen, alkyl, or amine;

Ri is OH, alkyl, halogen, alkoxy, amine, thioalkyi, thiol, nitrile, ketone, aldehyde, heterocycle, or cycloalkyl; and

n is 1 , or 2.

In certain embodiments, Ri is C1-6 alkyl, C1-6 thioalkyi, or C1-6 alkoxy.

In certain embodiments, Ri is methyl, thiomethyl, tert-butyl, or methoxy.

In certain embodiments, X is OH ; Ri is CrCe alkyl, halogen, CrCe alkoxy, NH2, N(H)Ci-C₆ alkyl, N(C C₆ alkyl)₂, d-C₆ thioalkyi, or thiol; and n is 1 or 2.

In an additional embodiment, the compound of Formula (I) is selected from the structure of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

X is OH , halogen, alkyl, or amine;

Ar is an optionally substituted phenyl, pyridine, furan, or thiophene; and

n is 1 , or 2.

In certain embodiments, Ar is a phenyl ring substituted with alkyl, alkoxy, thioalkyi, halogen, amide, amine, or haloalkyl.

In certain particular embodiments, Ar is a phenyl ring substituted with methyl, tert- butyl, thiomethyl, methoxy, fluoro, trifluoromethyl, difluoro, amide or amine.

In certain embodiments, X is OH ; Ar is a phenyl ring substituted with CrCe alkyl, Ci- C₆ alkoxy, Ci-C₆ thioalkyi, halogen, amide, NH₂, N(H)C C₆ alkyl, N(C C₆ alkyl)₂, haloalkyl, or thiol; and n is 1 or 2.

In another embodiment, the compound of Formula (I) is selected from the structure of Formula (V):

(V) or a pharmaceutically acceptable salt thereof, wherein:

X is OH, halogen, alkyl, or amine;

Ri is OH, methyl, methoxy, tert-butyl, thiomethyl, alkyl, halogen, alkoxy, amine, thioalkyl, thiol, nitrile, ketone, aldehyde, heterocycle, or cycloalkyl; and

n is 1 , or 2.

In certain embodiments, X is OH; Ri is methoxy, thiomethyl, NH2, N(H)Ci-C6 alkyl, N(Ci-C6 alkyl)2, or fluoro; and n is 1 or 2.

In any of the above mentioned embodiments, n can be 1.

In a particular embodiment, the compound of Formula (I) is selected from the compound, wherein:

X is OH, halogen, alkyl, or amine;

Y is H, alkyl, or halogen;

R is an alkene, aryl, alkyl, a substituted, or unsubstituted styrene group; and n is 1 or 2.

In any of the embodiments above, "optionally substituted" means that substituents can be substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, aldehyde, cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, thiol, alkylthio, arylthio, cyano, halogen (e.g., F, CI, Br, and I), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C- carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyi, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group, alkylaminoalkyi, dialkylaminoalkyi, di(alkyl)aminoalkyl, cyanato, alkylaminoalkylamino- alkylamino, arylaminoalkyl, aminoalkyloxy, aminoalkyloxyalkyl, aminoalkylcarboxy, aminoalkylaminocarbonyl, aminoalkylcarboxamido, guanidinoalkyloxy, hydroxyalkyi and protected derivatives thereof.

In any of the embodiments mentioned herein, each alkene group is independently or trans, or E or Z.

MD-3-A8 MD-3-A9 MD-3-A34 MD-3-A45 MD-3-A54 MD-3-A35

MD-3-A38 MD-3-A40 MD-3-A46 MD-3-A55 MD-3-A59 MD-3-A68

MD-3-A23 MD-3-A29 MD-3-A21 MD-3-A39 MD-3-A52

MD-3-A6 MD-3-A12 MD-3-A27 MD-3-A28 MD-3-A33

MD-3-A36 MD-3-A37 MD-3-A41 MD-3-A56 MD-3-A13

or pharmaceutically acceptable salts thereof.

Pharmaceutical compositions

In another aspect, the present disclosure provides a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The term "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds disclosed herein are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 % to 99.9% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

A compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) can be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. As used herein, "pharmaceutically acceptable carrier" can include any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with a compound of Formula (I), Formula (I I), Formula (III), Formula (IV), or Formula (V), such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Furthermore, the carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e.g. oral, nasal, rectal, vaginal, parenteral (including intravenous injections or infusions). In preparing compositions for oral dosage form any of the usual pharmaceutical media may be employed. Usual pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as for example, suspensions, solutions, emulsions and elixirs); aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations (such as for example, powders, capsules, and tablets).

Methods of Treatment

In another aspect, the present disclosure provides a method for treating a disorder associated with Fibroblast growth factor-23 (FGF-23) excess in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the disorder is selected from a phosphate wasting disorder, hereditary hypophosphatemic rickets, acquired hypophosphatemic rickets, Raine Syndrome (RNS) or chronic kidney disease (CKD).

In an embodiment, the disorder is a phosphate wasting disorder.

In a particular embodiment, the phosphate wasting disorder is hereditary hypophosphatemic disorder.

In another embodiment, the phosphate wasting disorder is acquired

hypophosphatemic disorder.

In certain embodiments, the disorder is selected from hereditary hypophosphatemic rickets, acquired hypophosphatemic rickets, or chronic kidney disease (CKD).

In an embodiment, the disorder is selected from X-linked hypophosphatemic rickets (XLH), autosomal recessive hypophosphatemic rickets (ARHR), or Raine Syndrome (RNS).

In an embodiment, the disorder is a renal phosphate wasting disorder.

In an embodiment of the method, the compound of any of Formula (I) to (IV) is used to inhibit FGF-23 activation of FGFRs/a-Klotho signaling.

In an embodiment of the method, the compound of any of Formula (I) to (IV) increases serum phosphate and 1 ,25D levels.

In an embodiment of the method, the subject is human.

In an embodiment of the method, the compound of any of Formula (I) to (IV) is used in combination with one or more existing treatment methods.

In an additional aspect, the present disclosure provides a method for treating chronic kidney disease in a subject in need thereof, comprising administering to the selected subject an effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating chronic kidney disease in a subject in need thereof, comprising administering to the selected subject an effective amount of the following compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the following compounds, or a pharmaceutically acceptable salt thereof:

MD-3-A8 MD-3-A9 MD-3-A34 MD-3-A45 MD-3-A54 MD-3-A35

MD-3-A23 MD-3-A29 MD-3-A21 MD-3-A39 MD-3-A52

Definitions

As used herein, the term "compound" is intended to mean a substance made up of molecules that further consist of atoms. A compound may be any natural or non-natural material, for example, peptide or polypeptide sequences, organic or inorganic molecules or compositions, nucleic acid molecules, carbohydrates, lipids or combinations thereof. A compound generally refers to a chemical entity, whether in the solid, liquid or gaseous phase, and whether in a crude mixture or purified and isolated. Compounds encompass the chemical compound itself as well as, where applicable: amorphous and crystalline forms of the compound, including polymorphic forms, said forms in mixture or in isolation; free acid and free base forms of the compound; isomers of the compound, including geometric isomers, optical isomers, and tautomeric isomers, said optical isomers to include enantiomers and diastereomers, chiral isomers and non-chiral isomers, said optical isomers to include isolated optical isomers or mixtures of optical isomers including racemic and non- racemic mixtures; said geometric isomers to include transoid and cisoid forms, where an isomer may be in isolated form or in admixture with one or more other isomers; isotopes of the compound, including deuterium- and tritium-containing compounds, and including compounds containing radioisotopes, including therapeutically- and diagnostically-effective radioisotopes; multimeric forms of the compound, including dimeric, trimeric, etc. forms; salts of the compound, including acid addition salts and base addition salts, including organic counterions and inorganic counterions, and including zwitterionic forms, where if a compound is associated with two or more counterions, the two or more counterions may be the same or different; and solvates of the compound, including hemisolvates, monosolvates, disolvates, etc. , including organic solvates and inorganic solvates, said inorganic solvates including hydrates; where if a compound is associated with two or more solvent molecules, the two or more solvent molecules may be the same or different.

As used herein, "alkyi" groups include saturated hydrocarbons having one or more carbon atoms, including straight-chain alkyi groups (e.g. , methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), cyclic alkyi groups (or "cycloalkyl" or "alicyclic" or "carbocyclic" groups) (e.g. , cyclopropyl, cyclopentyl, cyclohexyl, etc.), and branched-chain alkyi groups (isopropyl, tert- butyl, sec-butyl, isobutyl, etc.). In certain embodiments, a straight-chain or branched-chain alkyi group may have 8 or fewer carbon atoms in its backbone, e.g., d-Cs for straight-chain or C3-C8 for branched-chain. In certain embodiments, a straight-chain or branched-chain alkyi group may have 6 or fewer carbon atoms in its backbone, e.g., CrCe for straight-chain or C3-C6 for branched-chain. In still other embodiments, an alkyi group includes about 1 to 4 carbons. In other embodiments, an alkyi group includes about 1 to 3 carbons. In yet other embodiments, an alkyi group includes about 1 or 2 carbons. The term "lower alkyi" refers to alkyi groups having from 1 to 6 carbons in the chain, and to cycloalkyl groups having from 3 to 6 carbons in the ring structure. The term "d-Ce" as in "d-Ce alkyi" means alkyi groups containing 1 to 6 carbon atoms. The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous to alkyls, but which contain at least one double or triple carbon- carbon bond respectively.

The term "alkoxy" as used herein means an alkyi group having an oxygen atom attached thereto. In some embodiments, alkoxy groups include groups having 1 to about 8 carbon atoms. In other embodiments, alkoxy groups include groups having 1 to about 6 carbon atoms. In still other embodiments, alkoxy groups include groups having fewer than about 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. The alkoxy groups can be straight-chain or branched .

The term "amine" or "amino," as used herein, refers to a moiety of the

formula -NR^aR^b, in which R^a and R^b are each independently hydrogen , alkyi , or aryl. Thus, the term amino includes alkylamino (e.g., R^a is hydrogen and R^b is alkyi) and dialkylamino (e.g. , R^a is alkyi and R^b is alkyi). Alternatively, R^a and R^b, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring. Thus, the term amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated.

The terms "amide" or "amido" refers to a substituent group -C(0)-NR^aR^b, wherein R^a and R^b are defined as above, and wherein the point of connectivity of the substituent is the carbonyl carbon . Thus, the term amido includes alkylamido (e.g. , R^a is hydrogen and R^b is alkyi), dialkylamido (e.g., R^a is alkyi and R^b is alkyi) and arylamido (e.g., R^a is hydrogen and R^b is aryl). Alternatively, R^a and R^b, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring.

The terms "aryl" and "aryl group" include unsaturated and aromatic cyclic hydrocarbons as well as unsaturated and aromatic heterocycles containing one or more rings. Aryl groups include, for example C5-8 aryl groups. Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycycle (e.g. , tetralin).

Regarding connectivity, an "arylalkyl" group, for example, is an alkyi group substituted with an aryl group (e.g. , phenylmethyl (;^'.e. , benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyi group (e.g. , p-methylphenyl (;^'.e. , p-tolyl)).

"Treatment," "to treat" or "treating" as used herein , is defined as the application or administration of a therapeutic agent (e.g. , a compound of the invention) to a patient, or to an isolated tissue or cell line from a patient. The patient generally has a disease or disorder, a symptom of disease or disorder or a predisposition toward a disease or disorder. The purpose of treatment is generally to cure, heal, alleviate, relieve, remedy, ameliorate, or improve such disease, disorder, symptoms or predisposition. "Treated," as used herein, refers to the disease or disorder being cured, healed , alleviated, relieved, remedied, ameliorated, or improved. For example, methods of treatment of the instant invention provide for administration of an inhibitor as described herein , such that the progression of a specific disorder is slowed or stopped. Methods of treatment of the instant invention further include the administration of an inhibitor, such that a specific disorder is cured.

The term "effective amount" is defined as an amount sufficient to achieve a desired effect. The term "desired effect" refers generally to any result that is anticipated by the skilled artisan when a compound or composition of the invention is administered to a subject. In some embodiments, the desired effect is a complete remission of the disease or disorder. In other embodiments, the desired effect is a partial treatment of a disease or disorder. In still other embodiments, the desired effect is a full or partial treatment of the symptoms of a disease or disorder.

As used herein, the term "subject" refers to a human or a non-human mammal. Non- human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In a particular embodiment, the subject is a mammal. In another particular embodiment, the subject is human. EXAMPLES

Example 1:

This application employs a new computational drug discovery paradigm using homology modeling, molecular dynamics simulation and virtual high-throughput screening to identify small molecules that interact with FGF-23, and advances the translation of understanding of FGF-23 functions to the clinic by optimizing small-molecule effects to block FGF-23 and testing their efficacy and safety of inhibiting FGF-23 in preclinical disease models of FGF-23 excess, including Hyp and CKD models.

The disclosure will improve scientific knowledge by establishing the structural basis for FGF-23 binding to FGFRs, defining compounds that disrupt this binding, modifying these compounds that have the potential to be pharmacological tool to probe the functions of FGF- 23 and to develop drugs to treat disorders of FGF-23 excess. This will be helpful in establishing a path to clinical trials for the first small-molecule inhibitors of FGF-23 activity.

Specific Aim 1. Discovery and optimization of FGF-23 chemical antagonists.

Rationale: These studies will synergistically integrate computational QSAR and structure- based approaches with synthetic medicinal chemistry to improve the potency and toxicity profiles of existing leads. SAR studies establish the baseline for rational design using medicinal chemistry. Structural modifications to improve drug-like parameters (e.g., potency, metabolic stability, aqueous solubility, etc.) must be proposed that do not perturb the basic pharmacophore.

Rational design of FGF-23 antagonists: With experimental screening of the compounds that are predicted to directly bind to FGF-23, Zind 3407541 (also designated as MD-3) was identified as the lead FGF-23 antagonist (Fig. 1 , A), based on potency as well as drug- likeness. MD-3 at 10 μΜ markedly suppressed FGF-23-induced Elk1-Gal reporter activities in cells transfected with FGFR1/a-Klotho (Fig 1 , B), but not in cells lacking this complex. The effects of inhibiting FGF-23 dependent regulation of phosphate and vitamin D metabolism in a proximal tubule cell line (Fig 1 , C and D) were tested. It was found that FGF-23 inhibited Npt2a phosphate transporter expression and stimulated Cyp24a1 , the enzyme that degrades 1 ,25D in proximal tubular cells, and that MD-3 inhibited these effects of FGF-23. Finally, the effects of FGF-23 were tested in wild-type mice (Fig 1 , E and F). Administration of

Zind 3407541 at 100 mg/kg intraperitoneally, twice daily, resulted in increased serum phosphate and 1 ,25D levels, consistent with inhibition of FGF-23 effects. It was also found that Zind 3407541 when added to RAW264.7 macrophages, which express FGFR/oKlotho binary complexes dose-dependently inhibited FGF-23 stimulation of TNF-a production (Fig 1 , G), which provides another model for assessing FGF-23 responses. The effects of MD-3 were selective for FGF-23, and did not inhibit other FGF ligand activation of FGFRs at 2.5 μΜ (see data on specificity in reference ( Xiao, Z., et al. Sci Signal. 2016;9(455):ra1 13.).

Because of potency, selectivity and in vitro efficacy, MD-3 was selected as a starting point to generate lead series that will be evaluated in standard in vitro and in vivo ADME, PK, and toxicology assays to support discovery, lead candidate selection, preclinical testing and clinical programs. Medicinal chemistry data on lead compound (MD-3). The synthetic construction of MD-3 as a FGF-23 antagonist is anchored from a common scaffold derived in several synthetic steps from readily available cycloalkanone starting materials (Fig. 2). Retrosynthetic analysis of MD-3(1 ) using standard functional group interconversions of oxime formation (Aungst, R. A., Jr., et al. Org. Lett. 2001 ;3(16):261 1-3.) and metal-mediated coupling through the Suzuki-Miyaura cross-coupling (Molander, G. A., et al. Angew. Chem. Int. Ed. Engl. 2009;48(49):9240-61.; Molander, G. A., et al. Acc. Chem. Res. 2007;40(4):275-86.) via known chemistry was envisioned (Rawat, V. S. Synlett. 2014;25(08): 1 132-6.; Zhao, J., et al. Chem. Commun. (Camb). 2014;50(16):2058-60.). The convergence of the route allows maximum flexibility of functionality towards lead optimization.

Conversion of cyclopentanone to 2-bromocyclopentene carbaldehyde using a modified Vilsmeier protocol adapted from Lipton (Bekele, T., et al. J. Org. Chem. 2003, 68,

8471 -8479.) afforded the desired synthon for metal -mediated coupling (Salem, B., et al. Org. Lett. 2003, 5, 2307-2310.) in 70% yield. Moving forward, treatment of 1 and potassium styrenyltrifluoroborate using Suzuki-Miyaura cross-coupling (Molander, G. A., et al. Angew. Chem., Int. Ed. 2009, 48, 9240-9261 .; Molander, G. A., et al. Acc. Chem. Res. 2007, 40, 275-286.) conditions (Chin, A. L, et al. J. Org. Chem. 2016, 81 , 1 106-1 1 15.) resulted in the production of advanced aldehyde intermediate 2. Conversion to MD-3 through the oxime was successful resulting in a 46% yield over three steps from cyclopentanone. During route scouting and validation it was observed that 1 could be directly converted into the oxime 3 in high purity. Intermediate 3 was evaluated in parallel Suzuki-Miyaura cross-coupling reactions towards the production of MD-3, but did not afford the desired product in comparable yield or purity. The chemistry described in Fig. 8 was the basis for the production of all aldehydes (Fig. 9 and Fig. 10) and oxime analogues of MD-3.

Example 2:

Over 40 analogues of MD-3 were synthesized. To derive insights into the structure- activity relationships (SAR) of the series, in vitro efficacy (as measured by % inhibition) of select MD-3 analogues was assessed. Compounds were screened using HEK-293 cells expressing FGFRs/a-Klotho, and FGF-23-induced ERK activation was measured as the read out. Metabolic stability of these compounds was also assessed. Results of these analyses are shown in Table 1 . The data indicate that replacing the cyclopentene ring of MD-3 with a six-membered ring or an aromatic system increases the FGF-23 antagonizing potency. Removal of the ethylene bridge of MD-3 decreases compound efficacy but increases metabolic stability.

Table 1 : Inhibitory and metabolic stability analyses

Experimental Section

General Considerations: All reagents were purchased from U.S. chemical suppliers, stored according to published protocols, and used as received unless indicated otherwise. All experiments were performed in oven- or flame-dried glassware. Reaction progress was monitored using thin-layer chromatography on glass-backed silica gel plates and/or H NMR analysis of crude reaction mixtures. RF values for compounds that resulted in a concentrically observed spot on normal phase silica gel are reported using the conditions listed. All melting points are reported as observed and uncorrected. All reported yields listed are for pure compounds and corrected for residual solvent or stereoisomeric impurities, if applicable, from H NMR spectroscopy unless otherwise indicated. All H and ³C NMR data was acquired from a 500 MHz multinuclear spectrometer with broad-band N2 cryoprobe. Chemical shifts are reported using the δ scale and are referenced to the residual solvent signal: CDCI₃ (δ 7.26) and CD₃OD (3.31 ) for ¹H NMR and chloroform (δ 77.16), CD₃OD

(39.00), and (CD₃)₂CO (29.84) for ³C NMR. Splittings are reported as follows: (s) = singlet, (d) = doublet, (t) = triplet, (dd) = doublet of doublets, (ddd) = doublet of doublet of doublets, (dt) = doublet of triplets, (br) = broad, (m) = multiplet, and pent = pentet. Infrared spectral data was acquired from the (form) listed. High resolution mass spectrometry (HRMS) data was obtained utilizing electron impact ionization (El) with a magnetic sector (EBE trisector), double focusing-geometry mass analyzer.

General Procedure for Suzuki-Miyaura Cross-Coupling of Scaffolds: To an 8 ml_ reaction vial equipped with a magnetic stir bar at ambient temperature was charged Pd(OAc)2, RuPhos, CS2CO3 (3 equiv), the requisite substrate (0.857 mmol), and the desired organoboron reagent (equivalents listed for each reaction). The mixture was slurried in

Tol:H₂0 (4: 1 ) (0.2 M) and heated to 100 °C for 16 hours upon which time the crude mixture was analyzed by H NMR to ascertain percent conversion of the starting material.

Concentration of the crude reaction mixtures under reduced pressure at ambient temperature followed by purification on normal phase silica gel using automated flash- column chromatography with MTBE:hexanes, or EtOAc:hexanes gradient mobile phases afforded the compounds described in the listed yields.

Compounds 4, 16, 23 are known compounds in the primary literature (Knobloch, K., et al. Eur. J. Org. Chem. 2005, 13, 2715-2733.; Vogel, C, et al. Angew. Chem., Int. Ed. 1993, 32, 1051 -1052.; Yoshida, K. , et al. Chem. Eur. J. 2008, 14, 8246-8261 .).

2-Styryl-cyclopent-1-enecarbaldehyde (4): Prepared according to the general procedure discussed above with 1 (1 .71 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % Ruphos, and 1 .20 equiv potassium styryltrifluoroborate, RF = 0.62, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.235 g, 70%; orange solid; mp = 97.5-99.0 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.33 (s, 1 H), 7.68 (d, J = 16.0 Hz, 1 H), 7.51 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.35-7.30 (m, 1 H), 6.87 (d, J = 16.0 Hz, 1 H), 2.91 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.96 (pent, J = 7.5 Hz, 2H).

2-(2-p-Tolyl-vinyl)-cyclopent-1-enecarbaldehyde (5): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % Ruphos, and 1.05 equiv 4-methylstyrenylboronic acid, RF = 0.58, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.050 g, 42%; orange solid; mp = 104.2-107.3 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.33 (s, 1 H), 7.64 (d, J = 15.9 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 15.9 Hz, 1 H), 2.90 (br-t, J = 7.7 Hz, 2H), 2.71 (br-t, J = 7.7 Hz, 2H), 2.37 (s, 3H), 1 .95 (pent, J = 7.7 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 187.6, 158.2, 139.5, 136.8, 133.6, 129.8, 127.3, 1 19.2, 34.9, 31.2, 21.53, 21.48; IR (ATR- CDCI₃): 0_max = 3035, 2952, 2850, 1653, 1616, 1580, 804 cm^"1 ; HRMS (El): m/z calculated for CisHieO: 212.1201 ; found: 212.1208.

2-[2-(4-Methoxy-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde (6): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % Ruphos, and 1.05 equiv 4-methoxystyrenylboronic acid, RF = 0.35, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.090 g, 69%; orange solid; mp = 107.0-1 10.0 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.32 (s, 1 H), 7.56 (d, J = 15.7 Hz, 1 H), 7.48-7.44 (m, 2H), 6.93-6.89 (m, 2H), 6.83 (d, J = 15.7 Hz, 1 H), 3.84 (s, 3H), 2.89 (br-t, J = 7.5 Hz, 2H), 2.71 (br-t, J = 7.5 Hz, 2H), 1.95 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCI₃): δ 187.6, 160.6, 158.4, 138.9, 138.5, 129.2, 128.8, 1 18.0, 1 14.5, 55.5, 34.9, 31.2, 21.5; IR (ATR-CDCI3): O_max = 3035, 2918, 2833, 1643, 1604, 1580, 1512, 859 cm^"1 ; HRMS (El): m/z calculated for C15H16O2: 228.1 150; found: 228.1 144.

2-[2-(4-Fluoro-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde (7): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv 4-fluorostyrenylboronic acid, R_F = 0.48, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.050 g, 41%; brown oil; H NMR (500 MHz, CDCI₃): δ 10.31 (s, 1 H), 7.59 (d, J = 16.0 Hz, 1 H), 7.50-7.46 (m, 2H),

7.1 1 -7.04 (m, 2H), 6.82 (d, J = 16.0 Hz, 1 H), 2.89 (br-t, J = 7.5 Hz, 2H), 2.71 (br-t, J = 7.5 Hz, 2H), 1.96 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 187.5, 164.2, 162.4, 157.6, 139.9, 135.5, 132.6 (d, J = 3.6 Hz), 129.0 (d, J = 8.2 Hz), 120.0 (d, J = 2.5 Hz), 1 16.1 (d, J = 22.0 Hz), 34.9, 31.4, 21.5; IR (ATR-CDCI3): 0_max = 3044, 2955, 2849, 1652, 1618, 1600, 1592, 1575, 1233, 1217 cm^"1 ; HRMS (El): m/z calculated for C14H13FO: 216.0950; found: 216.0950.

2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde (8): Prepared according to the general procedure discussed above with 1 (0.857 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv 4-trifluoromethylstyrenylboronic acid, RF = 0.48, 20% MTBE:hexanes; purified using automated flash column chromatography with an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.205 g, 90%; pale-orange solid; mp = 98.9-101 .7 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.34 (s, 1 H), 7.75 (d, J = 16.0 Hz, 1 H), 7.63 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 16.0 Hz, 1 H), 2.91 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 1 .98 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI3): δ 187.4, 156.6, 141.0, 139.7, 134.8, 130.5, 127.29, 127.2X (overlaps with 127.29), 125.8, 123.4, 34.7, 31 .3, 21.3; IR (ATR-CDCI3): 0_max = 3051 , 3854, 2926, 1639, 1617, 1589, 1322, 1 167, 1 120, 1066 cm^"1 ; HRMS (El): m/z calculated for C15H3F3O:

266.0918; found: 266.0908.

2-Phenethyl-cyclopent-1-enecarbaldehyde (9): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1.05 equiv potassium phenethyltrifluoroborate, RF = 0.71 , 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.075 g, 66%; orange liquid; H NMR (500 MHz, CDCI3): δ 9.77 (s, 1 H), 7.31 -7.26 (m, 2H), 7.23-7.18 (m, 1 H), 7.17-7.12 (m, 2H), 2.92-2.86 (m, 2H), 2.85-2.80 (m, 2H), 2.61 (br-t, J =7.6 Hz, 2H), 2.52 (br-t, J = 7.6 Hz, 2H), 1 .85 (pent, J = 7.6 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 188.0, 164.9, 140.6, 139.1 , 128.7, 128.4, 126.6, 38.6, 34.8, 30.6, 30.3, 21.6; IR (ATR-CDC ): O_max = 3027, 2951 , 2855, 1661 , 1627, 750, 700 cm^"1; HRMS (El): m/z calculated for Ci₄Hi₆0 [M-H]: 199.1 1 17; found:

199.1 127.

2-(2-Cyclohexyl-vinyl)-cyclopent-1 -enecarbaldehyde (10): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .05 equiv cyclohexylvinyl boronic acid, RF = 0.70, 20% MTBE:hexanes;

purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 2.5% isocratic hold; isolated yield 0.068 g, 58%; orange solid; mp = 46.0-49.6 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.19 (s, 1 H), 6.94 (d, J = 16.0 Hz, 1 H), 6.02 (dd, J = 16.0, 7.5 Hz, 1 H), 2.75 (t, J = 7.5 Hz, 2H), 2.64 (br-t, J = 7.5 Hz, 2H), 2.20-2.12 (m, 1 H), 1 .88 (pent, J = 7.5 Hz, 2H), 1.81 -1 .73 (br-m, 4H), 1.73-1 .66 (br-m, 2H), 1.37-1.1 1 (br-m, 4H); ¹³C NMR (125 MHz, CDCI₃): δ 187.9, 159.1 , 146.3, 137.9, 120.0, 41.8, 35.1 , 32.7, 30.9, 26.1 , 26.0, 21.4; IR (ATR-CDC ): 0_max = 2924, 2851 , 1658, 1630 cm^"1 ; HRMS (El): m/z calculated for C14H20O: 204.1514; found: 204.1505.

2-(3-Phenyl-propenyl)-cyclopent-1-enecarbaldehyde (11): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .05 equiv 3-phenylpropenylboronic acid, RF = 0.57, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with a 5% isocratic hold; isolated yield 0.0952 g, 79%; yellow oil; H NMR (500 MHz, CDCI₃): δ 10.17 (s, 1 H), 7.33 (t, J = 7.5 Hz, 2H), 7.25-7.22 (m, 1 H), 7.20 (d, J = 7.5 Hz, 2H), 7.02 (d, J = 15.5 Hz, 1 H), 6.21 (dt, J = 15.5, 7.0 Hz, 1 H), 3.57 (d, J = 7.0 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 1.88 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 187.8, 158.1 , 139.1 , 138.7, 138.6, 128.81 , 128.80, 126.7, 123.4, 39.8, 35.0, 30.9, 21.4; IR (ATR-CDCI3): 0_max = 3028, 2953, 2857, 1656, 1633, 751 , 699 cm^"1 ; HRMS (El): m/z calculated for CisHieO: 212.1201 ; found: 212.1 191.

2-[2-(3-Methoxy-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde (12): Prepared according to the general procedure discussed above with 1 (0.571 ): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .05 equiv 3-methoxystyrenyl boronic acid pinacol ester, RF = 0.39, 20% MTBE:hexanes; purified using automated flash column chromatography with an

MTBE:hexanes gradient mobile phase with a 2.5% isocratic hold; isolated yield 0.044 g, 34%; orange solid; mp = 84.2-88.0 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.34 (s, 1 H), 7.66 (d, J = 15.8 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.1 1 (br-d, J = 7.5 Hz, 1 H), 7.04-7.02 (br-m, 1 H), 6.89 (dd, J = 8.0, 2.5 Hz, 1 H), 6.84 (d, J = 15.9 Hz, 1 H), 3.87 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.97 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 187.6, 160.1 , 157.7, 140.0, 137.8, 136.7, 130.0, 120.4, 120.0, 1 14.8, 1 12.6, 55.5, 34.9, 31.3, 21.4; IR (ATR-CDCb): O_max = 2955, 2837, 1651 , 1615, 1596, 1584, 779 cm^"1 ; HRMS (El): m/z calculated for Ci₅Hi₆0₂: 228.1 150; found: 228.1 140.

2-[2-(3,5-Difluoro-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde (13): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv 3,5-difluorostyrenyl boronic acid pinacol ester, RF = 0.58, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; yellow solid; isolated yield 0.081 g, 61 %; yellow solid; mp = 106.3-108.5 °C; ¹H NMR (500 MHz, CD₃OD): δ 10.33 (s, 1 H), 7.91 (d, J = 16.0 Hz, 1 H), 7.29-7.23 (m, 2H), 6.94 (d, J = 16.0 Hz, 1 H), 6.92-6.87 (m, 1 H), 2.94 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.97 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 187.5, 163.5 (dd, J = 250, 13 Hz), 156.3, 141.4, 139.8 (t, J = 10.9 Hz), 134.2 (t, J = 3.0 Hz), 122.6 (t, J = 3.1 Hz), 109.9 (dd, J = 19.5, 6.5 Hz), 104.2 (t, J = 25.5 Hz), 34.8, 31.5, 21.4; IR (ATR-CDCb): 0_max = 3092, 2959, 2854, 1646, 1623, 1593, 905, 726 cm^"1 ; HRMS (El): m/z calculated for C14H12F2O: 234.0856; found: 234.0861. 2-Styryl-cyclohex-1 -enecarbaldehyde (14): Prepared according to the general procedure discussed above with 2-bromo-cyclohex-1-ene carbaldehyde (0.747 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1.20 equiv potassium styrenyltrifluoroborate, R_F = 0.72, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5.0% isocratic hold; isolated yield 0.134 g, 85%; amorphous; ¹H NMR (500 MHz, CDC ): δ 10.48 (s, 1 H), 7.76 (d, J = 16.0 Hz, 1 H), 7.49-7.46 (m, 2H), 7.40-7.34 (m, 2H), 7.33-7.28 (m, 1 H), 6.87 (d, J = 16.0 Hz, 1 H), 2.60-2.54 (br-m, 2H), 2.39-2.34 (br-m, 2H), 1.77-1 .70 (m, 2H), 1.69-1.63 (m, 2H); ¹³C NMR (125 MHz, CDCb): δ =190.6, 151 .8, 136.8, 135.9, 133.6, 129.0, 128.8, 127.1 , 123.5, 27.7, 23.4, 22.1 , 21.7; IR (ATR-CDCb): 0_max = 3056, 3024, 2932, 2861 , 1658, 1614, 1583, 1 148, 749, 691 cm^"1 ; HRMS (El): m/z calculated for C₁₅H₁₆0: 212.1201 ; found: 212.1 196.

2-(2-p-Tolyl-vinyl)-cyclohex-1 -enecarbaldehyde (15): Prepared according to the general procedure discussed above with 2-bromo-cyclohex-1-ene carbaldehyde (0.747): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1.20 equiv of 4-methylstyrenylboronic acid, R_F = 0.72, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.104 g, 62%; pale-yellow solid; mp = 82.3-84.6 °C; ¹H NMR (500 MHz, CD₃OD): δ 10.41 (s, 1 H), 7.84 (d, J = 16.0 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 16.0 Hz, 1 H), 2.62-2.56 (br-m, 2H), 2.33 (s, 3H), 2.32-2.27 (br-m, 2H), 1.75-1.69 (m, 2H), 1 .67-1.61 (m, 2H); ¹³C NMR (125 MHz, CD₃OD): δ 192.5, 154.4, 139.9, 136.1 , 135.3, 135.1 , 130.5, 128.2, 123.2, 28.4, 24.2, 23.1 , 22.7, 21.3; IR (ATR-CD3OD): O_max = 3014, 2868, 2925, 1644, 1614, 1602, 1578, 1 150, 960, 804 cm-¹ ; HRMS (El): m/z calculated for Ci₆Hi₈0: 226.1358; found: 226.1353.

2-Phenyl-cyclopent-1-enecarbaldehyde (16): Prepared according to the general procedure discussed above with 1 (0.571 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv phenylboronic acid; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.146 g, 95%; H NMR (500 MHz, CDCI3): δ 9.82 (s, 1 H), 7.41 -7.38 (m, 3H), 7.36-7.33 (m, 2H), 3.01 -2.96 (m, 2H), 2.78-2.73 (m, 2H), 2.01 (pent, J = 7.5 Hz, 2H).

2-p-Tolyl-cyclopent-1-enecarbaldehyde (17): Prepared according to the general procedure discussed above with 1 (0.857 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv potassium 4-methylphenyltrifluoroborate, RF = 0.68, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.106 g, 66%; orange oil; H NMR (500 MHz, CDCI₃): δ 9.85 (s, 1 H), 7.28-7.26 (br-m, 2H), 7.24-7.20 (br-m, 2H), 3.01 -2.96 (m, 2H), 2.78-2.72 (m, 2H), 2.39 (s, 3H), 2.01 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCI3): δ 190.7, 162.7, 139.6, 139.2, 132.2, 129.3, 128.7, 39.7, 31.2, 21.8, 21.4; IR (ATR-CDCI3): Omax = 3028, 2954, 2852, 1658, 1607, 817 cm^"1 ; HRMS (El): m/z calculated for C₁₃H₁₄0: 186.1045; found: 186.1045.

2-(4-ferf-Butyl-phenyl)-cyclopent-1 -enecarbaldehyde (18): Prepared according to the general procedure discussed above with 1 (0.857 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .20 equiv potassium 4-ferf-butylphenyl trifluoroborate, RF = 0.70, 20% MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.142 g, 73%; yellow oil; ¹ H NMR (500 MHz, CDCI₃): δ 9.86 (s, 1 H), 7.45-7.41 (m, 2H), 7.34-7.29 (m, 2H), 3.02-2.97 (m, 2H), 2.79-2.73 (m, 2H), 2.01 (pent, J = 7.5 Hz, 2H), 1.36 (s, 9H); ³C NMR (125 MHz, CDCI3): δ 190.7, 162.6, 152.8, 139.3, 132.2, 128.6, 125.6, 39.7, 34.9, 31.4, 31.3, 21.8; IR (ATR-CDCI3): 0_max = 3034, 2960, 2905, 2868, 1659, 1607, 1508, 1233, 833 cm^"1 ; HRMS (El): m/z calculated for C₁₆H₂oO: 228.1514; found: 228.1514.

2-(4-Methoxy-phenyl)-cyclopent-1 -enecarbaldehyde (19): Prepared according to the general procedure discussed above with 1 (0.857): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .20 equiv of potassium 4-methoxyphenyltrifluoroborate, RF = 0.54, 20% MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.153 g, 88%; yellow film; H NMR (500 MHz, CDCI₃): δ 9.85 (s, 1 H), 7.40-7.30 (m, 2H), 6.95-6.91 (m, 2H), 3.84 (s, 3H), 2.99-2.93 (m, 2H), 1.99 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCI₃): δ 190.6, 162.4, 160.7, 138.6, 130.3, 122.5, 114.1 , 55.5, 39.6, 31.3, 21 .7; IR (ATR- CDC ): u_max = 2954, 2837, 1653, 1603, 1509, 1252, 1 177, 832 cm^"1 ; HRMS (El): m/z calculated for Ci₃Hi₄0₂: 202.0994; found: 202.0996.

2-(4-Dimethylamino-phenyl)-cyclopent-1-enecarbaldehyde (20): Prepared according to the general procedure discussed above with 1 (0.857 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv of potassium 4-A/,A/-dimethylaminophenyl trifluoroborate, RF = 0.46, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.096 g, 52%; yellow-orange solid; mp = 1 1 1.0-1 13.6 °C; ¹H NMR (500 MHz, CDCI₃): δ 9.89 (s, 1 H), 7.33-7.28 (m, 2H), 6.73-6.69 (m, 2H), 3.02 (s, 6H), 2.99-2.94 (m, 2H), 2.77-2.72 (m, 2H), 1.97 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDC ): δ 190.7, 163.0, 151.3, 137.0, 130.4, 122.7, 1 1 1.7, 40.3, 39.2, 31.3, 21.8; IR (ATR-CDCI3): 0_max = 2967, 2933, 2830, 1637, 1608, 1585, 1235, 824 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₁₇NO: 215.1310; found: 215.1309.

2-(4-Methylsulfanyl-phenyl)-cyclopent-1-enecarbaldehyde (21): Prepared according to the general procedure discussed above with 1 (0.857 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv of potassium 4-methylsulfanylphenyl trifluoroborate, RF = 0.54, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.135 g, 72%; yellow solid; mp = 51.2-52.3 °C; ¹H NMR (500 MHz, CDCI₃): δ 9.84 (s, 1 H),

7.30-7.25 (m, 4H), 3.00-2.94 (m, 2H), 2.78-2.73 (m, 2H), 2.51 (s, 3H), 2.00 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCb): δ 190.3, 161.9, 140.8, 139.4, 131.5, 129.2, 126.0, 39.6, 31.3, 21.8, 15.5; IR (ATR-CDCI3): 0_max = 2954, 2921 , 2833, 1656, 1592, 1096, 819 cm^"1 ; HRMS (El): m/z calculated for C13H14OS: 218.0765; found: 218.0759.

2-Benzo[1 ,3]dioxol-5-yl-cyclopent-1-enecarbaldehyde (22): Prepared according to the general procedure discussed above with 1 (0.89 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .20 equiv of potassium 2-benzo[1 ,3]dioxol-5-yltrifluoroborate, RF = 0.57, 20% MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.108 g, 56%; pale-yellow solid; mp = 84.9-86.7 °C; H NMR (500 MHz, CDCI₃): δ 9.85 (s, 1 H), 6.89-6.83 (m, 3H), 6.02 (s, 2H), 2.96-2.92 (m, 2H), 2.76-2.72 (m, 2H), 1.99 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCb): δ 190.4, 162.0, 148.8, 148.1 , 139.2, 129.0, 123.3, 108.9, 108.5, 101.6, 39.8, 31.3, 21.7; IR (ATR-CDCb): t = 2960, 2904, 2850, 1652, 1598, 1503, 1487, 1241 , 1037 cm^"1 ; HRMS (El): m/z calculated for C13H12O3: 216.0786; found: 216.0783.

2-Vinyl-cyclopent-1-enecarbaldehyde (23): Prepared according to the general procedure discussed above with 1 (0.86 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1.20 equiv of potassium vinyl trifluoroborates; purified using automated flash column

chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.094 g, 90%; H NMR (500 MHz, CDCb): δ 10.20 (s, 1 H), 7.26 (dd, J = 17.0, 10.8 Hz, 1 H), 5.55 (d, J = 17.0 Hz, 1 H), 5.54 (d, J = 10.8 Hz, 1 H), 2.77 (br-t, J = 7.5 Hz, 2H), 2.66 (br-t, J = 7.5 Hz, 2H), 1.91 (pent, J = 7.5 Hz, 2H). This compound is extremely unstable at ambient temperature outside of solution. Spectral data was acquired with residual solvent from purification to prevent compound degradation and is consistent with literature values (Yoshida, et al.).

Compounds 35 and 36 are known in the primary literature (Nallasivam, J. L, et al. Eur. J. Org. C em. 2015, 76, 3558-3567.; Kim, Y., et al. Bioorg. Med. C em. 2013, 27,

2568-2676.).

2-Styryl-pyridine-3-carbaldehyde (24): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.81 mmol): 2.5 mol % Pd(OAc)2, 5.0 mol % RuPhos, and 1 .20 equiv potassium styryltrifluoroborate, RF = 0.26, 20%

MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.138 g, 82%; yellow solid; mp = 59.3-63.1 °C; ¹ H NMR (500 MHz, CDCb): δ 10.40 (s, 1 H), 8.78 (dd, J = 4.8, 1.8 Hz, 1 H),

8.1 1 (dd, J = 7.8, 1.8 Hz, 1 H), 8.10 (d, J = 15.6 Hz, 1 H), 7.97 (d, J = 15.6 Hz, 1 H), 7.68-7.64 (m, 2H), 7.43-7.38 (m, 2H), 7.37-7.32 (m, 2H); ¹³C NMR (125 MHz, CDCb): δ 191.4, 156.2, 153.4, 139.8, 138.6, 136.4, 129.4, 129.0, 127.96, 127.93, 122.5, 122.3; IR (ATR-CDCb): 0_max = 3058, 2862, 2817, 2743, 1700, 1629, 1577, 1551 , 1450, 1435, 1398, 772, 690 cm^"1 ; HRMS (El): m/z calculated for C14H11 NO: 209.0841 ; found: 209.0833.

2-(2-p-Tolyl-vinyl)-pyridine-3-carbaldehyde (25): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.81 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .05 equiv trans-2-(4-methylphenyl)vinylboronic acid, RF = 0.26, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.041 g, 31 %; pale- yellow solid; mp = 80.0-82.2 °C; ¹ H NMR (500 MHz, CDCI₃): δ 10.41 (s, 1 H), 8.77 (dd, J = 4.7, 1.9 Hz, 1 H), 8.1 1 (dd, J = 7.8, 1.9 Hz, 1 H), 8.05 (d, J = 15.6 Hz, 1 H), 7.95 (d, J = 15.6 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.8, 4.7 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H); ³C NMR (125 MHz, CDCI₃): δ 191 .5, 156.6, 153.6, 139.5, 138.3, 138.3X

(overlaps with 138.3), 133.7, 129.7, 127.9, 127.8, 122.1 , 121 .7, 21.6; IR (ATR-CDCI₃): 0_max = 3023, 2857, 2734, 1691 , 1627, 1553, 1437, 81 1 cm^"1; HRMS (El): m/z calculated for C₁₅H₁₃NO: 223.0997; found: 223.0999.

2-[2-(4-Methoxy-phenyl)-vinyl]-pyridine-3-carbaldehyde (26): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.54 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1 .05 equiv trans-2-(4- methoxyphenyl)vinylboronic acid, RF = 0.14, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.101 g, 78%; pale-yellow solid; mp = 64.1-66.0 °C; ¹ H NMR (500 MHz, CDCI₃): δ 10.39 (s, 1 H), 8.75 (dd, J = 4.7, 1.8 Hz, 1 H), 8.09 (dd, J = 7.8, 1 .8 Hz, 1 H), 7.99 (d, J = 15.6 Hz, 1 H), 7.93 (d, J = 15.6 Hz, 1 H), 7.64-7.58 (m, 2H), 7.30 (dd, J = 7.8, 4.7 Hz, 1 H), 6.96-6.91 (m, 2H), 3.86 (s, 3H); ¹³C NMR (125 MHz, CDCI₃): δ 191.6, 160.7, 156.7, 153.6, 139.7, 138.0, 129.4, 129.3, 127.6, 121.8, 120.4, 1 14.4, 55.5; IR (ATR-CDCI3): 0_max = 2934, 2837, 2739, 1692, 1626, 1552, 1510, 1252, 1 173, 826 cm^-1 ; HRMS (El): m/z calculated for C₁₅H₁₃N0₂: 239.0946; found: 239.0954.

2-Phenyl-pyridine-3-carbaldehyde (27): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.81 mmol): 2.5 mol % Pd(OAc)2, 5.0 mol % RuPhos, and 1 .20 equiv potassium phenyltrifluoroborate, RF = 0.28, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.102 g, 68%; yellow oil; H NMR (500 MHz, CDCb): δ 10.07 (d, J = 0.8 Hz, 1 H), 8.89 (dd, J = 4.8, 1.8 Hz, 1 H), 8.32 (dd, J = 7.9, 1 .8 Hz, 1 H), 7.63-7.58 (m, 2H), 7.57-7.51 (m, 3H), 7.45 (ddd, J = 7.9, 4.8, 1.8 Hz, 1 H); ³C NMR (125 MHz, CDCI₃): δ 191.8, 162.4, 153.6, 137.2, 136.1 , 130.5, 129.8, 129.7, 128.8, 122.7; IR (ATR- CDCI3): 0_max = 3044, 2925, 2858, 2748, 1695, 1615, 1580, 1557, 1433, 1386, 1247, 828, 799, 770 cm^"1 ; HRMS (El): m/z calculated for C12H9NO: 183.0684; found: 183.0836.

2-p-Tolyl-pyridine-3-carbaldehyde (28): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.81 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, 1 .20 equiv potassium 4-methylphenyltrifluoroborate, R_F = 0.31 , 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with an isocratic hold at 25%; isolated yield 0.067 g, 43%; pale-yellow solid; mp = 78.4-81.5 °C; ¹H NMR (500 MHz, CDCb): δ 10.06 (d, J = 0.8 Hz, 1 H), 8.87 (dd, J = 4.8, 1 .8 Hz, 1 H), 8.29 (dd, J = 8.0, 1.8 Hz, 1 H), 7.51 -7.47 (m, 2H), 7.42 (ddd, J = 8.0, 4.8, 0.8 Hz, 1 H), 7.35-7.32 (m, 2H), 2.45 (s, 3H); ¹³C NMR (125 MHz, CDCI₃): δ 192.1 , 162.5, 153.6, 140.0, 136.0, 134.4, 130.6, 129.6, 129.5, 122.4, 21.5; IR (ATR-CDC ): 0_max = 3040, 2920, 2858, 2748, 1695, 1580, 1433, 1386, 1247, 828, 799, 770 cm^"1 ; HRMS (El): m/z calculated for C₁₃Hn NO: 197.0841 ; found: 197.0836.

2- (4-Methoxy-phenyl)-pyridine-3-carbaldehyde (29): Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde (0.81 mmol): 5.0 mol %

Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv potassium 4-methoxyphenyltrifluoroborate, RF = 0.18, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.1 18 g, 69%; white solid; mp = 67.0-68.4 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.06 (d, J = 0.8 Hz, 1 H), 8.85 (dd, J = 4.7, 1.9 Hz, 1 H), 8.28 (dd, J = 7.9, 1.9 Hz, 1 H), 7.57-7.54 (m, 2H), 7.39 (ddd, J = 7.9, 4.7, 0.8 Hz, 1 H), 7.07-7.03 (m, 2H), 3.91 (s, 3H); ³C NMR (125 MHz, CDCb): δ 192.1 , 162.0, 161.1 , 153.6, 136.1 , 132.1 , 129.7, 129.4, 122.2, 1 14.3, 56.6; IR (ATR-CDCb): 0_max = 3056, 2970, 2840, 2747, 1695, 1681 , 1607, 1580, 1515, 1432, 1387, 1251 , 1 176, 840, 776, 730 cm^"1; HRMS (El): m/z calculated for C13H11 NO2: 213.0790; found: 213.0797.

3-Styryl-thiophene-2-carbaldehyde (30): Prepared according to the general procedure discussed above with 3-bromo-thiophene-2-carbaldehyde (0.79 mmol): 5.0 mol %

Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv potassium styrenyltrifluoroborate, RF = 0.60, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.068 g, 41 %; light-brown solid; mp = 104.1 -106.5 °C; ¹H NMR (500 MHz, CDCI₃): δ 10.22 (s, 1 H), 7.69 (d, J = 16.3 Hz, 1 H), 7.68 (d, J = 5.0 Hz, 1 H), 7.56-7.52 (m, 2H), 7.46 (d, J = 5.0 Hz, 1 H), 7.42-7.37 (m, 2H), 7.35-7.31 (m, 1 H), 7.18 (d, J = 16.3 Hz, 1 H); ³C NMR (125 MHz, CDCI3): δ 182.8, 146.9, 137.7, 136.4, 134.9, 134.5, 129.1 , 129.0, 127.1 , 126.9, 1 19.5; IR (ATR-CDCI3): 0_max = 3101 , 3077, 3023, 2833, 1652, 1626, 1433, 1 196, 956, 758, 692 cm^"1 ; HRMS (El): m/z calculated for Ci₃HioOS: 214.0452; found: 214.0452.

3- phenyl-thiophene-2-carbaldehyde (31): Prepared according to the general procedure discussed above with 3-bromo-thiophene-2-carbaldehyde (0.52 mmol): 5.0 mol %

Pd(OAc)₂, 10.0 mol % RuPhos, and 1.05 equiv phenyl boronic acid, R_F = 0.64, 20%

MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with an isocratic hold at 10%; isolated yield 0.036 g, 37%; yellow oil; ¹H NMR (500 MHz, CDCI₃): δ 9.89 (s, 1 H), 7.74 (dd, J = 4.9, 1.2 Hz, 1 H), 7.51 -7.43 (m, 5H), 7.23 (d, J = 4.9 Hz, 1 H); ³C NMR (125 MHz, CDC ): δ 184.4, 151.6, 138.6, 134.3, 134.1 , 130.8, 129.7, 129.0, 128.9; IR (ATR-CDC ): 0_max = 3100, 3035, 2852, 2817, 1654, 1419, 1 198, 742, 700 cm^-1 ; HRMS (El): m/z calculated for CnHsOS: 188.0296; found: 188.0292.

3-(4-Methoxy-phenyl)-thiophene-2-carbaldehyde (32): Prepared according to the general procedure discussed above with 3-bromo-thiophene-2-carbaldehyde (0.79 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv potassium 4-methoxyphenyltrifluroborate, RF = 0.37, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with an isocratic hold at 25%; isolated yield 0.039 g, 23%; light-brown solid; mp = 65.7-68.5 °C; ¹H NMR (500 MHz, CDCI₃): δ 9.88 (s, 1 H), 7.73-7.71 (m, 1 H), 7.44-7.39 (m, 2H), 7.20 (d, J = 4.9 Hz, 1 H), 7.04-6.98 (m, 2H), 3.87 (s, 3H); ¹³C NMR (125 MHz, CDCI₃): δ 184.5, 160.4, 151.5, 138.0, 134.2, 131.0, 130.7, 126.6, 1 14.5, 55.6; IR (ATR-CDC ): 0_max = 2970, 2838, 1654, 1607, 1500, 1250, 1 178, 1029, 754 cm^"1 ; HRMS (El): m/z calculated for C12H10O2S: 218.0402; found: 218.0410. 2-(2-p-Tolyl-vinyl)-benzaldehyde (33): Prepared according to the general procedure discussed above with 2-bromo-benzaldehyde (0.81 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1 .20 equiv potassium 4-methoxyphenyltrifluroborate, RF = 0.78, 20%

MTBE:hexanes; purified using automated flash column chromatography employing an

MTBE:hexanes gradient mobile phase with an isocratic hold at 20%; isolated yield 0.108 g, 60%; yellow solid; ¹H NMR (500 MHz, CDCI₃): δ 10.34 (s, 1 H), 8.00 (d, J = 16.0 Hz, 1 H), 7.84 (dd, J = 7.8, 1.0 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1 H), 2.38 (s, 3H); ¹³C NMR (125 MHz, CDCI₃): δ 192.8, 140.4, 138.5, 134.3, 134.2, 133.8, 133.0,

132.3, 129.6, 127.5, 127.2, 127.0, 123.7, 21.4; IR (ATR-CDCI3): 0_max = 3022, 2919, 2855, 2733, 1689, 1628, 1564, 1594, 1513, 1478, 1449, 1 182, 963, 803, 754, 726, 535 cm^"1 ; HRMS (El): m/z calculated for C₁₆H₁₄0: 222.1045; found: 222.1043.

2-[2-(4-Methoxy-phenyl)-vinyl]-benzaldehyde (34): Prepared according to the general procedure discussed above with 2-bromo-benzaldehyde (0.81 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.05 equiv 4-methoxyphenylboronic acid, RF = 0.57, 20%

MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with an isocratic hold at 10%; isolated yield 0.104 g, 54%; amorphous; ¹H NMR (500 MHz, CDCI₃): δ 10.33 (s, 1 H), 7.91 (d, J = 16.3 Hz, 1 H), 7.82 (dd, J = 7.8, 1.3 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.57 (dt, J= 7.8, 1.3 Hz, 1H), 7.53-7.48 (m, 2H), 7.41 (dt, J = 7.8, 1.3 Hz, 1H), 7.01 (d, J= 16.3 Hz, 1H), 6.94-6.90 (m, 2H), 3.84 (s, 3H); ³C NMR (125 MHz, CDCb): δ 192.8, 159.9, 140.4, 133.8, 133.7, 132.8, 132.3, 129.8, 128.4, 127.3, 127.0, 122.3, 114.3, 55.4; IR (ATR-CDCb): O_max = 3035, 2934, 2836, 2740, 1693, 1605, 1594, 1511, 1250, 1175, 1032, 820 cm^"1; HRMS (El): m/z calculated for Ci₆Hi₄0₂: 238.0994; found: 238.0995.

Biphenyl-2-carbaldehyde (35): Prepared according to the general procedure discussed above with 2-bromo-benzaldehyde (1.62 mmol): 5.0 mol % Pd(OAc)₂, 10.0 mol % RuPhos, and 1.20 equiv phenylboronic acid, RF = 0.79, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase with an isocratic hold at 20%; isolated yield 0.358 g, 52%; yellow oil; H NMR (500 MHz, CDCb): 59.92 (s, 1H), 8.04 (dd, J= 7.8, 1.3 Hz, 1H), 7.64 (dt, J= 7.6, 1.4 Hz, 1H), 7.52-7.42 (m, 5H), 7.41-7.37 (m, 2H); HRMS (El): m/z calculated for C₁₃H₁₀O [M-H]:

181.0648; found: 181.0650. Spectral data acquired was consistent with literature values (Nallasivam, et al.).

4'-Methoxy-biphenyl-2-carbaldehyde (36): Prepared according to the general procedure discussed above with 2-bromo-benzaldehyde (0.81 mmol): 5.0 mol % Pd(OAc)2, 10.0 mol % RuPhos, and 1.20 equiv potassium 4-methoxyphenyl trifluoroborate, RF = 0.44, 20% MTBE:hexanes; purified using automated flash column chromatography employing an MTBE:hexanes gradient mobile phase; isolated yield 0.150 g, 87%; yellow solid; H NMR (500 MHz, CDCb): δ 10.00 (s, 1 H), 8.00 (dd, J = 7.5, 1.4 Hz, 1 H), 7.62 (dt, J = 7.5, 1.4 Hz, 1H), 7.47-7.72 (m, 2H), 7.36-7.29 (m, 2H), 7.05-6.97 (m, 2H), 3.88 (s, 3H); ¹³C NMR (125 MHz, CDCb): δ 192.8, 159.9, 145.8, 133.9, 133.7, 131.5, 130.9, 130.2, 127.8, 127.5, 114.1, 55.6; I R (ATR-CDCb): 0_max = 3035, 3961, 3838, 2755, 1691, 1610, 1597, 1515, 1474, 1247, 1179, 836, 766 cm^"1; HRMS (El): m/z calculated for C₁₄H₁₂0₂: 212.0837; found: 212.0828. Spectral data acquired was consistent with literature values (Kim, et al.).

General Procedure for Oxime Formation: To an 8 ml_ reaction vial equipped with a magnetic stir bar at ambient temperature was charged the required aldehyde, sodium acetate (1.50 equiv), and hydroxylamine hydrochloride (1.50 equiv) in ethanol:H20 (3:1) (10 vol) at ambient temperature. The reaction was continued for 16 hours upon which time an aliquot was removed and analyzed by H NMR. Concentration of the crude reaction mixtures under reduced pressure at ambient temperature followed by purification on normal phase silica gel using automated flash-column chromatography with MTBE:hexanes, EtOAc:hexanes, or MeOH:DCM gradient mobile phases to afford the compounds described in the listed yields.

2-Styryl-cyclopent-1-enecarbaldehyde oxime (MD-3): Prepared according to the general procedure discussed above with 4 (0.54 mmol) and hydroxylamine hydrochloride, RF = 0.58, 20% MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.195 g, 93%; orange solid; mp = 149.7-152.9 °C; ¹ H NMR (500 MHz, CDCI₃): δ 8.41 (s, 1 H), 7.45 (d, J = 7.5 Hz, 2H), 7.36-7.32 (m, 2H), 7.28-7.24 (m, 1 H), 7.23 (d, J = 16.0 Hz, 1 H), 6.62 (d, J = 16.0 Hz, 1 H), 2.78-2.69 (m, 4H), 1.98 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCI₃): δ 146.4, 145.8, 137.2, 133.5, 132.2, 128.9, 128.2, 126.8, 121.2, 33.8, 32.9, 21.9; IR (ATR-CDC ): 0_max = 3247, 3032, 2953, 2850, 1649, 1599, 1510, 1006, 948, 939, 753, 693 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₁₅NO: 213.1 154; found: 213.1 155.

2-Phenethyl-cyclopent-1-enecarbaldehyde oxime (MD-3-A4): Prepared according to the general procedure discussed above with 9 (0.25 mmol) and hydroxylamine hydrochloride, RF = 0.49, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.020 g, 37%; pale-brown oil; ¹H NMR (500 MHz, CDCI₃): δ 7.99 (s, 1 ), 6.60-6.53 (m, 2H), 6.51-6.43 (m, 3H), 2.02 (t, J = 7.5 Hz, 1 H), 1.88-1 .79 (m, 4H), 1.76 (t, J = 7.5 Hz, 2H), 1.15 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCI3): δ 149.9, 146.5, 141.5, 130.0, 128.5, 128.4, 126.2, 37.2, 34.7, 32.1 , 30.9, 22.0; IR (ATR-CDCI3): 0_max = 3204, 3062, 2948, 2921 , 1640, 1602, 1496, 1453, 968, 927, 745, 703 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₁₇NO: 215.1310; found: 215.1305.

2-[2-(4-Fluoro-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde oxime (MD-3-A6): Prepared according to the general procedure discussed above with 7 (0.30 mmol) and hydroxylamine hydrochloride. The crude mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc:H20 in a separatory funnel where the organic layer was separated. The aqueous layer was back extracted with 2 ^χ 10 ml_ portions of ethyl acetate. The combined organic layers were washed with 10 mL of a saturated aqueous NaCI solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford the title compound: RF = 0.49, 20%

MTBE:hexanes; isolated yield 0.067 g, 99%; tan solid; decomposed upon heating for mp analysis; ¹H NMR (500 MHz, CDCI₃): δ 8.40 (s, 1 ), 7.45-7.40 (m, 2H), 7.14 (d, J = 15.7 Hz, 1 H), 7.06-7.01 (m, 2H), 6.58 (d, J = 15.7 Hz, 1 H), 2.77 (m, 4H), 1.98 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 163.9, 161.7, 146.1 , 145.6, 133.5, 133.4 (J = 3.0 Hz), 128.3 (J = 8.5 Hz), 121.0 (J = 2.0 Hz), 1 15.9 (J = 21 .8 Hz), 33.8, 32.9, 21.8; IR (ATR-CDC ): O_max = 3255, 2964, 600, 1507, 1224, 855, 819 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₁₄FNO: 231.1059; found: 231.1062.

2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde oxime (MD-3-A7): Prepared according to the general procedure discussed above with 8 (0.86 mmol) and hydroxylamine hydrochloride. The crude mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc:H20 in a separatory funnel where the organic layer was separated. The aqueous layer was back extracted with 2 ^χ 10 ml_ portions of ethyl acetate. The combined organic layers were washed with 10 mL of a saturated aqueous NaCI solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford the title compound, RF = 0.47, 20%

MTBE:hexanes; isolated yield 0.132 g, 52%; gold solid; mp = 179.5-181.2 °C; ¹ H NMR (500 MHz, CDC ): δ 8.41 (s, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 16.0 Hz, 1 H), 6.63 (d, J = 16.0 Hz, 1 H), 2.80-2.72 (m, 4H), 2.00 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCb): δ 145.9, 144.9, 140.7, 135.3, 130.4, 129.8 (d, J = 31.8 Hz), 126.83, 126.8X (overlaps with 126.83), 125.8 (d, J = 3.6 Hz), 123.5, 33.7, 30.0, 21.8; IR (ATR- CDC ): u_max = 3240, 2965, 2838, 161 1 , 1457, 1320, 1 165, 1 1 19, 1 108, 1066, 867, 819 cm^"1; HRMS (El): m/z calculated for C₁₅H₁₄F₃NO: 281.1027; found: 281.1037.

2-(2-p-Tolyl-vinyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A8): Prepared according to the general procedure discussed above with 5 (0.30 mmol) and hydroxylamine hydrochloride, RF = 0.51 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.051 g, 75%; off-white solid; mp = 172.9-177.4 °C; ¹H NMR (500 MHz, CDCI3): δ 8.40 (s, 1 H), 7.35 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 16.0 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 2H), 6.60 (d, J = 16.0 Hz, 1 H), 2.78-2.68 (m, 4H), 2.35 (s, 3H), 1.97 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 146.4, 145.6, 138.0, 134.4, 132.9, 132.0, 129.5, 126.6, 120.2, 33.7, 32.7, 21.7, 21.2; IR (ATR-CDCI3): 0_max = 3200, 2955, 2847, 1615, 1583, 151 1 , 1465, 1006, 940, 801 cm^"1 ; HRMS (El): m/z calculated for C₁₅H₁₇NO: 227.1310; found: 227.1302.

2-[2-(4-Methoxy-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde oxime (MD-3-A9):

Prepared according to the general procedure discussed above with 6 (0.44 mmol) and hydroxylamine hydrochloride, RF = 0.30, 20% EtOAc:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase; isolated yield 0.074 g, 99%; off-white solid; mp = 151.2-153.0 °C; ¹ H NMR (500 MHz, CDCI₃): δ 8.40 (s, 1 H), 7.42-7.38 (m, 2H), 7.1 1 (d, J = 16.0 Hz, 1 H), 6.91-6.86 (m, 2H), 6.58 (d, J = 16.0 Hz, 1 H), 3.83 (s, 3H), 2.77-2.68 (m, 4H), 1.97 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDC ): δ 159.7, 146.5, 14538, 132.4, 131.7, 130.1 , 128.1 , 1 19.3, 1 14.4, 55.5, 33.8, 32.8, 21.8; IR (ATR-CDC ): O_max = 3260, 3032, 3002, 2841 , 1602, 1510, 1248, 1 174, 904, 819, 726 cm^"1; HRMS (El): m/z calculated for C15H17NO2: 243.1259; found: 243.1265.

2-(2-Cyclopentyl-vinyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A12): Prepared according to the general procedure discussed above with 2-(2-cyclopentyl-vinyl)-cyclopent-

1 - enecarbaldehyde (0.34 mmol) and hydroxylamine hydrochloride, RF = 0.66, 20%

MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.040 g, 57%; peach solid; mp = 123.4-128.0 °C; ¹H NMR (500 MHz, CDCb) major diastereomer. δ 8.26 (s, 1 H), 6.49 (d, J = 15.5 Hz, 1 H), 5.79 (dd, J = 15.5, 8.0 Hz, 1 H), 2.67-2.57 (m, 4H), 2.56-2.49 (m, 1 H), 1 .90 (pent, J = 7.5 Hz, 2H), 1.86-1 .78 (m, 2H), 1.71 -1.63 (m, 2H), 1 .62-1.55 (m, 2H), 1 .37-1 .28 (m, 2H); ¹³C NMR (125 MHz, CDCI₃) major diastereomer. δ 146.8, 146.5, 140.6, 130.2, 121.3, 44.2, 34.0, 33.4, 32.6, 24.4, 21.8; IR (ATR-CDCb): 0_max = 3261 , 2951 , 2868, 1637, 1617, 996, 956, 935 cm^"1 ; HRMS (El): m/z calculated for

C13H19NO: 205.1467; found: 205.1459.

2- (2-Cyclohexyl-vinyl)-cyclopent-1 -enecarbaldehyde oxime (MD-3-A13): Prepared according to the general procedure discussed above with 10 (0.49 mmol) and hydroxylamine hydrochloride, RF = 0.56, 20% EtOAc:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase; isolated yield 0.060 g, 56%; cream colored solid; mp = 136.2-137.9 °C; H NMR (500 MHz, CDCI₃) major diastereomer. 5 8.27 (s, 1 H), 6.47 (d, J = 15.5 Hz, 1 H), 5.74 (dd, J = 15.5, 7.5 Hz, 1 H), 2.63 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.90 (pent, J = 7.5 Hz, 2H), 1.78-1 .71 (m, 4H), 1 .70-1.63 (m, 1 H), 1 .35-1 .23 (m, 3H), 1.22-1.06 (m, 3H); ³C NMR (125 MHz, CDCI3) major diastereomer. δ 146.7, 146.1 , 141.1 , 130.6, 120.6, 41.5, 33.9, 33.0, 32.6, 26.2, 26.1 , 21.8; IR (ATR-CDCb): 0_max = 3267, 2994, 2921 , 2848, 1637, 1585, 1451 , 1003, 955, 933 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₂iNO: 219.1623; found: 219.1627.

2-[2-(3-Methoxy-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde oxime (MD-3-A21):

Prepared according to the general procedure discussed above with 12 (0.35 mmol) and hydroxylamine hydrochloride, RF = 0.41 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.040 g, 51 %; off-white solid; mp = 156.4-158.8 °C; H NMR (500 MHz, CDCb): δ 8.41 (s, 1 H), 7.28-7.24 (m, 1 H), 7.22 (d, J = 16.0 Hz, 1 H), 7.07-7.03 (m, 1 H), 6.99-6.97 (m, 1 H), 6.82 (ddd, J = 8.2, 2.4, 0.8 Hz), 6.58 (d, J = 16.0 Hz, 1 H), 3.85 (s, 3H), 2.78-2.68 (m, 4H), 1.98 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 160.1 , 146.6, 145.4, 138.7, 133.8, 132.0, 129.9, 121.5, 1 19.6, 1 14.0, 1 1 1.8, 55.4, 33.8, 32.9, 21.8; I R (ATR-CDCb): O_max = 3164, 3002, 2837, 1603, 1575, 1490, 1433, 1261 , 1044, 950, 770, 684 cm^"1; HRMS (El): m/z calculated for Ci₅Hi₇N0₂: 234.1259; found: 243.1258.

2-[2-(3,5-Difluoro-phenyl)-vinyl]-cyclopent-1-enecarbaldehyde oxime (MD-3-A22): Prepared according to the general procedure discussed above with 13 (0.30 mmol) and hydroxylamine hydrochloride, RF = 0.55, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.066 g, 88%; pale-pink solid; mp = 171.4-176.1 °C; H

NMR (500 MHz, CDCb): δ 8.38 (s, 1 H), 7.43 (br-s, 1 H), 7.20 (d, J = 16.0 Hz, 1 H), 6.97-6.92 (m, 2H), 6.72-6.67 (m, 1 H), 6.50 (d, J = 16.0 Hz, 1 H), 2.77-2.69 (m, 4H), 1 .99 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, (CD₃)₂CO): δ 164.1 (dd, J = 250.0, 13.0 Hz), 145.8, 143.1 , 142.6, 138.0, 129.6 (t, J = 3.0 Hz), 125.4, 1 10.2 (dd, J = 19.5, 5.5 Hz), 103.1 (t, J = 26.5 Hz), 33.9, 33.7, 23.3; IR (ATR-CDCb): 0_max = 3181 , 3078, 2921 , 2851 , 1612, 1590, 1437, 1 122, 980, 951 cm^"1 ; HRMS (El): m/z calculated for Ci₄Hi₃F₂NO: 249.0965; found: 249.0970. 2-Phenyl-cyclopent-1-enecarbaldehyde oxime (MD-3-A23): Prepared according to the general procedure discussed above with 2-phenyl-cyclopent-1-enecarbaldehyde (0.86 mmol) and hydroxylamine hydrochloride, RF = 0.34, 10% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.1 18 g, 74%; yellow solid; mp = 105.1 -107.1 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.10 (s, 1 H), 7.39-7.35 (m, 2H), 7.32-7.27 (m, 3H), 2.90-2.84 (m, 2H), 2.79-2.74 (m, 2H), 2.02 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCb): δ 148.6, 148.2, 136.7, 131.8, 128.4, 128.0, 127.8, 38.4, 33.0, 22.0; IR (ATR-CDCb): Umax = 3261 , 3055, 3953, 3849, 1601 , 1620, 1493, 967, 760, 698 cm^"1 ; HRMS (El): m/z calculated for C₁₂H₁₃NO: 187.0997; found: 187.1000.

2-Vinyl-cyclopent-1-enecarbaldehyde oxime (MD-3-A25): Prepared according to the general procedure discussed above with 2-vinyl-cyclopent-1-enecarbaldehyde (0.50 mmol) and hydroxylamine hydrochloride, RF = 0.54, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 7.5% isocratic hold; isolated yield 0.014 g, 20%; brown oil; H NMR (500 MHz, CDCb) major diastereomer. δ 8.28 (s, 1 H), 6.81 (dd, J = 17.0, 10.0 Hz, 1 H), 5.29 (d, J = 17.5 Hz, 1 H), 5.27 (d, J = 10.0 Hz, 1 H), 2.67 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1 .92 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCb) major diastereomer. δ 146.4, 145.6, 133.2, 129.5, 1 17.5, 33.2, 32.8, 21.6; IR (ATR-CDCI₃): i = 3271 , 3093, 2925, 2849, 1603, 1009, 992, 937, 909, 733 cm^"1 ; HRMS (El): m/z calculated for C₈HnNO (M-H): 136.0757; found: 136.0765. 4-[2-(Hydroxyimino-methyl)-cyclopent-1 -enyl]-W-(2-methoxy-ethyl)-benzamide (MD-3- A27): Prepared according to the general procedure discussed above with 4-(2-formyl- cyclopent-1-enyl)-A/-(2-methoxy-ethyl)-benzamide (0.37 mmol) and hydroxylamine hydrochloride, RF = 0.32, 75% EtOAc:hexanes; purified using automated flash column chromatography using an EtOAc:hexanes gradient mobile phase; isolated yield 0.050 g, 48%; white film; ¹H NMR (500 MHz, CDCI₃): δ 8.33 (br-s, 1 H), 8.07 (s, 1 H), 7.80-7.70 (m, 2H), 7.35-7.30 (m, 2H), 6.65 (br-t, J = 5.0 Hz, 1 H), 3.70-3.65 (m, 2H), 3.60-3.56 (m, 2H), 3.41 (s, 3H), 2.89-2.84 (m, 2H), 2.79-2.74 (m, 2H), 2.02 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDC ): δ 167.2, 147.5, 147.1 , 140.0, 133.7, 133.0, 128.3, 127.2, 71.4, 59.0, 38.8, 38.4, 32.3, 22.1 ; IR (ATR-CDCI₃): 0_max = 3289, 3047, 2926, 2852, 1638, 1609, 1542, 1304, 1 1 17, 966, 853, 732 cm^"1 ; HRMS (El): m/z calculated for C16H20N2O3: 288.1474; found: 288.1479.

2-(3,3-Dimethyl-butyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A28): Prepared according to the general procedure discussed above with 2-(3,3-dimethyl-butyl)-cyclopent-1 - enecarbaldehyde (0.33 mmol) and hydroxylamine hydrochloride, RF = 0.55, 20%

MTBE:hexanes; purified using automated flash column chromatography using an

MTBE:hexanes gradient mobile phase employing a 7.5% isocratic hold; isolated yield 0.032 g, 50%; amorphous; ¹H NMR (500 MHz, CDCI₃): δ 8.10 (s, 1 H), 2.54 (br-t, J = 7.5 Hz, 2H), 2.45 (br-t, J = 7.5 Hz, 2H), 2.24-2.18 (m, 2H), 1.86 (pentet, J = 7.5 Hz, 2H), 1.31 -1.24 (m, 2H), 0.92 (s, 9H); ¹³C NMR (125 MHz, CDCI₃): δ 152.2, 146.5, 128.6, 42.7, 37.2, 30.6, 29.3, 24.1 , 21.9; IR (ATR-CDCI3): 0_max = 3290, 2953, 2866, 1639, 1601 , 904, 727, 650 cm^"1 ; HRMS (El): m/z calculated for C₁₂H₂iNO: 195.1623; found: 195.1620.

2-(3-Phenyl-propenyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A29): Prepared according to the general procedure discussed above with 11 (0.40 mmol) and hydroxylamine hydrochloride: RF = 0.55, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.060 g, 66%; brown liquid; H NMR (500 MHz, CDCI₃); major diastereomer. δ 8.25 (s, 1 H), 7.33-7.27 (m, 2H), 7.24-7.13 (m, 3H), 6.56 (d, J = 15.5 Hz,

1 H), 5.93 (dt, J = 15.5, 7.0 Hz,, 1 H), 3.50 (d, J = 7.0 Hz, 2H), 2.65 (br-t, J = 7.5 Hz, 2H), 2.59 (br-t, J = 7.5 Hz, 2H), 1.89 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃) major diastereomer: δ 146.2, 145.8, 139.9, 133.7, 131.4, 128.8, 128.7, 126.5, 124.2, 39.8, 34.0, 32.6, 21.7; IR (ATR-CDCI₃): 0_max = 3526, 3026, 2845, 1602, 1495, 1452, 994, 957, 931 , 748, 698 cm^"1; HRMS (El): m/z calculated for C₁₅H₁₇NO: 227.1310; found: 227.1306.

2-Styryl-cyclohex-1 -enecarbaldehyde oxime (MD-3-A33): Prepared according to the general procedure discussed above with 14 (0.54 mmol) and hydroxylamine hydrochloride, RF = 0.50, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.061 g, 50%; white solid; mp = 142.0-143.0 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.61 (s, 1 H), 7.47-7.43 (m, 2H), 7.39-7.32 (m, 3H), 7.28-7.23 (m, 1 H), 6.70 (d, J = 15.9 Hz, 1 H), 2.49-2.41 (m, 4H), 1 .78-1 .65 (m, 4H); ¹³C NMR (125 MHz, CDCb): δ 149.1 , 139.1 , 167.5, 129.6, 129.3, 128.8, 127.9, 126.7, 125.0, 26.9, 25.5, 22.4, 22.1 ; IR (ATR-CDCb): 0_max =

3289, 3056, 2931 , 2861 , 1599, 1582, 1495, 950, 748, 691 cm^"1 ; HRMS (El): m/z calculated for C₁₅H₁₇NO: 227.1310; found: 227.1304.

2-(2-p-Tolyl-vinyl)-cyclohex-1 -enecarbaldehyde oxime (MD-3-A34): Prepared according to the general procedure discussed above with 15 (0.35 mmol) and hydroxylamine hydrochloride, RF = 0.49, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 7.5% isocratic hold; isolated yield 0.059 g, 69%; white solid; mp = 145.5-155.5 °C; ¹ H NMR (500 MHz, CDCb): δ 8.60 (s, 1 H), 7.34 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 16.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 16.0 Hz, 1 H), 2.49-2.40 (br-m, 4H), 2.35 (s, 3H), 1.77-1 .65 (m, 4H); ¹³C NMR (125 MHz, CDCI₃): δ 149.3, 139.3, 138.0, 134.7, 129.6, 129.6, 128.8, 126.7, 124.0, 26.9, 25.5, 22.4, 22.1 , 21.4; IR (ATR-CDCI3): 0_max = 3249, 3053, 3017, 2931 , 2861 , 161 1 , 1578, 1444, 950, 800 cm^"1 ; HRMS (El): m/z calculated for C₁₆H₁₉NO: 241 .1467; found: 241.1465.

2-(4-Methoxy-phenyl)-cyclopent-1 -enecarbaldehyde oxime (MD-3-A36): Prepared according to the general procedure discussed above with 19 (0.76 mmol) and hydroxylamine hydrochloride, RF = 0.32, 20% MTBE:hexanes; purified using automated flash column chromatography using an EtOAc:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.085 g, 51 %; yellow solid; mp = 103.0-106.0 °C; ¹H NMR (500 MHz, CDCb): δ 8.12 (s, 1 H), 7.24-7.21 (m, 2H), 6.92-6.88 (m, 2H), 3.83 (s, 3H), 2.86-2.82 (m, 2H), 2.78-2.73 (m, 2H), 2.00 (pent, J = 7.5 Hz, 2H); ³C NMR (125 MHz, CDCb): δ 159.5, 148.5, 148.1 , 130.1 , 129.4, 129.2, 1 14.0, 55.4, 38.4, 30.1 , 22.0; IR (ATR-CDC ): 0_max = 3270, 3044, 2838, 1607, 1510, 1462, 1441 , 1249, 1 178, 1033, 965, 832 cm^"1 ; HRMS (El): m/z calculated for C₁₃H₁₅N0₂: 217.1 103; found: 217.1098. 2-p-Tolyl-cyclopent-1-enecarbaldehyde oxime (MD-3-A37): Prepared according to the general procedure discussed above with 17 (0.46 mmol) and hydroxylamine hydrochloride, RF = 0.39, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.065 g, 70%; yellow solid; mp = 157.0-159.5 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.20 (s, 1 H), 7.34 (s, 4H), 2.96-2.91 (m, 2H), 2.87-2.82 (m , 2H), 2.45 (s, 3H), 2.09 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 149.2, 148.5, 137.9, 133.8, 130.7, 129.2, 128.1 , 38.5, 33.1 , 22.1 , 21 .4; IR (ATR-CDC ): 0_max = 3529, 2961 , 2853, 1620, 1513, 1447, 969, 822 cm^"1; HRMS (El): m/z calculated for C13H15NO: 201.1 154; found: 201.1 153.

2-(4-ferf-Butyl-phenyl)-cyclopent-1 -enecarbaldehyde oxime (MD-3-A38): Prepared according to the general procedure discussed above with 18 (0.58 mmol) and hydroxylamine hydrochloride, RF = 0.50, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.060 g, 47%; white solid; mp = 136.0-137.5 °C; ¹ H NMR (500 MHz, CDC ): δ 8.14 (s, 1 H), 7.41 -7.37 (m, 2H), 7.25-7.20 (m, 2H), 2.90-2.84 (m, 2H), 2.80-2.73 (m, 2H), 2.01 (pent, J = 7.5 Hz, 2H), 1.35 (s, 9H); ³C NMR (125 MHz, CDCb): δ 151.1 , 148.8, 148.2, 133.8, 130.9, 127.9, 125.4, 39.4, 34.8, 33.1 , 31.4, 22.1 ; IR (ATR-CDCI3): 0_max = 3270, 3036, 2960, 2868, 1617, 1508, 1462, 1442, 969, 834 cm^"1 ; HRMS (El): m/z calculated for C16H21 NO: 243.1623; found: 243.1620.

2-(4-Dimethylamino-phenyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A39): Prepared according to the general procedure discussed above with 20 (0.35 mmol) and hydroxylamine hydrochloride, RF = 0.43, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 2.5% isocratic hold; isolated yield 0.049 g, 60%; beige solid; mp = 186.0-187.5 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.20 (s, 1 H), 7.22-7.18 (m, 2H), 6.72 (br-d, J = 8.5 Hz, 2H), 2.98 (s, 6H),

2.86-2.81 (m, 2H), 2.77-2.72 (m, 2H), 1.98 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCb): δ 150.2, 148.8, 148.6, 129.22, 129.2X (overlaps with 129.22), 1 12.22, 40.6, 38.2, 33.1 , 22.0; IR (ATR-CDCI₃): 0_max = 3195, 2953, 2853, 1610, 1521 , 1359, 965, 905, 727 cm^"1; HRMS (El): m/z calculated for C14H18N2O: 230.1419; found: 230.1425.

2-(4-Methylsulfanyl-phenyl)-cyclopent-1-enecarbaldehyde oxime (MD-3-A40): Prepared according to the general procedure discussed above with 21 (0.73 mmol) and hydroxylamine hydrochloride, RF = 0.34, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 10% isocratic hold; isolated yield 0.097 g, 57%; yellow solid; mp = 141.0-142.5 °C; ¹H NMR (500 MHz, CDC ): δ 8.10 (s, 1 H), 7.26-7.22 (m, 2H), 7.21 -7.17 (m, 2H), 2.87-2.81 (m, 2H), 2.78-2.73 (m, 2H), 2.49 (s, 3H), 2.01 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 148.3, 148.2, 138.6, 133.4, 131.2, 128.6, 126.4, 38.3, 33.1 , 22.1 , 15.8; IR (ATR-CDCI3): O_max = 3256, 3002, 2951 , 2924, 2850, 1623, 1605, 1591 , 965, 818 cm^"1 ; HRMS (El): m/z calculated for C13H15NOS: 233.0874; found: 233.0875.

2-Benzo[1 ,3]dioxol-5-yl-cyclopent-1-enecarbaldehyde oxime (MD-3-A41): Prepared according to the general procedure discussed above with 22 (0.41 mmol) and hydroxylamine hydrochloride, RF = 0.34, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.062 g, 65%; tan solid; mp = 139.0-141 .5 °C; ¹H NMR (500 MHz,

CDCb): δ 8.10 (s, 1 H), 6.82-6.79 (m, 1 H), 6.77-6.74 (m, 2H), 5.98 (s, 2H), 2.84-2.79 (m, 2H), 2.77-2.71 (m, 2H), 2.00 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 148.5, 148.1 , 147.8, 147.5, 130.7, 122.03, 122. OX (overlaps with 122.03), 108.5, 108.4, 101.3, 38.6, 33.1 , 22.0; IR (ATR-CDCI3): 0_max = 3271 , 2957, 2895, 2850, 1621 , 1605, 1504, 1487, 1440, 1248, 1039, 936 cm^"1 ; HRMS (El): m/z calculated for C13H13NO3: 231.0895; found: 231.0889.

2- Styryl-cyclopent-1-enecarbaldehyde O-methyl-oxime (MD-3-A42): Prepared according to the general procedure discussed above with 4 (0.16 mmol) and methoxyamine hydrochloride, RF = 0.39, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; isolated yield 0.030 g, 89%; orange solid; mp = 139.0-141 .5 °C; ¹H NMR (500 MHz, CDCI3): δ 8.37 (s, 1 H), 7.46-7.42 (m, 2H), 7.36-7.31 (m, 2H), 7.27-7.23 (m, 1 H), 7.21 (d, J = 16.0 Hz, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 3.94 (s, 3H), 2.74 (t, J = 7.5 Hz, 4H), 1.97 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 145.1 , 144.8, 137.4, 133.9, 131.8, 128.9, 128.1 , 126.7, 121.4, 62.0, 33.8, 33.0, 21.9; IR (ATR-CDCI3): 0_max = 3031 , 2935, 2846, 2816, 1601 , 1588, 1495, 1448, 1055, 750, 691 cm^"1 ; HRMS (El): m/z calculated for C₁₅H₁₇NO: 227.1310; found: 227.1315.

3- Phenyl-6,7-dihydro-5H-[2]pyrindine (MD-3-A43): Material afforded as a byproduct to chromatographic purification of MD-3-A42 above. RF = 0.80, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 5% isocratic hold; film; H NMR (500 MHz, CD₃OD): δ 8.42 (s, 1 H), 7.88-7.84 (m, 2H), 7.71 (s, 1 H), 7.49-7.44 (m, 2H), 7.42-7.40 (m, 1 H), 3.05-2.98 (m, 4H), 2.17 (pent, J = 7.5 Hz, 2H); ¹³C NMR (125 MHz, CDCI₃): δ 157.5, 157.0, 145.5, 140.8, 140.7, 129.8, 129.7, 128.2, 1 18.9, 33.7, 30.8, 26.2; IR (ATR-CDCI3): 0_max = 3201 , 3029, 2847, 1606, 1556, 1475, 1448, 1073, 736, 694 cm^"1 ; HRMS (El): m/z calculated for C₁₄H₁₃N: 195.1048; found: 195.1048.

2-(2-p-Tolyl-vinyl)-benzaldehyde oxime (MD-3-A45): Prepared according to the general procedure discussed above with 33 (0.52 mmol) and hydroxylamine hydrochloride, RF = 0.36, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 10% isocratic hold; isolated yield 0.050 g, 41 %; pale-yellow solid; mp = 125.7-127.3 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.55 (s, 1 H), 7.70 (dd, J = 7.7, 1.3 Hz, 1 H0, 7.67 (d, J = 8.0 Hz, 1 H), 7.57 (br-s, 1 H), 7.49-7.37 (m, 4H), 7.34-7.26 (m, 1 H), 7.18 (d, J = 7.7 Hz, 2H), 6.96 (d, J = 16.0 Hz, 1 H), 2.38 (s, 3H); ³C NMR (125 MHz, CDC ): δ 149.5, 138.2, 137.3, 134.5, 132.5, 130.1 , 129.6, 129.5, 127.6, 126.9, 126.8, 124.6, 21.4; IR (ATR-CDC ): 0_max = 3307, 3056, 3027, 2920, 1634, 1597, 1515, 1485, 1451 , 1302, 961 , 804, 753 cm^"1 ; HRMS (El): m/z calculated for C₁₆H₁₅NO: (M-H) 236.1070; found: 236.1068.

2-[2-(4-Methoxy-phenyl)-vinyl]-benzaldehyde oxime (MD-3-A46): Prepared according to the general procedure discussed above with 34 (0.81 mmol) and hydroxylamine hydrochloride, RF = 0.36, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase; isolated yield 0.090 g, 65%; pale-yellow solid; mp = 142.3-144.2 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.52 (s, 1 H), 7.67 (dd, (J = 7.8, 1.3 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 1 H), 7.34 (d, J = 16.3 Hz, 1 H), 7.28-7.26 (m, 1 H), 6.95-6.88 (m, 3H), 3.83 (s, 3H); ¹³C NMR (125 MHz, CDCb): δ 159.7, 149.6, 137.4, 132.0, 130.0, 129.97, 129.3, 128.1 , 127.5, 127.4,

126.7, 123.4, 1 14.2, 55.4; IR (ATR-CDCI3): 0_max = 3193, 2990, 2966, 2912, 2838, 1603, 151 1 , 1246, 1 176, 1030, 980, 959, 824, 81 1 , 761 , 546, 517 cm^"1; HRMS (El): m/z calculated for C₁₆H₁₅N0₂: 253.1 103; found: 253.1091 .

4'-Methoxy-biphenyl-2-carbaldehyde oxime (MD-3-A52): Prepared according to the general procedure discussed above with 36 (0.65 mmol) and hydroxylamine hydrochloride, RF = 0.39, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 20% isocratic hold; isolated yield 0.074 g, 51 %; amorphous; H NMR (500 MHz, CDCb): δ 8.12 (s, 1 H), 7.89 (7.3, 1.8 Hz, 1 H), 7.42 (dt, J = 7.5, 1.3 Hz, 1 H), 7.38-7.31 (m, 2H), 7.26-7.21 (m, 3H), 7.00-6.96 (m, 2H), 3.87 (s, 3H); ¹³C NMR (125 MHz, CDCb): δ 159.3, 150.2, 142.1 , 132.0, 131.0, 130.5,

129.8, 129.75, 128.3, 127.4, 1 14.0, 55.1 ; IR (ATR-CDCI3): 0_max = 3299, 3068, 2835, 1610, 1515, 1482, 1442, 1298, 1245, 1 178, 955, 834, 763 cm^"1; HRMS (El): m/z calculated for C₁₄H₁₃N0₂: 227.0946; found: 227.0947. 2-Styryl-pyridine-3-carbaldehyde oxime (MD-3-A53): Prepared according to the general procedure discussed above with 24 (0.32 mmol) and hydroxylamine hydrochloride, RF = 0.23, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 30% isocratic hold; isolated yield 0.030 g, 42%; white solid; mp = 168.1 -171.1 °C; ¹H NMR (500 MHz, CDCb): δ 8.62 (dd, J = 4.7, 1 .8 Hz, 1 H), 8.54 (s, 1 H), 7.98 (dd, J = 8.0, 1.8 Hz, 1 H), 7.81 (d, J = 15.6 Hz, 1 H), 7.61 -7.57 (m, 2H), 7.56 (br-s, 1 H), 7.49 (d, J = 15.6 Hz, 1 H), 7.40-7.35 (m, 2H), 7.33-7.28 (m, 1 H), 7.18 (dd, J = 8.0, 4.7 Hz, 1 H); ¹³C NMR (125 MHz, CDCI₃): δ 153.2, 150.6, 147.7, 136.8, 135.9, 135.4, 128.9, 128.8, 127.6, 125.3, 123.3, 122.3; I R (ATR-CDCb): 0_max = 3058, 2879, 2772, 1634, 1578, 1494, 904, 727, 650 cm^"1; HRMS (El): m/z calculated for C₁₄H₁₂N₂0: (M-H) 223.0866; found: 223.0872.

2-(2-p-Tolyl-vinyl)-pyridine-3-carbaldehyde oxime (MD-3-A54): Prepared according to the general procedure discussed above with 25 (0.60 mmol) and hydroxylamine

hydrochloride, RF = 0.16, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 35% isocratic hold; isolated yield 0.101 g, 72%; white solid; mp = 143.9-146.5 °C; H NMR (500 MHz, CDCb): 5 8.62 (dd, J = 4.7, 1.8 Hz, 1 H), 8.56 (br-s, 1 H), 7.99 (dd, J = 7.9, 1.8 Hz, 1 H), 7.80 (d, J = 15.9 Hz, 1 H), 7.53-7.48 (m, 3H), 7.45 (d, J = 15.9 Hz, 1 H), 7.22-7.16 (m, 3H), 2.38 (s, 3H); ³C NMR (125 MHz, CDCb): δ 153.1 , 149.9, 147.3, 139.2, 136.7, 135.9, 133.8, 129.7, 127.6, 125.5, 122.1 , 121.5, 21 .5; I R (ATR-CDCb): 0_max = 2986, 2883, 1636, 1581 , 1510, 1477, 1407, 1066, 1058, 980, 812, 798 cm^"1 ; HRMS (El): m/z calculated for

C₁₅H₁₄N₂0: (M-H) 237.1022; found: 237.1029.

2-[2-(4-Methoxy-phenyl)-vinyl]-pyridine-3-carbaldehyde oxime (MD-3-A55): Prepared according to the general procedure discussed above with 26 (0.21 mmol) and hydroxylamine hydrochloride, RF = 0.1 1 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 15% isocratic hold; isolated yield 0.026 g, 47%; amorphous; H NMR (500 MHz, CDCb): δ 8.59 (dd, J = 4.7, 1.7 Hz, 1 H), 8.54 (s, 1 H), 7.96 (dd, J = 7.9, 1.7 Hz, 1 H), 7.77 (d, J = 15.7 Hz, 1 H), 7.56-7.52 (m, 2H), 7.44 (br-s, 1 H), 7.35 (d, J = 15.7 Hz, 1 H), 7.15 (dd, J = 7.9, 4.7 Hz, 1 H), 6.93-6.88 (m, 2H), 3.84 (s, 3H); ³C NMR (125 MHz, CDCb): δ 160.3, 153.6, 150.5, 147.6, 135.6, 135.3, 129.5, 129.0, 125.0, 121.9, 121.0, 1 14.3, 55.5; I R (ATR-CDCb): 0_max = 3162, 3064, 2837, 2771 , 1632, 1605, 1575, 151 1 , 1427, 1253, 1 174, 1031 , 971 , 826 cm^"1; HRMS (El): m/z calculated for dsHwNzOz: 254.1055; found: 254.1052. 2-Phenyl-pyridine-3-carbaldehyde oxime (MD-3-A56): Prepared according to the general procedure discussed above with 27 (0.44 mmol) and hydroxylamine hydrochloride, RF = 0.1 1 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 25% isocratic hold; isolated yield 0.061 g, 70%; white solid; mp = 103.2-104.7 °C; ¹H NMR (500 MHz, CDCI₃): δ 8.71 (dd, J = 4.8, 1 .8 Hz, 1 H), 8.22 (dd, J = 8.0, 1.8 Hz, 1 H), 8.16 (br-s, 1 H), 7.55-7.51 (m, 2H), 7.50-7.42 (m, 3H), 7.32 (dd, J = 8.0, 4.8 Hz, 1 H); ¹³C NMR (125 MHz, CDCI₃): δ 158.5, 150.5, 148.5, 138.6, 134.6, 129.8, 129.0, 128.6, 126.1 , 122.5; IR (ATR-CDCI₃): 0_max = 3060, 2865, 1564, 1439, 1420, 976, 880, 747, 701 cm^"1; HRMS (El): m/z calculated for C12H10N2O: 198.0793; found: 198.0793.

2-p-Tolyl-pyridine-3-carbaldehyde oxime (MD-3-A57): Prepared according to the general procedure discussed above with 28 (0.22 mmol) and hydroxylamine hydrochloride, RF = 0.21 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 15% isocratic hold; isolated yield 0.030 g, 63%; white solid; mp = 203.6-206.2 °C; ¹H NMR (500 MHz, CDCb): δ 8.70 (dd, J = 4.7, 1 .7 Hz, 1 H), 8.19 (dd, J = 8.0, 1.7 Hz, 1 H), 8.17 (s, 1 H), 7.45-7.41 (m, 2H), 7.35 (br-s, 1 H), 7.30-7.27 (m, 3H), 2.43 (s, 3H); ¹³C NMR (125 MHz, CDCb): δ 158.6, 150.6, 148.9, 138.9, 135.8, 134.6, 129.8, 129.3, 125.8, 122.2, 21.5; IR (ATR-CDCI3): 0_max = 3163, 3052, 2990, 2871 , 2764, 1615, 1582, 1512, 1424, 977, 881 , 827, 773 cm^"1 ; HRMS (El): m/z calculated for C₁₃H₁₂N₂0: 212.0950; found: 212.0951 .

2- (4-Methoxy-phenyl)-pyridine-3-carbaldehyde oxime (MD-3-A58): Prepared according to the general procedure discussed above with 29 (0.32 mmol) and hydroxylamine hydrochloride, RF = 0.08, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 10% isocratic hold; isolated yield 0.061 g, 84%; pale-yellow solid; mp = 208.4-212.1 °C; ¹H NMR (500

MHz, CDCb): δ 8.71 -8.68 (m, 1 H), 8.21 -8.16 (br-m, 2H), 7.52-7.47 (m, 2H), 7.30-7.26 (m, 1 H), 7.05-6.98 (m, 2H), 3.88 (s, 3H); ¹³C NMR (125 MHz, CDCb): δ 160.4, 158.2, 150.6, 149.0, 134.7, 131.3, 131.1 , 125.7, 122.0, 1 14.1 , 55.5; IR (ATR-CDCI3): 0_max = 3163, 3068, 2829, 2764, 1608, 1581 , 1515, 1423, 1250, 1 177, 903, 726 cm^"1 ; HRMS (El): m/z calculated for C13H12N2O2: 228.0899; found: 228.0907.

3- Styryl-thiophene-2-carbaldehyde oxime (MD-3-A59): Prepared according to the general procedure discussed above with 30 (0.27 mmol) and hydroxylamine hydrochloride, RF = 0.51 , 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 25% isocratic hold; isolated yield 0.038 g, 62%; light-brown solid; mp = 132.9-135.1 °C; H NMR (500 MHz, CDCI₃): δ 8.56 (s, 1 H), 7.51 (d, J = 8.1 Hz, 2H), 7.40-7.35 (m, 2H), 7.34-7.28 (m, 2H), 7.26-7.23 (m, 1 H), 7.14 (s, 1 H), 7.02 (d, J = 16.2 Hz, 1 H); ³C NMR (125 MHz, CDC ): δ 144.1 , 140.5, 137.0, 131.5, 130.4, 128.9, 128.3, 127.4, 126.7, 125.7, 120.0; HRMS (El): m/z calculated for C13H11 NOS: 229.0561 ; found: 229.0555.

3-(4-Methoxy-phenyl)-thiophene-2-carbaldehyde oxime (MD-3-A67): Prepared according to the general procedure discussed above with 31 (0.24 mmol) and hydroxylamine hydrochloride, RF = 0.20, 20% MTBE:hexanes; purified using automated flash column chromatography using an MTBE:hexanes gradient mobile phase employing a 15% isocratic hold; isolated yield 0.022 g, 38%; amorphous; ¹H NMR (500 MHz, CDCI₃): δ 7.70 (br-s, 1 H), 7.55 (dd, J = 5.8, 0.7 Hz, 1 H), 7.35-7.30 (m, 2H), 7.10 (d, J = 5.0 Hz, 1 H), 6.99-6.95 (m, 2H), 3.85 (s, 3H); ¹³C NMR (125 MHz, CDCI₃): δ 159.5, 146.1 , 141 .3, 131.0, 130.4, 128.53, 128.45, 124.9, 1 14.2, 55.5; IR (ATR-CDCI3): 0_max = 3215, 3100, 3002, 2932, 2841 , 1608, 1575, 1528, 1249, 1 178, 1031 , 833 cm^"1 ; HRMS (El): m/z calculated for C12H11 NO2S:

233.0510; found: 233.051 1.

The in vitro efficacy of these analogues was validated in the assay developed to study FGF-23 antagonism as described in Fig. 3, Fig. 6 and Fig. 7.

In vitro testing of novel compounds. Preliminary in vitro assay results using HEK-293 cells expressing FGFRs/a-Klotho and ERK activation as the read out provided substantive guidance towards the constituent arrangement of atoms required for FGF-23 antagonism. For example, electron donating functionality of MD-3 A8 and A9 (7) afforded 30% higher biological activity vs. MD-3. In the case of the vinyl analogue MD-3 A25 (10) and a saturated ring example MD-3 A13 (9) minimal biological activity was observed suggesting the aryl ring was significant. However, an analogue containing an aryl ring without extension of conjugation throughout the entire π-system (MD-3 A4) demonstrated slightly better activity to MD-3. MD-3 A23 (11 ), a direct connect aromatic analogue, demonstrated slightly lower biological activity compared to MD-3, but the excision of the interstitial trans-double bond alleviates two rotatable bonds and affords more rapid access to future functionally group diverse examples vide infra. As part of due diligence, the aldehyde precursor to MD-3 has also been screened and demonstrated lower biological activity than MD-3 which further underscores the significance of the oxime moiety to the MD-3 pharmacophore. With the ascertainment of critical data towards pharmacophore identification accomplished above, the proposed work will focus on refining novel chemical space towards final lead optimization. Study design. MD-3 was prioritized for its drug like properties and a synthetic approach for its construction and evaluation in an in vitro assay were undertaken. Here, computational structure-based methods using existing algorithms will concurrently be employed with synthetic efforts in lead optimization. The computational results will be used by the synthetic medical chemistry group to assist and prioritize the molecular design and the rationalization of activity data. These modifications will yield a compound library for QSAR development. QSAR data will be compared to structure-property relationship (SPR) data to determine orally available analogs with enhanced potency.

Persons of ordinary skill can utilise the disclosures and teachings herein to produce other embodiments and variations without undue experimentation. All such embodiments and variations are considered to be part of this invention.

Accordingly, one of ordinary skill in the art will readily appreciate from the disclosure that later modifications, substitutions, and/or variations performing substantially the same function or achieving substantially the same result as embodiments described herein may be utilised according to such related embodiments of the present invention. Thus, the invention is intended to encompass, within its scope, the modifications, substitutions, and variations to processes, manufactures, compositions of matter, compounds, means, methods, and/or steps disclosed herein.

The description herein may contain subject matter that falls outside of the scope of the claimed invention. This subject matter is included to aid understanding of the invention.

In this specification, where reference has been made to external sources of information, including patent specifications and other documents, this is generally for the purpose of providing a context for discussing the features of the present invention. Unless stated otherwise, reference to such sources of information is not to be construed, in any jurisdiction, as an admission that such sources of information are prior art or form part of the common general knowledge in the art.

Claims

1 . A compound having the structure of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

ring W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine;

X is OH;

Y is H; and

R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyl;

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl; or

a phenyl group optionally substituted with thiomethyl, methoxy, amine, or fluoro.

2. The compound of claim 1 , wherein the compound is selected from the structure of Formula (I I):

(II)

or a pharmaceutically acceptable salt thereof, wherein:

X is OH;

Y is H;

R is an alkyl; a heterocycle; an aryl; a heteroaryl; an alkene optionally substituted with a cycloalkyl; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl; and

n is 0, 1 , 2, 3, or 4.

3. The compound of claim 1 , wherein the compound is selected from the structure consisti

or a pharmaceutically acceptable salt thereof, wherein:

X is OH;

Y is H; and

R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyl; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl.

4. The compound of claim 1 , wherein the compound is selected from the structure consisting of:

X is OH;

Y is H; and R is an alkyl; a heterocycle; an aryl; a heteroaryl;

an alkene optionally substituted with a cycloalkyl; or

an alkene optionally substituted with a phenyl ring which is optionally substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl;

5. A compound having the structure of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

ring W is a 4 to 8 membered cycloalkene ring, thiophene, furan, phenyl or pyridine;

X is OH;

Y is H; and

wherein:

Ar is a five or six-membered aromatic or five or six-membered heteroaromatic ring;

Ri is an alkyl, hydrogen, halogen, hydroxy, alkoxy, amine, thioalkyl, thiol, nitrile, ketone, aldehyde, heterocycle, or cycloalkyl;

W is an alkyl, hydrogen, halogen, hydroxy, alkoxy, ketone, aldehyde, amine, or nitrile;

F¾ is H, alkyl, aryl, halogen, hydroxy, alkoxy, amine, heterocycle, ketone, aldehyde, or nitrile.

6. The compound of claim 1 or 2, wherein the compound is selected from the structure of Formula (III):

(III)

or a pharmaceutically acceptable salt thereof, wherein:

X is OH;

Ri is alkyl, halogen, alkoxy, amine, or thioalkyl,; and

n is 1 , or 2.

7. The compound of any one of claims 5 or 6, wherein Ri is methyl, thiomethyl, tert- butyl, or methoxy.

8. The compound of claim 1 having the structure of Formula (IV):

(IV) or a pharmaceutically acceptable salt thereof, wherein:

X is OH;

Ar is a phenyl ring substituted with alkyl, alkoxy, thioalkyl, halogen, amide, amine, or haloalkyl; and

n is 1 , or 2.

9. The compound of claim 1 or 2, wherein the compound is selected from the structure of Formula (V):

(V)

or a pharmaceutically acceptable salt thereof, wherein:

X is OH;

Ri is methoxy, thiomethyl, amine, or fluoro; and

n is 1 , or 2.

10. The compound of any one of the preceding claims, wherein n is 1.

1 1. The compound of any one of the preceding claims, wherein each alkene group is independently cis or trans, or E or Z.

12. A pharmaceutical composition comprising a compound of any one of claims 1 -1 1 and a pharmaceutically acceptable carrier.

13. A method for the treatment of a disorder associated with Fibroblast growth factor-23 (FGF-23) excess in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-1 1 , or a pharmaceutical composition of claim 12.

14. The method of claim 13, wherein the disorder is a phosphate wasting disorder.

15. The method of claim 14, wherein the phosphate wasting disorder is hereditary or acquired hypophosphatemic disorder.

16. The method of claim 13, wherein the disorder is hereditary hypophosphatemic rickets, acquired hypophosphatemic rickets, or chronic kidney disease (CKD).

17. The method of claim 13, wherein the disorder is X-linked hypophosphatemic rickets (XLH), autosomal recessive hypophosphatemic rickets (ARHR), or Raine Syndrome (RNS).

18. The method of claim 13, wherein the disorder is a renal phosphate wasting disorder.

19. The method of claim 13, wherein the compound is used to inhibit FGF-23 activation of FGFRs/a-Klotho signaling.

20. The method of claim 13, wherein the compound increases serum phosphate and 1 .25D levels.

21. The method of claim 13, wherein the subject is human.

22. The method of claim 13, wherein the method is used in combination with one or more existing treatment methods.

23. A method of treating chronic kidney disease in a subject in need thereof, comprising administering to the selected subject an effective amount of a compound of any one of claims 1-1 1 , or a pharmaceutical composition of claim 12.