NZ613504B2 - Bcl-2/bcl-xl inhibitors and therapeutic methods using the same - Google Patents

Bcl-2/bcl-xl inhibitors and therapeutic methods using the same Download PDF

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NZ613504B2
NZ613504B2 NZ613504A NZ61350412A NZ613504B2 NZ 613504 B2 NZ613504 B2 NZ 613504B2 NZ 613504 A NZ613504 A NZ 613504A NZ 61350412 A NZ61350412 A NZ 61350412A NZ 613504 B2 NZ613504 B2 NZ 613504B2
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New Zealand
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compound
bcl
nmr
pct
conr
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NZ613504A
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NZ613504A (en
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Angelo Aguilar
Longchuan Bai
Jianfang Chen
Xiaoqin Li
Liu Liu
Donna Mceacherm
Jennifer Lynn Meagher
Jeanne Stuckey
Duxin Sun
Shaomeng Wang
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The Regents Of The University Of Michigan
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Priority claimed from PCT/US2012/022315 external-priority patent/WO2012103059A2/en
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Publication of NZ613504B2 publication Critical patent/NZ613504B2/en

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Abstract

Disclosed are inhibitors of Bcl-2/Bcl-xL represented by the structural formula (I) shown herein, and compositions containing the same, wherein A is pyrrolyl, B, C, D, and E individually are substituted or unsubstituted phenyl, and X and Y taken together is as defined in the specification. These Bcl-2/Bcl-xL inhibitors are suitable in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers. 2/Bcl-xL inhibitors are suitable in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers.

Description

BCL-2/BCL-XL INHIBITORS AND THERAPEUTIC METHODS USING THE SAME Field of the Invention The present invention relates to Bcl-2/Bcl-xL inhibitors and to therapeutic methods of treating conditions and diseases wherein inhibition of Bcl-2/Bcl-xL provides a benefit.
Background of the Invention Any discussion of the prior art throughout the specification should in no way be ered as an admission that such prior art is widely known or forms part of common general dge in the field.
Apoptosis resistance is a hallmark of human cancer (1-3). Cancer cells must overcome a continual bombardment by cellular stresses, such as DNA damage, ne activation, aberrant cell cycle progression, and harsh microenvironments, that would cause normal cells to undergo apoptosis. One of the primary means by which cancer cells evade apoptosis is by up-regulation of anti-apoptotic proteins of the Bcl-2 family. Targeting key apoptosis regulators to overcome apoptosisresistance and promote apoptosis of tumor cells is a new cancer therapeutic strategy (4,5).
Bcl-2 ns on as critical regulators of sis in both cancer and normal cells (6-10). Bcl-2 ns serve as a check on apoptosis allowing healthy and useful cells to survive. This protein family includes poptotic proteins, such as Bcl-2, Bcl-xL, and Mcl-1, and pro-apoptotic molecules, including Bid, Bim, Bad, Bak and Bax (6-10). While normal cells have low expression levels of the anti- apoptotic Bcl-2 and Bcl-xL proteins, these proteins are found to be highly overexpressed in many different types of human tumors.6-10 This overexpression has been linked to poor prognosis in several types of cancer, and to clinical resistance to chemotherapeutic agents and radiation (6-10). Consistent with clinical observations, laboratory studies have established that overexpression of Bcl-2 or Bcl-xL causes cancer cells to become more resistant to herapeutic agents in vitro and in vivo (6-10). Inhibition of sis by Bcl-2 butes to cancer by inhibiting cell death.
Therefore, targeting Bcl-2 and/or Bcl-xL has been pursued as a cancer therapeutic strategy (11-34). Inhibiting Bcl-2 activity in cancer cells can reduce chemotherapeutic resistance and increase the killing of cancer cells.
Bcl-2 and Bcl-xL proteins inhibit apoptosis by heterodimerization with proapoptotic Bcl-2 family proteins, such as Bak, Bax, Bim, Bid, Puma, and Bad (6-10).
Experimentally determined dimensional structures of Bcl-xL and Bcl-2 have shown that these proteins possess a efined groove, which interacts with the BH3 (Bcl-2 Homology 3) domain of the pro-apoptotic Bcl-2 proteins ). It has been proposed that non-peptide small les designed to block the heterodimerization of Bcl-2/Bcl-xL proteins with their pro-death binding rs may be ive as antagonists of Bcl-2/Bcl-xL, and that such small molecule inhibitors may have a great therapeutic potential for the ent of human cancers in which Bcl-2 and/or Bcl-xL are highly expressed (18-37).
Although non-peptide, small molecule inhibitors of Bcl-2/Bcl-xL have been reported, most of the inhibitors have weak to modest affinities for these proteins and lack a well-defined mode of action for their cellular activity (18-37). The exceptions are ABT-737, ABT-263, and their ues (26-34). ABT-737 and ABT-263 bind to Bcl-2, Bcl-xL, and Bcl-w with very high affinities (Ki<1 nM) and have high specificity over Mcl-1 and A1, two other anti-apoptotic Bcl-2 proteins (26, 32, 34).
ABT-263 has advanced into Phase I/II clinical trials and shows promising antitumor activity in the clinic (45). e the discovery of ABT-737 and ABT-263, the design of potent, nonpeptide inhibitors of Bcl-2/Bcl-xL remains a significant challenge in modern drug discovery.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful ative.
It is an object of an especially red form of the present invention to provide for for Bcl-2/Bcl-xL inhibitors having physical and pharmacological properties that may permit use of the inhibitors in therapeutic applications. The present invention provides compounds designed to bind to Bcl-2/Bcl-xL and inhibit Bcl-2/Bcl-xL activity.
Although the present invention will be bed hereinafter with reference to its preferred embodiment, it will be appreciated by those of skill in the art that the spirit and scope of the invention may be embodied in many other forms.
Unless the context y requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as d to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.
Summary of the Invention According to a first aspect of the present invention there is provided a compound having a structural formula: , wherein A is pyrrolyl; B is ed from the group consisting of , , , , , , and - 2a - Cl ; C and D dually are phenyl, substituted with zero to four substituents independently selected from the group consisting of CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR’, SR’, NR’R’’, CO2R’, COR’, OCOR’’, CONR’R’’, O2R’’, NR’COR’’, NR’SO2Rn, C1-3alkyleneCH(OH)CH2OH, SO2R’, and SO2NR’R’’, wherein each R’ and R’’, independently, is H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, CF3, aryl, heteroaryl, C1- eneheterocycloalkyl, or heterocycloalkyl; or wherein two substituents on the same C and/or D ring can be taken together to form a ring; or wherein R’ and R’’, taken together with the atoms to which they are bound, form a 3 to 7 membered ring; E is substituted at a meta position to the –SO2NH- group with NO2 or SO2CF3; or wherein E is substituted at a para position to the –SO2NH- group with wherein Ra and Rb, individually, are H, methyl, and , or Ra and Rb are taken together to form , , , , , , , or ; - 2b - X and Y taken together form or a pharmaceutically acceptable salt thereof.
According to a second aspect of the present ion there is provided a compound having a structure - 2c - - 2d --2d_ - 2e --2C- - 2f --2f_ F HO S F HO N HN S NH F3CO2S - 2g - - 2h --2h_ - 2i - Cl HO S Cl HO N HN S NH F3CO2S - 2j - - 2k --2k_ - 2l --2]- - 2m -—2m— - 2n - - 2o - - 2p - - 2q - - 2r -_ N HN S NH F3CO2S - 2s - - 2t - - 2u - HN O S N N HN O O2N O H - 2v - HO N Cl N N O2N HN - 2w - - 2x --2X- - 2y - - 2z - - 2aa -—2aa— - 2bb -—2bb— - 2cc -—2cc— - 2dd -—2dd— - 2ee -—2ee— - 2ff -—2ff— - 2gg -_2gg_ - 2hh -—2hh— N HN S NH - 2ii - - 2jj - - 2kk -—2kk— N HCl O N HN S NH HCl O F3CO2S N HCl O N HN S NH N HN S NH HCl O - 2ll - O N HN S NH HCl O HO N HN S NH HCl O H O N HN S NH HCl O F3CO2S H O O N HN S NH HCl O F3CO2S - 2mm - H O HO N HN S NH HCl O F3CO2S - 2nn - - 2oo -—200— - 2pp - - 2qq - O N HN S NH HCl O - 2rr - N HN S NH HCl O - 2ss - - 2tt -—2tt— N HN S NH HCl O - 2uu - - 2vv --2VV— - 2ww --2WW— - 2xx -—2XX— - 2yy -_2yy_ - 2zz -—2zz— - 2aaa - - 2bbb - - 2ccc - - 2ddd - - 2eee - - 2fff - - 2ggg - - 2hhh - - 2iii - - 2jjj - - 2kkk - - 2lll - N HN S NH or . - 2mmm - According to a third aspect of the present invention there is provided a composition comprising (a) compound as defined according to the first aspect of the present invention, (b) a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Bcl-2 or Bcl-xL provides a t, and (c) an optional ent and/or pharmaceutically acceptable carrier.
According to a fourth aspect of the present invention there is provided a pharmaceutical composition comprising a compound as defined according to the first aspect of the present invention and a pharmaceutically acceptable r or vehicle.
According to a fifth aspect of the t invention there is provided a compound having a structure The present ion is directed to inhibitors of Bcl-2/Bcl-xL, to compositions comprising the inhibitors, and to methods of using the inhibitors in a therapeutic treatment of conditions and diseases wherein inhibition of Bcl-2/Bcl-xL activity provides a t. The present compounds are potent inhibitors of Bcl- 2/Bcl-xL activation, and induce sis of cancer cells that express Bcl-2 and/or Bcl-xL.
More particularly, the present ion is directed to compounds having a structural formula (I): - 2nnn - W0 20] 2/103059 PCT/U820 l 2/022315 0=S=O [001 1] wherein A is null, optionally substituted phenyl, or an optionally substituted five or six-membered aromatic ring in which 1 to 4 carbon atoms individually are replaced by nitrogen, oxygen, or sulfur, B,C, D, and E individually are optionally substituted phenyl or an optionally substituted five or six~mernbered aromatic ring in which 1 to 4 carbon atoms individually are replaced by nitrogen, , or sulfur, X and Y, independently, are null, 0, S, C0, 80;, SO, P03H, NR‘, BR', PR‘, POR', alkylene, cycloalkylene, lene, cycloalkenylene, alkynylene, or arylene; or X and Y can be taken together to form a 5-7 membered ring, or X and Y can be Z-(CH2)I.3-Z', wherein Z and 2', independently, are 0, S, NR',CO, SC, 802, P03H, PR', or POR'; and R' is H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, or heterocycloalkyl, or a phannaceutically acceptable salt, hydrate, or e thereof.
In various embodiments, rings A, B, C, D, and E n one to four substitucnts independently selected from the group consisting of CN, N02, halo, alkyl, lkyl, alkenyl, lkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR‘, SR', NR'R", COzR', PCT/USZOIZ/HZZSIS COR', OCOR’, CONR'R", CONR'SOzk", NR'COR", NR'SOzR", Cl-3alkyleneCH(OI-I)CH20H, SOzR', and SOzNR'R", wherein each R' and R", ndently, is H, alkyl, lkyl, alkenyl, cycloalkenyl, alkynyl, CF}, aryl, heteroaryl, Cl. galkyleneheterocycloalkyl, or heterocycloalkyl; In some embodiments, two substituents on the same A, B, C, D, or E ring can be taken together to form a ring. In other embodiments, R' and R" can be taken together with the atoms to which they are bound to form a 3 to 7 membered ring.
In one embodiment, the present invention provides a method of treating a condition or disease by administering a therapeutically effective amount of a compound of structural formula (I) to an individual in need thereof. The e or condition of interest is treatable by inhibition of Bel-2 and/or , for example, a cancer.
Another embodiment ofthe present invention is to provide a composition comprising (a) a Bcl-2/Bcl-xL inhibitor of structural formula (I) and (b) an excipient and/or pharmaceutically acceptable carrier useful in treating diseases or conditions wherein inhibition of Bcl-Z/Bcl-xL provides a .
Another embodiment ofthe present invention is to utilize a composition comprising a compound of structural formula (I) and a second therapeutically active agent in a method of treating an dual for a disease or ion n inhibition of Bel-2/Bcl—xL provides a benefit.
In a further embodiment, the ion provides for use of a composition comprising a Bcl-Z/Bcl-XL inhibitor of structural formula (I) and an optional second therapeutic agent for the manufacture of a medicament for treating a disease or condition of interest, e.g., a cancer.
Still another embodiment of the present invention is to provide a kit for human pharmaceutical use comprising (a) a container, (bl) a ed composition comprising a Bcl-Z/Bcl-xL inhibitor of structural formula (I), and, optionally, (b2) a packaged composition sing a second therapeutic agent useful in the treatment of a disease or condition of interest, and (c) a package insert containing directions for use of the ition or compositions, administered simultaneously or tially, in the treatment of the disease or condition.
The Bel-Z/Bcl-xL inhibitor of structural formula (I) and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, n the Bcl—Z/Bcl-xL inhibitor of structural formula (I) is administered before the second - 4 .
PCT/U320 l 2/022315 therapeutic agent or vice versa. It is envisioned that one or more dose of a Bcl—Z/Bcl-xL inhibitor of ural formula (I) and/or one or more dose of a second therapeutic agent can be administered.
In one embodiment, a Bcl-Z/Bcl-xL inhibitor of ural formula (I) and a second therapeutic agent are administered simultaneously. In related ments, a Bcl-Z/Bcl-xL inhibitor of structural formula (I) and second therapeutic agent are administered from a single composition or from separate compositions. In a fiirther embodiment, the Bcl-2/Bcl-xL tor of structural formula (I) and second therapeutic agent are administered sequentially.
A Bcl-Z/Bcl-XL inhibitor of ural formula (I), as used in the present invention, can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
These and other embodiments and es of the present invention will become apparent from the following detailed description of the preferred embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present ion is described in connection with preferred embodiments.
However, it should be appreciated that the invention is not limited to the disclosed embodiments. It is understood that, given the description of the embodiments of the invention herein, various modifications can be made by a person skilled in the art. Such modifications are encompassed by the claims below.
The term "Bcl-Z/Bcl-xL" as used herein means Bcl-2, Bcl-xL, or Bel-2 and Bel-XL, i.e., Bel-2 and/or Bel-XL.
The term "a disease or condition n inhibition of Bel-2 and/or Bcl-xL provides a benefit" pertains to a condition in which Bel-2 and/or Bel-XL, and/or an action of Bcl-2 and/or , is ant or necessary, e.g., for the onset, progress, expression ofthat disease or condition, or a disease or a condition which is known to be treated by a Bcl-2/Bcl- xL inhibitor (such as ART-737 or ABT-263). An example of such a condition es, but is not limited to, a cancer. One of ry skill in the art is readily able to determine whether a compound treats a disease or condition mediated by Bcl-xL for ular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds.
The term "second therapeutic agent" refers to a therapeutic agent different from a Bcl-2 and/or Bel-XL inhibitor of structural formula (I) and that is known to treat the disease or condition of interest. For example when a cancer is the disease or condition of interest, the W0 20] 2/103059 PCT/U320 l 2/022315 second therapeutic agent can be a known herapeutic drug, like taxol, or radiation, for example.
The term "disease" or “condition“ denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. As trated below, a compound of structural formula (I) is a potent inhibitor of Bcl-2/Bcl-xL and can be used in treating es and 'ons wherein inhibition of Bcl-xL provides a benefit.
As used herein, the terms "n'eat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely ated. As used herein, the terms " "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of loping a disease or condition, or of a recurrence of a previously-controlled disease or ion, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence ofthe disease or condition. The term "treat” and synonyms contemplate administering a therapeutically efi'ective amount of a nd of the invention to an individual in need of such treatment.
Within the meaning ofthe invention, "treatment" also includes relapse laxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
The term "therapeutically efiecfive amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method ofthe invention, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof. In the case of a cancer or other proliferation er, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number ofcancer cells; reduce the tumor size; t (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; reduce PCT/U32012/022315 Bcl-2/Bcl-xL signaling in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
The term "container" means any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a ceutical t.
The term "insert" means information accompanying a pharmaceutical product that provides a description ofhow to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.
"Concurrent administration," "administered in combination," taneous administration," and similar phrases mean that two or more agents are administered concrn-rently to the subject being treated. By "concurrently," it is meant that each agent is administered either simultaneously or sequentially in any order at difl‘erent points in time.
However, ifnot administered simultaneously, it is meant that they are administered to an individual in a sequence and sufliciently close in time so as to provide the desired therapeutic effect and can act in concert. For example, a Bcl-Z/Bcl-xL inhibitor of structural formula (I) can be stered at the same time or sequentially in any order at difl'erent points in time as a second therapeutic agent. A present Bcl-2/Bcl-xL inhibitor and the second therapeutic agent can be administered tely, in any appropriate form and by any suitable route.
When a present Bcl-2/Bcl-xL inhibitor and the second therapeutic agent are not administered rently, it is understood that they can be administered in any order to a subject in need f. For example, a present Bcl-2/Bcl-xL inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 s, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks. 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks afier) the administration of a second eutic agent treatment modality (e.g., radiotherapy), to an individual in need f. In various embodiments, a Bcl-2/Bcl-xL inhibitor of structural a (I) and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 PCT/U320 l 2/022315 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In one embodiment, the components of the combination therapies are administered at 1 minute to 24 hours apart.
The use of the terms "a", "an", "the", and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation ofranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.3., "such as") provided herein, is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the cation should be construed as indicating any non-claimed element as ial to the practice of the invention.
Over the past decade, ch into apoptosis has ished that targeting Bel-2 and/or Bel-XL using small le inhibitors is a viable cancer therapeutic strategy ).
The discovery of ABT-737 and ART-263, and the early clinical data on 3, have demonstrated that non-peptide, small molecule inhibitors of Bel-2 and/or Bcl-xL have great therapeutic potential for the treatment of many types ofhuman cancer in which Bcl-Z and/or Bcl-xL are overexpressed and for which t anticancer agents are largely ineffective (26- 36).
Despite the discovery of ABT-737 and ART-263, few new classes of highly , small molecule inhibitors of Bcl-Z/Bcl-xL with affinities to Bcl-2/Bcl-xL and cellular potencies ching that ed by ABT-737/ABT-263 have been reported. This is because the design of small molecule tors of Bcl-Z/Bcl-xL involves targeting and blocking the interactions of the Bcl-2/Bcl-XL proteins with their pro-apoptotic binding partners, a task which has been proven to be very challenging for at least three main reasons.
First, compared to typical binding sites in enzymes and receptors, the interfaces between Bcl- 2 or Bel-XL and their binding partners are very large (38-42). The interaction of Bcl-Z/Bcl- xL with its binding rs, such as BAD and Bim proteins, is mediated by a 20-25 residue BH3 domain in BAD and Bim and a large binding goove in Bcl-2/Bcl-xL. Second, the binding grooves in Bcl-xL are very hydrophobic in nature, making it difficult to design druglike small molecules (26, 38-42). Third, Bel-2 and Bcl-xL are extremely conformational]y flexible and can adopt quite distinct conformations in the ligand-free PCT/U320 I 2/022315 structure and when bound to different ligands (26, 38-42). Some of the binding pockets observed for Bel-XL in the l structures of its complexes with BAD (41), Him (43), and ABT-737(44) are induced by ligand binding and are not presented in a ligand-free crystal structure (3 8). These three factors make the design ofpotent and druglike small molecule inhibitors of Bcl-Z/Bcl-XL a paramount nge in modern drug ery.
The present invention is directed to new class of potent and specific inhibitors of Bcl-2/Bcl-xL. The present compounds can bind to Bel-2 and/or Bcl-xL with K.- values <1 nM and function as potent antagonists of Bcl-2 and Bcl-xL in 'ee functional assays. The compounds potently induce apoptosis in cancer cells and have a mechanism of action that is highly consistent with targeting Bel-2 and Bcl-xL. A tested nd trates robust apoptosis induction in viva in tumor tissues and shows strong antitumor activity against the H146 xenograft tumors. [0042) The Bcl-2/Bcl-xL inhibitors of the t ion therefore are useful in the treatment ofunwanted proliferating cells, including cancers and precanccrs, in subjects in need of such treatment. Also provided are methods oftreating a subject having unwanted proliferating cells comprising administering a therapeutically effective amount of a present compound to a subject in need ofsuch treatment. Also provided are methods of preventing the eration of unwanted proliferating cells, such as cancers and precancers. in a subject comprising the step of administering a therapeutically effective amount of a compound of structural formula (I) to a subject at risk ofdeveloping a condition terized by unwanted proliferating cells. In some embodiments, the compounds of structural formula (I) reduced the proliferation ofunwanted cells by inducing apotosis in those cells.
The present invention is directed to Bcl-2/Bcl-xL tors having a structural formula (I): PCT/U320 l 15 “'T' O=S=0 wherein A is null, optionally substituted phenyl, or an optionally substituted five or six-membered aromatic ring in which 1 to 4 carbon atoms individually are replaced by nitrogen, , or sulfur; B,C, D, and E individually are optionally substituted phenyl or an optionally substituted five or six—m-bered aromatic ring in which I to 4 carbon atoms individually are replaced by nitrogen, oxygen. or sulfur; X and Y, independently, are null, O, S, CO, 302, SO, P03H, NR', BR', PR’, POR', alkylene, cycloalkylene, alkenylene, cycloalkenylene, alkynylene, or arylene; or X and Y can be taken together to form a 5-7 membered ring, or X and Y can be Z-(CH2)1.3-Z', n Z and 2’, independently, are 0, S, , SO, 80;, P03H, PR', or POR'; and R' is H, alkyl, cycloalkyl, l, cycloalkenyl, alkynyl, aryl, heteroaryl, or heterocycloalkyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
Examples ofrings A, B, C, D, and E include, but are not limited to.
W0 20] 2/103059 PCT/U320 l 2/022315 N N @9179£2S H H Ear—U phenyl furanyl thienyl yl oxazolyl thiazolyl imidazolyl. pyrazolyl’ O S O H S t ‘N t ‘N r ‘N _( 7N _(_ 7 11/ —LJ/ it Li H isoxazolyl isothiazolyl 1,2, 3,-oxadiazolyl l,2,3,-triazolyl 1,3,4-thiadiazolyl O O O O _( ‘IN _NI _-/ ] _'/ is I—I'‘IN ‘1'.“ .u_~ xi—N l, 2, 4—oxadiazolyl l, 2, 5-oxadiazolyl l, 3, 4-oxadiazolyl l, 2, 3, 4-oxatriazolyl , , N N N N r rm f _r/ Li \J \J' \N] NJ 1, 2, 3, 5-oxatriazolyl pyridinyl nyl l, 3, S—triazinyl. ’ , pyridazinyl, ' and The compounds of structural formula (I) inhibit Bcl-2/Bcl-XL and are useful in the treatment of a variety of es and conditions. In particular, the nds of structural formula (I) are used in s of treating a disease or condition wherein inhibition of Bel- 2/Bcl-xL provides a benefit, for example, cancers. The method comprises administering a therapeutically effective amount of a compound of structural formula (I) to an individual in need thereof. The present methods also encompass stering a second therapeutic agent to the individual in addition to the compound of structural formula (I). The second therapeutic agent is selected fi'om drugs known as useful in treating the disease or condition afflicting the individual in need thereof; e.g., a herapeutic agent and/or ion known as useful in treating a particular cancer.
As used herein, the term "alkyl" refers to straight chained and branched saturated C1-10 hydrocarbon , nonlimiting examples ofwhich include methyl, ethyl, and straight chain and branched propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. The term Cu means the alkyl group has "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. An alkyl, e.g., methyl, or alkylene, e.g., —CH2——, group can be substituted with halo, trifluoromethyl, trifluoromethoxy, hydroxy, , nitro, cyano, alkylamino, or amino groups, for example.
The term "alkenyl" is defined cally as ," except for containing a carbon- carbon double bond, c.g., ethenyl, propenyl, and butenyl. The term "alkenylene" is defined -11.
PCT/U820 l 15 identically to "alkylene" except for containing a carbon-carbon double bond. The term "alkynyl" and "alkynylene" are defined identically as "alkyl" and ene" except the group contains a carbon-carbon triple bond.
As used herein, the term "halo" is defined as fluoro, chloro, bromo, and iodo.
The term "hydroxy" is defined as —OH.
The term y" is defined as —0R, wherein R is alkyl.
The term "amino" is defined as —NH2, and the term "alkylarnino" is defined as —NR2, wherein at least one R is alkyl and the second R is alkyl or hydrogen.
The term "nitro" is defined as —N02.
The term "cyano" is defined as —CN.
The term "trifluoromethyl" is defined as —CF3.
The term "trifluoromethoxy" is defined as —OCF3.
As used herein, groups such asQ is an abbreviation for CH3.
As used herein, the term "aryl" refers to a monocyclic or clic ic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four, groups independently selected from, for example, halo, alkyl, alkenyl, —0CF3, ——N02, —CN, -—NC, —0H, alkoxy, amino, alkylamino, —COZH, —C02alkyl, aryl, and aryl.
As used herein, the term oaryl" refers to a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents selected from, for example, halo, alkyl, alkenyl, —OCF3, —N02, —CN, —NC, —OH, alkoxy, amino, alkylamino, —C02H, —C02alky1, aryl, and heteroaryl.
As used herein, the term "cycloalkyl" means a clic aliphatic ring containing three to eight carbon atoms.
As used herein, the term "heterocycloalkyl" means a monocyclic or a bicyclic aliphatic ring containing 5 to 10 total atoms, ofwhich one to five of the atoms are PCT/U320 l 2/022315 independently selected from en, oxygen. and sulfur and the remaining atoms are carbon.
In accordance with the present invention, ring B is phenyl or a five- or six- membered aromatic ring in which one to four of the carbon atoms, independently, are replaced by nitrogen, oxygen, or sulfur. In one preferred embodiment, ring B is phenyl. In other preferred embodiments, ring B is phenyl substituted with one or more halo group.
Specific non-limiting es of ring B include: ©©¥§©atét©a£2s Ring A of the compound of structural formula (I) also is phenyl or a five- or six- membered aromatic ring in which one to four, and preferably one to three, ofthe carbon atoms, independently, are replaced by nitrogen, oxygen, or sulfur. In some red R1 / N’Ra ments, ring A is selected form the group consisting of fififiavi N\// R2 R1\‘/Rl:/N{Rik Ra RRRNN’Ra W0 20] 59 PCT/U320 l 2/022315 mfiT/tgqHR: RS‘N \RzRifiRaR1 WfiflRa 9:“3:“: 35:21:“:23;R3 wherein R. and R2, independently, are selected from the group consisting of H, CN, N02, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR', SR', NR'R", COR', COzR', OCOR', ", CONR‘SOZR", NR'COR", NR'CONR'R’", NR'C=SNR"R"', NR'SOzR", SO;R', and SOzNR'R"; R3 is selected from a group consisting ofH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, l, aryl, heteroaryl, heterocycloalkyl, OR', NR’R", COzR', COR', CONR'R", CONR'SOzR", Cl.3alkyleneCH(OH)CH20H. SOzR', and SOzNR'R"; R', R", and R'", independently, are H, alkyl, cycloalk‘yl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, C].3alkylenehetemcycloalkyl, or heterocycloalkyl; R' and R", or R" and R"', can be taken together with the atom to which they are bound to form a 3 to 7 membered ring.
N N C/jN [/ \N NAN (/ \O In some preferred embodiments, theAring is ‘ ‘ E] " , . , . or G In other preferred embodiments, a non-aromatic nitrogen atom of the A ring is substituted with CMalkyl, e.g., methyl, ethyl, yl, isopropyl, or n-butyl; cycloalkyl, e.g., cyclopropyl; x-3N(CH3)2, or —(CH2)1-3 CH(OH)CH20H. In another preferred embodiment, a non-aromatic nitrogen atom of the A ring and an nt carbon of the A ring are taken together to form a five or six membered ring, e.g., .
In still other preferred embodiments, one to three carbon atoms, and preferably one or two carbon atoms, of the A ring are substituted, independently, with CH3, C2H5, C3H7, PCT/U820 l 2/022315 CF}; NHZ, C19 CN, C02”) C(=O)CH39 C(=O)C2H5, C(=O)CF3, SOZCH}, SOZCZHS, 801C3H7’ SOZCF” SONCHW’ C(=0)NH302CH3, C(=0)NH2, C(=O)NHCH3, C(=0)NH(CH2)L 3N(CH3)2. C(=0)NH802CH3, NH—<, C(=O)—NH—O< C(=O)—N<>< ’ C(=0)—NH—CN—, C(=0)—NO, -\_/N’ ‘ ’ _ N- C(-0)N,_ ‘N cx-owmcwz)13—Nf ,N“(CH2MOH C(=0)N: XOH C(=O)- <:>—0H C(=0)NH(CH2)2-N/—\N—so,cn3 C(=0)NH~O-H—0H \_/ C(=O)NH-N > C(=O)—N/_\N-8020H3 I 3 C(—O)NH(CH— 21-3—) N N— H(CH— 2 2‘—) N: > i or - In some preferred embodiments, the C ring is phenyl, optionally substituted with one or two substituents selected from halo and C..3alkyl. Specific embodiments include a phenyl ring substituted with one or two fluoro, bromo, , or methyl.
In other preferred embodiments, the moiety -X-Y- is selected from the group -—N N— consisting of —CEC-, -CH2CH2-, -NHCH2CH1NH-, -OCH2CH2-O—, \—-/ , and —-N N— In yet r preferred embodiment, the D ring is phenyl, either unsubstituted or substituted. For example, an inhibitor of structural formula (I) n the D ring is phenyl has a structure W0 20] 2/103059 PCT/U820 I 2/022315 Fg\h R53) R4 O=S=O wherein R4 and R5, independently, are selected from a group consisting ofH, CN, N02, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl, cycloalkyl, OR', SR‘, NR‘R", COZR', OCOR', CONR'R", CONR'SOzk", NR‘COR", NR'CONR'R'", NR'C=SNR"R'", NR'SOZR", SOZR', and R". All other rings and R groups are defined as above.
One preferred R4 or R5 group is halo, 6.8., fluoro.
In still another preferred embodiment, the E ring is phenyl, preferably containing one to five, and more preferably one or two, substituents. For example, an inhibitor of structural formula (I), wherein D and E are both phenyl, has a structure: W0 20] 2/103059 PCT/U820 I 2/022315 O=S=O R10 R6 R9 R7 wherein R6, R7, R3, R9 and Rm, independently, are selected from the group consisn’ng ofH. CN, N02, halo, alkyl, cycloalkyl, l, cycloalkenyl, l, aryl, heteroaryl, heterocycloalkyl, OR', 811', NR'R", COzR', OCOR', CONR‘R", CONR'SozR", NR'COR", NR'CONR"R'", NR'C=SNR"R'", NR'SOzR", SOzR', and R". All other rings and R groups are defined as above.
In some preferred embodiments, a substituent on a phenyl ring E at a position meta to the SO; group ofcompound (I) is N02 or SOzCF]. In other preferred embodiments, a substituent on a phenyl ring E at a position para to the SO; group ofcompound (I) is [CHz‘S-CQH5 —NH—CH a ‘ IR (CH2)2‘N\ wherein R" and Rh, individually, are H, methyl, and 0H , or R‘I and R” are taken together to form —~o —~<X a — C>—°~, 0H, , , —N: X —N o‘ —N —N N—(CH)"'3 OH OH, \_/ \_/ a .01' _ .17.
W0 20] 2/103059 20 l 2/022315 A preferred inhibitor of the present invention has a structural (H): R _ .— 5 V R4 O=S= R10 Re R9 R7 T—R12 R2 ’33 R2 R R2 A 1 / R1 R1 \ R N N N’R3 1 \ / \ I _ N}, R1 R2 ’73 / R2 521%}. R1 , \N’Ra R1 \N\N R1 / ~ / W0 20] 2/103059 PCT/U820 l 2/022315 R2 Rt :R2 R2 R2 R2 R1 / N/ \N R3\N \ R1 R1 / R3 R1 \ R3 _ «2:34 __ / \ N N ‘14 >" R2 F33 N N N R1 ’N T‘KR2 / 1 R, R, N)S’ R1 N R3\NI \ 0/ \ \2LN \ / _. .. y ‘4 and ; rings B and C are optionally substituted phenyl; X, Y. R1, R2, R3, R4, R5, R4,. R7, R3, R9, R10, R', R", R'" are defined as above; and RH and R12, independently. are selected from the group consisting of H, CN, N02, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, l, aryl, heteroaryl, heterocycloalkyl, OR', SR', NR'R", COZR', OCOR', CONR'R", CONR'SOZR", NR'COR", NR‘CONR"R"‘, NR'C=SNR"R'", NR'SOzR", SOZR', and SOZNR'R"; or a pharmaceutically acceptable salt, hydrate, or e thereof.
Additionally, salts, hydrates, and solvates of the present nds also are ed in the present invention and can be used in the methods disclosed herein. The present invention further includes all possible stereoisomers and geometric isomers of the compounds of structural formula (I). The present invention includes both racemic compounds and Optically active isomers. When a compound of structural a (I) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis fiom either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883- 888 . Resolution ofthe final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. onally, in situations where tautomers of the compounds of structural formula (I) are possible, the t invention is intended to include all tautomeric forms of the compounds.
Compounds ofthe invention can exist a salts. aceutically acceptable salts of the compounds ofthe invention oflen are preferred in the methods of the invention. As used , the term "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the compounds of structural formula (I). Salts of nds of formula (I) can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salts of -19. 2012/022315 compounds of structural formula (I) can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically able salts e inorganic acids such as nitric, boric, hydrochloric, hydrobromic, ic, and phosphoric, and c acids such as oxalic, maleic, succinic, and citric.
Nonlimiting examples of salts of compounds of the invention include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen ate, acetate, adipate, te, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, ate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mssitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropn'onate, picrate, pivalate, propionate, oroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, esulfonate, ethanedisulfonate, benzene sulphonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the invention can be quaternized with methyl, ethyl, propyl, and butyl des, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, yl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference to compounds of the present invention appearing herein is intended to include compounds of structural formula (I) as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.
Specific nds ofthe present invention include, but are not limited to, compounds having the structure set forth below.
W0 2012/]03059 2012/022315 Compound No.
W0 03059 PCT/U820] 2/022315 W0 03059 PCT/U82012/022315 W0 03059 PCT/U82012/022315 W0 2012/103059 20] 2/022315 -25.
W0 03059 PCT/U820] 2/022315 W0 03059 PCT/U820] 2/0223 I 5 W0 03059 PCT/U82012/022315 W0 03059 PCT/U820] 2/022315 W0 2012/103059 20] 2/022315 W0 03059 PCT/U82012/022315 W0 03059 PCT/U820] 2/0223 I 5 W0 03059 PCT/U82012/022315 W0 03059 PCT!U820] 2/022315 W0 03059 PCT/U82012/022315 W0 03059 PCT/U820] 2/022315 WO 03059 PCT/U82012/022315 W0 03059 PCT/U82012/022315 -33.
WO 03059 PCT/U82012/022315 WO 03059 PCT/U82012/022315 W0 03059 PCT/U520] 2/0223 1 5 W0 03059 PCT/U820] 2/022315 W0 03059 PC17U820] 2/0223 1 5 W0 03059 PCT/U520] 2/022315 W0 03059 PCT/U820] 2/0223 I 5 W0 2012/103059 20] 2/022315 W0 2012/103059 20] 2/022315 W0 03059 PCT/U82012/022315 W0 03059 PCT/U820] 2/0223 1 5 W0 2012/103059 PCT/USZOIZ/OZZJIS The present invention es Bcl-2/Bcl-xL inhibitors, as exemplified by compounds of structural a (I), for the treatment of a variety of diseases and conditions wherein tion of Bcl—2 and/or Bcl-xL has a beneficial effect. In one embodiment, the present invention relates to a method of treating an individual suffering from a disease or condition wherein inhibition of the Bcl-2/Bcl-xL provides a benefit comprising administering PCT/U820 l 2/022315 a therapeutically effective amount of a compound of structural formula (I) to an individual in need thereof.
The method ofthe t ion can be accomplished by administering a compound of ural a (I) as the neat compound or as a pharmaceutical composition.
Administration of a pharmaceutical composition, or neat compound of structural formula (I), can be performed during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic nds that would cause an adverse reaction when administered. Further ed are kits comprising a compound of structural formula (I) and, optionally, a second therapeutic agent useful in the treatment ofdiseases and conditions wherein inhibition of Bcl-xl. provides a , packaged separately or together, and an insert having instructions for using these active agents.
In many embodiments, a compound of structural a (I) is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Bcl-2/Bcl-xL provides a benefit. The second therapeutic agent is different from the nd of ural formula (I). A compound of structural formula (I) and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the compound of structural formula (I) and second therapeutic agent can be stered from a single composition or two separate compositions.
The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such ished ranges.
A compound of structural formula (I) and the second therapeutic agent can be stered together as a single-unit dose or separately as multi-unit doses, wherein the compound of structural formula (I) is administered before the second therapeutic agent or vice versa. One or more dose of the compound of structural formula (I) and/or one or more dose of the second therapeutic agent can be stered. The compounds of structural formula (I) therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.
The diseases and conditions that can be treated in accordance to the invention include, for example, cancers. A variety of cancers can be treated including, but not limited .5].
PCT/U320 l 2/022315 to: carcinomas, including bladder (including accelerated and metastic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum. larynx. pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, renal, and skin (including us cell oma); hernatopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma, hematopoietic tumors ofmyeloid lineage, ing acute and chronic myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, and locytic leukemia; tumors of the l and peripheral nervous system, including ytorna, neuroblastoma, glioma, and schwannomas; tumors ofmecenchymal origin, including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma; and other tumors, including melanoma, xenoderma pigmentosum, ctanthoma, seminoma, thyroid follicular cancer, teratocarcinoma, renal cell carcinoma (RCC), pancreatic cancer, myeloma, myeloid and lymphoblastic leukemia, neuroblastoma, and glioblastoma.
Additional forms of cancer treatable by the Bcl-xL inhibitors ofthe present invention e, for example, adult and pediatric oncology. growth of solid tumors/malignancies, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell oma, particularly of the head and neck, esophageal squamous cell carcinoma, oral oma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer (including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin‘s lymphoma, non-Hodgkin's lymphoma, cancer ofthe adrenal cortex, ACTH-producing tumors, nonsmall cell cancers, breast , ing small cell carcinoma and ductal oma), intestinal cancers (including stomach cancer, colon , colorectal cancer, and polyps associated with colorectal neoplasia), pancreatic cancer, liver cancer, urological cancers (including bladder cancer, such as primary superficial bladder tumors, invasive transitional cell carcinoma of the r, and -invasive bladder cancer), prostate cancer, malignancies of the female genital tract (including ovarian carcinoma, primary peritoneal epithelial sms, cervical oma, e endometrial s, vaginal PCT/U320 l 15 cancer, cancer of the vulva, uterine cancer and solid tumors in the ovarian follicle), malignancies ofthe male genital tract (including testicular cancer and penile cancer), kidney cancer (including renal cell carcinoma, brain cancer (including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, and metastatic tumor cell invasion in the central nervous system), bone cancers (including osteomas and arcomas), skin cancers (including maligiant melanoma, tumor progression of human skin keratinocytes, and squamous cell cancer), thyroid cancer, retinoblastoma, neuroblastoma, peritoneal on, malignant pleural effusion, mesothelioma, Wilms's tumors, gall bladder cancer, trophoblastic neoplasms, hemangiopericytoma, and 's sarcoma.
Additional es and conditions, including cancers. that can be treated by administration of a present Bcl-Z/Bcl-xL inhibitor are disclosed in U.S. Patent Publication No. 2007/0027135; U.S. Patent No. 7,432,304; and U.S. Patent Publication No. 2010/0278921, each orated herein in its ty.
In the present method, a therapeutically ive amount of one or more nd (I), lly formulated in accordance with pharmaceutical practice, is administered to a human being in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into eration signs, ms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfimctions, and other s.
A compound of structural formula (I) can be administered by any suitable route, for example by oral, buccal. inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, aneous, i.e.. transdermal, or eral (including intravenous, intramuscular, subcutaneous, intracoronary, ermal, intrarnammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, inn‘apulmonary injection and/or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
Pharmaceutical compositions include those wherein a compound of structural formula (I) is administered in an ive amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound of structural formula (I) that is suflicient to maintain therapeutic effects. 20 l 2/022315 Toxicity and therapeutic efficacy of the compounds of structural formula (I) can be determined by standard ceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a nd, which defines as the highest dose that causes no toxicity in animals. The dose ratio between the m ted dose and therapeutic effects (e.g. inhibiting oftumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those sldlled in the art, ally in light of the detailed disclosure provided herein.
A therapeutically efi'ective amount of a compound of structural formula (I) required for use in therapy varies with the nature of the ion being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the ant ian. Dosage amounts and als can be adjusted individually to provide plasma levels of the Bcl-2/Bcl-xL inhibitor that are sufficient to in the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for e as one, two, three, four or more subdoses per day. Multiple doses ofien are desired, or required. For example, a present Bcl-Z/Bcl-xL inhibitor can be administered at a fiequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three- day intervals (q3d x 4); one dose delivered per day at five-day als (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance.
A compound of structural formula (I) used in a method of the present invention can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a compound of structural a (I) can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams, including all doses between 0.005 and 500 milligrams.
The dosage of a composition containing a Bcl-2/Bcl-xL inhibitor of structural formula (I), or a composition containing the same, can be from about 1 ng/kg to about 200 mg/kg, about l 11ng to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg. The dosage of a composition can be at any dosage including, but not limited to. about 1 ug/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 ug/kg, nag/kg. 25 rig/kg, 50 pig/kg, 75 its/kg, 100 its/kg. 125 its/kg, 150 nus/ks. 175 [lg/kg, 200 W0 20] 2/103059 PCT/U82012/022315 its/kg. 225 pig/kg. 250 [lg/k8, 275 its/kg, 300 its/kg, 325 ug/kg, 350 its/kg, 375 tie/kg, 400 its/kg. 425 its/kg, 450 lug/kg, 475 its/kg. 500 its/kg, 525 its/kg, 550 its/kg. 575 pig/kg, 600 its/kg. 625 llg/kB: 650 rig/kg, 675 its/kg, 700 [lg/k8, 725 its/kg. 750 . 775 its/k3, 800 pig/kg, 825 ug/kg, 850 ug/kg, 875 [Lg/kg, 900 [Lg/kg, 925 [Lg/kg, 950 pg/kg, 975 pg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg. 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, [25 rug/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg. The above s are exemplary of the average case, but there can be dual instances in which higher or lower dosages are merited, and such are within the scope of this invention. In practice, the physician determines the actual dosing regimen that is most suitable for an dual t, which can vary with the age, weight, and response of the particular patient.
In the treatment of a cancer, a compound of structural a (I) can be administered with a chemotherapeutic agent and/or radiation.
Embodiments ofthe present invention employ electromagnetic radiation of: radiation (10'20 to 10''3 m), X-iay radiation (10'l2 to 10‘9 m), ultraviolet light (10 nm to 400 nm), visible light (400 nm to 700 nm), infrared radiation (700 run to 1 mm), and microwave radiation (1 mm to 30 cm).
Many cancer treatment protocols currently employ radiosensitizers activated by electromagnetic radiation, e.g., X—rays. Examples of X—ray-activated radiosensitizeis e, but are not limited to, metronidazole, misonidazole, desmethylrnisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5- bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), eoxycytidine, fluorodeoxyuiidine (FUdR), hydroxyurea, atin, and eutically effective analogs and derivatives of the same.
Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator ofthe sensitizing agent. Examples ofphotodynamic radiosensitizers include the following, but are not limited to: hematoporphyxin derivatives, PHOTOFRIN”, benzoporphyrin derivatives, NPe6, tin etioporphyrin (SnET2), pheoborbide-a, bacteriochlorophyll—a, alocyanines, phthalocyaninss, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
Radiosensitizers can be administered in conjunction with a therapeutically effective amount of one or more compounds in addition to a present Bcl-2/Bcl~xL tor, such compounds including, but not limited to, nds that promote the incorporation of PCT/U820 l 2/022315 radiosensitizers to the target cells, compounds that control the flow of therapeutics, nutrients, and/or oxygen to the target cells, chemotherapeutic agents that act on the tumor with or without additional radiation, or other therapeutically ive compounds for treating cancer or other disease. Examples of additional therapeutic agents that can be used in conjunction with radiosensitizers e, but are not limited to, S-fluorouraeil (S-FU), leucovorin, oxygen, carbogen, red cell transfusions, perfluorocarbons (e.g., FLUOSOLW‘D-DA), 2,3- DPG, BW12C, calcium channel blockers, ifylline, antiangiogenesis compounds. hydralazine, and L-BSO.
The chemotherapeutic agent can be any pharmacological agent or compound that induces apoptosis. The pharmacological agent or compound can be, for example, a small organic molecule, peptide, polypeptide, c acid, or antibody. Chemotherapeutic agents that can be used include, but are not limited to, alkylating agents, antimetabolites, hormones and antagonists thereof, l products and their derivatives, radioisotopes, antibodies, as well as natural products, and combinations thereof. For example, a Bcl-xL tor of the t invention can be administered with otics, such as doxorubicin and other anthracycline analogs, nitrogen mustards, such as cyclophosphamide, pyrimidine analogs such as S-fluorouracil, cis-platin, hydroxyurea, taxol and its natural and synthetic derivatives, and the like. As another example, in the case ofmixed tumors, such as adenocarcinoma of the breast, where the tumors include gonadotropin-dependent and gonadotropin—independent cells, the nd can be administered in conjunction with leuprolide or goserelin (synthetic peptide s of LH-RH). Other antineoplastic protocols include the use of an inhibitor compound with another treatment modality, e.g., surgery or ion, also referred to herein as "adjunct anti-neoplastic modalities." Additional chemotherapeutic agents useful in the invention include es and antagonists thereof, radioisotopee, antibodies, natural products, and combinations thereof.
Examples of chemotherapeutic agents useful in a method of the present invention are listed in the following table.
-S6- W0 20] 2/103059 PCT/U82012/022315 TABLE 1 W Natural nroductg hmaagumumgb mechlorethamine cyclophosphamide Taxanes ifosfamide paclitaxel melphalan Vinca alkaloids chlorambucil vinblastine (VLB) uracil mustard stinc temozolomide vinorelbine vindcsine Nitmsom re® (docetaxel) tine (BCNU) estramustinc lomustine (CCNU) estramustinc phosphate scmustine (methyl-CCNU) chlormcthine E i odo lot xins streptozocin ctOposidc tem'poside Ethylenimine/Methyl-melaminc triethylenemelamine (TEM) Amflmnfla tn'ethylene thiophosphomnide actimomycin D (thiotcpa) daunomycin (mbidomycin) hexamethylmelamine doxorubicin mycin) (HMM, altrctamine) mitoxarmoncidarubicin bleomycin $1911 sulfonagg mycin amycin) busulfan mitromycin-C pipobroman dactinomycin colin Iflgéga epixubicin azine (DTIC) idarubicin daunorubicin Antimetlbolitg mitbramycin Folic Acid analogs deoxy co-formycin methotrexate tx'imctrexate Emnyus pemetrexed L-asparaginase (Mum-targeted antifolate) L-arginase hm'dine analogg Bmflmsnflgyag -fluoroumcil men-onidazole fluorodeoxyuridjne misonidazole gemcitabine hylmisonidazole cytosine arabinoside pimonidazolc (AraC, cytarabinc) etanidazolc S-azacyfidine nimomzole 2.2'- difluomdeoxy—cytidinc RSU 1069 floxuridine E09 pentostatine RB 6l45 hgnmgndmfi Nonsteroidal amiandrogens 6-mcrcaptopurine SR4233 guam'nc flutamide azathioprine nicotinamide 2'-deoxycoformycin S-bnomodeozyuridinc -57.
W0 2012/l0305‘) PCT/USZOIZ/(DZZSIS (pentostatin) 5-iododeoxyuridine erythrohydroxynonyl—adenine (EHNA) eoxycytidine fludarabine phosphate 2-cblorodeoxyadenosine Miscellaneous agents (cladribine, 2-CdA) Platinium coordination con_1plexes cisplatin Tm I Tomlsomergse Inhibitor; carboplatin camptothecin oxaliplatin tqmmxmi anthracenedione irinotecan mitoxantrone Biological rmnse modlflen Substituted urea G-CSF hydroxyura GM-CSF hxdrazine derivatives Differentiation Ageng N-methylhydrazine (MIH) retinoic acid derivatives procarbazine lhnnuuusandanyuuumn! Adrenocortical suppressant Adren co ‘ t i 'sts mitotane (o.p'- DDD) prednisone and equivalents ainoglutethimide dexamethasone . ainoglutethimide Ehnflhu! eron (a, B, y) Progestins interleukin-2 hydroxyprogestemne caproate medroxyprogesterone acetate Phgtolenmgg'n megestrol acetate hematoporphyrin derivatives PHOTOFR1N® Estrogens ben20porphyrin derivatives diethylstilbestrol NW5 ethynyl estradiol/ lents tin etioporphyrin (SnEI'2) pheoboride—a Amkummm bacteriochlorophyll-a fen naphthalocyanines phthalocyaninea Agmngn zinc phthalocyaninee testosterone propionate fluoxymesteronc/equivalents Rndlntlog X-ray Antiandrogens ultraviolet light flutamidc gamma radiation tmpin-relmsing visible light hormone analogs ed radiation leuprolide microwave radiation Microtubule affecting agents interfere with cellular mitosis and are well known in the art for their cytotoxic activity. Microtubule affecting agents useful in the invention include, but are not d to, allocolchicine (NSC 406042), halichondrin B (NSC 6093 95), colchicines (NSC 757), colchicines tives (e.g., NSC , dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (NSC ), TAXOL‘D derivatives (e.g., NSC 608832), thiocolchicine NSC 361792), trityl PCT/U320 l 2/022315 ne (NSC 83265), stine sulfate (NSC 49842), vincn'stine sulfate (NSC , l and synthetic epothilones ing but not limited to epothilone A, lone B, and discodermolide (see Service, (1996) Science, 274:2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in Bulinski (1997) J. Cell Sci. 110:3055 3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560—10564; Muhlradt (1997) Cancer Res. 4-3346; ou (1997) Nature 8-272; Vasquez (1997) Mol. Biol.
Cell. 8:973-985; and Panda (1996) J. Biol. Chem. 271 :29807-29812.
Cytostatic agents that may be used include, but are not limited to, hormones and steroids (including synthetic analogs): 17-a-ethinylestadiol, diethylstilbestrol, testosterone, prednisone, fluoxyrnesterone, tanolone propionate, testolactone, megestrolacetate, prednisolone, methyl-testosterone, prodnisolone, triamcinolone, hlorotn'anisene, hydroxyprogesterone, aminogluthimide, sstramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, zoladex.
Other cytostatic agents are antiangiogenics, such as matrix metalloproteinase inhibitors, and other VEGF inhibitors, such as anti-VEGF antibodies and small molecules such as ZD6474 and SU668. Anti-Her2 antibodies also may be utilized. An EGFR inhibitor is 9 (an irreversible inhibitor). Also included are antibody C225 immunOSpecific for the EGFR and Src inhibitors.
Also suitable for use as a cytostatic agent is CASODEX‘lo (bicalutamide, Astra Zeneca) which renders androgenodependent omas non-proliferative. Yet another example of a cytostatic agent is the antiestrogen FENQ which inhibits the proliferation or growth of estrogen dependent breast cancer. Inhibitors of the transduction of cellular proliferative signals are cytostatic agents. Representative examples include epidermal growth factor inhibitors, Her-2 tors, MEK-l ldnase inhibitors, MAPK kinase inhibitors, P13 inhibitors, Src kinase inhibitors, and PDGF inhibitors.
Additional second therapeutic agents that can be administered with a Bcl-2/Bcl-xL inhibitor of the present invention are disclosed in U.S. Patent Publication 2007/0027135; U.S.
Patent No. 7,432,304; and U.S. Patent Publication No. 2010/0278921, each incorporated herein by reference.
The compounds ofthe present invention typically are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention are formulated in a conventional manner using one or more W0 20] 2/103059 PCT/U82012/022315 physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing ofcompounds of structural formula (I).
These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper ation is dependent upon the route of administration chosen. When a therapeutically effective amount of the compound of structural formula (I) is stered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder n about 0.01% to about 95%, and preferably from about 1% to about 50%, of a nd of ural formula (I). When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide ons, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of structural formula (I).
When a eutically effective amount of a compound of structural formula (I) is stered by enous, cutaneous, or subcutaneous injection, the composition is in the form ofa pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred ition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
Compounds ofstructural formula (I) can be readily combined with pharrnaceutically acceptable carriers well-known in the art Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, s, gels, syrups, slurries, suspensions and the like, for oral ion by a patient to be treated. Pharmaceutical preparations for oral use can be ed by adding the compound of ural formula (I) to a solid excipient, optionally ng the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
A compound of structural formula (I) can be ated for eral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for PCT/U820 l 2/022315 injection can be presented in unit dosage form, e.g., in s or in multidose ners, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain forrnulatory agents such as suspending, stabilizing, and/or dispersing agents.
Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compound of structural formula (1) can be prepared as appropriate oily injection suspensions. Suitable lipophilic ts or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection sions can n substances which increase the viscosity of the suspension.
Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility ofthe compounds and allow for the preparation of highly concentrated solutions. atively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-fi'ee water, before use.
A compound of ural formula (1) also can be formulated in rectal compositions, such as suppositories or ion enemas, e.g., containing conventional suppository bases. In on to the formulations described previously, the compound of structural formula (I) also can be formulated as a depot ation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular ion. Thus, for example, the compounds of ural formula (I) can be formulated with suitable polymeric or hydrophobic materials (for example, as an on in an acceptable oil) or ion ge resins. ln particular, the compounds of structural formula (I) can be administered orally, buccally, or sublingually in the form of tablets ning excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable ves, such as suspending agents. The compounds of structural formula (I) also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Bcl-2/Bcl-xL inhibitors are best used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
As an additional embodiment, the present invention es kits which comprise one or more compounds or compositions packaged in a manner that facilitates their use to PCT/U320 l 2/022315 practice methods of the ion. In one simple embodiment, the kit includes a compound or composition described herein as useful for practice of a method (e. g., a composition comprising a compound of ural formula (I) and an optional second eutic agent), packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method ofthe invention. Preferably, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.
Prior Bcl-Z/Bcl-xL inhibitors possessed properties that hindered their development as eutic agents. In accordance with an important feature of the present invention, nds of structural formula (I) were synthesized and evaluated as inhibitors for Bcl-xL. For example, nds of the present invention typically have a bonding affinity (lC5o) to Bcl-2/Bcl-xL of less than 100 M, less than 50 uM, less than 25 M, and less than 5 uM.
SYNTHESIS OF COMPOUNDS Compounds of the present invention and were prepared as follows. The following synthetic schemes are representative of the reactions used to synthesize compounds of structural a (I). Modifications and alternate schemes to prepare Bcl-Z/Bcl-xL inhibitors of the ion are readily within the capabilities of persons skilled in the art.
Solvents and reagents were obtained commercially and used without fimher purification. Chemical shifis (8) ofNMR spectra are reported as 8 values (ppm) downfield relative to an internal standard, with multiplicities reported in the usual manner.
Unless otherwise stated all atures are in degrees Celsius.
In the synthetic methods, the es, and throughout the specification, the abbreviations have the following gs: dimethylformarnide CH2Clz/DCM methylene chloride sodium sulfate acetic acid mass ometry sodium carbonate W0 2012/103059 PCT/U82012/022315 lilmL milliliter tetramethylsilane TFA trifluoroacetic acid wa potassium hydroxide iiiiillfiilfifilNH20H-HCl hydroxylamine hydrochloride z o sodium ide n U deuterated methanol z molar 7< t= potassium tert-butoxide dimethyl sulfoxide SOClz thionyl chloride 0 z dcutcrated acetonitrile pa room temperatme O dimethyl ether a copper iodide z nuclear magnetic nce spectrometry W0 2012/103059 PCT/USZOIZ/OZZJIS mom): mom» Neon memo» l"DA m2 .9 “’ tin(II)chlonde Pd/C palladmm on carbon 2*?PPh3)4Pdfig tetmkis(u'iphenylphosphine)palladium(0) sodium azide n-BuLi n-butyl lithium mCPBA m-chloroperoxybenzoic acid s:0 acetic ide Pd(dba)z bis(dibenzylidene acetone)palladium(0) u'ibutyl phosphine NaOtBu sodium tert—butoxide Scheme, core-1 9 0 B0 0 O ‘ “' a R “avg—u «—~‘ Emu“ . mm _ H}? .R. (30' R3 R42“ a) AICHO. at. plpnddinl, alt. W. toluena. Mqu; b) ArCHO. EQN. mmlum mint. 70°C: c.) I. RgNHz. MOON. mom Dunn: IL 1M HCI.
H20: :1) NaOH. IEkOHIHzo. reflux; 11) Kym-01.. EDC. H031. DCM. DIPEA. room ml): 0 l. SOCI; reflux 2h ll. R,NHR.. DAMP. 1.2- didxloroemano. ruflux WO 03059 PCT/U820 l 2/022315 Scheme, core-2 R27\\_ I\’ (amp R5 Rah" R5~\ R3 R‘\_J R5/__\ (3')] 3) K2003, MeOH. reflux; b) CNCHZCOOEI. t-BuOK; c) Re-l. K2003; d) KOH. HzolTHF/MeOH; e) R7NHR3. EDCI. HOBt. DIEA. DCM; f) i. SOCI; reflux 2h il. R7NHR.. DMAP. 1.2-dichloroethane. reflux; 9) N05 or NIS or NBS. DMF RT; h) sonogashira coupling or suzuki coupling Scheme, core-3 O'IP pa QC“. “Gar—o @QO-Mfi hm“no. u no a." o .._, a "u“ :‘u j‘fu‘fl’ ., “’10"N M0 . wen % ' Rb 0 9.. .......—....T Q “bu dig: .9, .5 Winn—fl “-l-U‘m a) K2C03. DMSO. b) NalO.. NH¢OAC. c) HzN-NHMO. Audi: add. EthanoL d) NIS. CAN. MICN. o) )2. CICO: Scheme, core-4 a) HO—NHz. Acetic acid. Ethanol, b) NIS. CAN. MeCN. c) Pd(OAc)2, CSC03 ~65- PCT/U320 I 2/022315 Scheme, core—5 O N 0”“ *Q b <19 + 63 (9 C' :N Tos . Y H © l (3) Toluene, reflux; (b) K2003, MeOH/DME , core-6 °”© dm _.» u. (a) EDCI, Hoar. CHZCII, DIEA; (b) (i) KOtBu. THF, CIPO(OEt)z (ii) any: iaocyanoacnmn; (c) NaOH. dionno:E10I-1:H20(1:1:1)ruflux21: (d) (i) 5061!. reflux 2h (5) 1.2-dim1uorommne. mamylsulfommida reflux overnight Scheme, core-7 b N, \ ON'zNH Q R-- H or £025: 0' (a) N.N-Dimethylformamide dimethylacetal,Toluene, reflux; (b) Ethanol, reflux PCT/U820 I 2/022315 Scheme, core-8,9 (a) (i) SOCIZ, reflux. 2h (ii) chlorobenzene, AIC|3 0°C, 1 h; (b) methylformamide dimethyl acetal, Toluene, ; (c) Ethanol, reflux Scheme, core-10 (a) (I) (PhOhPONa. THF. RT ovenighl (ll) l-BuOH, Toluene. mflux overnight: (b) CH2C|2. TFA. RT 30 mln; (c) NCS, DMF. RT 2h: (d) EDCL HOBI. DIEA. Cchb. 0.5M NH3 in dioxane; (e) trifluoroacetic anhyddde. pyridine. dloxane 0°C to RT -57.
W0 20] 2/103059 PCT/U320 I 2/022315 Scheme, core-l l (a) NIS. DMF. RT overnight; (b) Methyl-2.2-difluoro(fluorosulfonyl)acetate. Cul, DMF 80°C overnight Scheme, 2 é“ c1 / N/ b 0 c.d.e HO —" —’ 0 O Eto)l\/’/~ 0 0 O CI I Cl (3) cnzch, Bra. AcOH; (b) K2C03, Acetone. RT; (c) 4.0M HCI in dioxane; (d) K2003, DMF, Mel. RT; (e) NaOH. ezEtonHzo (121:1) reflux overnight Scheme, core-13 (a) LDA. THF 48°C - RT; (1:) Tduene. pipeddlno. AcOH reflux outright (c) MW. mlunIiumm Eth. 70°C might (d) CHICII. TFA: (0) N80”. WZEtOHngo (111:1) mmmm W0 20] 2/103059 PCT/U820 I 2/022315 , core-14 (3 HN O\/ on d 6N _°_, {/74 m. « a Q Qb 07“ Q. 0 gm . . a Dim: a) AcCl. EtOH; b) HCI; c) heat, 16h; d) i. AcOH. ii. NaHC03; e) MnOz Scheme, core-15 I a \ I __. O NH2 HN’NH’ 3) NaOMe, MTBE: b) NaNOz, SnCIz, HCI; c) EtOH, reflux a \ o —» 0 Cl CFa Cl / NH2 HNINHz IQ D b a) NaOMe. MTBE: b) NaNOz. SnClz, HCI; c) EtOH. reflux WO 03059 PCT/U820 l 2/022315 General scheme 1 a) 1-(4-Nitrophenyl)piperazine, Cul. L-proline. K2C03. DMSO, 100°C; b) Fe. HCI. EtOH/HZO. 65°C: c) H2. PdIC; d) ArSOZCI. pyridine. 0°C; h) DIPEA. DMF, room temp: PCT/U820 I 2/022315 General Scheme 2 / Q‘ . and = ‘ _, , fr HT}: ‘03—“ f d :-/""~;Q§-~H 2M1»... °a~ {5” O“ Cg") 0* 43.30 __;__.,,.N Q _=- J,1 o _a- \N ~1 C \ 0 . QC}.
OH’ Oflz 3,_ I H “EcQ—é‘ a: F‘O‘E’“ J cm \NJ‘“ “I um.o)mummnnu=mm\ w” "5"”: :'~’\co,ao 0 "n“ »\ N '-' J \g I." an’ fi’mm —> é s] g. ' —. coon G o) ‘M HCI, Dkuln. man lulu: 0 unit... EDC. HOB. DIPEA DOM. mom W: 0) EW, CH36N. mom km: E!) 8H3. THF.
General scheme 3, triple bond as linker a) NaNa, Cul. L-Pmlina. DMSO; [3) CuSO4, Sodium ate. t-BUOH. H20 PCT/U820 l 2/022315 General scheme 4, plperazine as linker O G ' /—RyJu'ngE-NHQ.— mQ‘s QC) R‘R: R1_/""'l g R! Pd(dtn)2. Pans. Naomu. cum. our 3 Reagents and Conditions: I) I) nBuU. -76 °c, THF: u) RquRq. THEIR) omamynnmoauum. THF: b) mcwaa (2 sq). crack. 0-25 °c: cu, up. 120 °c. 2 h; a) a. NaH. our; 0) s, cm. L-pmlino. cho,. 120 °c. ovomight; r) we. H1. Moon; g) n, Pyridino: h) 13. DIPEA. DMF.
W0 201 2/103059 PCT/U52012/022315 Compound 136 Chemical Formula: C54H5.CIN90532 Exact Mass: 1017.42 Molecular Weight 1018.73 MS: 1019.50; ‘H-NMR z, CD3OD) 6 ppm 8.30 (d, J = 2.0, 1H), 7.61 (dd, .1 =2, 9 Hz, 1H), 7.31 (d, J = 8.4 Hz, 3H), 7.24-7.11 (m, 5H), 7.08-7.01 (111,411), 6.99-6.83 (m, 4H), 6.70-6.63 (m, 2H), 4.18-4.06 (m, 1H), 3.53-3.43 (m, 1111), 3.24-3.08 (m, 12H), 2.87 (s, 6H), 2.49 (s, 3H), 2.36-2.14 (m, 2H) 1.96-1.60 (m, 6H) Compound 135 Chemical Fonnula: CMH35CIN100783 Exact Mass: 1096.39 Molecular Weight 0 MS = 1098.42; lH-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.43 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.0, 9.0 Hz, 1H) 7.28-7.22 (m, 4H), .11 (m, 4H), 7.07-7.02(m, PCT/U820 l 2/022315 4H), 6.86 (d, J = 8.9 Hz, 2H), 6.80-6.75 (m, 2H), 6.67-6.64(m, 2H), 3.42-3.41 (m, SH), 3.30- 3.11 (m, 15H), 2.82 (s, 6H), 2.79 (s, 3H), 2.73-2.60 (m, 6H), 2.54 (s, 3H), 2.42-2.07 (m, 2H) Compound 133 Chemical Formula: C43H530lN307sa Exact Mass: 984.29 Molecular Weight: 985.63 MS = 986.58; 'H-NMR (300MHz, (10301)) 6 ppm 8.36 (d, J = 2.0112, 1H), 7.58 (dd, J = 2.0, 9.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.21-7.15 (m, 5H), 7.10-7.03 (m, 5H), 7.00-6.93 (m. 3H), 6.91 (d, J = 9.0 Hz, 1H), 6.88 (ha, 1H), 6.71 (d, J = 8.0 Hz, 1H), .02 (m, 1H), 3.44 (s, 3H), 3.22 (s, 3H), 2.87 (s, 6H), 2.54 (s, 3H), 2.28-2.12 (m, 2H) Compound 132 C} g~~ Chemiml Formula: CIN50582 Exact Mass: 906.31 Molecular Weight: 907.54 W0 20] 2/103059 PCT/U820 I 2/022315 MS = 907.67; lH-NMR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.45 (d, I = 2.2 Hz, 1H), 7.63 (dd, J = 2.3, 9.1 Hz, 1H), 7.28-7.22 (m, 4H), 7.19-7.13 (m, 4H), 7.10-7.03 (m, 4H), 6.95-6.86 (m, 3H), 6.78-6.76 (m, 3H), 4.13-4.05 (m, 1H), 3.43 (s, 3H), .22 (m, 9H), 3.17-3.11 (m, 3H), 2.82 (s, 6H), 2.62 (s, 3H), 2.40—2.08 (m, 2H) nd 131 {@021 = \NN‘ Chemiml Formula: C43H450IN50452 Exact Mass: 836.27 Molecular Weight 837.45 MS = 837.50; lH-NMR (300MHz, 10:1 CDCl32CD30D) 6 ppm 9.32 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.60 (dd, J = 2.0, 9.0 Hz, 1H), 7.55 (d, I = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.30- 7.16 (m, 3H), 7.12-7.00 (m, 6H), 7.00-6.90 (m, 3H). 6.80-6.71 (m, 2H), 4.19-4.04 (m, 1H), 3.28-3.12 (m, 12H), 2.87 (s, 6H), 2.35-2.09 (m, 2H) Compound 130 @C'Q \ £Q02N HNxb N§=o Chemiml Forrfula: C43H45C|N304Sz Exact Mass: 836.27 Molecular Weight 837.45 PCT/U820 l 2/022315 MS = 837.50; 'H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.35 (d, J = 2.0 Hz, 1H), 7.73 (d, .l = 1.8 Hz, 1H), 7.59 (dd, J = 2.0, 9.0 Hz, 1H), 7.40 (d, 1 = 8.8 Hz, 2H), 7.28- 7.24 (m, 3H), 7.21-7.18 (m, 2H), .05 (m, 4H), 7.02-6.98 (m, 3H), 6.95-6.90 (m, 2H), .76 (m, 2H), 6.60 (d, J = 1.9 Hz, 1H), 4.15-4.03 (m, 1H). .12 (m, 10H), 2.87 (s, 6H), 2.31-2.09 (m, 2H) Compound 129 Q 1 QC:N HN~-\:s 1114‘ Chemical Formula: C43H“ClN-,O5S¢ Exact Mass: 837.25 Molecular Weight 838.44 (0134] M8 = 839.33; ‘H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.45 (d, J = 2.2Hz, 1H), 8.38 (s, 1H), 7.64 (dd, J = 2.3, 9.1 Hz, 1H), 7.61-7.58 (m, 2H), 7.39-7.32 (m, 3H), 7.28- 7.24 (m, 2H), 7.17-7.10 (m, 5H), 7.50-7.01 (m, 3H), 6.98-6.91 (m, 2H), 6.78 (d, J = 9.4 Hz, 1H), 4.14-4.07 (m, 1H), 3.41-3.37 (m, 9H), 3.28-3.11 (m, 4H), 2.82 (s, 6H), 2.37-2.09 (m, W0 201 2/103059 2012/022315 Compound 128 Chemical Formula: C47H54CIN90482 Exact Mass: 907.34 Molecular Weight 908.57 MS = 908.25 Compound 127 al Formula: C47H9CIN90‘52 Exact Mass: 907.34 Molecular Weight 908.57 MS = 908.25; lH-NMR (300MHz, 10:1 CDClngD3OD) 6 ppm 8.30 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.47 (dd, J = 2.0, 9.0 Hz, 1H), 7.29-7.26 ( m, 2H), 7.17-7.05 (m, SH), 7.02- 6.95 (m, 3H), 6.91 (d, J = 9.0 Hz, 2H), 6.76-6.71 (m, 3H), 6.67-6.60 (m, 3H), 4.48 (t, J = 6.3 Hz, 2H), 3.50 (t, J = 6.0 Hz, 2 H), 3.15-2.95 (m, 11H), 2.69 (s, 6H), 2.66 (s, 6H), 2.21-1.96 (m, 4H) W0 20] 2/103059 PCT/U820 I 15 Compound 126 ox [/0 H _ C \ N 0 CF3 < Qosg HN ~ 1,550 <3 Chemical Formula: C49H530|F3N707$.
Exact Mass: 1071.25 Molecular Weight 1072.70 MS = 1073.42; ‘H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.02 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.2, 9.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.31-7.22 (m, 6H), .07 (m. 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.92-6.85 (m, 3H), 6.74-6.63(m, 3H), 4.00-3.87 (m, 1H), 3.46 (s, 3H), 3.28—3.18 (m, 9H), 3.15-3.00 (m, 5H), 2.80 (s, 6H), 2.65 (s, 3H), 2.34-2.17 (m, 1H), .93 (m, IR) Compound 125 H364" /_N’ Q:"£25 Chemical FormuI: C‘GH53ClN305SZ Exact Mass: 920.33 Molecular Weight 921.57 MS = 922.50; 'H-NMR (300MHz, 10:1 CDC132CD30D) 5 ppm 8.45 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 2.3, 9.1 Hz, 1H), 7.27-7.24 (m, 4H), 7.19-7.11 (m, 4H), 7.10-7.00 (m, 5H), -78..
PCT/U820 l 2/022315 6.90-6.79 (m, 3H), 6.76 (d, J = 9.3 Hz, 1H), 6.67-6.65 (m, 2H), .05(m, 1H), 3.42 (s, 3H), 3.24-3.06 (m, 13H), 2.32 (s, 6H), 2.66 (s, 3H), 2.58 (s, 3H), 2.32-2.09 (m, 2H) Compound 124 Chemical Formula: CmHMCINaOaSz Exact Mass: 962.34 Molecular Weight. 963.60 MS = 964.50; ‘H-NMR (300MHz, 10:1 CDCl;:CD3OD) 6 ppm 8.45 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 2.2, 9.1 Hz, 1H), 7.27-7.24 (m, 4H), 720-71 1 (m, 4H), 7.10-7.04 (m, 4H), 6.90-6.81 (m, 3H), 6.74-6.66 (m, 3H), 4.09-4.00 (m, 1H), 3.94 (bs, 4H), 3.42 (s, 3H), 3.27- 3.10 (m, 14H), 2.66 (s, 3H), 2.58 (5, 31-1), 2.38-2.11 (m, 2H) Compound 123 al Formula: C51H57CIN50582 Exact Mass: 976.35 Molecular Weight 977.63 PCT/U820 I 2/022315 MS = 978.75; ‘H-NMR (300MHz. 10:1 CD;;OD) 0‘ ppm 8.44 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 2.2, 9.1 Hz, 1H), 7.28-7.23 (m, 4H), 7.20-7.12 (m, 4H), 7.10-7.04 (m, 4H), 6.93-6.82 (m, 3H), 6.76 (d, J = 9.3 Hz, 1H), .67 (m, 2H), 4.10403 (m, 2H), 3.42 (s, 3H), 329-302 (m, 15H), 2.67 (s, 3H), 2.57 (s, 3H), 2.89-1.82 (m, 61-!) Compound 122 Chemmal Formula: C52H5QCIN30582 Exact Mass: 990.37 Molecular Weight 991.66 (0141] MS = 992.75; 'H-NMR (300MHz, 10:1 CDC131CD3OD) 6 ppm 8.44 (d, J = 2.1 Hz, 1H), 7.62 (dd, .1 = 2.1, 9.1 Hz, 1H), 7.27-7.23 (m, 4H), 7.19-7.12 (m, 4H), 7.07-7.03 (m, 4H), 6.88-6.74 (m, 4H), 6.66-6.63 (m, 2H), 4.11-4.01 (m, 1H), 3.42 (s, 3H), 3.29-3.06 (m, 1411), 2.66 (s, 311), 2.58 (s, 3H), .09 (m, 3H), 2.03-1.65 (m, 5H), 1.30 (s, 3H) Compound 12] Chemical Formula: CuHHCINaOfiz Exact Mass: 850.29 Molecular Weight 851.48 W0 20] 2/103059 PCT/U820 I 2/022315 MS = 851.58; 'H-NMR (300MHz, 10:1 CDCl31CD30D)6 ppm 8.45 (d, 1 = 2.2 Hz, 1H), 7.62 (dd, J = 2.2, 9.1 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.29-7.21 (m, 5H), 7.16-7.11 (m, 3H), 7.07 (d, J = 8.9 Hz, 2H), 6.92-6.74 (m, 6H), 4.11—4.04 (m, 1H), 3.97 (s, 3H), .10 (m, 12H), 2.82 (s, 6H), 2.36-2.08 (m, 2H) Compound 120 \ / N \ Q N~ CE2N HNis FROl Chemical Formula: C44H47CIN30482 Exact Mass: 850.29 Molecular Weight: 851.48 MS = 851.33; iH-NMR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.45 (ha, 1H), 7.72— 7.64 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.29-6.99 (m, 10H), 6.87-6.68 (m, 6H), 4.15-4.04(m, 1H), 3.77 (s, 3H), 3.34-3.00 (m, 12H), 2.81 (s, 6H), .04 (m, 2H) nd 119 01,0 :s" / N/ H30 fi __ O O OH LN N CF3 < Chemical Formula: C52H570IF3N70534 Exact Mass: 1127.28 Molecular Weight: 1 128.78 PCT/U82012/022315 MS = 8; 'H-NMR (300MHz, 101 CDC13:CD30D) 0‘ ppm 8.01 (d, 1 = 2.1 Hz, 1H), 7.71 (dd, J = 2.1, 9.1 Hz, 1H), 7.36-7.32 (m, 2H), 7.30-7.22 (m, 6H), 7.10-7.05 (m, 2H), 7.04-7.00 (m, 2H), 6.93-6.85 (m, 3H), 6.77-6.68 (m, 2H), 6.62 (d, J = 9.3 Hz, 1H), 4.10 (ha, 1H), 3.46 (s, 3H), 3.29-3.18 (m, 12H), 3.17-2.96 (m, 6H), 2.65 (s, 3H), 2.36-1.81 (m, 61-!) Compound 118 Chemical Formula: C53H59CIF3N70364 Exact Mass: 9 Molecular Weight: 1 142.79 M8 = 1143.75; lH-N'MR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.00 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 2.2, 9.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.22 (m, 6H), 7.10-7.06 (m, 2H), .00 (m, 2H), 6.94-6.85 (m, 3H), 6.77-6.68 (m, 2H), 6.63 (d, J = 9.3 Hz, 1H), 3.96- 3.87 (m, 1H), 3.45 (s, 3H), 3.34-3.18 (m, 13H), 3.16-2.98 (m, 6H), 2.65 (s, 3H), 2.35-1.70 (m, 6H), 1.29 (s, 3H) W0 201 2/103059 PCT/U52012/022315 Compound 209 O N\/\N £Qoz~o “NEG()It \NN5 Chemical Formula: C52H50CIN110582 Exact Mass: 1017.39 Molecular Weight: 1018.69 MS = 1018.25; lH—NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 9.32 (s, 1H), 8.45 (d, I = 2.2 Hz, 1H), 7.63 (dd, J = 2.3, 9.1, Hz, 1H), 7.48-7.42 (m, 3H), .30(m, 2H), .20 (m, 3H), 7.19-7.10 (m, 3H), 7.07-6.97 (m, 3H). .83 (m, 3H), 6.80-6.76 (m, 1H). 4.17-4.02 (m, 2H), 3.29-3.05 (m, 11H). 2.86-2.69 (m, 11H), 2.39-2.00 (m, 6H) Compound 134 O N\/\N OéOCIS Chemical Formoula. C52H60CIN110582 Exact Mass: 1017.39 Molecular Weight: 1018.69 WO 03059 PCT/U820 I 2/022315 MS = 1019.17; ‘H-NMR (300MHz, 10:1 cnchzcnaon) 6 ppm 9.32 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), .62 (m, 1H), 7.46-7.40 (m, 2H), 7.30-7.24 (m, 4H), 7.21-6.95 (m, 8H), 6.91-6.73 (m, 4H), 4.17-4.07 (m, 2H), 3.67-3.63 (m, 2H), .04 (m, 12H), 2.86-2.70 (m, 11H), 2.37-2.10 (m, 6H) Compound 117 ’CF3 ‘ (1'2S HNx8 1:0 Q Chemical Formula: C49H52CIF3N30384 Exact Mass: 1100.24 Molecular Weight 1101.69 [0148) MS = 1102.75; 'H-NMR (300MHz, 10:1 CDCIJZCD3OD) 5 ppm 8.24 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 2.1, 9.2 Hz, 1H), 7.35-7.23 (m, 8H), 7.17 (d, J = 8.8 Hz, 2H), 7.07-6.93 (m, 6H), 6.75 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 9.3 Hz, 1H), 4.10 (bs, 1H), 4.00-3.85 (m, 2H), 3.36-2.94 (m, 17H), 2.37-1.79 (m, 6H) W0 201 2/103059 PCT/U821" 2/022315 Compound 116 o“s”o \N H3C’ ‘N \ “I.
N \ Q "~ N < al Formula: C45H‘80lN90783 Exact Mass: 957.25 lar Weight 958.57 MS = 959.83; lH-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.45 (d, .1 = 2.1 Hz, 1H), 8.24 (s, 1H), 7.63 (dd, J = 2.0, 9.1 Hz, 1H), 7.32-7.24 (m, 5H), 7.18-7.01 (m, 8H), 6.97- 6.91 (m, 3H), 6.79-6.72 (m, 2H), 4.15-4.05 (m, 1H), 3.35-3.04 (m, 15H), 2.81 (s, 6H), 2.37- 2.08 (m, 2H) Compound 1 15 Chemical Formula: C45H4BCIN907$3 Exact Mass: 957.25 Molecular Weight 958.57 MS = 959.42; 'H-NMR(300M1‘IZ, 10:1 CDC13:CD30D) 6 ppm 8.45 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.63 (dd, J = 2.1, 9.1 Hz, 1H), 7.36 (d, J = 9.0, 2H), 7.28—7.06 (m, 10H), PCT/U820 l 2/022315 7.00-6.91 (m, 4H), 6.77 (d, J = 9.3 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.14-4.05 (m, 1H), 3.32 (s, 3H), 3.30305 (1n, 12H), 2.81 (s, 6H), 2.36-2.08 (m, 2H) Compound 114 Chemm‘ FOI'ITIUIa: C‘QH520lF3N803S‘ Exact M8381 1100.24 Molecular Weight 1101.69 MS = 1101.67; 'H-NMR (300MHz, 10:1 CDC132CD30D) 5 ppm 8.00 (d, 1 = 2.2 Hz, 1H), 7.73-7.69 (m, 2H), 7.38-7.32 (m, 4H), 7.29-7.18 (m, 4H), 7.10-6.93 (m, 5H), 6.89- 6.83 (m, 3H), 6.73 (d, 1 = 8.0 Hz, 1H), 6.62 (d, J = 9.3 Hz, 1H), 4.17 (bs, 1H), .87 (m, 2H), 3.34 (s, 3H), 3.21 (s, 7H), 3.13-2.99 (m, 5H), 2.38-1.81 (m, 7H) Compound 1 l3 O306' CH onzsCF3 Niko HNib Chemical Formula: Cl2F3N30783 Exact Mass: 1070.23 lar Weight 1072.07 PCT/U520 I 2/022315 MS = 1072.83; lH-NMR (300MHz, 10:1 CDC13:CD3OD)6 ppm 8.00 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 2.2, 9.1 Hz, 1H), .32 (m, 2H), 7.30-7.22 (m, 5H), 7.16-7.02 (m, 5H), 6.91-6.75 (m, 5H), 6.64 (d, 1 = 9.3 Hz, 1H), 4.10 (bs, 1H), .87 (m, 2H), 3.52 (s, 3H), 3.32-3.19 (m, 9H), 3.13-2.98 (m, 5H),2.85-2.62 (m, 1H), 2.36-1.81 (m. 6H) Compound 112 “0090'g/_N’ Chemical oa: CquCIZN-pasz Exact Mass: 927.24 Molecular Weight 928.94 MS = 929.83; ’H-NMR (300MHz, 10:1 CDC131CDJOD) 6' ppm 8.45 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 2.3, 9.1 Hz, 1H), 7.30-7.24 (m, 4H), 7.17-7.12 (m, 4H), 7.10-7.05 (m, 4H), 6.92-6.87 (m, 3H), 6.82-6.80 (m, 1H), 6.76 (d, J = 9.2 Hz, 2H), 4.13-4.04 (m, 1H), 3.51 (s, 3H), 3.28-3.08 (m, 12H), 2.81 (s, 6H), 2.35-2.08 (m, 2H) W0 201 2/103059 PCT/U82012/022315 Compound 1 11 ,CF. g 115:0 Q Chemical Formula: C51H53CIF3N70583 Exact Mass: 1031.29 lar Weight 1032.65 MS = 1033.50; lH-NMR (300MHz, 10:1 CDC132CD3OD) Jppm 8.02 (d, .1 = 2.1 Hz, 1H), 7.71 (dd, J = 2.2, 9.1 Hz, 1H). 7.38-7.33 (m, 3H), 7.27-7.24 (m, 3H), 7.20-7.12 (m, 3H), 7.02 (d, J = 8.9 Hz, 2H), 6.89-6.81 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 4.10 (bs, 1H), 3.98-3.85 (m, 1H), 3.43 (s, 3H), 3.28-3.15 (m, 9H), 3.14-2.91 (m, 6H), .62 (m, 1H), 2.49 (s, 3H), 2.39-1.27(m, 6H) Compound 110 Chemical Formula: clN304sz Exact Mass: 888.30 Molecular Weight 889.53 MS = 890.58; lI-I-NMR (300MHz, 10:1 CDClngD30D) 6 ppm 8.46 (d, I = 2.2 Hz. 1H), 7.61 (dd, J = 2.2, 9.1 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 7.27-7.24 (m, 2H), 7.19-7.11 (m, PCT/U820 l 2/022315 6H), 7.05 (d, H = 8.9 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6.81-6.70 (m, 4H), 4.12-4.02 (m, 1H), 3.43 (s, 3H), 3.25-3.11 (m, 12H), 2.82 (s, 6H), 2.49 (s, 3H), 2.39-2.09 (m, 2H) nd 109 /_N’\ @2383 Chemical Formula: CIN70552 Exact Mass: 921.31 Molecular Weight 922.55 MS = 922.42; 'H-NMR (300MHz, 10:1 CDC132C030D) 5 ppm 8.52 (d, J = 2.7 Hz, 1H), 7.97 (dd, J = 2.7, 9.3 Hz, 1H), 7.46-7.37 (m, 5H), 7.26 (d, J = 8.4 Hz, 2H), 7.12-7.07 (m, 3H), 7.02 (d, J = 8.9 Hz, 2H), 6.85-6.75 (m, 5H), 6.24 (d, J = 9.5 Hz, 1H), 3.88-3.81 (m, 2H), 3.72-3.61 (m, 1H), 3.33-2.88 (m, 13H), 2.83 (s, 6H), 2.64 (s, 3H), 2.53-2.10 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H) W0 20] 2/103059 PCT/U520 I 2/022315 Compound 108 £-"3 COzN ;: HN\ S §=o HN Chemical Formula: C49H540lN70552 Exact Mass: 935.33 lar Weight: 936.58 MS = 936.42; ‘H-NMR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.52 (d, J = 2.7 Hz, 1H), 7.97 (dd, J = 2.7, 9.3 Hz, 1H), 7.46-7.37 (m, 3H), 7.26-7.22 (m, 3H), 7.11-7.00 (m, 5H), 6.84-6.65 (m, 5H), 6.24 (d, J = 9.5 Hz, 1H), 3.71-3.60 (m, 2H), 3.30-2.92 (m, 13H), 2.83 (s, 6H), 2.62 (s, 3H), 2.52-2.42 (m, 1H), 2.21-2.12 (m, 1H), 1.62-1.48 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H) W0 201 59 PCT/U820 I 2/022315 Compound 107 HO /_ N/\/\ Q;"3 Q” Q HN\ s #0101 Chemical Formula: csoncmfiesz Exact Mass: 949.34 Molecular Weight 950.61 MS = 950.42; IH-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.53 (d, J = 2.7 Hz, 1H), 7.96 (dd, J = 2.7, 9.3 Hz, 1H), 7.46-7.35 (m, 4H), .22 (m, 2H), 7.15-7.00 (m, 5H), 6.85-6.67 (m, 5H), 6.20 (d, J = 9.5 Hz, 1H), 3.80-3.75 (m, 2H), 3.69-3.59 (m, 1H), 3.25-3.09 (m, 9H), 3.03-2.37 (m, 3H), 2.83 (s, 6H), 2.62 (s, 3H), 2.55-2.42 (m, 1H). 2.22-2.10 (m. 1H),] .54-1.42 (m, 2H), 1.23-1.10 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H) Compound 106 Chemical Formula: CQH51CIF3N70583 Exact Mass: 993.28 Molecular Weight 994.61 W0 20] 2/103059 PCT/U820 l 2/022315 (0159] MS = 994.25; 'H—NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.96 (s, 1H), 8.48 (dd, 1 = 2.2, 6.3 Hz, 1H), 8.37-8.32 (m, lH), 7.99 (d, J = 1.9 Hz, 1H), 7.74-7.69 (m, 1H), 7.57-7.53 (m, 2H), 7.43-7.36 (m, 4H), 7.27-7.16 (m, 3H), 7.03-6.90 (m, 3H), 6.86 (d, J = 9.0 Hz, 2H), 6.68 (1, 7.4 Hz, 2H), 4.15-4.07 (m, 1H), 4.00-3.95 (m, 2H), 3.73 (s, 3H), 3.31-2.98 (m, 14H), 2.40-1.81 (m, 6H) Compound 105 Chemical Formula: F3N50583 Exact Mass: 1040.26 Molecular Weight 1042.09 MS = 1043.17; ‘H-NMR (300MHz, 10:1 CD30D) 5 ppm 8.02 (d, J = 1.9 Hz, 1H), 7.73-7.68(m, 1H), 7.33-7.23 (m, 6H), .11 (m, 3H), 7.01 (0,1 = 8.9 Hz, 2H), 6.87-6.74 (m, 5H), 6.63 (d. J = 9.1 Hz, 1H), 4.15-4.06 (m, 1H), 4.00-3.89 (m, 1H), 3.43 (s, 3H), 3.26-2.97 (m, 13H), 2.34 (s, 3H), 2.31-1.80 (m. 6H) PCT/U820 I 2/022315 Compound 104 0 cm ~ d (30-. MS6 al Formula: CIF3N30183 Exact Mass: 1078.32 Molecular Weight: 1079.71 MS = 1080.33; 'H-NMR (300MHz, 10:1 CDCI31CD30D)6 ppm 8.01 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 2.3, 8.5 Hz, 111), 7.29-7.23 (m, 6H), 7.12-7.00 (m, 6H), 6.87-6.80 (m, 3H), 6.77-6.71 (m, 2H), 6.61 (d, J = 9.2 Hz, 1H), 4.15-4.04 (m, 1H), 3.95-3.85 (m, 1H), 3.78- 3.72 (m, 2H), 3.23-2.93 (m, 14H), 2.62 (s, 3H), .80 (m, 6H), 1.61-1.46 (m, 2H), 0.77 (1, J = 7.3 Hz, 311) Compound 103 Chemiml Formula: CwH49C|zN7O.Sz Exact Mass: 897.27 Molecular Weight: 896.96 MS = 900.17; lH-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.45 (d. J = 2.2 Hz, 1H), 7.62 (dd, J = 2.3 , 9.1 Hz, 1H), 7.30-7.24 (m, 4H), 7.18-7.02 (m, 8H), 6.90-6.75 (m, 6H), PCT/USlelZ/OZZJIS 4.17-4.07 (m, 1H), 3.43 (s, 3H), 3.29-3.06 (m, 13H), 2.81 (s, 6H). 2.33 (s, 3H), .10 (m, Compound 102 Chemical Formula: C49H5‘CIN70652 Exact Mass: 935.33 Molecular : 936.58 MS = 937.17; ‘H-NMR (300MHz, 101 CDC13:CD30D) 6 ppm 8.46 (d, J =22 Hz, 1H), 7.61 (dd, J = 2.2, 9.1 Hz, 1H), 7.27-7.23 (m, 4H), 7.20-7.13 (m, 411), 7.10-7.03 (111,411), 6.85 (d, J = 9.0 Hz, 2H), 6.78-6.69 (m, 4H), 4.12-4.04 (m, 1H), 3.74 (t, J = 7.8 Hz, 2H), 3.22- 3.03 (m, 13H), 2.81 (s, 6H), 2.37-2.09 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H) Compound 101 /_’N ”CO-QN30 OH {@050CF3oI= 101-LG Chemim' Formula: Cs1H51C|FaN507$3 Exact Mass; 1104.26 Molecular Weight 1 105.63 W0 20] 2/103059 20 I 2/022315 MS = 1106.08; lH-NMR (300MHz, 10:1 CDCl3zCD30D) 6 ppm 8.01 (d, J = 2.0 Hz, 1H), 7.73-7.69 (m, 1H), 7.29-7.21 (m, 4H), 7.16-7.06 (m, 4H), 7.01 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.81-6.60 (m, 4H), 4.15-4.05 (m, 1H), 4.00-3.91 (m, 2H), 3.59 (s, 3H), 3.20-2.89 (m, 15H), 2.37-1.80 (m, 6H) Compound 100 0 F30 /_N’ ONO< Chemical Fonnu: CIF3N7OGSZ Exact Mass: 961.27 Molecular Weight: 962.50 MS = 963.25; lH-NMR (300MHz, l0:l CDC13:CD30D) 6 ppm 8.45 (d, J = 1.7 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.27.7.03 (m, 10H), 6.87-6.60 (m, 6H), 4.12-4.04 (m, 1H), 3.58 (s, 3H), 3.27-3.05 (m, 12H), 2.81 (s, 6H), 2.36-2.07 (m, 2H) Compound 99 HO {—NM O Om {NEQ g o... .33”"13G Chemical Formula: CsonCIN7OGS; Exact Mass: 949.34 Molecular Weight: 950.61 PCT/U820 l 2/022315 MS = 951.17; ‘H-NMR (300MHz. 10:1 CD3OD) 5 ppm 8.46 (bs, 1H), 7.65- 7.59 (m, 1H), 7.30-6.97 (m, 12H), .61 (m, 6H), 4.12404 (m, 1H), 3.84-3.67(m, 2H), 3.18-3.02 (m, 8H), 2.81 (s, 6H), 2.65-2.62 (m, 2H), 2.38-2.03 (m, 7H), 1.74-1.63 (m, 2H), 1.22-1.10 (m, 2H), 0.79 (t, 7.1 Hz, 3H) Compound 98 Chemical Formula: C47H4gC'F3N7‘O4Sz Exact Mass: 931.29 Molecular Weight 932.51 MS = 932.42; 'H-NMR (300MHz, 10:1 CDClg:CD;OD) 6 ppm 8.46 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 2.2, 9.1 Hz, 1H), .24 (m, 4H), 7.17-7.12 (m, 4H), 7.09-7.02 (m, 4H), 6.089-6.69 (m, 6H), 4.12-4.04 (m, IH), 3.44 (s, 3H), 3.28-3.06 (m, 1211), 2.82 (s, 6H), 2.45 (d, J = 1.4 Hz, 3H), 2.37-2.08 (m, 2H) PCT/U52012/022315 Compound 97 F30 / N’ 0—Q 0..
N301 Q @025 HNxb "(i=0 Chemifll Formuola. 01F3N30583 Exact Mass: 1074.28 Moiecular Weight 1075.64 MS = 1076.08; lH-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.01 (d, J = 2.1 Hz, 1H), 7.71 (dd, .1 = 2.1, 9.1 Hz, 1H), 7.28—7.20011, 5H), 7.16-7.00 (m, 5H), 6.89-6.83 (m, 3H), 6.77-6.71 (m, 2H), 6.62 (d, J = 9.1 Hz, 1H), 4.10 (bs, 1H), 3.96-3.87 (m, 1H), 3.43 (s, 3H), 3.32-2.93 (m, 15H), 2.77-2.63 (m, 1H), 2.45 (d, .1 = 1.4 Hz, 3H). 2.36-1.79 (m, 6H) Compound 96 00' \NN“ 1:8 "”6 Né§=o Chemical Formula: C49H5ZCIN70382 Exact Mass: 933.31 lar Weight: 934.56 MS = 935.50; ‘H-NMR (300MHz, 10:1 CD30D) 6 ppm 8.45 (d, .1 = 2.1 Hz, 1H), 7.62 (dd, J = 2.1, 9.1 Hz, 1H), 7.28-7.22 (m, 4H), 7.18-7.01 (m, 8H), 6.95-6.82 (m, 4H), W0 20] 2/103059 PCT/U820 l 2/022315 6.76 (d, J = 9.3 Hz, 2H). 4.12404 (m, 1H), 3.78-3.72 (m, 2H). 3.29-3.05 (m, 14H), 2.81 (s, 6H), 2.35-2.08 (m, 2H), 2.00-1.87 (m. 4H) Compound 95 O 0 0.. ' (3 <~@023 3 <N N§=o Chemical Formula. C53H53C'F3N30753 Exact Mass: 1076.30 Molecular Weight: 1077.69 MS = 1078.33; 'H—NMR (300MHz, 10:1 CDCl3:CD30D) 6 ppm 8.00 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 2.0, 9.1 Hz, 1H), 7.29-7.12 (m, 6H), 7.08-6.81 (m, 8H), 6.63 (d, J = 9.3 Hz, 1H), 4.10 (bs, 1H), 4.00-3.84 (m, 1H), 3.80-3.72 (m, 2H), .86 (m, 16H), .47 (m, 1H), 2.37-1.81 (m, 10H) Compound 94 Chemical Formula: C43H51CIN30482 Exact Mass: 878.32 Molecular Weight 879.53 W0 20] 2/103059 PCT/U32012/022315 MS = ; Compound 93 Chemical Formula: C50H550|F3N70583 Exact Mass: 1021.31 Molecular Weight: 6 MS = 1022.33; Compound 92 O O OH Q ‘1. {j QHN‘iS 133:0 «3 Chemical Formula: C52H560lF3N50783 Exact Mass: 1064.30 Molecular Weight 1065.68 MS = 1066.42; lH-NMR (300MHz, 10:1 CDC1;:CD3OD)6 ppm 8.01 (113, 1H), 7.73-7.70 (m. 1H), .22 (m, 7H), 7.15—7.01 (m, 5H), 6.92-6.75 (m, 5H), 6.63 (d, J = 9.2 Hz, 1H), 4.00-3.90 (m, 1H), 3.43 (s, 3H), 3.32-2.97 (m, 15H), 2.63 (s, 3H), 2.35-1.67 (m, 6H), 1.47-1.37 (m. 1H), 1.29 (s, 3H) -99.
W0 201 2/103059 PCT/U82012/022315 Compound 91 Chemical Formula: C57H35CIF3N70753 Exact Mass: 1147.37 Molecular Weight 1148.81 MS = 1149.50; lH-NMR (300MHz, 10:1 CDC131CD30D) 6 ppm 8.00 (d, J = 2.0 Hz, 1H), 7.75-7.70 (m, 1H), 7.35-7.23 (m, 6H), 7.20-7.02 (m, 5H), 6.91-6.73 (m, 3H), 6.70- 6.56 (m, 3H), 4.26-4.17 (m, 1H), 4.09-3.92 (m 2H), 3.72-3.51 (m, 2H), 3.41 (s, 3H), 3.32- 2.85 (m, 18H), 2.70-2.57 (m, 1H), 2.37-1.67 (m, 11H), 1.29 (s, 3H), 1.11 (bs, 1H) Compound 90 <~@023CFaHN~-\:S N§=o :Q Chemical aI CsaHmClFaN707Sa Exact Mass: 1161.39 Molecular Weight: 4 MS = 8; lI-I-NMR (300MHz, 10:1 CDC13ZCD30D) 6 ppm 8.00 (d, J = 1.7 Hz, 1H), 7.72 (dd, .1 =2.2, 8.9 Hz, 1H), 7.35-7.23 (m, 7H), 7.20-7.01 (m, 5H), 6.92-6.75 W0 20] 2/103059 PCT/U320 I 2/022315 3H), 6.68-6.59 (m, 3H), 4.29-4.20 (m. 1H), 3.41 (s, 3H), 3.32-2.98 (m, 18H), 2.84-2.75 (m, 1H), 2.33-2.21 (m, 4H), 2.11-1.67 (m, 6H), 1.57-1.38 (m, 2H), 1.29 (s, 3H), 0.91 (s, 3H) Compound 89 Chemical a: CwH53ClFaN7O753 Exact Mass: 1133.36 Molecular Weight 1134.79 MS = 1134.83; ‘H-NMR (300MHz, 10:1 DJOD) 6 ppm 8.00 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 2.2, 9.1 Hz, 1H), .29 (m, 4H), 7.27-7.20 (m, 3H), 7.15-7.10 (m, 3H), 7.04 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.85-6.81 (m, 1H), 6.72 (bs, 1H), 6.66-6.62 (m, 2H), 3.86-3.79 (m, 1H), 3.40 (s, 3H), 3.33-2.97 (m, 16H), 2.39 (s, 3H), 2.34- 1.68 (m, 7H), 1.45-1.35 (m, 1H), 1.29 (s, 3H), 1.13 (s, 3H) Compound 88 °OO Om Q {“7 Q02“ ““1C390 Chemical Formula: C52H560IF3N30582 Exact Mass: 1044.34 Molecular Weight 1045.63 ~101- PCT/U820 l 2/022315 MS = 1046.00; ‘H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.45 (m, 1H), 7.65-7.60 (m, 1H), 7.28-7.02 (m. 10 H), 6.86 (d, J = 8.9 Hz, 2H), 6.78-6.67 (m, 3H), 6.53 (t, 6.8 Hz, 1H) .03 (m, 2H), 3.60 (s, 3H), 3.30-3.00 (m, 13H), 2.82 (s, 6H), 2.38-2.11 (111, 511) Compound 87 /-N’ O O 4 . Q N§=o 1Q Chemical Formula: C55He1CIF3N70583 Exact Mass: 1103.35 Molecular Weight: 1104.76 MS = 7; ‘H-NMR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.07 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.0 Hz. 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 2.2, 9.1 Hz, 1H), 7.66-7.60 (m, 1H), 7.54-7.48 (m, 1H), 7.36-7.20 (m, 5H), 7.17-7.03 (m, 4H), 6.93-6.82 (m, 2H), 6.69-6.63 (m, 2H), 6.41 (s, 1H), 4.00-3.84 (m, 1H), 3.40 (s, 3H), 3.33-3.00 (m, 12H), 2.39 (s, 3H), 2.34-1.67 (m, 7H), 1.41 (p, 7.0 Hz, 1H), 1.29 (s, 3H) W0 20] 2/103059 20 I 2/022315 Compound 86 HO 0 fl” /_~’ 0 O <6CH C7 1.
QHN~~\:S #0 Q Chemical Formula: C57H35CIF3N70733 Exact Mass: 7 Molecular Weight 1148.81 M5 = 1149.42; lH-NMR (300MHz, 10:] CDC13:CD30D) 6 ppm8.00 (d, J = 2.0 1H), 7.72 (dd, J = 2.2, 9.0 Hz, 1H), 7.35-7.32 (m, 2H), 7.28-7.17 (m, 6H), 7.10-7.02 (m, 4H), 6.91-6.85 (m, 3H). 6.74-6.62 (m, 3H), 4.00-3.88 (m, 2H), 3.42 (s, 3H), 3.32-2.98 (m, 16H) 2.57 (s, 3H), 2.34-2.24 (m, 3H), 2.12-1.48 (m, 8H), 1.29 (s, 3H), 1.27 (s, 3H) Compound 85 Chemical Formula: C51H570|N50582 Exact Mass: 976.35 Molecular Weight 977.63 M8 = 977.42; ‘H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.37 (d, J =2.1 Hz, 1H), 7.56 (dd, J = 2.0, 9.0 Hz, 1H), 7.25-7.17 (m, 4H), 7.09-6.98 (m. 8H), 6.84 (d, .l = 8.9 Hz, PCT/U820 I 2/022315 2H), 6.72-6.68 (m, 2H), 6.54-6.49 (m, 2H), 4.08-3.99 (m, 1H), 3.75-3.51 (m, 2H), 3.33 (s, 3H), 3.21-2.94 (m, 16H), 2.74 (s, 6H), .02 (m, 2H), 2.26 (s, 3H) Compound 84 Chemical Formula: ngH51CIN30532 Exact Mass: 1004.38 Molecular : 1005.68 MS = 1005.58; 'H-NMR (300MHz, 10:1 CDC13:CD30D) 8 ppm 8.36 (s, 1H), 7.53 (dd, 1 = 2.1, 9.1 Hz, 1H), 7.23-7.15 (m, 4H), .95 (m, 8H), 6.84-6.65 (m, 4H), 6.59-6.49 (m, 2H), 4.20-4.09 (m, 1H), 4.03-3.93 (m, 1H), 3.31 (s, 3H), 3.21-2.97 (m, 15H), 2.72 (s, 6H), 2.23-1.99 (m, 2H), 2.20 (s, 3H), 1.50-1.28 (m, 2H), 0.81 (s, 3H) Compound 83 Chemical Formula: C52H59C|N50582 Exact Mass: 990.37 Molecular Weight: 991.66 PCT/U82012/022315 MS = 991.42; lH-NMR (300MHz, 10:1 CDC132CD30D) 6 ppm 8.37 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 2.], 9.1 Hz, 1H), .15 (m, 4H). 7.14-7.05 (m, 4H), 7.03-6.95 (m, 4H), 6.85-6.79 (m, 3H), 6.70-6.60 (m, 3H), 4.06-3.96 (m, 1H), 3.80 (p, 7.9 Hz, 1H), 3.34 (s, 3H), 3.20-3.03 (m, 12H), 2.73 (s, 6H), 2.49 (s, 3H), 2.28-2.00 (m, 4H), 1.46-1.39 (m, 2H), 1.18 (s, Compound 82 Chemical Formula: C50H550|N30532 Exact Mass: 946.34 Molecular Weight 947.61 MS = 943.50; ‘H-NMR (300MHz, 10:1 0303033013) 6 ppm 8.45 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 2.2, 9.1 Hz, 1H), 7.32-7.24 (m, 4H), 7.18-7.01 (m, 8H), 6.90 (d, J = 9.0 Hz, 2H), 6.82-6.75 (m, 2H), 6.66-6.63 (m, 2H), .06 (m, 1H), 4.00 (t, J= 7.4 Hz, 2H), 3.39 (s, 3H), 3.29-3.10 (m, 12H), 2.32 (s, 6H), 2.39 (s, 3H), 2.36-2.10 (m, 2H), 1.96 (p, I = 7.5 Hz, W0 201 59 PCT/U82012/022315 Compound 81 Chemiwl Formula: C51 1157011430382 Exact Mass: 976.35 Molecular Weight: 977.63 MS = 977.17; ‘H-NMR (300MHz, 10:1 CDC13:CD30D) 6 ppm 8.45 (d, J =2.2 Hz, 1H), 7.63 (dd, J = 22, 9.1 Hz, 1H), 7.33-7.24 (m, 4H), 7.19-7.03 (m, 8H), 6.89 (d, J = 9.0 Hz, 2H), 6.81-6.75 (m, 2H), 6.67 (ha, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.13-4.05 (m, 1H), 3.83 (q, lOHz, 2H), 3.40 (s, 3H), 3.30-3.11 (m, 13H), 2.82 (s, 6H), 2.39 (s, 3H), 2.36-2.10 (m, 2H), 1.11 (s, 3H) Compound 13'] 4(4rchlorophenyl)((S)-3,4-dihydroxybdyl}3-(3-((+(4—(((R)-4—(dlmethylamlnoH~(phanylmlo)butanyl)amino)-3— nitrophanylaulfonamido)phanyI)ethynyl)phenyl)-N-(3-(4»mefl1ylpiperazin-1 -yl)propyl)-1H-pyn’ole-Z-carboxamide 1H NMR (300 MHz, CD3OD), 5 8.39 (d, J=2.2, 1H), 7.63 (dd, J=2.2, 9.0, 1H), 7.60~7.40 (m, 3H), .27 (m, 2H), 7.15~7.10 (m, 8H), 7.01~6.89 (m, 6H), 4.30~4.28 (m, W0 20] 2/103059 2012/022315 2H), 4.11~4.08 (m, 1H), 3.55~3.49 (m, 1H), 3.45~3.43 (m, 2H), 3.35~3.31 (m, 5H), 3.19~3.14 (m, 9H), 2.82 (s, 9H), .68 (m, 2H), 2.20~2.00 (m, 3H), 1.68~l.64 (m, 3H); ”C NMR (75 MHz, c0300), 5 165.4, 148.1, 139.4, 136.6, 136.2, 134.8, 134.4, 134.3, 133.7, 1327,1322, 1320,1315, 1312,1305, 130.1, 129.8, 129.3, 128.0, 127.9, 126.7, 125.2, 124.7, 124.6, 123.5, 121.1, 120.1, 116.3902, 90.0, 70.2, 67.3, 55.9, 55.4, 52.7, 52.3, 50.5, 46.1, 43.6, 43.5, 39.4, 37.6, 36.4, 30.1, 25.7; Compound 138 (4-chlorophenyl)(3-((4—(+((4—(dimothylamino}1-(phenyllhio)butan—2—yl)amino) nitrophenylsulfonamido)phenyl)ethynyI)phenyl)~1 ,2-dimathyl-N-(3o(4—memylplperazlnyl)propyl)-1H-pyrroIe carboxamide ‘11 NMR (300 MHz, CD30D), 5 8.38 (d, J=2.0, 1H), 7.62 (dd, J=1.9, 9.1, 1H), 7.37~6.90 (m, 18H), 4.09~4.o7 (m, 1H), 3.38~3.33 (m, 3H), 3.24314 (m, 14H), 2.82~2.80 (m, 1111), 2.41 (s, 3H), 2.2o~2.15 (m, 2H), 1.77~1.72 (m, 2H); l3c NMR (75 MHz, CD30D), 8170.3,148.1, 139.4, 137.1, 136.2, 134.9, 134.4, 1343,1338, 133.7, 133.3, 133.2,131.74, 131.68, 131.5, 13l.4,130.4,130.l,129.6,129.4,128.0,127.9,127.4,124.1,121.7, 121.1, 120.2, 116.4, 116.3, 90.2, 89.9, 55.9, 55.2, 52.4, 50.3, 43.5, 39.3, 37.3, 32.0, 30.1, 25.8, 11.4; PCT/U820 l 2/022315 Compound 139 (R)-4'(4chlorophenyl)—3-(3-((4-(4-((4-(dimethylamino)-1~(phenylthio)butan-2—yl)amino) nitrophenylsulfonamido)phenyl)ethynyl)phenyl)methyl-N-(3-(4-methylpiperaziny|)propyl)-1H-pyrrole- Zmrboxamide \N/\\ \\/N\\\\ ° / N’ BM-752 1H NMR (300 MHz, CD30D), 6 8.41 (d, J=2.3, 1H), 7.65 (dd, I=2.3, 9.2, 1H), 7.43~7.40 (m, 2H), .25 (m, 2H), 7.22~7.07 (m. 7H), 7.04-6.91 (m, 8H), 4.09-4.07 (m, 1H), 3.81 (s, 3H), 3.60633 (m, 4H), 3.24~3.05 (m, 12H), 2.84 (s, 6H), 2.73 (s, 3H), 2.29~2.16 (m, 2H), l.57~l.51 (m, 2H); WO 03059 PCT/U820 l 2/022315 Compound 140 (R)(4-chlorophenyl)-1 ,2—dimethyl-N—(3-(4-methylpiperazin—1-yl)propyl)—4-(3-((4-(4—((4-morphoIino~1- (phenylthio)butanyI)amino)((trifluoromethyl)sulfonyl)phenyIsulfonamido)phenyl)ethynyl)phenyl)o1H- ecarboxamide Facozs BIA-760 1H NNIR (300 MHZ, CD30D), 8 7.98 (d, J=1.9, 1H), 7.72 (dd, J=l.9, 9.1, 1H), 7.73~6.98 (m, 16H), 6.88 (d, J=8.9, 1H), 6.80 (d, J=9.4, 1H), 4.0l~3.90 (m, 3H), 3.79~3.69 (m, 3H), 3.52~3.30 (m, 12H), 325-3 .03 (m, 9H), 2.86~2.41 (m, 7H), 2.2l~2.l7 (m, 1H), 2.09~2.06 (m, 1H), l.79~l.74 (m, 2H); Compound 14] (R)(4-chlorophenyl)-4—(3—((4-(4-((4—(dimethylamino)—1~(phanylthio)butanyl)amino) ((tfifluoromethyl)sulfonyl)phenylsuIfonamido)phenyl)emynyl)phenyl)-1 .24imethyl-N—(3-(4- methylpiperazinyl)propyl)—1H—pyrrolecarboxamlde \ [In-l [NJ HN F3COZS WO 03059 PCT/U320 I 2/022315 BM-761: 'H NMR (300 MHz, CD30D), 5 8.01 (d, J=2.0, 1H), 7.71~7.7s (m, 2H), 7.43~6.81 (m, 13 H), 3.99~3.94 (m, 1H), 3.83~3.36 (m, SH), 3.18~3.06 (m, 11H), 2.89~2.44 (m, 15H), 2.2o~2.o7 (m, 2H), l.70~l.68 (m, 2H); nd 142 (RH-(34(4~(4~((4~(dimethylamino)—1-(phenylthio)butan—2-yl)amino) nitrophenylsulfonamido)phenyl)ethynyl)phenyl)(4-fluorophenyI)-1 ,2-dlmethyl—N-(3-(4— methylpiperaziny|)propyl)~1 H-pyrrole—S—carboxamide [01901 'H NMR (300 MHz, CD30D), 5 8.42 (d, J=2.3, 1H), 7.66 (dd, J=2.2, 9.2, 1H), 7.41~7.38 (m, 3H), 7.28~7.09 (m, 9H), 7.07~6.93 (m, 6H), 4,114.09 (m, 1H), 3.82~3.35 (m, 6H), 3.25~3.06 (m, 9H), 2.93~2.43 (m, 16H), 2.23~2.17 (m, 2H), 1.70~1.65 (m, 2H); ~110~ W0 20] 2/103059 PCT/U820 l 2/022315 Compound 143 (R)(3-((4-(4—((4-(dimethylamino)(phenylthio)butan-Z-yl)amino)—3- ((trifluoromemyl)sulfonyl)phenylsulfonamido)phenyl)ethynyI)phenyl)-5—(4-fluorophenyl)-1 ,2- dimethyl-N-(3-(4-methylpiperaziny|)propyI)-1H-pyrrole-a-carbommide BM-763 'H NMR (300 MHz, CD30D), 5 8.00 (d, J=2.0, 1H), 7.75 (d, J=9.2, 1H), 7.39~7.23 (m, 7H), .00 (m, 9H), 6.90 (d, J=9.0, 1H), 6.83 (d, J=9.3, 1H), 3.99~3.97 (m, 1H), 3.82~3.36 (m, SH), 3.28~3.04 (m. 12H). 2.91~2.44 (m, 14H), 2.20~2.04 (m, 2H), 1.75~1 .71 (m, 2H); Compound 144 (R)(4-fluorophenyI)-1,2-dimethyl-N-(3-(4-methylpiperazinyl)pr0pyl)(3-((4-(4—((4-morpholino (phenylthio)butanyl)amino)-3{(trifluoromethyl)aulfonyl)phenyIsulfonamido)phenyl)ethynyl)phony!)- 1 H-pyrrole-s-carboxamide 20 l 2/022315 'H NMR (300 MHz, colon), 5 7.98 (d, J=2.0, 1H), 7.73 (dd, J=2.0, 9.2, 1H), 7.36~6.88 (m, 17H), 6.81 (d, J=9.4, 1H), 3.99~3.95 (m, 3H), 3.80~3.48 (m, 13H), 3.26~2.93 (m, 11H), 2.84~2.42 (m, 7H), 2.22~2.19 (m, 1H), 2.09~2.05 (m, 1H), l.76~1.76 (m, 2H); Compound 145 (R)(4chlorophenyl)—1,241imethyl-N-(344-mefl1yIpiperazinyl)propyl)(3-((4-(4—((4— morpholino(phenylthio)butany|)amino)nitrophenylsulfonamido)phenyl)ethynyl)phenyl)-1H- pynole~3-carboxamide BM-765 1H NMR (300 MHz, CD3OD), 5 8.39 (d, J=2.3, 1H), 7.64 (dd, J=2.2, 9.2, 1H), .o7 (m, 13H), 7.00~6.9l (m, 5H), 4.10~3.71 (m, 6H), 3.53~3.33 (m, 8H), 3.21~3.12 (m, 13H), 2.83~2.4l (m, 7H), 2.28~2.l9 (m, 2H), 1.744 .70 (m, 2H); PCT/U820 l 15 Compound 146 (R)cyclopropyl(3-((4-(4-((4.(dimemylamlno)(phenylthio)butanyl)amino)- 3-nitrophenylsulfonamido)phenyl)ethynyl)phenyl)fluorophenyI)-2~methyl-N- (3-(4-methylpiperaziny|)propyl)-1H-pyrrole—S-carboxamide BM-767 1H NMR (300 MHz, CD30D), 8 8.41 (d. J=2.3, 1H), 7.66~7.63 (m, 1H), 7.40~7.24 (m, 4H), 7.20—7.09 (m, 7H), 7.04~6.92 (m, 7H), .09 (m, 1H), 3.41~3.34 (m, 4H), 3.23~2.89 (m, 12H), 2.84~2.51 (m. 13H), 2.26~2.14 (m. 2H), 1.80~1.64 (m, 2H), 0.96~O.83 (m, 2H), 0.60-0.47 (m, 2H); Compound 147 (R)-5.(4-chlorophenyI)(3-((4-(4-((4—(dimethylamino)—1-(phenylthio)butanyl)amino)«3- nitrophenylsulfonamido)phenyl)ethyny|)phenyl)-1 ,2-dlmethyl-N—(Z-(pyrrolidinyl)ethyl)-1H- pyrrole-a-carboxamide PCT/U820 l 2/022315 'H NMR (300 MHz, CD30D), 5 8.41 (d, J=2.3, 1H), 7.66 (dd, J=2.3, 9.2, 1H). 7.4l~7.10 (m, 13H), 7.02~6.93 (m, SH), 4.124.09 (m, 1H), 3.84~3.34 (m, 9H), 3.23~3.15 (m, 7H), 3.93~3.89 (m, 2H), 2.84 (s, 6H), 2.45 (s, 3H), 2.26 ~l.99 (m, 6H); Compound 148 3-((4-(4—((4-(dimethylarninoH-(pheny|thio)butan—2-yl)amino) nitrophenylsulfonamido)phenyl)ethynyl)phenyl)(4~fluorophenyI)-1{2-hydroxyethyl)-2— methyl-N-(3-(4-methylpiperazinyl)propyl)-1H-pyrrolemrboxamide O \ N\/\OH Oil 9.-.... F \/NJ NgzerV‘é BM-769 1H NMR (300 MHz, , 8 8.41 (d, J=2.3, 1H), 7.67~7.64 (m, 1H), 7.40~6.93 (m, 18H), 4.09~3.34 (m, 9H), 3.23~3.06 (m, 9H), ,2.85~2.47 (m, 15H), 2.20~2.14 (m, 2H), 1.71~1.60 (m. 2H); -114— PCT/U82012/022315 Compound 149 (R)-N—(4—(4—((4'-chloro-{1,1'-biphenyl]-2—yl)methyl)piperaziny|)phenyl)((4—(dimethylaminoM- (phenyImio)butanyl)amino)nitrobenzenesulfonamide BM-770 ‘H NMR (300 MHz, CD3OD), a 8.24 (s, 1H), .68 (m, 1H), 7.58~7.47 (m, 5H), 7.39~7.31 (m, 3H), 7.12 (d, J=7.0, 2H), 7.02-6.89 (m, 6H), 8.18 (d, J=8.7, 2H), 4.40 (s, 2H), 4.08 (hr. 111), 3.33~3.31 (m, 3H), 3.21~3.08 (m, 9H), 2.84 (s, 6H), 2.25~2.15 (m, 2H); I3c NMR (75 MHz,CD3OD),6148.6, 147.9, 144.4, 139.7, 136.2, 135.3, 134.4, 132.6, 132.3, 132.2, 132.1, 131.6, 131.4, 130.2, 130.1, 130.0, 128.0, 127.8, 127.6, 127.5, 124.3, 118.6, 116.2, 58.0, 55.9, 52.8, 52.4, 47.5, 43.5, 39.6, 30.1; Compound 150 (R)—5-(4—chlorophenyl)(3-(4-(4-(4-((4-(dimethylamino)—1-(phenyIfl1io)butanyl)amino)-3— nitrophenyIsulfonamido)phenyI)piperazinyl)phanyI)-1,2-dirnethyl-N-(3-(4-methylpiperazin y|)propyl)-1H-pyrrolecarboxamide PCT/U820 l 2/022315 1H NMR (300 MHz, CD30D), 6 8.29 (d, J=2.1, 1H), 7.58 (dd, 1:2.1, 9.0, 1H), 7.26 (11 J=8.3, 2H), 7.17~6.89 (m, 14H), 6.73~6.7O (m, 2H), 4.10~4.05 (m, 1H), .31 (m, 10H), 3.24~3.18 (m. 15H), 2.82~2.87 (m, 11H), 2.42 (s, 3H), 2.20~2.16 (m, 2H), l.78~1.71 (m, 2H); ”c NMR (75 MHz, cnsov), 8 170.3, 150.3, 148.5, 148.0, 137.7, 136.2, 134.8, 134.4, 133.8, 133.3, 132.5, 1322,1321, 131.6, 131.2, 130.2, 130.1, 129.6, 128.0, 127.9, 127.6, 125.1, 124.2, 122.6, 120.6, 118.9, 116.3, 116.2, 55.9, 55.3, 52.6, 52.4, 51.1, 50.9, 50.4, 43.6, 43.5, 39.5, 37.4, 32.0, 30.1, 25.9, 11.4; Compound 151 (R)(4-chlorophenyl)-4—(3—((H4-((4-(dimethylamino)-1{phenylthimbutan-Z-ynamino)—3— ((trifluoromethyl)sulfonyI)phenylsulfonamido)phenyl)ethynyl)phenyl)—N-(2- (dimethylamlno)ethyl)—1,2-dlmethyl-1H-pyrrole-a-carboxamide E81 MS: m/z 1005.5 (M + HY; ~116- W0 20] 2/103059 PCT/U820 l 2/022315 Compound 152 (R)(4-chIorophenyI)-4.(3-(4-(4-(4-((4-(dimethylaminoH-(phenylthio)butanyl)amino) ((tn'fluoromethyl)sulfonyl)phenylsulfonamido)phenyl)pipetazinyl)phenyI)-1.2-dimethyl—N—(3-(4- methylpiperazinyl)propyl)-1H-pynole-S-carboxamide BM-773 'H NMR (300 MHz, CD30D), a 7.86 (d, J=1.8, 1H), 7.69 (dd, J=2.0, 9.2, 1H), 7.29~2.26 (m, 4H). 7.20~7.08 (m, 6H), 174 (m, 8H), 3.97~3.94 (m, 1H), 3.52~3.3o (m, 7H), 3.25~3.01 (m, 18H), 2.84~2.80 (m, 11H), 2.42 (s, 3H), 2.l8~2.l4 (m, 1H), 2.05~2.01 (m, 1H), 1.79~1.75 (m, 2H); W0 20] 2/103059 PCT/U52012/022315 Compound 153 (R)-5—(4-chlorophenyl)«H3-(4-(4-(4-((4-(dimethylamino)-1~(phenylthio)butan yl)amino)nitrophenylsuIfonamido)phenyl)piperazin—1-yl)phenyl)-1,2—dimethyI-N-(2- lidiny|)ethyI)-1H-pyrrole-a-carbommide Q3 " "I"1 o Q :N—/ HN~Q~§-NH BM-774 IH NMR (300 MHz, CD30D), 5 8.30 (d, J=2.3, 1H), 7.58 (dd, J=2.3. 9.2, 1H), 7.29~7.26 (m, 2H), 7.l7~6.84 (m, 14H), 6.69~6.66 (m, 2H), .06 (m, 1H), 3.58~3.3l (m, 8H), 3.19~3.12 (m, 13H), 2.95~2.94 (m, 2H). 2.83 (s, 6H), 2.45 (s, 3H), 2.24—1.92 (m. 611); BS] MS: m/z 1004.7 (M + H)“; Compound 154 (MS-(444444(4-(dimethylamino)—1{phenylmimbutan-Z-yl)amino)«3- nitmphenylsulfonamido)phenyl)piperazinyl)phenyI)(4—fluorophanyl)-1,2—dimethyO-N-(3-(4- methylpiperazinyl)propyl)-1H~pyrrolemrboxamide PCT/U820 l 2/022315 ‘H NMR (300 MHz, CDJOD), 6 8.27 (d, J=2.2, 1H), 7.58 (dd, J=2.2, 9.2, 1H), 7.19~6.88 (m, 16H), 6.80~6.77 (m, 2H), 4.08~4.07 (m, 1H), 3.46~3.44 (m, 4H), .29 (m, 17H), 3.19~3.13 (m, 4H), 2.91~2.86(m, 5H), 2.8] (s, 6H), 2.40 (s, 3H), 2.18~2.13 (m, 2H), 1.81~l.77 (m, 2H); Compound 155 (R)(4—chIorophenyl)4-(3-(4-(4-(4-((4-(dimethylaminoH— lmio)butanyl)amino) nitrophenylsulfonamido)phenyl)piperazinyI)phenyI)-N-(2- (dimethylamino)ethyl)-1 .2—dimethyI-1H-pyrrole—a-carboxamide in o O \\N\ F} O BM-777 'H NMR (300 MHz, CD30D), 8 8.30 (d, J=2.2, 1H), 7.57 (dd, J=2.l, 9.1, 1H), 7.30~7.27 (m, 2H), 7.l6~6.80 (m, 14H), 6.644162 (m, 2H), 4.08—4.06 (m, 1H), 3.51~3.31 (m, 6H), 3.21~3.04 (m, 13H), 2.84 (s, 6H), 2.83 (s, 6H), 2.46 (s, 3H), 2.24~2.14 (m, 2H); ~119- W0 20] 2/103059 PCT/U82012/022315 Compound 156 (R)-4{3-(4-(4-(4-«4-(dimemylamino)(phenyIthio)butanyl)amino)—3- uoromethyl)suIfonyl)phenylsu|fonamido)phenyl)piperazin yI)phenyI)(4-fluorophenyl)-1 ,2-dimethyI-N-(3-(4-methylpiperazin y|)propyl)-1 H-pyrrole-Scarboxamide \N/fi k/‘\\\oN Q8 " \ _/"'l 9 O ,~ QHN fi-NH Facozs BM-779 BS! MS: m/z 1118.3 (M + HY; Compound 157 (R)(4-chlorophenyl)-1,2-dimethyI-N-(3-(4-methylpiperazinyl)propyl)(3-(4-(4-(4- ((4-morpholino-1{phenyllhio)butanyl)amino) nitrophenylsulfonamido)phenyl)piperazinyl)phenyl)-1H-pyrmle—S—carboxamide ~120— PCT/USZOI2/022315 lH NNIR (300 MHZ, CD3OD), 5 8.29 (d, J=2.2, 1H), 7.60 (dd, J=2.2, 9.2, 1H), 7.29~6.90 (m, 16H), .74 (m. 2H), 4.09~3.98 (m, 3H), 3.72~3.69 (m, 2H), 3.39~3.32 (m, 12H), 3.26~3.06 (m, 17H), 2.84w2.78 (m, 5H), 2.99 (s, 3H), 2.28~2.l8 (m, 2H), 1.79~1.74 (m, 2H); Compound 158 (R)(4-chlorophenyl)-1,2-dimethyI-N—(3-(4-mefl1ylpiperazin—1-yl)propyl)(3-(4- (4-(4-((4-morpholino(phenylthio)butanyl)amino)~3- ((trifluoromethybsulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyl)-1H- pyn’ole—S-mrboxamide \N/\\N K/ \ F3C028 BM-781 !H NMR (300 MHz, CDgOD), 5 7.88 (d, J=2.1, 1H), 7.70 (dd, J=2.2, 9.2, 1H), 7.30~7.26 (m, 4H), 7.19~7.09 (m, 6H), 7.04~6.88 (m, 5H), .7l (m, 3H), 3.99~3.97 (m, 3H), 3.72~3.70 (m, 2H), 3.4o~3.32 (m, 9H), 3.26~3.ll (m, 20H), 2.81 (s, 3H), 2.72 (t, J=7.l, 2H), 2.44 (s, 3H), 2.24~2.2o (m, 1H), 2.10~2.08 (m, 1H), l.76~1.71 (m, 2H); ~121- W0 2012/103059 PCT/U320 l 2/022315 Compound 159 (R).(4-fluorophenyl)_-1 .2-dimathyl-N-(3—(4-methylpiperazinyI)propyl)4—(3-(4—(4—(4-«4-morpholino—1- (phenyhhlo)butanyl)amIno)((trifluoromefluyl)sulfonyI)phenylsulfonamido)phenyl)piperazinyl)phenyI)-1H- e-S—carboxarnida BM-782 ‘H NMR (300 MHz, CD30D), 5 7.85 (d, J=2.0, 1H), 7.69 (dd, J=2.2,9.2,1H), 7.26~7.23 (m, 2H), 7.2o~7.10 (m, 6H), 7.05~6.93 (m, 7H), 6.80-6.77 (m, 3H), 3.97~3.94 (m, 3H), 3.69-3.67 (m, 2H), .29 (m, 18H), 3.25~3.04 (m, 11H), 2.90~2.86 (m, 5H), 2.40 (s, 3H), 2.21~2.17 (m, 1H), 2.07~2.03 (m, 1H), l.81~l.77 (m, 2H); W0 20] 59 20 l 2/022315 Compound 160 (R)(4-fluorophenyI)-1.2-dimethyl—N-(3—(4-methylpiperazinyl)propyl)4-(3—(4—(4-(4- ((4-morpholino(pheny|thio)bu{anyl)amino)—3- nitrophenylsulfonamido)pheny|)piperazinyl)phenyl)-1H—pyrrole-s-carboxanflde BM-783 ‘H NMR (300 MHz, c0300), 6 8.28 (d, J=2.3, 1H), 7.59 (dd, J=2.3, 9.2, 1H), 72045.39 (m, 16H), 6.79~6.77 (m, 2H), 4,114.08 (m, 1H), 3.97~3.94 (m, 2H), 3.73—8.69 (m, 2H), 3.49~3.29 (m, 18H), 3.24~3.o4 (m, 11H), 2.90~2.86 (m, 5H), 2.40 (s, 3H). 2.27~2.17 (m, 2H), l.81~l.77 (m, 2H); Compound 161 (R)—4-(3-(4-(4—(4-((4-(dimethylamino)-1(phenylthio)butan-2.yl)amino) nitrophenylsulfonamido)phenyl)piperazinyl)phenyI)(4-fluorophenyl)-N.1.2- trimethyl-1H-pyrrole-a-carboxamide PCT/U820 l 2/022315 ‘H NMR (300 MHz, c0300), 5 8.29 (d, J=2.3, 1H), 7.59 (dd, J=2.3, 9.2, 1H), 7.19~6.89 (m, 17H), 6.81 (d, J=7.7, 1H), 4.09~4.06 (m, 1H), 3.34~3.31 (m, 12H), . 13 (m, 3H), 2.82 (s, 6H), 2.67 (s, 3H), 2.38 (s, 3H), 2.23~2.14 (m, 2H); Compound 162 (4-fluorophenyl)-N.1 .2-trimethyl—4—(3—(4-(4-(4-«4—morpholinc-1 - (phenyIthlo)butanv2-yl)amino)nitrophenylsuIfonamido)phenyl)piperazin~1- yl)phenyl)-1H-pyrrole-S-carboxamide BM-785 IH NMR (300 MHz, CDgOD), 5 8.30 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.2, 1H), 7.18~6.88 (m, 17H), 6.79 (d, J=7.7, 1H), 4.10~4.07 (m, 1H), 3.99~3.95 (m 2H), 3.72~3.68 (m, 2H), 3.41~3.31 (m, 13H), 3.36~3.06 (m, 6H), 2.67 (s, 3H), 2.39 (s, 3H), 2.28~2.18 (m, 2H); W0 20] 2/103059 PCT/U520 l 2/022315 Compound 163 (R)(4-fluomphenyl)-4o(3-(44444((4—(4-hydroxypiperidinyl)(phenylthio)butan- 2-yl)amino)nitrophenylsulfonamido)phenyl)piperazin—1-yl)phenyl)-N.1,2-tn'methyl- 1H-pyrroIe-3arboxamide BM-786 'H NMR (300 MHz, CD30D), s 8.30 (d, J=2.2, 1H), 7.58 (dd, J=2.3, 9.2, 1H), 7.16~6.89 (m, 16H), 6.83 (s, 1H), 6.74 (d, J=7.7, 1H), 4.04-4.70 (m, 2H), 3.52~3.so (m, 1H), 3.36~3.29 (m, 7H), 3.26~3.14 (m, 10H), 2.99~2.91 (m, 1H), 2.67 (s, 3H), 2.40 (s, 3H), 2.28~2.06 (m, 3H), 1.90~1.87 (m, 2H), l.66~1.62 (m, IR); Compound 164 (R)—4-(3-(4.(4-(4-((4-(dlmemylamlno)-1(phenylthiomutan-Z-yl)amino)—3- ((trifluoromethyl)sulfonyI)phenylsulfonamido)phenyl)piperazinyl)phenyl)(4- fluorophenyl)-N,1 methyl-1H-pyrmIe-S-carboxamide HN §~NH Facozs BM-787 1H NMR (300 MHz, CD30D), 5 7.87 (d, J=2.0, 1H), 7.70 (m, J=2.2, 9.2, 1H), 7.28~7.25 (m, 2H), 7.20~7.12 (m, 6H), .99 (m, 7H), 6.90 (s, 1H), 6.81~6.78 (m, 2H), PCT/U820 l 2/022315 3.99~3.94 (m, 1H), 3,35~3,28 (m, 11H), 3.20~3.03 (m, 4H), 2.81 (s, 6H), 2.68 (s, 3H), 2.39 (s, 3H), 2.18~2.01 (m, 2H); Compound 165 (R)(4-fluorophenyl)—N, 1 ,2-trimethyl4-(3-(4«(4-(4-((4-morpholInc Ithio)butanyl)amino) ((trifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyl)-1H-pyrrole- oxamide BM-788 ‘H NMR (300 MHz, CD30D), 5 7.87 (d, J=1.9, 1H), 7.70 (dd, J=2.2, 9.2, 1H), 7.28~7.25 (m, 2H), 7.20~7.12 (m, 6H), 7.06~6.99 (m, 7H), 6.90 (s, 1H), 6.81~6.78 (m, 2H), 3.98~3.95 (m, 3H), 3.70~3.68 (m, 2H), 3.45~3.33 (m, 13H), 3.23~3.05 (m, 6H), 2.68 (s, 3H), 2.39 (s, 3H), 2.22~2.18 (m, 1H), 2.08~2.04 (m, 1H); PCT/U320 l 2/022315 Compound 166 (R)(4-f|uorophenyI)4-(3-(4—(4—(4-((4-(4—hydroxypiper1dinyl) (phenylthio)butanyl)amino) ((trifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)pheny|)-N.1,2- trimethyI-1 H~pyrrolearboxamide Os N HOOP/"“1 ° Q HN fi—NH Facozs BM-789 ‘H NMR (300 MHz. CDJOD), 5 7.88 (d, J=2.0, 1H), 7.69 (dd, J=2.0, 9.2, 1H), 7.27~7.26 (m, 2H), 7.18~7.12 (m, 6H), 7.05~6.95 (m, 7H), 6.87 (s, 1H), 6.8l~6.76 (m, 2H), 4.o3~3.75 (m, 2H), 3.50~3.30 (m, 13H), 3.2]~2.89 (m, 6H), 2.68 (s, 3H), 2.40 (s, 3H), 2.20~2.18 (m, 1H), 2.06~2.04 (m, 2H), l.89~1.86 (m, 2H), 1.65~1.62 (m, 1H) Compound 167 (R)-N-(4-(4-(3-(2-(4-chloropheny|)-1 ethyl-1 H-pyrrol—a- yl)phenyl)piperazinyl)phenylH-«Hdimethylamino) lthio)butan-Z-yl)amino) ((trifluorornemyl)sulfonyl)benzenesulfonamide BM-790 E51 MS: m/z 951.3 (M + H)‘; W0 20] 59 PCT/U820 l 2/022315 Compound 168 (R)-N-(4-(4-(3-(2—(4—chlorophenyl)—1,5-dimethyl-1H-peroI-S-yl)phenyl)piperazinyl)phenyl)- 4-((4-(dimethylamino)(phenylthio)butanyl)amino)-3—nitrobenzenesulfonamlde BM-791 ‘H NMR (300 MHz, CD300), 5 8.28 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.1, 1H), 7.34 (d, J=8.4, 2H), 7. l8~6.89 (m, 17H), 4.09~4.05 (m, 1H), 3.36~3.27 (m, 1H), .14 (m, 4H), 2.82 (s, 6H), 2.24 (s, 3H), 2.16~2.l4 (m, 2H); ”(3 NMR (75 MHz, (30301)), 5 148.02, 148.95, 147.2, 140.1, 136.2, 134.7, 134.4,134.0,133.7, 132.7,1322, 131.6, 131.2, 130.6, 130.1, 130.0,128.0, 127.9, 127.5, 125.5, 124.1, 122.0, 119.0, 118.9, 116.2, 55.9, 53.2, 52.4, 50.2, 43.5, 39.5, 31.6, 30.1, 12.4; Compound 169 (R)-5—(4-chloropheny|)4—(3-(4-(4—(4-«4-(4-hydroxypiperidinyI)-1{phenylthimbutan-Z- yl)amino)—3-((trifluorornethyl)sulfonyl)phenylsulfonamido)phenyl)piperaziny|)pheny|)- 1 ,2-dimethyl-1H~pynolecarboxylic acid PCT/U520 I 15 [0217) ‘H NMR (300 MHz, CD30D), a 7.86 (1H, s), 7.71 (d, J=9.2, 1H), 7.27~7.25 (m, 4H), 7.20~6.79 (m, 14H), 4.03~3.75 (m, 2H), .31 (m, 13H), 3.14~2.89 (m, 6H), 2.58 (s, 3H), 2.26~l.88 (m, 5H), l.67~l.63 (m, 1H); Compound 170 (R)-N-(4-(4-(3-(2-(4-chlorophenyl)(4-hydroxypiparidinacarbonyI)-1 ,5-dimethyl- 1H-pyrmlyl)phenyl)piperaziny|)phenylH-((4—(4-hydroxypiperidinyl) (phenylthio)butanyl)amino)—3-((n'ifluoromethyl)sulfonyl)benzenesulfonamide Ho—CNJ"WHNQg-NH F3C02$ BM-793 ‘H NMR (300 MHz, cogon), 5 7.88 (d, J=2.0, 1H), 7.70 (d, J=9.3, 1H), 7344.25 (m, 4H), 7.16~6.71 (m, 14H), 4.12~3.28 (m, 16H), 3.16~2.s9 (m, 10H), 2.27~2.24 (m, 4H), 2.06~2.02 (m, 2H), 1.88~l .86 (m, 2H), 1.73~1.06 (m, SH); W0 20] 2/103059 2012/022315 Compound 171 -(4-chlorophenyl)—N-((1r,4r)4-hydroxycyclohexylH—(3-(4-(4-(4-«(RH—(4— hydroxypipen‘dlnyl)—1-(phenyIthio)butanyl)amino) ((trifluoromethyl)sulfonyI)phenyIsuIfonamido)phenyl)piperazinyl)phenyl)-1.2- dimethyl-1H-pyrrole-mrboxamide <35 O 0.
HOCNJ"NZNQJ? F3C02$ BM-794 IH NMR (300 MHz, CDJOD), 8 7.86 (d, J=2.1, 1H), 7.67 (dd, J=2.2, 9.2, 1H), 7.27~7.24 (m, 4H), 7.18~7.04 (m, 6H), 7.014594 (m, 5H), 6.80-6.75 (In, 3H), 4.01~3.28 (m, 15H), 3.19~2.87 (m, 8H), 2.40 (s, 3H), 2.18~1.60(m, 10H), l.30-1.18 (m, 2H), 1.03-0.92 (m, 2H); -l30- PCT/U820 l 2/022315 Compound 172 (R)-N-(4-(4~(3-(2—(4-chlorophenyl)4-(4-hydroxy-4—memylpiperidine-1 carbonyl)- 1 ,5-dimethyl-1H-pyrroI-3—yl)phenyl)piperazin-1—yl)phenyl)((4—(4- ypiperidinyl)(phenyMio)butanyl)amino) ((trifluoromethyl)sulfonyl)benzenesulfonamide BM-795 'H NMR (300 MHz, 013301)), 5 7.89 (s, 1H), 7.69~7.67 (m, 1H), 7.35~7.27 (m, 4H), 7.]8~7.12 (m, 5H), 7.09~6.94 (m, 5H), 6.87—6.58 (m, 4H), 4.2742 (m, 1H), 4.08~3.95 (m, 2H), .50 (m, 2H), 3.40 (s, 3H), 3.31~3.29 (m, 6H), 3.22~2.9o (m, 11H), 2.28~2.25 (m, 4H), 2.1o~2.07 (m, 2H), 1.98~1.88 (m, 2H), 1.66-1.42 (m, 3H), 1.2s~0.86 (m, 5H); W0 20] 2/103059 PCT/U320 l 2/022315 Compound 173 (R)-N-(4-(4-(3-(2-(4-chlorophenyl)—1,5-dimethyI(4-(methylsulfonyl)piperazinecarbonyl)- 1H-pyrrol—3-yl)pheny|)piperazinyl)phenyI)44(4—(4-hydroxypiperidinyl) (phenylthio)butan-Z-yl)arnino)((trifluoromethyl)sulfonyI)benzenaulfonamide BM-798 ‘H NMR (300 MHz, CD30D), 6 7.90 (d, J=1.9, 1H), 7.67 (dd, J=I.9, 9.1, 1H), 7.34 (d, J=8.5, 2H), 7.28~7.25 (m, 2H), .83 (m, 11H), 6.77 (dd, J=3.4, 9.3, 1H), 6.68 (s, 1H), 6.57 (d, J=7.6, 1H), 4.09~3.76 (m, 3H), 3.56~3.29 (m, 9H), 3.24~2.83 (m, 16H), 2.59~2.57 (m, 1H), 2.56 (s. 3H), 2.29 (s, 3H), 2.23~2.o7 (m, 3H), 1.88 (br. 2H), l.66~1.61 (m, 1H); Compound 174 (R)-N—(4—(4—(:H2-(4-chlorophenyl)-1 .5-dimethyl(4—memylpiperazine-1 - yI)-1H-pyrroI-a-yl)phenyl)piperazinyl)phenylH—((4—(4—hydroxypiperidin- 1-y|)(phenylthlo)butanyl)amino) ((trifluoromethyl)sulfonyl)benzenesulfonarnide ..01.1 Facozs BM-797 -l32- PCT/U820 I 15 1H NMR (300 MHz, CD300), 5 7.87 (d, J=1.8, 1H), 7.69 (dd, J=l .9. 9.2, 1H), 7.34 (d, J=8.4, 2H), .26 (m, 2H), 7.18~7.15 (m, 6H), 7.04v-6.96 (m, 4H), 6.89 (d, J=7.4, 1H), 6.80 (d, J=9.2, 1H), 6.64 (s, 1H), 6.59 (d, J=7.5, 1H), 4.64 (br., 1H), 4.04~3.96 (m, 2H), 3.75~3.31 (m, 8H), 3.21~2.54 (m, 21H), 2.30 (s, 3H), 2.22~1.88 (m, 5H), l.67~l.63 (m, 1H); Compound 175 (R)-N—(4—(4-(3-(2-(4-chlorophenyl)-1.5-dimemyI4-(morpholinecarbonyl)-1 H-pyrrol-a- yl)phenyl)piperaziny|)phenyl)4-((4-(4-hydroxypiperidin—1-yl)(phenylthio)butan yl)amino)((trifluoromemyl)su|fonyl)benzenesulfonamlde BIN-798 'H NMR (300 MHz, CD30D), a 7.90 (d, J=2.0, 1H), 7.69 (dd. J=2.o, 9.2, 1H), 7.66 (d, J=8.6, 2H), 7.28~7.27 (m, 2H), 7.19-7.11 (m, 6H), 7.06~6.99 (m, 4H), 6.92~6.89 (m, 1H), 6.81~6.78 (m, 1H), 6.71 (s, 1H), 6.62 (d, J=7.7, 1H), 4.04~3.72 (m, 3H), 3.55~3.29 (m, 10H), 3.22~2.9o (m, 15H), 2.39 (br. 1H), 2.28 (s, 3H), 2.23~2.21 (m, 1H), 2.10~2.o7 (m, 2H), 1.88 (br. 2H), 1.66~l .62 (m, 1H); W0 20] 2/103059 PCT/U820 l 2/022315 nd 176 (R)-N-(4-(4-(3r(2-(4—chlorophenyl)-4—(4-(2-r1ydroxyethyl)piperazine—1 -carbonyI)-1 .5-dimethyl-1 H- pyrrol-B—yl)phenyl)piperazinyl)phenyl)((4-(4-hydroxypiperidinyl)(phenylthio)butan yl)amino)((tn‘fluoromethybsuIfonyl)benzenesulfonamide Hole 0 \\/N O \\N\ HOCNJWI Cl HN §—NH Facozs BM-799 1H NMR (300 MHz, CDJOD), 8 7.88 (d, J=2.0, 1H), 7.69 (dd, J=2.l, 9.2, 1H), 7.35 (d, J=8.6, 2H), 7.29~7.27 (m, 2H), 7.19~7.16 (m, 6H), 7.02 (d, J=9.1, 2H), 6.94 (d, J=9.1, 2H), 6.88~6.85 (m, 1H), 6.80 (d, J=9.2, 1H), 6.62 (s, 1H), 6.57 (d, J=7.7, 1H), 4.06~3.95 (m, 2H), 3.7l~3.32 (m, 10H), 3.18~2.9l (m, 21 H), 2.31 (s, 3H), 2.24~1.99 (m, 3H), 1.89 (br. 2H), 1.67~1.63 (m, 1H); Compound 177 (R)—4-((4—(dimethylamino)—1-(phenylthio)butanyl)amino)nitro-N- phenylbenzenesulfonamide Inn-Z 0 :N—/ HNQ§—NH BM-902 ‘11 NMR (300 MHz, CDJOD), 5 8.38 (d, J=2.2 Hz, 1H), 8.15 (d, J=9.3, 1H), 7.62 (dd, J=2.1, 9.1, 1H), 7.28~7.23 (m, 2H). 7.18~6.97 (m, 8H), 6.90, (d, J=9.3, 1H), 4.11407 (m, 1H), 3.4033 (m, 1H), .09 (m, 3H), 2.85 (s, 6H), .11 (m, 2H); 13c NMR (75 MHz, c0300), 5 147.9, 139.0, 136.1, 134.4, 132.3, 131.5, 1303,1280, 1279, 127.7, 125.8, 121.8, 116.1, 55.9, 52.3, 43.5, 39.4, 30.1; PCT/U820 I 2/022315 Compound 178 4-chlorophenyl)-4~(3-(4-(4—(4-((4—(dimethylamino)-1—(phenylthio)butan-Z-yl)amino) nitrophenylsulfonamido)phenyl)piperazin—1-yl)phenyl)-1,2—dimethyl-1 H-pyrrole—B—carboxylic acid BM-903 ‘H NMR (300 MHz, CD30D), 5 8.30 (d, J=2.2 Hz, 1H), 7.59 (dd, 1=2.2, 9.2, 1H), 7.26~7.23 (m, 2H), 7.18~7.13 (m, 3H), 7.09~6.88 (m, 1311), 4104.07 (m, 1H), 3.40 (s, 3H), 3.36-3.29 (m, 9H), 3.21-3.15(m, 3H), 2.83 (s, 6H), 2.58 (s, 3H), 2.26-2.10 (m, 2H); ”0 NMR (75 MHz, c0300), 5 169.1, 148.5, 148.0, 146.9, 139.0, 138.4,136.2, 134.8, 134.4, 134.0, 132.3, 1322,1321, 131.9,131.6,130.1,129.6,129.5, 129.0, 128.0,127.9, 127.6, 124.8. 124.3, 122.9. 118.9, 117.2, 116.2. 111.5. 55.9. 53.2, 52.4, 50.1. 43.5, 39.5, 32.2, 30.1, 12.1; -l35- PCT/U82012/022315 Compound 179 -(4chlorophenyl)—N-((1 s,35)hydroxy-3—methyIcyclobutyl)(3-(4-(4-(4.(((R) (4-hydroxypiperidiny|)(pheny|thio)butanyl)amino) ((trifluoromethyl)sulfonyl)phenylsuIfonamido)phenyl)piperaziny|)phenyl)o1.2- dimethyI-1H-pyrrole-a-carboxamide 2 O BM-904 lH NMR (300 MHz, CD30D), 5 7.90 (d, J=2.1, 1H), 7.38 (dd, J=2.0, 9.1, 1H), 7.31~7.28 (m, 4H), 7.21~7.ll (m, 6H), 7.07—6.97 (m, 5H), 6.34~6.75 (m, 3H), 4.04»~3.86 (m, 3H), 3.50~3.30 (m, 10H), 3.27~2.9l (m, 8H), 2.43 (s, 3H), 2.3 l~2.l9 (m, 3H), .07 (m, 2H), 1.88 (br., 2H), 1.73~1.62 (m, 3H), 1.25 (s, 3H); ~136- W0 20] 59 PCT/U820 l 2/022315 Compound 180 (R)—5-(4chlorophenyl)(3-(4—(4-(4-((4-(4—hydroxypiperidinyI)—1-(phenylfl1io)butan- 2-yl)amino)((trifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazin yl)phenyl)~1.2-dimethyI-N{1methylazetidinyl)-1H-pyrroIe-a-carboxamide W2 09 HN fi—NH Facozs ‘H NMR (300 MHz, CDJOD), 5 7.87 (s, 1H), 7.68 (d, J=9.1, 1H), 7.3o~7.24 (m, 4H), 7.18~7.09 (m, 5H), 7.00~6.87 (m, 5H), 6.79-6.66 (m, 4H). 4.19~3.4o (m, 12H), 3.20~2.43 (m, 19H), 2.24 ~2.21 (m, 1H), 2.09~2.05 (m, 2H), 1.87 (br., 2H), 1.64~1.60 (m, 1H); PCT/U820 l 2/022315 Compound 18] (R)4-(4-chlor0pheny|)(3-(4-(4-(4-((4-(dirnethylamino)(phenylthio)butanyl)amino) nitrophenylsulfonamido)phenyt)piperazinyl)pheny1)methyl-N43—(4-mefl1ylpiperazinyl)propyl)-1H- pynole-Z-carboxamide \N/fi k/NK 0 BM-SOB ‘H NMR (300 MHz, CD30D), 6 8.30 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.1, 1H), 7.28 (1, J=7.9, 1H), 7.16~6.89 (m, 16H), 6.82~6.77 (m, 2H), 4,094.06 (m, 1H), 3.82 (s, 1H), 3.33~3.28 (m, 6H), 3.25~3.09 (m, 16H), 2.83 (s, 9H), 2.62~2.57 (m, 2H), 2.24214 (m, 2H), l.65~l.61 (m, 2H);); 13C NMR (75 MHz, , 5 165.1, 151.6, 147.9, 137.4, 136.2, 135.0, 134.4.132.5,132.2, 131.6, 130.7, 130.4, 130.1, 129.2, 128.0,127.9, 127.6, 126.7, 126.4, 125.8, 124.2, 123.3, 120.1, 118.9, 116.9, 116.2, 55.9, 55.4, 52.9. 52.4, 51.1, 50.6, 50.5, 43.6, 43.5, 39.5, 37.5, 36.3, 30.1, 25.9; PCT/U820 I 2/022315 Compound 182 hlorophenyl)—1-((S)-3.4-dlhydroxybutyI)(3-(4-(4-(4—(((R)(dimethylamino) (phenylthio)butanyl)amino)nitrophenylsulfonamido)phenyl)piperazinyl)phenyI)-N-(3-(4- methylpiperazinyl)propy|)-1 H-pyrrole-Z-carboxamide ‘N’fi KINK 0H 0 /\/E {5 0 \ Ju.Q3 O ,N HN—Q—g-NH BM-907 'H NMR (300 MHz, CD30D), a 8.30 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 1H), 7.59 (dd, J=2.3, 9.2, 1H), 7.28 (t, J=7.9, 1H), 7.l8~6.98 (m, 14H), 6.91 (d, J=9.4, 1H), 6.83 (s, 1H), 6.78 (d, J=7.5, 1H), 4.384.28 (m, 2H), 4.09-4.08 (m, 2H), 3.55~3.32 (m, 11H), 3.21~3.15 (m, 14H), 2.84 (s, 3H), 2.83 (s, 6H), 2.70-2.65 (m, 2H), 2.25~1.99 (m, 3H), 1.78~l .64 (m, 3H); W0 20] 2/103059 PCT/U320 I 2/022315 Compound 183 4—(4—chlorophenyI)((S)-3,4»dihydroxybutyl)-3—(3-(4-(4-(4-(((R)4-(dimethylamino)- 1-(phenyIthio)butan-2—yl)amino)nitrophenylsulfonamido)phenyl)—1H-1.2.3—triazoi- 1-yl)phanyl)—N—(3-(4-methylpiperazinyl)propyI)-1H-pyrrole-2—carboxamide BM-908 ‘H NMR (300 MHz, CD30D), 5 8.67 (s, 1H), 8.38 (d, J=2.2, 1H), 7.78~7.7O (m, 4H), 7.62 (dd, J=2.2, 9.2, 1H), 7.47 (1, J=7.0, 1H), 7.24~7.21 (m, 3H), 7.12~7.o1 (m, 7H), 6.94~6.88 (m, 4H), .28 (m, 2H), 4.07~4.06 (m, 1H), 3.54~3.34 (m, 9H), 3.20~3.11 (m, 8H), 2.84~2.80 (m, 11H), 2.19~2.15 (m, 3H), l.7l~1.66 (m, SE); ”C NMR (75 MHz, ,6165.4,148.9, 148.1, 139.3, 138.3, 138.0, 136.1, 134.7, 134.3, 132.9, 132.4, 132.2, 131.5, 131.0, 130.8, 130.0, 129.4, 128.1, 127.8, 127.7,127.4, 127.1, 124.8, 124.5. 123.6, 123.4, 121.9, 120.1, 119.9, 116.4,70.2, 67.3, 55.9, 55.5, 52.4, 50.3, 46.1, 43.5, 39.4, 37.7, 36.4, 30.1, 25.7; PCT/U82012/022315 Compound 184 4-(4-chlorophenyl)—1-((S)-3,4-dihydroxybutyI)(4-((4-(4-(((R)—4- hylamlno)-1—(phenyIthio)butanyl)amino) nitrophenylsuIfonamido)phenyl)emynyl)phenyl)-N-(3-(4- methylpiperazinyl)propyl)-1 H-pyrrole-Z-carboxamide /\/\N \/ // Cl :NJ"‘I£NA©—§-NO 02111 'H NMR (300 MHz, CD3OD), 5 3.32 (d, J=1.8, 1H), 7.56 (d, J=9.1, 1H), 7.57 ~7.54 (m, 4H), 7.08~6.83 (m, 15H), 4.26417 (m, 2H), 4.01~3.09 (m, 1H), 3.43~3.25 (m, 7H), 3.12-3.00 (m, 10H), 2.74 (s, 6H), 2.67 (s, 3H), 2.39~2.37 (m, 2H), 2.16~2.07 (m, 3H), .54 (m, 3H); ”c NMR (75 MHz, CD30D), 5 164.0, 146.7, 138.0, 135.0, 134.8, 133.4, 132.9, 132.3, 131.3, 131.1, 130.8,130.5, 1301,1292, 128.7, 127.9, 126.6, 126.5,126.1, 125.4, 123.9, 123.3, 122.0, 121.6, 119.7, 118.9, 114.9, 89.0, 88.8, 68.8, 65.8, 54.5, 54.1, 51.7, 50.9, 49.4, 44.7, 42.2, 42.1, 38.0, 36.4, 35.0, 28.7, 24.5; PCT/U82012/022315 Compound 185 (R)-5—(4-chlorophenyl)—4—(3-(4-(4—(4-((4-(dimethylamino)(phenylthio)butan-2— yl)amino)—3-((trifluorornemyl)sulfonyl)phenylsulfonamido)phenyl)piperazln yl)phenyl)-1 ,2-dimethyI-1 H-pyrroIecarboxylic acid / §—NH Fscozs BM-910 ‘H NMR (300 MHz, CD30D), 5 7.35 (d, J=2.0, 1H), 7.70 (dd, J=2.2, 9.2, 1H), 6 (m, 16H), 6.86~6.78 (m, 2H), 3.98~3.91 (m, 1H), 3.42~3.31 (m, 11H), 3.2o~3.02 (m, 4H), 2.80 (s, 6H), 2.57 (s, 3H), 2.25~l.98 (m, 2H); Compound 186 (R)(4-chlorophenyI)-1 ,2-dimelhyl(3-(4-(4—(4-((4—morpholino(phenylthio)butan yl)amino)((trifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyI)-1H- pyrrole—S-carboxylic acid mg? Cl 0 N ll— , , HN (fin NH Facozs BM-911 ‘H NMR (300 MHz, CD30D), a 7.93 (d, J=2.1, 1H), 7.74 (dd, J=2.2, 9.2, 1H), 7.44~6.89 (m, 17H), 6.83 (d, J=9.4, 1H), 4.03—3.98 (m, 3H), 3.78~3.71 (m, 2H), 3.56~3.36 (m, 11H), 3.25~3.o9 (m, 8H), 2.64 (s, 3H), .24 (m, 1H). 2.13~2.09 (m, IR); PCT/U32012/022315 nd 187 (R)(4-chlorophenyl)—1 .2-dimethyl(3-(4-(4-(4-((4-morpholino (phenylthio)butanyI)amino)—3— nitrophenylsulfonamido)phenyl)piperazinyl)phenyI)-1H-pyrrole-3— carboxylic acid BM-91 2 1H NMR (300 MHz. CDgOD), 8 8.30 (d, J=2.3, 1H). 7.61 (dd, J=2.3, 9.2, 1H), 73845.91 (m, 18H), 4.1 l~3.99 (m, 3H), 3.7l~3.70 (m, 2H), 3.4l~3.32 (m, 13H), 3.25~3.08 (m, 6H), 2.58 (s, 3H), 2.29~2.18 (m, 2H); Compound 188 (R)-5—(4-chlorophenyl)4-(3—(4-(+(4-((4—(4-hydnoxypiperidinyl) (phanylthio)butan—2-yl)amino)nitrophenylsulfonamido)phenyl)piperazin yl)phenyl)-1.2-dlmethyI-1H-pyrrole-S-carboxylic acid BM-91 3 ’H NMR (300 MHz, CDgOD), a 8.29 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.1, 1H), 7.37~6.87 (m, 18H), 4.o7~3.75 (m, 2H), 3.53~3.50 (m, 1H). 2 (m. 11H), 3.2o~3.o4 W0 20] 2/103059 PCT/U820 l 2/022315 (m, 6H), 2.99~2.90 (m, 1H), 2.53 (s. 3H), 2.26~2.06 (m, 3H), l.89~1.83 (m, 2H), l.67~1.63 (m, 1H); Compound 189 (4-chlorophenyI)(3-(4-(4-(4-((4-(4-hydroxypiperidiny|)(phenylthio)butan- 2-yl)amlno)-3—((trifluoromethyI)sulfonyl)phonylsuIfonamldo)phenyl)piperazin—1- yl)phenyl)—1-methyl—1H-pyrroIe-Z-carboxylic acid BM-919 ‘H NMR (300 MHz, omen), a 7.88 (d, J=2.0. 1H), 7.72~7.69 (m, “-1), 7.30423 (m, 3H), 7.20~6.95 (m, 14H), 6.84~6.7S (m, 2H), 4.05-4.03 (m, 1H), 3.95 (s, 3H), 3.85~3.68 (m. 1H), 3.49~3.36 (m, 10H), 3.2]~2.89 (m, 6H), .88 (m, 5H), 1.66~1.62 (m, 1H); Compound 120 (R)—4-(4—chlorophenyI)(3-(4—(4-(4-((4—(dimethylaminoH -(phenylthio)butan yl)amino)nitrophenylsulfonamido)phenyl)piperazinyl)phenyI)methyl-1 H- pyrrolecarboxylic acid PCT/U82012/022315 lH NMR (300 MHz, CD30D), 8 8.29 (d, J=2.2, 1H), 7.58 (dd, J=2.3, 9.2, 1H), 7.27 (t, J=7.8, 1H), 7.15~6.89 (m, 18H), 4.08~4.05 (m, 1H), 3.93 (s, 3H), 3.67~3.30 (m, 9H), 3.20~3.14 (m, 3H), 2.82 (s, 6H), 2.23~2.14 (m, 2H); l3C NMR (75 MHz, CD30D), 5 164.3, 147.9, 138.9, 136.2, 134.8, 134.4, 132.8, 132.6, 132.2, 131.7, 131.6, 130.6, 130.1, 130.0, 129.2, 128.7, 128.3, 128.0, 127.9, 127.6, 124.1, 124.0, 122.4, 122.0, 119.1, 117.8, 116.2, 55.9, 52.8, 52.4, 50.6, 43.5, 39.5, 38.1, 30.1; Compound 121 (R)(4-chlorophenyl)-3—(3-(4-(4-(4-((4-(4-hydroxypiperidin-1~yl)(phenylthio)butan yl)amino)nitrophenylsulfonamido)pheny|)piperazinyl)pheny|)methyl—1H~pyrrole- oxylic acid Q ~ 0 ESI MS: m/z 950.3 (M + H)*; Compound 192 (R)chlore-4—(4—dwlorophenyl)-3—(3-(4—(4—(H(4~(dirnethylamino)—1- (phenylflwlo)butan-2—yl)amino)nitrophenylsulfonamido)phenyl)piperazin yl)phenyl)methyl-1H-pyrrole—2—carboxylic acid / N/ W0 20] 2/103059 PCT/U32012/022315 ‘H NMR (300 MHz, c0301», 5 8.34 (d, J=2.2, 1H), 7.55 (dd, J=2.3, 9.2, 1H), 7.28-6.60 (m, 18H), 4.084.06 (m, 1H), 3.97 (s, 3H), 3.56~3.51 (m, 2H), .os (m, 10H), 2.85 (s, 6H), 2.18~2.15 (m, 2H); Compound 193 chIoro(4chIorophenyl)-3«(3-(4-(4-(4-((4-(4-hydroxypiperidin—1-yI) (phenylthio)butan~2-yl)amlno) ((tfifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyl)- 1-methyl-1 H-pyrrole—Z-mrboxylic acid C) O BM-923 1H NMR (300 MHz, CD3OD), 5 7.91 (s, 1H), 7.62 (d, J=9.5, 1H), 7.28~6.59 (m, 18H), 3.93~3.52 (m, 5H), 3.23~3.05 (m, 16H), 2.20~2.14 (m, 1H), 2.02~l.97 (m, 2H), 1.75~1.58(m, 3H); -l46- W0 20] 2/103059 PCT/U320 l 2/022315 Compound 194 (R)-5—(4-chlorophenyl)-N-cyclopropyl4-(3-(4-(4-(4»((4—(4-hydroxypiperidinyl)-1 - (phenylthlo)bumnyl)amino) ((trifluoromethyI)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyl)-1 .2-dimethyl- ‘l H-pyrroIecarboxamide BM-951 ‘H NMR (300 MHz, CD300), a 7.89 (d, J=2.0, 1H), 7.70 (dd, J=2.0, 9.1, 1H), 7.3o~7.26 (m, 4H), 7.20~7.09 (m, 6H), 7.07~6.97 (m, 5H), 6.85~6.73 (m, 3H), 4.04~3.7o (m, 2H), 3.53~3.38 (m, 13H), 3.22~2.94 (m, 6H), 2.63~2.57 (m. 6H), 2.63~2.57 (m, 1H), 2.42 (s, 3H), 2.20~2.06 (m, 3H), 1.89~1.86 (m, 2H), 1.66~1.62 (m, 1H), O.64~0.S7 (m, 2H), 0.23~0.18 (m, 2H); nd 195 (4-(4—(3-(4-(azetidine-1carbonyl)(4—chlorophenyl)—1 ,5-dirnethyl-1H- pyrrolyl)phenyl)piperazinyl)phenyl)4-((4-(4-hydroxypiperidinyl) (phenylthio)butan-2—yl)amino)((trmuoromethy|)sulfonyl)benzenesulfonamide PCT/U320 l 2/022315 'H NMR (300 MHz, CDJOD), a 7.88 (d, J=2.1, 1H), 7.70 (dd, .I=2.l, 9.2, 1H), 7.34~7.26 (m, 4H), 7.20~7.12 (m, 6H), .96 (m, 5H), 6.85~6.79 (m, 2H), 6.72 (d, J=7.7, 1H), 4.08~3.71 (m, 4H), 3.52~3.47 (m, 3H), 3.38~3.29 (m. 12H). 3.21~2.90 (m, 6H), 2.33 (s, 3H), 2.27~1.88 (m, 7H), 1.66~1.62 (m, 1H); Compound 196 (R)—N-(4-(4-(3-(2-(4-chlorophenyl)(4-hydroxypiperidine-1carbonyl)—1 .5—dimethyl- 1 H-pyrrolyl)phenyl)piperazinyl)phenyl)((4-(dimathylamino) (phenylthio)butan-2—yl)amino)nitrobenzenesulfonamide HOCN BM-953 ‘H NMR (300 MHz, c0300), 5 8.32 (d, J=2.2, 1H), 7.60 (d, J=9.0, 1H). 7.32 (d, J=8.5, 1H), 7.l7~6.90 (m, 14H), .63 (m, 2H), 4.10~3.85 (m, 2H), 3.62~3.51 (m, 1H), 3.40~3.32 (m, 9H), 3.21~2.90 (m, 9H), 2.83 (s, 6H), 2.28~1.98 (m, 5H), l.73~l.06(m, 4H); W0 20] 59 20 l 2/022315 Compound 197 -(4-chlorophenylHHS-(444—(4-(((RH~(dimethylamino)-1 - (phenylthio)butan-z-yI)amlno)niu'ophenyIsulfonamido)phenyl)piperazin- 1-yl)phenyI)-N-((1r,4r)—4-hydroxycyclohexyl)-1,Z-dimemyI-1H-pytrole carboxamide BM-954 'H NMR (300 MHz, CDgOD), 5 8.32 (d, J=2.0, 1H), 7.60 (dd, J=2.0, 9.1, 1H), 7.27 (d, J=8.4, 2H), 7.20~6.90 (m. 14H), 6.82-6.77 (m, 2H), 4.09~4.06 (m, 1H). 3.65~3.57 (m, 1H), 3.38-8.30 (m, 9H), 3.22~3.09 (m, 7H), 2.84 (s, 6H), 2.43 (s, 3H), 2.25~2.l6 (m, 2H), l.78~1.75 (m, 4H), 1.27~l.19 (m, 2H), l.05~0.94 (tn, 2H); Compound 198 (R)(4—chlorophenylH.(3—(4-(4-(4—-((4-(dimethylaminoH - (phenylthio)butanyI)amino)niwophenylsulfonamidomhenyI)piperazin yl)phenyl)—1-ethylmethyI-1H-pyrrole-a-mrboxylic acid N 7 PCT/U820 l 2/022315 ‘H NMR (300 MHz. CD30D), a 8.31 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.1, 1H), 7.28~6.86 (m, 18H), 4.10~4.06 (m, 1H). 3.87 (q, J=7.1, 2H), 3.39~3.29 (m, 9H), 3.22~3. 15 (111,311), 2.84 (s, 6H), 2.60 (s, 3H), 2.20~2.18 (m. 2H), 1.10 (t, J=7.1, 3H); Compound 199 (R)(4-chlorophenyl)ethyl(3-(4-(4-(4-«4-(4-hydroxypiperidinyl) (phenylthio)butanyl)amino) luoromemyI)sulfonyl)phenylsulfonamido)phenyl)piperazin-1 -yl)pheny|)methyl- 1H-pyrrolecarboxylic acid 00 \\NV O? 9 O") CO HN fi—NH Facozs BM-957 [0247) ‘H NMR (300 MHz, CD30D), a 7.87 (s, 1H), 7.69 (d, J=9.1, 1H), 7.29~7.26 4H), 7.15~6.78 (m, 14H), 4.o4~3.77 (m, 4H), 3.49~3.28 (m, 8H), 3.17~2.94 (m, 8H), 2.60 (s, 3H), 2.05~1.69 (m, 6H), 1.10 (t, J=6.9. 3H); Compound 200 (R)-N-(4—(4-(3-(4-(4-chlorophenyl)-1 -1 H-pyrrol-a- yl)phenyl)piperazinyl)phenylH-((4-(dimethylamino)-1o (phenynhio)butanyl)amino)nitrobenzenesulfonamide , ISf-NH BM-958 PCT/U82012/022315 1H NMR (300 MHz, CD30D), 5 8.30 (d, J=2.2, 1H), 7.59 (dd, J=2.2, 9.2, 1H), 7.25 (m, 1H), 7.18~6.89 (m, 17H), 6.80 (dd, J=2.3, 9.7, 2H), 4.10~4.06 (m, 1H), 3.67 (s, 3H), 3.35~3.30 (m, 9H), 3.20~3.14 (m, 3H), 2.82 (s, 6H), 2.23~2.l4 (m, 2H); l3C NMR (75 MHz, CD30D), 5 148.0, 147.9, 139.3, 136.3, 136.2, 134.4, 133.0, 132.34, 132.25, 131.6, 131.0, 130.8, 130.1, 129.3, 128.0, 127.9, 127.6, 126.0, 124.1, 123.6, 123.4, 123.2, 123.1, 123.0, 119.7, 119.2, 116.8, 116.2, 55.9, 53.0, 52.4, 50.5, 43.5, 39.5, 36.4, 30.1; Compound 20! N—(4—(4—(3-(4-(4-chlorophenyl)((S)-3,4-dihydroxybutyl)-1H-pyrroly|)phenyI)-1.4- diazepanyl)phenyIH-(((R)(dimemylamino)-1—(phenylthio)butan-Z-yl)amino)~3— nitrobenzenesulfonamide 81 .9 HM fi-NH BM-959 'H NMR (300 MHz, CD300), 5 8.28 (d, J=2.2, 1H), 7.52 (dd, J=2.2, 9.1, 1H), 7.19~7.03 (m, 10H), 6.93 (d, J=8.9, 2H), .82 (m, 3H), 6.65~6.59 (m, 4H), 6.41 (s, 1H), 4.06-4.04 (m, 3H), 3.60~3.33 (m, 8H), 3.27~3.13 (111, 71-1), 2.84 (s, 6H), 2.25~2.oo (m, 3H), .73 (111,311); ~151- W0 20] 2/103059 PCT/U320 l 2/022315 nd 202 (R)—5—(4-chlorophenyl)(3-(4-(4-(4-((4-(dimethylamino)(pheny|thio)butan yl)amlno)nitrophenylsulfonamido)phenyl)piperaziny|)phenyI)isopropyl-2—methyl- 1H-pyrroleoa-wrboxylic acid 0 \\N (—N~3 0 Q Cl \ 51 o >/:/< ,N—/ HNQfé—NHo BM-SGO 'H NMR (300 MHz CDgOD), 8 8.29 (d, J=2.2, 1H), 7.60 (dd, J=2.2, 9.2, 1H), 7.26~6.90 (m, 18H), 4.41~4.36 (m, 1H), 4.10~4.08 (m, 1H), 3.38~3.3l (m, 9H), 3.21~3.15 (m, 3H), 2.83 (s, 6H), 2.68 (s, 3H), 2.24.2.14 (m, 2H), 1.39 (d, J=7.1, 6H); Compound 203 (R)(4-chlorophenyI)-1cyclopropyM-(3-(444-(4-«4-(dimethylamlnoy 1-(phenylthio)butanyl)amino) nitropheny|sulfonamido)phenyl)piperazinyl)phenyI)methyI-1H- e-a-carboxylic acid 0 \\N (—N~3 0 Q51 O c.
:NJWHN C g-NH BM-961 IH NMR (300 MHz, CD3OD), 5 8.29 (d, J=2.3, 1H), 7.60 (dd, J=2.3, 9.2, 1H), 7.24~6.91 (m, 18H), 4.12~4.07 (m, 1H), 3.39~3.31 (m, 9H), 3.24~3.14 (m, 4H), 2.83 (s, 6H), 2.67 (s, 3H), 2.24~2.15 (m, 2H), 0.89~0.82 (m, 2H), 0.50~0.44 (m, 2H); W0 20] 2/103059 PCT/U82012/022315 nd 204 (R)-5~(4-chlorophenylH-(3-(4-(4—(H(4-(4-hydroxypiperidin-1 -yI) (phenylthio)butanyl)amino) ((trifluoromethyl)sulfonyl)phenylsulfonamido)phenyl)piperazinyl)phenyl)- 1-isopropyI—2—methyl-1H-pyrrole-a-carboxylic acid N Y HN §—NH F3C02$ BM-962 ‘H NMR (300 MHz, €13,013), 5 7.84 (d, 1:2.0, 1H), 7.70 (dd, J=2. 1, 9.2, 1H), 7.26~7.22 (m, 4H), 7.2o~7.07 (m, 7H), 70445.95 (m, 6H), 6.80 (d, J=9.2, 1H), 4,424.33 (m, 1H), 4.02~3.73 (m, 2H), 3.48~3.3l (m, 10H), 3.25~2.88 (m, 6H), 2.67 (s, 3H), 2.37~1.87 (m, 5H), .62 (m, 1H), 1.38 (d, J=7.1, 6H); Compound 205 (R)-5~(4-chlorophenyI)-4—(3-(444-(4—((4—(dimethylamino)(phenylmio)butanyl)amino) nitrophenylsulfonamido)phenyl)piperazinyl)phenyl)-1~methyl-1 H-pyrazole—a-carboxylic acid BM-963 IH NMR (300 MHz, CD3OD), 5 8.31 (d, J=2.2, 1H), 7.60 (dd, J=2.3, 9.2, 1H), 7.38~7.35 (m, 2H), 7.26-6.90 (m, 15H), 6.85 (d, J=7.6, 1H), 4.11~4.07 (m, 1H), 3.82 (s, 3H), 3.45~3.33 (m, 9H), 3.21~3.l4 (m, 3H), 2.84 (s, 6H), 2.25~2.15 (m, 2H); PCT/U82012/022315 Compound 206 (4~chlorophenyl)—4-(3-(4—(4-(44(4-(dimethylarnino)—1-(phenylthio)butan—2-yl)amino) nitrophenylsulfonamido)phenyl)piperazin-1 -yl)phenyI)mathyI-1H-pyrazole—5-mrboxylic acid BM-964 1H NMR (300 MHz, , 5 8.32 (d, J=2.3, 1H), 7.58 (dd, J=2.3, 9.2, 1H), 7304.25 (m, 3H), 7.20~7.l4 (m, 4H). 7.09~6.96 (m, 9H), 6.90 (d. J=10.2, 1H), 6.85 (d, J=7.6, 1H), 4.18 (s, 3H), 4.104.06 (m, 1H), 3.37~3.3l (m, 9H), 3.21~3.15 (m, 3H), 2.84 (s, 6H), 2.24~2.13 (m, 2H); Compound 207 (R)-N-(4-(4-(3-(2-(4-chlorophenyIH-(B-hydroxy-a-memylazetidine—1-carbonyI)-1 .5- dimethyI-1H-pyrrolyl)phanyl)piperaziny|)phenyl)-4—((4-(4-hydroxypiperidin-1 - yI)(phenylthio)butan-Z-yl)amino) ((trifluoromethyl)sulfonyl)benzenesuIfonamide BM-965 IH NMR (300 MHz. CD3OD), 5 7.89 (d, J=2.1, 1H), 7.69 (dd, J=2.l, 9.1, 1H), 7.34-7.26 (m. 4H), 7.l8~6.78 (m, 13H), 6.67 (d, J=7.7, lH), 4.04~3.73 (m, 4H), 3.49~3.31 W0 20] 2/103059 PCT/U82012/022315 (m, 14H), 3.22~3.31 (m, 14H), 3.22~2.94 (m, 7H), 2.76 (s, 3H), 2.22~2.06 (m, 3H), 1.90~1.85 (m, 2H), 1.69~1.63 (m, 1H), 1.07 (s, 3H); Compound 208 chlorophenylH-(3-(4—(4-(4—«4—(dimethylamino)(phenylthio)butan no)nitrophenylsulfonamido)phenyl)piperazinyl)phenyl)methylfuran carboxyllc acid 0 \\o Q ~3 0 51 S Cl \ Inn 0 ,N HNQ§-NH6 ‘H NMR (300 MHz, CD30D), 6 8.32 (d, J=2.2, 1H), 7.58 (dd, J=2.3, 9.2. 1H), 7.35~6.97 (m, 16H), 6.91~6.88 (m, 2H), 4.094.07011, 1H), 3.34-3.31 (m, 9H), 3.21~3.15 (m, 3H), 2.84 (s, 6H), 2.65 (s, 3H), 2.25~2.15 (m, 2H); Compound 210 : ?\ (‘Jé‘rNH .0“ ” ° F3002 al Fonnula: CgchlFsmm33 Exact Mass: 1100.28 Moloculu deht 1 101 .66 3.4100 IBM-1160: 'H NMR (300 M Hz, CD3OD): 8 7.94 (s, 1H), 7.66 (d, J = 8.7Hz, 1H), 7.40-7.13 (m, 9H), 7.00-6.69 (m, 7H), 3.97 (br, 1H), 3.48 (s, 3H), 3.19-2.88 (m, 16H), 2.62 (s, 3H), 2.31-2.10 (m, 2H), 1.79 (br, 4H), 1.27 (s, 31-1).
W0 20] 2/103059 PCT/U82012/022315 Compound 21 l Chamlnl Fatmula: CuHuCIfiNgOrS: Elna Man: 108229 Molowlar “b19111: 1083.67 BI-‘I 161 BM-ll6l: ‘H NMR (300 M Hz, : 8 7.94 (s, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.45-6.77 (m, 1411), 3.95 (br, 1H), 3.48 (s, 3H), 3.40-2.93 (m, 16H). 2.60 (s, 3H), 2.35-2.10 (m, 2H), 1.81 (br, 4H), 1.33 (s, 3H).
Compound 212 Chem Formula: CgHuchsNgo-fig Exact Man: 1 100.28 MOIemlar Weight 1101.66 Bl-‘l 102 IBM-1162: lH NMR (300 M Hz, CD;OD): 5 7.94 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.33-6.67 (m, 15H), 6.31 (br, 1H), 3.97 (br, 1H), 3.45 (s, 3H), .88 (m, 16H), 2.63 (s, 3H), 2.62-2.06 (m, 2H), 1.79 (br, 4H), 1.28 (s, 3H).
PCT/U820 l 2/022315 Compound 213 Chemical Formula: 6lF5N50783 Exact Mass; 1086.27 Mobcuhr “Islam: 1 087.63 “-1183 BM-1163: 'H NMR (300 M Hz, : 6 7.94 (s, 1H), 7.68 (d, J= 9.0Hz, 1H), 7.33-6.67 (m, 15H), 6.30 (br, 1H), 4.08-3.79 (m, 2H), 3.53-3.42 (m, 1H), 3.46 (s, 3H), 3.20- 2.88 (m, 16H), 2.63 (s, 3H), 2314.10 (m, 3H), 1.81 (br, 2H), 1.69-1.65 (m, 1H).
Compound 214 6 ’ F3co,s HOOJ Chantal FOVTI'IIJIIZ CnHuClFsNgOySg Exact Meal: 1100.28 Molamlar Weight: 1101.68 “-11M 64: ‘H NMR (300 M Hz, 013301)): 5 7.95 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.34-6.60 (m, 15H), 6.34 (br, 1H), 3.98 (br, 1H), 3.46 (s, 3H), 3.23-3.09 (m, 16H), 2.63 (s, 3H), 2.30-2.10 (m, 2H), 1.80 (br, 4H), 1.28 (s, 3H).
PCT/U820 l 2/022315 Compound 215 Meal Fonnula: C5.H5,CIF5N50785 Exact Mass: 1086.27 Molecular Welgtt 1057.83 BI—i 163 BM-1165: ‘H NMR (300 M Hz, 13): 5 7.94 (s, 1H), 7.67 (d, J= 9.0132, 1H), 7.34-6.63 (m, 15H), 6.35—6.32 (m, 1H), 4.08-3.80 (m, 2H), 3.53 (br, 1H), 3.46 (s, 3H), 3.23- 2.88 (m, 16H), 2.63 (s, 3H), 2.30-2.10 (m, 3H), 1.91 (br, 2H), 1.69-1.65 (m, 1H). nd 216 Chom‘col Fonnula: CgHgFmng, Exact Man: 1084.31 Molecular : 1085.21 BI—H“ BM-1166: IH NMR (300 M Hz, CD30D): 6 7.95 (s. 1H), 7.66 (d, J= 9.6 Hz, 1H), 7.32-6.69 (m, 16H), 3.98 (br, 1H), 3.47 (s, 3H), 3.21-2.95 (m, 16H), 2.65 (s, 3H), 2.27-2.10 (m, 2H), 1.81 (br, 4H), 1.29 (s, 3H).
W0 20] 2/103059 PCT/U821" 2/022315 Compound 217 Chen-ital Formula: o°783 End Mesa: 1070.30 Molemlat Weight 1071.13 BI-1161 BM-1167: ‘H NMR (300 M Hz, CD3OD): a 7.95 (s, 1H), 7.69 (d, J= 9.0Hz, 1H), .69 (m, 16H), .79 (m, 2H), 3.56 (br, 1H), 3.46 (s, 3H), 3.26-3.00 (m, 16H), 2.64 (s, 3H), 2.26-2.10 (m, 3H), 1.92 (br, 2H), 1.70—1.66 (m, 1H).
Compound 218 Chum Famutaz CmHHCIF‘MOfi.
Exact Mass: 1102.26 Molecular Weight 1 100.73 Baa-11m IBM-1168: 1H NMR (300 M Hz, CD30D): 5 7.95 (d, J= 2.1 Hz, 1H), 7.70 (dd, J= 2.1, 9.0 Hz, 1H), 7.34-6.42 (m, 17H), 4.10-3.80 (m, 2H), 3.53 (bra, 1H), 3.46 (s, 3H), 3.34- 2.88 (m, 16H), 2.82 (s, 3H), 2.63 (s, 3H), 2.25-2.04 (m. 3H), 1.91 (bra, 2H), 1.69-1.65 (m, 11-1).
PCT/U820 l 2/022315 nd 219 Chemml Formal-2 CWCIF5N7038.
Exact Mass: 1 163.26 Molewlar Weight 1164.74 “11“ BM-1169: ‘H NMR (300 M Hz, c0309): 5 7.95 (s, 1H), 7.67 (d. J= 9.0112, 1H), 7.34-6.76 (m, 16H), 4.08-3.80 (m, 2H), 3.53-3.42 (m, 1H), 3.50 (s, 3H). 3.24-2.98 (m, 16H), 2.59 (s, 3H), 2.26-2.10 (m, 3H), 1.92 (br, 2H), 1.69-1.64 (m, 1H).
Compound 220 Chemical Formula: CnHuchsNemS; Exact Man: 11 14.30 Molawiar Weight 1115.69 “-1170 BM-1170: 1H NMR (300 M Hz, CD30D): 5 7.95 (s, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.32-6.73 (m, 16H), 3.98 (br, 1H), 3.56 (s, 3H), 3.49 (s, 3H), 3.28-2.99 (m, 16H), 2.64 (s, 3H), 2.30-2.07 (m, 2H), 1.81 (br, 4H), 1.29 (s, 3H).
W0 20] 2/103059 PCT/U82012/022315 Compound 221 Chamlul a: CnHMCIFsNQO-fig End Man: 1100.28 MoIaul-r Weight: 1101.66 “1171 BM-1171: I1'1 NMR (300 M Hz, CD30D): 5 7.95 (s, 1H), 7.68 (d, J = , 1H), 7.31-6.72 (m, 1611), 4.18-3.79 (m, 2H), 3.58-3.42 (m, 1H), 3.56 (s, 3H), 3.49 (s, 3H), 3.24- 2.98 (m, 16H), 2.59 (s, 3H), 2.26-2.10 (m, 3H), 1.92 (br, 2H), 1.69-1.64 (m, 1H).
Compound 222 Chemical Fonnula: CflHaC'FqNQOTS4 Exact Mass: 1116.28 Molecular Weight 1117.75 Ell-1112 BM-1172: 1H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.67 (d, J= 8.1 Hz. 1H), 7.34-6.34 (m, 17H), 3.97 (hr, 111), 3.46 (s, 3H), 3.21-2.95 (m, 16H), 2.82 (s, 3H), 2.64 (s, 3H), 2.30-2.10 (m, 2H), 1.81 (br, 4H), 1.29 (s, 311).
PCT/U820 I 2/022315 Compound 223 Chemical Formula: CgHgCngNgogsa Exaa Mm: 8 Molecular We19h1: 1103.65 BM-ll73: lH NMR (300 M Hz, CD3OD): 5 7.94 (s, 1H), 7.70 (d, J = 9.0Hz, 1H), 7.33-6.69 (m, 18H), 4.07-3.79 (m, 2H), 3.53-3.42 (m, 1H), 3.47 (s, 3H), 3.26-2.94 (m, 16H), 2.54 (s, 3H), 2.26-2.10 (m, 3H), 1.92 (br, 2H), 1.73-1.65 (m, 1H).
Compound 224 mm|Fm: C51H5‘GF5N07S4 Exact m2 1120.25 M01811!" Wflight‘ 1 121.72 BM-l 1 7‘ BM-1174: 'H NMR (300 M Hz, CD30D): 5 7.94 (d, J= 2.1Hz, 1H), 7.72 (dd, J= 2.1, 9.0Hz, 1H), 7.32-6.77 (m, 16H), 4.06-3.78 (m, 2H), 3.58-3.42 (m, 1H), 3.49 (s, 3H), .02 (m, 16H), 2.97 (s, 3H), 2.62 (s, 3H), 2.25-1.60 (m, 6H). -l62- PCT/U320 I 2/022315 Compound 225 Chemical FOHTIUIBZ C51H54CIF3N30533 Exact Mass: 1034.29 Molecular Weight 1035.65 “1179 13111-1179: 'H NMR (300 M Hz, : 5 7.93 (s, 1H), 7.69 (d, J= 9.0 Hz, 1H), 7.41-6.73 (m, 18H), 3.97 (bra, 1H), 3.57-2.88 (m, 16H), 3.44 (s, 3H), 2.61 (s, 3H), 2.29-1.46 (m, 8H).
Compound 226 J 0 CN F2025 Chemical Formula: CwH9CIF3N,0983 Exact Mass: 8 Molecular Weight: 1021.63 BIA-1180 IBM-1180: ‘H NMR (300 M Hz, CDgOD): 8 7.93 (s, 1H), 7.70 (d, J= 9.6 Hz, 1H), 7.41-6.74 (m, 18H), 3.99 (bra, 1H), 3.60 (bra, 2H), 3.44 (s, 3H). 3.37-3.01 (m, 14H), 2.61 (s, 3H), 2.29-2.02 (m, 6H).
PCT/U820 I 2/022315 Compound 227 Cheme Formula: CquCIF4N¢O7sg Exam Man: 108229 ar Walgm: 1063.87 3&1“! BM-usl: ‘H NMR (300 M Hz, CD30D): 5 7.95 (s, 1H), 7.68 (d, J= 9.0112, 1H), 7.46-6.78 (m, 14H), 6.51-6.37 (m, 3H), 4.07-3.79 (m, 4H), 3.54 (bra, 1H), 3.17-2.94 (m, 16H), 2.62 (s, 3H), 2.31-1.64 (m, 6H), 1.15 (u-i, J= 6.9Hz, 3H).
Compound 228 Chemical Formula: c.9HwCIF3N.0783 Exact Man: 1022.25 Molecular Weight: 1023.60 BM-1185: 1H NMR (300 M Hz, CD30D): 5 7.92 (s, 1H), 7.70 (d, J = 9.0Hz, 1H), 7.41-6.75 (m, 18H), .59 (m, 1H), 4.44 (bra, 1H), 4.14-3.79 (m, 4H), 3.44 (s, 3H), 3.36- 3.10 (m, 12H), 2.62 (s, 3H), 2.03-1.92 (m, 2H). ~164- PCT/U820 I 15 Compound 229 -é’go F - O \ NJ C.) c.
Os .Q ‘é—NH 1105”J 139:6 0 Chemical Formulm caHEfiIF‘NMA Exact Man: 1118.28 Molecular Weight 11 1 7.75 BIA-11M BM-1186: ‘11 NMR (300 M Hz, CD30D): 5 7.92 (d, J= 1.8Hz, 111), 7.71 (dd, J= 1.8, 9.0112, 111), 7.31-7.07 (m, 13H), 6.82-6.43 (m, 411), 4.05-3.76 (m, 4H), 3.50 (bra, 111), .91 (m, 16H), 2.8] (s, 3H), 2.63 (s, 311), 2.22-1.63 (m, 611), 1.14 (61, J= 6.9Hz, 3H).
Compound 230 c0211 0 \N\/ Chemical Fonnula: CgHngqusa Exact Mm: 1060.32 Molecular Wabht 106722 Bil-1191 BM—ll9l: '11 NMR (300 M Hz, c0300): 6 7.94 (s, 1H), 7.71 (d, J= 9.0112, 111), .79 (m, 1411), 6.50-6.35 (m, 3H), 4.07-3.76 (m, 411), 3.53 (bra. 1H), 3.35-2.93 (m, 16H), 2.62 (s, 311), 2.25-1.66 (m, 6H), 1.12 (tri, J= 6.9Hz, 311). -165o PCT/U820 I 2/022315 Compound 231 O \ N\/ .0051.“it?“OQs-NH Chemkal Formula. CquFsNgoys.
Exact M: 110031 Molemw Weight 1101.30 Bil-1102 IBM-1192: 1H NMR (300 M Hz, CD30D): 6 8.00 (s, 1H), 7.81 (d, J: 9.0Hz, 1H), 7.40-6.53 (m, 17H), .96 (m, 4H), 3.63 (bra, 1H), 3.42-3.03 (m, 16H), 2.93 (s, 3H), 2.74 (s, 3H), 2.36-1.78 (m, 6H), 1.23 (tri, J = 6.9Hz, 3H).
Compound 232 Chemkal Fumula: F5N00733 EndMm: 1080.34 MOIOGIU MUM: 105‘ 24 6‘11” BM-ll93: 'H NMR (300 M Hz, : 5 7.94 (s, 1H), 7.69 (d, J= 9.0Hz, 1H), 7.41-6.79 (m, 14H), 6.49-6.32 (m. 3H), 4.45-4.35 (m, 1H), 4.08-3.79 (m, 2H), 3.52 (bra, 1H), 3.35-2.93 (m, 16H), 2.70 (s, 3H), 2.25-1.66 (m, 6H), 1.43 (s, 3H). 1.41 (s, 3H).
WO 03059 PCT/U820 I 2/022315 Compound 233 Chemical a: C§WF4NO183 Exact Man: 1096.31 Molauflar Mom: 1091.70 3‘11“ BM-ll94: 'H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.68 (d, J= 9.011;, 1H), 7.32-6.78 (m, 14H), 6.48-6.32 (m, 3H), 4.46-4.37 (m, 1H), 4.08-3.79 (m, 2H), 3.54 (bra, 1H), 3.35-2.94 (m, 16H), 2.70 (s, 3H), 2.26-1.65 (m, 6H), 1.44 (s, 3H), 1.42 (s, 3H).
Compound 234 _§go F — o \ ”1” ~ 0 F.) .
C611,...
NJ :1 ° H0 racozs Chemimi FOI‘mUIZ Cg'thsNOys‘ Em MRI: 1114.32 Molecular \NOUI: 1 1 15.32 BH-‘l 196 IBM-1195: 'H NMR (300 M Hz, CD30D): a 7.94 (s, 1H), 7.68 (d, J= 9.0112, 1H), 7.30-6.38 (m, 17H), 4.51-4.42 (m, 1H), .79 (m, 2H), 3.53 (bra, 1H), 3.35-2.94 (m, 16H), 2.83 (s, 3H), 2.74 (s, 3H), 2.26-1.65 (m, 6H), 1.44 (s, 3H), 1.42 (s, 3H). -l67- PCT/U820 I 2/022315 nd 235 Chemical Formula: CsHanlw.
Exact Mat 1240.22 lar Weight: 1241.22 BM—HM BM-ll96: ‘H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.67 (d, J = 9.0Hz, 1H), 7.30-6.57 (m, 16H), 4.52-4.42 (m, 1H), 4.08-3.79 (m, 2H), 3.53 (bra, 1H), 3.35-2.94 (m, 16H), 2.94 (s, 3H), 2.73 (s, 3H), 2.26—1.65 (m, 6H), 1.44 (s, 3H), 1.42 (s, 3H).
Compound 236 al Formula: angch4Ngoys4 Exact Mast: 1 130.30 Moleculr Wight 1131.78 395-1197 BM-l 197: ‘H NMR (300 M Hz, CD30D): 6 7.94 (s, 1H), 7.68 (d, J= 9.0112, 1H), 7.33-6.39 (m, 1711), 4.51-4.42 (m, 1H), 4.08-3.79 (m, 2H), 3.53 (bra, 1H), 3.19-2.94 (m, 16H), 2.84 (s, 3H), 2.74 (s, 3H), 2.26-1.65 (m, 6H), 1.45 (s, 3H), 1.42 (s, 3H).
PCT/U820 I 2/022315 Compound 237 (“J O .0“..E... O ChemIGI a: CquCIFONQO'Is‘ Exact Mass 1 152.28 M!!! Weight 1 153.73 Bfl-Hfl BM-1198: 1H NMR (300 M Hz, CD30D): 5 7.95 (s, 1H), 7.7] (d, J= 9.0Hz, 1H), 7.34-6.79 (m, 18H), 4.08-3.96 (m, 4H), 3.54 (bra, 1H), 3.35-2.94 (m, 16H), 2.68 (s, 3H), 2.26-1.65 (m, 6H), 1.17 (tri, J= 6.9Hz, 3H).
Compound 238 05AO?“9. Q HO F30028 Chemlml FONTIUIOZ CgHqu&°rS4 Exact Mal: 0 Molowlar Wtight: 1119.29 BM-‘HO.
IBM-1199: ‘H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.70 (d, J= 9.0112, 1H), 7.31-6.79 (m, 19H), 4.08-3.96 (m, 4H), 3.54 (bra, 1H), 3.35-2.94 (m, 16H), 2.68 (s, 3H), 2.26-1.65 (111,611), 1.16 (111,1: 6.9Hz, 3H).
PCT/U820 I 2/022315 Compound 239 -égo (:4) c1 08\ o “‘11“ NJ £1 ° HO F3COzS Cherriaal Formula: CaHaClFaNgo-fi‘ Exact Mass: 1098.29 lar Weight 1099.76 8M42M 13151-1200: ‘H NMR (300 M Hz, : 5 7.92 (s, 1H), 7.69 (d, J= 9.0112, 1H), 7.29-6.80 (m, 18H), 4.06-3.74 (m, 4H), 3.52 (bra, 1H), 3.30-2.92 (m, 1611), 2.78 (s, 3H), 2.64 (s, 3H), 2.25-1.66 (m, 6H), 1.13 (m‘, J= 6.9Hz, 3H).
Compound 240 Chemkal Formulm CMQQFgfloogs, Exam M: 117034 Mdomw Weight 0 Bil-1202 BM-1202: 'H NMR (300 M Hz, CD3OD): s 7.91 (s, 1H), 7.68 (d, J= 9.0112, 1H), 7.46-6.60 (m, 22H), 6.25 (s, 1H), 4.43-4.39 (m, 1H), 4.08-3.90 (m, 2H), 3.54 (bra, 1H), 3.35- 2.88 (m, 16H), 2.70 (s, 3H), 2.30-1.65 (m, 6H), 1.44 (s, 3H). 1.42 (s, 3H).
PCT/U820 l 2/022315 Compound 24 l \_.égo O f?1. /\95 Chemical Formula: 3W‘ Exact Mint 1 112.30 Moloeula Weight 1113.79 3M4”! 3111-1205: ‘H NMR (300 M Hz, CD30D): 5 8.02 (s, 1H), 7.88 (d, J= 9.0112, 1H), .96 (m, 18H), 4.17-3.90 (m, 4H), 3.63-2.89 (m, 1811), 2.74 (s, 311), 2.36-1.80 (m, 6H), 1.26-1.90 (m, 6H).
Compound 242 D \ N\/ <5 0CI 08 .Q HO’C J" N’Q/BN H F:0023 Chemical Fotmula: CuMIF3Ng0734 Exact Mast 2 Molecdlr Weight 1127.81 8M4200 IBM-1206: lH NMR (300 M Hz, CD3OD): 5 7.94 (s, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.31-6.74 (m, 18H), 4.08-3.79 (m, 4H), 3.54 (bra, 1H), 3.27-2.73 (m, 17H), 2.65 (s, 3H), 2.26-1.65 (m, 6H), 1.16-1.09 (m, 9H). -17l— PCT/U82012/022315 Compound 243 ~é=o (”J O N Cl 05\ 0 Ci ‘érNH fl 7: 0 HOCNJ Fscozs Chemical Fonmla: Cg1HsgCIF3N507S‘ Exact Mm: 1084.27 : Mglt 1085.73 “-1207 BM-1207: 1H NMR (300 M Hz, CD30D): 5 7.93 (s, 1H), 7.70 (d, J= 9.0 Hz, 1H), 7.31—6.80 (m, 18H), 4.08-3.79 (m, 2H), 3.53 (bra, 1H), 3.47 (s, 3H), 3.20-2.94 (m, 16H), 2.78 (s, 3H), 2.64 (s, 3H), 2.25-1.65 (m, 6H). nd 244 Chemical Formuh: ngHmCIfiMOyS.
Exact Mun: 1112.30 Molecular Might 9 Bil-120' IBM-1208: ‘H NMR (300 M Hz, CD30D): 5 7.93 (s, 1H), 7.70 (d, J= 9.0Hz, 1H), 7.30-6.79 (m, 18H), 4.52-4.43 (m, 1H), 4.08-3.79 (m, 2H), 3.53 (bra, 1H), 3.20-2.94 (m, 16H), 2.80 (s, 3H), 2.75 (s, 3H), 2.26-1.65 (111,611), 1.45 (s, 3H), 1.43 (s, 3H).
WO 03059 PCT/U820 l 2/022315 Compound 245 ——é’=o \-NJ <53 0Cl QSR 0%,? “O’CNJ FIG? 0 Chantal Fan-null: CsaHuCIFSW4 Exam Mall: 1112.30 Molecular Weight 1113.79 BM-flm 09: ‘H NMR (300 M Hz, CD300): a 7.93 (s, 1H), 7.68 (bra, 1H), 7.28-6.80 (m, 18H), 4.06-3.79 (m, 4H), 3.52 (bra, 113), 3.35-2.92 (m, 18H), 2.75 (s, 3H), 2.25-1.66 (m. 6H), 1.30 (bra, 3H), 1.09 (bra, 3H).
Compound 246 Chemiul meflll CuHuCIFgNgo-ys.
Era Mm: 1128.32 Molecular Might 1127.81 374-1210 BM-1210: lH NMR (300 M Hz, CD3OD): 5 7.95 (s, 1H), 7.68 (d, J= 9.0Hz, 1H), 7.33-6.80 (m, 18H), .79 (m, 4H), 3.52 (bra, 1H), 3.25-2.94 (m, 18H), 2.66 (s, 3H), 2.25-1.66 (m, 8H), 1.14-1.06 (m, (SH).
WO 03059 PCT/U32012/022315 nd 247 Chemlml Formula cuwclssmm End Mas: 1128.32 Molealar Mont 1127.81 BM-‘lfl‘l [02941 BM-1211: 'H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.69 (d, J= 9.0Hz, 1H), 7.31-6.78 (m, 18H), 4.08-3.79 (m, 5H), 3.54 (bra, 1H), 3.26-2.94 (m, 18H), 2.81 (s, 3H), 2.25-1.66 (m, 6H), 1.53 (s, 3H), 1.51 (s, 3H), 1.09 (m', J= 6.9Hz, 3H).
Compound 248 Qku :Q H05"NJ 0 Chemical Formula: CaHsgCIFaNg0754 Emu Mass: 1098.27 Molecular Maht 1097.75 BI-I 211 10295] IBM-1212: 'H NMR (300 M Hz, CD30D): 6 8.04 (s, 1H), 7.86 (d, J= 9.0112, 1H), 7.40-7.23 (m, 15H), .94 (m, 3H), 4.20-3.89 (m, 5H), 3.57-3.04 (m, 16H), 2.85 (s, 3H), 2.74-2.62 (m, 2H), 2.36-1.74 (m, 6H).
W0 201 2/103059 PCT/U82012/022315 Compound 249 Chemical Formula: CuHaCWaNgofig Em Manx 1110.29 Molowlar W1: 1 1 1 1 .TI 3&1213 IBM-1213: lH NMR (300 M Hz, CD300): 5 7.94 (s, 1H). 7.71 (d, J= 9.0Hz. 1H), 7.30-6.81 (m. 18H), 4.08-3.80 (m, 4H), 3.53 (bra, 1H), .94 (m, 18H), 2.76 (s, 3H), 2.26-1.65 (m, 10H).
Compound 250 H0 F3CO;S Chemicd Formula 1CIF5N7078.
Exact Mass: 1127.32 Molecular Weight 1128.80 BIG-1210 BM—1216: 1H NMR (300 M Hz, CD30D): 5 7.94 (s, 1H), 7.71 (d, J= 9.0Hz, 1H), 7.31-6.80 (m, 18H), 4.08-3.79 (m, 4H), 3.54 (bra, 1H), 3.22-2.94 (m, 15H), 2.64 (s, 3H), 2.39 (s, 6H), 2.25-1.68 (m, 6H), 1.14 (hi, J= 6.9Hz, BB).
PCT/U820 I 2/022315 Compound 251 Chomlul Fumnul: CgHmCIFJMOyS; Eula Mm: 1092.33 Mahala: Want 1093.73 “1211 7: ‘H NMR (300 M Hz, CD30D): 5 7.92 (s, 1H), 7.73 (d, J= 9.0Hz, 1H), 7.33-6.81 (m, 18H), 4.08-3.79 (m, 4H), 3.54 (bra, 1H), 3.36-2.94 (m, 15H), 2.63 (s, 3H), 2.32-1.11 (m, 10H), 0.78 (tri, J= 6.9Hz, 3H).
Compound 252 Chemical Formula: IN100332 Exad Mass: 1134.46 Molecular Might: 1135.83 BM-977 ~176- PCT/U82012/022315 BM-977: lH NMR (300 MHz, CD3OD), 8 8.66 (d, J=2.2, 1H), 7.93 (dd, J=2.2, 9.2. 1H), 7.75 (d, J=9.0, 2H), 7.29~6.95 (m, 15H), 6.81 (s, 1H), 6.74 (d, J=7.4, 1H), 4.38~4.27 (m, 2H), 4,164.13 (m, 1H), 3.54~3.32 (m, 11H), 3.24~3.08 (m, 14H), 2.84 (s, 6H), 2.82 (s, 3H), 2.61 (t, J=7.1, 2H), 2.27~2.14 (m, 2H), 2.03~2.00 (m, 1H), 1.78~l.75 (m, 1H), 1.66~1.61 (m, 2H); 13C NMR (75 MHz, CD3OD), 8 167.2, 165.4, 155.8, 152.1, 148.5, 137.2, 136.2, 135.6, 135.0, 132.5, 132.2, 131.5, 130.6, 130.4, 130.1, 129.7, 127.8, 127.5, 126.8, 126.0, 124.9, 123.7, 123.5, 121.7, 119.7, 116.5, 115.7, 114.8, 70.2, 67.3, 55.9, 55.4, 53.0, 52.4, 50.7, 50.2, 48.0, 46.2, 43.6, 43.5, 39.3, 37.6, 36.4, 30.1, 25.9; ESI MS: m/z 1135.6 (M + HY ; nd 253 \’ OH - xi 0 ,1 C.NH O eta-MalFmWIN‘M End Mu: 10w.“ Mal—wk wag“: 1061.76 BM-9s7: 'H NMR (300 MHz, CD30D), 5 8.35 («L J=l .9, 1H), 7.65 (d, J=7.4, 1H), 7.33~6.94 (m, 14H), 6.78~6.6l (m, 5H), 4.45431 (m, 2H), .12 (m, 1H), 3.70~3.39 (m, 8H), 3.28~3.17 (m, 13H), 2.90~2.88 (m, 8H), 2.69~2.64 (m, 2H), 2.30~2.05 (m, 3H), 1.85~1.82(m, 1H), l.70~l.68 (m, 2H); 13C NMR (75 MHz, CD30D) 165.2, 147.9, 137.6, 136.2, 135.0,134.5,132.5, 132.3, 131.6,130.9, 130.3, 1301,1292, 128.02, 127.96, 127.7, 125.9, 125.1, 125.0, 123.4, 116.2, 70.2, 67.3, 55.9, 55.4, 53.0, 52.3, 50.7, 46.4, 43.7, 43.5, 39.6, 37.6, 36.4, 30.1, 25.8; ESI MS: m/z 1081.6 (M + HY; W0 20] 2/103059 PCT/U320 l 2/022315 Compound 254 °C~ 2° 0 \\N HOCNJ'ENQ‘? C;Q— C.
F3005 Chantal len: c,,H..c11=,N,o,s, Emu Mm: 1mm Hanan-r wuun: 1 14am BIA-988 BM-988: ‘H NMR (300 MHz. c0300), 5 7.92 (s, 1H), 7.75 (d, J=9.1, 1H), 7.35~7.29 (m, 4H), 7.21~7.12 (m, 9H), .83 (m, 3H), 6.76~6.72 (m, 2H), 4,434.34011, 1H), 4.06~3.73 (m, 3H), 3.58~3.30 (m, 9H), 3.20~2.92 (m, 13H), 2.62~2.41 (m, 4H), 2244.90 (m, 5H), 1.69—1.66 (m, 1H), .28 (m, 6H); Compound 255 HN 'fi—m Chadd Formal: .-°u 50de 1117.3 WW“: 1118.79 ISM-989: '11 NMR (300 MHz, CD30D), a 7.90 (s, 1H), 7.75 (d, J=9.0, 1H), 7.32~7.30 (m, 4H), 7.22~7.02 (m, 11H), 6087~6.83 (m, 3H), 4,404.31 (m, 1H), 4.0s~3.77 (m, 2H), 3.51~3.3s (m, 10H), 3.19~2.91 (m, 6H), 2.64 (br, 1H), 2.51 (s, 3H), 2.23~1.90 (m, 5H), l.69~l.65 (m, 1H), 1.38 (d, J=6.9, 6H), O.63~0.6l (m, 2H), 0.26-0.24 (m, 2H); -l78- W0 20] 2/103059 PCT/U82012/022315 Compound 256 "“an o n 7’ Q81 Q C» HO‘CNJWHN g—m acozs comma FumuI-z cmlfings.
End Mun: 1190.42 Monk Wohnt 1191.88 BM—SOO BM-990: 1H NMR (300 MHz, CD3OD), 8 7.90 (s, 1H), 7.74 (d, J=9.1, 1H), 7.34~7.09 (m. 1411), 6.944691 (m, 1H), 6.85-6.81 (m, 1H), 6.67~6.65 (m, 2H), .34 (m, 1H), 4.04~3.98 (m, 2H), 133 (In, 13H), .69 (m, 15H), 2.42 (s, 3H), 2.23~1.89 (m, 5H), 1.69~1.65 (m, 1H), 1.40 (d, J=5.5, 6H); Compound 257 cmFarmh: CQMMO-ys; an: Mun: 1050.43 mmW1051.75 BIA-991 BM-991: 1H NMR (300 MHz, CD30D), a 8.28 (d, J=l.9, 1H), 7.55 (dd, J=1.8, 9.1, 1H), 7.16 (t, J=7.6, 1H), 7.10~6.85 (m, 18H), 4.37~4.22 (m, 2H), 4.06~4.04 (m, 1H), 3.47~3.42 (m, 7H), 3.29~3.26 (m, SH), 3.17~3.11 (m, 5H), 2.88 (s, 3H), 2.80~2.69 (m, 12H), 2.22-4.97 (m, 3H), 1.76~1.64 (m, 3H);”C NMR (75 MHz, c0300), 5; E81 M8: m/z 1051.4 (M+H)‘; W0 201 2/103059 PCT/U32012/022315 Compound 258 A/‘u \N/ 9N O O N CI >NJMEN 90 g-NH Chomiml Fan-nun: CMHHCIN1°O732 and Man: 1108.46 Molemlardeht 1107.32 BM-992 ISM-992: 1H NMR (300 MHz, CD30D), 8 8.36 (s, 1H), 7.66 (d, J=9.1, 1H), 7.22~7.04 (m, 18H), 6.97 (d, J=9.2, 1H), 4.43-4.31 (m, 2H), .13 (m, 1H), 3.59~3.37 (m, 17H), 3.26~3.21 (m, 8H), 2.90~2.82 (m, 11H), 2.30~2.05 (m, 3H), .74 (m, 311); 13C NMR (75 MHz, CD30D), 8 165.6, 147.9, 136.2, 135.1, 134.4, 132.7, 132.5, 132.3, 131.6, 130.5, 130.1, 129.2, 128.0, 127.9, 127.7, 126.3. 125.9, 125.1, 124.2, 123.7, 119.2, 117.9, 116.2, 70.3, 67.3, 55.9, 55.5, 52.5, 52.4, 51.4, 50.6, 50.4, 46.3, 43.6, 43.5, 39.5, 37.5, 36.5. .1, 25.7; E81 MS: m/z 1107.7 (M + H)+; Compound 259 Chemical Fonnula: c..H,,c1N,o.sz Exact Mm: 921.31 Molecular Walgm: 922.55 BIA-993 WO 03059 PCT/U820 I 2/022315 BM-993: 1H NMR (300 MHz, CD30D), 5 8.33 (d. J=1.9, 1H), 7.59 (d, J=9.1, 1H), 7.28 (t, J=7.9, 1H), 7.18~6.87 (m, 18H), 4.08~3.95 (m, 6H), 3.34~3.33 (m, 4H), 3.32~3.30 (m, 8H), 2.85 (s, 6H), 2.21~2.16 (m, 2H), 0.94 (t, J=7.l, 3H); ESI MS: m/z 922.8 (M + HY; Compound 260 CM'T‘ICII FOI'HIUII: CangC‘NaOsSg Exact Mm: 906.31 Molowlar Weight 907.54 BM-994 BM-994: ‘H NMR (300 MHz, cngon), 6 8.32 (d, J=l .2, 1H), 7.58 (cL J=9.1, 1H), 7.28 (t, J=7.9, 1H), 7.17~6.99 (m, 15H), 6.90 (d, J=9.3, 1H), 6.86 (s, 1H), 6.80 (d, J=7.5, 1H), 4.09~4.O7 (m, III), 3.80 (s, 3H), 3.45~3.33 (m, 9H), 3.21~3.08 (m, 3H). 2.84 (s, 6H), 3.05 (s, 3H), 2.25~2.10 (m, 2H) ; 13c NMR (75 MHz, CD30D), 5 ; ESI MS: m/z 907.6 (M + H)*; Compound 261 Chemical Formuta: C‘aHuClNyogsg Exact Mus: 921.31 tu' Mght 922.55 BM-995: BS] MS: m/z 922.5 (M + H)+ ; To demonstrate the ability of the present Bcl-xL inhibitors to bind to BC!- 2/Bcl-xL, to induce apoptosis, and to inhibit tumor growth in viva, nds of the invention were assayed.
PCT/U820 I 2/022315 Compound 262 al Formula: C50H570|N30783 Exact Mass: 1012.32 Molecular Weight: 1013.68 [03101 13111-1074 ‘H-NMR (300MHz, CDJOD) 6 ppm 8.34 (d, 1 = 2.2 Hz, 1H), 7.65 (dd, J = 2.1, 9.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), .98 (m, 15H), 6.90 (d, J = 7.3 Hz, 1H), 4.40 (h, J = 7.0 Hz, 111), 4.21-4.10 (m, 1H), 3.62-3.34 (m, 9H), 3.27-3.15 (m, 6H), 2.99 (s, 1H), 2.87 (s, 7H), 2.61 (s, 3H), 2.34-2.10 (m, 2H), 1.42 (d, J = 7.0 Hz, 6H) Compound 263 Chemiml Formula: C49H55CIN307$3 Exact Mass: 998.30 Molecular Weight 999.66 BM-1075 lH-NMR (300MHz, CD30D) 6 ppm 8.35 (d, J = 2.2 Hz, 1H), 7.62 (dd, I = 2.1, 9.] Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.23-6.93 (m, 15H), 6.80 (d, J = 7.6 Hz, 11-1), PCT/U320 l 2/022315 4.19-4.08 (m, 1H), 3.89 (q, I = 7.0 Hz, 2H), 3.46-3.33 (m, 9H), 3.26-3.16 (m, 7H), 2.87 (s, 6H), 2.70 (s, 1H), 2.55 (s, 3H), 2.34-2.11 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H) Fluorescence polarization based binding assays for Bcl—Z/Bcl-xL/Mel—l proteins Sensitive and quantitative fluorescence polarization (FP)-based assays were developed and optimized to determine the binding affinities of Bel-2 family protein inhibitors to the recombinant Bel-2, Bcl-xL, and Mcl-l proteins.
Determine Kd values offluorescent probes to proteins Homemade fluorescein labeled BIM 6), Bak (72-87) and BED (79-99) peptides, named as Flu-BIM, Flu-BAK, and Flu-BID were used as the fluorescent probes in FP assays for Bcl-2, , and Mel-1 respectively. By monitoring the total fluorescence polarization of mixtures composed with fluorescent probes at fixed concentrations and proteins with sing concentrations up to the full saturation, the K4 values of Flu-BIM to Bel-2, Flu-BAK to Bcl-xL, and Flu-BID to Mel-1 were determined to be 0.55:0.15 nM, 4.4i0.8, and 6.8i1.5 nM, respectively. Fluorescence polarization values were ed using the Infinite M-lOOO multi-mode plate reader (Tecan U.S., Research Triangle Park, NC) in Micmfluor 2 l, black, round-bottom plates (Thermo Scientific). To each well, lnM of Flu-BLM or 2nM of Flu-BAK or 2nM of D and increasing concentrations of Bel-2 or Bcl-xL or Mel-l were added to a final volume of 125 pl in the assay buffer (lOOmM potassium ate, pH 7.5, 100 ug/ml bovine y—globulin, 0.02% sodium azide, Invitrogen, with 0.01% Triton X-100 and 4% DMSO). Plates were incubated at room temperature for 2 hours with gentle shaking to assure equilibrium. The polarization values in millipolarization units (mP) were measured at an excitation wavelength of485 nm and an emission wavelength of 530 nm. Equilibrium dissociation constants (Kd) were then calculated by fitting the sigmoidal dose-dependent FP increases as a function of protein concentrations using Graphpad Prism 5.0 software (Graphpad e, San Diego, CA).
Determine K; values of Bel-2 family protein tors K, values of Bel-2 family protein tors to Bcl-2/Bcl-xL/Mcl-l proteins were determined h an inhibitor dose-dependent itive binding experiment in which serial dilutions of inhibitors competed t the fluorescent probe with fixed concentration for binding to a fixed concentration ofthe protein. Mixtures of 5 pl of the tested inhibitor in DMSO and 120 pl ofpre-incubated protein/probe complex in the assay buffer were added into assay plates and incubated at room temperature for 2 hours with gentle shaking. Final concentrations ofthe protein and probe are 1.5nM and lnM for the Bel-2 assay, [W and WO 03059 PCT/U82012/022315 2nM for the Bcl-xL assay, and 20nM and 2nM for the Mcl-l assay, respectively. Negative controls ning protein/probe x only alent to 0% inhibition), and positive controls containing free probe only (equivalent to 100% inhibition), were included in each assay plate. FP values were measured as described above. ICSO values were determined by nonlinear regression fitting of the competition curves. K.- values of inhibitors were calculated using the home derived equation described before (Z. Nikolovska-Colcska et al., Analytical Biochemistry, 2004, 332, 261-273.), based upon the ICSO values obtained, the Kd values of the probes to the proteins, and the concentrations of the proteins and probes in the itive assays. K.- values were also calculated by using another very commonly used on present in the literaturcs (X. Y. Huang, Journal ofBiomolecular Screening, 2003, 8, 3438.), results from which consisted with our results extremely well.
Cell Growth Assay RS4;1 l and H146 cells were seeded in 96-well cell culture plates at a density of ,000 cells/well with serially diluted compounds and incubated at 37°C in an here of 95% air and 5% C02 for 4 days. Cell viability was determined using the WST-8 (2-(2- methoxy—4-nitrophenyl)(4-nitrophenyl)-S-(2,4-disulfophenyl)-2H-tetrazolium, monosodiurn salt) based Cell Counting-8 Kit do Molecular Technologies, Inc., Rockville, MD) according to the manufacture's instruction. Briefly, WST-8 was added to each well at a final tration of 10% (v/v), and then the plates were incubated at 37°C for 1-2 hourrs for color development. The absorbance was measured at 450 nm using a SPECTRAmax PLUS plate reader (Molecular Devices, Sunnyvale, CA). The halfmaximal inhibitory concentration (ICso) was calculated using the GraphPad Prism 5 software (GraphPad Software, La Jolla, CA).
Cell Death Assay Cell death assay was performed using a Trypan blue exclusion test of cell viability.
One million cells were seeded in 6-well plates and incubated at 37°C in an atmosphere of 95% air and 5% CO; with or t compounds for the indicated time . At the end of treatment, cells were collected and centrifuged at 1000 rpm for 5 minutes. The cell pellets were re-suspcnded in PBS and mixed with 0.4% Trypan blue (lnvitrogen) at 1:1 dilution to determine cell viability using Olympus CKX41 microscope (Olympus, Center Valley, PA).
Apoptosis Assay Apoptosis assay was performed using the Annexin-V—FLUOS Staining kit (Roche Diagnostics, Indianapolis, IN) according to the manufacturer's instruction. Briefly, cells were PCT/U320 l 2/022315 d with compounds for the indicated time points, harvested and washed with PBS. Cells were stained with Annexin V-FITC and Propidium iodide for 15 minutes at room temperature in the dark before analyzed with a BD Biosciences FACSCaliburs (Becton Dickinson).
Western Blot is Cells were lysed with lysis buffer (PBS ning 1% NP40, 0.5% Na- deoxycholate, and 0.1% SDS) supplemented with protease inhibitors (a-complete, Roche).
The protein extracts were fied using a metric assay (Bradford Reagent) (BioRad, Hercules, CA). Proteins were electrophoresed onto 4-20% SDS-PAGE gels (Invitrogen) and transferred onto polyvinylidene difluoride membranes ad). Following blocking in 5% milk, membranes were ted with a specific primary antibody, washed, and incubated with horseradish peroxidase-linked secondary antibody (Pierce). The signals were visualized with the chemiluminescent horseradish peroxidase antibody detection reagent (Denville Scientific).
Cytochrome c and Smae Release Assay Four million ofH146 or RS4;ll cells were treated with compounds at 37°C in an atmosphere of95% air and 5% C02 for the indicated time points, washed with PBS and re- suspended in 100 pl ofdigitonin bufi‘er (75 mM NaCl, 8 mM Na2HPO4, 1 mM NaH2P04, 1 mM EDTA, 350 rig/ml digitonin, and 250 mM sucrose). Cytosolic fractions were separated from lle ne on by centrifugation at 13,000 rpm for l min. The cytosolic fractions were resolved on a 12% SDS-PAGE and probed using ytochrome c antibody (BD Biosciences) and anti-Smac (Cell Signaling Technology, Danvers, MA) antibody.
In particular, a compound of the invention was assayed for afiinity to Bel-2, Bcl- XL, and Mcl-l. The assay results compared to assay results for ABT-737, a known, patent Bcl-Z/Bcl-xL inhibitor, and to these peptides. The results are summarized in Table l. -l85- PCT/U320 l 2/(l223l5 Table 2. Binding affinities to Bel-2, Bel-XL, and Mel-l proteins, as determined using ished FP-based assays. 3—5 independent experiments were performed for each compound for each protein. 7, BIM, BAD, and NOXA peptides were tested as controls.
Binding Affinitles 33““ mm sssm m ssm The data in Table 2 show that compound binds to Bel-2 and Bel-XL proteins with a high affinity, and has a very low affinity to Mel-l.
A present Bcl-2/Bcl—xL inhibitor also was assayed in three cancer cell lines to determine its activity. ABT-737 and ABT-263 are highly potent and effective inhibitors of cell growth in certain cell lines with low levels of Mel-l, including the RS4;11 acute lymphoblastic leukemia (ALL), H146 small-cell lung , and the ML-2 acute myeloid leukemia (AML) cell lines.26'”‘34 Compound 150 binds to Bel-2 and Bel-XL with high ies, has a very weak y for Mcl-l , and has the same binding profile as ABT-737.
Compound 150 therefore was assayed in these three cancer cell lines. Cell lines from different tumor types were used to illustrate that antitumor activity of the present Bcl- xL inhibitors is not limited to a simple tumor type, and also to directly compare a present Bcl- 2/Bcl-xL inhibitor to ART-737. The data are summarized in Table 3. -l86- PCT/U820 l 2/022315 Table 3. Inhibition of cancer cell growth in three cancer cell lines.
ABT-737 was used as a l Cell Growth Inhibition (leo i SD) Compound 38i24 (nM) 102i44(nM) 185184(nM) mar-737 12i6(nM) 62i39(nM) 16i2(nM) The data in Table 3 show that nd 150 inhibits all cell growth in all three cancer cell lines.
The fimctional antagonistm of a present compound against Bel-2, Bel-XL, and Mel-l also was tested. Cell-free functional assays using purified mitochondria, recombinant Bcl-2/Bcl-xUMcl-1 ns, and the high-affinity BIM BH3 e were used to e direct evidence that compound 150 ons as a potent antagonist to Bel-2 and Bel-XL, but not Mel-l. These cell-free functional assays were used to test the functional antagonism of Compound 150, ART-737, and BAD and Noxa BH3 peptides.
The Bim BH3 peptide at a concentration of 20 nM induces substantial release of cytochrome c and Smac proteins from mitochondria. Bel-2 at 60 nM and BCl-XL at 30 nM efficiently inhibit the release from mitochondria of cytochrome c and Smac proteins induced by 20 nM of the Bim BH3 peptide.
In the Bel-2 functional assay, ART-737 and compound 150 dose-dependently and effectively antagonize Bel-2 and e Bim-induced release ofcytochrome c and Smac ns from mitochondria The BAD BH3 peptide also is capable g so in a dosedependent manner, but the Noxa BH3 peptide fails to restore the release of cytochrome c and Smac.
In the Bel-XL functional assay. compound 150 and ART-737 are equally potent in restoring the release ofcytochrome c and Smac induced by Bim BH3 peptide, but both are 3- times less potent than the Bad BH3 peptide. The Noxa BH3 peptide fails to antagonize Bcl- In the Mel-l functional assay, Mel-1 at 60 nM effectively ts the release of cytochrome c and Smac induced by 20 nM ofthe BIM BH3 peptide. While the Noxa peptide PCT/U320 l 2/022315 can restore the release of cytochrome c and Smac induced by the BIM peptide in a dose- dependent manner, the BAD peptide, ART-73 7, and compound 150 at concentrations as high as 10 nM all fail to do so.
These data provide clear evidence that compound 150, ART-73 7, and the BAD peptide function as potent antagonists of Bcl-2 and Bcl-xL proteins, but not of Mel-l. On the other hand, the Nova BH3 peptide antagonizes Mel-l , but fails to antagonize both Bel-2 and BcI-xL proteins. These functional data are highly consistent with their binding profiles to these Bc1-2 proteins. sis/cell-death induction by compound 150 in the H146, RS4;l l, and ML—2 cell lines was also tested. 7 was included in the test as a control.
Both ABT-737 and nd 150 effectively induced cell death in the H146 cell lung cancer cell line as determined in a trypan blue assay. For example, compound 150 at 30 nM and 100 nM for 24-hr treatment induces 40% and >70% of H146 cells to undergo cell death, respectively.
Using Annexin-V/Propidium iodide (PI) double staining by flow cytometry, both ABT-737 and compound 150 effectively d apoptosis in the ML-2 AML cell line in a dose— and timedependent manner and about 50% ofML-2 cells underwent apoptosis when treated with both compounds at 300 nM for 24 hr.
Similarly, both nd 150 and ABT-737 are highly effective in induction of apoptosis in a time- and dose-dependent manner in the RS4;11 cell line by Annexin-V/PI double staining by flow cytometry. compound [50 at mo and 300 nM induced 30% and 60% of the RS4; ll cells to undergo sis within 4 hrs. compound 150 at 100 nM induced >50% ofthe RS4;ll tumor cells to undergo apoptosis at the16 hr time-point.
Western blot analysis was performed to examine cleavage ofPARP and caspase-3, two important mical markers of sis, in these three cancer cell lines when d with compound 150 or ABT-737. Both compound 150 and ART-737 were highly effective in induction ofcleavage ofPARP and caspase-3 at concentrations as low as 100 nM with 8-hr treatment in the RS4;11, H146 and ML-2 cell lines.
Taken together, these data show that nd 150 and ART-737 effectively induce apoptosis with similar potencies and kinetics in the RS4;11, H146 and ML-2 cancer cell lines. -l88- PCT/U320 l 2/022315 Potent and bana fide Bcl-2/Bcl-xL inhibitors are predicted to induce apoptosis in cancer cells by binding to cellular Bcl-2 and Bcl-xL proteins, antagonizing their anti- apoptotic function and triggering rapid release of Smac and cytochrome c from mitochondria.
Furthermore, the release of Smac and cytochrome c should take place before apoptosis.
Accordingly, compound 150 was tested for its ability to induce cytochrome c and Smac release in the RS4;ll and H146 cell lines. It was found that compound 150 induced rapid, time- and dose-dependent release of cytochrome c and Smac from mitochondria in both cancer cell lines. At 300 nM, compound 150 induces strong release of cytochrome c and Smac within 2 hr in the H146 cell line. In the RS4;11 cell line, compound 150 at 100 nM induced robust release of cytochrome c and Smac within 30 minutes. These data show that release of cytochrome c and Smac from mitochondria by compound 150 are early biochemical events in apoptosis induction by nd 150 in these cell lines.
To determine the cellular molecular targets for compound [50, biotinylated analogue of compound 150 (Biotin-150) was designed and synthesized. In FP binding assays,23 Biotin-150 binds to Bel-2 and Bcl-xL proteins with high aflinity, similar to that of nd 150, while showing no g to Mel-l at 100 pM, indicating that the biotin label does not affect the ction of compound 150 with these proteins.
Using Biotin-150, avidin-biotin pull.down experiments and competitive assays were performed to probe the ar targets of compound 150 and ABT-737 in the ML-2 and H146 cell lysates. Biotin-150 dose-dependently pulled down the cellular Bel-2 and Bel-XL proteins, but not Mel-l, in the avidin-biotin pull-down experiments. rmore, in the competitive ment, compound 150 and ABT-737 both blocked the interaction of cellular Bcl-2/Bcl-xL and -150 in a dose-dependent manner. These pull- down experiments provide evidence that compound 150 and ABT-737 bind to cellular Bel-2 and Bel-XL proteins with r high ies.
Additional compounds ofthe present invention were tested for binding affinities to Bel-2, Bcl-xL, and Mcl-l and for cell growth inhibition. The results are summarized below in Table 4. —l89v PCT/U820 l 2/022315 Table 4. Binding ies to Bel-2, Bcl-xL, and Mcl-l proteins in FP-based assays and inhibition of cell growth in three cancer cell lines.
Binding Affinities Cell Growth Inhibition (ICsozt: SD. nM) 9EE !iBcl to”: SD Kai SD leo :1: SD H146 ML—Z ) (nM) (mm (11M) Compound125 IIE51:1 IEKit so leozb SD 11i0.2 6:1:3 1.6i0.8 >10 74i44 362226 215i52 Compound 178 l i0.1 <1“ 6 :1: 4 1.6:h 1.0 > 10 26:124 87:1:60 124:1:62 CoE““1331102 <1. 5&1 0.3 >10 87119 38:22 160i53 CoE““1158 99:5 25:2 11 i 6 3 :t: l > 10 3373i1663 39443:]681 30141703 CoEund 185 2,211.6 <l‘ 5:4 Compound 186 14:3 3.41:0.6 613 compound 168 2 3:1 <1.
Compound 124 141:2 *Compound is more potent than the tracer based upon its [Cso value and the K; is an estimate.
Compounds 150, 133, and 169 were tested for their toxicity in severe combined immunodeficiency (SCID) mice. SCID mice bearing xenografi tumors were d with vehicle control, or a single dose of a compound, and tumors were removed at difi‘erent time- points for western blot analysis of cleavage ofPARP RP) and caspase-3 (CL Gas-3).
The data show that female SCID mice treated intravenously (IV), daily, s a week for 2 weeks with compound 150 01130 at 25 mg/kg, or with compound 169 at 50 mg/kg, sufi‘ered no or minimal weight loss or other signs of toxicity. Higher doses (50 mg/kg for compound 150 and compound 133 and 75 mg/kg for compound 169) caused weight loss of SCID mice. These experiments established the m tolerated doses (MTD).
The ability of compounds 150 and 169 to induce apoptosis at their MTD in RS4;ll or H146 xenografi tumors in SCID mice was tested. In these experiments, RS4;11 or H146 tumors were allowed to grow to 200-300 mm3 in female SCID mice. A single dose of the W0 20] 59 PCT/U32012/022315 compound was administered to the animals and tumor tissues were analyzed for cleavage of PARP and caspase-3.
Compound 169 had a strong effect in induction of cleavage ofPARP and e-3 in tumor tissues in both RS4;11 and H146 models. For e, a -dose ofcompound 169 at 50 :11ng IV induced cleavage ofPARP and caspase-3 at 3 hr and 6 hr-time points in both the H146 xenografi tumor tissues. These data suggest that compound 169 induces robust apoptosis in xenografl tumors in vivo.
The antitumor activity of compound 169 in the H146 xenograft tumor model also was tested. nd 169 showed significant antitumor activity, while causing minimal (<3%) weight loss and no other signs oftoxicity in mice during the entire experiment. At the end of the treatment (day 39), compound 169 inhibited the tumor growth by 100% (p < 0.0001, t—test). The strong antitumor activity ed by compound 169 also was tent.
At day 53, 2 weeks afier the treatment was stopped, compound 169 still inhibited the tumor growth by 79% versus the vehicle-treated tumors (p=0.0001, t-test). This preliminary in viva efficacy experiment provided evidence that compound 169 effectively inhibits tumor growth in the H146 xenograft model, while g no toxicity in animals.
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Claims (12)

CLAIMS 1. NG THE INVENTION ARE AS FOLLOWS:-
1. A compound having a structural formula: 5 wherein A is pyrrolyl; B is selected from the group ting of , , , , , , and C and D individually are phenyl, substituted with zero to four 10 substituents independently selected from the group consisting of CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR’, SR’, NR’R’’, CO2R’, COR’, OCOR’’, CONR’R’’, CONR’SO2R’’, NR’COR’’, NR’SO2Rn, C1-3alkyleneCH(OH)CH2OH, SO2R’, and SO2NR’R’’, wherein each R’ and R’’, independently, is H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, CF3, aryl, heteroaryl, C1- 5 eneheterocycloalkyl, or heterocycloalkyl; or wherein two substituents on the same C and/or D ring can be taken together to form a ring; or wherein R’ and R’’, taken together with the atoms to which they are bound, form a 3 to 7 membered ring; E is substituted at a meta on to the –SO2NH- group with NO2 or 10 SO2CF3; or n E is substituted at a para position to the - group with 15 wherein Ra and Rb, individually, are H, methyl, and or Ra and Rb are taken together to form , , , , , , , or ; X and Y taken together form or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein ring A is wherein R1 and R2, independently, are selected from the group 5 consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR', SR', NR'R'', COR', CO2R', OCOR', CONR'R'', CONR'SO2R'', NR'COR'', NR'CONR''R''', NR'C=SNR''R''', NR'SO2R'', SO2R', and SO2NR'R''; R3 is ed from a group consisting of H, alkyl, cycloalkyl, alkenyl, 10 cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR', NR'R'', CO2R', COR', CONR'R'', CONR'SO2R'', C1-3alkyleneCH(OH)CH2OH, SO2R', and SO2NR'R''; R', R'', and R''', ndently, are H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, CF3, aryl, heteroaryl, C1-3alkyleneheterocycloalkyl, or 15 heterocycloalkyl; R' and R'', or R'' and R''', can be taken together with the atom to which they are bound to form a 3 to 7 membered ring.
3. A nd according to claim 1, wherein the nitrogen atom of ring A is 20 tuted with C1-6alkyl, cycloalkyl, -(CH2)1-3N(C1-4alkyl)2 or –(CH2)1-3 CH2OH or the nitrogen atom of the A ring and an adjacent carbon atom of the A ring are taken together to form a five or six ed ring.
4. A compound according to claim 1, wherein one to three carbon atoms of ring 25 A are substituted, independently, with CH3, C2H5, C3H7, CF3, NH2, Cl, CN, CO2H, C(=O)CH3, C(=O)C2H5, C(=O)CF3, SO2CH3, SO2C2H5, SO2C3H7, SO2CF3, SO2N(CH3)2, C(=O)NHSO2CH3, H2, C(=O)NHCH3, C(=O)NH(CH2)1-3N(CH3)2, C(=O)NHSO2CH3, , , , , , , , , , 5 , , , , , , or 10 5. A compound ing to claim 1, having a structure: wherein R4 and R5, independently, are selected from a group consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR', SR', NR'R'', CO2R', OCOR', CONR'R'', CONR'SO2R'', NR'COR'', NR'CONR''R''', NR'C=SNR''R''',
5 R'', SO2R', and SO2NR'R''.
6. A compound according to claim 5, having a structure 10 wherein R6, R7, R8, R9 and R10, independently, are selected from the group consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, OR', SR', NR'R'', CO2R', OCOR', CONR'R'', CONR'SO2R'', NR'COR'', NR'CONR''R''', NR'C=SNR''R''', R'', SO2R', and SO2NR'R''.
7. A compound according to claim 6, having a structure wherein the A ring is rings B and C are substituted or unsubstituted phenyl; 5 X, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R', R", R''' are d as above; and R11 and R12, independently, are ed from the group consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR', SR', NR'R'', CO2R', OCOR', CONR'R'', 10 CONSO2R'R'', NR'COR'', NR'CONR''R''', NR'C=SNR''R''', NR'SO2R'', SO2R', and SO2NR'R''; or a pharmaceutically acceptable salt, f.
8. A compound having a structure —200— —201— —202— F HO S F HO N HN S NH F3CO2S —204— —205— —206— —207— —208— —209— —210— —2ll— —212— —2l3— —214— N HN S NH F3CO2S —2l6— —2l7— HN O S N N HN O O2N O H HO N Cl N N O2N HN —220— —22l— —222— —223— —224— —225— —226— —228— —229— —230— —23l— N HN S NH —233— N HCl O N HN S NH HCl O F3CO2S N HCl O N HN S NH N HN S NH HCl O O N HN S NH HCl O HO N HN S NH HCl O H O N HN S NH HCl O F3CO2S H O O N HN S NH HCl O F3CO2S H O HO N HN S NH HCl O F3CO2S —237— "".2NQO HCI Fgcozs HO N4 ;N F3COZS —238— —239— N HN S NH HCl O F3CO2S —241— N HN S NH HCl O HO N HN S NH HCl F3CO2S —243— —244— —245— —246— —247— —248— F3COZS —249— —250— —251— —252— —253— —254— —255— N Cl S NH N O N H HO F3CO2S —257— —258— 0 70H N \ / —259— —260— or .
9. A composition comprising (a) compound of claim 1, (b) a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of 5 Bcl-2 or Bcl-xL provides a benefit, and (c) an optional excipient and/or ceutically acceptable carrier.
10. A composition according to claim 9, wherein the second therapeutic agent comprises a chemotherapeutic agent useful in the treatment of cancer.
11. A ceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable r or vehicle.
12. A compound having a structure 5 Dated this 11th day of March 2015 Shelston IP Attorneys for: The Regents of the sity of Michigan
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