TECHNICAL FIELD

This application features pyrazol-3-one compounds that activate a pro-apoptotic function of BAX. Also featured are methods of using such compounds, e.g., for the treatment or prevention of diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., diseased or damaged cells; e.g., insufficient apoptosis of diseased or damaged cells or reduced apoptosis of diseased or damaged cells). Examples of such diseases, disorders, and conditions include, but are not limited to, those associated with blockade(s) of cell death pathways (e.g., over-expression of anti-apoptotic BCL-2 proteins), e.g., hyperproliferative diseases, such as cancer.

BACKGROUND

BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. The BCL-2 family includes both pro-apoptotic (e.g., BAX) and anti-apoptotic proteins that form a complex protein interaction network of checks and balances that dictate cell fate (see, e.g., Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points.Cell116, 205-19 (2004)).

The α-helical BCL-2 homology 3 (BH3) domains of pro-apoptotic members (e.g., BAX) function as death ligands. Pro-apoptotic member BAX is an executioner protein of the BCL-2 family that, when activated, undergoes a structural transformation, which converts it from an inactive cytosolic monomer into a lethal mitochondrial pore (see Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H. & Walensky, L. D. BH3-triggered structural reorganization drives the activation of pro-apoptotic BAX.Mol Cell40, 481-92 (2010)).

Oligomerization of BAX (and its close homologue BAK) within the mitochondrial outer membrane enables the release of apoptogenic factors such as cytochrome c and smac/diablo that turn on caspases, the enzymatic effectors of apoptosis (see Liu, X., Kim, C. N., Yang, J., Jemmerson, R. & Wang, X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.Cell86, 147-57 (1996); Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.Cell91, 479-89 (1997); Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.Cell102, 33-42 (2000); Wei, M. C. et al. Pro-apoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.Science292, 727-30 (2001)). The explicit mechanism by which BAX is triggered and how select pro-apoptotic BCL-2 proteins directly engage and activate BAX have been key questions in the apoptosis field (see, e.g., Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death.Nat Rev Mol Cell Biol9, 47-59 (2008)).

The α-helical BCL-2 homology 3 (BH3) domains of activated pro-apoptotic members (e.g., BAX) can, however, be intercepted and sequestered by structurally-defined surface grooves within the anti-apoptotic members (see, e.g., Sattler, M. et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis.Science275, 983-6 (1997)). The relative levels of death-activating (pro-apoptotic) BH3 domains and anti-apoptotic BH3-binding pockets dictate the cellular response to stress. Cancer cells hijack the survival circuitry of the BCL-2 family pathway, exploiting pathologic overexpression of anti-apoptotic proteins to stymie physiologic and pharmacologic pro-apoptotic stimuli. By overexpressing these anti-apoptotic proteins, cancer cells maintain a survival advantage in the face of pro-apoptotic stimuli. Thus, the over-expression of anti-apoptotic members is believed to contribute to cancer pathogenesis.

Whereas the mainstay of developmental BCL-2 family therapeutics has focused on the loss-of-function strategy of inhibiting anti-apoptotic proteins, direct activation of BAX by select pro-apoptotic BCL-2 members that only contain a conserved BH3 domain (“BH3-only” proteins) has also emerged as a physiologically relevant mechanism for inducing mitochondrial apoptosis during development and homeostasis (see Ren, D. et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program.Science330, 1390-3 (2010)).

SUMMARY

I

This application features pyrazol-3-one compounds that activate a pro-apoptotic function of BAX, making them therapeutically useful for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset of or reducing the risk of developing) diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., diseased or damaged cells; e.g., insufficient apoptosis of diseased or damaged cells; or lack of apoptosis of diseased or damaged cells). Examples of such diseases, disorders, and conditions include (but are not limited to) those associated with blockade(s) of cell death pathways (e.g., over-expression of anti-apoptotic BCL-2 proteins), e.g., hyperproliferative diseases, such as cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (“ALL”) or acute myelogenous leukemia (“AML”); e.g., chronic lymphoblastic leukemia (“CLL”) or chronic myelogenous leukemia (“CML”)). While not wishing to be bound by theory, it is believed that the compounds described herein induce and increase apoptosis in target cells (e.g., pathogenic cells including, but not limited to, cancer cells), thereby suppressing tumor growth and/or proliferation. It is further believed that increasing apoptosis in such target cells reestablishes the normal apoptotic control that, during homeostasis, is associated with a regulated balance between pro- and anti-apoptotic protein functions.

II

[A] In some embodiments, the compounds described herein directly activate BAX by direct binding to BAX.

In some embodiments, the compounds described herein selectively bind to and activate BAX. For example, the compounds described herein selectively bind to and activate BAX in the presence of one (or more) different BCL-2 proteins, e.g., in the presence of one (or more) other pro-apoptotic BCL-2 proteins (e.g., BAK) and/or in the presence of one (or more) anti-apoptotic BCL-2 proteins.

In some embodiments, the compounds described herein directly activate BAX by direct binding to BAX; and selectively bind to and activate BAX, e.g. selectively bind to and activate BAX in the presence of one (or more) different BCL-2 proteins, e.g., in the presence of one (or more) other pro-apoptotic BCL-2 proteins (e.g., BAK) and/or in the presence of one (or more) anti-apoptotic BCL-2 proteins.

[B] It has been discovered that BAX contains a geographically distinct BH3 binding groove, which has been shown to mediate the direct activation of BAX. Specifically, structural analysis of a BIM BH3 death domain in complex with pro-apoptotic BAX uncovered a BH3 interaction site that, when engaged, results in the direct activation of BAX (see Gavathiotis, E. et al. BAX activation is initiated at a novel interaction site.Nature455, 1076-81 (2008)). A BIM BH3 α-helix, structurally reinforced by hydrocarbon stapling, engages BAX at the opposite side of the protein from the canonical BH3-binding groove of anti-apoptotic proteins (see Gavathiotis, E. et al. BAX activation is initiated at a novel interaction site.Nature455, 1076-81 (2008)). SeeFIG. 1A. This BH3 trigger site on BAX is formed by the confluence of α-helices 1 and 6, and is structurally defined by a hydrophobic groove comprised of amino acids M20, A24, L25, I31, M137, and L141, and a perimeter of charged and hydrophilic residues, including K21, Q28, Q32, E131, and R134. SeeFIG. 1B. The flexible loop between α-helices 1 and 2 partially overlies the binding site and its displacement by BIM BH3 has been implicated as the first ligand-induced conformational change of the BAX activation mechanism (see Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H. & Walensky, L. D. BH3-triggered structural reorganization drives the activation of pro-apoptotic BAX.Mol Cell40, 481-92 (2010)). For ease of exposition, this activating binding groove that is discussed at the start of section [III] is sometimes referred to herein as the “BAX trigger site”.

In some embodiments, the compounds described herein directly activate BAX by binding to BAX at the BAX trigger site.

In some embodiments, the compounds described herein selectively activate BAX by binding to BAX at the BAX trigger site; e.g., selectively activate BAX in the presence of one (or more) different BCL-2 proteins, e.g., in the presence of one (or more) other pro-apoptotic BCL-2 proteins (e.g., BAK) and/or in the presence of one (or more) anti-apoptotic BCL-2 proteins.

[C] In some embodiments, the compounds described herein induce or activate BAX-dependent or mediated apoptosis (cell death).

[D] In some embodiments, the methods described herein can include in vitro methods, e.g., contacting a sample containing BAX (e.g., a cell or tissue containing BAX) with a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

In some embodiments, the methods described herein can include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)) to a subject (e.g., a subject in need thereof, e.g., a mammal, such as a human).

[E] Accordingly, in one aspect, methods for activating (e.g., directly, selectively, directly and selectively as defined anywhere herein) BAX and/or inducing or activating BAX-dependent apoptosis are featured, which include contacting BAX with a compound of formula (I) or a pharmaceutically acceptable salt thereof:



wherein:

A is N or CH;

X is heteroaryl, which contains 5 ring atoms, wherein from 1-2 of the ring atoms is/are independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein:X is connected to the pyrazolone nitrogen via a ring carbon atom in X; andX is optionally further substituted with 1 Ra;

or

X is phenyl optionally substituted with from 1-5 Ra;

or

X is heteroaryl, which contains from 8-10 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein:X is connected to the pyrazolone nitrogen via a ring carbon atom in X; andX is optionally further substituted with 1 Ra.

Y is:

(i) C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rb; or

(ii) heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected Rb; or

(iii) C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6thioalkoxy, C1-C6haloalkoxy, or C1-C6halothioalkoxy, each of which is optionally substituted with —OH, —NH2, or —SH;

R1is:

(i) C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rc; or

(ii) heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected Rc; or

(iii) —C(O)—(C6-C10aryl or heteroaryl, which contains from 5-10 ring atoms as defined in R1definition (i) and (ii), respectively, above); or

(iv) hydrogen;

each of R2and Rais, independently, selected from any one of the substituents delineated collectively in (a), (b), (c), (d), and (e) below:

(a) C1-C8alkyl or C1-C8haloalkyl, each of which is optionally substituted with from 1-2 Rd;

(b) phenyl that is optionally substituted with from 1-4 Re;

(c) heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re;

(d) C3-C8cycloalkyl or C3-C8cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected C1-C4alkyl groups; or

(e) —NHC(O)(C1-C6alkyl), —C(O)(C1-C6alkyl); or —C(O)O(C1-C6alkyl);

Rb, at each occurrence, is independently selected from any one the substituents delineated collectively in (aa), (bb) and (cc) below:

(aa) C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, C1-C6haloalkyl, —NH(C1-C6alkyl), N(C1-C6alkyl)2, or —NHC(O)(C1-C6alkyl), each of which is optionally substituted with —OH, —NH2, azido (—N3), or —SH;

(bb) halo; —OH; —CN; nitro; —NH2; azido; C2-C4alkenyl; C2-C4alkynyl; —C(O)H; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); —OC(O)(C1-C6alkyl); —SO2(C1-C6alkyl); —SO2(C1-C6haloalkyl); —C(O)NH2; —C(O)NH(C1-C6alkyl); C(O)N(C1-C6alkyl)2; —SO2(C1-C6alkyl); —SO2NH2; —SO2NH(C1-C6alkyl); —SO2N(C1-C6alkyl)2; —NHCO(C1-C6alkyl), or —NHSO2(C1-C6alkyl); and

(cc) C3-C6cycloalkyl, C3-C6cycloalkoxy, or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), O, and S; and each of said ring systems is optionally substituted with from 1-3 independently selected C1-C4alkyl groups;

each occurrence of Rcand Reis, independently, selected from any one the substituents delineated collectively in (aaa), (bbb), (ccc), and (ddd) below:

(aaa) C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, C1-C6haloalkyl, —NH(C1-C6alkyl), N(C1-C6alkyl)2, or —NHC(O)(C1-C6alkyl), each of which is optionally substituted with —OH, —NH2, or —SH; (and optionally benzyloxy);

(bbb) halo; —OH; —CN; nitro; —NH2; azido; C2-C4alkenyl; C2-C4alkynyl; —C(O)H; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); —OC(O)(C1-C6alkyl); —SO2(C1-C6alkyl); —SO2(C1-C6haloalkyl); —C(O)NH2; —C(O)NH(C1-C6alkyl); C(O)N(C1-C6alkyl)2; —SO2(C1-C6alkyl); —SO2NH2; —SO2NH(C1-C6alkyl); —SO2N(C1-C6alkyl)2; —NHCO(C1-C6alkyl), —NHSO2(C1-C6alkyl); —C(O)O—(CH2)1-3(e.g., 1)—C(O)-(phenyl optionally substituted as defined in (ddd) below (e.g., —C(O)O—CH2—C(O)-(phenyl);

(ccc) L-C3-C8cycloalkyl, C3-C6cycloalkoxy, or L-heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of said ring systems is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene; and

(ddd) phenyl, —O-(phenyl), or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, and C1-C6haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH2, or —SH; and

Rdat each occurrence is, independently, selected from hydroxyl, C1-C6alkoxy; C1-C6thioalkoxy; C1-C6haloalkoxy; C1-C6thiohaloalkoxy; —NH2; —NH(C1-C6alkyl); N(C1-C6alkyl)2; —NHC(O)(C1-C6alkyl); cyano; —C(O)H; —C(O)(C1-C6alkyl); —C(O)(C1-C6haloalkyl); C(O)OH; —C(O)O(C1-C6alkyl); —C(O)NH2; —C(O)NH(C1-C6alkyl); C(O)N(C1-C6alkyl)2; —SO2(C1-C6alkyl); —SO2NH2; —SO2NH(C1-C6alkyl); and —SO2N(C1-C6alkyl)2.

One or more of the following can apply.

In some embodiments, X is not phenyl optionally substituted with from 1-5 Ra.

In some embodiments, R1is not substituted directly or indirectly with one or more hydroxyl (—OH) groups.

In some embodiments, X is not phenyl optionally substituted with from 1-5 Ra; and R1is not substituted directly or indirectly with one or more hydroxyl (—OH) groups.

In some embodiments, when R1is 2-methoxyphenyl, and R2is C1-C8alkyl (e.g., CH3), then Y cannot be substituted phenyl, e.g., monosubstituted phenyl, e.g., phenyl monosubstituted at the para position, e.g., 4-chlorophenyl).

In some embodiments, when R1is 2-carboxyphenyl, and R2is C1-C8alkyl (e.g., CH3), then Y cannot be substituted phenyl, e.g., monosubstituted phenyl, e.g., phenyl monosubstituted at the para position, e.g., 4-methoxyphenyl).

In some embodiments, R1is other than 3-nitro-4-chlorophenyl. In certain embodiments, R1is other than 3-nitro-4-chlorophenyl when R2and Y are both unsubstituted phenyl.

In some embodiments, the compound is other than the compound sometimes referred to herein as “BAM7.”

In another aspect, compounds having formula (I-A), or a pharmaceutically acceptable salt thereof, are featured:



In some embodiments of formula (I-A):

X′ is S;

X′″ is unsubstituted phenyl,

X″ is H or C1-C4alkyl;

R2is:C1-C4alkyl; orphenyl that is optionally substituted with from 1-4 Re; orheteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re;

R1is:—C(O)OH;C2-C6alkoxy that is optionally substituted with —NH2; orheterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups;

each of R13and R14is H; and

each occurrence of Reis, independently, halo; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, C3-C6cycloalkyl; and C1-C6haloalkyl.

One or more of the following can apply.

In certain embodiments, it is provided that R12cannot be —C(O)OH when R2is unsubstituted phenyl.

In certain embodiments, it is provided that R12cannot be —OCH2CH3when R2is unsubstituted phenyl.

In certain embodiments, it is provided that R12cannot be —OCH2CH3when R2is CH3.

In other embodiments of formula (I-A):

X′ is NH;

X′″ is unsubstituted phenyl,

X″ is H or C1-C4alkyl;

R2is:C1-C4alkyl; orphenyl that is optionally substituted with from 1-4 Re; orheteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re;

R12is:—C(O)OH;C2-C6alkoxy that is optionally substituted with —NH2; orheterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups;

each of R13and R14is H; and

each occurrence of Reis, independently, halo; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, C3-C6cycloalkyl; and C1-C6haloalkyl.

[F] In one aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset of or reducing the risk of developing) diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., diseased or damaged cells; e.g., insufficient apoptosis of diseased or damaged cells; or the lack of apoptosis of diseased or damaged cells) in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

[G] In another aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset of or reducing the risk of developing) diseases, disorders, and conditions associated with blockade(s) of cell death pathways (e.g., over-expression of anti-apoptotic proteins BCL-2 proteins) in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

[H] In a further aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset of or reducing the risk of developing) a hyperproliferative disease in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

In an aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) a hyperproliferative disease in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

[I] In still another aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset of or reducing the risk of developing) cancer (e.g., leukemia, e.g., ALL or AML; e.g., CLL or CML) in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

In an aspect, methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) cancer (e.g., leukemia, e.g., ALL or AML) in a subject in need thereof are featured. The methods include administering to the subject (e.g., an effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)).

[J] In yet another aspect, methods of modulating (e.g., increasing) apoptosis in vitro or in vivo are featured. Also featured are methods of modulating (e.g., decreasing) cell division in vitro or in vivo are featured. The methods can include contacting a sample containing BAX (e.g., a cell or tissue containing BAX) with a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I)); or administering a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)) to a subject (e.g., a subject in need thereof, e.g., a mammal, such as a human).

[K] In some embodiments, the methods described above and throughout this disclosure can include one or more of the following features.

The cancer can include carcinomas (originating in the outer layer of cells of the skin and internal membranes, e.g., breasts, lungs, intestines, skin, prostate, etc.); sarcomas (arising from connective tissue such as bone, muscle, cartilage and blood vessels), and hematologic malignancies (e.g., lymphomas and leukemias, which arise in the blood or blood-forming organs such as the spleen, lymph nodes and bone marrow, e.g., leukemias, e.g., ALL or AML; e.g., CLL or CML). Cancer cells can include, for example, tumor cells, neoplastic cells, malignant cells, metastatic cells, and hyperplastic cells.

Non-limiting examples of cancers include breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.

In some embodiments, the patient has not been treated with an agent that causes a thrombocytopenia-associated condition. In some embodiments the patient is not suffering from and/or is not a risk from developing a thrombocytopenia-associated condition.

In some embodiments, the methods further include administering one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents) and/or techniques (e.g., radiation therapies, surgical interventions, and the like) to a subject or in vitro cells, tissues, and organs.

In certain embodiments, the methods further include administering one or more additional therapeutic agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biological mimetics (BH3 mimetics); agents that bind to and inhibit anti-apoptotic proteins (e.g., agents that inhibit anti-apoptotic BCL-2 proteins); alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins, etc.), toxins, radionuclides; biological response modifiers (e.g., interferons (e.g., IFN-.alpha., etc.) and interleukins (e.g., IL-2, etc.), etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); gene therapy reagents (e.g., antisense therapy reagents and nucleotides); tumor vaccines; angiogenesis inhibitors; proteasome inhibitors: NF kappa .beta. modulators; anti-CDK compounds; HDAC inhibitors; and the like.

In certain embodiments, the methods further include administering one or more additional therapeutic agents that bind to and inhibit anti-apoptotic proteins (e.g., agents that inhibit anti-apoptotic BCL-2 proteins), such as ABT-263, obatoclax, gossypol derivatives, IAP inhibitors, and stapled peptides that target anti-apoptotic proteins (MCL-1 SAHB (see, Stewart et al, Nature Chem Biol, 2010), BID SAHB (Walensky et al Science 2004), BAD SAHB (Danial et al Nature Medicine 2008), BIM SAHB (Gavathiotis et al Nature 2008), etc.).

In certain embodiments, the methods further include administering one or more additional therapeutic agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV); kinase inhibitors (e.g., Epidermal Growth Factor Receptor (EGFR) kinase inhibitor, Vascular Growth Factor Receptor (VGFR) kinase inhibitor, Fibroblast Growth Factor Receptor (FGFR) kinase inhibitor, Platelet-derived Growth Factor Receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors such as GLEEVEC); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (e.g., raloxifene and tamoxifen); anti-androgens (e.g., flutamide, bicalutamide, finasteride, aminoglutethimide, ketoconazole, and corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory drugs (e.g., butazolidin, DECADRON, DELTASONE, dexamethasone, dexamethasone intensol, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, oxyphenbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapeutic drugs (e.g., irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib, gefitinib, bevacizumab, TAXOTERE or TAXOL); cellular signaling molecules; ceramides and cytokines; and staurosporine, and the like.

In some embodiments, the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment, such as a subject having, or at risk of having, one or more of the diseases or conditions described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a mammal. In certain embodiments, the subject can be a human.

In certain embodiments, the subject has not previously undergone chemotherapy. In certain embodiments, the subject is not suffering from, or at risk of, thrombocytopenia, such as thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma.

[L] In another aspect, methods of screening for (thereby identifying) compounds that activate BAX are featured. Said methods generally include screening a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)) and a test compound. The methods include providing: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I)); a test compound; a first group of cells; and contacting the first group of cells with the formula (I) compound and the test compound; and observing the effects of contacting the first group of cells with the formula (I) compound and the test compound. In some of these embodiments, the methods further provide the additional step of comparing the effects observed in the first cells against a second group of the cells contacted with the formula (I) compound alone, or with the test compound alone. Effects that may be observed include, but are not limited to, those described in the Examples section.

[M] In one aspect, pharmaceutical compositions are featured, which include a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)) and a pharmaceutically acceptable carrier. In some embodiments, the compositions can include one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents) as defined anywhere herein.

In another aspect, methods of making the pharmaceutical compositions described herein are featured. In some embodiments, the methods include taking any one or more of the compounds of formula (I) (e.g., including any subgenera or specific compound thereof of formula (I), e.g., formula (I-A)) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein, and mixing said compound(s) with one or more pharmaceutically acceptable carriers.

[N] In one aspect, methods of making the compounds described herein are featured. In some embodiments, the methods include taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps to produce a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.

[O] In one aspect, the compounds of formula (I) themselves (e.g., including any subgenera or specific compound thereof of formula (I)) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein are featured. In another aspect, any of the formula (I) compounds specifically described herein are featured.

In some embodiments, the compounds of formula (I) are other than those described in the following printed publications:

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In some embodiments, the foregoing exclusions can be combined with any one or more of the exclusions described in section [E] above.

[P] Embodiments can include any one or more of the following features.

X can contain 2 ring atoms independently selected from N, NH, N(C1-C3alkyl), O, and S; e.g., N and S or N and NH.

One of the two ring atoms can be independently selected from N, NH, and N(C1-C3alkyl) (e.g., N), and the other ring atom is independently selected from N, NH, N(C1-C3alkyl), O, and S (e.g., S or NH, e.g., S).

X can have formula X-1:



in which:

X′ is NH, 0, or S; and

one of X″ and X′″ is Y, and the other of X″ and X′″ is H or Ra.

X′ can be S.

X′ can be NH.

X′″ can be Y.

X″ can be H or Ra.

X″ can be H.

X″ can be Ra. In embodiments, Racan be C1-C8alkyl (e.g., CH3). In other embodiments, Racan be phenyl that is optionally substituted with from 1-4 Re; or C3-C8cycloalkyl which is optionally substituted with from 1-4 independently selected C1-C4alkyl groups.

Y can be C6-C10aryl (e.g., phenyl), which is optionally substituted with from 1-5 independently selected Rb. In embodiments, Y can be unsubstituted phenyl.

R1can be C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rc.

R1can be phenyl, which is substituted with from 1-5 (e.g., 1-3, 1-2, or 1) independently selected Rc.

Each occurrence of Rccan be, independently, selected from any one the substituents delineated collectively in (aaa), (bbb), (ccc), and (ddd) below:

(aaa) C1-C6alkoxy, C1-C6alkyl, C1-C6haloalkyl, —NH(C1-C6alkyl), N(C1-C6alkyl)2, or —NHC(O)(C1-C6alkyl), each of which is optionally substituted with —OH, —NH2, or —SH;

(bbb) C(O)OH; —C(O)O(C1-C6alkyl); —OC(O)(C1-C6alkyl); —SO2NH2; —SO2NH(C1-C6alkyl); or —SO2N(C1-C6alkyl)2; or —C(O)O—(CH2)1-3(e.g., 1)—C(O)-(phenyl optionally substituted as defined in (ddd) below (e.g., —C(O)O—CH2—C(O)-(phenyl);

(ccc) C3-C6cycloalkoxy or L-heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene; and

(ddd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, and C1-C6haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH2, or —SH.

In embodiments, each occurrence of R is, independently, selected from:C1-C6alkoxy;C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy); or C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy) that is substituted with —NH2;C1-C6alkyl;—NHC(O)(C1-C6alkyl);—C(O)OH;L-heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene (e.g., a bond); e.g., Rcis optionally substituted morpholino or optionally substituted piperazinyl; andphenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, and C1-C6haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH2, or —SH.

In embodiments, Rccan be C1-C6alkoxy (e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy).

In embodiments, Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy).

In embodiments, Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy) that is substituted with —NH2.

R1can have formula A:



The following definitions apply to any formula described herein that contains formula (A).

One or two of R12, R13, and R14is(are) an independently selected Rc, and the other(s) is(are) hydrogen.

R12can be R (as defined anywhere herein).

R13can be H.

R14can be H.

R15can be R.

R12can be Rc(as defined anywhere herein), and each of R13and R14can be H.

R14can be Rc(as defined anywhere herein), and each of R12and R13can be H.

In embodiments, Rccan be C1-C6alkoxy (e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy).

In embodiments, Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy).

In embodiments, Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy; e.g., containing branched alkyl, such a iso-propoxy) that is substituted with —NH2.

Rccan be —C(O)OH.

Rccan be L-heterocyclyl containing from 5-7 (e.g., 6) ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene (e.g., a bond); e.g., Rcis morpholino or piperazinyl. In embodiments, L can be a bond or CH2(e.g., L can be a bond).

R13can be H, and each of R12and R14can be R (each independently as defined anywhere herein).

One of R12and R14can be C1-C6alkoxy (e.g., ethoxy), and the other of R12and R14can be independently selected from:C1-C6alkoxy;C1-C6alkyl;—C(O)OH;—NHC(O)(C1-C6alkyl);L-heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene (e.g., a bond); e.g., Rcis optionally substituted morpholino or optionally substituted piperazinyl; andphenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, and C1-C6haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH2, or —SH.

R1can be heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected Rc.

R1can be heteroaryl, which contains from 5-6 ring atoms, wherein from 1-4 (e.g., 1-2) of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 (e.g., 1-2 or 1) independently selected Rc. For example, R1can be thiazolyl.

R1can be heteroaryl, which contains from 8-10 ring atoms, wherein from 1-4 (e.g., 1-2) of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 (e.g., 1-2 or 1) independently selected Rc. For example, R1can be indazolyl.

R2can be C1-C8alkyl. For example, R2can be CH3.

R2can be phenyl that is optionally substituted with from 1-4 Re. In embodiments, R2can be unsubstituted phenyl.

R2can be C3-C8cycloalkyl which is optionally substituted with from 1-4 independently selected C1-C4alkyl groups.

R2is heteroaryl containing from 5-6 (e.g., 5) ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re. For example, R2can be furanyl, thienyl, or thiazolyl.

A can be N.

In some embodiments:

A is N;

X contains 2 ring atoms independently selected from N, NH, N(C1-C3alkyl), O, and S, and one of the ring atoms is independently selected from N, NH, and N(C1-C3alkyl), and the other ring atom is independently selected from N, NH, N(C1-C3alkyl), O, and S; and

R1is C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rc(e.g., R1can be phenyl, which is substituted with from 1-5 (e.g., 1-3, 1-2, or 1) independently selected R).

In certain embodiments, the compound can have formula I-A:



wherein:

X′ is NH, O, or S;

one of X″ and X′″ is Y, and the other of X″ and X′″ is H or Ra;

one or two of R12, R13, and R14is(are) an independently selected Rc, and the other(s) is(are) hydrogen; and

R2can be as defined anywhere herein.

X′ can be S or NH (e.g., S), X′″ is Y, and X″ is H or Ra(e.g., X″ can be H or C1-C3alkyl, e.g., CH3).

Y can be C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rb(e.g., Y can be unsubstituted phenyl).

R12can be Rc, and each of R13and R14is H; or R14is Rc, and each of R12and R13is H.

Each occurrence of Rcis, independently, selected from:C1-C6alkoxy;C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy); or C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy) that is substituted with —NH2;C1-C6alkyl;—C(O)OH;—NHC(O)(C1-C6alkyl);L-heterocyclyl containing from 5-7 (e.g., 6) ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups; and wherein L is a bond or C1-C6alkylene (e.g., a bond); e.g., Rcis an optionally substituted morpholino or optionally substituted piperazinyl ring; andphenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; —C(O)(C1-C6alkyl); C(O)OH; —C(O)O(C1-C6alkyl); nitro; —NH2; —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NHC(O)(C1-C6alkyl), C1-C6alkoxy; C1-C6haloalkoxy; C1-C6thioalkoxy; C1-C6thiohaloalkoxy; C1-C6alkyl, and C1-C6haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH2, or —SH.

Rccan be C1-C6alkoxy (e.g., ethoxy or iso-propoxy); or Rccan be —COOH; or Rccan be morpholino or piperazinyl.

Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy or iso-propoxy) that is optionally substituted with —NH2; or Rccan be —COOH; or Rccan be an optionally substituted morpholino or optionally substituted piperazinyl ring.

Rccan be C1-C6alkoxy (e.g., C2-C6alkoxy, e.g., ethoxy or iso-propoxy) that is optionally substituted with —NH2.

R2can be C1-C8alkyl (e.g., CH3).

R2can be phenyl or heteroaryl containing from 5-6 (e.g., 5) ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re(e.g., R2is heteroaryl as defined above, e.g., thienyl, furanyl, or thiazolyl).

X″ can be H or CH3.

R2can be C1-C4alkyl, such as CH3. R2can be unsubstituted phenyl. R2can be heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re, such as thienyl, furanyl, or thiazolyl.

R12can be —C(O)OH. R12can be C2-C6alkoxy that is optionally substituted with —NH2, such as —OCH2CH3or —OCH2CH2NH2. R12can be heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), 0, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups, such as an optionally substituted piperazinyl ring.

X″ can be H or CH3; and R2can be C1-C4alkyl, such as CH3; or R2can be unsubstituted phenyl; or R2can be heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re, such as thienyl, furanyl, or thiazolyl.

X″ can be H or CH3; and

R2can be C1-C4alkyl, such as CH3; or R2can be unsubstituted phenyl; or R2can be heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re, such as thienyl, furanyl, or thiazolyl; and

R12can be —C(O)OH; or R12can be C2-C6alkoxy that is optionally substituted with —NH2, such as —OCH2CH3or —OCH2CH2NH2; or R12can be heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), NC(O)O(C1-C6alkyl), O, and S; and each of which is optionally substituted with from 1-3 independently selected C1-C4alkyl groups, such as an optionally substituted piperazinyl ring.

X″ can be H or CH3; and

R2can be C1-C4alkyl, such as CH3; and

R12can be C2-C6alkoxy that is optionally substituted with —NH2, such as —OCH2CH3or —OCH2CH2NH2.

In some embodiments:

A is N;

X contains 2 ring atoms independently selected from N, NH, N(C1-C3alkyl), O, and S, and one of the ring atoms is independently selected from N, NH, and N(C1-C3alkyl), and the other ring atom is independently selected from N, NH, N(C1-C3alkyl), O, and S; and

R1is heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected Rc.

In certain embodiments, the compound can have formula I-B:



wherein:

X′ is NH, O, or S; and

one of X″ and X′″ is Y, and the other of X″ and X′″ is H or Ra;

X′ can be S, X′″ can be Y, and X″ can be H or Ra.

X″ can be H.

R1can be thiazolyl.

Y can be C6-C10aryl, which is optionally substituted with from 1-5 independently selected Rb(e.g., unsubstituted phenyl).

R2can be phenyl that is optionally substituted with from 1-4 Re; or heteroaryl containing from 5-6 (e.g., 5) ring atoms, wherein from 1-4 of the ring atoms is independently selected from N, NH, N(C1-C3alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-3 Re.

R2can be unsubstituted phenyl.

The compound can be selected from compounds delineated inFIGS. 11, 12, and 14.

The contacting can be in vitro.

The contacting is in vivo.

In some embodiments, any compound, composition, or method described herein can also include or further include any one or more of the other features delineated in the detailed description and/or in the claims.

[Q] Definitions

The term “mammal” includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

In embodiments, an amount of a compound of formula (I) or salt thereof can be an effective amount. “An effective amount” refers to an amount of a compound that confers a therapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates, alleviates, or slows the progression of; or prevents, e.g., delays the onset of or reduces the risk of developing, a disease, disorder, or condition or symptoms thereof) on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.

In general, and unless otherwise indicated, substituent (radical) prefix names are derived from the parent hydride by either (i) replacing the “ane” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc.; or (ii) replacing the “e” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc. (Here the atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent with any established numbering of the parent hydride). Accepted contracted names, e.g., adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein throughout. Conventional numbering/lettering systems are also adhered to for substituent numbering and the nomenclature of fused, bicyclic, tricyclic, and polycyclic rings.

The following definitions are used unless otherwise described. Specific and general values listed below for radicals, substituents, and ranges are for illustration only. They do not exclude other defined values or other values within defined ranges for the radicals and substituents. Unless otherwise indicated, alkyl, alkylene, alkoxy, alkenyl, and the like denote both straight and branched groups.

The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

As used herein, the term “Cn-malkylene,” employed alone or in combination with other terms, refers to a non-branched divalent alkyl linking group having n to m carbon atoms.

The term “haloalkyl” refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) is replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atom can be optionally substituted, e.g., by one or more substituents.

As referred to herein, the term “alkoxy” refers to a group of formula —O(alkyl). Alkoxy can be, for example, methoxy (—OCH3), ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term “thioalkoxy” refers to a group of formula —S(alkyl). The terms “haloalkoxy” and “thio-haloalkoxy” refer to —O(haloalkyl) and —S(haloalkyl), respectively. Finally, the terms “cycloalkoxy” and “heterocyclyloxy” refer to a group of the formula —O(cycloalkyl) and —O(heterocyclyl), respectively.

The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups can be optionally substituted, e.g., by one or more substituents. Alkynyl groups can include groups such as ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons can optionally be the point of attachment of the alkynyl substituent.

The term “heterocyclyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more constituent heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and/or form a salt), or S. The heteroatom or ring carbon can be the point of attachment of the heterocyclyl substituent to another moiety. Any atom can be optionally substituted, e.g., by one or more substituents. Heterocyclyl groups can include groups such as tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. By way of example, a phrase such as “heterocyclic ring containing from 5-6 ring atoms”, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected Rawould include (but not be limited to) tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon group. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl).

The term “cycloalkenyl” refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be optionally substituted e.g., by one or more substituents. Cycloalkenyl moieties can include, e.g., cyclohexenyl, cyclohexadienyl, or norbornenyl.

The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (>3 fused rings) hydrocarbon ring system. One or more ring atoms can be optionally substituted by one or more substituents for example. Aryl moieties include groups such as phenyl and naphthyl.

The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (>3 fused rings) hydrocarbon groups having one or more heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and/or form a salt), or S. One or more ring atoms can be optionally substituted, e.g., by one or more substituents. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, coumarinyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl.

As used herein, the descriptor “—CN” represents the cyano group (and vice versa), wherein the carbon and nitrogen atoms are bound together by a triple bond. As used herein, the descriptor “—OH” represents the hydroxy group (and vice versa). The descriptors “C═O” or “C(O)” refers to a carbon atom that is doubly bonded to an oxygen atom.

In general, when a definition for a particular variable includes hydrogen and non-hydrogen (halo, alkyl, aryl, etc.) possibilities, the term “substituent(s) other than hydrogen” refers collectively to the non-hydrogen possibilities for that particular variable.

The term “substituent” refers to a group “substituted” on groups such as an alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group at any atom of that group. In one aspect, the substituent(s) on a group are independently any one single or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent. In another aspect, a substituent may itself be substituted with any one of the above substituents.

Further, as used herein, the phrase “optionally substituted” means unsubstituted (e.g., substituted with hydrogen (H)) or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is understood that substitution at a given atom is limited by valency.

Descriptors such as “C6-C10aryl that is optionally substituted with from 1-4 independently selected Rb(and the like) is intended to include both an unsubstituted C6-C10aryl group and a C6-C10aryl group that is substituted with from 1-4 independently selected Rb. The use of a substituent (radical) prefix name such as alkyl without the modifier “optionally substituted” or “substituted” is understood to mean that the particular substituent is unsubstituted. However, the use of “haloalkyl” without the modifier “optionally substituted” or “substituted” is still understood to mean an alkyl group, in which at least one hydrogen atom is replaced by halo.

[R] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

