NZ750100B2 - N-(phenylsulfonyl)benzamides and related compounds as bcl-2 inhibitors - Google Patents

N-(phenylsulfonyl)benzamides and related compounds as bcl-2 inhibitors Download PDF

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Publication number
NZ750100B2
NZ750100B2 NZ750100A NZ75010017A NZ750100B2 NZ 750100 B2 NZ750100 B2 NZ 750100B2 NZ 750100 A NZ750100 A NZ 750100A NZ 75010017 A NZ75010017 A NZ 75010017A NZ 750100 B2 NZ750100 B2 NZ 750100B2
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New Zealand
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methyl
compound
bcl
oxy
pyrrolo
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NZ750100A
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NZ750100A (en
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Jianyong Chen
Shaomeng Wang
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The Regents Of The University Of Michigan
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Priority claimed from PCT/US2017/045428 external-priority patent/WO2018027097A1/en
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Publication of NZ750100B2 publication Critical patent/NZ750100B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present disclosure provides compounds having Formula I-A: and the pharmaceutically acceptable salts and solvates thereof, wherein A, X1 , X2, X3, R1a, R1b and E are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I-A for use to treat a disease, disorder, or condition responsive to BCL-2 protein inhibition such as cancer ase, disorder, or condition responsive to BCL-2 protein inhibition such as cancer

Description

N-(PHENYLSULFONYL)BENZAMIDES AND RELATED COMPOUNDS AS BCL-2 INHIBITORS BACKGROUND OF THE INVENTION Field of the Invention The present disclosure provides Bcl-2 protein inhibitors and therapeutic methods of ng diseases, ers, or conditions wherein inhibition of Bcl-2 proteins provides a benefit.
Background Apoptosis, the process of programmed cell death, is an essential biological process for tissue homeostasis. In mammals, it has been shown to regulate early embryonic development. Later in life, cell death is a default mechanism by which potentially dangerous cells, e.g., cells carrying ous defects, are removed. Several apoptotic pathways are known. One of the most important apoptotic pathways involves the Bcl-2 family of proteins which are key tors of the mitochondrial (also called "intrinsic") pathway of apoptosis. See Danial and Korsmeyer, Cell 116:205-219 (2004). The structural homology domains BH1, BH2, BH3 and BH4 are characteristic of Bcl-2 family proteins. The Bcl-2 family of proteins can be further fied into three subfamilies depending on how many of the homology domains each protein contains and on its biological activity, i.e., whether it has pro- or antiapoptotic function.
The first subgroup of Bcl-2 proteins contains proteins having all four homology domains, i.e., BH1, BH2, BH3 and BH4. Their general effect is anti-apoptotic, that is to ve a cell from starting a cell death process. Proteins such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1/A1 are members of this first up. Proteins belonging to the second subgroup of Bcl-2 ns contain the three homology domains BH1, BH2, and BH3, and have a pro-apoptotic effect. The two main entative proteins of this second subgroup are Bax and Bak. The third subgroup of Bcl-2 proteins is composed of proteins containing only the BH3 domain and s of this up are usually referred to as "BH3-only proteins." Their biological effect on the cell is optotic.
Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third subfamily of proteins. The exact mechanism by which the Bcl-2 family proteins regulate cell death 17301393_1 (GHMatters) P44803NZ00 is not entirely known. In one hypothesis of regulation of cell death by Bcl-2 family proteins, the ly proteins are further categorized as either "activator," e.g., Bim and Bid, or "sensitizer," e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma, proteins depending on their regulatory function.
One of the keys to tissue homeostasis is achieving a balance in the interactions among the three subgroups of Bcl-2 proteins in cells. Studies have elucidated the mechanisms by which pro-apoptotic and anti-apoptotic subgroups of Bcl-2 family proteins interact to allow a cell to undergo mmed cell death. After receiving intra- or extra-cellular signals in cells, post-translational or transcriptional activation of ly proteins occurs. The BH3-only proteins are the primary inducers of an apoptotic cascade that includes, as one step, the activation of the pro-apoptotic proteins Bax and Bak on the mitochondrial membrane in cells. Upon activation of Bax and/or Bak that are either already anchored to the mitochondrial membrane or migrate to this membrane, Bax and/or Bak oligomerize to result in mitochondrial outer membrane bilization (MOMP), the release of cytochrome C, and downstream activation of effector caspases, to ultimately result in cell apoptosis. Some researchers hypothesize that certain BH3-only proteins, e.g., Puma, Bim, Bid, are "activators" in that these ns directly engage pro-apoptotic proteins Bax and Bak to initiate MOMP, while other BH3-only proteins, e.g., Bad, Bik and Noxa, are "sensitizers" and induce Bax and Bak oligomerization ctly by binding poptotic proteins, e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and displacing and "freeing-up" the ator" BH3-only proteins, which subsequently bind to and activate pro-apoptotic proteins, e.g., Bax, Bak, to induce cell death. Other research suggests that anti-apoptotic proteins engage and seqeuester Bax and Bak directly and all BH3-only proteins tes this interaction by binding to anti-apoptotic proteins, e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, which results in the release Bax and Bak. See Adams and Cory, Oncogene 4-1337 (2007) and Willis et al., Science 315:856-859 (2007). Although the exact interactions through which the anti- and pro-apoptotic Bcl-2 family proteins regulate sis remain under investigation, there is a large body of scientific ce to show that compounds which inhibit the binding of BH3-only proteins to anti-apoptotic Bcl-2 family proteins promote sis in cells.
Dysregulated apoptotic pathways have been implicated in the pathology of many icant diseases such as neurodegenerative conditions (up-regulated apoptosis), such as for example, Alzheimer's disease; and proliferative diseases 93_1 (GHMatters) P44803NZ00 (down-regulated apoptosis) such as for e, cancer, autoimmune diseases and pro-thrombotic ions.
Down-regulated apoptosis (and more particularly the Bcl-2 family of proteins) may be involved in the onset of cancerous malignancy. ch has shown, for example, the anti-apoptotic proteins, Bcl-2 and Bcl-xL, are over-expressed in many cancer cell types. See Zhang, Nature Reviews Drug Discovery 1:101 (2002); Kirkin et al., Biochimica et Biophysica Acta 1644:229-249 (2004); and Amundson et al., Cancer Research 60:6101-6110 (2000). The effect of this deregulation is the survival of altered cells which would otherwise have undergone apoptosis in normal conditions. The tion of these defects associated with unregulated eration is thought to be the starting point of cancerous ion.
Additionally, research has shown that BH3-only proteins can act as tumor suppressors when expressed in diseased animals.
These findings have made possible new strategies in drug discovery for targeting cancer. If a small molecule that could mimic the effect of BH3-only proteins were able to enter the cell and overcome the anti-apoptotic n over-expression, then it could be possible to reset the apoptotic process. This strategy can have the advantage that it can alleviate the problem of drug resistance which is usually a consequence of tic deregulation (abnormal survival). Therapeutic strategies for targeting Bcl-2 and Bcl-XL in cancer to restore cancer cell sensitivity and overcome resistance of cancer cells to apoptosis have been reviewed. See Adams et al., e 281:1322 (1998) and Reed, Adv. col. 41:501 (1997); Reed et al., J. Cell.
Biochem. 60:23 (1996).
Platelets also contain the necessary apoptotic machinery, e.g., Bax, Bak, , Bcl-2, cytochrome c, caspase-9, caspase-3 and APAF-1, to execute programmed cell death through the intrinsic apoptotic pathway. Although circulating platelet production is a normal physiological process, a number of diseases are caused or exacerbated by excess of, or undesired tion of, platelets. This suggests that eutic agents e of inhibiting anti-apoptotic ns in platelets and reducing the number of platelets in mammals may be useful in treating pro-thrombotic conditions and diseases that are characterized by an excess of, or undesired activation of, platelets.
Small molecule BH3-only protein mimetics such as ABT-737 and ABT-263 bind strongly to a subset of anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w and 17301393_1 (GHMatters) P44803NZ00 Bcl-xL, and weakly to Mcl-1 and A1. These small molecules were tested in animal studies and demonstrated xic activity in certain xenograft models as single agents, as well as enhanced the effects of a number of chemotherapeutic agents on other aft models when used in combination. See Tse, C. et al., Cancer Res 68: 3421-3428 (2008) and van Delft, M. F. et al., Cancer Cell -399 (2006). These in vivo studies suggest the potential utility of inhibitors of anti-apoptotic Bcl-2 family proteins for the treatment of diseases that involve a dysregulated apoptotic pathway.
ABT-199 (Venetoclax) is a potent Bcl-2 inhibitor that has been approved by the U.S. Food and Drug Administration for the treatment of c lymphocytic leukemia. See Cang et al., Journal of Hematology & Oncology 8:129 (2015) and Souers et al., Nature Medicine 19:202–208 (2013).
The natural expression levels of anti-apoptotic Bcl-2 family proteins members vary in different cell types. For example, in young platelets, Bcl-xL protein is highly expressed and plays an ant role in regulating cell death (life span) of platelets.
Also, in certain cancer cell types, the cancer cell's survival is attributed to the dysregulation of the apoptotic pathway caused by the xpression of one or more anti-apoptotic Bcl-2 protein family members. In view of the important role for Bcl-2 family of ns in regulating apoptosis in both ous and normal, i.e., ncerous, cells, and the recognized inter-cell type variability of Bcl-2 family protein expression, it is advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2 protein(s), for example, to an anti-apoptotic Bcl-2 family member that overexpressed in a certain cancer type. Such a selective compound also may confer certain advantages in the clinical setting, by providing, for example, the flexibility to select a dosing regimen, a reduced on-target toxic effect in normal cells, among others, e.g., lymphopenia has been observed in Bcl-2 ent mice. See Nakayama, K. et al.
PNAS 91:3700-3704 (1994).
There is an ongoing need for small molecules that selectively t the ty of one type or a subset of Bcl-2 proteins for the treatment of hyperproliferative diseases such as cancer. 17301393_1 (GHMatters) P44803NZ00 BRIEF SUMMARY OF THE INVENTION In one aspect, the present disclosure provides compounds represented by any one of Formulae I-A or I-VIII, below, and the pharmaceutically acceptable salts and es, e.g., hydrates, thereof, collectively referred to herein as "Compounds of the sure." [0012a] In an aspect, the present disclosure provides a Compound of the Disclosure, or a pharmaceutically acceptable salt f, having a formula selected from the group consisting of: O NH N N Cl Formula II, or O NH N N Cl Formula III, or 17301393_1 (GHMatters) P44803NZ00 O NH N N Cl a IV, wherein Y is selected from the group consisting of -CH2- and -O-, R2 is selected from the group consisting of -NO2, -SO2CH3, and -SO2CF3; and R4a is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl or cycloalkenyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
In another aspect, the present disclosure provides a method of inhibiting Bcl-2 proteins, e.g., Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1/A1, or any combination thereof, in a t, e.g., a human, comprising administering to the subject an effective amount of at least one Compound of the sure.
In another aspect, the t disclosure provides methods for treating or preventing diseases, disorders, or conditions, e.g., a hyperproliferative disease, e.g., cancer, e.g., small cell lung cancer, dgkin's lymphoma (NHL), acute myelogenous leukemia (AML), chronic id (or lymphocytic) leukemia (CLL), or acute lymphoblastic leukemia (ALL), in a subject responsive to inhibition of Bcl-2 ns, e.g., Bcl-2 and/or Bcl-xL, comprising administering to the subject a therapeutically effective amount of a nd of the Disclosure.
In another aspect, the present disclosure provides the use of nds of the Disclosure as inhibitors of one or more Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL. 93_1 (GHMatters) P44803NZ00 In r , the present disclosure provides the use of Compounds of the Disclosure as inhibitors of Bcl-2.
In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of Bcl-xL.
In another aspect, the present disclosure provides a pharmaceutical composition for ng diseases, disorders, or conditions responsive to inhibition of Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL, wherein the ceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure optionally admixed with one or more pharmaceutically acceptable carriers.
In another aspect, the present disclosure provides Compounds of the Disclosure for use in treating or preventing a disease, disorder, or condition, e.g., a hyperproliferative disease, e.g., cancer, in a subject, e.g., a human.
In r aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating a disease, er, or condition, e.g., a hyperproliferative disease, e.g., cancer, in a subject, e.g., a human.
In another aspect, the present disclosure provides kit comprising a Compound of the Disclosure.
In another aspect, the present disclosure provides a kit comprising a Compound of the Disclosure and a second therapeutic agent useful in the treatment of a disease, disorder, or condition of st, and a package insert containing directions for use in the treatment of that disease, disorder, or condition.
In another aspect, the present disclosure provides a composition comprising: (a) a Compound of the Disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or pharmaceutically acceptable carrier.
Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The ments and advantages of the sure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the ing y and the ing detailed description are exemplary and explanatory only, and are not ctive of the invention as claimed. 17301393_1 (GHMatters) P44803NZ00 DETAILED DESCRIPTION OF DRAWINGS Fig. 1 is an illustration (Western blotting analysis) showing the expression of PARP, cleaved caspase-3, and Bcl-2 in RS4;11 xenograft tumor s obtained from mice following administration of nds of the Disclosure and ABT-199.
Fig. 2 is an illustration (Western blotting analysis) showing the sion of PARP and caspase-3 in RS4;11 xenograft tumor tissues obtained from mice following administration of Compounds of the Disclosure.
Fig. 3 is a line graph showing the antitumor activity of Cpd. No. 6 in the RS4;11 leukemia xenograft model.
Fig. 4 is a line graph showing the mouse weight following administration of Cpd. No. 6 in the RS4;11 leukemia xenograft model.
DETAILED DESCRIPTION OF THE INVENTION nds of the Disclosure inhibit Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL.
In view of this property, Compounds of the Disclosure are useful for treating or ting diseases, disorders, or ions, e.g., a hyperproliferative disease, e.g., cancer, responsive to the inhibition of Bcl-2 proteins in a subject. s responsive to the inhibition of Bcl-2 proteins include, but are not d to, small cell lung cancer, NHL, AML, CLL, and ALL.
In one embodiment, Compounds of the Disclosure are compounds having Formula I-A: O A O NH X2 X3 N N Cl I-A, or a pharmaceutically acceptable salt or solvate thereof, wherein: 17301393_1 (GHMatters) P44803NZ00 A is ed from the group consisting of: R2 R2 R6b N R5 N R6a A-1 , A-2 , A-3 , R2 R2 R2 R6f R2 N N N N R7 N R6c R6e R6e N N O R6d R6f A-4 , A-5 , A-6 , A-7 , R2 R6g R2 R6b N N A-8 , A-9 , and A-10 ; E is a carbon atom and is a double bond; or E is a -C(H)- and is a single bond; or E is a nitrogen atom and is a single bond; X1, X2, and X3 are each independently selected from the group consisting of -CR8= and -N=; R1a and R1b taken together with the carbon atom to which they are attached form a 3-, 4-, or ered optionally substituted cycloalkyl; or R1a and R1b taken er with the carbon atom to which they are attached form a 4- or 5-membered optionally substituted heterocyclo; R2 is selected from the group consisting of -NO2, -SO2CH3, and -SO2CF3; R2a is selected from the group consisting of hydrogen and halogen; R3 is selected from the group consisting of hydrogen, -CN, -C≡CH, and -N(R4a)(R4b); R4a is selected from the group consisting of optionally substituted C1-6 alkyl, optionally tuted C3-6 cycloalkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R4b is selected from the group consisting of hydrogen and C1-4 alkyl; 17301393_1 (GHMatters) P44803NZ00 R5 is selected from the group consisting of is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R6a, R6c, R6e, R6f, and R6g are each independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, ally substituted heteroaryl, heterocyclo, alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R6b and R6d are each independently selected from the group ting of en, C1-4 alkyl, and halogen; R7 is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, heteroalkyl, alkyl)alkyl, and (heterocyclo)alkyl; and R8 is selected from the group consisting of hydrogen and halogen.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, wherein: A is selected from the group consisting of A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, and A-9; R4a is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; and R6a, R6c, R6e, R6f, and R6g are each ndently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, cyclo, heteroalkyl, (cycloalkyl)alkyl, and ocyclo)alkyl.
In another embodiment, Compounds of the Disclosure are compounds having Formula I: 17301393_1 (GHMatters) P44803NZ00 O NH N N Cl I, or a pharmaceutically acceptable salt or solvate thereof, wherein: E is a carbon atom and is a double bond; or E is a -C(H)- and is a single bond; or E is a nitrogen atom and is a single bond; R1a and R1b taken together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered optionally substituted cycloalkyl; or R1a and R1b taken together with the carbon atom to which they are attached form a 4- or 5-membered optionally tuted heterocyclo; R2 is selected from the group consisting of -NO2, -SO2CH3, and -SO2CF3; R3 is selected from the group consisting of en, -CN, -C≡CH, and -N(R4a)(R4b); R4a is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, (cycloalkyl)alkyl, and (heterocyclo)alkyl; and R4b is ed from the group ting of hydrogen and C1-4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds having Formula II: 17301393_1 (GHMatters) P44803NZ00 O NH N N Cl II, or a ceutically acceptable salt or solvate thereof, wherein Y selected from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in connection with Formula I.
In another embodiment, Compounds of the Disclosure are compounds having Formula III: O NH N N Cl III, or a pharmaceutically acceptable salt or solvate thereof, n Y ed from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in connection with Formula I.
In another embodiment, Compounds of the Disclosure are compounds having Formula IV: 17301393_1 (GHMatters) P44803NZ00 O NH N N Cl IV, or a pharmaceutically acceptable salt or solvate thereof, wherein Y selected from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in connection with Formula I.
In another embodiment, Compounds of the Disclosure are compounds having Formula V: O A O NH X2 X3 N N Cl V, or a ceutically acceptable salt or solvate thereof, wherein Y selected from the group consisting of -CH2- and -O-, and A, X1, X2, and X3 are as defined in connection with Formula I-A.
In another ment, Compounds of the Disclosure are compounds having Formula VI: 17301393_1 (GHMatters) P44803NZ00 O NH N NH Cl VI, or a pharmaceutically acceptable salt or solvate thereof, n Y selected from the group ting of -CH2- and -O-, and A is as defined in connection with Formula I-A.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-1.
In r embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-2.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-3.
In another embodiment, Compounds of the Disclosure are nds having a I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, n A is A-4.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate f, wherein A is A-5.
In another embodiment, Compounds of the sure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate f, wherein A is A-6.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-7. 17301393_1 (GHMatters) P44803NZ00 In another embodiment, nds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-8.
In another embodiment, Compounds of the sure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-9.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-10.
In another embodiment, Compounds of the Disclosure are compounds having Formula VII: O S F O NH X2 X3 N N Cl VII, or a pharmaceutically acceptable salt or e thereof, wherein Y selected from the group consisting of -CH2- and -O-, and X1, X2, X3, R2, and R4a are as defined in connection with Formula I-A.
In another embodiment, Compounds of the Disclosure are nds having a I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3 are each -CH=.
In r ment, Compounds of the Disclosure are compounds having Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is -CF=, and X2 and X3 are each -CH=. 17301393_1 (GHMatters) P44803NZ00 In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VII, or a pharmaceutically acceptable salt or e thereof, wherein X1 and X3 are each -CH=, and X2 is -CF=.
In r embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VII, or a ceutically acceptable salt or solvate thereof, wherein X1 and X2 are each -CH=, and X3 is -CF=.
In another embodiment, Compounds of the Disclosure are nds having Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is -N=, and X2 and X3 are each -CH=.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X3 are each -CH=, and X2 is -N=.
In another embodiment, Compounds of the Disclosure are compounds having Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are each -CH=, and X3 is -N=.
In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-.
In another embodiment, nds of the Disclosure are compounds having any one of Formulae II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2-.
In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-A or I-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -NO2.
In r embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R4a is ed from the group consisting of: O O , , , O O , , N , O O O 93_1 (GHMatters) P44803NZ00 N O O , , , , , , N NH and O .
In another embodiment, Compounds of the sure are compounds having any one of Formulae I-A or V-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R4a, R5, R6a, and R7 are each independently selected from the group consisting of: O O , , , O O , , N , O O N O O , , , , , , N NH , O , , O O O and O .
In another embodiment, Compounds of the Disclosure are compounds having Formula VIII: 93_1 (GHMatters) P44803NZ00 O S R2a O NH N N Cl VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R2a is hydrogen or fluoro and R4a is as defined in tion with Formula I-A.
In another embodiment, Compounds of the Disclosure are compounds having Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, n R4a is selected from the group ting of: O O , , , O O , , N , O O N O O , , , , , , N NH , O , , O O O and O .
In another embodiment, Compounds of the Disclosure are compounds selected from one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
Table 1 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O O O NH O O (R)-N-((4-(((1,4-dioxanyl)methyl)amino) N N nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 1 H b]pyridinyl)oxy)(1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)- N 1,2,3,6-tetrahydropyridinyl)benzamide O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- (4-chlorophenyl)oxaspiro[3.5]nonen 2 N N H yl)methyl)piperazinyl)-N-((3-nitro N (((tetrahydro-2H-pyran N hyl)amino)phenyl)sulfonyl)benzamide O NH O O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- N N (4-chlorophenyl)spiro[3.5]nonen 3 H N yl)methyl)piperazinyl)-N-((3-nitro (((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- 4 N N (4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((3- nitrophenyl)sulfonyl)benzamide O O O NH O O (R)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- N N H b]pyridinyl)oxy)(1-((6-(4-chlorophenyl) oxaspiro[3.5]nonenyl)methyl)-1,2,3,6- N tetrahydropyridinyl)benzamide O O O NH O O (S)-N-((4-(((1,4-dioxanyl)methyl)amino) N N henyl)sulfonyl)((1H-pyrrolo[2,3- 6 H N b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH O O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6- (4-chlorophenyl)spiro[3.5]nonenyl)methyl)- 7 N N H 1,2,3,6-tetrahydropyridinyl)-N-((3-nitro (((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide O O O NH O O (R)-N-((4-(((1,4-dioxanyl)methyl)amino) henyl)sulfonyl)((1H-pyrrolo[2,3- 8 N N H b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) N oxaspiro[3.5]nonenyl)methyl)piperazin N yl)benzamide O NH O O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6- (4-chlorophenyl)oxaspiro[3.5]nonen 9 N N H yl)methyl)-1,2,3,6-tetrahydropyridinyl)-N-((3- nitro(((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- N N (4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((4-(methylamino) nitrophenyl)sulfonyl)benzamide O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- 11 N N (4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((4-(dimethylamino)- 3-nitrophenyl)sulfonyl)benzamide O NH O O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6- (4-chlorophenyl)spiro[3.5]nonen 12 N N H yl)methyl)piperidinyl)-N-((3-nitro (((tetrahydro-2H-pyran N hyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O O O NH O O ((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 13 N N H b]pyridinyl)oxy)(4-((6-(4- N phenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)benzamide O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- (4-chlorophenyl)spiro[3.5]nonen 14 N N H yl)methyl)piperazinyl)-N-((3-nitro N ((tetrahydro-2H-pyran N yl)amino)phenyl)sulfonyl)benzamide O NH NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- (4-chlorophenyl)spiro[3.5]nonen N N H yl)methyl)piperazinyl)-N-((3-nitro N ((piperidin N ylmethyl)amino)phenyl)sulfonyl)benzamide O NH N 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- (4-chlorophenyl)spiro[3.5]nonen 16 N N H yl)methyl)piperazinyl)-N-((4-(((1- N methylpiperidinyl)methyl)amino) N nitrophenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH N 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- O (4-chlorophenyl)spiro[3.5]nonen 17 N N H yl)methyl)piperazinyl)-N-((3-nitro(((1- N (tetrahydro-2H-pyranyl)piperidin N yl)methyl)amino)phenyl)sulfonyl)benzamide O NH N -pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- O (4-chlorophenyl)spiro[3.5]nonen 18 N N H yl)methyl)piperazinyl)-N-((3-nitro(((1- N (oxetanyl)piperidin N yl)methyl)amino)phenyl)sulfonyl)benzamide O O O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- 19 N N (4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((3-nitro((oxetan- 3-ylmethyl)amino)phenyl)sulfonyl)benzamide O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- (4-chlorophenyl)spiro[3.5]nonen N N N yl)methyl)piperazinyl)-N-((4-cyano henyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6- N N (4-chlorophenyl)spiro[3.5]nonen 21 H N hyl)piperazinyl)-N-((4-ethynyl N nitrophenyl)sulfonyl)benzamide In another embodiment, Compounds of the Disclosure are compounds selected from one or more of the compounds of Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.
Table 1-A Cpd.
Structure Name NO2 F O N O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 22 N N yl)methyl)piperazinyl)-N-((3-fluoro(2- N (2-methoxyethoxy)ethyl)nitro-2H-indazol- N ulfonyl)benzamide O N O O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen yl)methyl)piperazinyl)-N-((7-nitrooxo 23 N N N (tetrahydro-2H-pyranyl)-2,3,3a,7atetrahydro-1H-isoindol N yl)sulfonyl)benzamide 93_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O N O S O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 24 N N H yl)methyl)piperazinyl)-N-((5-nitro(2- N (tetrahydro-2H-pyranyl)ethyl)-1H-pyrrol N yl)sulfonyl)benzamide O N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen N N H hyl)piperazinyl)-N-((5-nitro N ((tetrahydro-2H-pyranyl)methyl)-1H- N pyrrolyl)sulfonyl)benzamide H O O O O NH ((4-(((1,4-dioxanyl)methyl)amino) O nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 26 F N N H b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)fluorobenzamide H O O O O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino) N nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 27 N N H b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)picolinamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name H O O O O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino) O nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 28 N N N H dinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)nicotinamide O O O S F O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 29 N N H yl)methyl)piperazinyl)-N-((3-fluoronitro- N 4-(((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide O O O NH 3-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- N ((6-(4-chlorophenyl)spiro[3.5]nonen N N H hyl)piperazinyl)-N-((3-nitro N (((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)picolinamide NO2 H N O O O O NH 3-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- N ((6-(4-chlorophenyl)spiro[3.5]nonen 31 N N H yl)methyl)piperazinyl)-N-((4-((2-(2- N methoxyethoxy)ethyl)amino) N nitrophenyl)sulfonyl)picolinamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name NO2 H O O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 32 N N N H yl)methyl)piperazinyl)-N-((3-nitro N (((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)nicotinamide N O O O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 33 N N N H yl)methyl)piperazinyl)-N-((4-((2-(2- N methoxyethoxy)ethyl)amino) N nitrophenyl)sulfonyl)nicotinamide O N O O S O 3-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O NH O ((6-(4-chlorophenyl)spiro[3.5]nonen 34 N N H yl)methyl)piperazinyl)-N-((4-((2-(2- N methoxyethoxy)ethyl)amino) nitrophenyl)sulfonyl)picolinamide O N O S O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen N N H yl)methyl)piperazinyl)-N-((1-(2- N methoxyethyl)nitro-1H-pyrrol N fonyl)benzamide 93_1 (GHMatters) P44803NZ00 Cpd.
Structure Name H O O O O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 36 N N F H b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N hyl)piperazinyl)fluorobenzamide N O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 37 N F N H yl)methyl)piperazinyl)fluoro-N-((4-((2- N (2-methoxyethoxy)ethyl)amino) N nitrophenyl)sulfonyl)benzamide O N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O -chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((7-nitrooxo 38 N N ((tetrahydro-2H-pyranyl)methyl)-2,3,3a,7atetrahydro-1H-isoindol N yl)sulfonyl)benzamide H O O O O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 39 N F N H b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)fluorobenzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name H O O O O S F O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino) fluoronitrophenyl)sulfonyl)((1H- 40 N N H pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)benzamide NO2 H O NH F 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- -chlorophenyl)spiro[3.5]nonen 41 N N H yl)methyl)piperazinyl)fluoro-N-((3-nitro- N 4-(((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide NO2 H O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 42 N F N H yl)methyl)piperazinyl)fluoro-N-((3-nitro- N 4-(((tetrahydro-2H-pyran N yl)methyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd. ure Name NO2 H N O O O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 43 N F N H yl)methyl)piperazinyl)fluoro-N-((4-((2- N (2-methoxyethoxy)ethyl)amino) N nitrophenyl)sulfonyl)benzamide O O O NH F O (S)-N-((4-(((1,4-dioxanyl)methyl)amino) fluoronitrophenyl)sulfonyl)((1H- 44 N N H pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)benzamide F N O O O NH O (S)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H- 45 N N H pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- N chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)benzamide O N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- 46 N ((6-(4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((2-methyl nitro-2H-indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- N N ((6-(4-chlorophenyl)spiro[3.5]nonen 47 H N yl)methyl)piperazinyl)-N-((7-nitro-1H- benzo[d]imidazolyl)sulfonyl)benzamide O N O O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 48 N N H yl)methyl)piperazinyl)-N-((7-nitro N hydro-2H-pyranyl)-2H-indazol N yl)sulfonyl)benzamide O N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- 49 N N ((6-(4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-((1-methyl nitro-1H-indazolyl)sulfonyl)benzamide O NH O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 50 N N N hyl)piperazinyl)-N-((7-nitro-2H- indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O NH O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 51 N N N yl)methyl)piperazinyl)-N-((4-nitro-2H- lyl)sulfonyl)benzamide O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 52 N N H yl)methyl)piperazinyl)-N-((1-methyl N nitro-1H-benzo[d]imidazol N yl)sulfonyl)benzamide O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- ((6-(4-chlorophenyl)spiro[3.5]nonen 53 N N H yl)methyl)piperazinyl)-N-((7-nitro N ((tetrahydro-2H-pyranyl)methyl)-1H- N benzo[d]imidazolyl)sulfonyl)benzamide O N O S N 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O NH O ((6-(4-chlorophenyl)spiro[3.5]nonen 54 N N H hyl)piperazinyl)-N-((2-(2-(2- N methoxyethoxy)ethyl)nitro-2H-indazol N yl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O N O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- O ((6-(4-chlorophenyl)spiro[3.5]nonen 55 N N H hyl)piperazinyl)-N-((2-(2- N methoxyethyl)nitro-2H-indazol N yl)sulfonyl)benzamide O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4- 56 N N ((6-(4-chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)-N-(naphthalen ylsulfonyl)benzamide In another embodiment, a Compound of the Disclosure is the compound of Table 1-B, or a pharmaceutically acceptable salt or solvate thereof.
Table 1-B Cpd.
Structure Name H O O O O NH (S)-N-((4-(((1,4-dioxanyl)methyl)amino)- 3-nitrophenyl)sulfonyl)((1H-pyrrolo[2,3- 57 O b]pyridinyl)oxy)(4-((6-(4- N N H chlorophenyl)spiro[3.5]nonen N yl)methyl)piperazinyl)picolinamide In another embodiment, Compounds of the sure are compounds selected from one or more of the compounds of Table 1-C, or a pharmaceutically acceptable salt or solvate thereof.
Table 1-C 93_1 (GHMatters) P44803NZ00 Cpd.
Structure Name O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 58 N N H 7-yl)methyl)piperazinyl)-N-((2- N isopropylnitro-1H-benzo[d]imidazol N yl)sulfonyl)benzamide O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 59 N N H 7-yl)methyl)piperazinyl)-N-((2- N cyclopropylnitro-1H-benzo[d]imidazol- N 5-yl)sulfonyl)benzamide O N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- N N 7-yl)methyl)piperazinyl)-N-((7-nitro N ((tetrahydro-2H-pyranyl)methyl)-1H- lyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O NH O -pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 61 N N H 7-yl)methyl)piperazinyl)-N-((7-nitro N ((tetrahydro-2H-pyranyl)methyl)-2H- N indazolyl)sulfonyl)benzamide O N O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 62 N N 7-yl)methyl)piperazinyl)-N-((4-nitro N ((tetrahydro-2H-pyranyl)methyl)-3a,7adihydro-1H-indazol N yl)sulfonyl)benzamide O N O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 63 N N H 7-yl)methyl)piperazinyl)-N-((4-nitro N ((tetrahydro-2H-pyranyl)methyl)-2H- N indazolyl)sulfonyl)benzamide O N O S N O NH O 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 64 N N H 7-yl)methyl)piperazinyl)-N-((4-nitro N hydro-2H-pyranyl)-3a,7a-dihydro- N 1H-indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) O (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 65 N N H 7-yl)methyl)piperazinyl)-N-((4-nitro N (tetrahydro-2H-pyranyl)-2H-indazol N yl)sulfonyl)benzamide O N O S N O NH 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) (4-((6-(4-chlorophenyl)spiro[3.5]nonen- 66 N N H ethyl)piperazinyl)-N-((7-nitro N (pyridinyl)-1H-benzo[d]imidazol N yl)sulfonyl)benzamide In another embodiment, Compounds of the sure are selected from the group consisting of: NO2 H H N O O O O O S O NH NH O N N N H and H Cl . or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, Compounds of the Disclosure are selected from the group consisting of: 17301393_1 (GHMatters) P44803NZ00 NO2 NO2 NO2 H H H N N N O O O O O O O S O O S S F O NH O O NH O O NH O O O O N N N , N N N H H and H N N N N N N Cl Cl Cl . or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, a Compound of the Disclosure is: O O O S F O NH O N N Cl . or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the disclosure provides a pharmaceutical composition comprising a nd of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. tions In the present disclosure, the term "halo" as used by itself or as part of r group refers to -Cl, -F, -Br, or -I.
In the present disclosure, the term "nitro" as used by itself or as part of another group refers to -NO2.
In the t disclosure, the term "cyano" as used by itself or as part of another group refers to -CN. 17301393_1 (GHMatters) P44803NZ00 In the t disclosure, the term "hydroxy" as used by itself or as part of another group refers to -OH.
In the present sure, the term " as used by itself or as part of another group refers to -NH2.
In the present disclosure, the term "alkyl" as used by itself or as part of another group refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing one to twelve carbon atoms, i.e., C1-12 alkyl, or the number of carbon atoms designated, e.g., a C1 alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, a C1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, and so on.
In one ment, the alkyl group is a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C1-4 alkyl group. In another embodiment, the alkyl group is a branched chain C3-4 alkyl group. In another embodiment, the alkyl group is a straight or branched chain C3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are ed with deuterium atoms.
Non-limiting exemplary C1-12 alkyl groups e methyl, -CD3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl. Non-limiting exemplary C1-4 groups include methyl, ethyl, , pyl, and tert-butyl.
In the present disclosure, the term "optionally substituted alkyl" as used by itself or as part of another group refers to an alkyl that is tituted or substituted with one, two, or three substituents ndently selected from the group consisting of halo, nitro, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, and optionally substituted aryl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In r embodiment, the optionally substituted alkyl is unsubstituted. Non-limiting exemplary optionally substituted alkyl groups include -CH2Ph, -CH2CH2NO2, -CH2CH2OH, -CH2CH2OCH3, and -CH2CH2F.
In the present disclosure, the term "cycloalkyl" as used by itself or as part of r group refers to unsubstituted saturated cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms, i.e., C3-12 cycloalkyl or the number of carbons designated. The term “cycloalkenyl” as used by 17301393_1 (GHMatters) P44803NZ00 itself or as part of another group refers to partially unsaturated cyclic aliphatic hydrocarbons, e.g., containing one or two double bonds, and containing one to three rings having from three to twelve carbon atoms, i.e., C3-12 cycloalkenyl, or the number of carbons designated. In one embodiment, the lkyl or cycloalkenyl group has two rings. In one embodiment, the cycloalkyl or cycloalkenyl group has one ring. In another embodiment, the cycloalkyl or cycloalkenyl group is, respectively, a C3-8 cycloalkyl or C3-8 cycloalkenyl. In another embodiment, the cycloalkyl or cycloalkenyl group is, respectively, a C3-6 cycloalkyl or C3-6 cycloalkenyl. In another embodiment, the cycloalkyl or cycloalkenyl group is, tively, a C3-5 cycloalkyl or C3-5 cycloalkenyl. Th e term "cycloalkyl" is meant to include groups wherein a ring -CH2- is replaced with a -C(=O)-. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentanone, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.
Non-limiting ary lkenyl groups include cyclohexenyl and cyclopentenyl.
In the present sure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group refers to a lkyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclo. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another ment, the optionally substituted cycloalkyl is unsubstituted.
In the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is a C1-4 haloalkyl group. miting exemplary haloalkyl groups e fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, luoroethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, trifluoropropyl, trifluorobutyl, and trichloromethyl groups.
In the present disclosure, the term "alkoxy" as used by itself or as part of another group refers to an optionally substituted alkyl ed to a terminal oxygen atom. In one embodiment, the alkoxy group is a C1-6 alkyl attached to a terminal oxygen atom. In another embodiment, the alkoxy group is a C1-4 alkyl attached to a 17301393_1 (GHMatters) P44803NZ00 al oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.
In the present disclosure, the term "aryl" as used by itself or as part of another group refers to unsubstituted monocyclic or bicyclic aromatic ring systems having from six to fourteen carbon atoms, i.e., a C6-14 aryl. miting exemplary aryl groups include phenyl (abbreviated as "Ph"), yl, phenanthryl, anthracyl, l, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl.
In the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group refers to an aryl that is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclo. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally tuted phenyl has one tuent. In another embodiment, the optionally substituted phenyl is unsubstituted. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, and 4-chlorophenyl.
In the present disclosure, the term "heterocyclo" as used by itself or as part of another group refers to unsubstituted saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups ning one, two, or three rings having from three to fourteen ring members, i.e., a 3- to 14-membered heterocyclo, wherein at least one carbon atom of one of the rings is replaced with a heteroatom. The term "heterocyclo" is meant to include cyclic ureido groups such as imidazolidinylone, cyclic amide groups such as am, γ-lactam, δ-lactam and εlactam , and cyclic carbamate groups such as oxazolidinylone. In one embodiment, the cyclo group is a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the cyclo group is an 8-, 9-, 10-, 11-, or bered cyclic group containing two rings and one or two nitrogen atoms. In one embodiment, the heterocyclo group is a 4- or 5-membered cyclic group containing one ring and one oxygen atom. The cyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo 17301393_1 (GHMatters) P44803NZ00 groups include 1,4-dioxane, 2-oxopyrrolidinyl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, icyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, piro[3.4]octane, indolinyl, indolinylone, and 1,3-dihydro-2H-benzo[d]imidazolone.
In the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group refers to a heterocyclo that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, y, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclo. Non-limiting exemplary optionally substituted heterocyclo groups include: , and N N O O In the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to -NHR10, wherein R10 is C1-6 alkyl. In one embodiment, R10 is C1-4 alkyl. Non-limiting exemplary alkylamino groups include H3 and -N(H)CH2CH3.
In the present disclosure, the term ylamino" as used by itself or as part of another group refers to -NR11aR11b, wherein R11a and R11b are each independently C1-6 alkyl. In one embodiment, R11a and R11b are each independently C1-4 alkyl.
Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.
In the present disclosure, the term "(cycloalkyl)alkyl" as used by itself or as part of r group refers to an alkyl substituted with one ally substituted cycloalkyl group. In one embodiment, the (cycloalkyl)alkyl is a C1-4 alkyl substituted with one optionally tuted C3-6 lkyl. In one embodiment, the optionally substituted cycloalkyl group is substituted with a heterocyclo group. Non-limiting exemplary (cycloalkyl)alkyl groups include: In the present disclosure, the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl substituted with one ally substituted 17301393_1 (GHMatters) P44803NZ00 heterocyclo group. In one embodiment, the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted 4- to 6-membered heterocyclo group. The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. miting exemplary (heterocyclo)alkyl groups e: O O , , , O O , N , O , O O N O O , , , , and .
N NH In the present disclosure, the term "heteroalkyl" as used by itself or part of another group refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from six to twelve chain atoms, i.e., 6- to 12-membered heteroalkyl, or the number of chain atoms designated, wherein at least two -CH2- groups are independently replaced with -O-, -N(H)-, or -S-. The -O-, -N(H)-, or -S- can independently be placed at any interior position of the aliphatic hydrocarbon chain so long as each -O-, N(H)-, or -S- group is ted by at least two -CH2- . In one embodiment, two -CH2- groups are replaced with two -O- . In another embodiment, three -CH2- groups are replaced with three -O- groups. Non-limiting exemplary heteroalkyl groups include -CH2CH2OCH2CH2OCH3, -CH2CH2OCH2CH2N(H)CH3, and -CH2CH2OCH2CH2OCH2CH2OCH3.
The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass . Examples of isotopes that can be incorporated into the disclosed nds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively, e.g., 3H, 11C, and 14C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an 93_1 (GHMatters) P44803NZ00 atom having a different atomic mass or mass number. In another embodiment, provided is a ition wherein a portion of the atoms at a on within the nd of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number.
Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms including racemic and resolved forms, and mixtures thereof. The individual stereoisomers, e.g., enantiomers, can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other s of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also intended to be encompassed by the present disclosure.
As used herein, the term "stereoisomers" or oisomeric forms" are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term "chiral center" or etric carbon atom" refers to a carbon atom to which four different groups are attached.
The terms "enantiomer" and iomeric" refer to a molecule that cannot be mposed on its mirror image and hence is optically active wherein the omer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
The term "absolute uration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
The stereochemical terms and conventions used in the ication are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated. 17301393_1 (GHMatters) P44803NZ00 The term iomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the l rotation of a chiral substance, the percent enantiomeric excess is defined as s/[α]max)*100, where [α]obs is the optical rotation of the mixture of enantiomers and [α]max is the optical rotation of the pure enantiomer. ination of enantiomeric excess is le using a variety of ical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense. In one embodiment, Compounds of the Disclosure having one or more chiral centers are enantiopure.
The terms "enantiomerically enriched" or ioenriched" refer to a sample of a chiral substance whose enantiomeric excess is r than 50%, e.g., about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more. Enantiomerically enriched compounds may be enantiomerically pure. In one embodiment, Compounds of the Disclosure having one or more chiral centers are enantioenriched.
The terms "a" and "an" refer to one or more.
The term "about," as used , includes the d number ± 10%. Thus, "about 10" means 9 to 11.
The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts.
Examples of pharmaceutically acceptable addition salts e inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; c amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, 17301393_1 (GHMatters) P44803NZ00 mandelate, acetate, dichloroacetate, trifluoroacetate, e, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate and the like. The term "pharmaceutically acceptable salt" as used herein, refers to any salt, e.g., ed by reaction with an acid or a base, of a Compound of the Disclosure that is logically tolerated in the target patient (e.g., a mammal, e.g., a human).
Acid addition salts can be formed by mixing a solution of the particular nd of the Disclosure with a solution of a pharmaceutically acceptable nontoxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, roacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline ide, sodium carbonate and the like.
The t disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g., a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, tively. This physical association involves varying degrees of ionic and covalent bonding, ing en bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are orated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both on-phase and isolatable es. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically able solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
In one embodiment, the solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can on as pharmacological equivalents. Preparation of solvates is known in the art.
See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which bes the preparation of solvates of fluconazole with ethyl acetate and with water. 17301393_1 (GHMatters) P44803NZ00 r preparation of solvates, hemisolvates, hydrates, and the like are bed by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L.
Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a e thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a l of the solvate.
Compounds of the Disclosure are inhibitors of Bcl-2 proteins, such as Bcl-2, and/or Bcl-XL, and thus a number of diseases, ions, or disorders mediated by Bcl-2 proteins can be d or prevented by administering these compounds to a subject. The present sure is thus directed generally to a method for treating or preventing a e, ion, or disorder responsive to the inhibition of Bcl-2 proteins, such as Bcl-2, and/or Bcl-XL, in an animal suffering from, or at risk of suffering from, the disease, ion, or disorder The method comprises administering to the animal an effective amount of one or more Compounds of the Disclosure.
The present disclosure is r directed to a method of inhibiting Bcl-2 proteins in an , e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one nd of the Disclosure.
The present disclosure is further directed to a method of inhibiting Bcl-2 in an animal, e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically ive amount of at least one Compound of the Disclosure.
The present disclosure is further directed to a method of inhibiting Bcl-XL in an animal, e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
As used herein, the terms "treat," "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 eliminated. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a Compound of the sure to a subject in need 17301393_1 (GHMatters) P44803NZ00 of such treatment. The treatment can be orientated symptomatically, for e, 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 e within the context of a maintenance therapy.
As used , the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," nting," and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "prevent," "preventing" and "prevention" may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a ence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or ion.
The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when stered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the ent of condition or disease of interest to an individual in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (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 ; modulate protein methylation in the target cells; and/or e, 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 therefore suitable for storing, shipping, dispensing, and/or ng a pharmaceutical product.
The term "insert" means information accompanying a ceutical product that provides a description of how to administer the product, along with the safety and efficacy data ed to allow the physician, pharmacist, and t to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product. 17301393_1 (GHMatters) P44803NZ00 In the present disclosure, the term "Bcl-2 proteins" or "Bcl-2 family of proteins" refers to any one or more of the following proteins: Bax, Bak, Bid, Bcl-2, Bcl-xL, Mcl-1, Bcl-w, A1, Bim, Puma, Bad, Bik/Blk, Noxa, Bmf, Hrk/DP5, and Beclin-1. See Cold Spring Harb Perspect Biol 2013;5:a008714.
The term "disease" or "condition" or "disorder" 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. Compounds of the Disclosure inhibit Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL, and can be used in treating or preventing diseases, conditions, or disorders such as hyperproliferative diseases, wherein inhibition of Bcl-2 proteins provides a benefit.
The term "hyperproliferative disease" refers to any ion in which a localized population of proliferating cells in an animal is not governed by the usual limitations of normal . In one embodiment, the roliferative e is cancer.
In some embodiments, the Compounds of the Disclosure can be used to treat a "Bcl-2 protein mediated disorder," e.g., a Bclmediated disorder and/or a Bcl-xL-mediated disorder. A Bcl-2 protein mediated er is any pathological condition in which a Bcl-2 protein is known to play a role. In one embodiment, a Bcl-2 mediated disorder is a hyperproliferative disease. In one embodiment, a Bcl-2 mediated disorder is cancer.
In one ment, Compounds of the sure have a Bcl-2 and/or Bcl-xL IC50 of less than about 10 μM. In another embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 5 μM. In another embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 1 μM. In r embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.5 μM. In another embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.1 μM. In another embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.05 μM. In another embodiment, nds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.025 μM. In another embodiment, Compounds of the sure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.010 μM. In another embodiment, nds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.005 μM. In another embodiment, Compounds of the 17301393_1 (GHMatters) P44803NZ00 sure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.0025 μM. In another embodiment, Compounds of the Disclosure have a Bcl-2 and/or Bcl-xL IC50 of less than about 0.001 μM.
In one embodiment, the present disclosure provides a method of treating or ting a hyperproliferative disease in a subject, e.g., a human, comprising administering a therapeutically effective amount of a Compound of the sure.
In another embodiment, the present disclosure es a method of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure can treat or prevent cancer by inhibiting Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 2.
Table 2 adrenal cancer lymphoepithelioma acinic cell carcinoma lymphoma acoustic neuroma acute lymphocytic leukemia acral lentigious melanoma acute eous ia acrospiroma chronic cytic leukemia acute eosinophilic leukemia liver cancer acute erythroid leukemia small cell lung cancer acute lymphoblastic leukemia non-small cell lung cancer acute megakaryoblastic leukemia MALT lymphoma acute monocytic leukemia ant fibrous histiocytoma acute promyelocytic leukemia malignant peripheral nerve sheath tumor adenocarcinoma malignant triton tumor adenoid cystic carcinoma mantle cell lymphoma adenoma marginal zone B-cell lymphoma adenomatoid odontogenic tumor mast cell leukemia adenosquamous carcinoma mediastinal germ cell tumor adipose tissue neoplasm medullary carcinoma of the breast adrenocortical carcinoma medullary thyroid cancer, adult T-cell leukemia/lymphoma medulloblastoma aggressive NK-cell leukemia melanoma, AIDS-related lymphoma meningioma, alveolar myosarcoma merkel cell cancer alveolar soft part sarcoma mesothelioma ameloblastic a metastatic lial carcinoma anaplastic large cell lymphoma mixed Mullerian tumor anaplastic thyroid cancer mucinous tumor angioimmunoblastic T-cell lymphoma, multiple a angiomyolipoma muscle tissue neoplasm angiosarcoma mycosis fungoides 17301393_1 ters) P44803NZ00 astrocytoma myxoid liposarcoma atypical teratoid rhabdoid tumor myxoma B-cell chronic lymphocytic leukemia myxosarcoma B-cell phocytic leukemia aryngeal carcinoma B-cell lymphoma neurinoma basal cell carcinoma neuroblastoma biliary tract cancer neurofibroma bladder cancer neuroma blastoma nodular melanoma bone cancer ocular cancer Brenner tumor oligoastrocytoma Brown tumor oligodendroglioma Burkitt's lymphoma toma breast cancer optic nerve sheath meningioma brain cancer optic nerve tumor oma oral cancer carcinoma in situ osteosarcoma carcinosarcoma n cancer cartilage tumor Pancoast tumor cementoma papillary thyroid cancer myeloid a paraganglioma chondroma pinealoblastoma chordoma pineocytoma choriocarcinoma pituicytoma choroid plexus papilloma pituitary adenoma clear-cell sarcoma of the kidney pituitary tumor craniopharyngioma plasmacytoma cutaneous T-cell lymphoma polyembryoma cervical cancer sor T-lymphoblastic lymphoma colorectal cancer primary central nervous system lymphoma Degos disease primary effusion lymphoma desmoplastic small round cell tumor ry peritoneal cancer diffuse large B-cell ma prostate cancer dysembryoplastic neuroepithelial tumor, pancreatic cancer dysgerminoma pharyngeal cancer embryonal carcinoma pseudomyxoma periotonei endocrine gland neoplasm renal cell oma endodermal sinus tumor renal medullary carcinoma pathy-associated T-cell lymphoma retinoblastoma esophageal cancer rhabdomyoma fetus in fetu rhabdomyosarcoma fibroma Richter's transformation fibrosarcoma rectal cancer follicular lymphoma sarcoma follicular thyroid cancer Schwannomatosis ganglioneuroma seminoma gastrointestinal cancer Sertoli cell tumor germ cell tumor sex cord-gonadal stromal tumor 93_1 (GHMatters) P44803NZ00 gestational choriocarcinoma signet ring cell carcinoma giant cell fibroblastoma skin cancer giant cell tumor of the bone small blue round cell tumors glial tumor small cell carcinoma astoma multiforme soft tissue a glioma somatostatinoma gliomatosis cerebri soot wart glucagonoma spinal tumor gonadoblastoma c marginal zone ma granulosa cell tumor squamous cell carcinoma gynandroblastoma synovial sarcoma gallbladder cancer Sezary's disease gastric cancer small intestine cancer hairy cell leukemia squamous carcinoma hemangioblastoma stomach cancer head and neck cancer T-cell lymphoma hemangiopericytoma testicular cancer hematological malignancy thecoma hepatoblastoma thyroid cancer splenic T-cell lymphoma transitional cell carcinoma Hodgkin's lymphoma throat cancer non-Hodgkin's lymphoma urachal cancer ve lobular carcinoma urogenital cancer intestinal cancer urothelial carcinoma kidney cancer uveal melanoma laryngeal cancer uterine cancer lentigo a verrucous carcinoma lethal midline carcinoma visual pathway glioma leukemia vulvar cancer leydig cell tumor vaginal cancer liposarcoma Waldenstrom's macroglobulinemia lung cancer Warthin's tumor ngioma Wilms' tumor lymphangiosarcoma In another embodiment, the cancer is breast, , colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
In another embodiment, the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder oma, or cervical carcinoma.
In r embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous ia, chronic 17301393_1 (GHMatters) P44803NZ00 myelogenous leukemia, c lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer . In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.
In another embodiment, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung arcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, renal clear cell carcinoma, skin ous melanoma, h adenocarcinoma, uterine carcinosarcoma, or uterine corpus endometrial carcinoma.
In another embodiment, the present disclosure provides a therapeutic method of modulating gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in a cancer, e.g., in the cancers ned above, by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
Compounds of the Disclosure can be administered to a t in the form of a raw chemical without any other components present. Compounds of the Disclosure can also be administered to a subject as part of a pharmaceutical composition containing the compound combined with one or more suitable ceutically acceptable carriers. Such carriers can be selected from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, tants, or vehicles. le ceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their ations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.
Pharmaceutical compositions within the scope of the present disclosure e all itions where a nd of the Disclosure is ed with one or more 17301393_1 (GHMatters) P44803NZ00 pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art. lly, a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the , or an equivalent amount of a pharmaceutically able salt or solvate thereof, per day to treat the particular disorder. A useful oral dose of a Compound of the Disclosure stered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an lent amount of the pharmaceutically able salt or solvate thereof. For intramuscular injection, the dose is typically about one-half of the oral dose.
A unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the nd. The unit dose can be administered one or more times daily, e.g., as one or more s or capsules, each ning from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate f.
A Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the Disclosure can be administered to any patient or subject that may experience the beneficial effects of a nd of the Disclosure. st among such patients or subject are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient or subject is a human.
A Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the Disclosure can be administered by any means that achieves its intended purpose. For example, stration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation. The dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. 17301393_1 (GHMatters) P44803NZ00 In one embodiment, a Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the Disclosure can be administered . In another ment, a ceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid ation. In one embodiment, the oral formulation comprises ed multiparticulates comprising the Compound of the Disclosure.
Alternatively, a Compound of the Disclosure or a ceutical composition comprising a Compound of the Disclosure can be administered rectally, and is formulated in suppositories.
Alternatively, a Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the sure can be administered by injection.
Alternatively, a Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the Disclosure can be administered transdermally.
Alternatively, a Compound of the Disclosure or a pharmaceutical composition sing a Compound of the Disclosure can be stered by inhalation or by intranasal or transmucosal administration.
Alternatively, a Compound of the Disclosure or a ceutical composition comprising a Compound of the Disclosure can be administered by the intravaginal route.
A pharmaceutical composition of the t disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
A pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant sure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the e of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients include fillers such as rides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for 17301393_1 (GHMatters) P44803NZ00 example, cium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned es and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts f (e.g., magnesium stearate or calcium stearate), and polyethylene . Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic ts or solvent mixtures. In order to produce coatings resistant to c juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses. es of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of n and a plasticizer such as glycerol or sorbitol. The push-fit es can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium te and, optionally, stabilizers, or in the form of extruded multiparticulates. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added. le pharmaceutical preparations for rectal administration include, for example, itories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, and in hydrocarbons, among others. It is also possible to use n rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid ceride, polyethylene glycol, or paraffin hydrocarbon. 17301393_1 (GHMatters) P44803NZ00 Suitable formulations for parenteral administration include aqueous solutions of the active compound in a soluble form such as, for e, a water-soluble salt, alkaline solution, or acidic solution. Alternatively, a suspension of the active compound can be prepared as an oily suspension. Suitable ilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), cerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400). An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. The suspension may ally contain stabilizers.
In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a pharmaceutical composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present sure. In one embodiment, the kit includes a Compound of the Disclosure (or a pharmaceutical composition comprising a Compound of the Disclosure) 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 of the sure. In one embodiment, 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.
In another embodiment, a Compound of the Disclosure is administered to a t in conjunction with a second therapeutic agent. The second therapeutic agent is different from the Compound of the Disclosure. A Compound of the sure and the second therapeutic agent can be stered simultaneously or sequentially to achieve the desired effect. In addition, the nd of the sure and second therapeutic agent can be administered 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 established ranges.
A Compound of the sure and the second therapeutic agent can be administered together as a single-unit dose or tely as multi-unit doses, wherein 17301393_1 (GHMatters) P44803NZ00 the Compound of the Disclosure is stered before the second eutic agent or vice versa. One or more doses of the Compound of the Disclosure and/or one or more dose of the second therapeutic agent can be administered. The Compound of the Disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.
In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators e the histone lysine methyltransferases, e arginine methyl transferases, histone demethylases, histone ylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.
In another embodiment, chemotherapeutic agents or other anti-proliferative agents can be combined with Compound of the Disclosure to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with Compounds of the Disclosure include surgery, radiotherapy (e.g., radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, therapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved herapeutic drug.
Examples of oliferative compounds include, but are not limited to, an aromatase inhibitor; an anti-estrogen; an anti-androgen; a gonadorelin t; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an ting agent; a retinoid, a carontenoid, or a tocopherol; a xygenase inhibitor; an MMP inhibitor; an mTOR tor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a some inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a compound targeting/decreasing protein or lipid kinase activity, a compound targeting/decreasing protein or lipid phosphatase ty, or any further anti-angiogenic compound. iting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and eroids, such as 17301393_1 (GHMatters) P44803NZ00 aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists e, but are not limited to, abarelix, goserelin, and goserelin acetate. ary topoisomerase I inhibitors include, but are not d to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the olecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not d to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not d to, taxanes, such as paclitaxel and xel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and stine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and tives thereof.
Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and ine.
Exemplary nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, -alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as xib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkylarylaminophenylacetic acid, such as lumiracoxib.
Exemplary nonlimiting matrix metalloproteinase inhibitors ("MMP inhibitors") include en peptidomimetic and tidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, imus, CCI-779, and .
Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, rexate and edatrexate, and folic acid antagonists, such as pemetrexed. 17301393_1 (GHMatters) P44803NZ00 Exemplary iting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a tive thereof and PPI-2458.
Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, onic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and onic acid.
Exemplary iting antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
The term "an inhibitor of Ras oncogenic isoforms," such as H-Ras, K-Ras, or N-Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, 7, tipifarnib, and lonafarnib.
Exemplary nonlimiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of rase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
Exemplary nonlimiting proteasome inhibitors include compounds that target, se, or inhibit the ty of the proteasome including, but not limited to, bortezomid.
The phrase "compounds used in the treatment of hematologic malignancies" as used herein includes FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the ty of FMS-like tyrosine kinase receptors R); interferon, Ι-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.
Exemplary nonlimiting Flt-3 tors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
Exemplary nonlimiting HSP90 inhibitors include nds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, 93_1 ters) P44803NZ00 targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or ting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17- demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
The phrase "a compound targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or any further anti-angiogenic compound" as used herein includes a protein tyrosine kinase and/or serine and/or threonine kinase tor or lipid kinase inhibitor, such as a) a compound ing, decreasing, or inhibiting the activity of the platelet- derived growth -receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenylpyrimidine-amine derivatives, such as imatinib, SUlOl, SU6668, and GFB-111; b) a compound targeting, decreasing, or inhibiting the activity of the last growth factor-receptors (FGFR); c) a compound ing, decreasing, or inhibiting the ty of the insulin-like growth factor receptor I (IGF-IR), such as a compound that targets, decreases, or inhibits the activity of IGF-IR; d) a compound targeting, decreasing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound targeting, decreasing, or inhibiting the activity of the Axl receptor tyrosine kinase family; f) a nd ing, decreasing, or ting the activity of the Ret or tyrosine kinase; g) a compound targeting, decreasing, or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) a compound targeting, decreasing, or inhibiting the activity of the c-Kit receptor tyrosine kinases, such as ib; i) a compound targeting, decreasing, or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. Bcr-Abl kinase) and mutants, such as an N-phenyl pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or ting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the -dependent kinase family (CDK), such as a staurosporine tive disclosed in U.S. Patent No. 5,093,330, such as midostaurin; examples of further nds include UCN-01, ol, BAY 43- 9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 17301393_1 (GHMatters) P44803NZ00 3521; LY333531/LY379196; a isochinoline compound; a yl erase inhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin 2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) a nd targeting, decreasing, or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; zumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compound targeting, decreasing, or inhibiting the activity of the c-Met receptor.
Exemplary compounds that , decrease, or inhibit the activity of a protein or lipid atase include inhibitors of atase 1, phosphatase 2A, or CDC25, such as c acid or a derivative thereof.
Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.
Additional, nonlimiting, exemplary chemotherapeutic nds, one or more of which may be used in combination with a Compound of the Disclosure, include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, ntrone, icin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, tatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, l-(4-chloroanilino)(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, , macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer , anecortave, triamcinolone, hydrocortisone, 11-aepihydrocotisol , cortex olone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, terone, estrone, dexamethasone, fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, a biological response modifier, such 17301393_1 (GHMatters) P44803NZ00 as a lymphokine or interferon, an antisense oligonucleotide or oligonucleotide derivative, shRNA, and siRNA.
Other examples of second therapeutic agents, one or more of which a Compound of the Disclosure also can be combined, include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine; a treatment for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, ide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta eron (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti -inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, hosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, enolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and alazine; a rophic factor, such as an acetylcholinesterase tor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular e, such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver e, such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood ers, such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders, such as gamma globulin.
The above-mentioned second therapeutically active agents, one or more of which can be used in ation with a Compound of the Disclosure, are prepared and administered as described in the art.
General Synthesis of Compounds Compounds of the sure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In the General Schemes, R2 and R4a are as defined in connection with Formula I, and Y is as defined in connection with Formula II. 17301393_1 (GHMatters) P44803NZ00 General Scheme 1 R2 R2 F H O R4aNH2 R4a O S O S NH2 Et3N/THF A B In General Scheme 1, Compound A is reacted with R4aNH2 in the presence of a base, e.g., triethylamine, to give Compound B.
General Scheme 2 CO2CH3 CO2CH3 N N F O ioxane C TIPS N N Br K3PO4/diglyme Br N R2 O R4a N O R4a CO2H O B O NH2 S O O NH N N Br EDCI/DMAP/DCM N N In General Scheme 2, methyl 4-bromofluorobenzoate is reacted with Compound C to give Compound D, and the ester of Compound D is hydrolyzed to give Compound E. Compound E is coupled with Compound B from General Scheme 1 to give nd F. 17301393_1 (GHMatters) P44803NZ00 General Scheme 3 O O Ph3P=CHCOCH3 CH2(CO2CH3)2 i) KOH Y O Y ii) HCl Y CO2CH3 Y = -CH2- or -OO OH O RedAl H2/Pd-C O Y O Y TsOH/Toluene Y O O O K2CO3/PhN(Tf)2 O O O Y NaH/THF Y DMF O OTf Cl B /CsF OH CO2CH3 LiBH4/THF Y (PPh4)4Pd/DME/MeOH Y CH2OH Y CH2Cl MsCl/Et3N Cl H In General Scheme 3, Compound G is transformed Compound H. 17301393_1 ters) P44803NZ00 General Scheme 4 Y CH2Cl N K2CO3/DMF H Cl Cl I R2 H R2 N R4a H N R4a O O S O S O NH O NH O O N N H N N Br F H N Formula IV Pd(dppf)Cl2/K2CO3/DME-H2O In General Scheme 4, Compound H from General Scheme 3 is reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-tetrahydropyridine to give Compound I. Compound I is coupled with Compound F from General Scheme 2 to give a compound having Formula IV. 17301393_1 ters) P44803NZ00 General Scheme 5 N Boc H N N Y CH2Cl H N N TFA/DCM K2CO3/DMF Y Y H Cl Cl J Cl CO2CH3 CO2CH3 O N N N N N F 1) 1M KOH/dioxane K3PO4/diglyme 2) HCl Cl L R2 H CO2H R4a O H O N R4a O S N O O NH H O S N B O N N N EDCI/DMAP/DCM Formula II Y N In l Scheme 5, Compound H from General Scheme 3 is reacted with Boc-protected piperidine to give nd J, and the Boc group is removed to give Compound K. Compound K is reacted with methyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)fluorobenzoate to give Compound L, and the ester of Compound L is hydrolyzed to give Compound M. nd M is coupled with Compound B from General Scheme 1 to give a compound having Formula II. 17301393_1 (GHMatters) P44803NZ00 EXAMPLES EXAMPLE 1 Synthetic Intermediates INTERMEDIATE 1: Synthesis of 1-cyclobutylidenepropanone To a solution of cyclobutanone (5.0 g, 71.4 mmol) in toluene (200 ml) was added 1-(triphenylphosphoranylidene)propanone (22.7 g, 71.4 mmol) and the mixture was refluxed overnight. Solvent was removed under reduced pressure and the e was purified by silica gel column chromatography (ethyl e/hexane 1/10- 1/5) to afford 1-cyclobutylidenepropanone (5.0 g) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.95-5.93 (m, 1H), 3.19 - 3.13 (m, 2H), 2.91 -2.84 (m, 2H), 2.21 (s, 3H), 2.21 - 2.11 (m, 2H).
INTERMEDIATE 2: Synthesis of Spiro[3.5]nonane-6,8-dione.
To a solution of 1-cyclobutylidenepropanone (23.1 g, 0.21 mol) and methyl malonate (30.3 g, 0.23 mol) in methanol (150 ml) was added sodium methoxide (41.4 g, 30% in methanol). The mixture was heated to reflux under N2 for 4h and trated. The ing residue was hydrolyzed in 2 N potassium hydroxide (200 ml) at 70 ℃ for 4h. The mixture was extracted with ethyl acetate (100 ml), then titrated to pH 3-5 with 1N hydrochloride. The resulting solution was heated to 70 ℃ for 5h and extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated to afford spiro[3.5]nonane-6,8-dione (19.8 g, 62.3%) as yellow solid. This product was used directly in the next step without further cation. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 5.17 (s, 1H), 2.50 – 2.35 (m, 4H), 1.92 – 1.79 (m, 2H), 1.79 – 1.72 (m, 4H).
INTERMEDIATE 3: 8-Isobutoxyspiro[3.5]nonenone. 17301393_1 (GHMatters) P44803NZ00 To a solution of spiro[3.5]nonane-6,8-dione (19.8 g, 0.13 mol) in e (150 ml) was added 4-toluenesulfonic acid (248 mg, 0.0013 mol) and iso-butyl alcohol (14.5 g, 0.2 mol). The mixture was heated to reflux and water was removed by azeotropic distillation. Solvent was removed under vacuum and the e was purified by silica gel column chromatography (ethyl acetate/petrol ether 1/10-1/3) to afford 8-isobutoxyspiro[3.5]nonenone (25.0 g, 92.7%) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 1H), 3.59 (d, J = 6.8 Hz, 2H), 2.51 (s, 2H), 2.45 (s, 2H), 2.12 – 1.96 (m, 1H), 1.93 - 1.83 (m, 6H), 0.99 (d, J = 6.8 Hz, 6H).
INTERMEDIATE 4: Synthesis of Spiro[3.5]nonenone.
To a solution of 8-isobutoxyspiro[3.5]nonenone (25.0 g, 0.12 mol) in toluene (100 ml) was added Red-Al® (40 ml, 70% in toluene, 0.18 mol) dropwise at room temperature. The mixture was heated to 45 ℃ for 4h, then quenched by 1N hydrochloride. The e was filtered and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/petrol ether 1/10) to afford spiro[3.5]nonenone (9.0 g, 55 %) as light yellow oil.
INTERMEDIATE 5: Synthesis of Spiro[3.5]nonanone.
Spiro[3.5]nonenone (9.0 g) was hydrogenated under 1 atm H2 catalyzed by 10 % Pd/C (1.0 g) in methanol (80 ml) for 5.5 h. Pd/C was removed by tion and the filtrate was concentrated to afford spiro[3.5]nonanone (8.8 g, 96.4 %) as colorless oil which was used ly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 2H), 2.23 – 2.20 (m, 2H), 1.89 – 1.75 (m, 10H).
INTERMEDIATE 6: Synthesis of Methyl 6-oxospiro[3.5]nonane carboxylate. 17301393_1 ters) P44803NZ00 O O To a suspension of sodium hydride (5.1 g, 0.13 mol) in tetrahydrogen furan (150 ml) was added methyl carbonate (28.7 g, 0.32 mol) at room temperature, followed by spiro[3.5]nonanone in tetrahydrogen furan (30 ml). The mixture was ed for 2h. The reaction was quenched by saturated aqueous ammonium chloride and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine and concentrated. The resulting residue was purified by silica gel column chromatography to afford methyl 6-oxospiro[3.5]nonanecarboxylate (4.0 g, 32%) as light yellow oil.
INTERMEDIATE 7: Synthesis of Methyl rifluoromethyl)sulfonyl)oxy) spiro[3.5]nonenecarboxylate.
O OTf To a solution of methyl 6-oxospiro[3.5]nonanecarboxylate (4.0 g, 0.02 mol) in tetrahydrogen furan (25 ml) were added potassium carbonate (5.6 g, 0.04 mol) and N,N-bis(trifluoromethylsulfonyl)aniline (7.9 g, 0.022 mol). The mixture was stirred at room ature overnight, diluted with water, and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with ted brine, dried over ium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl e/petrol ether 1/50-1/10) to afford methyl 6- (((trifluoromethyl)sulfonyl)oxy)spiro[3.5]nonenecarboxylate (5.0 g, 76 %) as light yellow oil.
INTERMEDIATE 8: Synthesis of Methyl 6-(4-chlorophenyl)spiro[3.5]non enecarboxylate. 17301393_1 (GHMatters) P44803NZ00 The mixture of methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.5]nonene- oxylate (5.0 g, 0.015 mol), 4-chlorophenyl boronic acid (2.58 g, 0.017 mol), CsF (4.63 g, 0.03 mol) and Pd(PPh3)4 (173 mg, 0.15 mol) in methoxy-ethan (30 ml) and methanol (15 ml) was heated to 70 ℃ under N2 for 2h. Solvents were removed under reduced pressure and the residue was ed bysilica gel column chromatography (ethyl e/petrol ether 1/10) to afford methyl 6-(4- chlorophenyl)spiro[3.5]nonenecarboxylate (4.0 g, 92%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 3.48 (s, 3H), 2.50 – 2.44 (m, 2H), 2.43 (t, J = 2.3(2.3 or 6.3?) Hz, 2H), 2.02 – 1.80 (m, 6H), 1.74 (t, J = 6.3 Hz, 2H).
INTERMEDIATE 9: Synthesis of (6-(4-Chlorophenyl)spiro[3.5]nonen yl)methanol.
To a solution methyl 6-(4-chlorophenyl)spiro[3.5]nonenecarboxylate (4.0 g, 0.014 mol) in tetrahydrogen furan (20 ml) was added a solution of LiBH4 (910 mg, 0.042 mol) in tetrahydrogen furan (10 ml). The mixture was stirred at room temperature overnight, quenched by 1N aqueous hydrochloride and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The ing residue was purified by silica gel column chromatography (ethyl acetate/petrol ether 1/10-1/3) to afford (6-(4- chlorophenyl)spiro[3.5]nonenyl)methanol (3.0 g, 81.7%) as white solid. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.93 (d, J = 4.2 Hz, 2H), 2.37 – 2.26 (m, 2H), 2.01 – 1.77 (m, 8H), 1.74 (t, J = 6.3 Hz, 2H).
INTERMEDIATE 10: Synthesis of 7-(Chloromethyl)(4- chlorophenyl)spiro[3.5]nonene. 17301393_1 (GHMatters) P44803NZ00 To a on of (6-(4-chlorophenyl)spiro[3.5]nonenyl)methanol (3.5 g, 0.013 mol) and trimethylamine (2.7 g, 0.026 mol) in dichloromethane (20 ml) was added methylsulfonyl chloride (3.0 g, 0.026 mol) dropwise. The mixture was stirred at room temperature for 5h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to afford 7-(chloromethyl)(4- chlorophenyl)spiro[3.5]nonene (2.75 g, 75.5%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 3.93 (s, 2H), 2.34 – 2.25 (m, 4H), 1.97 – 1.78 (m, 6H), 1.74 (t, J = 6.3 Hz, 2H).
INTERMEDIATE 11: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)fluorobenzoate.
O O N N A mixture of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridinol (2.2 g), ethyl 2,4-difluorobenzoate (1.96 g), and K3PO4 (2.14 g) in diglyme (20 mL) was stirred at 115 ºC for 1h. The reaction was cooled, diluted with ethyl e (100 mL), and washed with water, brine, and concentrated. The residue was ed by silica gel chromatography (ethyl acetate/hexane 1/3) to afford ethyl 2-((1H-pyrrolo[2,3- b]pyridinyl)oxy)fluorobenzoate (1.9 g) as white solid. 1H NMR (400 MHz, CDCl3) δ 10.13 – 10.08 (m, 1H), 8.23 (d, J = 2.6 Hz, 1H), 7.98 (dd, J = 8.8, 6.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 3.5, 2.5 Hz, 1H), 6.84 (ddd, J = 8.8, 7.6, 2.4 Hz, 1H), 6.55 (dd, J = 10.3, 2.4 Hz, 1H), 6.52 (dd, J = 3.5, 2.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
INTERMEDIATE 12: Synthesis of Methyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)bromobenzoate. 17301393_1 ters) P44803NZ00 O O N N A e of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridinol (1.91 g), methyl 4-bromofluorobenzoate (1.70 g), and K3PO4 (1.86 g) in diglyme (20 mL) was stirred at 115 ºC for 1h. The reaction was cooled, diluted with ethyl acetate (100 mL), and washed with water, brine, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1/3) to afford methyl - pyrrolo[2,3-b]pyridinyl)oxy)bromobenzoate (1.8 g) as white solid. 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.18 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.40-6.96 (m, 2H), 6.96 (d, J=1.7 Hz, 1H), 6.51-6.48 (m, 1H), 3.89 (s, 3H).
INTERMEDIATE 13: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromobenzoic acid.
O OH N N To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromobenzoate (300 mg, 0.867 mmol) in dioxane (10 mL) was added 1 N NaOH (2.2 mL, 2.2 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was acidified by 1 N HCl and extracted with ethyl acetate, washed with brine, and dried over anhydrous MgSO4. Evaporation under reduced pressure afforded crude 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)bromobenzoic acid as a ess oil. This t was used directly in the next step t further purification.
INTERMEDIATE 14: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl) benzamide. 17301393_1 (GHMatters) P44803NZ00 O NH N N To a solution of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)bromobenzoic acid (100 mg, 0.3 mmol) in DCM (10 mL) were added 3-nitro(((tetrahydro-2H-pyran yl)methyl)amino)benzenesulfonamide (95 mg, 0.3 mmol), DMAP (55 mg, 0.45 mmol) and EDCI (115 mg, 0.6 mmol) and the mixture was stirred at room temperature for 24 h. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 95/5) to afford 2-((1H-pyrrolo[2,3-b]pyridin )bromo-N-((3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl) sulfonyl)benzamide as a yellow oil (80 mg). MS m/z 630 [M+H]+.
INTERMEDIATE 15: Synthesis of (S)-N-((4-(((1,4-Dioxan yl)methyl)amino)nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy) enzamide.
O S O O NH O N N The title nd was prepared using a procedure similar to the one described for INTERMEDIATE 14, and purified by silica gel chromatography (DCM/MeOH 95/5). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.59 – 8.52 (m, 2H), 8.05 (d, J = 2.6 Hz, 1H), 7.85 (dd, J = 9.2, 2.4 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.59 – 7.49 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.50 – 6.40 (m, 1H), 3.83 – 3.37 (m, 2H), 3.72 – 3.56 (m, 2H), 3.56 – 3.42 (m, 2H), 3.37 – 3.01 (m, 3H). 17301393_1 (GHMatters) P44803NZ00 EDIATE 16: Synthesis of (R)-N-((4-(((1,4-dioxan yl)methyl)amino)nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromobenzamide.
O S O O NH O N N The title compound was prepared using a procedure similar to the one described for INTERMEDIATE 14, and ed by silica gel chromatography (DCM/MeOH 95/5). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.59 – 8.52 (m, 2H), 8.05 (d, J = 2.6 Hz, 1H), 7.85 (dd, J = 9.2, 2.4 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.59 – 7.49 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.50 – 6.40 (m, 1H), 3.83 – 3.37 (m, 2H), 3.72 – 3.56 (m, 2H), 3.56 – 3.42 (m, 2H), 3.37 – 3.01 (m, 3H).
INTERMEDIATE 17: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((3-nitro(((1-(oxetanyl)piperidin yl)methyl)amino)phenyl)sulfonyl)benzamide.
O NH N N N The title compound was prepared using a procedure similar to the one described for INTERMEDIATE 14, and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 685 [M+H]+.
INTERMEDIATE 18: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((4-(((4-morpholinocyclohexyl)methyl)amino) henyl)sulfonyl)benzamide. 17301393_1 (GHMatters) P44803NZ00 O NH N N The title compound was prepared using a procedure similar to the one described for EDIATE 14, and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 713 [M+H]+.
INTERMEDIATE 19: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((3-nitro(((1-(tetrahydro-2H-pyranyl)piperidin yl)methyl)amino)phenyl)sulfonyl)benzamide.
O NH N N N The title compound was ed using a procedure similar to the one bed for INTERMEDIATE 14, and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 713 [M+H]+.
INTERMEDIATE 20: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl) benzamide.
O S O O NH N N 17301393_1 (GHMatters) P44803NZ00 The title compound was prepared using a procedure similar to the one described for INTERMEDIATE 14, and purified by silica gel tography (DCM/MeOH 95/5). MS m/z 630 .
EDIATE 21: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromo-N-((4-(((1-methylpiperidinyl)methyl)amino)nitrophenyl)sulfonyl) benzamide.
O NH N N N The title compound was prepared using a ure similar to the one described for INTERMEDIATE 14, and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 643 [M+H]+.
INTERMEDIATE 23: Synthesis of tert-Butyl(3-((1H-pyrrolo[2,3- b]pyridinyl)oxy)(ethoxycarbonyl)phenyl)piperazinecarboxylate.
O O N N The mixture of ethyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)fluorobenzoate (2.1 g, 7 mmol), N-Boc-piperazine (2.61 g, 0.014 mol) and dipotassium hydrogenphosphate (2.44 g, 0.014 mol) in dimethyl sulfoxide was heated to 135 ℃ overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, trated and purified by silica gel column chromatography to afford tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(ethoxycarbonyl)phenyl)piperazine carboxylate (2.4 g, 73%) as white solid. 1H NMR (400 MHz, CDCl 3) δ 9.42 (br s, 1H), 8.20 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.37 (dd, J 17301393_1 (GHMatters) P44803NZ00 = 3.5, 2.5 Hz, 1H), 6.66 (dd, J = 8.9, 2.5 Hz, 1H), 6.46 (dd, J = 3.5, 2.0 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.55 – 3.50 (m, 4H), 3.21 – 3.17 (m, 4H), 1.47 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H).
INTERMEDIATE 24: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)(piperazinyl)benzoate.
O O N N Trifluoroacetic acid (6 ml) was added to a solution of tert-butyl 4-(3-((1H- pyrrolo[2,3-b]pyridinyl)oxy)(ethoxycarbonyl)phenyl)piperazinecarboxylate (2.1 g) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 3h. Solvent was d under reduced pressure and the crude ethyl 2-((1H- pyrrolo[2,3-b]pyridinyl)oxy)(piperazinyl)benzoate (2.5 g) was used directly in the next step without further purification.
INTERMEDIATE 25: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)(4-((6-(4-chlorophenyl)spiro[3.5]nonenyl)methyl)piperazin zoate.
O O N N To a solution of 7-(chloromethyl)(4-chlorophenyl)spiro[3.5]nonene (851 mg, 3 mmol) in N,N-dimethyl ide (10 ml) were added potassium carbonate (1.26 g, 9 mmol), ium iodide (100 mg, 0.6 mmol) and ethyl 2-((1H- pyrrolo[2,3-b]pyridinyl)oxy)(piperazinyl)benzoate (1.53 g, 3.3 mmol). The 17301393_1 (GHMatters) P44803NZ00 mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, concentrated and ed by silica gel column chromatography (ethyl acetate/petrol ether 1/5-1/1) to afford ethyl 2-((1H-pyrrolo[2,3- b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)spiro[3.5]nonenyl)methyl) piperazinyl)benzoate (1.3 g, 71%) as white solid. 1H NMR (400 MHz, CDCl 3) δ 9.98 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.38 (t, J = 3.5 Hz, 1H), 7.28 (d, J= 8.3 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 6.62 (dd, J = 9.0, 2.5 Hz, 1H), 6.45 (dd, J = 3.5, 2.0 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.20 – 3.12 (m, 4H), 2.77 (s, 2H), 2.31 – 2.17 (m, 8H), 1.98 – 1.72 (m, 6H), 1.68 (t, J = 6.3 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).
INTERMEDIATE 26: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) (4-((6-(4-chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid.
HO O N N The solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- phenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzoate (1.3 g, 2.1 mmol) and 2N potassium ide (12 ml, 0.042 mol) in dioxane (15 ml) was heated to 60 ℃ overnight. The mixture was neutralized with 1N aqueous hydrochloride to pH 7 and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to afford 2-((1H- pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)spiro[3.5]nonen yl)methyl)piperazinyl)benzoic acid (1.1 g, 88.7 %) as white solid. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 2.6 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 6.63 (dd, J = 9.0, 2.4 Hz, 1H), 6.44 (dd, J = 3.5, 1.5 Hz, 1H), 6.22 (d, J = 2.4 Hz, 17301393_1 (GHMatters) P44803NZ00 1H), 3.81 (s, 2H), 3.17 – 3.10 (m, 4H), 2.80 (s, 2H), 2.30 – 2.20 (m, 6H), 1.98 – 1.72 (m, 6H), 1.67 (t, J = 6.3 Hz, 2H).
INTERMEDIATE 27: Synthesis of 1-(Oxetanylidene)propanone.
To a solution of oxetanone (20.6 g, 0.28 mol) in DCM (300 mL) was added 1-(triphenylphosphoranylidene)propanone (98.6 g, 0.31 mol). The mixture was stirred at room temperature overnight. DCM was removed under reduced re until solid was precipitated. The solid was removed by filtration and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetae/heptane 1/5~1/3) to afford tanylidene)propanone (23.3 g, 74.3%) as yellow oil.
INTERMEDIATE 28: Synthesis of 2-Oxaspiro[3.5]nonane-6,8-dione.
O O To a solution of 1-(oxetanylidene)propanone (23.3 g, 0.21 mol) and methyl malonate (30.2 g, 0.23 mol) in ol (150 mL) was added sodium methoxide (41.3 g, 30% MeOH solution). The mixture was heated to reflux under N2 for 1h. Solvent was removed under reduced pressure to afford methyl oxy oxooxaspiro[3.5]nonenecarboxylate which was used in the next step ly without purification. To an aqueous solution of KOH (2 mol/L, 200 ml) was added methyl 6-hydroxyoxooxaspiro[3.5]nonenecarboxylate . After stirring at room temperature for 30 min, the aqueous solution was extracted with ethyl acetate (150 ml x 3). The aqueous layer was ed to pH 3-5 with 1 N hydrochloride and heated at 50 ℃ for 4h. Water was removed under reduced pressure and the residue was ed by silica gel column chromatography to afford 2-oxaspiro[3.5]nonane-6,8- dione (2.5 g, 77.0 %) as light yellow solid. This product was used directly in the next step without further purification.
INTERMEDIATE 29: Synthesis of 8-Isobutoxyoxaspiro[3.5]nonen one. 17301393_1 (GHMatters) P44803NZ00 O O To a solution of 2-oxaspiro[3.5]nonane-6,8-dione (25 g, 0.16 mol) in toluene (150 ml) were added TsOH (238 mg, 0.0016 mol) and isobutyl alcohol (18 g, 0.24 mol). The reaction was completed after stirring at room temperature for 1h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/petrol ether 1/5~1/3) to afford 8-isobutoxy oxaspiro[3.5]nonenone (6 g, 43%) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.34 (s, 1H), 4.47 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 6.1 Hz, 2H), 3.60(d, J=6.8Hz 2H), 2.80(s, 2H), 2.68(s, 2H), 2.09-2.01(m, 1H), 0.98(d, J=6.8Hz, 6H).
INTERMEDIATE 30: Synthesis of 2-Oxaspiro[3.5]nonenone.
To a solution of 8-isobutoxyoxaspiro[3.5]nonenone (14.7 g, 0.07 mol) in e (100 ml) was added Red-Al® (40.4 g, 70% in Toluene) dropwise. The mixture was heated to 45 ºC for 2h and quenched by 1N HCl on. The mixture was concentrated and purified by silica gel column chromatography (ethyl acetae/petrol ether 1/10~1/5) to afford 2-oxaspiro[3.5]nonenone (8.8 g, 91%) as ess oil. This product was used directly in the next step without further purification.
INTERMEDIATE 31: Synthesis of 2-Oxaspiro[3.5]nonanone.
To a solution of 2-oxaspiro[3.5]nonenone (8.8 g) in tetrahydrogen furan (80 ml) was added Pd/C (1 g). The mixture was hydrogenated under 1atm H2 at room temperature for 2h. After the reaction was completed, Pd/C was removed by filtration and the on was trated to afford 2-oxaspiro[3.5]nonanone (8.0 g, 89.6%) as colorless oil. This t was used directly in the next step without further purification. 17301393_1 (GHMatters) P44803NZ00 INTERMEDIATE 32: Synthesis of Methyl 6-oxooxaspiro[3.5]nonane carboxylate.
O O To a suspension of sodium hydride (4.6 g, 0.11 mol) in tetrahydrogen furan (150 ml) under N2 was added methyl ate (25.7 g, 0.28 mol) dropwise. After dropping was completed, the mixture was heated to reflux. A solution of 2- ro[3.5]nonanone (11.2 g, 0.057 mol) in tetrahydrogen furan (30 ml) was then added. The reaction was heated at reflux for 2h and quenched by saturated aqueous um chloride, and extracted with ethyl acetate (100 ml x 3). The ed organic layer was washed with brine, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford methyl 6-oxo oxaspiro[3.5]nonanecarboxylate (4.5 g, 69%) as colorless oil. This product was used directly in the next step without r purification.
INTERMEDIATE 33: Synthesis of Methyl 6-(((trifluoromethyl)sulfonyl)oxy)- 2-oxaspiro[3.5]nonenecarboxylate.
O OTf To a suspension of methyl 6-oxooxaspiro[3.5]nonanecarboxylate (4.5 g, 0.02 mol) and potassium carbonate (6.3 g, 0.046 mol) in DMF (30 ml) was added N,N-bis(trifluoromethylsulfonyl)aniline (8.9 g, 0.025 mol). The mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated under reduced re. The residue was purified by silica gel column chromatography (ethyl acetate/Petrol ether 1/10~1/3) to afford methyl 6- (((trifluoromethyl)sulfonyl)oxy)oxaspiro[3.5]nonenecarboxylate (6.6 g, 86 %) as light yellow oil. This product was used directly in the next step without further purification.
INTERMEDIATE 34: Synthesis of Methyl 6-(4-chlorophenyl) oxaspiro[3.5]nonenecarboxylate. 93_1 (GHMatters) P44803NZ00 To a solution of methyl rifluoromethyl)sulfonyl)oxy)oxaspiro[3.5]non- 6-enecarboxylate (6.6 g, 0.02 mol) in 1,2-dimethoxy-ethan (30 ml) and methanol (10 ml) were added 4-chloro-phenyl boronic acid (3.13 g, 0.02 mol), CsF (6.08 g, 0.04 mol) and Pd(PPh3)4 (231 mg, 0.2 mmol) and the mixture was heated to 70 ºC under N2 for 30 min. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/petrol ether 1/5-1/3) to afford methyl hlorophenyl)oxaspiro[3.5]nonenecarboxylate (5.1 g, 87.3%) as light yellow solid. 1H NMR (400 MHz, CDCl 3) 7.33 (d, J=8.4Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 4.54 (d, J=5.6Hz, 2H), 4.48 (d, J=5.6Hz, 2H), 3.48 (s, 3H), 2.74- 2.70(m, 2H), 2.55-2.50 (m, 2H), 2.04 (t, J=6.4Hz, 2H).
EDIATE 35: Synthesis of (6-(4-Chlorophenyl)oxaspiro[3.5]non- -yl)methanol.
To a solution of methyl 6-(4-chlorophenyl)oxaspiro[3.5]nonene carboxylate (2.1 g, 0.0072 mol) in tetrahydrogen furan (20 ml) was added LiBH4 (475 mg, 0.022 mol) in tetrahydrogen furan (10 ml) dropwise at room temperature. The mixture was d at room temperature for 4h, quenched by 1N HCl solution, and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petrol ether 1/5-1/1) to afford (6-(4- chlorophenyl)oxaspiro[3.5]nonenyl)methanol (1.5 g, 78.9%) as white solid. 1H NMR (400 MHz, CDCl 3) 7.34 (d, J=8.4Hz, 2H), 7.07 (d, 2H, J=8.4Hz), 4.54 (d, 2H, z), 4.46 (d, 2H, J=5.6Hz), 3.93 (s, 2H), 2.62 (s, 2H), 2.40-2.33 (m, 2H), 2.03 (t, 2H, J = 6.4 Hz). 17301393_1 (GHMatters) P44803NZ00 INTERMEDIATE 36: Synthesis of 7-(Chloromethyl)(4-chlorophenyl) oxaspiro[3.5]nonene.
To a solution of (6-(4-chlorophenyl)oxaspiro[3.5]nonenyl)methanol (1.5 g, 5.7 mmol) and triethylamine (836 mg, 8.6 mmol) in dichloromethane (15 ml) was added methylsulfonyl chloride (980 mg, 8.6 mmol) and the mixture was stirred at room temperature for 3.5h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to afford 7-(chloromethyl)- 6-(4-chlorophenyl)oxaspiro[3.5]nonene (1.4 g, 87.0 %) as white solid. 1H NMR (400 MHz, CDCl3) 7.35 (d, 2H, J=8.4Hz), 7.16 (d, 2H, J=8.4Hz), 4.53 (d, 2H, J=6.0Hz), 4.45 (d, 2H, z), 3.86 (s, 2H), 2.64 (s, 2H), 2.40-2.33 (m, 2H), 2.03 (t, 2H, J=6.4Hz).
EDIATE 37: sis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)(4-((6-(4-chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazin yl)benzoate.
O O N N To a solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(piperazin yl)benzoate (382 mg, 0.82 mmol) in DMF (10 ml) were added 7-(chloromethyl)(4- chlorophenyl)oxaspiro[3.5]nonene (200 mg, 0.75 mmol), ium carbonate (310 mg, 2.25 mmol), DIPEA (290 mg, 2.25 mmol) and potassium iodide (24.9 mg, 0.15 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and ted with ethyl acetate (50 ml x 3). The combined 17301393_1 (GHMatters) P44803NZ00 organic layers were washed with brine, concentrated and purified by silica gel column tography (ethyl acetate/petrol ether 1/5-1/1) to afford ethyl 2-((1H-pyrrolo[2,3- b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)oxaspiro[3.5]nonen yl)methyl)piperazinyl)benzoate (370 mg, 80.6%) as white solid. MS m/z 613 [M+H]+.
INTERMEDIATE 38: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) (4-((6-(4-chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid.
HO O N N To a solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzoate (370 mg, 0.6 mmol) in dioxane (10 ml) was added 2 N ium hydroxide (6 ml, 12 mmol) and the e was stirred at 60 ℃ overnight. The on was neutralized with 1 N hydrochloride to pH 7 and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to afford 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid (1.1 g, 88.7 %) as white solid. MS m/z 585 [M+H]+.
INTERMEDIATE 55: Synthesis of Methyl 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)(1-((6-(4-chlorophenyl)spiro[3.5]nonenyl)methyl)piperidin yl)benzoate. 17301393_1 (GHMatters) P44803NZ00 O O N N To as solution of oromethyl)(4-chlorophenyl)spiro[3.5]nonene (850 mg, 3.04 mmol) in N,N-dimethyl formamide (10 ml) were added potassium carbonate (1.26 g, 2.2 mmol), potassium iodide (100 mg, 0.61 mmol), and methyl 2- yrrolo[2,3-b]pyridinyl)oxy)(piperidinyl)benzoate (1.0 g, 3.34 mmol) the mixture was stirred at room temperature overnight. Then the mixture was diluted with water and extracted with ethyl e. The combined organic layers were washed with brine, concentrated. The resulting residue was purified by silica gel column chromatography to afford methyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperidinyl)benzoate (1.0 g, 55.2 %) as light yellow solid. 1H NMR (400 MHz, CDCl 3) δ 9.39 (br s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.39 (dd, J = 3.5, 2.5 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.04 – 6.93 (m, 3H), 6.72 (d, J = 1.6 Hz, 1H), 6.49 (dd, J = 3.5, 2.0 Hz, 1H), 3.87 (s, 3H), 2.81 – 2.75 (m, 2H), 2.73 – 2.71 (m, 2H), 2.28 (s, 2H), 2.25 – 2.15 (m, 2H), 1.98 – 1.76 (m, 6H), 1.75 – 1.51 (m, 9H).
EXAMPLE 2 Synthesis of (R)-N-((4-(((1,4-dioxanyl)methyl)amino)nitrophenyl)sulfonyl) ((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4-chlorophenyl)spiro[3.5]nonen yl)methyl)-1,2,3,6-tetrahydropyridinyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O O O NH O N N To a solution of (R)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)bromobenzamide in 1,2-dimethoxy-ethan (10 ml) and water (1 ml) were added 1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,2,3,6-tetrahydropyridine, Pd(dppf)Cl2, and K2CO3, and the mixture was d at 80 ºC for 12 h. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with ethyl e (30 mL x 3), dried over anhydrous MgSO4, and concentrated. The residue was purified by C18 reversed phase preparative HPLC to give (R)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)-1,2,3,6-tetrahydropyridin yl)benzamide. 1H NMR (400 MHz, Methanol-d 4) δ 8.68 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.88 (dd, J = 9.3, 2.3 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.46 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 8.2, 1.7 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 9.3 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 6.41 (d, J = 3.5 Hz, 1H), 5.94-5.90 (m, 1H), 3.95-3.40 (m, 14H), 3.15-3.03 (m, 1H), 2.68- 2.45 (m, 2H), 2.43 (s, 2H), 2.30 – 2.20(m, 2H), 2.03 – 1.77 (m, 8H) EXAMPLE 3 -pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4-chlorophenyl) oxaspiro[3.5]nonenyl)methyl)-1,2,3,6-tetrahydropyridinyl)-N-((3-nitro (((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O NH O N N The title compound was prepared using a procedure similar to the one bed for EXAMPLE 2. 1H NMR (400 MHz, Methanol-d 4) δ 8.70 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.90 (dd, J = 9.2, 2.3 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 3.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.20 – 7.10 (m, 3H), 6.96 (d, J = 9.2 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), .93 – 5.86 (m, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 5.9 Hz, 2H), 4.00 – 3.90 (m, 2H), 3.77 – 3.33 (m, 7H), 3.26 (d, J = 7.0 Hz, 2H), 3.15 – 3.00 (m, 1H), 2.70 – 2.65 (m, 2H), 2.63-2.25 (m, 4H), 2.07 (t, J = 6.3 Hz, 2H), 2.00 – 1.85 (m, 1H), 1.75 – 1.65 (m, 2H), 1.46 – 1.30 (m, 2H).
EXAMPLE 4 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)-1,2,3,6-tetrahydropyridinyl)-N-((3- nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide O NH O N N 17301393_1 (GHMatters) P44803NZ00 The title nd was prepared using a procedure similar to the one described for E 2. 1H NMR (400 MHz, Methanol-d 4) δ 8.71 (t, J = 1.9 Hz, 1H), 8.00-7.95 (m, 1H), 7.90 (dd, J = 9.3, 1.9 Hz, 1H), 7.63 (dd, J = 8.1, 1.4 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.46 (dd, J = 3.5, 1.4 Hz, 1H), 7.33 – 7.26 (m, 2H), 7.18 – 7.06 (m, 3H), 6.96 (dd, J = 9.3, 1.4 Hz, 1H), 6.81 (s, 1H), 6.43 (dd, J = 3.5, 1.5 Hz, 1H), .93 – 5.86 (m, 1H), 4.00-3.94 (m, 2H), 3.83 – 3.36 (m, 7H), 3.26 (d, J = 7.0 Hz, 2H), 3.10 – 3.04 (m, 1H), 2.67-2.40 (m, 4H), 2.30 – 2.24 (m, 2H), 2.02 – 1.77 (m, 9H), 1.74 – 1.67 (m, 2H), 1.45 – 1.30 (m, 2H).
EXAMPLE 5 Synthesis of (R)-N-((4-(((1,4-dioxanyl)methyl)amino)nitrophenyl)sulfonyl) yrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4-chlorophenyl)oxaspiro[3.5]non enyl)methyl)-1,2,3,6-tetrahydropyridinyl)benzamide O O O NH O N N The title compound was prepared using a procedure similar to the one described for EXAMPLE 1. 1H NMR (400 MHz, Methanol-d 4) δ 8.68 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 9.2, 2.3 Hz, 1H), 7.65 (d, J = 8.2 Hz,1H), 7.54 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 3.4 Hz,1H), 7.33 (d, J = 8.4 Hz, 2H), 7.21-7.16 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.3 Hz, 1H), 6.86 (d, J =1.6 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 5.94-5.90 (m, 1H), 4.60 – 4.43 (m, 4H), 3.95 – 3.40 (m, 14H), 3.15-3.00 (m, 1H), 2.80 – 2.60 (m, 4H), 2.38 – 2.25 (m, 2H), 2.08 (t, J = 6.3 Hz, 2H).
EXAMPLE 6 17301393_1 (GHMatters) P44803NZ00 sis of (R)-N-((4-(((1,4-dioxanyl)methyl)amino)nitrophenyl)sulfonyl) ((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)oxaspiro[3.5]non enyl)methyl)piperazinyl)benzamide O O O NH O N N A mixture of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid (290 mg, 0.5 mmol), (((1,4-dioxanyl)methyl)amino)nitrobenzenesulfonamide (236 mg, 0.75 mmol), EDCI (191 mg, 1 mmol), 4-(N,N-dimethylamino)pyridine (591 mg, 0.75 mmol) in dichloromethane (15 ml) was stirred at room temperature overnight.
The solvent was removed under vacuum and the resulting residue was purified through a silica gel column to afford (R)-N-((4-(((1,4-dioxanyl)methyl)amino) nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzamide (150 mg, 34.1 %) as yellow solid. 1H NMR (400 MHz, Methanol-d 4) δ 8.67 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 9.3, 2.3 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.3 Hz, 1H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H), 6.41 (d, J = 3.5 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.48 (d, J = 5.9 Hz, 2H), 3.93-3.35 (m, 19H),2.70 – 2.65 (m, 2H), 2.33 (s, 2H), 2.08 (t, J = 6.3 Hz, 2H).
EXAMPLE 7 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) oxaspiro[3.5]nonenyl)methyl)piperazinyl)-N-((3-nitro(((tetrahydro-2H- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O NH N N A mixture of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)oxaspiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid (250 mg, 0.43 mmol), 3-nitro(((tetrahydro-2H-pyran yl)methyl)amino)benzenesulfonamide (202 mg, 0.64 mmol), EDCI (164 mg, 0.86 mmol), 4-(N,N-dimethylamino)pyridine (78 mg, 0.64 mmol) in dichloromethane (10 ml) was stirred at room temperature for overnight, followed by concentration. The resulting residue was purified through silica gel column to afford 2-((1H-pyrrolo[2,3- b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)oxaspiro[3.5]nonenyl)methyl) piperazinyl)-N-((3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl) sulfonyl) benzamide (150 mg, 39.6 %) as yellow solid. 1H NMR (400 MHz, ol-d4) δ 8.70 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 9.2, 2.3 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9.2 Hz, 1H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.03 – 3.94 (m, 2H), 3.67 (s, 2H), 3.55 – 3.27 (m, 12H), 2.69 (s, 2H), 2.35 – 2.25 (m, 2H), 2.08 (t, J = 6.3 Hz, 2H), 2.05 – 1.93 (m, 1H), 1.76-1.69 (m, 2H), 1.45 – 1.35 (m, 2H).
Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((3-nitro (((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide 93_1 (GHMatters) P44803NZ00 O NH N N A mixture of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzoic acid (1.75 g, 3 mmol), 3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)benzenesulfonamide (1.43 g, 4.5 mmol), EDCI (1.15 g, 6 mmol) and -dimethylamino)pyridine (550 mg, 4.5mmol) and dichloromethane (40 ml) was d at room temperature for overnight, followed by adding water. The water layer was extracted with dichloromethane. The combined organic layers were washed with brine, concentrated and ed through silica gel column to afford 2-((1H-pyrrolo[2,3-b]pyridin yl)oxy)(4-((6-(4-chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N- ((3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide (1.7 g, 64.4 %) as yellow solid. 1H NMR (400 MHz, Methanol-d 4) δ 8.70 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 9.2, 2.3 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9.2 Hz, 1H), 6.77 (dd, J = 8.9, 2.4 Hz, 1H), 6.44 (d, J = 3.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 4.02 – 3.94 (m, 3H), 3.66 (s, 3H), 3.49 – 3.38 (m, 2H), 3.41 – 3.25 (m, 7H), 2.42 (s, 3H), 2.26 (s, 3H), 2.00 – 1.67 (m, 4H), 1.45 – 1.38 (m, 2H).
EXAMPLE 9 Synthesis of (R)-N-((4-(((1,4-dioxanyl)methyl)amino)nitrophenyl)sulfonyl) ((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl)spiro[3.5]nonen yl)methyl)piperazinyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O O O NH O N N The title compound was prepared using a procedure similar to the one described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d 4) δ 8.66 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 9.2, 2.4 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 2.4 Hz, 2H), 7.45 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 9.2 Hz, 1H), 6.76 (dd, J = 8.9, 2.3 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 3.87 (dd, J = 11.8, 4.2 Hz, 3H), 3.83 – 3.70 (m, 3H), 3.67 (s, 2H), 3.62 (dd, J = 11.7, 2.9 Hz, 1H), 3.51 – 3.41 (m, 2H), 3.40 – 3.35 (m, 1H), 3.29 (dq, J = 3.2, 1.6 Hz, 1H), 2.41 (s, 2H), 2.26 (s, 2H), 2.00 – 1.77 (m, 6H).
EXAMPLE 10 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) 3.5]nonenyl)methyl)piperazinyl)-N-((3-nitrophenyl)sulfonyl)benzamide O NH N N 17301393_1 (GHMatters) P44803NZ00 The title compound was prepared using a procedure similar to the one described for EXAMPLE 8. 1H NMR (400 MHz, DMSO-d 6) δ 11.70 (s, 1H), 9.47 (s, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.02- 7.97 (m, 1H), 7.84 – 7.75 (m, 1H), 7.56 – 7.43 (m, 3H), 7.40 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.9 Hz, 1H), 6.40 – 6.35 (m, 1H), 6.30 (s, 1H), 3.80 – 3.65 (m, 2H), 3.55 (s, 2H), 3.28 – 2.95 (m, 4H), 2.82-2.65 (m, 2H), 2.31 (s, 2H), 2.22 – 2.15 (m, 2H), 1.93 – 1.60 (m, 8H).
EXAMPLE 11 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) 3.5]nonenyl)methyl)piperazinyl)-N-((4-(methylamino)nitrophenyl) sulfonyl)benzamide O NH N N The title compound was prepared using a procedure similar to the one described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d 4) δ 8.78 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.96 (dd, J = 9.2, 2.3 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 2.6 Hz, 1H), 7.46 (d, J = 3.5 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.68 (dd, J = 8.9, 2.4 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 3.60 (s, 2H), .12 (m, 8H), 3.06 (s, 3H), 2.38 (s, 2H), 2.30 – 2.16 (m, 2H),1.97-1.73 (m, 8H).
EXAMPLE 12 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4-chlorophenyl) spiro[3.5]nonenyl)methyl)piperazinyl)-N-((4-(dimethylamino)nitrophenyl) sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O NH N N The title compound was prepared using a procedure similar to the one described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d 4) δ 8.41 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 9.4, 2.3 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 3.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.71 – 6.63 (m, 1H), 6.51 (d, J = 3.5 Hz, 1H), 6.15 (d, J = 1.9 Hz, 1H), 3.59 (s, 2H), 3.52-3.20 (m, 8H), 2.98 (s, 6H), 2.38 (s, 2H), .17 (m, 2H), 1.96 – 1.72 (m, 8H).
EXAMPLE 13 Synthesis of -pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4-chlorophenyl) spiro[3.5]nonenyl)methyl)piperidinyl)-N-((3-nitro(((tetrahydro-2H-pyran- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide O NH O N N A mixture of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperidinyl)benzoic acid (200 mg, 0.34 mmol), 3-nitro(((tetrahydro-2H-pyranyl)methyl)amino)benzenesulfonamide (162 mg, 0.52 mmol), EDCI (130 mg, 0.68 mmol), 4-(N,N-dimethylamino)pyridine (63.4 mg, 0.52 mmol) in dichloromethane (15 ml) was stirred at room temperature for overnight, followed by purification by silica gel column chromatography to afford 17301393_1 (GHMatters) P44803NZ00 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(1-((6-(4-chlorophenyl)spiro[3.5]nonen- 7-yl)methyl)piperidinyl)-N-((3-nitro(((tetrahydro-2H-pyran yl)methyl)amino)phenyl)sulfonyl)benzamide (170 mg, 57.3 %) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.64 (s, 1H), 8.50 – 8.42 (m, 2H), 7.97 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.2, 2.2 Hz, 1H), 7.52 – 7.36 (m, 5H), 7.11 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 9.2 Hz, 1H), 6.91 – 6.86 (m, 1H), 6.55 (s, 1H), 6.37 (s, 1H), 3.89 – 3.79 (m, 2H),3.35-2.90 (m, 10H), 2.32-2.10 (m, 5H), 1.95-1.15 (m, 17H).
EXAMPLE 14 The following Compounds of the Disclosure were prepared using the methodologies described in es 1-13: Cpd. No. 40: (S)-N-((4-(((1,4-dioxanyl)methyl)amino)fluoro nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzamide O O O S F O NH O N N 1H NMR (400 MHz, ol-d 4) δ 8.49-8.46 (m, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.70 (dd, J=13.6, 2.3 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.45 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.79 (dd, J=8.8, 2.3 Hz, 1H), 6.41-6.37 (m, 2H), 3.83-2.70 (m, 19H), 2.42 (s, 2H), 2.30-2.22 (m, 2H), .78 (m, 8H).
Cpd. No. 44: (S)-N-((4-(((1,4-dioxanyl)methyl)amino)fluoro nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O O O NH F O N N 1H NMR (400 MHz, methanol-d 4) δ 8.75 (d, J=7.5 Hz, 1H), 8.08-8.02 (m, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.80-6.72 (m, 2H), 6.50 (d, J=3.4 Hz, 1H), 6.29 (d, J=2.2 Hz, 1H), 3.90-2.70 (m, 19H), 2.41 (s, 2H), .20 (m, 2H), 2.00-1.78 (m, 8H).
Cpd. No. 45: (S)-N-((4-(((1,4-dioxanyl)methyl)amino)fluoro nitrophenyl)sulfonyl)((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)benzamide F N O O O NH O N N MS m/z = 900 [M+H].
Cpd. No. 46: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((2-methylnitro- 2H-indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.80 (d, J=1.6 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.69 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.75 (dd, J=8.9, 2.3 Hz, 1H), 6.34 (d, J=2.3 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 4.35 (s, 3H), 3.3.67-2.70 (m, 8H), 3.66 (s, 2H), 2.41 (s, 2H), 2.32-2.22 (m, 2H), 2.02-1.75 (m, 8H).
Cpd. No. 47: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((7-nitro-1H- benzo[d]imidazolyl)sulfonyl)benzamide O S N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.70 (d, J=1.3 Hz, 1H), 8.64 (d, J=1.3 Hz, 1H), 8.57 (s, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.40 (d, J=3.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.74 (dd, J=8.9, 2.2 Hz, 1H), 6.35 (d, J=2.2 Hz, 1H), 6.33 (d, J=3.4 Hz, 1H), .72 (m, 8H), 2.40 (s, 2H), 2.34-2.20 (m, 2H), 2.00-1.77 (m, 8H).
Cpd. No. 48: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((7-nitro (tetrahydro-2H-pyranyl)-2H-indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.87 (d, J=1.6 Hz, 1H), 8.84 (s, 1H), 8.75 (d, J=1.6 Hz, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.75 (dd, J=8.9, 2.3 Hz, 1H), 6.35 (d, J=3.4 Hz, 1H), 6.31 (d, J=2.3 Hz, 1H).4.20-4.14 (m, 2H), 3.75-2.70 (m, 13H), 2.41 (s, 2H), .76 (m, 14H).
Cpd. No. 49: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((1-methylnitro- 1H-indazolyl)sulfonyl)benzamide O N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.71 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.42 (d, J=3.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.76 (dd, J=8.9, 1.7 Hz, 1H), 6.36 (d, J=3.4 Hz, 1H), 6.34 (d, J=1.7 Hz, 1H), 4.20 (s, 3H), 3.75- 2.70 (m, 8H), 3.70 (s, 2H), 2.41 (s, 2H), 2.30-2.23 (m, 2H), 2.00-1.76 (m, 8H).
Cpd. No. 50: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((7-nitro-2H-indazol- -yl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O NH O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.82 (s, 2H), 8.41 (s, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.40-7.34 (m, 3H), 7.09 (d, J=8.4 Hz, 2H), 6.76 (dd, J=9.0, 2.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H), 6.29 (d, J=3.4 Hz, 1H), 3.70-2.70 (m, 8H), 3.66 (s, 2H), 2.41 (s, 2H), 2.30-2.20 (m, 2H), 2.02-1.77 (m, 8H).
Cpd. No. 51: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((4-nitro-2H-indazol- ulfonyl)benzamide O NH O S N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 9.19 (s, 1H), 8.84 (s, 1H), 8.73 (d, J=1.2 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.43- 7.37 (m, 3H), 7.12 (d, J=8.4 Hz, 2H), 6.81 (dd, J=8.7, 2.1 Hz, 1H), 6.41 (d, J=3.4 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 3.71-2.70 (m, 8H), 3.69 (s, 2H), 2.43 (s, 2H), 2.30-2.24 (m, 2H), 2.02-1.76 (m, 8H).
Cpd. No. 52: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((1-methylnitro- 1H-benzo[d]imidazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O S N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.66 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.35 (d, J=2.6 Hz, 1H), 7.33 (d, J=3.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.77 (dd, J=8.9, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 6.27 (d, J=3.5 Hz, 1H), 4.01 (s, 3H), 3.70- 2.70 (m, 8H), 3.66 (s, 2H), 2.42 (s, 2H), .23 (m, 2H), 2.03-1.80 (m, 8H).
Cpd. No. 53: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((7-nitro ((tetrahydro-2H-pyranyl)methyl)-1H-benzo[d]imidazolyl)sulfonyl)benzamide O S N O NH O N N 1H NMR (400 MHz, methanol-d 4) δ 8.67 (d, J=1.5 Hz, 1H), 8.56 (d, J=1.5 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.74 (dd, J=8.9, 2.3 Hz, 1H), 6.34 (d, J=3.4 Hz, 1H), 6.30 (d, J=2.3 Hz, 1H), 4.00-3.85 (m, 2H), 3.70-2.70 (m, 10H), 3.65 (s, 2H), 2.98 (d, J=7.3 Hz, 2H), 2.41 (s, 2H), 2.35-2.20 (m, 3H), 2.02-1.40 (m, 12H).
Cpd. No. 54: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((2-(2-(2- methoxyethoxy)ethyl)nitro-2H-indazolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O S N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.85 (s, 1H), 8.70 (s, 1H), 8.53 (d, J=1.2 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.42- 7.35 (m, 3H), 7.10 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.9, 2.3 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.30 (d, J=3.4Hz, 1H), 4.80 (t, J=5.0, 2H), 4.09 (t, J=5.0Hz, 2H), 3.70-3.65 (m, 4H), 3.64-2.70 (m, 10H), 3.29 (s, 3H), 2.42 (s, 2H), 2.30-2.25 (m, 2H), 2.02-1.76 (m, 8H).
Cpd. No. 55: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((2-(2-methoxyethyl)- 4-nitro-2H-indazolyl)sulfonyl)benzamide O N O S N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.80 (d, J=0.8 Hz, 1H), .72 (m, 1H), 8.54 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.40-7.35 (m, 3H), 7.10 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.9, 2.4 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 6.30 (d, J=3.4 Hz, 1H), 4.79 (t, J=5.0Hz, 2H), 3.99 (t, J=5.0 Hz, 2H), .70 (m, 8H), 3.67 (s, 2H), 3.38 (s, 3H), 2.42 (s, 2H), 2.32-2.25 (m, 2H), 2.02-1.76 (m, 8H).
Cpd. No. 25: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-((5-nitro ((tetrahydro-2H-pyranyl)methyl)-1H-pyrrolyl)sulfonyl)benzamide 17301393_1 (GHMatters) P44803NZ00 O N O NH N N 1H NMR (400 MHz, methanol-d 4) δ 8.04 (d, J=2.5 Hz, 1H), 7.72-7.68 (m, 2H), 7.61 (d, J=2.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 6.80 (dd, J=8.9, 2.3 Hz, 1H), 6.47 (d, J=3.5 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.27 (d, J=7.2 Hz, 2H), 3.85-2.70 (m, 12H), 3.66 (s, 2H), 2.42 (s, 2H), .25 (m, 2H), 2.03-1.77 (m, 9H), 1.48-1.26 (m, 4H).
Cpd. No. 56: 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((6-(4- chlorophenyl)spiro[3.5]nonenyl)methyl)piperazinyl)-N-(naphthalen ylsulfonyl)benzamide O NH N N 1H NMR (400 MHz, methanol-d 3) δ 8.61 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.92-7.70 (m, 4H), 7.78 (d, J=9.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.47 (d, J=3.5 Hz, 1H), 7,32 (d, J=8.4 Hz, 2H), 6.98 ((d, J=8.4 Hz, 2H), 6.62 (dd, J=9.0, 2.3 Hz, 1H), 6.48 (d, J=3.5 Hz, 1H), 6.13 (d, J=2.3 Hz, 1H), 3.57 (s, 2H), 3.56-2.71 (m, 8H), 2.36 (s, 2H), 2.24-2.14 (m, 2H), 1.96-1.71 (m, 8H).
E 15 Bcl-2 and Bcl-xL Inhibition: Fluorescein labeled BIM (81-106), BAK (72-87), and BID (79-99) peptides, named as Flu-BIM, Flu-BAK, and Flu-BID, respectively, were used as the fluorescent probes in FP assays for Bcl-2, Bcl-xL, and Mcl-1, respectively. By monitoring the total fluorescence polarization values of mixtures 17301393_1 (GHMatters) P44803NZ00 composed of fluorescent probes at fixed concentrations and proteins with sing concentrations up to the full saturation, the Kd values of Flu-BIM to Bcl-2, Flu-BAK to Bcl-xL and Flu-BID to Mcl-1 were determined to be 0.55 ± 0.15, 4.4 ± 0.8 and 6.9 ± 0.9 nM, respectively. Fluorescence polarization values were measured using the Infinite M-1000 plate reader (Tecan U.S., Research Triangle Park, NC) in luor 1 96-well, black, round-bottom plates (Thermo Scientific). To each well, 1 nM of Flu- BIM, or 2 nM of Flu-BAK or 2 nM of Flu-BID and increasing concentrations of Bcl-2, or Bcl-xL, or Mcl-1 were added to a final volume of 125 µl in the assay buffer (100 mM potassium phosphate, pH 7.5, 100 µg/ml bovine γ-globulin, 0.02% sodium azide, Invitrogen, with 0.01% Triton X-100 and 4% DMSO). Plates were mixed and incubated at room temperature for 1 hour with gentle g to assure equilibrium.
The polarization values in millipolarization units (mP) were measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Equilibrium dissociation constants (Kd) were then calculated by fi tting the sigmoidal dosedependent FP ses as a function of n concentrations using Graphpad Prism .0 software (Graphpad Software, San Diego, CA).
Ki values of representative Compounds of the Disclosure to Bcl-2, Bcl-xL, and Mcl-1 were determined from competitive binding experiments in which serial dilutions of inhibitors were added into 96-well plates containing fixed concentration of the fluorescent probes and proteins in each well. Mixtures of 5 µl of the tested tors in DMSO and 120 µl of pre-incubated protein/probe xes in the assay buffer were added into assay plates and incubated at room temperature for 2 hours with gentle shaking. Final concentrations of the protein and probe are 1.5 nM and 1 nM for the Bcl-2 assay, 10 nM and 2 nM for the Bcl-xL assay, and 20 nM and 2 nM for Mcl-1 assay, respectively. Negative controls ning protein/probe complex only (equivalent 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. IC50 values were determined by nonlinear regression g of the ition . The Ki values of competitive inhibitors were calculated using an equation described in Nikolovska-Coleska et al., Analytical Biochemistry 332: 261-73 (2004), based upon the measured IC50 values, the Kd values of the probes to the proteins, and the concentrations of the proteins and probes in the 17301393_1 (GHMatters) P44803NZ00 competitive assays. Ki values were also calculated using the equation of Huang, Journal of Biomolecular Screening 8:34-38 (2003).
The inhibitory ties of representative Compounds of the sure against Bcl-2, Bcl-xL, and Mcl-1 are provided in Table 4.
Table 4 Inhibitory ty IC50 (nM) Cpd. No.
Bcl-2 Bcl-xL Mcl-1 1 1.4 9.2 2 0.76 10.6 3 1.2 13.7 4 3.1 8.6 2.1 14 6 2.0 5.9 >5000 7 2.4 15.7 8 2.4 6.4 >5000 9 1.9 20.6 3.3 14.0 11 11.9 77.8 12 4.4 139 13 1.3 14.8 58 3.8 19.2 59 5.0 20.7 60 2.1 67.5 61 2.1 13.1 62 1.6 4.0 63 1.3 7.1 64 2.4 8.7 65 1.4 9.9 66 2.7 12.0 EXAMPLE 16 RS4;11 Inhibition RS4;11 cells were obtained from American Type Culture Collection (ATCC).
They were used within three months of thawing fresh vials. Cells were maintained in the recommended culture medium with 10% FBS at 37 °C and an atmosphere of % CO2.
The effect of representative Compounds of the Disclosure on cell viability was determined using Cell Counting Kit-8 (CCK-8) assay (Dojindo, Rockville, MD) according to the manufacturer’s instructions. 200 µL of a RS4;11 cell suspension 17301393_1 ters) P44803NZ00 (10000 cells/well) in culture medium were seeded into l plates and cultured overnight. Each tested compound was serially diluted in culture medium, and 20 μL of the compound dilution was added to the corresponding well of the cell plate. After the addition of the tested compound, the cells were incubated at 37 °C in an atmosphere of % CO2 for 4 days. At the end of 4 days, 10 µL of CCK-8 solution was added to each well of the plate and incubated for 1-4 hours. The plates were read at 450 nm on the microplate spectrophotometer (Epoch2, BioTek). The gs were normalized to the vehicle cells, and the IC50 was calculated by nonlinear regression analysis using GraphPad Prism 5 software.
The inhibitory activities of entative Compounds of the Disclosure against the RS4;11 cell line are provided in Table 5.
Table 5 RS4;11 Cpd. No. IC50 (nM) (Bcl-2 dependent) 1 3 2 5.5 3 26 4 427 22 6 5.5 7 35 8 3.7 9 28 32 11 61 12 78 13 2.8 22 20 23 19 1,090 27 5.2 28 968 29 12 19 31 34 32 1,381 34 552 611 36 13 37 68 38 66 17301393_1 ters) P44803NZ00 RS4;11 Cpd. No. IC50 (nM) (Bcl-2 dependent) 39 31 40 1.4 41 52 42 111 43 80 44 7,157 58 35 59 65 60 252 61 43 62 46 63 55 64 37 65 11 66 243 EXAMPLE 17 Molm13 Inhibition Molm13 cells were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ). They were used within three months of thawing fresh vials. Cells were maintained in the recommended culture medium with 10% FBS at 37 °C and an atmosphere of 5% CO2.
The effect of entative Compounds of the Disclosure on cell viability was determined using Cell Counting Kit-8 (CCK-8) assay (Dojindo, Rockville, MD) according to the manufacturer’s instructions. 200 µL of a Molm13 cell suspension (10000 well) in culture medium were seeded into 96-well plates and cultured ght. Each tested compound was serially d in culture medium, and 20 μL of the compound dilution was added to the corresponding well of the cell plate. After the addition of the tested compound, the cells were incubated at 37 °C in an here of % CO2 for 4 days. At the end of 4 days, 10 µL of CCK-8 solution was added to each well of the plate and incubated for 1-4 hours. The plates were read at 450 nm on the microplate spectrophotometer (Epoch2, BioTek). The readings were normalized to the vehicle cells, and the IC50 was calculated by nonlinear regression analysis using GraphPad Prism 5 software. 17301393_1 (GHMatters) P44803NZ00 The inhibitory activities of representative Compounds of the Disclosure against the Molm13 cell line are provided in Table 6.
Table 6 Molm13 Cpd. No. IC50 (nM) (Bcl-2 dependent) 1 47 2 85 6 6.4 182 11 1024 12 253 13 1.8 58 250 59 468 EXAMPLE 18 RS4;11 xenograft model RS4;11 xenograft tumor s ed from mice treated with Compounds of the Disclosure or ABT-199 at 25 mg/kg po, were examined for the expression of PARP, (Cell Signaling Technology (CST), #9523) caspase-3 (CST, #9661), and Bcl-2 (CST, #4223) by western blotting analysis. GAPDH was used as a loading control.
The results are shown in Fig. 1 and Fig. 2.
The antitumor ty of Cpd. No. 6 (compound 6) was also studied in the RS4;11 leukemia xenograft model. Human RS4;11 tumor cells were injected into nude mice and ent started on day 11 when the tumor size reached approximately 100 mm3. Cpd. No. 6 was administered via oral gavage at indicated doses and schedules. Cpd. No. 6 inhibits tumor growth (Fig. 3) and does not cause weight loss in mice (Fig. 4).
EXAMPLE 19 Pharmacokinetics The pharmacokinetics of ABT-199 and representative Compounds of the Disclosure were evaluated in rats at an IV dose of 2 mg/kg and an oral dose of mg/kg. The results are shown in Table 3. 17301393_1 ters) P44803NZ00 Table 3 AUC0-t AUC0-∞ Tmax (h) Cmax(ng/mL) t 1/2 (h) (ng·h/mL) (ng·h/mL) Vss CL (iv) MRTINF Compound (iv) F(AUC0-t) IV PO IV PO IV PO IV PO IV PO (L/h/kg) ) (L/kg) ABT-199 0.083 1.67 8737 5999 5435 20786 5446 20812 4.32 3.22 0.394 0.496 1.23 38.2% Cpd. No. 3 0.083 2.00 4202 1318 2656 7630 2683 7775 4.94 4.46 0.769 1.86 2.37 29.0% Cpd. No. 6 0.083 2.67 4174 2623 2899 13424 2915 13475 4.39 3.12 0.695 1.44 2.09 46.2% 17301393_1 (GHMatters) P44803NZ00 EXAMPLE 20 MV4;11 tion The inhibitory activities of representative Compounds of the Disclosure against the MV4;11 cell line are provided in Table 7.
Table 7 MV4;11 Cpd. No. IC50 (µM) 22 0.05894 23 0.05457 24 243.0 5.154 26 6.711 27 0.01694 28 1.295 29 0.04819 0.02249 31 0.1161 34 5.674 3.598 36 4 37 0.1544 38 0.1030 39 0.03374 40 0.002455 41 0.01811 42 0.08810 43 0.1260 66 >1000 Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of ions, formulations, and other parameters t affecting the scope of the invention or any embodiment thereof.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed .
It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. 17301393_1 (GHMatters) P44803NZ00 All s and publications cited herein are fully incorporated by reference herein in their entirety. 17301393_1 (GHMatters) P44803NZ00

Claims (10)

What is Claimed Is:
1. A nd, or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: NO2 NO2 H H N N O H O O N O O O S S O NH O O O NH S O O NH O O O N N N H H N N H N N N Cl , Cl , Cl , H NO2 N H O O O O S O NO2 O H S O O NH O O NH O O O O S O NH N N N N O H H N N N N N N N Cl , Cl , Cl , and H O O O O S F O NH N N Cl .
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 17301393_1 (GHMatters) P44803NZ00 NO2 NO2 NO2 H H H N N N O O O O O O O S O O S S F O NH O O NH O O NH O O O O N N N N N N H , H and H N N N N N N Cl Cl Cl .
3. The compound of claim 2, or a ceutically acceptable salt or solvate thereof, which is: O O O NH O N N Cl .
4. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, which is: O O O NH O , N Cl . 17301393_1 (GHMatters) P44803NZ00
5. The compound of claim 2, or a ceutically acceptable salt or solvate thereof, which is: O O O S F O NH O N N Cl .
6. A pharmaceutical composition comprising the compound of any one of claims 1-5, or a pharmaceutically able salt thereof, and a pharmaceutically acceptable carrier.
7. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a ment for treatment of a hyperproliferative disease.
8. The use of claim 7, wherein the hyperproliferative disease is cancer.
9. The use of claim 8, wherein the cancer is selected from one or more of the cancers of Table 2.
10. The use of claim 8 or 9, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, lastoma, Burkitt's lymphoma, cervical cancer, esophageal , ovarian , colorectal cancer, prostate cancer, and breast cancer.
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