BINDING FUNCTION 3 (BF3) SITE COMPOUNDS AS THERAPEUTICS AND METHODS FOR THEIR USE

Abstract

This invention provides compound having a structure of Formulas:

Description

TECHNICAL FIELD

This invention relates to therapeutics, their uses and methods for the treatment of various indications, including various cancers. In particular the invention relates to therapies and methods of treatment for cancers such as prostate cancer.

BACKGROUND

Androgens are known to mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses, for example, male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Also, androgens are associated with the development of prostate carcinogenesis. Induction of prostatic carcinogenesis in rodent models has been associated with androgens (R. L. Noble, Cancer Res 37, 1929-1933 (1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receiving androgens in the form of anabolic steroids are reported to have a higher incidence of prostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986); J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Furthermore, prostate cancer does not develop if humans or dogs are castrated before puberty (J. D. Wilson & C. Roehrborn, J Clin EndocrinolMetab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (i.e. androgen ablation).

Prostate cancer is the second leading cause of male cancer-related death in Western countries (Damber, J. E. and Aus, G. Lancet (2008) 371:1710-1721). Numerous studies have shown that the androgen receptor (AR) is central not only to the development of prostate cancer, but also the progression of the disease to the castration resistance state (Taplin, M. E. et al. J. Clin. Oncol. (2003) 21:2673-8; and Tilley, W. D. et al. Cancer Res. (1994) 54:4096-4102). Thus, effective inhibition of human AR remains one of the most effective therapeutic approaches to the treatment of advanced, metastatic prostate cancer. The AR possesses a modular organization characteristic of all nuclear receptors. It is comprised of an N-terminal domain, a central DNA binding domain, a short hinge region, and C-terminal domain that contains a hormone ligand binding pocket and the Activation Function-2 (AF2) site (Gao, W. Q. et al. Chem. Rev. (2005) 105:3352-3370). The latter represents a hydrophobic groove on the AR surface which is flanked with regions of positive and negative charges—“charge clamps” that are significant for binding AR activation factors (Zhou, X. E. et al. J. Biol. Chem. (2010) 285:9161-9171). Recent studies have identified a novel site on the AR called Binding Function 3 (BF3) that is involved into AR transcriptional activity.

It has been proposed a small molecule bound to the BF3 site could cause the AR protein to undergo an allosteric modification that prevents AR interactions with co-activators. Importantly, the BF3 site is located near, but distinct from, the ligand-binding site that is normally targeted by conventional anti-androgen drugs. Chemicals such as flufenamic acid (FLUF), thriiodothyronine (T3) and 3,3′,5-triiodo thyroacetic acid (TRIAC), can bind to the BF3 cleft, inhibit AF2 interactions and interfere with AR activity (Estebanez-Perpina, E. et al. Proc Natl Acad Sci USA (2007) 104:16074-16079). While these compounds revealed the importance of the BF3 site, they have shown a low potency (IC₅₀>50 μM) and were found to bind non-specifically to the AR.

The activation of AR follows a well characterized pathway: in the cytoplasm, the receptor is associated with chaperone proteins that maintain agonist binding conformation of the AR (Georget, V. et al. Biochemistry (2002) 41:11824-11831). Upon binding of an androgen, the AR undergoes a series of conformational changes, disassociation from chaperones, dimerization and translocation into the nucleus (Fang, Y. F. et al. J. Biol. Chem. (1996) 271:28697-28702; and Wong, C. I. et al. J. Biol. Chem. (1993) 268:19004-19012) where it further interacts with co-activator proteins at the AF2 site (Zhou, X. E. et al. J. Biol. Chem. (2010) 285:9161-9171). This event triggers the recruitment of RNA polymerase II and other factors to form a functional transcriptional complex with the AR.

Notably, the current anti-androgens such as bicalutamide, flutamide, nilutamide and MDV3100, all target this particular process. However, instead of affecting the AR-cofactor interaction directly, these anti-androgens act indirectly, by binding to the AR ligand binding site. Thus, by preventing androgens from binding they also prevent conformational changes of the receptor that are necessary for co-activator interactions. While treatment with these AR inhibitors can initially suppress the prostate cancer growth, long term hormone therapy becomes progressively less effective (Taplin, M. E. et al. J. Clin. Oncol. (2003) 21:2673-8; and Tilley, W. D. et al. Cancer Res. (1994) 54:4096-4102). Factors that make the AR less sensitive to conventional anti-androgens include resistance mutations at the ligand binding site that can even lead AR antagonists to act as agonists further contributing to cancer progression (Chen, Y. et al. Lancet Oncol. (2009) 10:981-991).

Androgens also play a role in female cancers. One example is ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, et al., JAMA 274, 1926-1930 (1995); R. J. Edmondson, et al, Br J Cancer 86, 879-885 (2002)). The AR has been detected in a majority of ovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.

SUMMARY

This invention is based in part on the fortuitous discovery that compounds described herein modulate androgen receptor (AR) activity. Specifically, compounds identified herein, show inhibition of Androgen Receptor Binding Function-3 (BF3).

In accordance with a first aspect, there is provided a method of modulating AR activity, the method comprising administering a compound having the structure of Formula I:

wherein, is either a single or a double bond between D₂ and D₃;

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

I, OH,

or ═O;

A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

or ═O; D₁ is

wherein

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, are each independently CH or N;

E₂, E₃, E₄, E₅, and E₆, are each independently H, OH,

Br, Cl, F, I, or CH₃;

E₇ is CH₂, O, NH, or C═O;

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₁₅ is CH₂, O, NH, or C═O;

E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₂₃ is CH, CH₂, O, N, NH, or C═O;

where is either a single or a double bond between E₂₂ and E₂₃;

E₂₄ is CH₂, O, NH, or C═O;

E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₃₁ is N, CH, CBr, CCl, CF, COH, C═O, or CCH₃;

E₃₂ is NH, CH₂, O, or S;

E₃₃, E₃₄, E₃₅, and E₃₆, are each independently H, OH,

Br, Cl, F, I, or CH₃;

E₃₇ is S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₈ is NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or;

E₃₉ is CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃;

E₄₀ is CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃;

E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, are each independently H,

OH, Br, Cl, F, I, or CH₃;

D₂ is

G₁ is CH, N, CCH₃, CH₂,

O, S, or NH;

G₂ is C, CH, or N;

G₃ is CH,

CH₂, or N;

G₄ is

G₅, G₆, and G₇, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₈ is NH, CH₂, O, or S;

G₉, G₁₀, G₁₁, and G₁₂, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₁₃ is C, CH, or N;

G₁₄ is C═O, CH₂, or NH;

G₁₅ is C═O, CH₂, or NH;

G₁₆ is

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I, or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀, and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃;

G₂₂ is NH, CH₂, O, or S;

G₂₃, G₂₄, G₂₅, and G₂₆, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₂₇ is C, CH, CCH₃, CC(O)OCH₂CH₃, or N;

G₂₈ is C, CH, or N;

G₂₉ is CH, CH₂, C═O, CCH₃, or N;

where is either a single or a double bond between G₂₈ and G₂₉;

G₃₀ is CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH;

G₃₁, G₃₂, and G₃₃, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃,

CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N;

G₃₄, is H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N;

G₃₅, G₃₆, G₃₇, and G₃₈, are each independently C or N;

G₃₉ is C, CH, or N;

G₄₀ is CH, or N;

G₄₁ is NH, S, O, or CH₂;

G₄₂, G₄₃, G₄₄, and G₄₅, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₄₆ is C, CH, or N;

G₄₇, G₄₈, G₅₀, and G₅₁, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₄₉ is OH, Br, Cl, F, I or CH₃;

G₅₂ is C, CH, or N;

G₅₃ is CH₂, NH, S, or O;

G₅₄, G₅₅, G₅₆, G₅₇, and G₅a, are each independently H, OH, Br, Cl, F, I, or CH₃;

D₃ may be

D₃ may be

Alternatively, D₃ may be

provided that A₁ is H, CH₃, F, Cl or Br and A₂ is H, CH₃, NH₂, OH or OCH₃, A₃ is H, F, Cl or Br and A₄ is H, F, Cl or Br.

Alternatively, D₃ may be

provided A₁ is CH₃, A₂ is F, A₃ is H and A₄ is H.

Alternatively, D₃ may be

provided that at least one of A₁, A₃ or A₄ is F, Cl or Br and A₂ is H, CH₃, NH₂, OH or OCH₃.

Alternatively, D₃ may be

provided that at least one of A₂ or A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₄ is H.

Alternatively, D₃ may be

provided that A₁ is CH₃.

Alternatively D₃ may be

provided that at least one of A or A₂ is F, Cl, Br or CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is H, OH, CH₂OH,

CF₃, F, Cl or Br, A₃ is H, Br, NH₂, F, Cl, OCH₃,

CF₃, I, OH,

CF₃,

or ═O and A₄ is H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

or ═O.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then at least one or both of A₁ and A₃ are F, Cl or Br.

Alternatively, D₃ may be

provided that if A₁ is CH₃ then A₂ is not F, Br or Cl.

Alternatively D₃ may be

provided that if A₁ is CH₃ then A₂ is H.

Alternatively, D₃ may be

provided that A₁ is F, Br or Cl.

Alternatively, D₃ is

provided that A-A₄ are all H.

Alternatively, D₃ may be

provided that if A₄ is CH₃, then A₁ is CH₂OH,

CF₃, F, Cl or Br, A₂ is Br, NH₂, F, Cl,

CF₃, I or

and A₃ is Br, Cl, F, I, CH₃, NH₂,

CF₃,

or ═O.

Alternatively, D₃ may be

provided that A₄ is H, and A_1-4 are independently selected from Br, Cl, F, I, CH₃, NH₂,

CF₃,

or ═O.

Alternatively, D₃ may be

provided that A₂ is F and A₃ is F.

Alternatively, D₃ may be

provided that A₂ is F, Cl or Br and A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₁ is F, A₃ is F and A₄ is F.

Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl or Br.

Alternatively, D₃ is

provided that A₂ is H, if A₁ is CH₃.

J₁ is CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S, or NH.

J₂ is CH, C, or N.

J₃ is C═S, C═O, NH, or CH₂.

J₄ is CH or N;

J₅ is CH₂, NH, S or O;

J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ are each independently H, OH, Br, Cl, F, I, or CH₃;

J₁₄ is CH, C, or N;

J₁₅ is C═S, C═O, NH, or CH₂;

J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ are each independently H, OH, Br, Cl, F, I,

or CH₃;

J₂₁ is CH, C, or N;

J₂₂ is CH₂, or NH;

J₂₃ is CH, or N;

J₂₄, J₂₅, J₂₆, and J₂₇ are each independently H, OH, Br, Cl, F, I, or CH₃;

J₂₈ is CH, C, or N;

J₃₁ is H, OH, Br, F, I, C(O)NH₂, OCH₃, or CH₃;

J₂₉, J₃₀, J₃₂, and J₃₃ are each independently H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₃₄ is CH, C, or N;

J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ are each independently H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₄₀ is CH, C, or N;

J₄₁ is H, OH, Br, Cl, F, I, NH₂, or CH₃, or

J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ are each independently H, OH, Br, Cl, F, I, NH₂, or CH₃;

J₄₇ is CH, C, or N;

J₄₉ is S, CH₂, C═O, O, or NH;

J₄₉ is CH₂, C═O, S, O, or NH;

J₅₅ is C, or N;

J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃ or is absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N;

J₅₆ is CH, C, or N;

J₅₇ is N, or CH;

J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃;

J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃;

J₆₃ is CH, C, or N;

J₆₄ is CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N;

J₆₅ is CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₇₀ is CH, C, or N;

J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₇₅ may be CH, or N;

J₇₇ is

and

provided that one or more of D₁-D₃ links to at least one ring in addition to the bicyclic structure of Formula I. For example, compounds 13720-13726, do not link to at least one ring in addition to the bicyclic structure of Formula I, whereas, for example, 13566 and 13742 do link to at least one ring in addition to the bicyclic structure of Formula I.

In accordance with a further aspect, there is provided a use of a compound having the structure of Formula I as described herein for modulating AR activity.

In accordance with a further aspect, there is provided a use of a compound having the structure of Formula I as described herein for the manufacture of a medicament for modulating AR activity.

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

or CF₃. Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A may be H, CH₃, OH, CH₂OH, OCH₃,

or CF₃. A₁ may be H, CH₃, OH, CH₂OH, OCH₃, or

A₁ may be H, CH₃, OH, CH₂OH, or OCH₃. A₁ may be H, CH₃, OH, CH₂OH, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

CH₃,

or ═O. A₂ may be H, Br, OH, Cl, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃ or ═O. A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂ or OCH₃. A₂ may be H, Br, OH, or Cl. A₂ may be H, Br, OH, Cl, or F.A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, I, OH,

or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

or CF₃. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, or CH₃.A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O. A₄ may be H, Br. A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃ or ═O. A₄ may be H, Br, Cl, F, CH₃, NH₂, OH, OCH₃, or ═O. A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH or OCH₃. A₄ may be H, Br, Cl, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O.

D₁ may be

D₁ may be

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may each independently be CH or N. E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may be N. E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may be CH.E₂, E₃, E₄, E₅, and E₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₂, E₃, E₄, E₅, and E₆, may each independently be H, OH, or

E₂, E₃, E₄, E₅, and E₆, may each independently be H or OH.E₇ may be CH₂, O, NH, or C═O. E₇ may be CH₂. E₇ may be CH₂, O or C═O. E₇ may be CH₂ or O. E₇ may be CH₂, O, NH or C═O. E₇ may be CH₂, NH or C═O.E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H or

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H, OH, Br, Cl, F, I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H, OH, or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H or CH₃.E₁₅ may be CH₂, O, NH or C═O. E₁₅ may be NH. E₁₅ may be CH₂, O or NH. E₁₅ may be O, NH, or C═O. E₁₅ may be NH or C═O.E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, OH, Br, Cl, F, I or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, Cl, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, OH, Br, Cl, F or CH₃.E₂₃ may be CH, CH₂, O, N, NH, or C═O. E₂₃ may be N. E₂₃ may be O, N, NH, or C═O. E₂₃ may be CH, CH₂, O, N or NH. E₂₃ may be N or NH.E₂₄ may be CH₂, O, NH, or C═O. E₂₄ may be NH. E₂₄ may be CH₂, NH, or C═O. E₂₄ may be O or NH. E₂₄ may be CH₂, O or NH. E₂₄ may be NH, or C═O. E₂₄ may be CH₂ or NH.E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Br, Cl, F, I or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H or Cl. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Br, Cl, F, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Cl or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, Br, Cl or CH₃.E₃₁ may be N, CH, CBr, CCl, CF, COH, C═O, or CCH₃. E₃₁ may be N. E₃₁ may be N, CH, COH, C═O, or CCH₃. E₃₁ may be N, CH, CCl, COH, C═O, or CCH₃. E₃₁ may be N, CH, COH or CCH₃.E₃₂ may be NH, CH₂, O, or S. E₃₂ may be NH or O. E₃₂ may be NH, CH₂ or O. E₃₂ may be NH. E₃₂ may be O. E₃₂ may be NH, O or S.E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH, Br, Cl, F, I or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH or CH₃.E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃ or

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, or N—CH₂—C(O)—O—CH₂—CH₃.E₃₈ may be NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or

E₃₈ may be NH₂, O—CH₃ or O—NH₂. E₃ may be NH₂ or O—CH₃.E₃₉ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃ or C(O)—O—CH₂—CH₃. E₃₉ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, or CH₂—CH₃. E₃₉ may be CH₃, CH₂—CH₃, OH, OOH, NH₂, O—CH₃, O—NH₂, C—O—CH₃ or C(O)—O—CH₃.E₄₀ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, CO—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃. E₄₀ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃ or O—NH₂.E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, OH, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H or Cl. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, OH or Cl.

D₂ may be

D₂ may be

D₂ may be

G₁ may be CH, N, CCH₃, CH₂,

O S or NH. G₁ may be CH N CCH₃, CH₂, or

G₁ may be CH N CCH₃, CH₂,

G₁ may be CH, N, CCH₃, CH₂, O, S, or NH. G₁ may be CH, N, CCH₃ or CH₂.G₂ may be C, CH, or N. G₂ may be C. G₂ may be C. G₂ may be C or CH. G₂ may be C or N.

G₃ may be CH,

CH₂, or N. G₃ may be CH,

G₄ may be

G₄ may be

G₄ may be

G₅, G₆, and G₇, may each independently be H, OH, Br, Cl, F, I, or CH₃. G₅, G₆, and G₇, may each independently be H or CH₃. G₅, G₆, and G₇, may each independently be H, OH, or CH₃. G₅, G₆, and G₇, may each independently be H, Br, Cl, F, or CH₃. G₅, G₆, and G₇, may each independently be H, OH, Br, CH₃.G₈ may be NH, CH₂, O, or S. G₈ may be NH. G₈ may be NH, O, or S. G₈ may be NH, CH₂, or S. G₈ may be NH or S. G₈ may be NH or CH₂.G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F, I or CH₃. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H or Br. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl or F. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F or CH₃. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH or Br.G₁₃ may be C, CH, or N. G₁₃ may be C or N. G₁₃ may be N. G₁₃ may be C.G₁₄ may be C═O, CH₂, or NH. G₁₄ may be NH. G₁₄ may be CH₂. G₁₄ may be NH.G₁₅ may be C═O, CH₂, or NH. G₁₅ may be C═O. G₁₅ may be CH₂. G₁₅ may be NH.

G₁₆ may be

G₁₆ may be

G₁₆ may be

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I, or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀, and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃.G₂₂ may be NH, CH₂, O, or S. G₂₂ may be NH. G₂₂ may be NH or S. G₂₂ may be NH, O or S. G₂₂ may be NH or CH₂. G₂₂ may be NH, O, or S. G₂₂ may be NH or O.G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, I or CH₃. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H or Br. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, or CH₃. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, Br, Cl, F or I. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br or CH₃.G₂₇ may be C, CH, CCH₃, CC(O)OCH₂CH₃, or N. G₂₇ may be C, CH, CCH₃ or CC(O)OCH₂CH₃. G₂₇ may be C. G₂₇ may be CH. G₂₇ may be CCH₃. G₂₇ may be CC(O)OCH₂CH₃.G₂₈ may be C, CH, or N. G₂₈ may be C or N. G₂₉ may be C. G₂₈ may be N.G₂₉ may be CH, CH₂, C═O, CCH₃, or N. G₂₉ may be CH. G₂₉ may be CH₂. G₂₉ may be C═O, CCH₃.G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O, or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, or NH.G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, OCH₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N.G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂, OCH₃, CH₃, CH₂OH, or absent when G₃₅ is N.G₃₅, G₃₆, G₃₇, and G₃₈, may each independently be C or N. G₃₅, G₃₆, G₃₇, and G₃₈, may each be N. G₃₅, G₃₆, G₃₇, and G₃₈, may each be C.G₃₉ may be C, CH or N. G₃₉ may be C. G₃₉ may be C or CH. G₃₉ may be C or N.G₄₀ may be CH, or N. G₄₀ may be N. G₄₀ may be CH.G₄₁ may be NH, S, O, or CH₂. G₄₁ may be NH, S or O. G₄₁ may be NH. G₄₁ may be S.G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br, Cl, F, I or CH₃. G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H or Br. G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br or CH₃.G₄₆ may be C, CH, or N. G₄₆ may be C. G₄₆ may be C or N. G₄₆ may be CH or N.G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H, OH, Br, Cl, F, I or CH₃. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H or OH. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H, OH or CH₃. G₄₇, G₄₈, G₅₀, and G₅₁, are each be H. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be OH. G₄₉ is OH, Br, Cl, F, I or CH₃. G₄₉ is Br, Cl, F or I. G₄₉ is OH or CH₃.G₅₂ may be C, CH or N. G₅₂ may be C. G₅₂ may be C or N. G₅₂ may be C or CH.G₅₃ may be CH₂, NH, S or O. G₅₃ may be NH. G₅₃ may be CH₂ or NH. G₅₃ may be NH or O. G₅₃ may be NH or S.G₅₄, G₅₅, G₅₆, G₅₇, and G₅, may each independently be H, OH, Br, Cl, F, I or CH₃. G₅₄, G₅₅, G₅₆, G₅₇, and G₅, may each independently be H, Cl or F. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be H. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be Cl. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be F. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, Br, Cl, F or CH₃.

D₃ may be

D₃ may be

D₃ may be

J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S or NH. J₁ may be CH, N, CH₂, NCH₃, CN═O, C═O,

or NH.

J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

O, S or NH. J₂ may be CH, C, or N. J₂ may be CH. J₂ may be CH or C. J₂ may be CH, or N. J₃ may be C═S, C═O, NH, or CH₂. J₃ may be C═S. J₃ may be C═S or CH₂. J₃ may be C═S or C═O. J₃ may be C═S or NH. J₄ may be CH or N. J₄ may be N. J₄ may be CH. J₅ may be CH₂, NH, S or O. J₅ may be O. J₅ may be CH₂ or O. J₅ may be NH, S or O. J₅ may be S or O. J₅ may be NH or O. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H, OH, Br, Cl, F, I or CH₃. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H, OH, Br, Cl, F or CH₃. J₁₄ may be CH, C, or N. J₁₄ may be N. J₁₄ may be CH or N. J₁₄ may be C or N. J₁₅ may be C═S, C═O, NH or CH₂. J₁₅ may be CH₂. J₁₅ may be NH or CH₂. J₁₅ may be C═S or CH₂. J₁₅ may be C═O or CH₂.J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H, OH, Br, CF, I,

or CH₃. J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H or

J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H, OH, Br, Cl, F,

or CH₃. J₂₁ may be CH, C or N. J₂₁ may be CH. J₂₁ may be CH or N. J₂₁ may be CH or C. J₂₂ may be NH. J₂₂ may be CH₂. J₂₂ may be CH₂ or NH. J₂₃ may be CH or N. J₂₃ may be CH. J₂₃ may be N. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH, Br, Cl, F, I or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH, Br, Cl or CH₃. J₂₉ may be CH, C or N. J₂₉ may be C. J₂₉ may be CH or C. J₂₉ may be C or N. J₃₁ may be H, OH, Br, F, I, C(O)NH₂, OCH₃ or CH₃. J₃₁ may be H, Br, OCH₃ or CH₃. J₃₁ may be H, OH, Br, Cl, F, I, C(O)NH₂, OCH₃ or CH₃. J₃₁ may be Cl. J₃₁ may be H. J₃₁ may be Br. J₃₁ may be OCH₃. J₃₁ may be CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OH, Br, Cl, C(O)NH₂, CF₃ or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, NH₂, or CH₃. J₃₄ may be CH, C, or N. J₃₄ may be C. J₃₄ may be CH or C. J₃₄ may be C or N. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, Cl or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, OCH₃, OH, Br, Cl, F, NH₂ or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each be H, Cl or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be Cl. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be CF₃. J₄₀ may be CH, C, or N. J₄₀ may be C. J₄₀ may be CH or C. J₄₀ may be C or N. J₄₁ may be H, OH, Br, Cl, F, I, NH₂, CH₃ or

J₄₁ may be H. J₄₁ may be H, OH, Br, Cl, F, NH₂ or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, F, I, NH₂ or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, NH₂, or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, NH₂ or CH₃. J₄₇ may be CH, C or N. J₄₇ may be C. J₄₇ may be CH, C or N. J₄₇ may be CH or C. J₄₇ may be C or N. J₄₈ may be S, CH₂, C═O, O, or NH. J₄₈ may be S, CH₂ or NH. J₄₈ may be S. J₄ may be CH₂. J₄₈ may be NH. J₄₉ may be CH₂, C═O, S, O, or NH. J₄₉ may be CH₂ or C═O. J₄₉ may be S, O, or NH. J₄₉ may be CH₂, C═O or NH. J₄₉ may be CH₂, C═O or S. J₄₉ may be CH₂, C═O or O. J₅₅ may be C, or N. J₅₅ may be C. J₅₅ may be N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each independently be H, OH, Br, F, CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be H or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be OH or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be Br or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be F or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₆ may be CH, C or N. J₅₆ may be C. J₅₆ may be CH or C. J₅₆ may be C or N. J₅₇ may be N or CH. J₅₇ may be CH. J₅₇ may be N. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, F or CF₃. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, OH, NH₂, Br, Cl, F, I, OCH₃ or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, F or CF₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, OH, NH₂, Br, Cl, F, OCH₃ or CH₃. J₆₃ may be CH, C, or N. J₆₃ may be C or N. J₆₃ may be C. J₆₃ may be N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, NCH₃, NC(O)OCH₃,

or N. J₆₅ may be CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₅ may be CH₂, NH, C═O, O, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, Br or CF₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, C(O)NH₂, NH₂ or CH₃. J₇₀ may be C. J₇₀ may be CH or C. J₇₀ may be C or N. J₇₀ may be CH, C, or N. J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, Br, CF₃, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may be H. J₇₁, J₇₂, J₇₃, and J₇₄ may be Br. J₇₁, J₇₂, J₇₃, and J₇₄ may be CF₃. J₇₁, J₇₂, J₇₃, and J₇₄ may be CH₃. J₇₅ may be CH, or N. J₇₅ may be CH.

J₇₇ may be

J₇₇ may be

One or more of D₁-D₃ links to at least one ring in addition to the bicyclic structure of Formula I.In accordance with a further aspect of the invention, there is provided a compound having the structure of Formula I as described herein, but provided that the compound is not one of the compounds in TABLE 1.

TABLE 1
Known AR BF3 Interactors.
Internal	External
Number	Identifier	STRUCTURE
13312	ZINC 00298052
13309	ZINC 01234071
13310	ZINC 00297221
13232	ZINC 02992016
13050	ZINC 03365783
13300	ZINC 00270867
13299	ZINC 00499454
13304	ZINC 00270887
13258	ZINC 18191564
9125	ZINC 30469682
13186	ZINC 00513042
13224	ZINC 04106386
13250	ZINC 03149578
13303	ZINC 00270884
13257	ZINC 12345945
13243	ZINC 00253227
13424	ZINC 12346351
6054	ZINC 08718421
13029	ZINC 00210926
9128	ZINC 47424036
13216	ZINC 06025409
13260	ZINC 49491101
13416	ZINC 01869964
13411	ZINC 04106386
13214	ZINC 26472877
13235	ZINC 01037115
13127	ZINC 00392643
13261	ZINC 48546225
13215	ZINC 05504717
13167	NSC 105329
13206	ZINC 04962047
13145	ZINC 34603778
13245	ZINC 00555700
13036	ZINC 14961821
13166	ZINC 01723993
13164-B	ZINC 02046058
13254	ZINC 18191551
13410	ZINC 04106383
13423	ZINC 18191568
13222	ZINC 02718340
13247	ZINC 48090221
13412	ZINC 02718340
13434	ZINC 00069102
13164-A	ZINC 02046058
13220	ZINC 48544111
13225	ZINC 18191568
13436	ZINC 00068959
13255	ZINC 18191553
13163-A	ZINC 02043019
13163-B	ZINC 02043019
13256	ZINC 05848672
13427	ZINC 00588219
13259	ZINC 18191559
13226	ZINC 18191571
13562	Known see U.S. Pat. No. 6,207,679
13566	Known see U.S. Pat. No. 6,207,679

The compound may be selected from one or more of the active synthetic derivatives set out in TABLE 2.

TABLE 2
List of Active Synthetic AR BF3 Interactor Derivatives
Internal
Number STRUCTURE
9040
9034
13551
13550
9026
13544
13561
9028
9027
13538
13559
13512
13542
13524
13508
13530
13503
13502
9037
13543
13516
13505
13522
13548
13525
13532
13511
9043
13509
13510
13540
13560
13536
13556
13504
13549
13558
13535
13500
13552
13534
13537
13554
13541
13521
13506
13567
13568
13570
13569
13571
13573
13574
13576
13577
13579
13580
13582
13585
13587
13589
13591
13592
13593
13594
13595
13597
13600
13601
13602
13603
13606
13607
13610
13611
13612
13613
13614
13618
13619
13621
13622
13624
13625
13626
13627
13628
13629
13630
13633
13634
13639
13640
13641
13642
13643
13644
13645
13646
13650
13651
13652
13653
13654
13655
13656
13658
13660
13665
13674
13677
13680
13681
13682
13683
13684
13688
13691
13692
13693
13694
13695
13696
13697
13698
13699
13702
13704
13708
13710
13713
13717
13718
13719
13730
13731
13732
13733
13736
13738
13741
13742
13743
13744
13745
13749
13752
13753
13754
13755
13759
13760
13761
13762
13764
13766
13770
13771
13772
13773
13774
13775
13776
13782
13785
13786
13787

Alternatively, the compound may be selected from one or more of the following:

The compound may have the structure of Formula II:

wherein,L₁ may be H, Cl, F, Br, OH, CF₃, NH₂, OCH₃, or CH₃;L₂ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;L₃ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;L₄ may be H, Cl, F, Br, OH, NH₂, C(O)NHCH₃, CH₂OH, OCH₃, CF₃, CH₃,

L₅ may be H, OH, NH₂, OCH₃, CH₂CH₃, or CH₃;L₆ may be H, OH, NH₂, OCH₃, CH₂CH₃, or CH₃;

L₇ may be H, F, Cl or Br;

L₈ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;L₉ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃; andL₁₀ may be H, Cl, F, Br, OH, NH₂, I, CN, CH₂CH₃, CF₃, OCH₃,

or CH₃,

provided that the compound is not one of the following:

The compound may be:

The compound may be:

The compound may have the structure of Formula III:

wherein,

R₁ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

R₂ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

or R₁ and R₂ form

M₁ is C or N;

M₂ is C or N;

Q₁ is H;

Q₂ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₃ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₄ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃; and

Q₅ is H, CH₃, CH₂CH₂OH,

OH, F, Br, Cl I, or

The compound may be selected from one or more of the following:

The compound may be

The compound may be for use in the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.The modulating AR activity is for the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.The modulating AR activity may be for the treatment of prostate cancer. The mammalian cell may be a human cell. The cell may be a prostate cell. The cell may be a prostate cancer cell.The compound may be for use in the treatment of at least one indication selected from the group consisting of: cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age related macular degeneration. The cancer may be AR-mediated cancer. The cancer may be selected from the group including of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer and bladder cancer. The cancer may be Taxene resistant triple negative breast cancer.In accordance with a further aspect, there is provided a pharmaceutical composition for modulating AR activity, the composition including a compound described herein, and a pharmaceutically acceptable carrier.In accordance with a further aspect, there is provided a method of modulating AR activity, the method including (a) administering a compound described herein or a pharmaceutical composition described herein to a subject in need thereof.In accordance with a further aspect, there is provided a method for modulating AR activity, the method including administering to a mammalian cell a compound or pharmaceutically acceptable salt thereof as described herein.In accordance with a further aspect, there is provided a use of a compound described herein, for modulating AR activity.In accordance with a further aspect, there is provided a use of a compound described herein, for the manufacture of a medicament for modulating AR activity.In accordance with a further aspect, there is provided a pharmaceutical composition including a compound or pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable excipient.In accordance with a further aspect, there is provided a commercial package including (a) a compound described herein; and (b) instructions for the use thereof for modulating AR activity.In accordance with a further aspect, there is provided a commercial package including (a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier; and (b) instructions for the use thereof for modulating AR activity.

DETAILED DESCRIPTION

The BF3 site is an attractive target for direct inhibition of the AR co-activation. In silico computational drug discovery methods were used to conduct a virtual screen of ˜4 million purchasable lead-like compounds from the ZINC database (Irwin, J. et al. Abstracts of Papers Am. Chem. Soc. (2005) 230:U1009) to identify potential BF3 binders. The in silico methods included large-scale docking, in-site rescoring and consensus voting procedures.

It will be understood by a person of skill that COOH and NR₂ may include the corresponding ions, for example carboxylate ions and ammonium ions, respectively. Alternatively, where the ions are shown, a person of skill in the art will appreciate that the counter ion may also be present.

Those skilled in the art will appreciate that the point of covalent attachment of the moiety to the compounds as described herein may be, for example, and without limitation, cleaved under specified conditions. Specified conditions may include, for example, and without limitation, in vivo enzymatic or non-enzymatic means. Cleavage of the moiety may occur, for example, and without limitation, spontaneously, or it may be catalyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH. The moiety may be, for example, and without limitation, a protecting group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mechanisms, or a group that acts to impart or enhance a property of the compound, for example, solubility, bioavailability or localization.

In some embodiments, compounds of Formula I or Formula II above may be used for systemic treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty and age-related macular degeneration. In some embodiments compounds of Formula I or Formula II may be used in the preparation of a medicament or a composition for systemic treatment of an indication described herein. In some embodiments, methods of systemically treating any of the indications described herein are also provided.

Compounds as described herein may be in the free form or in the form of a salt thereof. In some embodiment, compounds as described herein may be in the form of a pharmaceutically acceptable salt, which are known in the art (Berge S. M. et al., J. Pharm. Sci. (1977) 66(1):1-19). Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable). Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a pharmaceutically acceptable salt. Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonic acid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid. Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theobromine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine, N-ethylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine or polyamine resins. In some embodiments, compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwitterions, for example, and without limitation, betaines. Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, polymorphs, isomeric forms) as described herein may be in the solvent addition form, for example, solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof. The solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, polymorphs) as described herein include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.

In some embodiments, pharmaceutical compositions as described herein may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents (used interchangeably herein) are those known in the art for use in such modes of administration.

Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20^th ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

Compounds or pharmaceutical compositions as described herein or for use as described herein may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.

An “effective amount” of a pharmaceutical composition as described herein includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to an androgen-independent form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.

It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

In some embodiments, compounds and all different forms thereof as described herein may be used, for example, and without limitation, in combination with other treatment methods for at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty and age-related macular degeneration. For example, compounds and all their different forms as described herein may be used as neoadjuvant (prior), adjunctive (during), and/or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam), or other therapies (eg. HIFU).

In general, compounds as described herein should be used without causing substantial toxicity. Toxicity of the compounds as described herein can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be appropriate to administer substantial excesses of the compositions. Some compounds as described herein may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations. Toxicity may be evaluated by examining a particular compound's or composition's specificity across cell lines using PC3 cells as a negative control that do not express AR. Animal studies may be used to provide an indication if the compound has any effects on other tissues. Systemic therapy that targets the AR will not likely cause major problems to other tissues since anti-androgens and androgen insensitivity syndrome are not fatal.

Compounds as described herein may be administered to a subject. As used herein, a “subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration are known to those of ordinary skill in the art.

Definitions used include ligand-dependent activation of the androgen receptor (AR) by androgens such as dihydrotestosterone (DHT) or the synthetic androgen (R1881) used for research purposes. Ligand-independent activation of the AR refers to transactivation of the AR in the absence of androgen (ligand) by, for example, stimulation of the cAMP-dependent protein kinase (PKA) pathway with forskolin (FSK).

Some compounds and compositions as described herein may interfere with a mechanism specific to ligand-dependent activation (e.g., accessibility of the ligand binding domain (LBD) to androgen) or to ligand-independent activation of the AR.

Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

Materials and Methods

In Silico Screening

Ten million commercially available compounds from the ZINC12.0 structural libraries (Irwin, J. J. and Shoichet, B. K. ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 2005, 45, 177-182) were imported into a molecular database using Molecular Operating Environment (MOE) version 2007.09 (MOE, Chemical Computing Group, Inc., 2008, www.chemcomp.com). These structures were energy minimized using an MMFF94x force field, exported in SD format and rigidly docked into the BF3 site of the protein structures 4HLW with Glide software (Friesner, R. A. et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004, 25, 739-49). About 2 million molecules that had a GlideScore<−5.0 were then re-docked into the same BF3 binding cavity using the electronic high-throughput screening (eHiTS) docking module (Zsoldos, Z. et al. eHiTS: a new fast, exhaustive flexible ligand docking system. J Mol Graph Model 2007, 26, 198-212). From this, 500,000 structures with eHiTS docking scores <−3.0 threshold were identified. They were scored by the LigX™ module of the MOE to account for the receptor/ligand flexibility. The pKi binding affinity was scored after energy minimization to select the ligands that showed the best binding characteristics defined mainly by the energy of hydrogen bonds and hydrophobic interactions. The virtual hits were scored using Molecular Mechanics, the Generalized Born model and Solvent Accessibility (MM-GB/SA) method with OPLS_2005 and GB/SA in MacroModel™ to calculate the free energies of the optimal chemical poses (Maestro, Schrodinger, LLC, New York, N.Y., 2008. www.schrodinger.com). The root mean square deviation (RMSD) was calculated between the Glide poses and the eHiTS poses to evaluate the docking consistency and thus to establish the most probable binding pose for a given ligand. Finally, very large and very small molecules were penalized based on a heavy atom count.

With this information, a cumulative scoring of five different predicted parameters (RMSD, heavy atoms count, LigX, Macromodel, pKi) was generated where each molecule receive a binary 1.0 score for every ‘top 10% appearance’. The final cumulative vote (with the maximum possible value of 5) was then used to rank the training set entries. Based on the cumulative score 5000 compounds were selected and subjected to visual inspection. After this final selection step 200 compounds were selected out of which 150 chemical substances could be readily purchased in sufficient purity and quantity.

General Synthesis and Characterization of Compounds

Exemplary Scheme 1: Synthesis of Compound 13163.

At 0° C., a solution of para-toluenesulfonic acid (13.4 g, 0.55 eq, 70.4 mmol) in acetonitrile (150 mL) was added drop-wise over 1 h to a solution of indole (15 g, 1.0 eq, 128.0 mmol) in acetonitrile (500 mL). The mixture was kept for additional 6 h at 0° C. The subsequent precipitate was filtered (at 0° C.) and washed with acetonitrile (three times). The precipitate was neutralized with saturated NaHCO₃ solution and extracted with AcOEt (3×100 mL). The organic extracts were combined, washed with brine, dried over Na₂SO₄; filtered and concentrated under reduced pressure. Any purification was needed and the crude was transformed in corresponding hydrochloride with HCl2 M solution in ether and the precipitate salt was filtered to afford 14.8 g of the white solid (54.7 mmol, 85%).

Analysis

M.p.=169-170° C.

t_R (HPLC)=3.01 min

MS (ESI+) m/z=235.12 [(M+H)+]

HRMS (ESI+): calculated for C₁₆H₁₅N₂, m/z=235.1230; found, 235.1237; calculated for C₁₆H₁₄N₂Na, m/z=257.1049; found, 257.1058

¹H NMR (400 MHz, DMSO-d₆): δ (ppm)=11.45 (s, 1H, H₁₂), 7.77 (d, J=8.0 Hz, 1H, H₁₈), 7.68 (d, J=2.6 Hz, 1H, H₁₁), 7.58-7.50 (m, 1H, H₆), 7.45 (d, J=8.4 Hz, 1H, H₁₅), 7.43-7.38 (m, 4H, H_1,2), 7.35-7.33 (m, 1H, H₃), 7.17 (ddd, J=8.2, 7.1, 1.1 Hz, 1H, H₁₆), 7.07 (ddd, J=8.0, 7.1, 1.0 Hz, 1H, H₁₇), 5.58 (t, J=8.7 Hz, 1H, H₁₈), 3.67 (d, J=8.7 Hz, 2H, H₉).

¹³C NMR (101 MHz, DMSO-d₆): δ (ppm)=137.96 (C₄-arom.), 137.00 (C₁₃-arom.), 135.72 (C₅-arom.), 128.74 (C₁H-arom.), 128.50 (C₂H-arom.), 126.36 (C₁₄-arom.), 126.11 (C₆H-arom.), 125.72 (C₁₁H-arom.), 122.31 (C₁₆H-arom.), 119.69 (C₁₇H-arom.), 119.48 (C₁₈H-arom.), 119.38 (C₃H-arom.), 112.30 (C₁₅H-arom.), 110.24 (C₁₀-arom.), 56.55 (C₈H), 35.37 (C₉H₂).

General Synthesis Methods

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded with Bruker Avance III™ 400 MHz. Processing of the spectra was performed with MestRec™ software and data are reported as follows: chemical shifts (6) in parts per million, coupling constants (J) in hertz (Hz). The high-resolution mass spectra were recorded in positive ion-mode with an ESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer. HPLC analyses and purity of >95% were performed by analytical reverse-phase HPLC with a Agilent™ instrument with variable detector using column Agilent Zorbax 4.6×5 mm, Sum; flow: 2.0 mL·min⁻¹, H₂O (0.1% FA)/CH₃CN (0.1% FA), gradient 2-98% (6 min) and 98% (0.3 min). Melting points were determined with a Fischer-Jonhs.

Analytical Methods:

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded with Bruker Avance III™ 400 MHz. Processing of the spectra was performed with MestRec™ software and data are reported as follows: chemical shifts (6) in parts per million, coupling constants (J) in hertz (Hz). The high-resolution mass spectra were recorded in positive ion-mode with an ESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer. HPLC analyses and purity of >95% were performed by analytical reverse-phase HPLC with a Agilent™ instrument with variable detector using column Agilent Zorbax 4.6×5 mm, Sum; flow: 2.0 mL·min⁻¹, H₂O (0.1% FA)/CH₃CN (0.1% FA), gradient 2-98% (6 min) and 98% (0.3 min).

Dimethyl- & Cyclohexyl-Hydroindole Moiety

General Procedure 1

Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde or cyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Reaction mixture containing imine intermediate was allowed to reach r.t. and indole (1.0 eq) was added to the mixture which was stirred additional 2 h at r.t. (until complete conversion). Acetic acid was removed under vacuo. Then, the residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, crude was purified by automated combi-flash to afford the good compound.

General Procedure 2

Benzyloxy compound (1.0 eq) was dissolved in mixture of MeOH (0.05 M) and the system was purged with vacuum/N₂ (×3). Then, Pd/C (20% w/w) was added to the mixture and purged again with vacuum/H₂ and put under H₂ atmosphere. The reaction was stirred overnight at r.t. under H₂ atmosphere. The reaction mixture was filtered on a plug of Celite which was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by combi-flash to afford the good compound.

General Procedure 3

Imine compound (1.0 eq) was dissolved in AcOH (0.1 M) and the system was put under argon atmosphere. Then, NaBH₃CN (1.1 eq) was added quickly. Then, the reaction was stirred at r.t. After overnight, the reaction mixture was concentrated and the crude was quenched with H₂O. Aqueous layer was neutralized with saturated NaHCO₃ solution until pH 7 and extracted with AcOEt (×2). The combined organic layers were washed with brine, dried over Na₂SO₄ and rotary evaporated. The crude was purified by automated combi-flash to afford the good compound.

General Procedure 4

From ester compound (1.0 eq) was diluted in mixture of MeOH/Acetone (1:3, 0.1 M). The mixture was stirred and a solution of LiOH (2.0 eq) in H₂O (0.85 M) was added drop-wise over 5 min. Then, the mixture was stirred overnight at r.t. The reaction mixture was diluted in a mixture of Et₂O and H₂O and the aqueous phase was washed and then acidified with concentrated HCl solution until pH 3. The aqueous layer was extracted with Et₂O (×2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give pure product.

General Procedure 5

A dried vessel was charged with LiAlH₄ (4.0 eq), enclosed with condenser and rubber cap and put under argon atmosphere. Then, carboxylic acid (1.0 eq) was dissolved in anhydrous THE (0.28 M) and was added in system which was stirred 2 h at 70° C. The excess of LiAlH₄ was destroyed by adding AcOEt drop-wise (exothermic reaction) and then by adding H₂O. Aqueous saturated NH₄Cl solution was added and the whole was extracted with AcOEt (×2). The combined organic layers were washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by automated combi-flash to afford the good compound.

General Procedure 6

Phenylhydrazine (1.0 eq) and isobutyraldehyde (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Reaction mixture containing imine intermediate was allowed to reach r.t. Acetic acid was removed under vacuo. The residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, residue corresponding to imine intermediate was diluted in ACN (0.5 M). Azaindole (0.9 eq) and ZnCl₂ (0.9 eq) were introduced in microwave vessel. The mixture was stirred and heated by microwave 3 h at 120° C. The resulting crystals (after avernight at r.t.) was filtered and washed with 1 N aqueous NaOH solution (50 mL) and extracted with AcOEt (×2). The organic layers were combined, washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to provide pure compound.

Dimethyl-Hydroindole Moiety

3-(3,3-dimethylindolin-2-yl)-5-methyl-1H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 1.5
13 535	CA 2-36 F9-15 (yield = 63%)	✓ IC50 (PSA) = 1.87
	✓ tR (HPLC) = 4.07 min      ✓ MS (ESI+) m/z = 277.1719              [(M + H)+] ✓ HRMS (ESI+): calculated for C19H21N2O, m/z = 277.1699; found, 277.1708 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.83 (s, 1H, H14), 7.33 (d, J = 0.6 Hz, 1H, H20), 7.26 (d, J = 2.0 Hz, H13), 7.25 (d, J = 8.0 Hz, 1H, H17), 7.01 (d, J = 7.2 Hz, 1H, H6), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.88 (dd, J = 8.3, 1.5 Hz, 1H, H18), 6.60 (td, J = 7.6, 1.2 Hz, 1H, H1), 6.59 (d, J = 7.6 Hz, 1H, H3), 5.82 (d, J = 2.4 Hz, 1H, H7), 4.76 (d, J = 2.2 Hz, 1H, H8), 2.33 (s, 3H, H21), 1.39 (s, 3H, H10), 0.74 (s, 3H, H11). ✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.99 (C4-arom.), 138.68 (C5-
	arom.), 135.33 (C15-arom.), 127.54 (C19-arom.), 127.29 (C2H-arom.), 127.01 (C16-
	arom.), 124.09 (C13H-arom.), 122.80 (C18H-arom.), 122.45 (C6H-arom.), 119.77
	(C20H-arom.), 117.53 (C1H-arom.), 113.64 (C12-arom.), 111.60 (C17H-arom.),
	108.85 (C3H-arom.), 68.17 (C8H), 45.20 (C9), 27.15 (C10H3), 25.01 (C11H3), 21.87
	(C21H3).

3-(3,3-dimethylindolin-2-yl)-5-methoxy-1H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 2.2
13 536	CA 2-38 F10-19 (yield = 46%)	✓ IC50 (PSA) = 2.52
	✓ tR (HPLC) = 3.82 min    ✓ MS (ESI+) m/z = 293.1668               [(M + H)+] ✓ HRMS (ESI+): calculated for C19H21N2O, m/z = 293.1648; found, 293.1654 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.79 (s, 1H, H14), 7.27 (d, J = 2.5 Hz, 1H, H13), 7.24 (d, J = 8.8 Hz, 1H, H17), 7.02 (br d, J = 7.2 Hz, 1H, H6), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.88 (d, J = 2.4 Hz, 1H, H20), 6.70 (dd, J = 8.8, 2.4 Hz, 1H, H18), 6.61 (td, J = 7.6, 1.2 Hz, 1H, H1), 6.59 (d, J = 7.6 Hz, 1H, H3), 5.82 (d, J = 2.0 Hz, 1H, H7), 4.73 (d, J = 1.9 Hz, 1H, H8), 3.62 (s, 3H, H22), 1.38 (s, 3H, H10), 0.78 (s, 3H, H11). ✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 153.22 (C19-arom.), 151.10 (C4- arom.), 138.59 (C5-arom.), 132.18 (C15-arom.), 127.37 (C2H-arom.), 127.36
	(C16-arom.), 124.83 (C13H-arom.), 122.32 (C6H-arom.), 117.51 (C1H-arom.),
	114.38 (C12-arom.), 112.44 (C17H-arom.), 111.21 (C18-arom.), 108.72
	(C3H-arom.), 102.31 (C20H-arom.), 68.27 (C8H), 55.63 (C22H3), 45.21 (C9),
	27.73 (C10H3) 24.58 (C11H3).

3-(3,3-dimethylindolin-2-yl)-5-amine-H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 7.7
13 538	CA 2-47 F7-17 (yield = 45%)	✓ IC50 (PSA) = No Data
	✓ tR (HPLC) = 2.56 min    ✓ MS (ESI+) m/z = 278.1668              [(M + H)+] ✓ HRMS (ESI+): calculated for C18H20N3, m/z = 278.1652; found, 278.1657 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.53 (d, J = 1.6 Hz, 1H, H14), 7.14 (d, J = 2.4 Hz, 1H, H13), 7.08 (d, J = 8.4 Hz, 1H, H17), 7.00 (dd, J = 7.2, 0.7 Hz, 1H, H6) 6.95 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.86 (d, J = 2.0 Hz, 1H, H20), 6.60 (td, J = 7.6, 0.8 Hz, 1H, H2,) 6.57 (d, J = 7.6 Hz, 1H, H3), 6.51 (dd, J = 8.5, 2.0 Hz, 1H, H18), 5.78 (s, 1H, H7), 4.86 (s 2H, H21), 4.69 (s, 1H, H8), 1.39 (s, 3H, H10), 0.75 (s, 3H, H11). ✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.97 (C4-arom.), 138.81
	(C5-arom.), 140.00 (C19-arom.), 131.08 (C15-arom.), 128.25 (C16-arom.),
	127.21 (C2H-arom.), 123.86 (C13H-arom.), 122.47 (C6H-arom.), 117.47
	(C1H-arom.), 112.50 (C12-arom.), 112.36 (C18H-arom.), 111.97
	(C17-arom.), 108.86 (C3H-arom.), 104.09 (C20H-arom.), 68.29 (C8H),
	45.21 (C9), 27.00 (C10H3, 25.15 (C11H3).

3-(3,3-dimethylindolin-2-yl)-6-(benzyloxy)-1H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 11.4
13 544	CA 2-54 Precipitate (yield = 53%)	✓ IC50 (PSA) = No Data
	✓ tR (HPLC) = 4.60 min      ✓ MS (ESI+) m/z = 369.1981                [(M + H)+] ✓ HRMS (ESI+): calculated for C25H25N2O, m/z = 369.1961; found, 369.1979 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.77 (s, 1H, H14), 7.47 (d, J = 7.1 Hz, 2H, H24, 28), 7.42-7.38 (m, 3H, H20, 25, 27), 7.35-7.31 (m, 1H, H26) 7.18 (d, J = 2.1 Hz, 1H, H13), 6.99 (d, J = 6.8 Hz, 1H, H6), 6.98-6.94 (m, 2H, H2, 17), 6.69 (dd, J = 8.7, 2.3 Hz, 1H, H19), 6.63-6.55 (m, 2H, H1, 3,), 5.83 (d, J = 2.3 Hz, 1H, H7), 5.11 (s, 2H, H22),
	4.73 (d, J = 2.2 Hz, 1H, H8), 1.37 (s, 3H, H10), 0.73 (s, 3H, H11).
	✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 154.69 (C18-arom.), 150.96
	(C4-arom.), 138.64 (C5-arom.), 138.14 (C23-arom.), 137.52 (C15-arom.),
	128.84 (C25, 27H-arom.), 128.08 (C26H-arom.), 127.96 (C24, 28H-arom.),
	127.32 (C2H-arom.), 122.77 (C13H-arom.), 122.41 (C6H-arom.),
	121.88 (C16-arom.), 120.79 (C20H-arom.), 117.54 (C1H-arom.), 114.22
	(C12-arom.), 109.60 (C19H-arom.), 108.83 (C3H-arom.), 96.33
	(C17H-arom.), 69.92 (C22H2), 68.20 (C8H, 45.15 (C9), 27.16 (C10H3),
	24.91 (C11H3).

3-(3,3-dimethylindolin-2-yl)-7-(benzyloxy)-1H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 3.7
13 543	CA 2-55 F7-10 (yield = 61%)	✓ IC50 (PSA) = 3.19
	✓ tR (HPLC) = 4.67 min    ✓ MS (ESI+) m/z = 369.1976              [(M + H)+] ✓ HRMS (ESI+): calculated for C25H25N2O, m/z = 369.1961; found, 369.1957 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.10 (d, J = 1.6 Hz, 1H, H14), 7.58 (d, J = 7.8 Hz, 2H, H24, 28), 7.46-7.39 (m, 2H, H25, 27), 7.38-7.31 (m, 1H, H26) 7.22 (d, J = 2.4 Hz, 1H, H13), 7.15 (d, J = 8.0 Hz, 1H, H20), 7.00 (d, J = 7.0 Hz, 1H, H6), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.85 (t, J = 7.8 Hz, 1H, H19), 6.73 (d, J = 7.6 Hz,
	1H, H18, 6.62-6.56 (m, 2H, H1, 3), 5.85 (d, J = 2.4 Hz, 1H, H7),
	5.26 (s, 2H, H22), 4.77 (d, J = 2.2 Hz, 1H, H8), 1.38 (s, 3H, H10),
	0.74 (s, 3H, H11).
	✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.95 (C4-arom.), 145.54
	(C17-arom.), 138.61 (C5-arom.), 137.89 (C23-arom.), 128.97 (C16-arom.),
	128.83 (C25, 27H-arom.), 128.17 (C26H-arom.), 128.01 (C24, 28H-arom.),
	127.32 (C2H-arom.), 127.15 (C15-arom.), 123.71 (C13H-arom.), 122.43
	(C6H-arom.), 119.23 (C19H-arom.), 117.57 (C1H-arom.), 114.81
	(C12-arom.), 113.19 (C20H-arom.), 108.83 (C3H-arom.), 103.08
	(C18H-arom.), 69.56 (C22H2), 68.03 (C8H), 45.20 (C9), 27.19 (C10H3),
	24.89 (C11H3).

3-(3,3-dimethylindolin-2-yl)-6-hydroxy-1H-indole (Procedure 2)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 5.7
13 542	CA 2-61 F3-8 (yield = 62%)	✓ IC50 (PSA) = No Data
	✓ tR (HPLC) = 3.25 min   ✓ MS (ESI+) m/z = 279.1485             [(M + H)+] ✓ HRMS (ESI+): calculated for C18H19N2O, m/z = 279.1492; found, 279.1485 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.55 (s, 1H, H14), 8.84 (s, 1H, H21), 7.28 (d, J = 8.5 Hz, 1H, H20), 7.08 (d, J = 2.0 Hz, 1H, H13), 6.99 (d, J = 6.8 Hz, 1H, H6), 6.95 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.71 (d, J = 2.0 Hz, 1H,H17), 6.62-6.54 (m, 2H, H1, 3), 6.47 (dd, J = 8.6, 2.2 Hz, 1H, H19), 5.79 (d, J = 2.4 Hz, 1H, H7) 4.70 (d, J = 2,1 Hz, 1H, H8),
	1.37 (s, 3H, H10), 0.73 (s, 3H, H11).
	✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 153.20 (C18-arom.), 150.98
	(C4-arom.), 138.70 (C5-arom.), 138.04 (C15-arom.), 127.28 (C2H-arom.),
	122.40 (C6H-arom.), 121.88 (C13H-arom.), 120.84 (C16-arom.), 120.50
	(C20H-arom.), 117.48 (C1H-arom.), 114.08 (C12-arom.), 109.39
	(C19H-arom.), 108.78 (C3H-arom.), 96.92 (C17H-arom.), 68.27 (C8H), 45.10
	(C9), 27.17 (C10H3), 24.90 (C11H3).

3-(3,3-dimethylindolin-2-yl)-7-hydroxy-1H-indole (Procedure 2)

VPC Number	LabBook Code	✓ IC50 (eGFP) = 0.5
13 541	CA 2-62 F6-11 (yield = 37%)	✓ IC50 (PSA) = 0.94
	✓ tR (HPLC) = 3.51 min    ✓ MS (ESI+) m/z = 279.1525              [(M + H)+] ✓ HRMS (ESI+): calculated for C18H19N2O, m/z = 279.1492; found, 279.1496 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.76 (s, 1H, H14), 9.46 (s, 1H, H21), 7.19 (d, J = 2.4 Hz, 1H, H13), 7.02-6.98 (m, 2H, H6, 20), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.73 (t, J = 7.7 Hz, 1H, H19), 6.62-6.55 (m, 2H, H1, 3), 6.48 (dd, J = 7.5, 0.6 Hz, 1H, H18), 5.82
	(d, J = 2.4 Hz, 1H, H7), 4.75 (d, J = 2.2 Hz, 1H, H8), 1.38
	(s, 3H, H10), 0.74 (s, 3H, H11).
	✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.98 (C4-arom.), 143.94
	(C17-arom.), 138.67 (C5-arom.), 129.24 (C16-arom.), 127.29 (C2H-arom.),
	126.97 (C13H-arom.), 123.40 (C13H-arom.), 122.41 (C6H-arom.), 119.42
	(C19H-arom.), 117.52 (C1H-arom.), 114.60 (C12-arom.), 111.24
	(C20H-arom.), 108.80 (C3H-arom.), 105.55 (C18H-arom.), 68.08 (C8H),
	45.16 (C9), 27.17 (C10H3), 24.88 (C11H3).

3-(3,3-dimnethylindolin-2-yl)-7-ethyl-H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = No Data
13 546	CA 2-67 F4-10 (yield = 62%)	✓ IC50 (PSA) = No Data
	✓ tR (HPLC) = 4.16 min    ✓ MS (ESI+) m/z = 277.1705              [(M + H)+] ✓ HRMS (ESI+): calculated for C19H21N2, m/z = 277.1699; found, 277.1707 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.94 (s, 1H, H14), 7.39-7.35 (m, 1H, H20), 7.31 (d, J = 2.4 Hz, 1H, H13), 7.01 (d, J = 7.2 Hz, 1H, H6), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.87-6.83 (m, 2H, H18, 19), 6.61 (td, J = 7.2, 0.8 Hz, 1H, H1), 6.58 (d, J = 7.6 Hz, 1H, H3), 5.84 (d, J = 2.4 Hz, 1H, H7), 4.80 (d, J = 2.2 Hz, 1H, H8), 2.46 (s, 3H, H21),
	1.39 (s, 3H, H10), 0.74 (s, 3H, H11).
	✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.97 (C4-arom.), 138.68
	(C5-arom.), 136.42 (C15-arom.), 127.32 (C2H-arom.), 126.97 (C16-arom.),
	123.73 (C13H-arom.), 122.42 (C6H-arom.), 121.72 (C19H-arom.), 120.90
	(C17-arom.), 118.96 (C18H-arom.), 117.73 (C20H-arom.), 117.57
	(C1H-arom.), 114.63 (C12-arom.), 108.85 (C3H-arom.), 68.11 (C8H),
	45.17 (C9), 27.16 (C10H3), 24.95 (C11H3), 17.27 (C21H3).

3-(3,3-dimethylindolin-2-yl)-7-fluoro-1H-indole (Procedure 1)

VPC Number	LabBook Code	✓ IC50 (eGFP) = No Data
13 555	CA 2-90 F4-7 (yield = 62%)	✓ IC50 (PSA) = No Data
	✓ tR (HPLC) = 4.12 min    ✓ MS (ESI+) m/z = 281.1456              [(M + H)+] ✓ HRMS (ESI+): calculated for C18H18FN2, m/z = 281.1449; found, 281.1454 ✓ 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.49 (s, 1H, H14), 7.41-7.34 (m, 2H, H13, 20), 7.01 (d, J = 7.2 Hz, 1H, H6), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.94-6.86 (m, 2H, H18, 19), 6.65-6.57 (m, 2H, H1, 3), 5.91 (d, J = 2.5 Hz, 1H H7), 4.79 (d, J = 2.2 Hz, 1H, H8), 1.38 (s, 3H, H10), 0.74 (s, 3H, H11). ✓ 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.85 (C4-arom.), 148.48 (C17-
	arom.), 138.51 (C5-arom.), 131.28 (d, J = 5.9 Hz, C16-arom.), 127.39 (C2H-
	arom.), 125.19 (d, J = 0.6 Hz, C13H-arom.), 124.70 (d, J = 13.1 Hz, C15-
	arom.), 122.45 (C6H-arom.), 119.05 (d, J = 6.3 Hz, C19H-arom.), 117.70 (C1H-
	arom.), 116.45 (d, J = 3.2 Hz, C20H-arom.), 115.49 (d, J = 1.9 Hz, C12-arom.),
	108.91 (C3H-arom.), 106.02 (d, J = 15.9 Hz, C18H-arom.), 67.86 (C8H), 45.25
	(C9), 27.12 (C10H3), 24.90 (C11H3).

3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 3)

VPC Number	LabBook Code	IC50 (eGFP) = 2.1
13 556	CA 2-100 F3-7 (yield = 76%)	IC50 (PSA) = 2.18
	tR (HPLC) = 3.52 min        MS (ESI+) m/z = 264.1501                 [(M + H)+] HRMS (ESI+): calculated for C17H18N3, m/z = 264.1495; found, 264.1500 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.51 (s, 1H, H14), 8.18 (dd, J = 4.6, 1.5 Hz, 1H, H20), 7.86 (dd, J = 7.9, 1.1 Hz, 1H, H18), 7.44 (d, J = 2.4 Hz, 1H, H13), 7.02 (d, J = 7.2 Hz, 1H, H6), 7.00-6.96 (m, 2H, H2,19), 6.63 (td, J = 7.4, 0.9 Hz, 1H, H1), 6.60 (d, J = 7.7 Hz, 1H, H3), 5.92 (d, J = 2.3 Hz, 1H, H7), 4.74 (d, J = 2.0 Hz, 1H, H8), 1.38 (s, 3H, H10), 0.74 (s, 3H, H11). 13C NMR (151 MHz, DMSO-d6): δ (ppm) = 150.38 (C4-arom.), 148.74 (C15-
	arom.), 142.28 (C20H-arom.), 137.95 (C5-arom.), 127.99 (C18H-arom.),
	126.96 (C2H-arom.), 123.93 (C13H-arom.), 121.97 (C6H-arom.), 118.98 (C16-
	arom.), 117.26 (C1H-arom.), 114.92 (C19H-arom.), 112.80 (C12-arom.),
	108.47 (C3H-arom.), 67.77 (C8H), 44.77 (C9), 26.62 (C10H3), 24.34 (C11H3).

3-(3,3-dimethyindolin-2-yl)-1H-indole-7-carboxyic Acid (Procedure 4)

VPC Number	LabBook Code	IC50 (eGFP) = No Data
13 557	CA 2-104 Ap Tmt (yield = 82%)	IC50 (PSA) = No Data
	tR (HPLC) = 3.74 min         MS (ESI+) m/z = 307.1442                  [(M + H)+] HRMS (ESI+): calculated for C19H19N2O2, m/z = 307.1441; found, 304.1442 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.01 (br s, 1H, H22), 10.98 (s, 1H, H14), 7.87 (d, J = 7.8 Hz, 1H, H20), 7.74 (d, J = 6.8 Hz, 1H, H18), 7.35 (d, J = 2.3 Hz, 1H, H13), 7.07 (t, J = 7.7 Hz, 1H, H19), 7.02 (d, J = 7.2 Hz, 1H, H6), 6.98 (td, J = 7.6, 1.1 Hz, 1H, H2), 6.65-6.58 (m, 2H, H1,3), 5.93 (br s, 1H, H7), 4.83 (s, 1H, H8), 1.39 (s, 3H, H10), 0.73 (s, 3H, H11).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 168.45 (C21O), 150.89 (C4-
	arom.), 138.46 (C5-arom.), 135.63 (C15-arom.), 128.93 (C16-arom.), 127.41
	(C2H-arom.), 125.68 (C20H-arom.), 125.66 (C13H-arom.), 124.20 (C18H-
	arom.), 122.48 (C6H-arom.), 118.42 (C19H-arom.), 117.69 (C1H-arom.),
	114.65 (C12-arom.), 113.89 (C17-arom.), 108.90 (C3H-arom.), 67.76 (C8H),
	45.25 (C9), 27.08 (C10H3), 24.91 (C11H3).

(3-(3,3-dimethylindolin-2-yl)-1H-indole-7-yl)methanol (Procedure 5)

VPC Number	LabBook Code	IC50 (eGFP) = 1.6
13 558	CA 2-105 F6-11 (yield = 81%)	IC50 (PSA) = No Data
	tR (HPLC) = 3.45 min        MS (ESI+) m/z = 293.1651                  [(M + H)+] HRMS (ESI+): calculated for C19H21N2O, m/z = 293.1648; found, 293.1651 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.82 (s, 1H, H14), 7.45 (d, J = 7.8 Hz, 1H, H20), 7.29 (d, J = 2.4 Hz, 1H, H13), 7.05 (d, J = 6.8 Hz, 1H, H18), 7.01 (d, J = 7.2 Hz, 1H, H6), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H2), 6.92 (dd, J = 7.8, 6.8 Hz, 1H), 6.61 (m, 2H, H1,3), 5.84 (d, J = 2.4 Hz, 1H, H7), 5.14 (t, J = 5.7 Hz, 1H, H18), 4.81 (d, J = 2.1 Hz, 1H, H8), 4.78 (d, J = 5.7
	Hz, 2H, H21), 1.39 (s, 3H, H10), 0.74 (s, 3H, H11).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.97 (C4-arom.), 138.66
	(C5H-arom.), 134.66 (C15-arom.), 127.36 (C2H-arom.), 127.32 (C16-arom.),
	125.92 (C17-arom.), 123.87 (C13H-arom.), 122.43 (C6H-arom.), 119.41
	(C18H-arom.), 118.92 (C20H-arom.), 118.62 (C19H-arom.), 117.57 (C1H-
	arom.), 114.36 (C12-arom.), 108.85 (C3H-arom.), 68.06 (C8H), 60.82
	(C21H2), 45.19 (C9), 27.15 (C10H3), 24.94 (C11H3).

(3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 6)

VPC Number	LabBook Code	IC50 (eGFP) = 10.7
13 561	CA 2-121 Ap Tmt (yield = 35%)	IC50 (PSA) = No Data
	tR (HPLC) = 3.07 min         MS (ESI+) m/z = 264.1497                  [(M + H)+] HRMS (ESI+): calculated for C17H18N3, m/z = 264.1495; found, 264.1498 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.52 (s, 1H, H9), 8.73 (s, 1H, H3), 8.03 (s, 1H, H5), 7.59 (d, J = 1.7 Hz, 1H, H8), 7.49 (d, J = 4.3 Hz, 1H, H6), 7.04-6.95 (m, 2H, H11,15), 6.66-6.58 (m, 2H, H10,12), 5.94 (d, J = 1.9 Hz, 1H, H16), 4.78 (d, J = 2.3 Hz, 1H, H17), 1.38 (s, 3H, H19), 0.72 (s, 3H, H20). 13C NMR (151 MHz, DMSO-d6): δ (ppm) = 150.34 (C13-arom.), 137.94
	(C14-arom.), 137.08 (C5H-arom.), 134.44 (C3H-arom.), 133.68 (C2-arom.),
	130.91 (C1-arom.), 127.79 (C8H-arom.), 126.96 (C11H-arom.), 121.98
	(C15H-arom.), 117.32 (C10H-arom.), 114.54 (C6H-arom.), 113.67 (C7-
	arom.), 108.51 (C12H-arom.), 67.25 (C17H), 44.83 (C18), 26.51 (C19H3),
	24.33 (C20H3).

(3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 6)

VPC Number	LabBook Code	IC50 (eGFP) = 2.3
13 560	CA 2-123 Ap Tmt (yield = 72%)	IC50 (PSA) = No Data
	tR (HPLC) = 3.05 min         MS (ESI+) m/z = 264.1502                  [(M + H)+] HRMS (ESI+): calculated for C17H18N3, m/z = 264.1495; found, 264.1502 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.16 (s, 1H, H9), 8.32 (dd, J = 4.6, 1.5 Hz, 1H, H5), 7.75 (dd, J = 8.2, 1.5 Hz, 1H, H3), 7.58 (d, J = 2.1 Hz, 1H, H8), 7.09 (dd, J = 8.2, 4.6 Hz, 1H, H4), 6.99 (d, J = 7.2 Hz, 1H, H15), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H11), 6.63-6.57 (m, 2H, H10,12), 5.86 (d, J = 2.7 Hz, 1H, H16), 5.06 (dd, J = 2.8, 0.6 Hz, 1H, H17), 1.51 (s, 3H, H19), 0.72 (s, 3H, H20).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.85 (C13H-arom.), 145.29
	(C1-arom.), 142.28 (C5H-arom.), 139.08 (C14-arom.), 129.27 (C2-arom.),
	127.40 (C8H-arom.), 127.23 (C11H-arom.), 122.51 (C15H-arom.), 118.77
	(C3H-arom.), 117.72 (C10H-arom.), 116.55 (C4H-arom.), 115.09 (C7-arom.),
	108.96 (C12H-arom.), 65.98 (C17H), 45.02 (C18), 27.20 (C19H3), 25.21
	(C20H3).

Cyclohexyl-Hydroindole Moiety

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-indole (Procedure 1)

VPC Number	LabBook Code	IC50 (eGFP) = 0.8
13 534	CA 2-8 F18-23 (yield = 47%)	IC50 (PSA) = 1.25
(Beige Solid)	tR (HPLC) = 4.39 min     MS (ESI+) m/z = 303.1775                [(M + H)+] HRMS (ESI+): calculated for C21H23N2, m/z = 303.1856; found, 303.1852 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.92 (s, 1H, H12), 7.32 (d, J = 8.0 Hz, 1H, H18), 7.27 (d, J = 2.4 Hz, 1H, H11), 7.17 (d, J = 7.1 Hz, 1H, H6), 7.02-6.96 (m, 3H, H2,15,17), 6.78 (td, J = 7.6, 0.8 Hz, 1H, H16), 6.61 (td, J = 7.4, 1.0 Hz, 1H, H1), 6.53 (d, J = 7.4 Hz, 1H, H3), 5.71 (s, 1H, H7), 4.83 (s, 1H, H8), 1.82-1.14 (m, 2H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 151.59 (C4-arom.), 137.65 (C5-arom.), 137.07 (C13-arom.), 127.58 (C2H-arom.), 126.78 (C14-arom.), 124.83 (C11H-arom.), 123.58 (C6H-arom.), 121.08 (C17H-arom.), 120.68 (C15H-arom.), 118.75 (C16H- arom.), 117.00 (C1H-arom.), 115.58 (C10-arom.), 111.86 (C18H-arom.), 108.32 (C3H-arom.), 65.96 (C8H), 48.29 (C9), 37.43 (C19H2), 31.94 (C23H2), 25.99 (C21H2), 22.96 (C20H2), 22.81 (C22H2).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-5-methyl-1H-indole (Procedure 1)

VPC Number	LabBook Code	IC50 (eGFP) = 3.2
13 548	CA 2-72 F12-18 (yield = 69%)	IC50 (PSA) = 4.24
(Beige Solid)	tR (HPLC) = 4.57 min     (MS (ESI+) m/z = 317.1950 [(M + H)+] HRMS (ESI+): calculated for C22H25N2, m/z = 317.2012; found, 317.2008 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.78 (d, J = 1.4 Hz, 1H, H9), 7.22-7.19 (m, 2H, , H3,8), 7.17 (d, J = 7.6 Hz, 1H, H15), 7.00 (td, J = 7.6, 1.2 Hz, 1H, H11), 6.82 (dd, J = 8.3, 1.5 Hz, 1H, H4), 6.75 (br s, 1H, H6), 6.62 (td, J = 7.4, 1.0 Hz, 1H, H10), 6.53 (d, J = 7.6 Hz, 1H, H12), 5.65 (s, 1H, H16), 4.78 (s, 1H, H17), 2.18 (s, 3H, H24), 1.80-1.16 (m, 10H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 151.69 (C13-arom.), 137.72 (C14-arom.), 135.43 (C2-arom.), 127.45 (C11H-arom.), 127.03 (C5-arom.), 126.85 (C1-arom.), 124.83 (C8H-arom.), 123.64 (C15H-arom.), 122.62 (C4H-arom.), 120.51 (C6H-arom.), 116.95 (C10H-arom.), 114.98 (C7- arom.), 111.51 (C3H-arom.), 108.44 (C12H-arom.), 66.18 (C17H), 48.25 (C18), 37.22 (C19H2), 31.96 (C23H2), 26.00 (C21H2), 23.01 (C20H2), 22.75 (C22H2), 21.88 (C24H3).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-methyl-H-indole (Procedure 1)

VPC Number	LabBook Code	IC50 (eGFP) = 1.7
13 549	CA 2-73 F9-15 (yield = 72%)	IC50 (PSA) = 2.57
(Beige Solid)	tR (HPLC) = 4.58 min     MS (ESI+) m/z = 317.1932 [(M + H)+] HRMS (ESI+): calculated for C22H25N2, M/Z = 317.2012; found, 317.2022 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.88 (s, 1H, H9), 7.25 (d, J = 2.5 Hz, 1H, H8), 7.16 (d, J = 7.0 Hz, 1H, H15), 6.98 (td, J = 7.6, 1.2 Hz, 1H, H11), 6.85 (d, J = 7.9 Hz, 1H, H6), 6.80 (d, J = 7.0 Hz, 1H, H4), 6.70 (t, J = 7.6 Hz, 1H, H5), 6.60 (td, J =7.4, 1.0 Hz, 1H, H10), 6.53 (dd, J = 7.6, 0.4 Hz, 1H, H12),5.67 (s, 1H, H16), 4.82 (s, 1H, H17), 2.43 (s, 3H, H24), 1.83-1.17 (m, 10H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 151.60 (C13-arom.), 137.67 (C14-arom.), 136.53 (C2-arom.), 127.56 (C11H-arom.), 126.48 (C1-arom.), 124.52 (C8H-arom.), 123.60 (C15H-arom.), 121.61 (C4H-arom.), 120.80 (C3-arom.), 118.95 (C5H-arom.), 118.30 (C6H-arom.), 116.98 (C10H- arom.), 116.02 (C7-arom.), 108.33 (C12H-arom.), 66.00 (C17H), 48.28 (C18), 37.44 (C19H2), 31.95 (C23H2), 26.00 (C21H2), 22.97 (C20H2), 22.80 (C22H2), 17.25 (C24H3).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-(benzyloxy)-1H-indole (Procedure 1)

VPC Number	LabBook Code	IC50 (eGFP) = 11.8
13 550	CA 2-76 F13-24 (yield = 55%)	IC50 (PSA) = No Data
(Beige Solid)	tR (HPLC) = 5.07 min     MS (ESI+) m/z = 409.2254 [(M + H)+] HRMS (ESI+): calculated for C28H29N2O, m/z = 409.2274; found, 409.2278 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.72 (d, J = 1.7 Hz, 1H, H12), 7.46- 7.42 (m, 2H, H22,26), 7.41-7.36 (m, 2H, H23,25), 7.34-7.30 (m, 1H, , H24), 7.17- 7.12 (m, 2H, , H6,11), 6.98 (td, J = 7.6, 1.2 Hz, 1H, H2), 6.89 (d, J = 2.2 Hz, 1H, H15), 6.82 (br d, J = 8.7 Hz, 1H, H18), 6.60 (td, J = 7.4, 1.0Hz, 1H, H1), 6.54-6.50 (m, 2H, , H3-17), 5.67 (s, 1H, H7), 5.07 (s, 2H, H20), 4.76 (s, 1H, H8), 1.80-1.15 (m, 10H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 154.56 (C16-arom.), 151.55 (C4-arom.), 138.16 (C21-arom.), 137.71 (C5-arom.), 137.65 (C13-arom.), 128.82 (C23,25H-arom.), 128.04 (C24H-arom.), 127.88 (C22,26H-arom.), 127.58 (C2H-arom.), 123.67 (C6H- arom.), 123.54 (C11H-arom.), 121.34 (C14-arom.), 121.31 (C18H-arom.), 116.98 (C1H-arom.), 115.58 (C10-arom.), 109.47 (C17H-arom.), 108.32 (C3H-arom.), 96.43 (C15H-arom.), 69.87 (C20H2), 66.04 (C8H), 48.22 (C9), 37.40 (C19H2), 31.91 (C23H2), 25.99 (C21H2), 22.95 (C20H2), 22.83 (C22H2).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-hydroxy-1H-indole (Procedure 2)

VPC Number	LabBook Code	IC50 (eGFP) = 15.5
13 551	CA 2-83 F2-7 (yield = 38%)	IC50 (PSA) = No Data
(Beige Solid)	tR (HPLC) = 3.57 min    MS (ESI+) m/z = 319.1824              [(M + H)+] HRMS (ESI+): calculated for C21H23N2O, m/z = 319.1805; found, 319.1802 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.51 (d, J = 1.5 Hz, 1H, H12), 8.79 (s, 1H, H24), 7.15 (d, J = 7.0 Hz, 1H, H6), 7.04 (d, J = 2.3 Hz, 1H, H11), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H2), 6.72 (d, J = 8.5 Hz, 1H, H18), 6.67 (d, J =2.0 Hz, 1H, H15), 6.59 (td, J = 7.4, 1.0 Hz, 1H, H1), 6.51 (d, J = 7.7 Hz, 1H,H3), 6.30 (dd, J = 8.6, 2.2 Hz, 1H, H17), 5.64 (s, 1H, H7), 4.73 (s, 1H, H8), 1.81-1.16 (m, 10H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 153.10 (C16-arom.), 151.57 (C4-arom.), 138.21 (C13-arom.), 137.70 (C5-arom.), 127.52 (C2H-arom.), 123.55 (C6H- arom.), 122.74 (C11H-arom.), 121.06 (C18H-arom.), 120.26 (C14-arom.), 116.91 (C1H-arom.), 115.43 (C10- arom.), 109.35 (C17H-arom.), 108.29 (C3H-arom.), 96.85 (C15H-arom.), 66.16 (C8H), 48.18 (C9), 37.38 (C19H2), 31.91 (C23H2), 26.01 (C21H2), 22.97 (C20H2), 22.83 (C22H2).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-hydroxy-1H-indole (Procedure 2)

VPC Number	LabBook Code	IC50 (eGFP) = 1.1
13 552	CA 2-84 Precipitate	IC50 (PSA) = 1.14
	(yield = 28%)
(Brown Solid)	tR (HPLC) = 3.81 min    MS (ESI+) m/z = 319.1728              [(M + H)+] HRMS (ESI+): calculated for C21H23N2O, m/z = 319.1805; found, 319.1814 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.72 (d, J = 1.8 Hz, 1H, H12), 9.42 (s, 1H, H24), 7.14 (d, J = 7.1 Hz, 1H, H6), 7.12 (d, J = 2.5 Hz, 1H, H11), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H2), 6.59 (m, 2H, H1,17), 6.52 (m, 2H, H3,18), 6.42 (dd, J = 7.4, 0.8 Hz, 1H, H16), 5.65 (s, 1H, H7), 4.79 (s, 1H, H8), 1.82-1.16 (m, 10H, H19,20,21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 151.60 (C4- arom.), 143.87 (C15-arom.), 137.66 (C5-arom.), 128.78 (C14-arom.), 127.50 (C2H-arom.), 127.06 (C13-arom.), 124.10 (C11H-arom.), 123.60 (C6H-arom.), 119.38 (C17H- arom.), 116.93 (C1H-arom.), 115.94 (C10-arom.), 111.78 (C18H-arom.), 108.29 (C3H-arom.), 105.41 (C16H-arom.), 65.88 (C8H), 48.33 (C9), 37.45 (C19H2), 31.93 (C23H2), 26.00 (C21H2), 22.98 (C20H2), 22.79 (C22H2).

Unexpected Compounds—General Procedure 7

Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde or cyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Then, 7-azaindole or 1,5,6,7-Tetrahydro-4H-indol-4-one (1.0 eq) was added and the reaction mixture was stirred additional 24 h at 100° C. (until complete conversion). Acetic acid was removed under vacuo. Then, the residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, crude was purified by automated combi-flash to afford the good compound.

3-(3,3-dimethyl-3H-indol-2-yl)-1H-pyrrolo[2,3-b]pyri dine (Procedure 7)

VPC Number	LabBook Code	IC50 (eGFP) = 0.7
13 537	CA 2-39 F9-15 (yield = 25%)	IC50 (PSA) = 0.81
(Yellow Solid)	tR (HPLC) = 3.17 min      MS (ESI+) m/z = 262.1345                [(M + H)+] HRMS (ESI+): calculated for C17H16N3, m/z =262.1339; found, 262.1345 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.40 (s, 1H, H14), 8.94 (dd, J = 7.9, 1.7 Hz, IH, H18), 8.40 (s, IH, H13), 8.35 (dd, J = 4.6, 1.6 Hz, 1H, H20), 7.56 (d, J = 7.5 Hz, 1H, H3), 7.49 (d, J = 6.8 Hz, 1H, H6), 7.32 (td, J = 7.6, 1.2 Hz, 1H, H2), 7.28 (dd, J = 7.9, 4.7 Hz, 1H, H19), 7.20 (td, J = 7.4, 1.0 Hz, 1H, H1), 1.54 (s, 6H, H10,11). 3C NMR (101 MHz, DMSO-d6): δ (ppm) = 180.97 (C8), 154.77 (C4-arom.), 149.39 (C15-arom.), 146.90 (C5-arom.), 144.50 (C20H-arom.), 131.69 (C18H-arom.), 130.45 (C13H-arom.), 127.92 (C2H-arom.), 124.80 (C1H-arom.), 121.61 (C6H- arom.), 119.71 (C3H-arom.), 119.05 (C16-arom.), 117.73 (C19H-arom.), 108.26 (C12-arom.), 53.39 (C9), 25.82 (C10,11).

Tetrahydro-3-(3,3-dimethyl-3H-indol-2-yl)-1H-indol-4-one (Procedure 7)

VPC Number	LabBook Code	IC50 (eGFP) = No Data
13 539	CA 2-48 F19-22 (yield = 9%)	IC50 (PSA) = No Data
(Yellow Solid)	tR (HPLC) = 3.54 min    MS (ESI+) m/z = 279.1498              [(M + H)+] HRMS (ESI+): calculated for C18H19N2O, m/z = 279.1492; found, 279.1498 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.27 (s, 1H, H14), 7.54-7.48 (m, 2H, H3,6), 7.33 (td, J = 7.6, 1.3 Hz, 1H, H2), 7.22 (td, J = 7.4, 1.0 Hz, 1H, H1), 7.05 (d, J = 1.8 Hz, 1H, H13), 2.85 (t, J = 6.1 Hz, 2H, H17), 2.39 (t, J = 6.4 Hz, 2H, H17), 2.09-2.02 (m, 2H, H18), 1.46 (s, 6H, H10,11). 3C NMR (101 MHz, DMSO-d6): δ (ppm) = 193.35 (C20O), 176.21 (C8), 153.76 (C4-arom.), 148.19 (C15-arom.), 147.25 (C5-arom.), 128.13 (C2H-arom.), 126.38 (C12-arom.), 125.40 (C1H-arom.), 121.96 (C6H-arom.), 121.76 (C16-arom.), 119.76 (C3H-arom.), 109.82 (C13H-arom.), 52.57 (C9), 38.25 (C19H2), 25.49 (C10,11H3), 23.71 (C18H2), 22.70 (C17H2).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 7)

VPC Number	LabBook Code	IC50 (eGFP) = 6.6
13 559	CA 2-110 F18-27	IC50 (PSA) = No Data
	(yield = 23%)
(Brown Solid)	tR (HPLC) = 3.70 min    MS (ESI+) m/z = 302.1654              [(M + H)+] HRMS(ESI+): calculated for C20H20N3, m/z = 302.1652; found, 302.1654 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.39 (s, 1H, H17), 9.00 (dd, J = 7.9, 1.7 Hz, 1H, H21), 8.45 (d, J = 2.0 Hz, 1H, H16), 8.35 (dd, J = 4.6, 1.6 Hz, 1H, H23), 7.87 (d, J = 7.3 Hz, 1H, H6), 7.62 (dd, J = 7.6, 0.6 Hz, 1H, H3), 7.38 (td, J = 7.6, 1.0 Hz, 1H,H2), 7.27 (dd, J = 7.9, 4.7 Hz, 1H, H22), 7.17 (td, J = 7.5, 1.1Hz, 1H, H1), 2.34-2.25 (m, 2H, H10), 2.07- 1.77 (m, 6H, H11,12,13), 1.32-1.26 (m, 2H, H14). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 180.61 (C8), 155.41 (C4-arom.), 149.19 (C18-arom.), 145.63 (C5-arom.), 144.45 (C23H-arom.), 132.08 (C21H-arom.), 130.23 (C16H-arom.), 127.95 (C2H-arom.), 124.74 (C6H-arom.), 123.93 (C1H-arom.), 120.36 (C3H-arom.), 119.45 (C19-arom.), 117.71 (C22H-arom.), 107.92(C15-arom.), 57.86 (C9), 33.53 (C10,14H2), 24.81 (C12H2), 21.89 (CH11,13H2).

Quinoline Moiety—General Procedure 9

In microwave vessel, quinoline (2.0 eq) and indole (1.0 eq) were mixed together and the system was sealed and placed under nitrogen, after a purge with vacuum/N₂ (3 times). Then, HCl solution 4M in 1,4-dioxane (1.2 eq) was added with the needle immersed in the mixture (exothermic reaction). The reaction mixture was heated with microwave during 2 h at 160° C. The reaction mixture was taken up with a minimum of MeOH and when the residue was dissolved, it was transferred in mixture of AcOEt and saturated NaHCO₃ solution. The resulting solution was extracted and the aqueous phase was washed with AcOEt (×2). The organic layers were combined, washed with 0.01 M critic acid solution, saturated NaHCO₃ solution, dried over Na₂SO₄ and concentrated to dryness under reduced pressure. Finally, the crude was purified by automated combi-flash to afford the good compound.

General Procedure 10

Halogenated-compound (1.0 eq), boronic acid (or boronate) (1.1 eq) and Pd(PPh₃)₄ (10% mol) was added in microwave vessel (10-20 mL). The vial was sealed with a cap and the system was purged with vacuum and placed under N₂. Then, the solids were dissolved in mixture of Toluene/EtOH (4.5:2.0, 0.11 M) and purged with vacuum/N₂ one more time. Then, a solution of K₂CO₃ (3.0 eq) in H₂O (1.8 M) was added. The reaction mixture was stirred and heated overnight at 95° C. with oil bath. The reaction mixture was filtered on plug of celite. The filtrate was was poured with water and was extracted with AcOEt (×3). The organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. The residue was taken up in DCM/TFA (5:5) for 2 h at r.t. The solvents were evaporated under reduced pressure. The residue was then neutralized with saturated NaHCO₃ solution and extracted with AcOEt (×2). The organic layers were washed, dried and concentrated in vacuo. The residue was precipitate in DCM or purified by automated combi-flash to afford the good compound.

2-(1H-indol-3-yl)-4-methylquinoline

VPC Number	LabBook Code	IC50 (eGFP) = 5.6
13 547	CA 2-69 F6-11	IC50 (PSA) = No Data
	(yield = 62%)
(Beige Solid)	tR (HPLC) = 3.20 min    MS (ESI+) m/z = 259.1243              [(M + H)+] Mp = 168-180° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1237 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.63 (s, 1H, H14), 8.90-8.85 (m, 1H, H20), 8.32 (d, J = 2.8 Hz, 1H, H13), 8.04-7.98 (m, 2H, H3,6), 7.94 (d, J = 0.9 Hz, 1H, H9), 7.71 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H, H2), 7.53-7.44 (m, 2H, H1,17), 7.24-7.16 (m, 2H, H18,19), 2.71 (d, J = 0.8 Hz, 3H, H12). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 155.74 (C8- arom.), 148.21 (C4-arom.), 143.61 (C10-arom.), 137.64 (C15-arom.), 129.51 (C2H-arom.), 129.39 (C3H-arom.), 127.98 (C13H-arom.), 126.42 (C5-arom.), 126.13 (C16- arom.), 125.18 (C1H-arom.), 124.35 (C6H-arom.), 123.12 (C20H-arom.), 122.48 (C18H-arom.), 120.68 (C19H-arom.), 119.90 (C9H-arom.), 115.97 (C11-arom.), 112.16 (C17H-arom.), 18.76 (C12H3).

2-(7-methoxy-1H-indol-3-yl)-4-methylquinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.6
13 554	CA 2-87 F7-10	IC50 (PSA) = 0.67
	(yield = 22%)
(Yellow Solid)	tR (HPLC) = 3.37 min    MS (ESI+) m/z = 289.1336              [(M + H)+] Mp = 146-152° C. HRMS (ESI+): calculated for C19H17N2O, m/z = 289.1335; found, 289.1335 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.73 (s, 1H, H14), 8.45 (d, J = 8.0 Hz, 1H, H20), 8.21 (d, J = 2.9 Hz, 1H, H13), 8.03-7.99 (m, 2H, H3,6), 7.95 (d, J = 0.8 Hz, 1H, H9), 7.70 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H, H2), 7.50 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, H1), 7.11 (t, J = 7.9 Hz, 1H, H19), 6.79 (d, J = 7.5 Hz, 1H, H18), 3.97 (s, 3H, H22), 2.70 (d, J = 0.8 Hz, 3H, H12). 13C NMR (151 MHz, DMSO-d6): δ (ppm) = 155.23 (C8- arom.), 147.71 (C4-arom.), 146.06 (C17-arom.), 143.11 (C10-arom.), 129.00 (C2H-arom.), 128.91 (C3H-arom.), 127.23 (C15-arom.), 127.14 (C16-arom.), 126.97 (C13H- arom.), 125.95 (C5-arom.), 124.69 (C1H-arom.), 123.85 (C6H-arom.), 120.76 (C19H-arom.), 119.52 (C9H-arom.), 116.09 (C11-arom.), 115.37 (C20H-arom.), 102.58 (C18H- arom.), 55.18 (C22H3), 18.24 (C12H3).

2-(1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.06
13 562	CA 2-128 F8-12	IC50 (PSA) = 0.14
	(yield = 46%)
(Beige Solid)	tR (HPLC) = 2-91 min    MS (ESI+) m/z = 245.1073              [(M + H)+] Mp = 184-187° C. HRMS (ESI+): calculated for C17H13N2, m/z = 245.1073; found, 245.1075 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.65 (s, 1H, H13), 8.88 (d, J = 8.5 Hz, 1H, H19), 8.35 (d, J = 2.7 Hz, 1H, H12), 8.26 (d, J = 8.6 Hz, 1H, H10), 8.06 (d, J = 8.7 Hz, 1H, H9), 8.04 (d, J = 8.3 Hz, 1H, H3), 7.89 (d, J = 7.9 Hz, 1H, H6), 7.72 (t, J = 7.6 Hz, 1H, H2), 7.51 -7.46 (m, 2H, H1,16), 7.24-7.18 (m, 2H, H17,18). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 155.56 (C8- arom.), 147.75 C4-arom.s), 137.21 (C14-arom.), 135.59 (C10H-arom.), 129.34 (C2H-arom.), 128.34 (C3H-arom.), 27.79 (C6H-arom.), 127.61 (C12H-arom.), 125.80 (C5- arom.), 125.58 (C15-arom.), 124.88 (C1H-arom.), 122.57 (C19H-arom.), 122.08 (C17H-arom.), 120.31 (C18H- arom.), 119.21 (C9H-arom.), 115.49 (C11H-arom.), 111.73 (C16H-arom.).

2-(7-fluoro-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number	LabBook	CodeIC50 (eGFP) = 1.6
13 569	CA 3-45 F13-23 Precipitate	IC50 (PSA) = Not Tested
	(yield = 34%)
(Red Solid)	tR (HPLC) = 3.02 min    MS (ESI+) m/z = 263.1009              [(M + H)+] Mp = 152-154° C. HRMS (ESI+ ): calculated for C17H12FN2, m/z = 263.0979; found, 263.0976 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 12.17 (s, 1H, H13), 8.71 (d,J = 8.0 Hz, 1H, H19), 8.44 (d, J = 2.8 Hz, 1H, H12), 8.29 (d, J = 8.7 Hz, 1H, H10), 8.10 (d, J = 8.7 Hz, 1H, H9), 8.05 (d, J = 8.3 Hz, 1H, H3), 7.91 (d, J = 7.5 Hz, 1H, H6), 7.73 (t, J = 7.5 Hz, 1H, H2), 7.51 (t, J = 7.5 Hz, 1H, H1), 7.21-7.15 (m, 1H, H18), 7.06 (dd, J = 11.4, 7.8 Hz, 1H, H17). 13C NMR (126 MHz, DMSO-d6): δ (ppm) = 155.50 (C8-arom.), 149.63 (d, J = 243.4 Hz, C16-arom.), 148.13 (C4-arom.), 136.29 (C10H-arom.), 129.92 (C2H-arom.), 129.85 (d, J = 5.2 Hz, C15- arom.), 129.18 (C12H-arom.), 128.90 (C3H-arom.), 128.14 (C6H- arom.), 126.41 (C5-arom.), 125.63 (C1H-arom.), 125.52 (d, J = 13.2 Hz, C14-arom.), 121.14 (d, J = 6.2 Hz, C18H-arom.), 119.76 (C9H-arom.), 119.30 (d, J = 3.0 Hz, C19H-arom.), 116.97 (d, J = 1.3 Hz, C11-arom.), 107.43 (d, J = 15.6 Hz, C17H-arom.).

2-(7-ethyl-1H-indol-3-yl)quinoline

VPC Number	LabBook	CodeIC50 (eGFP) = 0.2
13 567	CA 3-46 P2 F6-13	IC50 (PSA) = 0.23
	(yield = 45%)
(Yellow Solid)	tR (HPLC) = 3.16 min    MS (ESI+) m/z = 273.1719              [(M + H)+]. Mp = 159-162° C. HRMS (ESI+: calculated for C19H17N2, m/z = 273.1386; found, 273.1389 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 11.63 (s, 1H, H13), 8.73 (d, J = 7.9 Hz, 1H, H19), 8.34 (d, J = 2.9 Hz, 1H, H12), 8.25 (d, J = 8.7 Hz, 1H, H10), 8.09 (d, J = 8.7 Hz, 1H, H9), 8.03 (d, J = 8.4 Hz, 1H, H3), 7.88 (d, J = 7.2 Hz, 1H, H6), 7.71 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, H2), 7.48 (ddd, J = 7.5, 6.5, 1.0 Hz, 1H, H1), 7.15 (t, J = 7.8 Hz, 1H, H18), 7.05 (d, J = 6.9 Hz, 1H, H17), 2.93 (q, J = 7.5 Hz, 2H, H20), 1.32 (t, J = 7.5 Hz, 3H, H21). 13C NMR (126 MHz, DMSO-d6): δ (ppm) = 156.14 (C8-arom.), 148.27 (C4-arom.), 136.38 (C14-arom.), 135.97 (C10H-arom.), 129.76 (C2H-arom.), 128.86 (C3H-arom.), 128.07 (C6H-arom.), 127.98 (C12H- arom.), 127.62 (C16-arom.), 126.28 (C5-arom.), 126.00 (C15-arom.), 125.30 (C1H-arom.), 121.28 (C17H-arom.), 121.08 (C18H-arom.), 120.74 (C19H- arom.), 119.80 (C9H-arom.), 116.39 (C11-arom.), 24.09 (C20H2), 15.01 (C21H3).

2-(2-methyl-1H-indol-3-yl)quinoline

VPC Number	LabBook	CodeIC50 (eGFP) = 20.0
13 570	CA 3-47 F35-40 (yield = 29%)	IC50 (PSA) = Not Tested
(Brown Solid)	tR (HPLC) = 2.91 min    MS (ESI+) m/z = 259.1435              [(M + H)+] Mp = 67-75° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1230 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.48 (s, 1H, H13), 8.34 (d, J = 8.6 Hz, 1H, H10), 8.21 (dd, J = 6.5, 2.4 Hz, 1H, H19), 8.01 (d, J = 8.4 Hz, 1H, H3), 7.94 (d, J = 7.6 Hz, 1H, H6), 7.85 (d, J = 8.6 Hz, 1H, H9), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H, H2), 7.52 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H, H1), 7.40 (dd, J = 6.4, 2.2 Hz, 1H, H16), 7.15- 7.11 (m, 2H, H17,18), 2.77 (s, 3H, H20). 13C NMR (126 MHz, DMSO-d6): δ (ppm) = 156.19 (C8-arom.), 148.41 (C4-arom.), 137.38 (C12-arom.), 136.27 (C10H-arom.), 135.74 (C14-arom.), 129.85 (C2H-arom.), 128.87 (C3H-arom.), 128.13 (C6H-arom.), 127.46 (C15-arom.), 125.97 (C5-arom.), 125.58 (C1H- arom.), 121.69 (C9H-arom.), 121.53 (C17H-arom.) 120.38 (C18H-arom.), 120.18 (C19H-arom.), 112.46 (C11-arom.), 111.34 (C16H-arom.), 14.36 (C20H3).

2-(6-bromo-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 1.3
13 568	CA 3-49 F44-63 Precipitate (yield = 46%)	IC50 (PSA) = 1.56
	tR (HPLC) = 3.29 min            MS (ESI+) m/z =                       323.0190, 325.0174                       [(M + H)+] Mp = 189-194° C. HRMS (ESI+): calculated for C17H12BrN2, m/z = 323.0178, 325.0159; found, 323.0183, 325.0167 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 11.79 (s, 1H, H13), 8.84 (d, J =
(Yellow Solid)	8.5 Hz, 1H, H19), 8.39 (d, J = 2.8 Hz, 1H, H12), 8.28 (d, J = 8.7 Hz, 1H, H10),
	8.05 (m, 2H, H3, 9), 7.90 (d, J = 7.5 Hz, 1H, H6), 7.72 (t, J = 7.5 Hz, 1H, H2),
	7.67 (d, J = 1.6 Hz, 1H, H16), 7.50 (t, J = 7.5 Hz, 1H, H1), 7.34 (dd, J = 8.5,
	1.8 Hz, 1H, H18).
	13C NMR (126 MHz, DMSO-d6): δ (ppm) = 155.52 (C8-arom.), 148.15 (C4-
	arom.), 138.58 (C14-arom.), 136.27 (C10H-arom.), 129.91 (C2H-arom.),
	129.11 (C12H-arom.), 128.88 (C3H-arom.), 128.13 (C6H-arom.), 126.37 (C5-
	arom.), 125.59 (C1H-arom.), 125.11 (C15-arom.), 124.82 (C19H-arom.),
	123.65 (C18H-arom.), 119.57 (C9H-arom.), 116.11 (C11-arom.), 115.31 (C17-
	arom.), 114.82 (C16H-arom).

2-(1-methyl-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 1.1
13 571	CA 3-56 Precipitate (yield = 53%)	IC50 (PSA) = Not Tested
	tR (HPLC) = 3.05 min          MS (ESI+) m/z = 259.1355                   [(M + H)+] Mp = 175-179° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1232 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 8.88 (d, J = 8.5 Hz, 1H, H19), 8.34 (s, 1H, H12), 8.27 (d, J = 8.7 Hz, 1H, H10), 8.03 (d, J = 8.3 Hz, 1H, H3), 7.98 (d, J = 8.7 Hz, 1H, H9), 7.89 (d, J = 7.2 Hz, 1H, H6), 7.72 (t, J = 7.6 Hz, 1H, H2),
(Yellow Solid)	7.54 (d, J = 7.5 Hz, 1H, H16), 7.49 (t, J = 7.6 Hz, 1H, H2), 7.29-7.26 (m, 2H,
	H17, 18), 3.91 (s, 3H, H20).
	13C NMR (126 MHz, DMSO-d6): δ (ppm) = 155.64 (C8-arom.), 148.28 (C4-
	arom.), 138.16 (C14-arom.), 136.21 (C10H-arom.), 132.24 (C12H-arom.), 129.88
	(C2H-arom.), 128.84 (C3H-arom.), 128.11 (C6H-arom.), 126.43 (C15-arom.),
	126.27 (C5-arom.), 125.40 (C1H-arom.), 123.16 (C19H-arom.), 122.66 (C17H-
	arom.), 121.07 (C18H-arom.), 119.50 (C9H-arom.), 115.00 (C11-arom.), 110.58
	(C16H-arom.), 33.40 (C20H3-arom.).

2-(1H-indazol-1-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.7
13 572	CA 3-59 F11 (yield = 25%)	IC50 (PSA) = Not Tested
	tR (HPLC) = 4.44 min      MS (ESI+) m/z = 246.1019               [(M + H)+] Mp = 91-96° C. HRMS (ESI+): calculated for C16H12N3, m/z = 246.1026; found, 246.1028 1H NMR (500 MHz, CDCl3): δ (ppm) = 9.18 (d, J = 8.5 Hz, 1H, H16), 8.28 (d, J = 9.0 Hz, 1H, H9), 8.25-8.21 (m, 2H, H10, 11), 8.11 (d, J = 8.4 Hz, 1H, H3), 7.82-7.77 (m, 2H, H6, 19), 7.72 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, H2), 7.59 (ddd, J =
(White Solid)	8.3, 7.0, 1.0 Hz, 1H, H17), 7.48 (ddd, J = 8.1, 7.0, 1.3 Hz, 1H, H1), 7.32 (ddd,
	J = 8.0, 7.0, 1.0 Hz, 1H, H18).
	13C NMR (126 MHz, CDCl3): δ (ppm) = 152.95 (C8-arom.), 146.66 (C4-
	arom.), 139.00 (C4-arom.), 138.46 (C10H-arom.), 137.18 (C11H-arom.), 130.05
	(C2H-arom.), 128.36 (C3H-arom.), 128.22 (C17H-arom.), 127.67 (C6H-arom.),
	126.28 (C5-arom.), 126.14 (C15-arom.), 125.51 (C1H-arom.), 122.95 (C18H-
	arom.), 120.82 (C19H-arom.), 116.03 (C16H-arom.), 113.48 (C9H-arom.).

2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number	LabBook Code	IC50 (eGFP) = 0.095
13 566	CA 3-67 Precipitate (yield = 48%)	IC50 (PSA) = 0.056
	tR (HPLC) = 3.10 min        MS (ESI+) m/z = 259.1255                 [(M + H)+] Mp = 146-150° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1229 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 11.63 (s, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.74-7.68 (m, 1H),
(Yellow Solid)	7.48 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H),
	2.54 (s, 3H).
	13C NMR (126 MHz, DMSO-d6): δ (ppm) = 156.14, 148.27, 137.19, 135.98,
	129.77, 128.86, 128.08, 128.02, 126.28, 125.82, 125.31, 123.10, 121.27,
	120.98, 120.70, 119.79, 116.41, 17.27.

2-(5-methyl-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 3.2
13 577	CA 3-73 Precipitate (yield = 55%)	IC50 (PSA) = 1.73
	tR (HPLC) = 3.12 min        MS (ESI+) m/z = 259.1248                 [(M + H)+] HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1218 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.64 (s, 1H, H13), 8.97 (s, 1H, H12), 8.89 (d, J = 8.1 Hz, 1H, H10), 8.58 (d, J = 8.2 Hz, 1H, H3), 8.42 (d, J = 8.9 Hz, 1H, H9), 8.22 (d, J = 8.0 Hz, 1H, H6), 8.10 (s, 1H, H19), 8.02 (t, J = 7.6 Hz, 1H, H2), 7.77 (t, J = 7.5 Hz, 1H, H1), 7.52 (d, J = 8.3 Hz, 1H, H16), 7.18 (dd, J = 8.3, 0.9 Hz, 1H, H17), 2.51 (s, 3H, H20).
(Yellow Solid)	13C NMR = Done but unreadable and it was the same for every
	compound made with this procedure

2-(6-fluoro-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.144
13 576	CA 3-75 Precipitate2 (yield = 30%)	IC50 (PSA) = 0.048
	tR (HPLC) = 3.08 min         MS (ESI+) m/z = 263.1223                  [(M + H)+] Mp = 259-266° C. HRMS (ESI+): calculated for C17H11FN2Na, m/z = 285.0798; found, 285.0810 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 8.71 (s, 2H, H10, 12), 8.49 (s, 1H, H19), 8.31 (s, 2H, H3, 9), 8.14 (s, 1H, H6), 7.95 (s, 1H, H2), 7.71 (s,
(Yellow Solid)	1H, H1), 7.40 (d, J = 8.3 Hz, 1H, H16), 7.18 (t, J = 8.5 Hz, 1H, H18).
	13C NMR = Done but unreadable and it was the same for every
	compound made with this procedure, even proton spectra looked
	bad.

2-(6-(trifluoromethyl)-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 2.9
13 580	CA 3-78 Precipitate (yield = 8%)	IC50 (PSA) = Not Tested
	tR (HPLC) = 3.50 min        MS (ESI+) m/z = 313.0949                 [(M + H)+] HRMS (ESI+): calculated for C18H12F3N2, m/z = 313.0947; found, 313.0947 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.83 (s, 1H, H12), 8.75 (s, 2H, H10, 19), 8.31 (s, 2H, H3, 9), 8.11 (s, 1H, H6), 7.93 (s, 2H, H2, 16), 7.70 (s, 1H, H1), 7.58 (d, J = 7.9 Hz, 1H, H18).
(Yellow Solid)	13C NMR Done but unreadable and it was the same for every
	compound made with this procedure, even proton spectra looked
	bad.

2-(7-methyl-1H-indazol-1-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 3.5
13 575	CA 3-90 F4-12 Precipitate (yield = 21%)	IC50 (PSA) = 1.36
	tR (HPLC) = 4.54 min           MS (ESI+) m/z = 260.1176                    [(M + H)+] Mp = 147-152° C. HRMS (ESI+): calculated for C17H14N3, m/z = 260.1182; found, 260.1172 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 9.42 (s, 1H, H11), 8.69 (d, J = 8.8 Hz, 1H, H10), 8.49 (d, J = 8.8 Hz, 1H, H9), 8.12 (d, J = 8.0 Hz, 1H, H6), 8.09 (d, J = 8.5 Hz, 1H, H3), 7.89 (ddd, J = 8.0, 6.5, 1.0 Hz, 1H, H2), 7.71-7.65 (m,
(Pale Yellow Solid)	2H, H1, 9), 7.14 (d, J = 6.6 Hz, 1H, H17), 7.05 (dd, J = 8.3, 6.7 Hz, 1H, H18),
	2.62 (s, 3H, H20).
	13C NMR (126 MHz, DMSO-d6): δ (ppm) = 150.74 (C14-arom.), 150.56 (C8-
	arom.), 146.38 (C4-arom.), 140.60 (C10H-arom.), 131.47 (C2H-arom.), 128.69
	C6H-arom.), 128.66 (C3H-arom.), 127.92 (C5-arom.), 127.89 (C16-arom.),
	127.33 (C1H-arom.), 126.89 (C17H-arom.), 123.64 (C18H-arom.), 122.62 (C15-
	arom.), 121.65 (C11H-arom.), 119.49 (C19H-arom.), 113.50 (C9H-arom.), 17.22
	(C20H3).

2-(6-(benzyloxy)-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 5.3
13 589	CA 3-94 Precipitate (yield = 20%)	IC50 (PSA) = Not Tested
	tR (HPLC) = 3.66 min         MS (ESI+) m/z = 351.1707                  [(M + H)+] Mp = 264-269° C. HRMS (ESI+): calculated for C24H19N2O, m/z = 351.1492; found, 351.1494 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.50 (s, 1H, H13), 8.85 (s, 2H, H10), 8.52 (d, J = 5.6 Hz, 1H, H3), 8.37 (d, J = 8.7 Hz, 1H, H9), 8.20 (d, J = 7.2 Hz, 2H, H6, 19), 8.00 (t, J = 7.3 Hz, 1H, H2), 7.75 (t, J = 7.3 Hz, 1H, H1),
(Orange Solid)	7.51 (d, J = 7.2 Hz, 2H, H22, 26), 7.42 (t, J = 7.4 Hz, 2H, H23, 25), 7.35 (t, J = 7.3
	Hz, 1H, H24), 7.19 (d, J = 1.7 Hz, 1H, H16), 7.06 (dd, J = 8.8, 2.0 Hz, 1H, H18),
	5.21 (s, 2H, H27).
	13C NMR Done but unreadable and it was the same for every
	compound made with this procedure, even proton spectra looked
	bad.

3-(pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 4.9
13 581	CA 3-105 Purified (yield = 64%)	IC50 (PSA) = Not Tested
	tR (HPLC) = 1.45 min         MS (ESI+) m/z = 196.0861                  [(M + H)+] Mp = 71-80° C. HRMS (ESI+): calculated for C12H10N3, m/z = 196.0869; found, 196.0862 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 12.21 (s, 1H, H13), 8.99 (s, 1H, H3), 8.90 (s, 1H, H9), 8.49 (s, 1H, H2), 8.25 (s, 1H, H7), 8.21 (s, 1H, H14), 8.16- 8.12 (m, 1H, H5), 7.94 (d, J = 4.0 Hz, 1H, H12), 7.48 (dd, J = 7.7, 4.8 Hz, 1H,
(White Solid)	H6).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 147.26 (C3H-arom.), 146.80 (C2H-
	arom.), 137.78 (C7H-arom.), 134.44 (C9H-arom.), 133.82 (C10-arom.), 133.41
	(C5H-arom.), 130.47 (C4-arom.), 129.35 (C11-arom.), 128.95 (C14H-arom.),
	123.95 (C6H-arom.), 113.91 (C12H-arom.), 111.96 (C15-arom.).

3-(pyridin-3-yl)-1H-indazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = No Data
13 590	CA 3-106 Precipitate (yield = 45%)	IC50 (PSA) = No Data
	tR (HPLC) = 2.53 min        MS (ESI+) m/z = 196..0889                 [(M + H)+] Mp = 176-179° C. HRMS (ESI+): calculated for C12H10N3, m/z = 196.0869; found, 196.0871 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 9.21 (d, J = 1.5 Hz, 1H, H5), 8.62 (dd, J = 4.7, 1.6 Hz, 1H, H2), 8.38 (td, J = 8.4, 1.8 Hz, 1H, H3), 8.12 (d, J = 8.2 Hz, 1H, H12), 7.64 (d, J = 8.4 Hz, 1H, H9), 7.56 (ddd, J = 7.9, 4.8, 0.7
(White Solid)	Hz, 1H, H1), 7.45 (ddd, J = 8.4, 7.2, 0.6 Hz, 1H, H8), 7.25 (ddd, J = 7.8,
	6.6, 0.6 Hz, 1H, H8).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 148.59 (C2H-arom.), 147.42
	(C5H-arom.), 141.50 (C10-arom.), 140.45 (C4-arom.), 133.90 (C3H-arom.),
	129.63 (C15-arom.), 126.35 (C8H-arom.), 124.02 (C1H-arom.), 121.41
	(C7H-arom.), 120.43 (C12H-arom.), 120.06 (C11-arom.), 110.72
	(C9H-arom.).

2-(7-bromo-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.052
13 582	CA 3-107 F9-17 Precipitate (yield = 20%)	IC50 (PSA) = 0.041
	tR (HPLC) = 3.25 min          MS (ESI+ ) m/z = 323.0177,                   325.0158 [(M + H)+] Mp = 178-180° C. HRMS (ESI+): calculated for C17H12BrN2, m/z = 323.0178, 325.0159; found, 323.0172, 325.0153 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.87 (s, 1H, H13), 8.94 (d, J = 7.9 Hz, 1H, H19), 8.42 (d, J = 2.8 Hz, 1H, H12), 8.29 (d, J = 8.6 Hz, 1H, H10),
(Pale Yellow Solid)	8.13 (d, J = 8.7 Hz, 1H, H9), 8.06 (d, J = 8.4 Hz, 1H, H3), 7.91 (d, J = 8.0 Hz,
	1H, H6), 7.73 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H2), 7.51 (ddd, J = 7.8, 6.6, 0.6
	Hz, 1H, H1), 7.45 (dd, J = 7.5, 0.5 Hz, 1H, H17), 7.17 (t, J = 7.8 Hz, 1H, H18).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 155.00 (C8-arom.), 147.65 (C4-
	arom.), 135.81 (C10H-arom.), 135.51 (C14H-arom.), 129.43 (C2H-arom.),
	128.78 (C12H-arom.), 128.46 (C3H-arom.), 127.65 (C6H-arom.), 127.36 (C15-
	arom.), 125.96 (C5-arom.), 125.19 (C1H-arom.), 124.73 (C17H-arom.), 122.17
	(C19H-arom.), 121.76 (C18H-arom.), 119.31 (C9H-arom.), 116.67 (C11-arom.),
	104.34 (C16-arom.).

2-(1H-pyrrolo[2,3-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 1.1
13 583	CA 3-109 F22-31 Precipitate (yield = 19%)	IC50 (PSA) = 0.93
	tR (HPLC) = 2.52 min           MS (ESI+) m/z = 246.1028                    [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C16H12N3, m/z = 246.1026; found, 246.1017 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 12.12 (s, 1H, H17), 8.85 (d, J = 0.8 Hz, 1H, H13), 8.72 (dd, J = 5.4, 0.9 Hz, 1H, H16), 8.58 (d, J = 2.4 Hz, 1H, H18), 8.31 (m, 2H, H10, 11), 8.09 (d, J = 8.7 Hz, 1H, H9), 8.07 (d, J = 8.3 Hz, 1H, H3),
(White Solid)	7.92 (d, J = 8.0 Hz, 1H, H6), 7.74 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H, H2), 7.52 (ddd,
	J = 7.8, 7.2, 1.2 Hz, 1H, H1).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 154.73 (C8-arom.), 147.73 (C4-
	arom.), 139.35 (C11H-arom.), 136.01 (C10H-arom.), 134.88 (C13H-arom.), 134.37
	(C14-arom.), 130.89 (C18H-arom.), 129.92 (C15-arom.), 129.51 (C2H-arom.),
	128.46 (C3H-arom.), 127.69 (C6H-arom.), 125.97 (C5-arom.), 125.24 (C1H-
	arom.), 119.03 (C9H-arom.), 116.77 (C16H-arom.), 115.22 (C19-arom.).

tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Intermediate LabBook Code
             CA 3-111 F1-14 (yield = 86%)
             tR (HPLC) = 4.66 min        MS (ESI+) m/z = 345.0074                 [(M + H)+] 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.44 (dd, J = 4.7, 1.5 Hz, 1H, H2), 8.03 (s, 1H, H8), 7.79 (dd, J = 7.9, 1.6 Hz, 1H, H6), 7.39 (dd, J = 7.9, 4.7 Hz, 1H, H1), 1.62 (s, 9H, H13, 14, 15). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 147.14 (C16 = O), 147.04 (C4- arom.), 146.16 (C2H-arom.), 131.54 (C8H-arom.), 130.04 (C6H-arom.), 125.25 (C5-arom.), 120.04 (C1H-arom.), 84.57 (C12-(CH3)3), 63.79 (C9-arom.), 28.08
(Brown Oil)  (C13, 14, 15H3).

3-(1H-pyrrolo[3,2-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 637	CA 3-115 Precipitate (yield = 51%)	IC50 (PSA) = Inactive
	tR (HPLC) = 2.22 min        MS (ESI+) m/z = 246.1020                 [(M + H)+] Mp = 233-239° C. HRMS (ESI+): calculated for C16H12N3, m/z = 246.1026; found, 246.1016 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.04 (s, 1H, H13), 9.43 (s, 1H, H12), 9.37 (d, J = 2.3 Hz, 1H, H5), 8.76 (d, J = 1.9 Hz, 1H, H3), 8.31 (d, J = 5.7 Hz, 1H, H8), 8.19 (d, J = 1.7 Hz, 1H, H14), 8.13 (d, J = 7.6 Hz, 1H, H19), 8.03
(White Solid)	(d, J = 8.3 Hz, 1H, H16), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H, H17), 7.63 (ddd,
	J = 8.0, 7.2, 1.2 Hz, 1H, H18), 7.51 (dd, J = 5.7, 0.7 Hz, 1H, H9).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.40 (C5H-arom.), 146.38 (C2-
	arom.), 142.88 (C12H-arom.), 141.29 (C8H-arom.), 140.94 (C10-arom.),
	131.31 (C3H-arom.), 129.08 (C17H-arom.), 129.04 (C16H-arom.), 128.62 (C1-
	arom.), 128.60 (C19H-arom.), 128.35 (C4-arom.), 127.31 (C18H-arom.),
	126.19 (C14H-arom.), 122.63 (C11-arom.), 112.66 (C15-arom.), 107.80 (C9H-
	arom.).

3-(5-bromo-2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyri dine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 638	CA 3-116 Precipitate (yield = quant.)	IC50 (PSA) = Inactive
	tR (HPLC) = 2.91 min        MS (ESI+) m/z = 303.0118,                  305.0099 [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C14H12BrN2O, m/z = 303.0128, 305.0108; found, 303.0119, 305.0100 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.03 (s, 1H, H13), 8.82 (d, J = 0.6 Hz, 1H, H12), 8.20 (d, J = 5.7 Hz, 1H, H8), 7.70 (d, J = 2.0 Hz, 1H, H14), 7.65 (d, J = 2.5 Hz, 1H, H2), 7.47 (dd, J = 8.8, 2.6 Hz, 1H, H6), 7.44 (dd, J = 5.7, 1.0 Hz, 1H, H9), 7.12 (d, J = 8.8 Hz, 1H, H3), 3.82 (s, 3H, H18).
(White Solid)	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 155.97 (C5-arom.), 143.25
	(C12H-arom.), 140.41 (C8H-arom.), 140.06 (C10-arom.), 132.27 (C3H-
	arom.), 130.31 (C6H-arom.), 127.00 (C14H-arom.), 126.07 (C4-arom.),
	123.24 (C11-arom.), 114.24 (C2H-arom.), 112.46 (C1-arom.), 110.90 (C15-
	arom.), 107.57 (C9H-arom.), 56.13 (C18H3).

3-(7-bromo-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 1.13
13 653	CA 3-123 Precipitate (yield = 39%)	IC50 (PSA) = 0.29
	tR (HPLC) = 3.79 min       MS (ESI+) m/z = 323.0176,                 325.0157 [(M + H)+] Mp = 217-223° C. HRMS (ESI+): calculated for C17H12BrN2, m/z = 323.0178, 325.0159; found, 323.0179, 325.0160 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.86 (s, 1H, H13), 9.33 (d, J = 2.2 Hz, 1H, H5), 8.66 (d, J = 1.9 Hz, 1H, H3), 8.12-8.06 (m, 3H,
(Pale Yellow Solid)	H12,14,19), 8.03 (d, J = 8.3 Hz, 1H, H16), 7.72 (t, J = 8.2 Hz, 1H, H17),
	7.63 (t, J = 7.4 Hz, 1H, H18), 7.47 (d, J = 7.5 Hz, 1H, H8), 7.14 (t, J =
	7.8 Hz, 1H, H7).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.63 (C5H-arom.),
	146.32 (C2-arom.), 135.72 (C10-arom.), 131.21 (C3H-arom.),
	129.11 (C17H-arom.), 128.99 (C1-arom.), 128.86 (C12H-arom.),
	128.57 (C4-arom.), 128.48 (C19H-arom.), 127.28 (C18H-arom.),
	127.19 (C11-arom.), 126.42 (C14H-arom.), 125.01 (C8H-arom.),
	121.96 (C7H-arom.), 119.28 (C12H-arom.), 114.08 (C15-arom.),
	105.30 (C9-arom.).

3-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.92
13 654	CA 3-125 Precipitate (yield = 56%)	IC50 (PSA) = 0.16
	tR (HPLC) = 3.43 min       MS (ESI+) m/z = 259.1236                 [(M + H)+] Mp = 215-219° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1234 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.59 (s, 1H, H13), 9.34 (d, J = 2.3 Hz, 1H, H5), 8.62 (d, J = 2.1 Hz, 1H, H3), 8.07 (m, 2H, H14,19),
(White Solid)	8.01 (d, J = 8.4 Hz, 1H, H16), 7.92 (d, J = 7.9 Hz, 1H, H12), 7.69 (td,
	J = 8.4, 1.5 Hz, 1H, H17), 7.61 (td, J = 8.1, 1.2 Hz, 1H, H18), 7.12
	(t, J = 7.6 Hz, 1H, H7), 7.03 (d, J = 7.0 Hz, 1H, H8), 2.54 (s, 3H, H20).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.68 (C5H-arom.),
	146.10 (C2-arom.), 136.96 (C10-arom.), 130.41 (C3H-arom.), 129.74
	(C17H-arom.), 129.08 (C16H-arom.), 128.72 (C1-arom.), 128.64
	(C4-arom.), 128.37 (C19H-arom.), 127.19 (C18H-arom.), 125.16 (C11-
	arom.), 125.01 (C14H-arom.), 122.86 (C8H-arom.), 121.80 (C9-arom.),
	120.77 (C7H-arom.), 117.24 (C12H-arom.), 113.06
	(C15H-arom.), 17.30 (C20H3).

7-methyl-3-(pyridin-3-yl)-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 1.66
13 655	CA 3-127 F5 Precipitate (yield = 25%)	IC50 (PSA) = 0.61
	tR (HPLC) = 2.69 min         MS (ESI+) m/z = 209.1076                   [(M + H)+] Mp = 164-166° C. HRMS (ESI+): calculated for C14H13N2, m/z = 209.1073; found, 209.1075 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.49 (s, 1H, H13), 8.94 (d, J = 1.7 Hz, 1H, H5), 8.43 (dd, J = 4.7, 1.5 Hz, 1H, H2), 8.09 (dt, J = 8.0, 1.9 Hz, 1H, H3), 7.84 (d, J = 2.7 Hz, 1H, H14), 7.70 (d, J = 7.8 Hz, 1H,
(White Solid)	H12), 7.44 (ddd, J = 7.9, 4.8, 0.6 Hz, 1H), 7.08-6.96 (m, 2H, H7,8), 2.51
	(s, 3H, H16).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 147.81 (C5H-arom.), 146.63
	(C2H-arom.), 136.86 (C10-arom.), 133.75 (C3H-arom.), 132.32 (C4-arom.),
	124.99 (C11-arom.), 124.40 (C14H-arom.), 124.28 (C1H-arom.), 122.66
	(C8H-arom.), 121.74 (C9-arom.), 120.62 (C7H-arom.), 116.87 (C12H-
	arom.), 113.02 (C15-arom.), 17.28 (C16H3).

tert-butyl 7-(benzyloxy)-3-iodo-1H-indole-1-carboxylate

Intermediate      LabBook Code
                  CA 3-128 F1-4 (yield = 88%)
(Pale Orange Oil) tR (HPLC) = 5.03 min         MS (ESI+) m/z = 450.0575                    [(M + H)+] 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.84 (s, 1H, H8), 7.57-7.52  (m, 2H, H14,18), 7.40-7.27 (m, 4H, H1,15,16,17), 7.11 (d, J = 7.6 Hz, 1H,  H2), 6.98 (dd, J = 7.8, 0.8 Hz, 1H, H6), 5.25 (s, 2H, H12), 1.50 (s, 9H, H21,22,23). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 148.11 (C24O), 147.18 (C3- arom.), 137.44 (C13-arom.), 134.78 (C5-arom.), 132.89 (C8H-arom.),  128.67 (C15,17H-arom.), 128.16 (C16H-arom.), 127.88 (C14,18H-arom.),  124.89 (C1H-arom.), 124.45 (C4-arom.), 114.11 (C6H-arom.), 109.43 (C2H-arom.), 84.39 (C20(CH3)3), 70.58 (C12H2), 65.68 (C9-arom.),  27.68 (C21,22,23H3).

5,8-dibromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 679	CA 3-137 F24-30 Precipitate (yield = 20%)	IC50 (PSA) = Inactive
	tR (HPLC) = 5.30 min          MS (ESI+) m/z =                     414.9448, 416.9430,                     418.9416 [(M + H)+] Mp = 218-221° C. HRMS (ESI+): calculated for C18H13Br2N2, m/z = 414.9440, 416.942., 418.9402; found, 414.9448, 416.9430, 418.9415 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.84 (s, 1H, H13), 9.01 (d, J = 7.9 Hz, 1H, H19), 8.54 (d, J = 2.9 Hz, 1H, H12), 8.38 (d, J = 9.0 Hz, 1H, H10), 8.33 (d, J = 9.0 Hz, 1H, H9), 8.04 (d, J = 8.1 Hz, 1H, H2),
(Yellow Solid)	7.73 (d, J = 8.1 Hz, 1H, H1), 7.16 (t, J = 7.6 Hz, 1H, H18), 7.05 (d,
	J = 7.1 Hz, 1H, H17), 2.55 (s, 3H, H20).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 157.55 (C8-arom.), 145.79
	(C4-arom.), 137.28 (C14-arom.), 135.21 (C10H-arom.), 133.70 (C2H-arom.),
	129.80 (C12H-arom.), 129.33 (C1H-arom.), 126.24 (C5-arom.), 125.67
	(C15-arom.), 124.03 (C3-arom.), 123.58 (C17H-arom.), 122.06 (C9H-arom.),
	121.65 (C18H-arom.), 121.42 (C16-arom.), 121.18 (C6-arom., C19H-arom.),
	115.73 (C11-arom.), 17.24 (C20H3).

5-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 678	CA 3-139 F15-21 Precipitate (yield = 21%)	IC50 (PSA) = Inactive
	tR (HPLC) = 4.55 min          MS (ESI+) m/z = 337.0363,                    339.0354 [(M + H)+] Mp = 200-204° C. HRMS (ESI+): calculated for C18H14BrN2, m/z = 337.0335, 339.0316; found, 337.0345, 339.0331 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.74 (s, 1H, H13), 8.69 (d, J = 8.0 Hz, 1H, H19), 8.42 (d, J = 3.0 Hz, 1H, H12), 8.36 (dd, J = 9.0, 0.7 Hz, 1H, H10), 8.23 (d, J = 9.0 Hz, 1H, H9), 8.06 (dt, J = 8.4, 0.9 Hz, 1H, H1), 7.81 (dd, J = 7.5, 1.0 Hz, 1H, H3), 7.64 (dd, J = 8.4, 7.6 Hz,
(Pale Yellow Solid)	1H, H2), 7.13 (t, J = 7.6 Hz, 1H, H18), 7.03 (d, J = 7.0 Hz, 1H, H17),
	2.54 (s, 3H, H20).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 156.97 (C8-arom.), 149.20
	(C4-arom.), 137.24 (C14-arom.), 134.47 (C10H-arom.), 130.54 (C2H-arom.),
	129.10 (C1H-arom.), 129.01 (C3H-arom.), 128.88 (C12H-arom.), 125.74
	(C5-arom.), 125.10 (C15-arom.), 123.32 (C17H-arom.), 121.45 (C9H-arom.),
	121.43 (C16-arom.), 121.37 (C6-arom.), 121.24 (C18H-arom.), 120.60
	(C19H-arom.), 115.71 (C11-arom.), 17.25 (C20H3).

3-iodo-7-methyl-1-tosyl-1H-indole

Intermediate  LabBook Code
              CA 3-140 P1-3 (yield = 48%)
(White Solid) tR (HPLC) = 5.50 min          MS (ESI+) m/z = 411.9835                   [(M + H)+] 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 8.07 (s, 1H, H8), 7.68 (d, J = 8.3 Hz, 2H, H13,17), 7.41 (d, J = 8.1 Hz, 2H, H14,16), 7.29-7.21 (m, 2H,  H6,1), 7.17 (d, J = 6.7 Hz, 1H, H2), 2.49 (s, 3H, H11), 2.35 (s, 3H, H18). 13C NMR (126 MHz, DMSO-d6): δ (ppm) = 145.86 (C15-arom.), 135.85  (C12-arom.), 134.57 (C5-arom.), 134.23 (C4-arom.), 133.76 (C8H-arom.),  130.85 (C14,16H-arom.), 129.76 (C2H-arom.), 126.92 (C13,17H-arom.),  125.12 (C1H-arom.), 124.81 (C3-arom.), 120.38 (C6H-arom.), 69.54 (C9- arom.), 21.53 (C18H3), 21.47 (C11H3).

8-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number	LabBook Code	IC50 (eGFP) = 0.156
13 677	CA 3-141 F34-54 Precipitate (yield = 20%)	IC50 (PSA) = 0.11
	tR(HPLC) = 5.03 min         MS (ESI+) m/z = 337.0361,                   339.0345 [(M + H)+] Mp = 214-217° C. HRMS (ESI+): calculated for C18H14BrN2, m/z = 337.0335, 339.0316; found, 337.0341, 339.0324 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.72 (s, 1H, H13), 9.04 (d, J = 8.0 Hz, 1H, H19), 8.47 (d, J = 3.0 Hz, 1H, H12), 8.30 (d, J = 8.8 Hz,
(Yellow Solid)	1H, H10), 8.20 (d, J = 8.7 Hz, 1H, H9), 8.09 (dd, J = 7.5, 1.3 Hz, 1H,
	H2), 7.92 (dd, J = 8.1, 1.2 Hz, 1H, H6), 7.39 (t, J = 7.8 Hz, 1H, H1),
	7.14 (t, J = 7.4 Hz, 1H, H18), 7.03 (d, J = 7.0 Hz, 1H, H17),
	2.54 (s, 3H, H20).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 156.88 (C8-arom.), 144.96
	(C4-arom.), 137.23 (C14-arom.), 136.61 (C10H-arom.), 133.25 (C2H-
	arom.), 128.92 (C12H-arom.), 128.20 (C6H-arom.), 127.68 (C5-arom.),
	125.91 (C1H-arom.), 125.77 (C15-arom.), 123.97 (C3-arom.), 123.36
	(C17H-arom.), 121.38 (C18H-arom.), 121.33 (C19H-arom.), 121.23 (C16-
	arom.), 120.45 (C9H-arom.), 116.31 (C11-arom.), 17.25 (C20H3).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.45
13 675	CA 3-144 Precipitate (yield = 83%)	IC50 (PSA) = 0.468
	tR (HPLC) = 3.26 min       MS (ESI+) m/z = 245.1334                 [(M + H)+] Mp = 243-247° C. HRMS (ESI+): calculated for C17H13N2, m/z = 245.1073; found, 245.1079 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.99 (s, 1H, H13), 8.86 (s, 1H, H9), 8.27 (s, 1H, H3), 8.25 (d, J = 5.2 Hz, 1H, H7), 8.17 (s, 1H, H14), 8.05 (dd, J = 5.6, 1.0 Hz, 1H, H12), 8.02 (d, J = 8.1 Hz, 1H, H19), 8.00-
(Pale Yellow Solid)	7.90 (m, 3H, H5,6,16), 7.53 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H, H18), 7.47
	(ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H17).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 139.14 (C7H-arom.), 135.56
	(C9H-arom.), 134.64 (C10-arom.), 134.14 (C1-arom.), 132.82 (C4-arom.),
	131.87 (C2-arom.), 129.56 (C11-arom.), 128.76 (C6H-arom.), 128.43
	(C14H-arom.), 128.18 (C19H-arom.), 127.96 (C16H-arom.), 126.72
	(C18H-arom.), 126.01 (C17H-arom.), 125.73 (C5H-arom.), 124.12 (C3H-
	arom.), 115.47 (C15-arom.), 114.55 (C12H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.053
13 676	CA 3-146 Precipitate (yield = 61%)	IC50 (PSA) = 0.034
	tR (HPLC) = 4.50 min       MS (ESI+) m/z = 245.1077                 [(M + H)+] Mp = 207-211° C. HRMS (ESI+): calculated for C17H13N2, m/z = 245.1073; found, 245.1077 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.01 (s, 1H, H13), 8.50 (dd, J = 8.0, 1.1 Hz, 1H, H12), 8.32 (dd, J = 4.6, 1.5 Hz, 1H, H8), 8.27 (s, 1H, H3), 8.06 (d, J = 2.7 Hz, 1H, H14), 8.00 (d, J = 8.0 Hz, 1H, H19), 7.97-
(Yellow Solid)	7.92 (m, 2H, H5,6), 7.91 (d, J = 8.0 Hz, 1H, H16), 7.52 (ddd, J = 8.2,
	6.9, 1.4 Hz, 1H, H18), 7.47 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H17),
	7.22 (dd, J = 8.0, 4.6 Hz, 1H, H7).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 149.69 (C10-arom.), 143.50
	(C8H-arom.), 134.16 (C1-arom.), 133.12 (C4-arom.), 131.85 (C2-arom.),
	128.70 (C6H-arom.), 128.31 (C12H-arom.), 128.17 (C19H-arom.), 127.94
	(C16H-arom.), 126.68 (C18H-arom.), 125.89 (C17H-arom.), 125.66 (C5H-
	arom.), 124.90 (C14H-arom.), 123.88 (C3H-arom.), 117.81 (C11-arom.),
	116.62 (C7H-arom.), 114.55 (C15-arom.).

2-(5-bromo-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 2.6
13 683	CA 3-147 F36-46 Precipitate (yield = 39%)	IC50 (PSA) = 1.906
(Yellow Solid)	tR (HPLC) = 3.60 min       MS (ESI+) m/z = 323.0169,                 325.0153 [(M + H)+] Mp = 200-203° C. HRMS (ESI+): calculated for C17H12BrN2, m/z = 323.0178, 325.0159; found, 323.0184, 325.0169 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.86 (s, 1H, H13), 9.06 (d, J = 2.0 Hz, 1H, H19), 8.42 (d, J = 2.8 Hz, 1H, H12), 8.27 (d, J = 8.5 Hz, 1H, H10), 8.05 (d, J = 8.8 Hz, 1H, H9), 8.02 (d, J = 9.0 Hz, 1H, H3), 7.89 (dd, J = 8.1, 1.2 Hz, 1H, H6), 7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, H6), 7.50 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H, H1), 7.45 (dd, J = 8.4, 0.4 Hz, 1H, H17), 7.34 (dd, J = 8.6, 2.0 Hz, 1H, H17). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 155.03 (C8-arom.), 147.62 (C4-arom.), 135.92 (C10H-arom.), 135.83 (C14-arom.), 129.50 (C2H-arom.), 129.15 (C12H-arom.), 128.36 (C3H-arom.), 127.67 (C6H-arom.), 127.30 (C15-arom.), 125.88 (C5-arom.), 125.12 (C1H-arom.), 124.71 (C19H-arom.), 124.62 (C17H-arom.), 119.07 (C9H-arom.), 115.02 (C11-arom.), 113.79(C18-arom.), 113.07 (C16H-arom.).

3-(1H-indazol-3-yl)quinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 1.4
13 684	CA 4-13 F3-5 (yield = 46%)	IC50 (PSA) = 6.609
(White Solid)	tR (HPLC) = 3.59 min    MS (ESI+) m/z = 246.1322              [(M + H)+] Mp = 212-215° C. HRMS (ESI+): calculated for C16H12N3, m/z = 246.1026; found, 246.1027 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.53 (s, 1H, H13), 9.60 (d, J = 2.2 Hz, 1H, H5), 8.98 (d, J = 2.0 Hz, 1H, H3), 8.33 (d, J = 8.2 Hz, 1H, H12), 8.21 (d, J = 7.9 Hz, 1H, H19), 8.09 (d, J = 8.3 Hz, 1H, H16), 7.8.79 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H17), 7.71-7.66 (m, 2H, H9,18), 7.48 (t, J = 7.4 Hz, 1H, H8), 7.31 (t, J = 7.5 Hz, 1H, H7). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 149.67 (C5H-arom.), 147.27 (C2-arom.), 142.03 (s C10-arom.), 141.01 (C1-arom.), 132.67 (C3H-arom.), 129.94 (C17H-arom.), 129.20 (C16H-arom.), 129.01 (C19H-arom.), 128.24 (C4-arom.), 127.52 (C18H-arom.), 127.29 (C15-arom.), 126.96 (C8H-arom.), 121.96 (C7H-arom.), 121.23 (C12H-arom.), 120.81 (C11-arom.), 111.26 (C9H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-c]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 685	CA 4-15 Precipitate2 (yield = 71%)	IC50 (PSA) = Inactive
(Pale Orange Solid)	tR (HPLC) = 3.17 min       MS (ESI+) m/z = 245.1082                  [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C17H13N2, m/z = 245.1073; found, 245.1073 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.85 (s, 1H, H13), 9.39 (s, 1H, H12), 8.33 (s, 1H, H3), 8.28 (d, J = 5.6 Hz, 1H, H8), 8.05 (d, J = 8.0 Hz, 1H, H19), 8.02-7.94 (m, 3H, H4,6,14), 7.92 (d, J = 8.0 Hz, 1H, H16), 7.53 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H, H18), 7.51-7.45 (m, 2H, H9,17). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 142.94 (C12H-arom.), 141.01 (C8H-arom.), 140.93 (C10-arom.), 134.16 (C1-arom.), 132.62 (C4-arom.), 131.97 (C2-arom.), 128.76 (C6H-arom.), 128.30 (C19H-arom.), 127.92 (C16H-arom.), 126.71 (C18H-arom.), 126.21 (C17H-arom.), 125.79 (C5H- arom.), 125.55 (C14H-arom.), 124.55 (C3H-arom.), 115.92 (C15-arom.), 107.71 (C9H-arom.).

2-phenyl-1H-benzo[d]imidazole

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 686	CA 4-16 F3-14 Precipitate (yield = 22%)	IC50 (PSA) = Inactive
	tR (HPLC) = 2.39 min         MS (ESI+) m/z = 195.1040                   [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C13H11N2, m/z = 195.0917; found, 195.0919 1H NMR (400 MHz, DMOS-d6): δ (ppm) = 12.91 (s, 1H, H13), 8.22-8.17
(Pink Solid)	(m, 2H, H3,5), 7.67 (br s, 1H, H9), 7.59-7.47 (m, 4H, H1,2,6,12), 7.22-7.19
	(m, 2H, H7,8).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 151.19 (C14-arom.), 143.79
	(C10-arom.), 134.98 (C11-arom.), 130.15 (C4-arom.), 129.81 (C2H-arom.),
	128.92 (C1,6H-arom.), 126.40 (C3,5H-arom.), 122.50 (C7H-arom.), 121.64
	(C8H-arom.), 118.85 (C9H-arom.), 111.30 (C12H-arom.).

2-naphthalen-3-ol-1H-benzo[d]imidazole

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 687	CA 4-17 Precipitate2 (yield = 14%)	IC50 (PSA) = Inactive
	tR (HPLC) = 3.32 min        MS (ESI+) m/z = 261.1080                  [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C17H13N2O, m/z = 261.1022; found, 261.1022 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.46 (s, 1H, H20), 13.01 (s, 1H, H13), 8.72 (s, 1H, H3), 7.90 (d, J = 8.2 Hz, 1H, H19), 7.79 (d, J = 8.4 Hz, 1H, H16), 7.74 (br s, 2H, , H9,12), 7.51 (t, J = 7.5 Hz, 1H, H17), 7.43 (s, 1H, H6), 7.39 (t, J = 7.5 Hz, 1H, H18), 7.34 (br s, 2H, H7,8). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 154.60 (C5-arom.), 151.15 (C14- arom.), 141.03 (C10-arom.), 135.16 (C2-arom.), 133.41 (C11-arom.), 128.13
	(C19H-arom.), 127.65 (C17H-arom.), 126.99 (C1-arom.), 126.80 (C3H-arom.),
	126.05 (C16H-arom.), 123.77 (C18H-arom.), 123.60 (C7H-arom.), 122.57
	(C8H-arom.), 118.21 (C9H-arom.), 115.21 (C4-arom.), 111.72 (C12H-arom.),
	110.80 (C6H-arom.).

tert-butyl 3-iodo-7-nitro-1H-indole-1-carboxylate

Intermediate LabBook Code
             CA 4-18 F4-18 (yield = 90%)
             tR (HPLC) = 5.24 min      MS (ESI+) m/z = 410.9828 [(M + Na)+] 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.10 (s, 1H, H8), 7.99 (dd, J = 7.9, 0.7 Hz, 1H, H2), 7.78 (dd, J = 7.9, 1.0 Hz, 1H, H6), 7.56 (t, J = 7.9 Hz, 1H, H1), 1.56 (s, 9H, H13,14,15). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 147.76 (C16O), 138.62 (C3- arom.), 135.66 (C5-arom.), 134.29 (C8H-arom.), 127.30 (C6H-arom.), 124.77 (C4-arom.), 124.25 (C1H-arom.), 121.63 (C2H-arom.), 86.64 (C12(CH3)3), 66.56 (C9-arom.), 27.76 (C13,14,15H3).

3-((2H-tetrazol-5-yl)methyl)-1H-indole

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 700	CA 4-21 F3-4 (yield = 66%)	IC50 (PSA) = Inactive
	tR (HPLC) = 2.80 min        MS (ESI+) m/z = 200.0936                   [(M + H)+] Mp = 174-181° C. HRMS (ESI+): calculated for C10H10N5, m/z = 200.0931; found, 200.0929 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.03 (s, 1H, H9), 7.43 (d, J = 8.0 Hz, 1H, H6), 7.38 (d, J = 8.1 Hz, 1H, H3), 7.27 (d, J = 2.4 Hz, 1H, H8), 7.09 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H, H5), 6.98 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H, H4), 4.38 (d, J = 0.6 Hz, 2H, H10). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 156.20 (C11-arom.), 136.70 (C2- arom.), 126.98 (C8H-arom.), 124.34 (C1-arom.), 121.75 (C4H-arom.), 119.11 (C5H-arom.), 118.57 (C6H-arom.), 112.02 (C3H-arom.), 108.78 (C7-arom.), 19.99 (C10H2).

3-(2H-tetrazol-5-yl)-1H-indole

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 701	CA 4-22 F9-16 (yield = 33%)	IC50 (PSA) = Inactive
	tR (HPLC) = 2.86 min       MS (ESI+) m/z = 186.2227                 [(M + H)+] Mp = 220-224° C. HRMS (ESI+): calculated for C9H8N5, m/z = 186.0774; found, 186.0776 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.88 (s, 1H, H9), 8.25-8.22 (m, 1H, H6), 8.11 (d, J = 2.9 Hz, 1H, H11), 7.57-7.53 (m, 1H, H3), 7.28- 7.20 (m, 2H, H4,5). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 151.72 (C10-arom.), 136.86 (C2H-arom.), 127.53 (C8H-arom.), 124.91 (C1-arom.), 123.08 (C4H-arom.), 121.27 (C5H-arom.), 120.77 (C6H-arom.), 112.73 (C3H-arom.), 99.91 (C7- arom.).

tert-butyl 3-iodo-7-methyl-1H-indole-1-carboxylate

Intermediate LabBook Code
             CA 4-23 P1-3 (yield = 81%)
             tR (HPLC) = 5.78 min        MS (ESI+) m/z =  1H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.88 (s, 1H, H8), 7.30-7.19 (m, 3H, H1,2,6), 2.54 (s, 3H, H11), 1.61 (s, 9H, H14,15,16). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 148.55 (C17O), 134.13 (C4- arom.), 133.33 (C5-arom.), 132.74 (C8H-arom.), 128.83 (C2H-arom.), 125.22 (C3-arom.), 124.29 (C1H-arom.), 119.45 (C6H-arom.), 84.70 (C13(CH3)3), 66.84 (C9-arom.), 27.90 (C14,15,16H3), 21.68 (C11H3).

tert-butyl 3-iodo-H-pyrrolo[3,2-b]pyridine-1-carboxylate

Intermediate LabBook Code
             CA 4-24 F1-6 (yield = 77%)
             tR (HPLC) = 4.59 min     MS (ESI+) m/z = 345.0111              [(M + H)+] 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz, 1H, H1), 8.32 (dd, J = 8.3, 1.3 Hz, 1H, H3), 8.19 (s, 1H, H8), 7.43 (dd, J = 8.3, 4.7 Hz, 1H, H2), 1.64 (s, 9H, H13,14,15). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 148.26 (C16O), 147.90 (C4- arom.), 146.39 (C1H-arom.), 133.51 (C8H-arom.), 128.04 (C5-arom.), 122.61 (C3H-arom.), 120.60 (C2H-arom.), 85.59 (C12(CH3)3), 69.42 (C9-arom.), 28.05 (C13,14,15H3).

3-(naphthalen-2-yl)-7-nitro-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.2
13 702	CA 4-27 F20-51 Precipitate3 (yield = 56%)	IC50 (PSA) = 0.14
	tR (HPLC) = 4.40 min             MS (ESI+) m/z = 289.0915                      [(M + H)+] Mp = 166-171° C. HRMS (ESI+): calculated for C18H13N2O2, m/z = 289.0972; found, 289.0975 1H NMR (400 MHz, CDCl3): δ (ppm) = 10.13 (s, 1H, H13), 8.38 (d, J = 7.8 Hz, 1H, H12), 8.28 (d, J = 8.1 Hz, 1H, H8), 8.11 (s, 1H, H3), 7.99 (d, J = 8.4 Hz, 1H, H6), 7.95-7.90 (m, 2H, H16,19), 7.78 (dd, J = 8.5, 1.8 Hz, 1H, H5), 7.67 (d, J = 2.4 Hz, 1H, H14), 7.59-7.50 (m, 2H, H17,18), 7.35 (t, J = 8.0 Hz, 1H, H7).
	13C NMR (101 MHz, CDCl3): δ (ppm) = 133.82 (C4-arom.), 133.21 (C9-
	arom.), 132.41 (C2-arom.), 131.32 (C1-arom.), 130.08 (C10-arom.), 129.92
	(C11-arom.), 128.67 (C6H-arom.), 128.16 (C12H-arom.), 127.83 (C19H-
	arom.), 127.78 (C19H-arom.), 126.48 (C5H-arom.), 126.42 (C18H-arom.),
	126.14 (C3H-arom.), 125.86 (C17H-arom.), 124.23 (C14H-arom.), 119.88
	(C15-arom.), 119.81 (C7H-arom.), 119.77 (C8H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.1
13 703	CA 4-28 Precipitate (yield = 84%)	IC50 (PSA) = 0.097
	tR (HPLC) = 4.28 min           MS (ESI+) m/z = 245.1068                    [(M + H)+] Mp = 221-224° C. HRMS (ESI+): calculated for C17H13N2, m/z = 245.1073; found, 245.1068 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.66 (s, 1H, H14), 8.97 (d, J = 0.8 Hz, 1H, H3), 8.53 (dd, J = 4.6, 1.5 Hz, 1H, H7), 8.35 (dd, J = 8.6, 1.7 Hz, 1H, H5), 8.33 (d, J = 2.9 Hz, 1H, H14), 7.95-7.90 (m, 2H, H6,19), 7.89-7.84 (m, 2H, H9,16), 7.50 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H, H18), 7.44 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H17), 7.22 (dd, J = 8.2, 4.6 Hz, 1H, H8).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 144.11 (C11-arom.), 143.30
	(C7H-arom.), 134.01 (C1-arom.), 132.82 (C4-arom.), 131.77 (C2-arom.),
	130.16 (C10-arom.), 128.07 (C6,16H-arom.), 128.06 (C19H-arom.), 127.67
	(C14H-arom.), 126.53 (C18H-arom.), 125.51 (C5H-arom.), 125.34 (C17H-
	arom.), 123.77 (C3H-arom.), 119.47 (C9H-arom.), 117.21 (C8H-arom.),
	114.52 (C15-arom.).

7-bromo-3-(naphthalen-2-yl)-1H-indole (Procedure 10)

LabBook Code
CA 4-29 P2 F3-7 (yield = 12%)
tR (HPLC) = 5.13 min        MS (ESI+) m/z = 323.0095,                 325.0076 [(M + H)+] 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.70 (s, 1H, H13), 8.24 (s, 1H, H3), 8.07 (d, J = 8.0 Hz, 1H, H12), 8.00 (d, J = 8.3 Hz, 1H, H19), 7.98 (d, J = 8.6 Hz, 1H, H6), 7.94-7.89 (m, 3H, H5,14,16), 7.53 (ddd, J = 8.1, 6.7, 1.4 Hz, 1H, H18), 7.48 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H, H17), 7.44 (d, J = 7.4 Hz, 1H, H8), 7.12 (t, J = 7.8 Hz, 1H, H7). 13C NMR → n.d.

3-(naphthalen-2-yl)-1H-indol-7-amine

LabBook Code
CA 4-34 F6-10 (yield = 28%)
tR (HPLC) = 4.04 min        MS (ESI+) m/z = 259.1295                 [(M + H)+] 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.22 (s, 1H, H13), 8.18 (s, 1H, H7), 7.96-7.88 (m, 3H, H3,6,10), 7.85 (dd, J = 8.5, 1.7 Hz, 1H, H9), 7.62 (d, J =  7.9 Hz, 1H, H19), 7.57-7.49 (m, 2H, H1,2), 7.36 (s, 1H, H12), 7.21 (t, J = 7.8 Hz, 1H, H18), 6.69 (d, J = 7.5 Hz, 1H, H17). 13C NMR → n.d.

tert-butyl 7-methyl-3-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate

Intermediate LabBook Code
             CA 4-35 F5-7 (yield = Quant %)
             tR (HPLC) = 5.48 min          MS (ESI+) m/z =  1H NMR (400 MHz, CDCl3): δ (ppm) = 7.77 (s, 1H, H8), 7.54 (d, J = 7.6 Hz, 1H, H6), 7.25 (t, J = 7.5 Hz, 1H, H1), 7.18 (d, J = 7.3 Hz, 1H, H2), 2.67 (s, 3H), 1.66 (s, 9H), 0.33 (s, 9H). 13C NMR (101 MHz, CDCl3): δ (ppm) = 148.78 (C22O), 134.06 (C4-arom.), 131.84 (C5-arom.), 131.67 (C8H-arom.), 128.58 (C2H-arom.), 125.44 (C3- arom.), 123.61 (C1H-arom.), 117.80 (C6H-arom.), 103.32 (C9-arom.), 97.93 (C12≡), 96.91 (C10≡), 83.94 (C18(CH3)3), 28.01 (C19,20,21H3), 22.09 (C11H3), 0.14 (C14,15,16H3).

3-([1,1′-biphenyl]-4-yl)-7-methyl-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 3.815
13 733	CA 4-38 Precipitate (yield = 25 %)	IC50 (PSA) = 0.919
	tR (HPLC) = 4.50 min           MS (ESI−) m/z = 282.1207                     [(M + H)−] Mp = 199-202° C. HRMS (ESI−): calculated for C21H16N, m/z = 282.1288; found, 282.1286 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.38 (s, 1H, H13), 7.84-7.79 (m, 2H, H3,5), 7.78-7.70 (m, 6H, H1,6,12,14,18,22), 7.52-7.46 (m, 2H, H19,21), 7.40-7.34 (m, 1H, H20), 7.04 (t, J = 7.2 Hz, 1H, H7), 6.98 (d, J = 7.0 Hz, 1H, H8), 2.52 (s, 3H, H17). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 140.51 (C16-arom.), 137.29 (C2- arom.), 136.90 (C10-arom.), 135.75 (C4-arom.), 129.40 (C19,21H-arom.), 127.57 (C20H-arom.), 127.43 (C1,6H-arom.), 127.33 (C3,5H-arom.), 126.79 (C18,22H-arom.), 125.14 (C11-arom.), 123.85 (C14H-arom.), 122.44 (C8H-
	arom.), 121.62 (C9-arom.), 120.37 (C7H-arom.), 117.16 (C12H-arom.),
	116.06 (C15-arom.), 17.31 (C17H3).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 4.08
13 715	CA 4-39 Precipitate3 (yield = 51%)	IC50 (PSA) = 0.35
	tR (HPLC) = 4.23 min           MS (ESI−) m/z = 271.1232                    [(M + H)+] Mp = <270° C. HRMS (ESI+): calculated for C19H15N2, m/z = 271.1230; found, 271.1232 1H NMR (500 MHz, DMSO-d6): δ (ppm) = 11.97 (s, 1H, H13), 8.35 (d, J = 7.9 Hz, 1H, H12), 8.30 (dd, J = 4.6, 1.4 Hz, 1H, H8), 7.96 (d, J = 2.6 Hz, 1H, H14), 7.84 (d, J = 8.3 Hz, 2H, H3,5), 7.79-7.71 (m, 4H, H1,6,17,21), 7.49 (t, J = 7.7 Hz, 2H, H20,18), 7.38 (t, J = 7.4 Hz, 1H, H19), 7.19 (dd, J = 7.9, 4.6 Hz, 1H, H7). 13C NMR (126 MHz, DMSO-d6): δ (ppm) = 149.60 (C10-arom.), 143.42 (C8- arom.), 140.39 (C16-arom.), 137.73 (C2-arom.), 134.78 (C4-arom.), 129.43 (C18,20H-arom.), 128.02 (C12H-arom.), 127.68 (C19H-arom.), 127.55 (C1,6H-
	arom.), 127.11 (C3,5H-arom.), 126.84 (C17,21H-arom.), 124.41 (C14H-arom.),
	117.74 (C11H-arom.), 116.57 (C7H-arom.), 114.24 (C15-arom.).

3-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.067
13 716	CA 4-40 Precipitate (yield = 37%)	IC50 (PSA) = 0.058
	tR (HPLC) = 3.96 min          MS (ESI−) m/z = 273.0029,                   275.0010 [(M + H)+] Mp = 262-266° C. HRMS (ESI+): calculated for C13H10BrN2, m/z = 273.0022, 275.0002; found, 273.0024, 275.0005 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.00 (s, 1H, H13), 8.30-8.27 (m, 2H, H8,12), 7.95 (d, J = 2.7 Hz, 1H, H14), 7.72-7.68 (m, 2H, H1,6), 7.63- 7.59 (m, 2H, H3,5), 7.20-7.15 (m, 1H, H7). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 149.54 (C10-arom.), 143.52 (C8H-arom.), 134.83 (C4-arom.), 132.14 (C3,5H-arom.), 128.60 (C1,6H-
	arom.), 127.89 (C12H-arom.), 124.70 (C14H-arom.), 118.79 (C2-arom.),
	117.47 (C11-arom.), 116.64 (C7H-arom.), 113.46 (C15-arom.).

3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 11.01
13 734	CA 4-48 Precipitate (yield = 39%)	IC50 (PSA) = 4.129
	tR (HPLC) = 4.34 min          MS (ESI−) m/z = 271.1226                   [(M + H)+] Mp = 182-185° C. HRMS (ESI+): calculated for C19H15N2, m/z = 271.1230; found, 271.1227 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.97 (s, 1H, H13), 8.34 (dd, J = 8.0, 1.5 Hz, 1H, H12), 8.30 (dd, J = 4.6, 1.5 Hz, 1H, H8), 8.01 (s, 1H, H14), 7.95 (d, J = 0.7 Hz, 1H, H3), 7.80-7.75 (m, 2H, H17,21), 7.74-7.71 (m, 1H, H5), 7.57-7.47 (m, 4H, H2,6,18,20), 7.43-7.39 (m, 1H, H19), 7.18 (dd, J = 7.9, 4.7 Hz, 1H, H7). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 149.56 (C10-arom.), 143.39
	(C8H-arom.), 141.37 (C1-arom.), 140.88 (C16-arom.), 136.18 (C4-arom.),
	129.97 (C6H-arom.), 129.38 (C18,20H-arom.), 127.94 (C12,19H-arom.), 127.37
	(C17,21H-arom.), 125.87 (C5H-arom.), 125.07 (C3H-arom.), 124.62 (C2,14H-
	arom.), 117.79 (C11-arom.), 116.59 (C7H-arom.), 114.66 (C15-arom.).

4-(4-bromothiazol-2-yl)morpholine

	LabBook Code
	CA 4-50 Ap Tmt (yield = Quant
Intermediate	%)
(Beige Solid)	tR (HPLC) = 3.44 min	MS (ESI+) m/z = 248.9720; 250.9700 [(M + H)+]
	1H NMR (400 MHz, DMSO-d6): δ (ppm) = 6.92 (s, 1H, H2),
	3.72-3.67 (m, 4H, H8,10), 3.38-3.34 (m, 4H, H7,11).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 171.17 (C4-arom.),
	121.03 (C1-arom.), 105.37 (C2H-arom.), 65.72 (C8,10H2),
	48.08 (C7,11H2).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 3.86
13 735	CA 4-55 Precipitate (yield = 79%)	IC50 (PSA) = 1.433
(White Solid)	tR (HPLC) = 3.55 min	MS (ESI−) m/z = 271.1169 [(M + H)+]
	Mp = 254-259 ° C.
	HRMS (ESI+): calculated for C19H15N2, m/z = 271.1230; found, 271.1225
	1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.62 (s, 1H, H13), 8.48 (dd, J =
	4.6, 1.5 Hz, 1H, H7), 8.43-8.39 (m, 2H, H3,5), 8.24 (s, 1H, H14), 7.85 (dd, J =
	8.2, 1.5 Hz, 1H, H9), 7.72 (m, 4H, H1,6,17,21), 7.49 (m, 2H, H18,20), 7.39-7.35
	(m, 1H, H19), 7.20 (dd, J = 8.2, 4.6 Hz, 1H, H8).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 144.02 (C11-arom.), 143.19 (C7H-
	arom.), 140.64 (C16-arom.), 137.19 (C2-arom.), 134.48 (C4-arom.), 130.04 (C10-
	arom.), 129.36 (C18,20H-arom.), 127.50 (C19H-arom.), 127.16 (C14H-arom.),
	126.99 (C1,6H-arom.), 126.77 (C17,21H-arom.), 126.69 (C3,5H-arom.),
	119.42 (C9H-arom.), 117.09 (C8H-arom.), 114.21 (C15-arom.).

3-(4-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

	LabBook Code
VPC Number	CA 4-64 Precipitate (yield = 25	IC50 (eGFP) = 0.08
13 737	%)	IC50 (PSA) = 0.037
(Pale Yellow Solid)	tR (HPLC) = 2.84 min	MS (ESI−) m/z = 273.0043, 275.0023 [(M + H)+]
	Mp = 213-221° C.
	HRMS (ESI+): calculated for C13H10BrN2, m/z = 273.0022, 275.0002;
	found, 273.0015, 274.9995
	1H NMR (400 mHz, DMSO-d6): δ (ppm) = 11.66 (s, 1H, H13), 8.46 (dd,
	J = 4.6, 1.5 Hz, 1H, H7), 8.32-8.27 (m, 2H, H1,6), 8.24 (s, 1H, H14), 7.84
	(dd, J = 8.2, 1.5 Hz, 1H, H9), 7.61-7.55 (m, 2H, H3,5), 7.19 (dd, J = 8.2,
	4.6 Hz, 1H, H8).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 143.76 (C11-arom.), 143.27
	(C7H-arom.), 134.53 (C4-arom.), 131.61 (C3,5H-arom.), 130.02 (C10-arom.),
	128.10 (C1,6H-arom.), 127.44 (C14H-arom.), 119.53 (C9H-arom.), 118.24
	(C2-arom.), 117.19 (C8H-arom.), 113.32 (C15-arom.).

3-(4-bromophenyl)-7-nitro-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.083
13 738	CA 4-65 Precipitate (yield = 12%)	IC50 (PSA) = 0.062
(Orage Solid)	tR (HPLC) = 4.29 min	MS (ESI−) m/z = 314.9732, 316.9703 [(M + H)−]
	Mp = 192-196° C.
	HRMS (ESI−): calculated for C14H8BrN2O2, m/z = 314.9775, 316.9755;
	found, 314.9769, 316.9748
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 12.21 (s, 1H, H13), 8.34 (dd, J =
	7.9, 0.8 Hz, 1H, H12), 8.20 (dd, J = 8.0, 0.5 Hz, 1H, H8), 7.89 (s, 1H, H14),
	7.71-7.63 (m, 4H, H1,3,5,6), 7.36 (t, J = 8.0 Hz, 1H, H7).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 133.24 (C4-arom.), 132.90 (C9-
	arom.), 131.78 (C1,6H-arom.), 129.25 (C3,5H-arom.), 129.11 (C11-arom.),
	128.95 (C10-arom.), 127.65 (C12H-arom.), 126.89 (C14H-arom.), 119.58 (C7H-
	arom.), 119.26 (C2-arom.), 119.13 (C8H-arom.), 116.42 (C15-arom.).

methyl 3-(4-bromophenyl)-1H-indole-7-carboxylate (Procedure 10)

	LabBook Code
VPC Number	CA 4-74 Precipitate (yield = 36	IC50 (eGFP) = 0.62
13 736	%)	IC50 (PSA) = 0.68
(Grey Solid)	tg (HPLC) = 4.37 min	MS (ESI−) m/z = 327.9978 [(M + H)−]
	Mp = 149-155° C.
	HRMS (ESI−): calculated for C16H11BrNO2, m/z = 327.9979; found,
	327.9978
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.49 (s, 1H, H13), 8.16 (d,
	J = 7.9 Hz, 1H, H12), 7.87 (d, J = 6.8 Hz, 1H, H8), 7.78 (d, J = 2.6 Hz,
	1H, H14), 7.70-7.67 (m, 2H, H3,5), 7.65-7.61 (m, 2H, H1,6),
	7.26 (t, J = 7.7 Hz, 1H, H7), 3.97 (s, 3H, H7).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 166.39 (C17O), 135.02
	(C10-arom.), 134.18 (C4-arom.), 131.67 (C1,6H-arom.), 128.88
	(C3,5H-arom.), 126.54 (C11-arom.), 125.42 (C14H-arom.),
	124.83 (C12H-arom.),
	124.30 (C8H-arom.), 119.49 (C7H-arom.), 118.57 (C2-arom.),
	115.07 (C15-arom.), 113.07 (C9-arom.), 51.94 (C20H3).

3-phenyl-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.66
13 739	CA 4-75 Precipitate (yield = 54%)	IC50 (PSA) = 0.67
(Beige Solid)	tR (HPLC) = 3.40 min	MS (ESI+) m/z = 195.0920 [(M + H)+]
	Mp = 92-94° C.
	HRMS (ESI+): calculated for C13H11N2, m/z = 195.0917; found, 195.0919
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.90 (s, 1H, H13), 8.30-8.26 (m,
	2H, H8,12), 7.87 (d, J = 2.6 Hz, 1H, H14), 7.73 (dd, J = 8.2, 1.1 Hz, 2H, H3.5),
	7.45 (dd, J = 8.0, 7.5 Hz, 2H, H1,6), 7.26 (tdd, J = 7.2, 6.0, 1.2 Hz, 1H, H2),
	7.16 (dd, J = 7.9, 4.7 Hz, 1H, H7).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 149.06 (C10-arom.), 142.87 (C8H-
	arom.), 135.05 (C4-arom.), 128.84 (C1,6H-arom.), 127.43 (C12H-arom.), 126.23
	(C3,5H-arom.), 125.63 (C2H-arom.), 123.67 (C14H-arom.), 117.25 (C11-arom.),
	116.00 (C7H-arom.), 114.25 (C15-arom.).

tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

	LabBook Code
Intermediate	CA 4-76 F2-6 (yield = 68%)
(White Solid)	tR (HPLC) = 4.99 min	MS (ESI+) m/z = n.d.
	1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.11-8.06 (m, 1H, H3), 7.88 (s,
	1H, H8), 7.87-7.82 (m, 1H, H6), 7.37-7.32 (m, 1H, H2), 7.31-7.26 (m, 1H,
	H1), 1.64 (s, 9H, H21,22,23), 1.33 (s, 12H, H15,16,17,18).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 149.11 (C24O), 135.87 (C4-
	arom.), 135.33 (C8H-arom.), 133.22 (C5-arom.), 124.86 (C2H-arom.), 123.48
	(C1H-arom.), 122.66 (C6H-arom.), 115.06 (C3H-arom.), 107.92 (C9-arom.),
	84.79 (C20(CH3)3), 83.74 (C12,13(CH3)2), 28.07 (C21,22,23H3),
	25.14 (C15,16,17,18H3).

3-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.12
13 740	CA 4-85 Precipitate (yield = 50%)	IC50 (PSA) = 0.12
(Beige Solid)	tR (HPLC) = 3.59 min	MS (ESI+) m/z = 213.0830 [(M + H)+]
	Mp = 188-192° C.
	HRMS (ESI+): calculated for C13H10FN2, m/z = 213.0823; found, 213.0823
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.91 (s, 1H, H13), 8.28 (dd, J =
	4.6, 1.3 Hz, 1H, H12), 8.26 (dd, J = 8.0, 1.1 Hz, 1H, H8), 7.86 (d, J = 2.6 Hz,
	1H, H14), 7.77-7.73 (m, 2H, H3.5), 7.29-7.24 (m, 2H, H1,6), 7.16 (dd, J =
	7.9, 4.6 Hz, 1H, H7).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 160.52 (d, J = 242.3 Hz, C2F-
	arom.), 148.96 (C10-arom.), 142.92 (C8H-arom.), 131.49 (d, J = 3.0 Hz, C4-
	arom.), 127.99 (d, J = 7.8 Hz, C3,5H-arom.), 127.27 (C12H-arom.), 123.66
	(C14H-arom.), 117.15 (C11-arom.), 116.02 (C7H-arom.), 115.61 (d, J = 21.2 Hz,
	C1,6H-arom.), 113.28 (C15-arom.).

3-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.29
13 741	CA 4-88 Crystals (yield = 22%)	IC50 (PSA) = 0.29
(Colorless Solid)	tR (HPLC) = 4.03 min	MS (ESI+) m/z = 263.0793 [(M + H)+]
	Mp = 154-157° C.
	HRMS (ESI+) : calculated for C14H210F3N2, m/z = 263.0791; found,
	263.0789
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.77 (s, 1H, H13),
	8.94-8.92 (m, 1H, H1), 8.50 (d, J = 7.7 Hz,
	1H, H12), 8.32 (d, J = 2.9 Hz, 1H, H14), 8.02-8.04
	(m, 2H, H5,6), 7.49 (d, J = 7.8 Hz, 1H, H9), 7.23-7.16 (m, 2H, H7,8).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 159.25 (d, J = 1.2 Hz,
	C4-arom.), 145.86 (q, J = 4.2 Hz, C1H-arom.),
	137.12 (C10-arom.), 133.25 (q, J = 3.1 Hz, C6H-arom.), 128.17
	(C14H-arom.), 125.13 (C11-arom.), 124.31 (q, J = 271.5 Hz,
	C16F3), 122.14 (C8H-arom.), 121.63 (C12H-arom.), 120.55 (C7H-arom.),
	120.30 (q, J = 32.1 Hz, C2-arom.), 119.02 (C5-arom.),
	114.24 (C15-arom.), 111.99 (C9H-arom.).

tert-butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

	LabBook Code
Intermediate	CA 4-89 F10-24 (yield = 68%)
(White Solid)	tR (HPLC) = 5.20 min	MS (ESI+) m/z = n.d.
	1H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.85 (s, 1H, H8), 7.71 (d, J =
	7.1 Hz, 1H, H6), 7.19 (t, J = 7.5 Hz, 1H, H1), 7.11 (d, J = 7.1 Hz, 1H,
	H2), 2.53 (s, 3H, H19), 1.62 (s, 9H, H22,23,24), 1.33 (s, 12H, H15,16,17,18).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 148.60 (C25O), 137.15 (C8H-
	arom.), 134.66 (C4-arom.), 133.93 (C5-arom.), 127.27 (C2H-arom.), 124.23
	(C3-arom.), 123.28 (C1H-arom.), 119.88 (C6H-arom.), 107.29 (C9-arom.),
	84.18 (C20(CH3)3), 83.18 (C12,13(CH3)2), 27.42 (C22,23,24H3), 24.67
	(C15,16,17,18H3, 21.39 (C19H3).

3-(2-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 1.01
13 745	CA 4-95 F4-8 (yield = 50%)	IC50 (PSA) = 0.95
(Beige Solid)	tR (HPLC) = 4.15 min	MS (ESI+) m/z = 260.0687 [(M + H)+]
	Mp = 62-67° C.
	HRMS (ESI−): calculated for C15H9F3N, m/z = 260.0693; found, 260.0687
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.39 (s, 1H, H13), 7.85 (d, J = 7.9
	Hz, 1H, H1), 7.72 (t, J = 7.4 Hz, 1H, H6), 7.59 (d, J = 7.5 Hz, 1H, H5), 7.55 (t,
	J = 7.5 Hz, 1H, H2), 7.49 (d, J = 8.1 Hz, 1H, H9), 7.40 (s, 1H, H14), 7.36 (d,
	J = 7.9 Hz, 1H, H12), 7.16 (t, J = 7.5 Hz, 1H, H8), 7.04 (t, J = 7.4 Hz, 1H, H7).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 135.73 (C10-arom.), 134.23 (d, J =
	1.3 Hz, C4-arom.), 133.18 (C5H-arom.), 132.04 (C6H-arom.), 127.71 (q, J =
	28.6 Hz, C3-arom.), 127.01 (C11-arom.), 126.89 (C2H-arom.), 126.26 (q, J = 5.4
	Hz, C1H-arom.), 124.40 (d, J = 2.9 Hz, C14H-arom.), 124.39 (q, J = 273.6 Hz,
	C16F3), 121.46 (C8H-arom.), 119.42 (C7H-arom.), 118.32 (C12H-arom.),
	112.44 (C15-arom.), 111.70 (C9H-arom.).

2,3,4-trifluoro-6-iodoaniline

	LabBook Code
Intermediate	CA 4-100 F6-11 (yield = 36%)
(Dark Solid)	tR (HPLC) = 3.78 min	MS (ESI+) m/z = 273.9338 [(M + H)+]
	1H NMR( 600 MHz, CDCl3): δ (ppm) = 7.33 (ddd, J = 9.3, 7.6, 2.5 Hz, 1H,
	H6), 4.07 (s, 2H, H7).
	13C NMR (151 MHz, CDCl3): δ (ppm) = 143.20 (ddd, J = 244.0, 10.8, 2.8
	Hz, C3-arom.), 139.98 (ddd, J = 250.5, 161.1, 13.7 Hz, C2-arom.), 138.48
	(ddd, J = 247.1, 12.6, 3.3 Hz, C1-arom.), 133-43 (dd, J = 11.2 2.4 Hz,
	C4-arom.), 119.96 (dd, J = 20.1, 3.9 Hz, C6H-arom.),
	73.21 (ddd, J = 8.2, 4.5, 2.1 Hz, C5-arom.).

2-(5,6,7-trifluoro-1H-indol-3-yl)quinoline

	LabBook Code
	CA 4-101 F4-6 (yield = 13%)
(White Solid)	tR (HPLC) = 4.32 min	MS (ESI+) m/z = 299.0820 [(M + H)+]
	HRMS (ESI+): calculated for C17H10F3N2, m/z = 299.0791; found, 299.0791
	1H NMR (600 MHz, CDCl3): δ (ppm) = 9.99 (s, 1H, H15), 8.21 (d, J = 8.4 Hz,
	1H, H10), 8.12 (d, J = 8.1 Hz, 1H, H3), 7.87 (d, J = 8.4 Hz, 1H, H9), 7.84 (d,
	J = 8.4 Hz, 1H, H6), 7.77 (t, J = 7.5 Hz, 1H, H2), 7.57 (t, J = 7.3 Hz, 1H, H1),
	7.23 (ddd, J = 9.7, 6.5, 1.6 Hz, 1H, H19), 7.12 (s, 1H, H14).
	13C NMR (151 MHz, CDCl3): δ (ppm) = 148.30 (C8-arom.),
	147.32 (C4-arom.), 146.70 (dd,
	J = 240.3, 12.2 Hz, C16-arom.), 138.72 (C13-arom.), 137.53 (ddd, J = 249.3,
	13.6, 4.5 Hz, C17-arom.), 136.93 (ddd, J = 244.8, 17.1, 11.3 Hz, C16-
	arom.), 136.35 (C10-arom.), 129.70 (C2H-arom.), 128.58 (C3H-arom.), 127.22
	(C6H-arom.), 127.06 (C5-arom.), 126.14 (C1H-arom.), 124.01 (dd, J = 6.9, 5.5
	Hz, C12-arom.), 121.44 (dd, J = 7.7, 2.9 Hz, C11-arom.), 117.52 (C9H-arom.),
	101.92 (m, C14,19H-arom.).

7-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

	LabBook Code
VPC Number	CA 4-102 Precipitate (yield = 32	IC50 (eGFP) = 0.76
13 744	%)	IC50 (PSA) = 0.75
(Green Solid)	tR (HPLC) = 2.94 min	MS (ESI+) m/z = 259.1272 [(M + H)+]
	Mp = 199-201° C.
	HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1228
	1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.54 (s, 1H, H13), 8.89 (dd, J =
	4.2, 1.7 Hz, 1H, H19), 8.34 (dd, J = 8.2, 0.9 Hz, 1H, H17), 8.30 (s, 1H, H3),
	8.04-8.00 (m, 2H, H5,6), 7.98 (d, J = 2.4 Hz, 1H, H14), 7.87 (d, J = 8.0 Hz, 1H,
	H12), 7.47 (dd, J = 8.2, 4.2 Hz, 1H, H18), 7.10 (t, J = 7.5 Hz, 1H, H8), 7.02 (d,
	J = 7.0 Hz, 1H, H8), 2.54 (s, 3H, H16).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 150.65 (C19H-arom.), 148.56 (C1-
	arom.), 137.35 (C4-arom.), 136.61 (C10-arom.), 135.55 (C17H-arom.), 128.24
	(C6H-arom.), 126.41 (C5H-arom.), 125.92 (C2-arom.), 124.71 (C14H-arom.),
	124.62 (C11-arom.), 124.05 (C3H-arom.), 122.23 (C8H-arom.), 121.36 (C9-
	arom.), 120.40 (C7H-arom.), 120.28 (C18H-arom.), 116.64 (C12H-arom.),
	115.27 (C15-arom.), 16.83 (C16H3).

tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

	LabBook Code
Intermediate	CA 4-104 F1-21 (yield = 83%)
(White Solid)	tR (HPLC) = 4.07 min	MS (ESI+) m/z = 345.0106 [(M + H)+]
	1H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz,
	1H, H1), 8.32 (dd, J = 8.3, 1.3 Hz, 1H, H3), 8.19 (s, 1H, H8), 7.43 (dd,
	J = 8.3, 4.7 Hz, 1, H2), 1.64 (s, 9H, H13,14,15).
	13C NMR = n.d.

3-(4-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.38
13 743	CA 4-105 F8-16 (yield = 51%)	IC50 (PSA) = 0.39
	tR (HPLC) = 4.34 min      MS (ESI+) m/z = 262.0850               [(M + H)+] Mp = 126-129° C. HRMS (ESI+): calculated for C15H11F3N, m/z = 262.0838; found, 262.0850 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.59 (s, 1H, H13), 7.94 (d, J = 8.2 Hz, 3H, H3,5,12), 7.90 (d, J = 2.6 Hz, 1H, H14), 7.76 (d, J = 8.2 Hz, 2H, H1,6), 7.50 (d, J = 8.0 Hz, 1H, H9), 7.22-7.18 (m, 1H, H8), 7.17-7.13 (m, 1H, H7).
(Pale Orange Solid)	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 140.18 (d, J= 0.8 Hz, C4-arom.),
	137.04 (C10-arom.), 126.48 (C3,5H-arom.), 125.58 (q, J= 3.7 Hz, C1,6H-arom.),
	125.25 (d, J= 31.7 Hz, C2-arom.), 125.00 (C14H-arom.), 124.66 (C11H-arom.),
	124.62 (q, J = 271.5 Hz, C16F3), 121.76 (C8H-arom.), 120.11 (C7H-arom.),
	118.92 (C12H-arom.), 114.12 (C15-arom.), 112.19 (C9H-arom.).

1-methyl-5-(naphthalen-2-yl)-1H-indole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 2.0
13 756	CA 4-108 Precipitate (yield = 45%)	IC50 (PSA) = 1.49
	tR (HPLC) = 4.56 min         MS (ESI+) m/z = 258.1260                  [(M + H)+] Mp = 200-204° C. HRMS (ESI+): calculated for C19H16N, m/z = 258.1277; found, 258.1276 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 8.21 (d, J = 0.7 Hz, 1H, H7), 8.00- 7.97 (m, 3H, H6,10,16), 7.93 (d, J = 8.0 Hz, 1H, H3), 7.91 (dd, J= 8.5, 1.7 Hz, 1H, H9), 7.64 (dd, J = 8.5, 1.6 Hz, 1H, H14), 7.57 (d, J = 8.5 Hz, 1H, H13), 7.54 (t, J = 7.3 Hz, 1H, H1), 7.49 (t, J = 7.3 Hz, 1H, H2), 7.39 (d, J = 3.0 Hz, 1H, H18), 6.53 (d, J = 3.0 Hz, 1H, H19), 3.85 (s, 3H, H20).
(Pale Yellow lid)	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 139.02 (C8-arom.), 136.09 (C11-
	arom.), 133.52 (C5-arom.), 131.70 (C4-arom.), 131.12 (C15-arom.), 130.43
	(C18H-arom.), 128.68 (C12-arom.), 128.20 (C10H-arom.), 127.95 (C6H-arom.),
	127.41 (C3H-arom.), 126.19 (C1H-arom.), 125.62 (C2H-arom.), 125.50 (C9H-
	arom.), 124.60 (C7H-arom.), 120.61 (C14H-arom.), 118.75 (C16H-arom.),
	110.20 (C13H-arom.), 100.86 (C19H-arom.), 32.58 (C20H3).

3-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) =
13	CA 4-109 Precipitate (yield = 69%)	IC50 (PSA) =
	tR (HPLC) = 2.89 min         MS (ESI+) m/z = 263.0792                  [(M + H)+] Mp = 223-226° C. HRMS (ESI+): calculated for C14H10F3N2, m/z = 263.0791; found, 263.0790 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.78 (s, 1H, H11), 8.55 (d, J = 8.2 Hz, 2H, H3,5), 8.49 (dd, J = 4.5, 1.3 Hz, 1H, H13), 8.36 (s, 1H, H7), 7.87 (dd, J = 8.2, 1.4 Hz, 1H, H15), 7.75 (d, J = 8.3 Hz, 2H, H2,6), 7.22 (dd, J = 8.2, 4.5
(Pale Yellow Solid)	Hz, 1H, H14).
	13C NMR (101 MHz, DMSO-d6): δ (ppm) = 143.41 (C9-arom.), 143.07 (C13H-
	arom.), 139.02 (d, J = 0.9 Hz, C4-arom.), 129.64 (C10-arom.), 128.07 (C7H-
	arom.), 125.77 (C3,5H-arom.), 125.16 (q, J = 3.7 Hz, C2,6H-arom.), 125.14 (q,
	J = 31.6 Hz, C1-arom.), 124.67 (q, J = 271.4 Hz, C16F3), 119.23 (C15H-arom.),
	116.93 (C14H-arom.), 112.60 (C8-arom.).

3-(2-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

              LabBook Code
              CA 4-110 Precipitate2 (yield = 37%)
              tR (HPLC) = 2.61 min      MS (ESI+) m/z = 273.0018,                274.9998 [(M + H)+] HRMS (ESI+): calculated for C13H10BrN2, m/z = 2273.0022, 275.0002; found, 273.0018, 274.9998 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.61 (s, 1H, H11), 8.37 (d, J = 4.4 HZ, 1H, H13), 7.99 (s, 1H, H7), 7.90 (d, J = 7.7 Hz, 1H, H5), 7.85 (d, J = 8.1 Hz, 1H, H15), 7.74 (d, J = 7.9 Hz, 1H, H2), 7.45 (t, J = 7.5 Hz, 1H, H6), 7.24 (t, J =
(Beige Solid) 7.6 Hz, 1H, H1), 7.18 (dd, J = 8.1, 4.5 Hz, 1H, H14).
              13C NMR (101 MHz, DMSO-d6): δ (ppm) = 143.75 (C9-arom.), 142.71 (C13H-
              arom.), 134.57 (C4-arom.), 132.93 (C2H-arom.), 132.70 (C5H-arom.), 128.75
              (C7H-arom.), 128.29 (C10-arom.), 127.86 (C1H-arom.), 127.21 (C6H-arom.),
              122.57 (C3-arom.), 118.89 (C15H-arom.), 116.70 (C14H-arom.), 113.74 (C8-
              arom.).

6-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 757	CA 4-114 F9-15 Precipitate (yield = 27%)	IC50 (PSA) = Inactive
	tR (HPLC) = 4.02 min            MS (ESI+) m/z = 265.0787                     [(M + H)+] Mp = 183-185° C. HRMS (ESI+): calculated for C16H13N2S, m/z = 265.0794; found, 265.0793 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.42 (s, 1H, H14), 9.32 (s, 1H, H8), 8.48 (d, J = 0.8 Hz, 1H, H6), 8.12 (d, J = 8.5 Hz, 1H, H3), 7.90 (dd, J = 8.5, 1.6 Hz, 1H, H4), 7.84-7.80 (m, 2H, H13,18), 7.05 (t, J = 7.5 Hz, 1H, H17), 6.99 (d,
(Beige Solid)	J = 7.0 Hz, 1H, H16), 2.52 (s, 3H, H19).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 154.81 (C8H-arom.), 150.95 (C1-
	arom.), 136.43 (C10-arom.), 134.50 (C2-arom.), 133.67 (C5-arom.), 125.37
	(C4H-arom.), 124.63 (C11-arom.), 123.87 (C13H-arom.), 123.01 (C3H-arom.),
	122.07 (C16H-arom.), 121.15 (C15-arom.), 119.98 (C17H-arom.), 119.15 (C6H-
	arom.), 116.70 (C18H-arom.), 115.44 (C12-arom.), 16.81 (C19H3).

2-(quinolin-5-yl)thiazole

LabBook Code
CA 4-116 F14-17 (yield = 36%)
tR (HPLC) = 2.95 min  MS (ESI+) m/z = 213.0468           [(M + H)+] 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 9.31 (d, J = 8.7 Hz, 1H, H6), 9.00 (dd, J = 4.0, 1.6 Hz, 1H, H4), 8.18 (d, J = 8.4 Hz, 1H, H10), 8.13 (d, J = 3.3 Hz, 1H, H12), 8.05 (d, J = 7.2 Hz, 1H, H8), 7.98 (d, J = 3.3 Hz, 1H, H11), 7.89 (dd, J = 8.3, 7.4 Hz, 1H, H9), 7.67 (dd, J = 8.7, 4.1 Hz, 1H, H5). 13C NMR (101 MHz, DMSO-d6): δ (ppm) = 165.68 (C14-arom.), 150.97 (C4H- arom.), 148.04 (C2-arom.), 143.95 (C12H-arom.), 134.04 (C6H-arom.), 131.25 (C10H-arom.), 130.17 (C7-arom.), 129.09 (C9H-arom.), 128.68 (C8H-arom.), 124.92 (C1-arom.), 122.51 (C5H-arom.), 121.55 (C11H-arom.).
(Pale Yellow
Solid)

5-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = Inactive
13 758	CA 4-118 F18-25 (yield = 68%)	IC50 (PSA) = Inactive
	tR (HPLC) = 3.93 min           MS (ESI+) m/z = 265.0790                    [(M + H)+] Mp = 133-136° C. HRMS (ESI+): calculated for C16H13N2S, m/z = 265.0794; found, 265.0790 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.43 (s, 1H, H15), 9.41 (s, 1H, H8), 8.39 (d, J = 1.1 Hz, 1H, H6), 8.20 (d, J = 8.3 Hz, 1H, H3), 7.87 (dd, J = 8.4, 1.5 HZ, 1H, H4), 7.86 (d, J = 2.6 Hz, 1H, H13), 7.79 (d, J = 8.0 Hz, 1H, H18), 7.06
(Orange Solid)	(t, J = 7.5 Hz, 1H, H17), 6.99 (d, J = 7.0 Hz, 1H, H16), 2.54 (s, 3H, H19).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 156.22 (C8H-arom.), 153.99 (C2-
	arom.), 136.44 (C10-arom.), 134.47 (C5-arom.), 130.24 (C1-arom.), 124.84
	(C4H-arom.), 124.70 (C11-arom.), 123.76 (C13H-arom.), 122.52 (C3H-arom.),
	122.05 (C16H-arom.), 121.21 (C15-arom.), 120.04 (C6H-arom.), 120.01 (C17H-
	arom.), 116.45 (C18H-arom.), 115.56 (C12-arom.), 16.83 (C19H3).

5-(7-methyl-1H-indol-3-yl)benzo[d]oxazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.3
13 759	CA 4-119 Precipitate (yield = 26%)	IC50 (PSA) = 0.27
	tR (HPLC) = 3.87 min           MS (ESI+) m/z = 249.1041                    [(M + H)+] Mp = 171-172° C. HRMS (ESI+): calculated for C16H13N2O, m/z = 249.1022; found, 249.1016 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.35 (s, 1H, H14), 8.75 (s, 1H, H8), 8.03 (d, J = 1.3 Hz, 1H, H6), 7.82 (d, J = 8.4 Hz, 1H, H3), 7.77 (dd, J = 8.4, 1.6 Hz, 1H, H4), 7.75 (d, J = 2.6 Hz, 1H, H13), 7.72 (d, J = 8.0 Hz, 1H, H18), 7.03
(Mauve Solid)	(t, J = 7.5 Hz, 1H, H17), 6.98 (d, J = 7.0 Hz, 1H, H16), 2.52 (s, 3H, H19).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 154.42 (C8H-arom.), 147.60 (C1-
	arom.), 140.40 (C2-arom.), 136.31 (C10-arom.), 132.98 (C5-arom.), 124.75
	(C4H-arom.), 124.70 (C11-arom.), 123.40 (C13H-arom.), 121.95 (C16H-arom.),
	121.11 (C15-arom.), 119.88 (C17H-arom.), 117.38 (C6H-arom.), 116.32 (C18H-
	arom.), 115.79 (C12-arom.), 111.18 (C3H-arom.), 16.81 (C19H3).

2-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.1
13 760	CA 4-120 F12-18 Precipitate (yield = 30%)	IC50 (PSA) = 0.52
	tR (HPLC) = 4.02 min             MS (ESI+) m/z = 265.0788                      [(M + H)+] Mp = 179-182° C. HRMS (ESI+): calculated for C16H13N2S, m/z = 265.0794; found, 265.0790 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.95 (s, 1H, H5), 8.25 (d, J = 2.9 Hz, 1H, H4), 8.22 (d, J = 7.9 Hz, 1H, H9), 8.06 (d, J = 7.9 Hz, 1H, H13), 7.97 (d, J = 8.1 Hz, 1H, H16), 7.49 (t, J = 7.6 Hz, 1H, H15), 7.37 (t, J = 7.6 Hz, 1H,
(Grey Solid)	H14), 7.17 (t, J = 7.5 Hz, 1H, H8), 7.07 (d, J = 7.1 Hz, 1H, H7), 2.54 (s, 3H, H10).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 162.90 (C18-arom.), 153.68 (C12-
	arom.), 136.26 (C1-arom.), 133.03 (C11-arom.), 128.52 (C4H-arom.), 126.09
	(C15H-arom.), 124.32 (C2-arom.), 124.17 (C14H-arom.), 123.25 (C7H-arom.),
	121.71 (C13H-arom.), 121.63 (C6-arom.), 121.53 (C16H-arom.), 121.30 (C8H-
	arom.), 118.22 (C9H-arom.), 110.81 (C3-arom.), 16.74 (C10H3).

3-(3-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number    LabBook Code
13 760        CA 4-124 Precipitate (yield = 30%)
              tR (HPLC) = 2.71 min      MS (ESI+) m/z = 273.0006,               274.9986 [(M + H)+] HRMS (ESI+): calculated for C13H10BrN2, m/z = 273.0022, 275.0002;  found, 273.0023, 275.0003 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.69 (s, 1H), 8.65 (s, 1H), 8.49 (d, J = 3.5 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.85 (dd,  J = 8.2, 1.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.20 (dd, J = 8.1, 4.6 Hz, 1H).
(White Solid) 13C NMR = n.d.

4-bromo-2-(7-methyl-1H-indol-3-yl)thiazole (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = 0.045
13766	CA 4-125 F7-11 (yield = 43%)	IC50 (PSA) = 0.02
	tR (HPLC) = 4.00 min           MS (ESI+) m/z = 292.9743,                    294.9724 [(M + H)+] Mp = 127-130° C. HRMS (ESI+): calculated for C12H10BrN2S, m/z = 292.9743, 294.9722; found, 292.9743, 294.9723 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.86 (s, 1H, H5), 8.16 (s, 1H, H4), 7.93 (d, J = 7.7 Hz, 1H, H9), 7.62 (s, 1H, H14), 7.13 (t, J = 7.3 Hz, 1H, H8), 7.04 (d, J = 6.6 Hz, 1H, H7), 2.52 (s, 3H, H10). 13C NMR (151 MHz, DMSO-d6): δ (ppm) = 164.43 (C11-arom.), 136.06 (C1-
(Green Solid)	arom.), 126.82 (C4H-arom.), 123.71 (C13-arom.), 123.69 (C2-arom.), 123.09
	(C7H-arom.), 121.67 (C6H-arom.), 121.19 (C8H-arom.), 117.45 (C9H-arom.),
	113.69 (C14H-arom.), 110.13 (C3-arom.), 16.71 (C10H3).

tert-butyl 6-fluoro-3-iodo-1H-indole-1-carboxylate

Intermediate       LabBook Code
                   CA 4-126 F1-6 (yield = 95%)
                   tR (HPLC) = 4.80 min      MS (ESI+) m/z = n.d. 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 7.90 (s, 1H, H8), 7.82 (dd, J = 10.2, 2.0 Hz, 1H, H3), 7.40 (dd, J = 8.7, 5.3 Hz, 1H, H6), 7.24 (td, J = 9.1, 2.4 Hz, 1H, H1), 1.64 (s, 9H, H14,15,16). 13C NMR (151 MHz, DMSO-d6): δ (ppm) = 160.69 (d, J = 239.6 Hz, C2- arom.), 147.88 (C17O), 134.17 (d, J = 13.2 Hz, C4-arom.), 130.75 (d, J = 3.8 Hz, C8H-arom.), 128.47 (C5-arom.), 122.61 (d, J = 10.3 Hz, C6H-arom.), 111.66 (d, J = 24.4 Hz, C1H-arom.), 101.61 (d, J, = 28.9 Hz, C3H-arom.),
(Pale Brown Solid) 84.90 (C13), 66.05 (C9-arom.), 27.55 (s C14,15,16H3).

3-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) =
13	CA 4-127 Precipitate (yield = 89%)	IC50 (PSA) =
	tR (HPLC) = 2.54 min        MS (ESI+) m/z = 225.1037                  [(M + H)+] Mp = 202-206° C. HRMS (ESI+): calculated for C14H13N2O, m/z = 225.1022; found, 2251027 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.42 (s, 1H, H11), 8.43 (dd, J = 4.5, 1.5 Hz, 1H, H13), 8.22-8.18 (m, 2H, H2,6), 8.04 (d, J = 2.8 Hz, 1H, H7), 7.80 (dd, J = 8.2, 1.5 Hz, 1H, H15), 7.16 (dd, J = 8.1, 4.5 Hz, 1H, H14), 7.01-
(Pale Brown Solid)	6.96 (m, 2H, H3,5), 3.79 (s, 3H, H17).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 157.12 (C1-arom.), 143.36 (C9-
	arom.), 142.39 (C13H-arom.), 129.37 (C10-arom.), 127.28 (C4-arom.), 127.01
	(C2,6H-arom.), 125.43 (C7H-arom.), 118.69 (C15H-arom.), 116.38 (C14H-
	arom.), 114.10 (C8-arom.), 113.76 (C3,5H-arom.), 55.01 (C17H3).

6-(7-methyl-1H-indol-3-yl)isoquinoline (Procedure 10)

VPC Number	LabBook Code	IC50 (eGFP) = inactive
13765	CA 4-128 Precipitate (yield = 34%)	IC50 (PSA) = inactive
	tR (HPLC) = 3.01 min           MS (ESI+) m/z = 259.1230                    [(M + H)+] Mp = 222-225° C. HRMS (ESI+): calculated for C18H15N2, m/z = 259.1230; found, 259.1231 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.59 (s, 1H, H5), 9.25 (s, 1H, H16), 8.47 (d, J= 5.7 Hz, 1H, H12), 8.27 (s, 1H, H17), 8.15-8.09 (m, 2H, H19,20), 8.01 (d, J = 2.7 Hz, 1H, H4), 7.95 (d, J = 8.0 Hz, 1H, H9), 7.88 (d, J =
(Yellowish Solid)	5.8 Hz, 1H, H13), 7.11 (t, J = 7.5 Hz, 1H, H9), 7.03 (d, J = 7.0 Hz, 1H, H7),
	2.54 (s, 3H, H10).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 151.69 (C16H-arom.), 143.10
	(C12H-arom.), 138.20 (C18-arom.), 136.65 (C1-arom.), 136.13 (C14-arom.),
	127.81 (C20H-arom.), 127.20 (C19H-arom.), 126.42 (C15-arom.), 125.23
	(C4H-arom.), 124.55 (C2-arom.), 122.35 (C7H-arom.), 121.35 (C6-arom.),
	121.17 (C17H-arom.), 120.35 (C8H-arom.), 120.20 (C13H-arom.), 116.98
	(C9H-arom.), 115.17 (C3-arom.), 16.81 (C10H3).

2-(6-fluoro-1H-indol-3-yl)quinoline

VPC Number	LabBook Code	IC50 (eGFP) = 0.1
13764	CA 4-131 F25-28 Precipitate (yield = 5%)	IC50 (PSA) = 0.082
	tR (HPLC) = 3.07 min          MS (ESI+) m/z = 263.0968                   [(M + H)+] Mp = 195-198° C. HRMS (ESI+): calculated for C17H12FN2, m/z = 263.0979; found, 263.0981 1H NMR (600 MHz, DMSO-d6): δ (ppm) = 11.71 (s, 1H, H17), 8.90 (dd, J = 8.7, 5.9 Hz, 1H, H16), 8.36 (d, J = 2.6 Hz, 1H, H18), 8.27 (d, J = 8.7 Hz, 1H, H10), 8.06-8.02 (m, 2H, H3,9), 7.90 (d, J = 7.7 Hz, 1H, H6), 7.72 (ddd, J =
(Pale Yellow Solid)	8.3, 7.2, 1.3 Hz, 1H, H6), 7.49 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H1), 7.26 (dd, J =
	9.8, 2.4 Hz, 1H, H13), 7.07 (td, J = 9.6, 2.4 Hz, 1H, H11).
	13C NMR (151 MHz, DMSO-d6): δ (ppm) = 159.13 (d, J = 235.8 Hz, C12-
	arom.), 155.18 (C8-arom.), 147.68 (C4-arom.), 137.16 (d, J = 12.5 Hz, C14-
	arom.), 135.69 (C10H-arom.), 129.38 (C2H-arom.), 128.39 (C3H-arom.),
	128.32 (d, J = 2.8 Hz, C18H-arom.), 127.63 (C6H-arom.), 125.87 (C5-arom.),
	125.02 (C1H-arom.), 123.78 (d, J = 9.8 Hz, C16H-arom.), 122.40 (C15-arom.),
	119.08 (C9H-arom.), 115.58 (C19-arom.), 108.64 (d, J = 23.6 Hz, C11H-
	arom.), 97.73 (d, J = 25.4 Hz, C13H-arom.).

A person of skill in the art based on the general knowledge in the art and the information provided herein would be able to synthesize the compounds described herein or modify the compounds described herein.eGFP Cellular Transcription AssayAR transcriptional activity was assayed as previously described (Tavassoli, P. et al. Rapid, non-destructive, cell-based screening assays for agents that modulate growth, death, and androgen receptor activation in prostate cancer cells. Prostate 2007, 67, 416-426). Briefly, stably transfected eGFP-expressing LNCaP human prostate cancer cells (LN-ARR2PB-eGFP) containing an androgen responsive probasin-derived promoter (ARR2PB) were grown in phenol red free RPMI 1640 supplemented with 5% CSS. After 5 days, the cells were plated into a 96-well plate (35,000 cells/well) with 0.1 nM of the synthetic androgen R1881 and increasing concentrations (0-100 μM) of compound. The cells were incubated for three days and the fluorescence was then measured (excitation 485 nm, emission 535 nm). The viability of these cells was assayed by MTS cell proliferation assay (CellTiter 961™ Aqueous One Solution Reagent, Promega™)

Structure Solution and Refinement

The ternary complex structure was solved by molecular replacement using the Phaser program (McCoy, A. J. et al. Phaser crystallographic software. J Appl Crystallogr 2007, 40, 658-674) and the coordinate of an apo-protein structure of AR-testosterone complex (Protein Data Bank entry 2AM9) as the search model. The structures were refined with iterative cycles of manual density fitting with COOT and refinement with Refmac (Murshudov, G. N. et al. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997, 53, 240-255). The extra density of testosterone was clearly observed at the initial refinement step. A characteristic electron density of the compound was observed at the BF3 binding site.

Heterologous Expression of Androgen Receptor

The AR ligand binding domain was expressed and purified as previously described (Estebanez-Perpina, E. et al. Proc. Nat. Acad. Sci. USA (2007) 104:16074-16079).eGFP Cellular AR Transcription Assay:

AR transcriptional activity was assayed as previously described.²¹ Briefly, stably transfected eGFP-expressing LNCaP human prostate cancer cells (LN-ARR2PBeGFP) containing an androgen-responsive probasin-derived promoter (ARR2PB) were grown in phenol-red-free RPMI 1640 supplemented with 5% CSS. After 5 days, the cells were plated into a 96-well plate (35,000 cells/well) with 0.1 nM R1881 and increasing concentrations (0-100 M) of compound. The cells were incubated for 3 days, and the fluorescence was then measured (excitation, 485 nm; emission, 535 nm). The viability of these cells has been assayed by the MTS cell proliferation assay (CellTiter 961 Aqueous One Solution Reagent, Promega) according to the instructions of the manufacturer.

Prostate Surface Antigen Assay:

The evaluation of PSA excreted into the media was performed in parallel to the eGFP assay using the same plates (see above description). After the cells were incubated for 3 days 150 μl of the media was taken from each well, and added to 150p of PBS. PSA levels were then evaluated using Cobas e 411 analyzer instrument (Roche Diagnostics) according to the manufacturer's instructions.

EXAMPLES

Example 1—Virtual Screen for Potential BF3 Binders

Using a previously described (Axerio-Cilies, P. et al. Inhibitors of Androgen Receptor Activation Function-2 (AF2) Site Indentified Through Virtual Screening. J Med Chem 2011 54(18):6197-205), consensus-based in silico methodology we conducted a virtual screen of ˜10 million purchasable chemical substances from the ZINC database to identify BF3-specific binders (also one NCI compound). The screening method used a combination of large-scale docking, ligand-based QSAR modeling, pharmacophore search, molecular field analysis, molecular-mechanic and molecular dynamic simulations (Cherkasov, A. et al. Progressive docking: a hybrid QSAR/docking approach for accelerating in silico high throughput screening. J Med Chem. 2006, 49, 7466-7478; Cherkasov, A. et al. ‘Inductive’ charges on atoms in proteins: comparative docking with the extended steroid benchmark set and discovery of a novel SHBG ligand. J Chem Inf Model 2005, 45, 1842-1853; and Santos-Filho, O. A. and Cherkasov, A. Using molecular docking, 3D-QSAR, and cluster analysis for screening structurally diverse data sets of pharmacological interest. J Chem Inf Model 2008, 48, 2054-2065). The results from each stage of this multi-parametric approach were compiled and the compounds were ranked using a consensus scoring procedure. The highest ranked compounds were visualized and initial candidates, predicted to have a high potential for binding to the BF3 pocket, were selected for empirical testing.

Example 2—Cell-Based Testing

All compounds were screened for their ability to inhibit AR transcriptional activity using a non-destructive, cell-based eGFP screening assay (Tavassoli, P. et al. Rapid, non-destructive, cell-based screening assays for agents that modulate growth, death, and androgen receptor activation in prostate cancer cells. Prostate 2007, 67, 416-426). In this assay, the expression of eGFP is under the control of an androgen responsive probasin-derived promoter and can quantify AR transcriptional activity. From the compounds tested, 7 showed sub-μM IC50 values in the eGFP assay. Compounds that exhibited non-specific cellular toxicity were removed from further analysis. The most potent molecules had IC₅₀'s ranging in from 0.11 to 50 μM range (TABLE 3). Some compounds were also tested in the PSA assay (TABLE 3).

TABLE 3
Structural and experimental data for the AR BF3 interactors.
			eGFP
Internal	ZINC		IC50	PSA IC50
Number	Number	STRUCTURE	(μM)	(μM)
13555	Synthetic derivative		Inactive	Not tested
13557	Synthetic derivative		Inactive	Not tested
9039	Synthetic derivative		>200	Not tested
13312	ZINC00298052		200.0	Not tested
9040	Synthetic derivative		39.13	Not tested
13309	ZINC01234071		27.2	Not tested
9034	Synthetic derivative		20	Not tested
13551	Synthetic derivative		15.5	Not tested
13550	Synthetic derivative		11.75	Not tested
9026	Synthetic derivative		11.67	Not tested
13544	Synthetic derivative		11.4
13561	Synthetic derivative		10.7	Not tested
13310	ZINC00297221		10.3	Not tested
13232	ZINC02992016		10	Not tested
9028	Synthetic derivative		10	Not tested
13050	ZINC03365783		9.725	Not Determined
13300	ZINC00270867		9.3	6.76
13299	ZINC00499454		8.2	Not tested
9027	Synthetic derivative		7.721	Not tested
13538	Synthetic derivative		7.7
13304	ZINC00270887		7.3	4.54
13258	ZINC18191564		6.8	Not tested
13559	Synthetic derivative		6.6	Not tested
13512	Synthetic derivative		6.0
13542	Synthetic derivative		5.7
9125	ZINC30469682		5.2	2.4
13186	ZINC00513042		5	Not determined
13224	ZINC04106386		5	Not determined
13524	Synthetic derivative		4.9	6.65
13508	Synthetic derivative		4.8	2.7
13250	ZINC03149578		4.7	Not tested
13530	Synthetic derivative		4.7	1.60
13303	ZINC00270884		4.5	Not tested
13503	Synthetic derivative		4.5	Not tested
13257	ZINC12345945		4.2	Not tested
13502	Synthetic derivative		4.1	Not tested
9037	Synthetic derivative		4.093	Not tested
13243	ZINC00253227		3.9	Not tested
13543	Synthetic derivative		3.7	3.19
13424	ZINC12346351		3.7	3.58
13516	Synthetic derivative		3.6	Not tested
6054	ZINC08718421		3.4	Not Determined
13505	Synthetic derivative		3.4	Not tested
13522	Synthetic derivative		3.4	2.19
13029	ZINC00210926		3.221	Not Determined
13548	Synthetic derivative		3.21	4.24
9128	ZINC47424036		3.2	3.5
13525	Synthetic derivative		3.1	7.09
13511	Synthetic derivative		3.0	1.9
13216	ZINC06025409		2.8	Not Determined
13532	Synthetic derivative		2.8	3.10
13260	ZINC4941101		2.7	Not tested
13416	ZINC01869964		2.7	2.32
13509	Synthetic derivative		2.6	3.1
9043	Synthetic derivative		2.503	Not tested
13202	ZINC01768344		2.5	Not Determined
13510	Synthetic derivative		2.5	1.54
13540	Synthetic derivative		2.5	Not tested
13411	ZINC04106386		2.4	2.4
13560	Synthetic derivative		2.3	7.5
13214	ZINC26472877		2.2	Not Determined
13235	ZINC01037115		2.2	1.01
13536	Synthetic derivative		2.2	2.521
13556	Synthetic derivative		2.112	2.18
13127	ZINC00392643		2.1	0.11
13261	ZINC48546225		2.1	Not tested
13215	ZINC05504717		2	Not Determined
13504	Synthetic derivative		2.0	1.69
13167	NSC105329		1.9	1.25
13206	ZINC04962047		1.8	Not Determined
13145	ZINC34603778		1.7	2.46
13549	Synthetic derivative		1.7	2.57
13245	ZINC00555700		1.7	1.69
13036	ZINC14961821		1.602	Not Determined
13166	ZINC01723993		1.6	2.12
13558	Synthetic derivative		1.6	2.1
13535	Synthetic derivative		1.5	1.873
13164-B	ZINC02046058		1.3	1.59
13500	Synthetic derivative		1.23	0.41
13254	ZINC18191551		1.2	Not tested
13410	ZINC04106383		1.2	2.03
13552	Synthetic derivative		1.125	1.14
13423	ZINC18191568		1.1	1.2
13222	ZINC02718340		0.95	0.74
13247	ZINC48090221		0.9	0.43
13412	ZINC02718340		0.9	1.23
13534	Synthetic derivative		0.8	1.251
13434	ZINC00069102		0.8	0.73
13164-A	ZINC02046058		0.77	0.67
13220	ZINC48544111		0.7	Not Determined
13225	ZINC18191568		0.7	0.9
13537	Synthetic derivative		0.7	0.8057
13436	ZINC00068959		0.6	0.4
13554	Synthetic derivative		0.59	0.67
13541	Synthetic derivative		0.5	0.94
13255	ZINC18191553		0.5	0.46
13163-A	ZINC02043019		0.48	0.16
13163-B	ZINC02043019		0.48	0.24
13256	ZINC05848672		0.4	0.13
13521	Synthetic derivative		0.4	0.26
13427	ZINC00588219		0.4	0.31
13259	ZINC18191559		0.3	0.25
13506	Synthetic derivative		0.18	0.6
13226	ZINC18191571	23	0.11	0.076
13562	Known see U.S. Pat. No. 6,207,679		0.06	0.14
13566	Known see U.S. Pat. No. 6,207,679		0.004	0.011
13567	Synthetic derivative		0.200	0.230
13568	Synthetic derivative		1.300	1.560
13569	Synthetic derivative		1.600	Not tested
13570	Synthetic derivative		20.000	Not tested
13571	Synthetic derivative		1.100	Not tested
13573	Synthetic derivative		0.560	Not tested
13574	Synthetic derivative		2.570	Not tested
13576	Synthetic derivative		0.144	0.048
13577	Synthetic derivative		3.200	1.730
13579	Synthetic derivative		0.101	0.043
13580	Synthetic derivative		2.900	Not tested
13582	Synthetic derivative		0.052	0.041
13585	Synthetic derivative		0.110	0.039
13587	Synthetic derivative		0.760	0.530
13589	Synthetic derivative		5.300	Not tested
13591	Synthetic derivative		0.042	0.085
13592	Synthetic derivative		1.590	1.220
13593	Synthetic derivative		0.198	0.130
13594	Synthetic derivative		0.166	0.099
13595	Synthetic derivative		0.177	Not tested
13596	Synthetic derivative		Inactive	Inactive
13597	Synthetic derivative		0.236	0.132
13598	Synthetic derivative		Inactive	Inactive
13599	Synthetic derivative		Inactive	Inactive
13600	Synthetic derivative		1.249	0.929
13601	Synthetic derivative		0.233	0.165
13602	Synthetic derivative		0.240	0.182
13603	Synthetic derivative		0.633	0.339
13604	Synthetic derivative		Inactive	Inactive
13605	Synthetic derivative		Inactive	Inactive
13606	Synthetic derivative		1.649	1.427
13607	Synthetic derivative		0.168	0.087
13608	Synthetic derivative		Inactive	Inactive
13609	Synthetic derivative		Inactive	Inactive
13610	Synthetic derivative		0.032	0.013
13611	Synthetic derivative		0.297	0.121
13612	Synthetic derivative		1.44	0.813
13613	Synthetic derivative		11.540	1.738
13614	Synthetic derivative		1.117	0.597
13615	Synthetic derivative		Inactive	Inactive
13616	Synthetic derivative		Inactive	Inactive
13617	Synthetic derivative		Inactive	Inactive
13618	Synthetic derivative		0.194	0.13
13619	Synthetic derivative		2.170	Not tested
13620	Synthetic derivative		Inactive	Inactive
13621	Synthetic derivative		0.02	0.008
13622	Synthetic derivative		0.1	0.075
13623	Synthetic derivative		Inactive	Inactive
13624	Synthetic derivative		0.100	0.042
13625	Synthetic derivative		1.900	1.230
13626	Synthetic derivative		2.700	1.650
13627	Synthetic derivative		1.500	1.160
13628	Synthetic derivative		0.800	0.610
13629	Synthetic derivative		4.900	1.780
13630	Synthetic derivative		0.600	0.430
13631	Synthetic derivative		Inactive	Inactive
13632	Synthetic derivative		Inactive	Inactive
13633	Synthetic derivative		6.000	Not tested
13634	Synthetic derivative		5.000	Not tested
13635	Synthetic derivative		Inactive	Inactive
13636	Synthetic derivative		Inactive	Inactive
13637	Synthetic derivative		Inactive	Inactive
13638	Synthetic derivative		Inactive	Inactive
13639	Synthetic derivative		0.549	0.544
13640	Synthetic derivative		12.670	Not tested
13641	Synthetic derivative		0.132	0.403
13642	Synthetic derivative		0.033	0.025
13643	Synthetic derivative		0.1638	0.156
13644	Synthetic derivative		3.000	Not tested
13645	Synthetic derivative		0.261	0.247
13646	Synthetic derivative		0.179	0.224
13647	Synthetic derivative		Inactive	Inactive
13648	Synthetic derivative		Inactive	Inactive
13649	Synthetic derivative		Inactive	Inactive
13650	Synthetic derivative		1.631	Not tested
13651	Synthetic derivative		0.404	Not tested
13652	Synthetic derivative		3.54	1.76
13653	Synthetic derivative		1.13	0.29
13654	Synthetic derivative		0.92	0.16
13655	Synthetic derivative		1.66	0.61
13656	Synthetic derivative		0.99	0.46
13657	Synthetic derivative		Inactive	Inactive
13658	Synthetic derivative		2.85	2.21
13659	Synthetic derivative		Inactive	Inactive
13660	Synthetic derivative		2.5	1.89
13661	Synthetic derivative		Inactive	Inactive
13662	Synthetic derivative		Inactive	Inactive
13663	Synthetic derivative		Inactive	Inactive
13664	Synthetic derivative		Inactive	Inactive
13665	Synthetic derivative		0.27	0.21
13666	Synthetic derivative		Inactive	Inactive
13667	Synthetic derivative		Inactive	Inactive
13668	Synthetic derivative		Inactive	Inactive
13669	Synthetic derivative		Inactive	Inactive
13670	Synthetic derivative		Inactive	Inactive
13671	Synthetic derivative		Inactive	Inactive
13672	Synthetic derivative		Inactive	Inactive
13673	Synthetic derivative		Inactive	Inactive
13674	Synthetic derivative		0.075	0.051
13677	Synthetic derivative		0.156	0.11
13678	Synthetic derivative		Inactive	Inactive
13679	Synthetic derivative		Inactive	Inactive
13680	Synthetic derivative		0.8	Not tested
13681	Synthetic derivative		2.5	1.7
13682	Synthetic derivative		0.89	0.99
13683	Synthetic derivative		2.6	1.906
13684	Synthetic derivative		1.4	6.609
13685	Synthetic derivative		Inactive	Inactive
13686	Synthetic derivative		Inactive	Inactive
13687	Synthetic derivative		Inactive	Inactive
13688	Synthetic derivative		0.069	0.068
13689	Synthetic derivative		Inactive	Inactive
13690	Synthetic derivative		Inactive	Inactive
13691	Synthetic derivative		0.4	0.48
13692	Synthetic derivative		0.1	0.082
13693	Synthetic derivative		0.11	0.12
13694	Synthetic derivative		0.07	0.067
13695	Synthetic derivative		0.069	0.087
13696	Synthetic derivative		0.042	0.042
13697	Synthetic derivative		0.029	0.029
13698	Synthetic derivative		0.041	0.041
13699	Synthetic derivative		0.073	0.073
13700	Synthetic derivative		Inactive	Inactive
13701	Synthetic derivative		Inactive	Inactive
13702	Synthetic derivative		0.21	0.14
13704	Synthetic derivative		0.35	0.169
13705	Synthetic derivative		Inactive	Inactive
13706	Synthetic derivative		Inactive	Inactive
13707	Synthetic derivative		Inactive	Inactive
13708	Synthetic derivative		0.29	0.29
13709	Synthetic derivative		Inactive	Inactive
13710	Synthetic derivative		0.23	0.25
13711	Synthetic derivative		Inactive	Inactive
13712	Synthetic derivative		Inactive	Inactive
13713	Synthetic derivative		0.037
13714	Synthetic derivative		Inactive	Inactive
13717	Synthetic derivative		0.49	0.33
13718	Synthetic derivative		0.37	0.11
13719	Synthetic derivative		0.11	0.13
13720	Synthetic derivative		Inactive	Inactive
13721	Synthetic derivative		Inactive	Inactive
13722	Synthetic derivative		Inactive	Inactive
13723	Synthetic derivative		Inactive	Inactive
13724	Synthetic derivative		Inactive	Inactive
13725	Synthetic derivative		Inactive	Inactive
13726	Synthetic derivative		Inactive	Inactive
13727	Synthetic derivative		Inactive	Inactive
13728	Synthetic derivative		Inactive	Inactive
13729	Synthetic derivative		Inactive	Inactive
13730	Synthetic derivative		0.149	0.198
13731	Synthetic derivative		0.304	0.255
13732	Synthetic derivative		0.42	Not tested
13733	Synthetic derivative		3.815	0.9194
13736	Synthetic derivative		0.62	0.68
13738	Synthetic derivative		0.083	0.062
13741	Synthetic derivative		0.29	0.29
13742	Synthetic derivative		0.22	0.2
13743	Synthetic derivative		0.38	0.39
13744	Synthetic derivative		0.76	0.75
13745	Synthetic derivative		1.01	0.95
13746	Synthetic derivative		Inactive	Inactive
13747	Synthetic derivative		Inactive	Inactive
13748	Synthetic derivative		Inactive	Inactive
13749	Synthetic derivative		0.29	0.22
13750	Synthetic derivative		Inactive	Inactive
13751	Synthetic derivative		Inactive	Inactive
13752	Synthetic derivative		0.37	0.26
13753	Synthetic derivative		0.16	0.098
13754	Synthetic derivative		0.09	0.051
13755	Synthetic derivative		0.47	0.47
13757	Synthetic derivative		Inactive	Inactive
13758	Synthetic derivative		Inactive	Inactive
13759	Synthetic derivative		0.3	0.27
13760	Synthetic derivative		0.1	0.052
13761	Synthetic derivative		0.5481	0.3829
13762	Synthetic derivative		0.4792	0.429
13764	Synthetic derivative		0.1	0.082
13765	Synthetic derivative		Inactive	Inactive
13766	Synthetic derivative		0.045	0.020
13769	Synthetic derivative		Inactive	Inactive
13770	Synthetic derivative		0.1	0.017
13771	Synthetic derivative		0.2	0.090
13772	Synthetic derivative		0.2	0.172
13773	Synthetic derivative		0.3	0.303
13774	Synthetic derivative		0.7	0.773
13775	Synthetic derivative		3.7	Not tested
13776	Synthetic derivative		0.21	0.19
13777	Synthetic derivative		Not tested	Not tested
13778	Synthetic derivative		Not tested	Not tested
13779	Synthetic derivative		Not tested	Not tested
13780	Synthetic derivative		Not tested	Not tested
13781	Synthetic derivative		Not tested	Not tested
13782	Synthetic derivative		0.11	Not tested
13783	Synthetic derivative		Not tested	Not tested
13784	Synthetic derivative		Not tested	Not tested
13785	Synthetic derivative		0.036	Not tested
13786	Synthetic derivative		0.013	Not tested
13787	Synthetic derivative		0.19	Not tested
13788	Synthetic derivative		Not tested	Not tested
13507	Synthetic derivative		Not tested	Not tested
13513	Synthetic derivative		Not tested	Not tested
13514	Synthetic derivative		Not tested	Not tested
13515	Synthetic derivative		Not tested	Not tested
13517	Synthetic derivative		Not tested	Not tested
13518	Synthetic derivative		Not tested	Not tested
13519	Synthetic derivative		Not tested	Not tested
13520	Synthetic derivative		Not tested	Not tested
13523	Synthetic derivative		Not tested	Not tested
13526	Synthetic derivative		Not tested	Not tested
13527	Synthetic derivative		Not tested	Not tested
13531	Synthetic derivative		Not tested	Not tested
13539	Synthetic derivative		Not tested	Not tested
13545	Synthetic derivative		Not tested	Not tested
13546	Synthetic derivative		Not tested	Not tested
13547	Synthetic derivative		Not tested	Not tested

Where a compound is described as “inactive”, no activity was detected for the compound in the assays on which it was tested.Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word “comprising” is used herein as an open-ended term, substantially equivalent to the phrase “including, but not limited to”, and the word “comprises” has a corresponding meaning. As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a thing” includes more than one such thing. Citation of references herein is not an admission that such references are prior art to an embodiment of the present invention. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

1-20. (canceled)

21. A compound having the structure of Formula I:

22. The compound of claim 21, wherein D is

23. The compound of claim 22, wherein D3 is

24. The compound of claim 22, wherein D3 is

25. The compound of claim 22, wherein D3 is

26. The compound of claim 22, wherein D3 is

27. A compound selected from the group consisting of

28. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

29. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 27 and a pharmaceutically acceptable excipient.

30. A method of modulating AR activity, the method comprising (a) administering a compound of claim 1 to a subject in need thereof.

31. The method of claim 30, wherein the modulating AR activity is for the treatment of at least one indication selected from the group consisting of: AR-mediated cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, Taxene resistant triple negative breast cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.

32. The method of claim 31, wherein the modulating AR activity is for the treatment of prostate cancer.

33. The method of claim 31, wherein the modulating AR activity is for the treatment of Taxene resistant triple negative breast cancer.

34. The method of claim 31, wherein the modulating AR activity is for the treatment of ovarian cancer.

35. The method of claim 31, wherein the modulating AR activity is for the treatment of endometrial cancer.