ES2645367T3

Compositions and methods for the prevention and treatment of cancer

Abstract

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is present in an amount from about 100 mg to about 400 mg in the composition.

Term

4.5 yearsto projected expiry

Projected expiry 11 March 2031, counted from filing; an application has no term until it is granted.

14 claims: 6 independent, 8 dependent

1
ES 2 645 367 T3 REIVINDICACIONES 1. Una composición farmacéutica que comprende un compuesto o una sal, solvato o hidrato farmacéuticamente aceptable del mismo, en la que el compuesto está presente en una cantidad desde aproximadamente 100 mg a aproximadamente 400 mg en la composición.
2
La composición farmacéutica de la reivindicación 1, en la que la composición farmacéutica está formulada para administración oral, Intravenosa, Intramuscular o subcutánea, preferiblemente para administración oral.
3
La composición farmacéutica de la reivindicación 1, en la que el compuesto está presente en una cantidad desde aproximadamente 200 mg a aproximadamente 300 mg, preferiblemente en una cantidad de aproximadamente 250 mg.
4
Un compuesto N o una sal, solvato o hidrato farmacéuticamente aceptable del mismo, para su uso en el tratamiento de un trastorno prollferatlvo celular en un sujeto, en el que el compuesto está presente en una cantidad desde aproximadamente 100 mg a aproximadamente 400 mg y se administra una vez por un período de 24 horas.
5
El compuesto para el uso de la reivindicación 4, en el que el compuesto está presente en una cantidad desde aproximadamente 200 mg a aproximadamente 300 mg, preferiblemente aproximadamente 250 mg.
6
El compuesto para el uso de la reivindicación 4, en el que el tratamiento produce memoria ¡nmunológlca en el sujeto, preferiblemente en el que el tratamiento produce células B de memoria o células T en el sujeto.
7
El compuesto para el uso de cualquiera de las reivindicaciones 4-6, en el que el trastorno prollferatlvo celular es un cáncer, preferiblemente cáncer de cerebro;o un tumor hematológlco o maligno;o un tumor sólido (o tumores), preferiblemente en el que el tumor sólido (o tumores) es un glloblastoma, ollgodendroglloma, astrocltoma o meduloblastoma.
8
El compuesto para el uso de la reivindicación 7, en el que el tratamiento del cáncer comprende una reducción en el tamaño del tumor o una reducción de la Invasión de células cancerosas metastásicas.
9
El compuesto para el uso de una cualquiera de las reivindicaciones 4-8, en el que el tratamiento comprende además un segundo agente antlprollferatlvo o radioterapia.
10
Un compuesto ES 2 645 367 T3 o una sal, solvato o hidrato farmacéuticamente aceptable del mismo, para su uso en la prevención de la recurrencia de un trastorno prollferatlvo celular en un sujeto previamente diagnosticado con un trastorno prollferatlvo celular en el que el compuesto está presente en una cantidad desde aproxlmadamente 100 mg a aproxlmadamente 400 mg, 5
11
El compuesto para el uso de la reivindicación 10, en el que el compuesto está presente en una cantidad desde aproxlmadamente 200 mg a aproxlmadamente 300 mg, preferiblemente aproxlmadamente 250 mg, en la que opclonalmente el compuesto se administra una vez por período de 24 horas.
12
El compuesto para el uso de la reivindicación 10 u 11, en el que el sujeto se trató previamente para el trastorno de proliferación celular, preferiblemente en el que el sujeto estaba en remisión después del tratamiento para el 10 trastorno de proliferación celular.
13
El compuesto para el uso de la reivindicación 10, en el que el tratamiento previo produce memoria ¡nmunológlca en el sujeto, preferiblemente en el que el tratamiento produce células B de memoria o células T en el sujeto.
14
El compuesto para el uso de una cualquiera de las reivindicaciones 10-13, en el que el trastorno prollferatlvo celular es un cáncer, preferiblemente cáncer de cerebro;o un tumor hematológlco o maligno;o un tumor sólido (o 15 tumores), preferiblemente un glloblastoma, ollgodendroglloma, astrocltoma o meduloblastoma. 27596204v.3

Independent claims14

1,100 paragraphs in 93 sections, as filed

ES 2 645 367 T3

DESCRIPTION

Compositions and methods for the prevention and treatment of cancer.

Background of the Invention

Cancer is the second leading cause of death in the United States, second only to heart disease. (Cancer Facts and Figures 2004, American Cancer Soclety, Inc.). Despite recent advances in cancer diagnosis and treatment, surgery and radiation therapy can be curative if cancer is detected early, but current drug therapies for metastatic disease are mostly palliative and rarely offer a cure to long term. Even with the introduction of new chemotherapies on the market, the need continues for new effective drugs in monotherapy or in combination with existing agents as first line therapy and as second and third line therapies in the treatment of resistant tumors.

Cancer cells are, by definition, heterogeneous. For example, within a single tissue or cell type, multiple mutaclonal mechanisms can lead to the development of cancer. As such, heterogeneity often exists between cancer cells taken from tumors of the same tissue and of the same type that originated in different individuals. The frequently observed mutaclonal mechanisms associated with some cancers may differ from one tissue type to another (for example, the frequently observed mutaclonal mechanisms that lead to colon cancer may differ from the frequently observed mechanisms that lead to leukemias). Therefore, it is often difficult to predict whether a particular cancer will respond to a particular chemotherapeutic agent (Cancer Medicine, 5th edition, Bast et al., BC Decker Inc., Hamllton, Ontario).

Bruised gillomas cause more than 15,000 cancer deaths in the United States each year. These brain tumors are among the most difficult human cancers to treat. Even with extensive surgery, radiation therapy, and chemotherapy, survival remains poor. The most commonly used chemotherapeutic drug for treating patients with glloma is Temodar (Temozolamide). Even with the best current therapy available, the probability that a glloblastoma patient will survive at least two years is 9%. Cerebral edema is also a serious problem for these patients with brain cancer and they often require treatment with corticosteroids to reduce the edema but are then subjected to the common spheroidal side effects of immunosuppression, hypertension, and steroldependence. . A major challenge in developing new therapies for the treatment of gillomas and brain metastases is that very few small molecule anti-tumor drugs are able to penetrate the brain well enough to provide therapeutically effective drug levels. Consequently, the development of more effective drugs to treat brain cancer and brain metastases is a great unmet medical need. The present invention addresses these needs.

In accordance with the foregoing, there is a need for new compositions and methods to treat and prevent the recurrence of proliferation disorders, including cancer. The present invention addresses these needs. WO 2006/071960 describes compounds of formula I and salts, solvates, hydrates or prodrugs thereof:

Formula I

Summary of the Invention

The Invention provides a pharmaceutical composition including a compound and a compound for use in a certain dosage as defined in the appended claims. Also described, but not claimed, is a pharmaceutical composition that includes a compound according to formula IB:

xa-Xa

Xe x> (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein the compound is present in an amount of from 50 mg to 500 mg in the composition and wherein:

ES 2 645 367 T3

T is a link;

XY is CY, N, or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5, or Ce), C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl-aryl (C1, C2 , C3, C4, C5, or Ce) Lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Rc, Rd, Re, R4, R5, and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4 alkoxy, C5, or Ce, Ο-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C2, C3, C4, C5, or C alkyl6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alk (C1, C2, C3, C4, C5, or Ce) Lower,

VHO, 0 w

where W is H, or C1, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4, C5 alkyl, or Ce;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-L , NH-(C1, C2, C3, C4, C5, or Ce) lower alkyl-M, or O-aryl-Q, further wherein the Lower alkyl is linear or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, Ci, C2, C3, C4, C5 alkoxy, Lower Ce, tetrazole, or

L is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

M is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

I heard

ES 2 645 367 T3

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR-ig, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, lower Ce, tetrazole, or

H

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R20 taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi) nC (O) -NR2(CHR3)m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are independently H or C1, C alkyl2, C3, C4, C5, or Ce; y and n are independently 0, 1, or 2.

Preferably, Z is

n'- (Chrjl,

Rl1

Y

Ri ~ <CHRu¡h in which R7, R8, Rg, R10, and R11 are independently hydrogen, hydroxyl, halogen, P, C1, C alkyl2, C3, C4, C5, or C8, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, COOH, COO-alkyl (C-ι, C2, C3, C4, C5, or Οθ) lower, SO2H, S02-alkyl (C-ι, C2, C3, C4, C5, or Οθ) lower, /

V — M where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce;

P is SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR-ig, NR20R21, v4

ES 2 645 367 T3 tetrazole, O-alkyl (Ci, C2, C3, C4, C5, or Ce) lower-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) lower-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) lower-M, or O-aryl-Q, further wherein alkyl (C1, C2, C3, C4, C5, or Ce) Lower straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, Ci alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

L is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

More preferably, Z is (CHRjn—(

as defined above. Preferably Xf is CR4, Xg is CR5, and Xh is CR6. Preferably, R4, R5, and F? 6 are each H. Preferably, m and n are each 1 and R2 and R3 are each H.

Preferably, the compound is selected from

ES 2 645 367 T3

More preferably, the compound is

The pharmaceutical composition can be formulated for oral, intravenous, intramuscular, or subcutaneous administration. Preferably, the pharmaceutical composition is formulated for oral administration.

The compound may be present in the pharmaceutical composition in an amount from about 100 mg to about 400 mg. More preferably, the compound is present in an amount from about 200 mg to about 300 mg. More preferably, the compound is present in an amount of about 250 mg or 250 mg.

The pharmaceutical composition may include a pharmaceutically acceptable excipient or carrier.

Also described is a method of treating a cell proliferative disorder that includes administering to a subject in need thereof, a therapeutically effective amount of a compound according to formula IB:

Xb.

xy (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein:

T is a link;

XY is CY, N, or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5, or Ce), C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl-aryl (C1, C2 , C3, C4, C5, or Ce) Lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

ES 2 645 367 T3

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Re, Rd, Re, R4, Rs, and Re are independently hydrogen, hydroxyl, halogen, P, Ci alkyl, C2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) Lower,

N— W, VN /

Or V-

-w where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR2OR21,

tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferior-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) lower-M, or O-aryl, further wherein the Lower alkyl is linear or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

<td>L is aryl, heteroaryl, glucoside, C1, C alkoxy2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Οβ Lower, Tetrazole, 0</td><td>PO3H2,</td><td>oppos3h2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>M is aryl, heteroaryl, glucoside, C1 alkoxy, C2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Οβ Lower, Tetrazole, 0</td><td>po3h2,</td><td>oppos3h2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>Q is aryl, heteroaryl,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H,</td><td>po3h2,</td><td>oppos3h2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

glucoside, C1, C alkoxy2, C3, C4, C5, Lower Ce, tetrazole, or

H

R19, R2o and R2i are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R20 taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi)n-C (O) -NR2(CHR3) m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are Independently H or C1, C alkyl2, C3, C4, C5, or Ce; ynym are Independently 0, 1, or 2.

wherein the therapeutically effective amount is between about 50 mg and about 500 mg and wherein the compound is administered once over a 24 hour period.

ES 2 645 367 T3

Also described is a method of preventing the recurrence of a cell proliferative disorder in a subject previously diagnosed with a cell proliferative disorder which includes administering to the subject a therapeutically effective amount of a compound according to formula IB:

W-Xc Xe— Xy (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein:

T is a link;

XY is CY, N, or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5, or Ce), C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl-aryl (C1, C2 , C3, C4, C5, or Ce) Lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Rc, Rd, Re, R4, Rs, and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4 alkoxy, C5, or Ce, Ο-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C2, C3, C4, C5, or C alkyl6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alk (C1, C2, C3, C4, C5, or Ce) Lower,

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) inferior-M, or O-aryl-Q, further wherein the Lower alkyl is straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1, C2, C alkoxy3, C4, C5, Lower Ce, tetrazole, or

H

ES 2 645 367 T3

M is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR-ig, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, C3 lower, tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, C3 lower, tetrazole, or

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R2or taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi) nC (O) -NR2(CHR3)m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are Independently H or C1, C alkyl2, C3, C4, C5, or C3; ynym are Independently 0, 1, or 2.

The therapeutically effective amount can be between about 50 mg and about 500 mg. Preferably, the therapeutically effective amount can be between about 100 mg and about 400 mg. More preferably, the therapeutically effective amount is between about 200 mg and about 300 mg. More preferably, the therapeutically effective amount is about 250mg or 250mg.

Preferably the compound is

F or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The treatment, or the above treatment, can produce immune memory or produce memory B cells and / or memory T cells in the subject. Treatment may include a reduction in tumor size or a reduction in invasion of metastatic cancer cells.

The subject may have been previously treated for the proliferation disorder. The subject may have been in complete or partial remission after treatment for proliferation disorder. Preferably, the subject was pretreated with a compound of formula IB.

The subject can be a mammal. Preferably the subject is a human.

The cell proliferative disorder can be a cancer, a hematological or malignant tumor, or a solid tumor (or tumors). Preferably, the cancer is brain cancer. Preferably, the solid tumor (or tumors) is a glioblastoma, oligodendroglioma, astrocytoma, or medulloblastoma. Most preferably, the solid tumor (or tumors) is a glioblastoma.

Treatment may further include administration of a second antiproliferative agent and / or radiation therapy.

The compound can be administered four times, twice, or once a day (for a 24-hour period).

ES 2 645 367 T3

Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, appropriate methods and materials are described below. The references cited in this document are not admitted as prior techniques to the claimed invention. In case of conflict, this specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

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

Brief description of the drawings

Figure 1 is a graph showing the survival of C57BL / 6 mice with intracranial GL261 gliomas over a period of 40 days.

Figures 2A-F are a series of graphs showing the weight gain in each of the C57BL / 6 mice in the different treatment groups of the GL261 glioma intracranial survival study. Panel (A) shows the weight on the carrier. Panel (B) shows the group treated with Temodar. Panel (C) shows the group treated with compound 134 (2.5 mg / kg). Panel (D) shows the group treated with compound 76 (15 mg / kg). Panel (E) shows the group treated with compound 134 (5 mg / kg). Panel (F) shows the group treated with compound 76 (30 mg / kg).

Figure 3 is a graph showing the average weights over a 40-day period for each of the treatment groups in the GL261 intracranial glioma survival study.

Figures 4A-C are a series of graphs showing survival of C57BL6 mice with intracerebral GL261 glioma implants. Mice received intracerebral implants of 1x10 GL261 cells5 by stereotactic injection at 2 mm lateral, 1 mm anterior to bregma at a depth of 3 mm. After 4 days, the mice started the indicated regimen of oral compound 76. Panel (A) shows oral compound 76 (30 mg / kg sid) started 4 days after tumor cell implantation and was repeated twice daily . Compound 76 prolonged the median survival from 21 to 29 days (range). n = 10. Panel (B) shows oral compound 76 (30 mg / kg sid) started 4 days after tumor cell implantation and was repeated once a day. Compound 76 prolonged median survival> 100 days (interval), and up to 60% of drug-treated mice experienced complete tumor regression, n = 10. Long-term survivors were confirmed tumor-free by MRI high-field in Figure 6. Panel (C) shows oral compound 76 (30 mg / kg sid) started 4 days after tumor cell implantation in B6.CB17 -Prkdc micescid/ SzJ (C57BL / 6-SCID verion) and were repeated once a day. Compound 76 prolonged the median survival to 21-29 days (interval), however, there were no long-term survivors, n = 10. See high-field MRI in Figure 6

Figure 5 is a graph of the redesign of surviving mice treated long-term with compound 76 of Figure 4B at 1x106 sc GL261 glioma cells. Litter and age matched controls were implanted. Long-term surviving C57BL / 6 mice subsequently rejected the second GL261 tumor challenge.

Figures 6A-B are representative MRI images (T2-weighted spin echo) of mice treated with implanted compound 76 GL261 (30 mg / kg sid). Panel (A) shows arrows in mice 1-4 indicating tumor boundaries in C57BL / 6 carrier mice; arrows in mice 5-8 indicate the tumor cell injection site in C57BL / 6 mice treated with compound 76, no residual tumor is observed. Panel (B) shows arrows on tumor forming d25 and tumor d32 indicates reappearance of tumor in B6.CB17 Prkdc micescid/ SzJ treated with compound 76.

Figures 7A-D are a series of images showing the histopathology of residual GL261 glioma from mice treated with compound 76 showing large areas of necrosis and lymphocytic infiltration. Panel (A) shows the control at 20x. Panel (B) shows the control at 40x. Panel (C) shows treated with compound 76 at 20x. Panel (D) shows treated with compound 76 treated at 40x.

Detailed description of the invention

The present invention provides pharmaceutical compositions containing compounds of the invention and various uses of the disclosed compounds.

1. Pharmaceutical compositions

The disclosure provides a pharmaceutical composition comprising a compound according to formula IB, I, IA, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII.

ES 2 645 367 T3

The disclosure provides a pharmaceutical composition comprising a compound according to formula IB:

XíJ-xc xe-xy (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein the compound is present in an amount of from 50 mg to 500 mg in the composition and wherein:

T is a link;

XY is CY, N, or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5, or Ce), C1, C2, C3, C4, C5 alkoxy, or Ce, Ο-alkyl-aryl (C1, C2 , C3, C4, C5, or Ce) Lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Re, Rd, Re, R4, Rs, and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4 alkoxy, C5, or Ce, Ο-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, Ci, C2, C3, C4, C5, or C alkyl6-OH, COOH, COO-alkyl (Ci, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alk (C1, C2, C3, C4, C5, or Ce) Lower, v

N-W, VN n-vy, where W is H, or C1, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4, C5 alkyl, or Ce; P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

L is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, Ci alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

ES 2 645 367 T3

M is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR-ig, NR19R20, SO2R2i, glucoside, C1, C alkoxy2, C3, C4, C5, C3 Inferior, tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, C3 Inferior, tetrazole, or

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R2or taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi) nC (O) -NR2(CHR3)m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are Independently H or C1, C2, C3, C4, C5, or C3; ynym are Independently 0, 1, or 2.

The disclosure provides the pharmaceutical composition comprising a compound according to formula IB, wherein Z is z [CHRj ^., R' TO

R10- ^ Y ^ Rn

R »

Neither

R11

λ (CHRiK

Í zN(GHR3^

N ^ N

ES 2 645 367 T3 where

Ri, R2, and R3 are independently H or C1, C2, C3, C4, C5 alkyl, or Ce;

n and m are, Regardless 0, 1, or 2;

R7, Re, R9, R10, and R11 are, independently, hydrogen, hydroxyl, halogen, P, C1, C2, C3, C4, C5, or Ce, C1, C2, C3, C4, C5, or Ce alkoxy, Lower O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce), O-benzyl, C1, C2, C3, C4, C5, or C alkyl6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alk (C1, C2, C3, C4, C5, or Ce) Lower, /

u you

V —- do \ / / you.

0. v — nn — yv where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce; P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

N you

N tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) inferior-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-M, or O-arlI-Q, furthermore wherein alkyl (C1, C2, C3, C4, C5, or Ce) Lower straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

<td>L is aryl, heteroaryl, glucoside, C1, C alkoxy2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Lower Ce, tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>M is aryl, heteroaryl, glucoside, C1 alkoxy, C2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Lower Ce, tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>Q is aryl, heteroaryl, glucoside, C1 alkoxy, C2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Lower Ce, tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

R19, R20 and R21 are independently C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R20 taken together with the attached nitrogen atom form a five-membered ring; Y

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2-, or - OCH2CH2CH2-. The disclosure provides the pharmaceutical composition, wherein m is 1.

ES 2 645 367 T3

The disclosure provides the pharmaceutical composition, wherein n is 1.

The disclosure provides the pharmaceutical composition according to formula IB, wherein at least one of Xto, Xb, Xc, Xd, Xe, Xf, Xg, Xh, and Xy is N.

The disclosure provides a pharmaceutical composition, wherein Xto is N. The disclosure provides the pharmaceutical composition, where Xb is N. The disclosure provides the pharmaceutical composition, where Xc is N. The disclosure provides the pharmaceutical composition, where Xd is N. The disclosure provides the pharmaceutical composition, where Xand is N. The disclosure provides the pharmaceutical composition, where Xf is N. The disclosure provides the pharmaceutical composition, where Xg is N. The disclosure provides the pharmaceutical composition, where Xh is N.

The disclosure provides the pharmaceutical composition according to formula IB, wherein Xto and XY are each N. The disclosure provides the pharmaceutical composition, wherein Xand and Xf are each N. The disclosure provides the pharmaceutical composition, wherein Xc and Xg are each N. The disclosure provides the pharmaceutical composition, wherein Xd and Xh are each N.

The disclosure provides the pharmaceutical composition, wherein each of Xand, Xf, Xc and Xg is N.

The disclosure provides the pharmaceutical composition wherein, Rto, Rb, Rc, Rd, Re, R4, Rs, and R6 are not P.

The disclosure provides a pharmaceutical composition, wherein Xz is CZ and Z is

where R7, Rs, Rg, R10, and R11 are selected from hydrogen, hydroxyl, halogen, C1, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl- Lower aryl (C1, C2, C3, C4, C5, or Ce), O-benzyl, C1, C2, C3, C4, C5 alkyl, or

Ce-ΟΗ, C1, C2, C3, C4, C5 alkyl, or Ce-O-C1, C2, C3, C4, C5, or C6 alkyl,

where W is H, or C1, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4, C5, or C6 alkyl aryl.

The disclosure provides a pharmaceutical composition, wherein Xf is CR4, Xg is CR5, and Xh is CR6.

The disclosure provides a pharmaceutical composition, wherein R4, Rs, and R6 are each H.

The disclosure provides a pharmaceutical composition, wherein at least one of R7, Rs, Rg, R10 and R11 is halogen, C1, C2, C3, C4, C5 alkyl, or Ce, or O-benzyl.

The disclosure provides the pharmaceutical composition, wherein m and n are each 1 and R2 and R3 are each H.

The disclosure provides the pharmaceutical composition, wherein Rb is not hydrogen.

The disclosure provides the pharmaceutical composition, wherein the compound is selected from

ES 2 645 367 T3

The disclosure provides the pharmaceutical composition, wherein the compound is selected from

The invention provides the pharmaceutical composition, wherein the compound is

F

[Compound 76).

The disclosure provides the pharmaceutical composition, wherein the compound is not jO

[Compound 134).

ES 2 645 367 T3

The pharmaceutical composition is formulated for oral, intravenous, intramuscular, or subcutaneous administration. Preferably, the pharmaceutical composition is formulated for oral administration. The pharmaceutical composition can include at least one pharmaceutically acceptable excipient or carrier. The formulation can be a tablet or a capsule.

The compound may be present in an amount from about 50 mg to about 500 mg (or any integer within that range (eg, 50, 51, 52, ...)). Preferably, the compound of the invention may be present in an amount from about 100 mg to about 400 mg. Preferably, the compound of the invention may be present in an amount from about 200 mg to about 300 mg. More preferably, the compound of the invention may be present in an amount of about 250 mg. More preferably, the compound of the invention may be present in an amount 250 mg. The compound may be present in an amount of 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg or 250mg. The compound can be present in an amount of 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, or 500mg.

The compound is administered up to four times a day (for a 24 hour period). The compound is administered twice a day (for a period of 24 hours). In a preferred embodiment, the compound of the invention is administered once a day (for a period of 24 hours).

Preferably the compound is

F

The disclosure provides a pharmaceutical composition comprising a compound according to formula 1:

XFz = Xa // '

Xe — Xy

Xz (Formula I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein the compound is present in an amount of from 50 mg to 500 mg in the composition and wherein:

T is a bond, CR12R13, C (O), O, S, S (O), S (O) 2, NR14, C (RisRi6) C (Ri7Ri8), CH2O, or OCH2;

XY is CZ, CY, N, or NO;

Xz is CZ, CY, N, or NO; at least one of XY and Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (C1, C2, C3, C4, C5, or Ce), C1, C2, C3, C4 alkoxy,

C5, or Ce, O-lower alkyl (C1, C2, C3, C4, C5, or Ce), and O-benzyl;

<td>Xe</td><td>it is</td><td>CRand,</td><td>N, 0 NO;</td>

XF is CR4, Nerd; Xg is CR5, Nerd;

ES 2 645 367 T3

Xh is CRe, N, or NO;

Rto, Rb, Rc, Rd, Re, R4, R5, and Re are independently hydrogen, hydroxyl, halogen, P, Ci alkyl, C2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, Ο-alkyl-aryl (C1, C2, C3, C4, C5, or C @) Lower, O-benzyl, C1 alkyl, C2, C3, C4, C5, or C6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alk (C1, C2, C3, C4, C5, or Ce) Lower,

VHO, 0 w

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Οβ; P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21, tetrazole, Ο-alkyl (C1, C2, C3, C4, C5, or Ce) inferior-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or C @) inferlor-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) lower-M, or O-aryl-Q, further wherein the Lower alkyl is straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Οβ, tetrazole, or

<td>L is aryl, heteroaryl, glucoside, C1, C alkoxy2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Lower Οβ, tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>M is aryl, heteroaryl, glucoside, C1 alkoxy, C2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Lower Οβ, tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>Q is aryl, heteroaryl,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H,</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

glucoside, C1, C alkoxy2, C3, C4, C5, Lower Οβ, tetrazole, or

H

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R20 taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

R12, R13, R14, R15, Laugh, R17, and Laugh, are, independently, H or C1, C alkyl2, C3, C4, C5, or Οβ;

The disclosure provides the pharmaceutical composition of formula I, wherein m is 1.

ES 2 645 367 T3

The disclosure provides the pharmaceutical composition of formula I, wherein n is 1.

The disclosure provides the pharmaceutical composition of formula I, wherein Rb is not hydrogen.

The disclosure provides the pharmaceutical composition, wherein Xto is N. The disclosure provides the pharmaceutical composition, where Xb is N. The disclosure provides the pharmaceutical composition, where Xc is N. The disclosure provides the pharmaceutical composition, where Xd is N. The disclosure provides the pharmaceutical composition, where Xand is N. The disclosure provides the pharmaceutical composition, where Xf is N. The disclosure provides the pharmaceutical composition, where Xg is N. The disclosure provides the pharmaceutical composition, where Xh is N.

The disclosure provides the pharmaceutical composition, wherein Xto and XY are each N. Disclosure 10 provides the pharmaceutical composition, wherein Xand and Xf are each N. The disclosure provides the pharmaceutical composition, wherein Xc and Xg are each N. The disclosure provides the pharmaceutical composition, wherein Xd and Xh are each N.

The disclosure provides the pharmaceutical composition, wherein each of Xand, Xf, Xc and Xg is N.

The disclosure provides the pharmaceutical composition wherein, Rto, Rb, Rc, Rd, Re, R4, Rs, and R6 are not P.

The disclosure provides the pharmaceutical composition, wherein the compound is selected from

The disclosure provides the pharmaceutical composition, wherein the compound is selected from

The invention provides the pharmaceutical composition, wherein the compound is

ES 2 645 367 T3

F

[Compound 76).

The compound of formula I may be present in an amount of from about 50 mg to about 500 mg (or any integer within that range (eg, 50, 51, 52, ...)). Preferably, the compound may be present in an amount from about 100 mg to about 400 mg. Preferably, the compound may be present in an amount from about 200 mg to about 300 mg. More preferably, the compound may be present in an amount of about 250 mg. More preferably, the compound may be present in an amount 250 mg. The compound can be present in an amount of 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg or 250mg. The compound can be present in an amount of 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, or 500mg.

Compounds are administered up to four times a day (for a 24-hour period). Compounds are administered twice daily (for a 24 hour period). In a preferred embodiment, the compounds of the invention are administered once a day (for a period of 24 hours).

Preferably the compound is

The disclosure provides a pharmaceutical composition comprising a compound according to formula IA:

zXa //

Xe— Xy

Xf =

Xz (Formula IA), in which: T is absent (that is, the rings are connected by a bond), CR12R13, C (O), O, S, S (O), S (O) 2, NR14, C (Ri5Rie) C (Ri7Ri8), CH2O, or OCH2;

XY is CZ, CY, N, or NO;

Xz is CZ, CY, N, or NO;

at least one of XY and Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (C1, C2, C3, C4, C5, or Ce), C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl-aryl (C1, C2 , C3, C4, C5, or C &) lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

ES 2 645 367 T3

Xf is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Re, Rd, Re, R4, Rs, and Re are independently hydrogen, hydroxyl, halogen, P, Ci, C2, C3, C alkyl4, C5, or Ce, C1, C2, C3, C alkoxy4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) lower, O-benzyl, C1, C2, C3, C alkyl4, C5, or C6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) lower,

where W is H, or C1, C2, C3, C alkyl4, C5, or Ce, C1, C2, C3, C alkyl-aryl4, C5, or Οβ; P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

Ntetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) lower-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) lower-L, NH-(C1, C2, C3, C) alkyl4, C5, or Ce) lower-M, or O-aryl-Q, furthermore wherein the alkyl (C1, C2, C3, C4, C5, or Ce) lower is straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1, C2, C3, C alkoxy4, C5, Lower Οβ, tetrazole, or

<td>L is aryl, heteroaryl, glucoside, C1, C alkoxy2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Οβ Lower, Tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>M is aryl, heteroaryl, glucoside, C1, C alkoxy2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Οβ Lower, Tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

<td>Q is aryl, heteroaryl, glucoside, C1 alkoxy, C2,</td><td>OH, C (O) NH2, COOH, SO3H, OSO3H, C3, C4, C5, Οβ Lower, Tetrazole, 0</td><td>PO3H2,</td><td>OPO3H2,</td><td>nh2,</td><td>NHR19,</td><td>NR19R20,</td><td>SO2R2 '</td>

H

R19, R20 and R21 are C1, C2, C3, C alkyl4, C5, or Οβ or R-ig and R20 taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

R12, R13, R14, R15, Laugh, R17, and Laugh, are independently H or C1, C alkyl2, C3, C4, C5, or Οβ;

Z is (CHRi)n-C (O) -NR2(CHR3) m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are independently H or C1, C alkyl2, C3, C4, C5, or Οβ; Y

ES 2 645 367 T3 n and m are independently 0, 1, or 2.

provided that at least one of Rto, Rb, Rc, Rd, Re, R4, Rs, and R6 is P.

The disclosure provides a pharmaceutical composition comprising a compound according to formula I, IA or IB, having a structure according to one of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII:

Formula III

ES 2 645 367 T3

HS lifl

or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, where: Rb, R4, Rs, Rs, and R10 are independently hydrogen, hydroxyl, halogen, P, C1, C alkyl2, C3, ¿4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or Ce-ΟΗ, COOH, COO5 (C1, C2, C3, C4, C5, or Ce) lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) lower,

ES 2 645 367 T3 v

VM (3, O w

where W is H, or Ci, C2, C3, C alkyl4, C5, or Ce, C1, C2, C3, C alkyl4, C5, or Ce; P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21, tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferior-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-M, u Ο-arll-Q, in addition where the alkyl (C1, C2, C3, C4Lower, C5, or C @) is straight or branched alkyl;

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Οβ, tetrazole, or

H

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Ce or R19 and R20 taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII are within the scope of Formula I, IA or IB. The disclosure includes a solvate of a compound according to formula I, IA, or IB.

The disclosure also includes a hydrate of a compound according to formula I, IA, or IB.

The disclosure also includes an acid addition salt of a compound according to formula I, IA, or IB. For example, a hydrochloride salt, for example, dihydrochloride.

The disclosure includes a meslato salt of a compound according to formula I, IA, or IB.

The disclosure also includes a prodrug of a compound according to formula I, IA, or IB.

ES 2 645 367 T3

The disclosure also includes a pharmaceutically acceptable salt of a compound of formula I, IA, or IB.

The disclosure also includes a composition of a compound according to formula I, IA, or IB and at least one pharmaceutically acceptable excipient.

For example, in the compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, Rs is hydrogen, F, Cl, Br, or I. For example, Rs is F. In certain compounds, Rs is H.

In certain compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, Rb is Ci, C alkoxy2, C3, C4, C5, or C6. For example, Rb is methoxy or ethoxy.

In certain compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, Rb is hydrogen, Cl, Br, or I. In other compounds, in the compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, Rb is

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce, and V is a bond, -CH2-, CH2CH2 -, - CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-.

In certain compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R4 is hydrogen, C1, C alkoxy2, C3, C4, C5, or Ce, F, Cl, Br, or I. In other compounds, in the compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R4 is, v — N

N— W, where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce; and V is a bond, -CH2-, CH2CH2 -, - CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-.

In certain compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R5 is hydrogen, C1, C alkoxy2, C3, C4, C5, or Ce, F, Cl, Br, or I. In other compounds, in the compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R5 it is

/ where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce; and V is a bond, -CH2-, CH2CH2 -, - CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-.

In certain compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R10 is hydrogen, C1, C alkoxy2, C3, C4, C5, or Ce, F, Cl, Br, or I. For example, R10 is methoxy, ethoxy, or ¡sobutoxy.

In other compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, R10 is, v — N

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce; and V is a bond, -CH2-, CH2CH2 -, - CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-.

For example, in the compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, W is hydrogen, or C1 alkyl,

C2, C3, C4, C5, or Ce.

Certain compounds of the disclosure include compounds according to formula II.

The disclosure refers to a solvate of a compound according to one of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII. The disclosure also refers to a hydrate of a compound according to one of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII.

The disclosure also refers to an acid addition salt of a compound according to one of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII. For example, a hydrochloride salt.

ES 2 645 367 T3

Furthermore, the disclosure refers to a prodrug of a compound according to one of the formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII.

The disclosure also refers to a pharmaceutically acceptable salt of a compound of one of the formulas II,

III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII.

The disclosure includes compositions comprising a compound according to one of formulas I, II, III,

IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII and at least one pharmaceutically acceptable excipient.

In one embodiment of the disclosure in a compound of formula I, at least one of Xto, Xb, Xc, Xd, Xand, Xf, Xg, Xh, Xy and Xz is N. In another embodiment, at least two of Xto, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xy, and Xz are N. In another embodiment, at least one of Xa and Xy is N. For example, both Xto and XY are N. In another embodiment, Xto, Xb, Xc, Xd, and Xe are not each N or NO. In another embodiment, Xc, Xd, and Xand they are not each N or NO.

In one embodiment, Xto is N. In one embodiment, Xb is N. In one embodiment, Xc is N. In one embodiment, Xd is N. In one embodiment, Xand is N. In one embodiment, Xf is N. In one embodiment, Xg is N. In one embodiment, Xh is N.

In one embodiment, Xto and XY are each N. In one embodiment, Xand and Xf are each N. In one embodiment, Xc and Xg are each N. In one embodiment, Xd and Xh are each N.

In one embodiment, Xand, Xf, Xc, and Xg are each N.

In one embodiment, a compound of formula I has T as a bond. In another embodiment, Xb is CRb. In another embodiment, Rb is P. For example, in one embodiment, P is Ο-alkyl (Ci, C2, C3, C4, C5, or C3) Inferlor-K. In one embodiment, (C1, C2, C3, C4, C5, or C3) Lower CH2CH2CH2. In one embodiment, (C1, C2, C3Lower, C4, C5, or Ce) is branched alkyl. For example, branched alkyl is

In another embodiment, K, L, M, or Q, if present, is C1, C alkoxy2, C3, C4, C5, or Lower Ce. For example, K is methoxy. In one embodiment, the branched alkyl is and K is methoxy. In another embodiment, K, L, M, or Q, if present, is COOH. For example, in one embodiment, K is COOH. In another embodiment, K, L, M, or Q, if present, is aryl or heteroaryl. For example, the heteroaryl is tetrazole.

In one embodiment, Rb is

In another embodiment, Rb is

In one embodiment, V is -OCH2CH2. In another embodiment, V is a bond. In one embodiment, W is C1, C alkyl2, C3, C4, C5, or Ce. For example, W is methyl or ethyl.

In one embodiment, Xz is CZ, also where Z is

ES 2 645 367 T3

and R7, R8, Rg, Rio, and Ri are selected from hydrogen, hydroxyl, halogen, Ci, C2, C3, C4, C5 alkyl, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, C1, C alkyl2, C3, C4, C5, or Ce-O-C1, C alkyl2, C3, C4, C5, or C6,

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce. In another embodiment, at least one of R7, R3, Rg, R10, and R11 is halogen, C1, C alkoxy2, C3, C4, C5, or Ce, or O-benzyl. In another embodiment, at least one of R3 or R10 is halogen. For example, halogen is fluorine. In another embodiment, at least one of R7 or Rn is C1, C alkoxy2, C3, C4, C5, or U6 or O-benzyl. For example, at least one of R7 or Rn is ethoxy or at least one of R7 or Rn is

O-benzyl. In one embodiment, R1 is H. In one embodiment, n is 1. In one embodiment, R2 is H. In one embodiment, R3 is H. In one embodiment, m is 1. In another embodiment, m and n are each 1 and R2 and R3 are each H.

In one embodiment, R4 and R6 are each H. In another embodiment R5 is selected from halogen and C1, C alkyl2, C3, C4, C5, or Ce. In one embodiment, R5 is halogen. For example, R5 is Cl or F. In another embodiment, R5 is C1, C alkyl2, C3, C4, C5, or Ce. For example, R5 is methyl or ethyl.

In one embodiment, at least one of Xto, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xy and Xz is N. In another embodiment, Xz is CZ, also where Z is

and R7, R3, Rg, R10, and R11 are selected from hydrogen, hydroxyl, halogen, C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, C1, C alkyl2, C3, C4, C5, or Ce-O-C1, C alkyl2, C3, C4, C5, or Ce,

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl aryl2, C3, C4, C5, or Ce. In one embodiment, at least one of R7, R3, Rg, R10, and R1 is halogen, C1, C alkoxy2, C3, C4, C5, or Ce, or O-benzyl. In another embodiment, m and n are each 1 and R2and R3 are each H. In one embodiment, R4 and R6 are each H.

Certain compounds of the disclosure include compounds according to formula II.

The compounds of the disclosure include those listed in Table 1:

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

<td> 20</td><td></td><td></td><td colspan="2">7xrFor. -J_IM cr 'oh</td><td colspan="2"></td>

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

<td> 41</td><td></td><td>Hj¿x x. «^^orXLx</td>

ES 2 645 367 T3

ES 2 645 367 T3

<td> 50</td><td>0 -X Χγ'ΧγίχΧΧ xxx or /\Oh</td>

ES 2 645 367 T3

<td> 59</td><td></td><td>CHtoÓ Á xxrr 'Ύ</td>

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

Other compounds are listed in Table 2.

ES 2 645 367 T3

Table 2

ES 2 645 367 T3

<td>Ν \ ίΑ%ΛχΛγ% / F fifteen"</td><td>Z ^ Vil Tz 159</td>

ES 2 645 367 T3

ES 2 645 367 T3

ES 2 645 367 T3

<td>ΆΛ ΰ 206</td><td>TIiC.ñA ΝΐΛγΑ 0 «Xy</td>

<td>N ν--Μγ ^ 208</td><td>r, ^ Y -f] ¡ÍC.nA N <^ Y> or '^χκΑΛι11 ^N 209</td>

<td>Α ^ 'Ά UAN'x~TOfrA M 222</td><td>r ¡Air ' TO nJAi1 n nA 223</td>

ES 2 645 367 T3

<td>sS '' LF O CL » HjC ^ iT 3 ° G *N 226</td><td>,,, - O ^ 'txG oruGfiV, G>n 227</td>

<td>HjC-N ^ Uy O!G * M © -yNyFHN^ 228</td><td> „σΟ ^ ΌΕ orN ^ 229</td>

<td>HiC.n © 230</td><td> .0^30© or^ CÜ neither</td>

<td>Hj (..ñ ^> OνΛλπνί238</td><td>a- ^ yyHjf:-N © NiJV> o fa239</td>

<td> <rrG, ... 'T n J 244</td><td>/ Λ - / © u ^ n ^ G ^ YG o GGVyV-FÑ 245</td>

ES 2 645 367 T3

The compounds of the disclosure include compounds of formula IA, and pharmaceutically acceptable salts, solvates, hydrates or prodrugs:

Xb,

xs— (Formula IA), in which: T is absent (that is, the rings are connected by a bond), CR12R13, C (O), O, S, S (O), S (O)2, NR14, C (Ri5Rie) C (Ri7Rie), CH2O, or OCH2;

XY is CZ, CY, N, or NO;

Xz is CZ, CY, N, or NO;

at least one of XY and Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, (C1, C2, C3, C4, C5, or Ce) lower, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Rc, Rd, Re, R4, Rs, and Re are independently hydrogen, hydroxyl, halogen, P, Ci alkyl, C2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) lower,

V

N— W, VN where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or Ce;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

ES 2 645 367 T3 tetrazole, Ο-alkyl (Ci, C2, C3, C4, C5, or Ce) inferlor-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-L, NH-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-M, or O-arylQ, in addition where the alkyl (C1, C2, C3 , C4, C5, or Ce) Lower is straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Lower Ce, tetrazole, or

R19, R20 and R21 are independently C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R2or taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

R12, R13, R14, R15, Laugh, R17, and Laugh, are, independently, H or C1, C alkyl2, C3, C4, C5, or Ce; Y

Z is (CHRi) nC (O) -NR2(CHR3) m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are Independently H or C1, C alkyl2, C3, ¿4, C5, or Οθ; ynym are regardless

O, 1, or 2;

provided that at least one of Rto, Rb, Rc, Rd, Re, R4, Rs, and R6 is P.

In one embodiment, only one of Rto, Rb, Rc, Rd, Re, R4, Rs, and R6 is P.

In one embodiment, at least one of Xto, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xy and Xz is N. In another embodiment, at least two of Xto, Xb, Xc, Xd, Xand, Xf, Xg, Xh, Xy and Xz are N. In another embodiment, at least one of Xto and XY is N. For example, both Xto and XY are N. In another embodiment, Xto, Xb, Xc, Xd, Xe, Xf, Xg and Xh are not each N or NO. In another embodiment, Xc, Xd, and Xand they are not each N or NO.

In one embodiment, Xand, Xf, Xc, and Xg are each N.

In one embodiment, T is absent, eg, a bond. In another embodiment, Xb is CRb. In another embodiment, Rb is

P. For example, in one embodiment, P is Ο-alkyl (C1, C2, C3, C4, C5, or Ce) inferlor-K. In one embodiment, (C1, C2, C3, C4, C5, or Ce) Lower is CH2CH2CH2. In one embodiment, (C1, C2, C3Lower, C4, C5, or Ce) is branched alkyl. For example, branched alkyl is

ES 2 645 367 T3

In another embodiment, K, L, M, or Q, if present, is Ci, C alkoxy2, C3, C4, C5, or C3 Lower. For example, K is methoxy. In one embodiment, the branched alkyl is and K is methoxy. In another embodiment, K, L, M, or Q, if present, is COOH. For example, in one embodiment, K is

COOH. In another embodiment, K, L, M, or Q, if present, is aryl or heteroaryl. For example, heteroaryl is tetrazole.

and K is methoxy. In another embodiment, K, L, M, or Q, if present, is COOH. For example, in one embodiment, K is

COOH. In another embodiment, K, L, M, or Q, if present, is aryl or heteroaryl. For example, heteroaryl is tetrazole.

In one embodiment, Rb is

VN O \ /

In another embodiment, Rb is

In one embodiment, Xz is CZ, also where Z is o

and R7, R3, Rg, R10, and R1 are selected from hydrogen, hydroxyl, halogen, C1 alkyl, C2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, C1, C alkyl2, C3, C4, C5, or Ce-O-C1, C alkyl2, C3, C4, C5, or Ce,

where W is H, or C1, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl aryl2, C3, C4, C5, or Ce. In another embodiment, at least one of R7, R3, Rg, R10, and R11 is halogen, C1, C alkoxy2, C3, C4, C5, or Ce, or O-benzyl. In another embodiment, at least one of R3 or R10 is halogen. For example, halogen is fluorine. In another embodiment, at least one of R7 or Rn is Ci, C alkoxy2, C3, C4, C5, or C6 or O-benzyl. For example, at least one of R7 or R1 is ethoxy or at least one of R7or Rn is O57

ES 2 645 367 T3 benzyl. In one embodiment, Ri is H. In one embodiment, n is 1. In one embodiment, R2 is H. In one embodiment, R3 is H. In one embodiment, m is 1. In another embodiment, m and n are each 1 and R2 and R3 are each H.

In one embodiment, R4 and R6 are each H. In another embodiment R5 is selected from halogen and C1, C alkyl2, C3, C4, C5, or Οβ. In one embodiment, R5 is halogen. For example, R5 is Cl or F. In another embodiment, R5 is C1, C alkyl2,

C3, C4, C5, or Οβ. For example, R5 is methyl or ethyl.

In another embodiment, Rb is not hydrogen.

The disclosure includes a solvate of a compound according to formula *. The disclosure includes a compound hydrate according to formula *. The disclosure includes an acid addition salt of a compound according to formula *. For example, a hydrochloride salt. In another embodiment, the invention includes a pharmaceutically acceptable salt. The disclosure includes a composition comprising a compound of formula * and at least one pharmaceutically acceptable excipient.

Certain compounds of the disclosure include compounds selected from Table 3.

Table 3.

<td>Composite #</td><td>Structure</td>

ES 2 645 367 T3

<td> 256</td><td>í'n'TOtoiiuqpj-F</td>

<td> 257</td><td>H faith.</td>

<td> 262</td><td>Fefefe „ 'ιΑΧρXfF</td>

<td> 264</td><td>crxcl „</td>

ES 2 645 367 T3

With respect to the chemical compounds described in the present invention, the terms used herein, where applicable, are described in US Patent No. 7,300,931 and PCT Publication No. WO 2008/144045. The methods of preparing the compounds described herein are described in US Patent No: 7,300,931 and PCT Publication No. WO 2008/144045 A1.

For example, compound 134 and its salts can be prepared in the following manner.

The synthesis of 4- (2- (4- (6-fluoroplr¡d¡n-3-¡l) phenox¡) etll) morpholin is shown in the following scheme:

ES 2 645 367 T3

Rd [PPh3h

F

4- (2- (4- (6-fluoropır¡d¡n-3-¡l) phenox¡) eth¡l) morpholin (5) was synthesized in 3 steps. Intermediate 2 was synthesized using an ether coupling reaction, eg, using Williamson's ether synthesis. Ether formation between 4- (2-chloroethylmorpholine (1) and 4-bromophenol was carried out in the presence of potassium carbonate and DMF to provide 4- (2- (4-bromophenoxy) ethyl) morpholine (2). Strictly dry conditions were not essential for this reaction and a basic sodium hydroxide wash was used to remove the remaining 4-bromophenol. In another aspect of the invention, intermediate 2 is synthesized using any ether-forming reaction. Intermediate 2 is synthesized from compound 1 that contains any leaving groups. For example, the skilled chemist would start with compounds of the general formula:

wherein the leaving group LG includes, but is not limited to, halogen, tosylate, mesylate, triflate, etc.

Compound 5 was formed using a Suzuki reaction. The formation of the aryl borate, 6-fluoropyridin-3-yl3-boronic acid (4), was carried out by forming the aryl anion using n-BuLi followed by cooling in situ with triisopropylborate (Li, et al., J. Org. Chem. 2002, 67, 5394-5397). The resulting 6-fluoropyridin-3-yl-3-boronic acid (4) was coupled to 4- (2- (4-bromophenoxy) ethyl) morpholine (2) in a solution of DME and aqueous sodium carbonate using tetrakis (triphenylphosphine ) palladium to provide 4- (2- (4- (6-fluoropyridin-3-yl) phenoxy) ethyl) morpholine (5), which was purified using silica gel chromatography. The skilled chemist would know that another transition metal coupling reaction is used to prepare compound 5.

The synthesis of 2- (5- (4- (2-morpholinoethoxy) phenyl) pyridin-2-yl) - / \ / - benzylacetamide dihydrochloride is shown below:

ES 2 645 367 T3

NF

McCN

NaHMDS

N

40% H2SOj MeOH

two. HCl solution

N

CO2Mt

2- (5- (4- (2-morphollnoethoxy) phenyl) p¡r¡dln-2-¡l) - / \ / - benzyl acetamide (compound 134-HCl) was synthesized in four linear stages. The fluorine of 4- (2- (4- (6-fluoropyr¡d¡n-3-¡l) phenoxy) etll) morpholin (5) was displaced by the acetonitrile anion formed using commercially available NaHMDS. Acetonite was slowly added to a cooled mixture of compound 5 and the base to form 2- (5- (4- (2-morpholnoethoxl) phenyl) p¡r¡d¡n-2-¡l) aceton¡ trio (6). In another aspect of the disclosure, Intermediate 5 may have a leaving group other than fluorine. Thus, the compounds of the general formula:

LG would be pursued where LG includes other leaving groups known to the skilled chemist.

2- (5- (4- (2-morpholnoethoxy) phenyl) p¡r¡d¡n-2-ll) acetonitric acid-catalyzed methanol (6) was carried out using a mixture of concentrated sulfuric acid and fuming sulfuric acid. The use of fuming sulfuric acid removed residual water from the reaction mixture and reduced the amount of carboxylic acid by-product formed. The reaction mixture was inactivated by adding the reaction mixture to a solution of saturated sodium bicarbonate and dichloromethane while keeping the temperature below 20 ° C. Any carboxylic acid contaminant was easily removed with the aqueous treatment. In another aspect of the disclosure, other acid catalyzed conditions are used by one of ordinary skill in the art for the alcohol content of compound 6 to produce compound 7.

The resulting methyl 2- (5- (4- (2-morpholnoethoxy) phenyl) p¡r¡d¡n-2-¡l) acetate (7) and benzylamine were coupled in anlsol at high temperature to provide 2- (5- (4- (2-morphollnoethoxy) phenyl) p¡r¡dln-2-¡l) - / \ / - benzyl acetamide (compound 134). An HCl solution formed by the addition of acetyl chloride to absolute ethanol was added to compound 134 to form the bls-HCl salt, 2- (5- (4- (2-morpholnoethoxy) phenl) p ¡R¡d¡n-2-¡l) - / \ / - benc¡lacetam¡da, (KX2-d¡HCI).

The synthesis of the meslato salt of compound 134 (compound 134 MSA) is represented in the following scheme:

ES 2 645 367 T3

2- (5- (4- (2-morphollnoethox¡) phen¡l) p¡r¡dln-2-¡l) - / \ / - benzyl acetamide (compound 134-MSA) mesylate was synthesized in four linear steps from compound 5. The first 3 steps were carried out in a similar way to the procedure described above for compound 134MSA to provide the 2- (5- (4- (2-morfollnoethoxy) phenyl) pi r¡d¡n-2-¡l) methyl acetate (compound 134). Compound 134 was converted to the methanesulfonate salt by treatment with methanesulfonic acid (MSA) in acetone at 50 ° C to provide the mesylate of 2- (5- (4- (2-morphollnoethoxy) phenyl) p¡r Dln-2-l) - / \ / - benzyl acetamide (compound 134-MSA).

In another aspect of the disclosure, Intermediate 7 can be synthesized with a group other than -C (O) OMe. The skilled chemist would look for Intermediate compounds of the general formula:

wherein the R group includes, but is not limited to, hydrogen and alkyl.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where they are soluble in water) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, appropriate carriers include physiological saline, bacterostatic water, Cremophor EL ™ (BASF, Parslppany, NJ) or phosphate buffer saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that there is an easy ability to be injected. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and appropriate mixtures thereof. Adequate fluidity can be maintained, for example, by the use of a coating such as lectin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, polymer salt, and the like. In many cases, it will be preferable to Include isotonic agents, for example, sugars, polyols such as mannitol, sorbltol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be accomplished by Inclusion in the composition of an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile Injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of Ingredients listed above, as necessary, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and the required other Ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions,

ES 2 645 367 T3 preparation methods are vacuum drying and lyophilization which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. They can be packed into gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a flowable carrier for use as a mouthwash, wherein the compound is applied to the flowable carrier orally and shaken and expectorated or swallowed. Pharmaceutically compatible binders and / or adjunct materials can be included as part of the composition. Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or cornstarch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or a dispenser, which contains an appropriate propellant, for example, a gas such as carbon dioxide or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and derivatives of fusidic acid. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams, as is generally known in the art.

Active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid clearance from the body, such as a controlled release formulation, which includes implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for the preparation of such formulations will be apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Patent No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically appropriate discrete units as unit doses for the subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for dosage unit forms of the disclosure is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the doses of the pharmaceutical compositions used according to the invention vary depending on the agent, the age, weight and clinical condition of the recipient patient, and the experience and judgment of the physician or professional administering the therapy, among others. factors affecting the selected dosage. In general, the dose should be sufficient to cause a slowdown, and preferably a regression, of the growth of the tumors and also, preferably, cause a complete regression of the cancer. The doses described in this document can be given in single, divided or continuous doses (the dose of which can be adjusted for the patient's weight in kg, the body surface area in m2 and age in years). The dose can be provided in an effective amount of a pharmaceutical agent that provides an objectively identifiable improvement as indicated by the physician or other qualified observer. For example, regression of a tumor in a patient can be measured with reference to the diameter of a tumor. Decreasing the diameter of a tumor indicates regression. Regression is also indicated by the failure of tumors to reoccur after treatment has stopped. As used herein, the term "effective dosage form" refers to the amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack or dispenser together with instructions for administration.

The compounds of the present invention are capable of forming additional salts. All of these forms are also contemplated within the scope of the claimed invention.

ES 2 645 367 T3

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention in which the parent compound is modified by making acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acid residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, disulfonic ethane, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, arsanilic glycol, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxamic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsilic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, sulfuric, sulfuric, sulfuric, succinic , tannic, tartaric, toluenesulfonic, and the commonly occurring amino acids, eg, glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid. , 4-methylbicyclo- [2.2.] - oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid and the like. The present invention also encompasses salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same salt.

The compounds of the present invention can also be prepared as esters, for example pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, eg, a methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, for example, an acetate, propionate, or other ester.

The compounds of the present invention can also be prepared as prodrugs, eg, pharmaceutically acceptable prodrugs. The terms pro-drug and pro-drug are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be administered in prodrug form. The present disclosure is intended to cover the prodrugs of the currently claimed compounds, the methods of administration thereof, and the compositions containing them. Prodrugs are intended to include any covalently linked carrier that releases an active parent drug of the present invention in vivo when such a prodrug is administered to a subject. Prodrugs are prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved, either on routine manipulation or in vivo, in the parent compound. Prodrugs include compounds of the present invention in which a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is attached to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy, or carbonyl group. free respectively.

Examples of prodrugs include, but are not limited to, esters (eg, acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (eg, N, N-dimethylaminocarbonyl) of hydroxy functional groups, esters ( e.g. ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of the invention, and the like, see Bundegaard, H., Design of Prodrugs, p1-92, Elesevier, New YorkOxford (1985).

The compounds, or pharmaceutically acceptable salts, esters, or prodrugs thereof, are administered orally, nasal, transdermal, pulmonary, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenteral. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen using the compounds is selected according to a variety of factors including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the kidney and liver function of the patient; and the particular compound or salt of the same employee. An ordinarily qualified physician or veterinarian can easily determine and prescribe the effective amount of medication required to prevent, counteract, or halt the progress of the condition.

ES 2 645 367 T3

Techniques for the formulation and administration of the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All percentages and proportions used in this document, unless otherwise indicated, are by weight. Other features and advantages of the present invention are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present disclosure, the person skilled in the art can identify and employ other components and a useful methodology for the practice of the present invention.

two. Treatment methods

The present disclosure provides a method of treating a cell proliferative disorder which comprises administering to a subject in need thereof a compound of the present invention.

The present disclosure provides a method of treating a cell proliferative disorder which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to formula IB:

Y ^ = - '9 Xf-Xj () T0 zw — xc xe— (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein:

T is a link;

XY is CY, N or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, alkyl (Ci, C2, C3, C4, C5, or Ce) lower, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or C &) lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Rc, Rd, Re, R4, Rs, and Re are independently hydrogen, hydroxyl, halogen, P, Ci alkyl, C2, C3, C4, C5, or Ce, C1, C alkoxy2, C3, C4, C5, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or C &) lower, O-benzyl, C1, C alkyl2, C3, C4, C5, or C6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) lower,

ES 2 645 367 T3 where W is H, or Ci, C alkyl2, C3, C4, C5, or Ce, C1, C alkyl-aryl2, C3, C4, C5, or C3;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21,

tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) lower-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or C @) lower-L, NH-(C1, C2, C3, C4, C5, or Ce) lower-M, or O-aryl-Q, further wherein lower alkyl is straight or branched alkyl;

M is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Οθ Lower, Tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, Οθ Lower, Tetrazole, or

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβο R-ig and R2or taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi)n-C (O) -NR2 (CHR3) m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are independently H or C1, C alkyl2, C3, C4, C5, or C3; y and n are independently 0, 1, or 2.

wherein the therapeutically effective amount is between about 50 mg and about 500 mg (or any integer within said range and wherein the compound is administered once over a 24 hour period.

The present disclosure provides a method of preventing the recurrence of a cell proliferative disorder in a subject previously diagnosed with a cell proliferative disorder which comprises administering to the subject a therapeutically effective amount of a compound of the present invention.

ES 2 645 367 T3 xt

Μ-te (Formula IB) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein:

T is a link;

XY is CY, N, or NO;

Xz is CZ;

Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5, or C @), C1, C2, C3, C4, C5 alkoxy, or Ce, O-alkyl-aryl (C1, C2, C3, C4, C5, or Ce) Lower, and O-benzyl;

Xto is CRto, Nerd;

Xb is CRb, Nerd;

Xc is CRc, Nerd;

Xd is CRd, Nerd;

Xand is CRand, Nerd;

XF is CR4, Nerd;

Xg is CR5, Nerd;

Xh is CR6, Nerd;

Rto, Rb, Re, Rd, Re, R4, Rs, and Re are independently hydrogen, hydroxyl, halogen, P, Ci, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4 alkoxy, C5, or Ce, O-lower alkyl (C1, C2, C3, C4, C5, or C @), O-benzyl, C1, C2, C3, C4, C5, or C alkyl6-OH, COOH, COO-alkyl (C1, C2, C3, C4, C5, or Ce) Lower, SO2H, S02-alkyl (C1, C2, C3, C4, C5, or Ce) lower, v

, V — N

N — W where W is H, or C1, C2, C3, C4, C5 alkyl, or Ce, C1, C2, C3, C4, C5 alkyl-aryl, or Οβ;

P is SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR20R21 tetrazole, O-alkyl (C1, C2, C3, C4, C5, or Ce) lower-K, 0-C (0) -alkyl (C1, C2, C3, C4, C5, or C @ ) lower-L, NH-(C1, C2, C3, C4, C5, or Ce) lower-M, or O-aryl-Q alkyl, further wherein the lower alkyl is straight or branched alkyl;

K is aryl, heteroaryl, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1, C2, C3, C4, C5 alkoxy, Lower Οβ, tetrazole, or

ES 2 645 367 T3

M is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR-ig, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, C3 Inferior, tetrazole, or

Q is aryl, heteroaryl, OH, C (O) NH2, COOH, SO3H, BEAR3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glucoside, C1 alkoxy, C2, C3, C4, C5, C3 Inferior, tetrazole, or

R19, R20 and R21 are C1, C alkyl2, C3, C4, C5, or Οβ or R-ig and R2or taken together with the attached nitrogen atom form a five-membered ring;

V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-;

Z is (CHRi) nC (O) -NR2(CHR3)m-Ar, where Ar is a nitrogen-containing heteroaryl group or substituted or unsubstituted aryl, R1, R2, and R3 are Independently H or C1, C alkyl2, C3, C4, C5, or C3; ynym are Independently 0, 1, or 2.

Preferably the compound is

F or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The therapeutically effective amount can be between about 50 mg and about 500 mg (or any integer within said Range (eg 50, 51, 52, 53 ...)), between about 100 mg to about 400 mg, between about 200mg to about 300mg, about 250mg or 250mg.

The treatment, or the above treatment, can produce immune memory and / or produce in the subject. The above treatment or treatment can produce memory B cells and / or memory T cells in the subject.

As used herein, Immune memory or immunological memory refers to the ability of the immune system to respond more quickly and efficiently to pathogens such as tumor cells that have been previously encountered, and reflects the preexistence of a population of specific lymphocytes of clonally expanded antigen. The memory responses, which can be called secondary, tertiary, and so on, depend on the number of antigen exposures, they also differ qualitatively from the primary responses. Immune memory or immunological memory refers to when a subject develops a protective or defensive system against tumor cells after the subject has been treated with a pharmaceutical composition comprising a compound of the Invention. Immune Memory or Immunological Memory as used herein includes memory activation and replication of memory B cells and / or memory T cells, where some of their descendants are converted into long-lived memory cells. These memory cells can remember the specific cancer or proliferative disorder found and can generate a strong response if the cancer or proliferative disorder is detected again (Janeway, CA et al., Immunobiology: The Immune System in Heath and Dlsease, (Garland, 3rd ed. 1997)).

ES 2 645 367 T3

As used herein, "immunocompetent" refers to a subject whose immune system contains B and T cells. Immunocompromised refers to a subject whose immune system lacks B and T cells. Preferably, the subject is immunocompetent.

The subject can be pre-treated for the cell proliferation disorder. Preferably, the subject was pre-treated for the cell proliferation disorder with a compound of the Invention. More preferably, the subject was previously treated for the cell proliferation disorder with the compound having the formula o 'or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The subject can be described as being in remission after treatment for proliferation disorder. As used herein, remission refers to the state of absence of disease or disorder activity or absence of symptoms or signs of a disease or disorder in a subject known to have the disease or disorder. A partial remission for cancer can be defined as a reduction in the size of the tumor by 5% or more in relation to its size before treatment; more preferably, the size of the tumor is reduced by 10% or more; more preferably, it is reduced by 20% or more; more preferably, it is reduced by 30% or more; more preferably, it is reduced by 40% or more; Even more preferably, it is reduced by 50% or more or greater reduction in medial parameters of tumor growth as can be found on physical examination, radiological study, or by levels of markers from a blood or urine test. The size of a tumor can be measured by any reproducible means of measurement. The size of a tumor can be measured as a diameter of the tumor. A complete remission is defined as the complete disappearance of all these manifestations of the disease. To be considered in remission, a subject must not have recurrence of the disease or disorder within 30 days of the last treatment for said disease or disorder.

Cellular proliferative disorder can be cancer or a precancerous condition. The present disclosure further provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, derivative, analog or solvate thereof, for the preparation of a medicament useful for the treatment of a cellular proliferative disorder. .

The present disclosure also provides methods of protecting against a cellular proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof. to a subject in need of such treatment. Cellular proliferative disorder can be cancer or a precancerous condition. The present disclosure also provides the use of the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, for the preparation of a medicament useful for the prevention of a cellular proliferative disorder.

As used herein, a subject in need is a subject who has a cellular proliferative disorder, or a subject who has an increased risk of developing a cellular proliferative disorder relative to the general population. A subject in need may have a precancerous condition. Preferably, a subject in need has cancer. A subject includes a mammal. The mammal can be, for example, any mammal, for example, a human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably the mammal is human.

As used herein, the term "cellular proliferative disorder" refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may be cancerous or not. Exemplary cell proliferative disorders of the invention encompass a variety of conditions in which cell division is deregulated. Exemplary Cellular Proliferative Disorder Includes, but is not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, intra-sltu tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunologic tumors, hematologic tumors, cancers. , carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term rapidly dividing cell, as used herein, is defined as any cell that divides at a rate that exceeds or is greater than is expected or observed between neighboring or juxtaposed cells within the same tissue. A cellular proliferative disorder includes a precancerous or precancerous condition. A cellular proliferative disorder includes cancer. Preferably, the methods provided herein are used to treat or alleviate a cancer symptom. The term cancer includes solid tumors, as well as hematologic tumors and / or malignant neoplasms.

ES 2 645 367 T3

A precancerous cell or precancerous cell is a cell that manifests a cellular proliferative disorder which is a precancerous or precancerous condition. A cancer cell or cancer cell is a cell that manifests a cell proliferative disorder that is cancer. Any reproducible means of measurement can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (eg, a biopsy sample). Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

For example, the solid tumor (or tumors) is a glioblastoma, oligodendroglioma, astrocytoma, or medulloblastoma. The solid tumor may be glioblastoma.

Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; septicemia; septic shock; endotoxic shock; gram-negative septicemia; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic lung inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme's desease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; hernia, rupture or prolapse of intervertebral disc syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis; graft versus host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus

Example cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDs-related lymphoma, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, cerebellar astrocytoma, cerebellar astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentothalamic primitive neuroectodesimal tumors and hypothalamic glioma , breast cancer, bronchial adenomas / carcinoids, carcinoid tumor, gastrointestinal cancer, nervous system, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasia, mycosis fungoides , Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, glioma gestational trophoblastic tumor, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumors (endocrine pancreas), Kaposi's sarcoma, kidney cancer, kidney cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia , lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, Primary central nervous system lymphoma, Waldenstram's macroglobulinemia, medulloblastoma, melanoma, intraocular melanoma (eye), Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, mouth cancer, tongue cancer, neoplasia syndrome multiple endocrine, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, low malignant potential ovarian tumor, pancreatic cancer, islet cell pancreatic cancer , nasal and paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasia / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewing family of sarcoma tumors, Kaposi's sarcoma, sarcoma soft tissue, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin carcinoma, cancer of the small intestine, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilm's tumor.

ES 2 645 367 T3

A cell proliferative disorder of the hematological system is a cell proliferative disorder that involves cells of the hematological system. A cell proliferative disorder of the hematologic system may include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasia, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, agnogenic essential myeloid metaplasia, and essential thrombocythemia. A cell proliferative disorder of the hematological system can include hyperplasia, dysplasia and metaplasia of cells of the hematological system. Preferably, the compositions of the present invention can be used to treat a cancer selected from the group consisting of a hematological cancer of the present invention or a hematological cell proliferative disorder of the present invention. A hematological cancer of the present invention can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphatic and skin origin), leukemia (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.

A cell proliferative disorder of the lung is a cell proliferative disorder that involves the cells of the lung. Cellular proliferative disorders of the lung can include all forms of cell proliferative disorders that affect lung cells. Cellular proliferative disorders of the lung may include lung cancer, a precancerous or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in the body's tissue and organs other than the lung. lung. Preferably, the compositions of the present invention can be used to treat lung cancer or cell proliferative disorders of the lung. Lung cancer can include all forms of lung cancer. Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous carcinoma, and mesothelioma. Lung cancer can include scar carcinoma, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung neoplasms with histological and ultrastructural heterogeneity (eg, mixed cell types).

Cellular proliferative disorders of the lung can include all forms of cell proliferative disorders that affect lung cells. Cell proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung. Cellular proliferative disorders of the lung can include pulmonary hyperplasia, metaplasia, and dysplasia. Cellular proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Cellular proliferative disorders of the lung may include replacement of the columnar epithelium with stratified squamous epithelium, and mucosal dysplasia. People exposed to inhaled harmful environmental agents, such as cigarette smoke and asbestos, may be at increased risk for developing lung cell proliferative disorders. Previous lung diseases that may predispose individuals to the development of cell proliferative disorders of the lung may include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomas, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

A colon cell proliferative disorder is a cell proliferative disorder that affects the cells of the colon. Preferably, the colon cell proliferative disorder is colon cancer. Preferably, the compositions of the present invention can be used to treat colon cancer or colon cell proliferative disorders. Colon cancer can include all forms of colon cancer. Colon cancer can include sporadic and hereditary colon cancer. Colon cancer can include colon malignancies, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous carcinoma. Colon cancer may be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis.

Colon cell proliferative disorders can include all forms of cell proliferative disorders that affect colon cells. Cellular proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. A cell proliferative disorder of the colon can include adenoma. Cellular proliferative disorders of the colon can be characterized by colon hyperplasia, metaplasia, and dysplasia. Previous colon diseases that can predispose individuals to the development of colon cell proliferative disorders may include previous colon cancer. Current disease that can predispose individuals to the development of colon cell proliferative disorders may include Crohn's disease and ulcerative colitis. A colon cell proliferative disorder can be associated with a mutation in a gene selected from the group consisting of p53, ras,

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FAP and DCC. An individual may be at increased risk of developing a colon cellular proliferative disorder due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP, and DCC.

A cell proliferative disorder of the pancreas is a cell proliferative disorder involving cells of the pancreas. Cell proliferative disorders of the pancreas can include all forms of cell proliferative disorders that affect pancreatic cells. Cellular proliferative disorders of the pancreas may include pancreatic cancer, a precancerous or precancerous condition of the pancreas, hyperplasia of the pancreas and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in the tissues and organs of the pancreas. body other than the pancreas. Pancreatic cancer includes all forms of pancreatic cancer. Pancreatic cancer may include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoma, small cell carcinoma, pancreatoma mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include pancreatic neoplasms with histological and ultrastructural heterogeneity (eg, mixed cell types).

A cell proliferative disorder of the prostate is a cell proliferative disorder involving the cells of the prostate. Cell proliferative disorders of the prostate can include all forms of cell proliferative disorders that affect the cells of the prostate. Cell proliferative disorders of the prostate can include prostate cancer, a precancerous or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in the tissues and organs of the body that other than the prostate. Cellular proliferative disorders of the prostate can include prostate hyperplasia, metaplasia, and dysplasia.

A skin cell proliferative disorder is a cell proliferative disorder that involves skin cells. Cell proliferative disorders of the skin can include all forms of cell proliferative disorders that affect skin cells. Cell proliferative disorders of the skin may include a precancerous or precancerous skin condition, benign skin growths or lesions, melanoma, malignant melanoma, and other malignant skin growths or lesions, and metastatic lesions to body tissue and organs. other than skin. Cellular proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

A cell proliferative disorder of the ovary is a cell proliferative disorder that involves the cells of the ovary. Cell proliferative disorders of the ovary can include all forms of cell proliferative disorders that affect the cells of the ovary. Cellular proliferative disorders of the ovary may include a precancerous or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions to body tissue and organs other than the ovary. Cellular proliferative disorders of the skin can include ovarian cell hyperplasia, metaplasia, and dysplasia.

A cell proliferative disorder of the breast is a cell proliferative disorder that involves the cells of the breast. Cell proliferative disorders of the breast can include all forms of cell proliferative disorders that affect cells of the breast. Cell proliferative disorders of the breast can include breast cancer, a precancerous or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in the tissues and organs of the body that not the chest. Cellular proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

A cell proliferative disorder of the breast can be a precancerous condition of the breast. The compositions of the present invention can be used to treat a precancerous condition of the breast. A precancerous condition of the breast may include atypical breast hyperplasia, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia and growth stage 0 or grade 0 or lesion of the breast (for example, stage 0 or grade 0 breast cancer, or carcinoma in situ). A precancerous condition of the breast can be classified according to the TNM classification scheme accepted by the American Joint Committee on Cancer (AJCC), where the primary tumor (T) has been assigned a stage of T0 or Tis; and where regional lymph nodes (N) have been assigned a stage of N0; and where distant metastasis (M) has been assigned a stage of M0.

The cell proliferative disorder of the breast can be breast cancer. Preferably, the compositions of the present invention can be used to treat breast cancer. Breast cancer includes all forms of breast cancer. Breast cancer can include primary epithelial breast cancer. Breast cancer can include cancers in which the breast is affected by other tumors, such as lymphoma, sarcoma, or melanoma. Breast cancer may include breast carcinoma, ductal breast carcinoma, lobular breast carcinoma, undifferentiated breast carcinoma, phyllodes cystosarcoma of the breast, angiosarcoma of the breast, and primary lymphoma of the breast. Breast cancer can include stage I, II, IIIA, IIIB, IIIC, and IV breast cancer. Ductal carcinoma of the breast may include invasive carcinoma, invasive carcinoma in situ with a predominant intraductal component, inflammatory breast cancer, and a ductal carcinoma of the breast with a histological type selected from the group consisting of comedones, mucinous (colloid), medullary, and medullary with lymphocytic, papillary, and scirrous infiltrate

ES 2 645 367 T3 tubular. Lobular carcinoma of the breast can include invasive lobular carcinoma with predominant in situ component, invasive lobular carcinoma, and infiltrating lobular carcinoma. Breast cancer can include Paget's disease, Paget's disease with intraductal carcinoma, and Paget's disease with invasive ductal carcinoma. Breast cancer can include breast neoplasms with histological and ultrastructural heterogeneity (eg, mixed cell types).

Preferably, the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can be used to treat breast cancer. A breast cancer to be treated may include familial breast cancer. A breast cancer to be treated may include sporadic breast cancer. A breast cancer to be treated can arise in a male subject. A breast cancer to be treated can arise in a female subject. A breast cancer to be treated can arise in a premenopausal female subject or in a postmenopausal female subject. A breast cancer to be treated can arise in a subject equal to or older than 30 years, or a subject younger than 30 years. A breast cancer to be treated has occurred in a subject 50 years of age or older, or a subject less than 50 years of age. A breast cancer to be treated can arise in a subject equal to or greater than 70 years of age, or a subject less than 70 years of age.

A breast cancer to be treated can be typed to identify a familial or spontaneous mutation in BRCA1, BRCA2, or p53. A breast cancer to be treated can be typified as having HER2 / neu gene amplification, HER2 / neu overexpressing, or low, intermediate, or high level of HER2 / neu expression. A breast cancer to be treated can be typed for a marker selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, Ki-67, CA15 -3, CA 27-29 and c-Met. A breast cancer to be treated can be typified as ER-unknown, ER-rich, or ER-poor. A breast cancer to be treated can be classified as ER negative or ER positive. ER typing of a breast cancer can be performed by any reproducible means. The eR typing of a breast cancer can be performed as set forth in Onkologie 27: 175179 (2004). A breast cancer to be treated can be typified as PR-unknown, PR-rich, or PR-poor. A breast cancer to be treated can be typified as PR-negative or PR-positive. A breast cancer to be treated can be typed as receptor positive or receptor negative. A breast cancer to be treated can be typified as associated with elevated blood levels of CA 15-3, or CA 27-29, or both.

A breast cancer to be treated may include a localized tumor of the breast. A breast cancer to be treated may include a breast tumor that is associated with a negative sentinel lymph node (SLN) biopsy. A breast cancer to be treated may include a breast tumor that is associated with a positive sentinel lymph node (SLN) biopsy. A breast cancer to be treated may include a breast tumor that is associated with one or more positive axillary lymph nodes, where the axillary lymph nodes have been arranged by any applicable method. A breast cancer to be treated may include a breast tumor that has been typified as having a node-negative status (eg, node-negative) or a node-positive status (eg, node-positive). A breast cancer to be treated may include a breast tumor that has metastasized to other locations in the body. A breast cancer to be treated can be classified as metastasis to a site selected from the group consisting of bone, lung, liver, or brain. A breast cancer being treated can be classified according to a characteristic selected from the group consisting of metastatic, local, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.

A compound of the present invention , or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can be used to treat or prevent a cell proliferative disorder of the breast, or to treat or prevent breast cancer, in a subject who has an increased risk of developing breast cancer relative to the general population. A subject at an increased risk of developing breast cancer relative to the general population is a female subject with a family or personal history of breast cancer. A subject at an increased risk of developing breast cancer relative to the general population is a female subject who has a germ line or a spontaneous mutation in BRCA1 or BRCA2, or both. A subject at an increased risk of developing breast cancer relative to the general population is a female subject with a family history of breast cancer and a germline or spontaneous mutation in BRCA1 or BRCA2, or both. A subject with a higher risk of developing breast cancer in relation to the general population is a woman older than 30 years, older than 40 years, older than 50 years, older than 60 years, older than 70 years, older than 80 years or older than 90 years. A subject with an increased risk of developing breast cancer relative to the general population is a subject with atypical breast hyperplasia, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia or a stage 0 growth or lesion of the breast (for example, stage 0 or grade 0 breast cancer or carcinoma in situ).

A breast cancer to be treated can be graded histologically according to the Scarff-Bloom Richardson system, in which a breast tumor has been assigned a mitosis count score of 1, 2, or 3; a nuclear pleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or 3; and a total Scarff-Bloom-Richardson score between 3 and 9. A tumor grade can be assigned to cancer of

ES 2 645 367 T3 breast to be treated according to the International Consensus Panel on the Treatment of Breast Cancer selected from the group consisting of grade 1, grade 1-2, grade 2, grade 2-3 or grade 3.

A cancer to be treated can be arranged according to the American Joint Committee on Cancer (AJCC) TNM classification system, in which the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c or T4d; and where regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where a distant metastasis (M) can be assigned a stage of MX, M0 or M1. A cancer to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. A cancer to be treated can be graded according to an AJCC classification as Grade GX (for example, the grade cannot be assessed), Grade 1, Grade 2, Grade 3, or Grade 4. A cancer to be treated can be according to the AJCC (pN) pathological classification of pNX, pN0, PN0 (I-), PN0 (I +), PN0 (mol-), PN0 (mol +), PN1, PN1 ( mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b or pN3c.

A cancer to be treated may include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer to be treated may include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. A cancer to be treated may include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer to be treated may include a tumor that has been determined to be larger than 5 centimeters in diameter. A cancer to be treated can be classified by microscopic appearance, well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer to be treated can be classified by microscopic appearance in relation to the count of mitosis (eg, amount of cell division) or nuclear pleiomorphism (eg, change in cells). A cancer to be treated can be classified by microscopic appearance as associated with areas of necrosis (for example, areas of cells that die or degenerate). A cancer to be treated can be classified as an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer to be treated can be classified as aneuploid, triploid, tetraploid, or altered ploidy. A cancer to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication, or amplification of a portion of a chromosome.

A cancer to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer to be treated can be typified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% cells in the synthesis stage of division. cellular (for example, in the S phase of cell division). A cancer to be treated can be typified as having a low S-phase fraction or a high S-phase fraction.

As used herein, a normal cell is a cell that cannot be classified as part of a cell proliferative disorder. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. Preferably, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.

As used herein, contacting a cell refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell. .

As used herein, "candidate compound" refers to a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, that has been or will be tested in one or more in vitro biological assays. or in vivo, in order to determine whether that compound is likely to elicit a desired biological or medical response in a cell, tissue, system, animal, or human that a researcher or clinician is looking for. A candidate compound is a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof. The biological or medical response may be cancer treatment. The biological or medical response can be the treatment or prevention of a cell proliferative disorder. In vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

As used herein, monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof. Preferably, monotherapy will involve the administration of a therapeutically effective amount of an active compound. For example, monotherapy against cancer with one of the compounds of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to a subject in need of cancer treatment. Monotherapy can be contrasted with combination therapy, in which a combination of multiple active compounds is administered, preferably with each component of the combination present in a therapeutically effective amount. In one aspect, monotherapy with a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is more effective than combination therapy in inducing a desired biological effect.

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As used herein, "treating" or treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes administration of a compound of the present invention, or a salt, prodrug, metabolite, pharmaceutically acceptable polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.

A compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can also be used to prevent a disease, condition, or disorder. As used herein, "preventing or preventing" describes reducing or eliminating the onset of symptoms or complications of the disease, condition, or disorder.

As used herein, the term "relieve" is intended to describe a process by which the severity of a sign or symptom of a disorder is lessened. Importantly, a sign or symptom can be alleviated without being eliminated. In a preferred embodiment, the administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not required. Effective doses are expected to lessen the severity of a sign or symptom. For example, a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer decreases in at least one of multiple locations.

As used herein, the term "severity" is intended to describe the potential for cancer to transform from a precancerous or benign state to a malignant state. Alternatively, or additionally, the severity is intended to describe a stage of cancer, for example, according to the TNM system (accepted by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art recognized methods. The stage of cancer refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, the size of the tumor, the number of tumors, and the involvement of the lymph nodes (spread of the cancer to the lymph nodes ). Alternatively, or in addition, the severity is intended to describe the grade of the tumor by art recognized methods (see, National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute, www.cancer.gov). In addition, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that divide (see, National Cancer Institute, www.cancer.gov).

In another aspect of the invention, severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, became vascularized, lost adherence to juxtaposed tissues, or metastasized. Additionally, severity describes the number of places where a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of different types and locations. For example, inoperable tumors, those cancers that have greater access to multiple body systems (hematologic and immune tumors), and those that are more resistant to traditional treatments are considered more severe. In these situations, the prolongation of the life expectancy of the subject and / or the reduction of pain, the decrease in the proportion of cancer cells or the restriction of cells to one system and the improvement of the cancer stage / tumor grade / histological grade / nuclear grade is considered to alleviate a sign or symptom of cancer

As used herein, the term symptom is defined as an indication of illness, disease, injury, or that something is not right in the body. Symptoms are palpated or noticed by the individual experiencing the symptom, but cannot be easily noticed by others. Others define themselves as professionals who are not health professionals.

As used in this document, the term sign is also defined as an indication that something is wrong with the body. But signs are defined as things that a doctor, nurse, or other health professional can see.

Cancer is a group of diseases that can cause almost any sign or symptom. Signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects nearby organs or structures. If a cancer spreads (metastasizes), then symptoms can appear in different parts of the body.

As the cancer grows, it begins to press on nearby organs, blood vessels, and nerves. This pressure creates some of the signs and symptoms of cancer. If the cancer is in a critical area, such as certain parts of the brain, even the smallest tumor can cause initial symptoms.

But sometimes cancers start in places where they don't cause any symptoms until the cancer has grown quite large. Pancreatic cancers, for example, often do not grow large enough to feel

ES 2 645 367 T3 from outside the body. Some pancreatic cancers do not cause symptoms until they begin to grow around nearby nerves (this causes back pain). Others grow around the bile duct, which blocks the flow of bile and leads to a yellowing of the skin known as jaundice. When pancreatic cancer causes these signs or symptoms, it has usually reached an advanced stage.

Cancer can also cause symptoms such as fever, fatigue, or weight loss. This may be because cancer cells absorb much of the body's energy supply or release substances that change the body's metabolism. Or cancer can cause the immune system to react in a way that produces these symptoms.

Sometimes cancer cells release substances into the bloodstream that cause symptoms that are not generally thought of as a result of cancers. For example, some pancreatic cancers can release substances that cause blood clots to form in the veins of the legs. Some lung cancers produce hormone-like substances that affect blood calcium levels, affect nerves and muscles, and cause weakness and dizziness.

Cancer has several general signs or symptoms that occur when a variety of cancer cell subtypes are present. Most people with cancer will lose weight at some point with their disease. An unexplained (unintended) weight loss of 10 pounds or more can be the first sign of cancer, particularly cancers of the pancreas, stomach, esophagus, or lung.

Fever is very common with cancer, but it is seen more often in advanced disease. Almost all cancer patients will have a fever at some point, especially if the cancer or its treatment affects the immune system and makes it difficult for the body to fight the infection. Less often, fever can be an early sign of cancer, such as with leukemia or lymphoma.

Fatigue can be a major symptom as cancer progresses. However, it can happen soon, in cancers such as leukemia, or if the cancer is causing ongoing blood loss, as in some colon or stomach cancers.

Pain can be an early symptom with some types of cancer, such as bone cancers or testicular cancer. But most of the time pain is a symptom of advanced disease.

Along with skin cancers (see next section), some internal cancers can cause skin signs that can be seen. These changes include skin that appears darker (hyperpigmentation), yellow (jaundice), or red (erythema); itch; or excessive hair growth.

Alternatively, or additionally, cancer subtypes exhibit specific signs or symptoms. Changes in bowel habits or bladder function could indicate cancer. Long-term constipation, diarrhea, or a change in stool size can be a sign of colon cancer. Painful urination, blood in the urine, or a change in bladder function (such as more or less frequent urination) could be related to prostate or bladder cancer.

Changes in the condition or appearance of the skin from a new skin condition could indicate cancer. Skin cancers can bleed and look like sores that don't heal. A long-lasting mouth ulcer could be oral cancer, especially in patients who smoke, chew tobacco, or frequently drink alcohol. Ulcers on the penis or vagina can be signs of infection or early cancer.

Unusual bleeding or discharge can indicate cancer. Unusual bleeding can occur in early or advanced cancer. Blood in sputum (phlegm) can be a sign of lung cancer. Blood in the stool (or a black or black stool) could be a sign of colon or rectal cancer. Cancer of the cervix or endometrium (lining of the uterus) can cause vaginal bleeding. Blood in the urine can be a sign of bladder or kidney cancer. A bloody discharge from the nipple can be a sign of breast cancer.

A thickening or lump in the breast or other parts of the body could indicate the presence of cancer. Many cancers can be felt through the skin, mainly in the breast, testicles, lymph nodes (glands), and soft tissues of the body. A lump or thickening can be an early or late sign of cancer. Any lump or thickening could be indicative of cancer, especially if the formation is new or has grown in size.

Indigestion or trouble swallowing could indicate cancer. While these symptoms commonly have other causes, indigestion or swallowing problems can be a sign of cancer of the esophagus, stomach, or pharynx (throat).

Recent changes in a wart or mole could be indicative of cancer. Any wart, mole, or freckle that changes color, size, or shape, or loses its defined edges indicates the potential development of cancer. For example, the skin lesion may be a melanoma.

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A persistent or hoarse cough could be indicative of cancer. A cough that doesn't go away can be a sign of lung cancer. Hoarseness can be a sign of cancer of the larynx (voice box) or thyroid.

While the signs and symptoms listed above are the most common seen with cancer, there are many others that are less common and are not listed in this document. However, all art recognized signs and symptoms of cancer are contemplated and encompassed by the present invention.

Cancer treatment can result in a reduction in the size of a tumor. A reduction in the size of a tumor can also be called tumor regression. Preferably, after treatment, the size of the tumor is reduced by 5% or more relative to its size before treatment; more preferably, the size of the tumor is reduced by 10% or more; more preferably, it is reduced by 20% or more; more preferably, it is reduced by 30% or more; more preferably, it is reduced by 40% or more; even more preferably, it is reduced by 50% or more; and most preferably, it is reduced by more than 75% or more. The size of a tumor can be measured by any reproducible means of measurement. The size of a tumor can be measured as a diameter of the tumor.

Cancer treatment can result in a reduction in tumor volume. Preferably, after treatment, the volume of the tumor is reduced by 5% or more relative to its size before treatment; more preferably, the tumor volume is reduced by 10% or more; more preferably, it is reduced by 20% or more; more preferably, it is reduced by 30% or more; more preferably, it is reduced by 40% or more; even more preferably, it is reduced by 50% or more; and most preferably, it is reduced by more than 75% or more. Tumor volume can be measured by any reproducible measurement means.

Cancer treatment results in a decrease in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to the number before treatment; more preferably, the tumor number is reduced by 10% or more; more preferably, it is reduced by 20% or more; more preferably, it is reduced by 30% or more; more preferably, it is reduced by 40% or more; even more preferably, it is reduced by 50% or more; and most preferably, it is reduced by more than 75%. The number of tumors can be measured by any reproducible means of measurement. The number of tumors can be measured by counting tumors visible to the naked eye or at a specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

Cancer treatment can result in a decrease in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, it is reduced by 20% or more; more preferably, it is reduced by 30% or more; more preferably, it is reduced by 40% or more; even more preferably, it is reduced by 50% or more; and most preferably, it is reduced by more than 75%. The number of metastatic lesions can be measured by any reproducible means of measurement. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

Cancer treatment can result in an increase in the average survival time of a population of treated subjects compared to a population that receives a carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, in more than 60 days; more preferably, in more than 90 days; and most preferably, in more than 120 days. An increase in the average survival time of a population can be measured by any reproducible means. An increase in the average survival time of a population can be measured, for example, by calculating for a population the average duration of survival after the start of treatment with an active compound. An increase in the average survival time of a population can also be measured, for example, by calculating for a population the average duration of survival after completing a first round of treatment with an active compound.

Cancer treatment can result in an increase in the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, in more than 60 days; more preferably, in more than 90 days; and most preferably, in more than 120 days. An increase in the average survival time of a population can be measured by any reproducible means. An increase in the average survival time of a population can be measured, for example, by calculating for a population the average duration of survival after the start of treatment with an active compound. An increase in the average survival time of a population can also be measured, for example, by calculating for a population the average duration of survival after completing a first round of treatment with an active compound.

Cancer treatment can result in an increase in the average survival time of a population of treated subjects compared to a population receiving monotherapy with a drug that is not a compound of the present invention, or a salt, prodrug, metabolite, analog or derivative thereof

ES 2 645 367 T3 pharmaceutically acceptable. Preferably, the average survival time is increased by more than 30 days; more preferably, in more than 60 days; more preferably, in more than 90 days; and most preferably, in more than 120 days. An increase in the average survival time of a population can be measured by any reproducible means. An increase in the average survival time of a population can be measured, for example, by calculating for a population the average duration of survival after the start of treatment with an active compound. An increase in the average survival time of a population can also be measured, for example, by calculating for a population the average duration of survival after completing a first round of treatment with an active compound.

Cancer treatment can result in a decrease in the mortality rate of a population of treated subjects compared to a population that receives a carrier alone. Cancer treatment can result in a decrease in the mortality rate of a population of treated subjects compared to an untreated population. Cancer treatment can result in a decrease in the mortality rate of a population of treated subjects compared to a population receiving monotherapy with a drug that is not a compound of the present invention, or a salt, prodrug, metabolite, pharmaceutically acceptable analog or derivative thereof. Preferably, the mortality rate decreases by more than 2%; more preferably more than 5%; more preferably more than 10%; and most preferably, by more than 25%. A decrease in the mortality rate of a population of treated subjects can be measured by any reproducible means. A decrease in the death rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit of time after the start of treatment with an active compound. A decrease in the mortality rate of a population can also be measured, for example, by calculating for a population the average number of disease-related deaths per unit of time after completing a first round of treatment with an active compound.

Cancer treatment can result in a decrease in the growth rate of the tumor. Preferably, after the treatment, the growth rate of the tumor is reduced by at least 5% relative to the number before the treatment; more preferably, the growth rate of the tumor is reduced by at least 10%; more preferably, it is reduced by at least 20%; more preferably, it is reduced by at least 30%; more preferably, it is reduced by at least 40%; more preferably, it is reduced by at least 50%; even more preferably, it is reduced by at least 50%; and most preferably, it is reduced by at least 75%. The growth rate of the tumor can be measured by any reproducible means of measurement. Tumor growth rate can be measured as a change in tumor diameter per unit of time.

Cancer treatment can result in a decrease in tumor regrowth. Preferably, after treatment, the growth of the tumor is less than 5%; more preferably tumor regrowth is less than 10%; more preferably less than 20%; more preferably less than 30%; more preferably less than 40%; more preferably less than 50%; even more preferably less than 50%; and most preferably, less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a previous reduction of the tumor that followed treatment. A decrease in tumor regrowth is indicated by the failure of tumors to reoccur after treatment has stopped.

Treatment or prevention of a cell proliferative disorder can result in a reduction in the rate of cell proliferation. Preferably, after treatment, the cell proliferation rate is reduced by at least 5%; more preferably, at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%; and most preferably, at least 75%. The rate of cell proliferation can be measured by any reproducible means of measurement. The rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit of time.

Treatment or prevention of a cell proliferative disorder can result in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%; and most preferably, at least 75%. The proportion of proliferating cells can be measured by any reproducible means of measurement. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of undivided cells in a tissue sample. The proportion of proliferating cells can be equivalent to the mitotic index.

Treatment or prevention of a cell proliferative disorder can result in a decrease in the size of an area or zone of cell proliferation. Preferably, after treatment, the size of an area or zone of cell proliferation is reduced by at least 5% in relation to its size before treatment; more preferably, it is reduced by at least 10%; more preferably, it is reduced by at least 20%; more preferably, it is reduced by at least 30%; more preferably, it is reduced by at least 40%; more 79

ES 2 645 367 T3 preferably is reduced by at least 50%; Even more preferably, it is reduced by at least 50%; and most preferably, it is reduced by at least 75%. The size of an area or zone of cell proliferation can be measured by any reproducible means of measurement. The size of an area or zone of cell proliferation can be measured as a diameter or width of an area or zone of cell proliferation.

Treatment or prevention of a cell proliferative disorder can result in a decrease in the number or proportion of cells that have an abnormal appearance or morphology. Preferably, after treatment, the number of cells having abnormal morphology is reduced by at least 5% in relation to their size before treatment; more preferably, it is reduced by at least 10%; more preferably, it is reduced by at least 20%; more preferably, it is reduced by at least 30%; more preferably, it is reduced by at least 40%; more preferably, it is reduced by at least 50%; even more preferably, it is reduced by at least 50%; and most preferably, it is reduced by at least 75%. An abnormal cell appearance or morphology can be measured by any reproducible means of measurement. Abnormal cell morphology can be measured by microscopy, for example, using an inverted tissue culture microscope. An abnormal cell morphology can take the form of nuclear pleiomorphism.

As used herein, the term "selectively" means that it tends to occur at a higher frequency in one population than in another population. The populations compared can be cell populations. Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, acts selectively on a cancer or precancerous cell but not on a normal cell. Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, acts selectively to modulate one molecular target (eg, a target kinase) but does not significantly modulate another molecular target (eg. , a non-target kinase). The disclosure also provides a method of selectively inhibiting the activity of an enzyme, such as a kinase. Preferably, an event occurs selectively in population A relative to population B if it occurs more than twice as often in population A as compared to population B. An event occurs selectively if it occurs more than five times more frequently in population TO. An event occurs selectively if it occurs more than ten times more frequently in population A; more preferably more than fifty times; even more preferably, more than 100 times; and most preferably, more than 1000 times more frequently in population A compared to population B. For example, cell death would be what would selectively occur in cancer cells if it occurred more than twice as often in cancer cells compared to normal cells.

A compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can modulate the activity of a molecular target (eg, a target kinase). Modulation refers to stimulating or inhibiting an activity of a molecular target. Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, modulates the activity of a molecular target by stimulating or inhibiting the activity of the molecular target by at least 2-fold relative with the activity of the molecular target under the same conditions, but lacking only the presence of the compound. More preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5 times, at least 5 times. least 10 times, at least 20 times, at least 50 times, at least 100 times relative to the activity of the molecular target under the same conditions, but lacking only the presence of the compound. The activity of a molecular target can be measured by any reproducible means. The activity of a molecular target can be measured in vitro or in vivo. For example, the activity of a molecular target can be measured in vitro by an enzyme activity assay or a DNA binding assay, or the activity of a molecular target can be measured in vivo by the assay of the expression of a reporter gene. .

A compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, does not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibit the activity of the molecular target by more than 10 % in relation to the activity of the molecular target under the same conditions, but lacking only the presence of the compound.

As used herein, the term "isozyme selective" means preferential inhibition or stimulation of a first isoform of an enzyme compared to a second isoform of an enzyme (e.g., preferential inhibition or stimulation of an isozyme kinase alpha compared to a beta isoenzyme kinase). Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, demonstrates a minimum of a four-fold differential, preferably a ten-fold differential, more preferably a fifty-fold differential, in the dosage required to achieve a biological effect. Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, demonstrates this differential across the inhibition range, and the differential is exemplified in the IC50, that is, an inhibition 50%, for a molecular target of interest.

ES 2 645 367 T3

The present disclosure provides methods for evaluating the biological activity of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof. In one method, an assay based on enzyme activity can be used. In a specific enzyme activity assay, the enzyme activity is that of a kinase. As used herein, kinase refers to a large class of enzymes that catalyze the transfer of γ-phosphate from ATP to the hydroxyl group on the Ser / Thr or Tyr side chain in proteins and peptides and are intimately involved in control of various important cellular functions, perhaps most notably: signal transduction, differentiation, and proliferation. It is estimated that there are approximately 2,000 distinct protein kinases in the human body, and although each of them phosphorylates particular protein / peptide substrates, they all bind to the same second ATP substrate in a highly conserved pocket. Approximately 50% of the known oncogene products are protein tyrosine kinases (PTKs), and their kinase activity has been shown to lead to cell transformation. Preferably, the kinase tested is a tyrosine kinase.

A change in enzyme activity caused by a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, can be measured in the assays described. The change in enzyme activity can be characterized by the change in the extent of phosphorylation of certain substrates. As used herein, phosphorylation refers to the addition of phosphate groups to a substrate, which includes proteins and organic molecules; and, plays an important role in regulating the biological activities of proteins. Preferably, the assayed and measured phosphorylation involves the addition of phosphate groups to tyrosine residues. The substrate can be a peptide or protein.

In some assays, immunological reagents are used, for example, antibodies and antigens. Fluorescence can be used in the measurement of enzyme activity in some assays. As used herein, fluorescence refers to a process through which a molecule emits a photon as a result of the absorption of a higher energy incoming photon by the same molecule. Specific methods for evaluating the biological activity of the disclosed compounds are described in the examples.

As used herein, a c-Met activity refers to any biological function or activity that is carried out by c-Met. For example, one function of c-Met includes phosphorylation of target proteins in the 3 'direction. Other functions of c-Met include autophosphorylation, binding of adapter proteins such as Gab-1, Grb-2, Shc, SHP2, and c-Cbl, and activation of signal transducers such as Ras, Src, PI3K, PLC-γ, STATs, ERK1 and 2 and FAK

Administration of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a cell or subject in need thereof results in modulation (i.e., stimulation or inhibition) of a activity of an intracellular target (eg, substrate). Various intracellular targets can be modulated with the compounds of the present invention, including, but not limited to, adapter proteins such as Gab-1, Grb-2, Shc, SHP2, and c-Cbl, and signal transducers such as Ras , Src, PI3K, PLC-γ, STATs, ERKS and 2 and FAK.

Activation refers to placing a composition of matter (eg, protein or nucleic acid) in an appropriate state to carry out a desired biological function. A composition of matter capable of being activated also has an inactivated state. An activated matter composition may have an inhibitory or a stimulating biological function, or both.

Elevation refers to an increase in the desired biological activity of a composition of matter (eg, a protein or a nucleic acid). Elevation can occur through an increase in the concentration of a composition of matter.

As used herein, a "cell cycle checkpoint" pathway refers to a biochemical pathway that is involved in modulation of the cell cycle checkpoint. A cell cycle checkpoint pathway can have stimulatory or inhibitory effects, or both, on one or more functions that comprise a cell cycle checkpoint. A cell cycle checkpoint pathway is composed of at least two compositions of matter, preferably proteins, which contribute to modulation of the cell cycle checkpoint. The cell cycle checkpoint pathway can be activated by activating one or more members of the cell cycle checkpoint pathway. Preferably, a cell cycle checkpoint pathway is a biochemical signaling pathway.

As used herein, "cell cycle checkpoint regulator" refers to a composition of matter that can function, at least in part, in modulating the cell cycle checkpoint. A cell cycle checkpoint regulator can have stimulatory or inhibitory effects, or both, on one or more functions that comprise a cell cycle checkpoint. A cell cycle checkpoint regulator may or may not be a protein.

ES 2 645 367 T3

Treatment of cancer or a cell proliferative disorder can result in cell death, and preferably, cell death results in a decrease of at least 10% in the number of cells in a population. More preferably, cell death means a decrease of at least 20%; more preferably, a decrease of at least 30%; more preferably, a decrease of at least 40%; more preferably, a decrease of at least 50%; more preferably, a decrease of at least 75%. The number of cells in a population can be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy, and light microscopy. Cell death measurement methods are as shown in Li et al., Proc Natl Acad Sci US A. 100 (5): 2674-8, 2003. In one aspect, cell death occurs by apoptosis.

Preferably, an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is not significantly cytotoxic to normal cells. A therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in more than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in more than 10% of normal cells. In one aspect, cell death occurs by apoptosis.

Contact of a cell with a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce or activate cell death in cancer cells. Administration to a subject in need thereof of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce or activate cell death in cancer cells. Contact of a cell with a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce cell death in one or more cells affected by a cell proliferative disorder. Preferably, administration to a subject in need of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, selectively induces cell death in one or more cells affected by a proliferative disorder. mobile.

The present disclosure relates to a method of treating or preventing cancer by administering a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, to a subject in need thereof, where the Administration of the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, results in one or more of the following: accumulation of cells in G1 and / or S phase of the cell cycle, cytotoxicity through cell death in cancer cells without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2, and activation of a cell cycle checkpoint. As used herein, "therapeutic index" is the maximum tolerated dose divided by the effective dose.

One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts, of course, can also be referred to when making or using an aspect of the invention. As used herein, combination therapy or co-therapy includes administration of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, and at least one second agent as part of a specific treatment regimen intended to provide the beneficial effect of the joint action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, the joint pharmacokinetic or pharmacodynamic action resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination generally takes place over a defined period of time (generally minutes, hours, days or weeks depending on the combination selected). Combination therapy may be, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.

Combination therapy is intended to include the administration of these therapeutic agents in a sequential manner, in which each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneously. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple individual capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent may be effected by any appropriate route including, but not limited to, routes

ES 2 645 367 T3 oral, intravenous routes, intramuscular routes and direct absorption through the tissues of the mucous membrane. Therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not strictly critical.

Combination therapy also encompasses the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-pharmacological therapies (eg, surgery or radiation treatment). When the combination therapy further comprises a non-pharmacological treatment, the non-pharmacological treatment can be carried out at any appropriate time provided that a beneficial effect is achieved from the joint action of the combination of therapeutic agents and the non-pharmacological treatment. . For example, in appropriate cases, the beneficial effect is still achieved when non-drug treatment is temporarily removed from the administration of therapeutic agents, perhaps for days or even weeks.

A compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, can be administered in combination with a second chemotherapeutic agent. The second chemotherapeutic agent (also called an antineoplastic agent or an antiproliferative agent) can be an alkylating agent; an antibiotic; an antimetabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTOR inhibitor; a multikinase inhibitor; a serine / threonine kinase inhibitor; a tyrosine kinase inhibitor; a VEGF / VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a venous topoisomerase drug, an enzyme or molecular target inhibitor (e.g., a kinase inhibitor), a cytidine or any chemotherapeutic, antineoplastic, or antiproliferative agent listed at www.cancer.org/docroot/cdg/cdg_0.asp.

Exemplary alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan (Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU); dacarbazine (DTICDome); oxaliplatin (Eloxatin); carmustine (Gliadel); ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran); carboplatin (Paraplatin); cisplatin (CDDP; platinol); temozolomide (Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin (Zanosar).

Exemplary antibiotics include, but are not limited to, doxorubicin (Adriamycin); liposomal doxorubicin (Doxil); mitoxantrone (Novantrone); bleomycin (Blenoxane); daunorubicin (cerubidin); liposomal daunorubicin (DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); Idarubicin (Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin (Nipent); or valrubicin (Valstar).

Exemplary antimetabolites include, but are not limited to, fluorouracil (Adrucil); Capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine (Arranon); cladribine (Cladribine Novaplus); Clofarabine (Chlolar); cytarabine (Cytosar-U); decitabine (Dacogen); liposomal cytarabine (DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine (FUDR); gemcitabine (Gemzar);

cladribine (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall); thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

Exemplary detoxifying agents include, but are not limited to, amifostine (Ethyol) or mesna (Mesnex).

Exemplary interferons include, but are not limited to, interferon alfa-2b (Intron A) or interferon alfa-2a (RoferonA).

Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); rituximab (Ritual); cetuximab (Erbitux); Panitumumab (Vectibix); tositumomab / iodine131 tositumomab (Bexxar); alemtuzumab (Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab (Mylotarg); eculizumab (Soliris) Ordenosumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva); Panitumumab (Vectibix); PKI-166; canertinib (CI-1033); Matuzumab (Emd7200) or EKB569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb) or AC480.

Histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron; Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); Letrozole (Femara); 83

ES 2 645 367 T3 triptorelin (Trelstar LA; Trelstar Depot); exemestane (Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole (Arimidex); fluoxymesterone (Androxy; Halotestin); Medroxyprogesterone (Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin); toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron); Abarelix (Plenaxis); or testolactone (Teslac).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin; Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos; VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole; epothilone; vinorelbine (Navelbine); camptothecin (CPT); Irinotecan (Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; or AP23573.

Exemplary multikinase inhibitors include, but are not limited to, sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474; PKC-412; motesanib; or AP24534.

Exemplary serine / threonine kinase inhibitors include, but are not limited to, ruboxistaurin; eryl / easudil hydrochloride; flavopiridol; seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412; bryostatin; KAI-9803; SF1126; VX-680; And1152; Arry-142886 (AZD-6244); SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.

Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS354825; SKI-606 CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

Exemplary VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; Péptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epothilones, and navelbine.

Exemplary topoisomerase poisonous drugs include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin, and idarubicin.

Illustrative taxanes or derivatives of taxanes include, but are not limited to, paclitaxel and docetaxol.

Exemplary general antiproliferative, antineoplastic, and chemotherapeutic agents include, but are not limited to, altretamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase (Elspar); levamisole (Ergamisole); mitotane (Lysodren); procarbazine (Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak); Porfimer (Photofrin); Aldesleukin (Proleukin); Lenalidomide (Revlimid); bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel); arsenic trioxide (Trisenox); verteporfin (Visudyne); mimosine (leucenol); (tegafur1M -5-chloro-2,4-dihydroxypyrimidine 0.4M potassium oxonate 1M) or lovastatin.

In another aspect, the second chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor). In another aspect, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, can be administered in combination with radiation therapy. Radiation therapy can also be administered in combination with a compound of the present invention and another chemotherapeutic agent described herein as part of multiple agent therapy. In yet another aspect, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, can be administered in combination with standard chemotherapy combinations such as, but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel), rituximab, Xeloda (capecitabine), cisplatin (CDDP), carboplatin, TS-1 (tegafur, gimestat and potassium otastat in a molar ratio of 1: 0.4: 1), camptothecin 11 (CPT-11, Irinotecan or Camptosar ™) or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone).

In preferred embodiments, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can be administered with an inhibitor of an enzyme, such as a receptor or non-receptor kinase. Receptor and non-receptor kinases are, for example, tyrosine kinases or serine / threonine kinases. Kinase inhibitors are small molecules, polynucleic acids, polypeptides, or antibodies.

Exemplary kinase inhibitors include, but are not limited to, Bevacizumab (targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab / Erbitux (targets Erb1), Imatinib / Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2), Gefitinib / Iressa (targets EGFR), Ranibizumab (targets VEGF), Pegaptanib (targets

ES 2 645 367 T3

VEGF), Erlotinib / Tarceva (targets Erb1), Nilotinib (targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2 / Her2), GW-572016 / lapatinib ditosylate (targets HER2 / Erb2), Panitumumab / Vectibix (targets EGFR), Vandetinib (targets RET / VEGFR), E7080 (targets multiples including RET and VEGFR), Herceptin (targets HER2 / Erb2), PKI-166 (targets EgFR ), Canertinib / CI-1033 (targets EGFR), Sunitinib / SU-11464 / Sutent (targets EGFR and FLT3), Matuzumab / Emd7200 (targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR), PKC-412 (targets VEGR and FLT3), Vatalanib / Ptk787 / ZK222584 (targets VEGR), CEP-701 (targets to FLT3), SU5614 (going to FLT3), MLN518 (going to FLT3), XL999 (going to FLT3), VX-322 (going to FLT3), Azd0530 (going to SRC), BMS-354825 ( targets sRc), SKI-606 (targets sRc), CP-690 (targets JAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 ( addresses JAK), sorafenib / Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3, and RET), Dasatinib / Sprycel (BCR / ABL and Src), AC-220 ( targets Flt3), AC-480 (targets all HER, panHER proteins), Motesanib diphosphate (targets VEGF1-3, PDGFR and c-kit), Denosumab (targets RANKL, inhibits SRC) AMG888 ( targets HER3), and AP24534 (targets multiple including Flt3).

Exemplary serine / threonine kinase inhibitors include, but are not limited to, Rapamune (targets mTOR / FRAP1), Deforolimus (targets mTOR), Certican / Everolimus (targets mTOR / FRAP1), AP23573 (targets mTOR / FRAP1), targets mTOR / FRAP1), Eril / Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK), Seliciclib / CYC202 / Roscovitrine (targets CDK), SNS-032BMS-387032 (targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets pKc), Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K), VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase), Arry-142886 / AZD-6244 (targets MAP / MEK), SCIO-469 (targeting MAP / MEK), GW681323 (targeting MAP / MEK), CC-401 (targeting JNK), CEP-1347 (targeting JNK) and PD 332991 (targeting JNK) directs CDK).

Compound 76 is a novel, synthetic, orally bioavailable small molecule microtubule polymerization inhibitor with very high CNS penetration. Compound 76 is shown in Table 1. The efficacy of compound 76 as a novel anticancer agent is directly tested using the malignant glioma mouse model. Compound 76 is an orally administered tubulin polymerization inhibitor that binds to a new site on heterodimeric tubulin, and to a new conformation of the dimer. Compound 76 can inhibit Src signaling in tumors. Compound 76 has been evaluated in various brain tumor cell lines. In all cases, compound 76 inhibited proliferation with GI50 <55 nM. When administered orally to mice at a dose of 10 mg / kg, the ratio of drug levels in the brain compared to plasma levels was 0.76, indicating excellent penetration of BBB as in Example 1 .

Compound 76 was evaluated in various human and mouse brain tumor cells derived from glioblastoma multiforme, astrocytoma, and medulloblastoma. Compound 76 potently inhibited the growth of these brain tumor cells. When administered to mice, compound 76 penetrated the brain by 76%, successfully tackling the first major challenge in brain cancer drug discovery. Drugs used to treat brain tumors often penetrate only 20% or less. In mice with aggressive brain tumors, compound 76 not only very significantly slows the rate of tumor growth, but also up to 60% of mice treated with the drug experience a complete regression of the tumor and do not reappear within their normal life (approximately 2 years for mice). Temodar has also been evaluated in this mouse model for comparison, and it does not cause complete tumor regression, but rather slows the growth rate of tumors. Furthermore, mice treated with compound 76 were observed to have much less brain edema than placebo or mice treated with Temodar.

Compound 76 was also evaluated in the orthotropic GL261 glioma model in immunocompetent, syngeneic C57BL / 6 mice. Mice implanted intracerebrally with 1x1005 GL261 cells treated with carrier alone (saline) have a median survival time (MeST) of 21 days (range 18-28). Mice treated with oral compound 76 (30 mg / kg, bid) have a MeST of 30.5 days ranging from 23 to 32 days. In contrast, when compound 76 is administered orally (30 mg / kg, sid) the MeST increases beyond 120 days, with more than 60% of the treatment group still alive 12 months later (p <0.0001). Samples from these mice also showed lymphocytic infiltration of the tumor site. Further experiments were performed using a SCID version of C57BL / 6 mice (B6.CB17-Prkdcscid/ SzJ), a B6 reference mouse model, but it is immunocompromised. In this SCID model, mice with GL261 intracerebral tumors and treated with vehicle alone had similar survival to the immunocompetent C57BL / 6 counterpart, however, mice treated with compound 76 now only had a MeST of 40 days (interval 29- 75). SCID mice that survived longer than 45 days all proceeded to develop lethal GL261 gliomas (seen by MRI) shortly after the drug was discontinued. C57BL / 6 mice cured in the above group (immunocompetent) also subsequently rejected a second GL261 tumor implant challenge. Additional molecular studies show that compound 76 increased the expression and altered the localization of intracellular survivin, a molecule that can be targeted by immunotherapy.

ES 2 645 367 T3 greater progression. Subsequent rejection of a second tumor in these mice is indicative of immune memory. This magnitude of the antitumor effect was not observed in the SCID models leading to the possibility that compound 76 could be involved in an antitumor immune response.

Compound 76 slows the growth rate of intracerebral GL261 glioma relative to control groups. When given a single dose per day (sid) compound 76 led to complete tumor regression in up to 60% of treated mice without further progression. Long-term surviving C57BL / 6 mice subsequently rejected a second GL261 tumor implant challenge, consistent with the generation of productive immune memory. This magnitude of the antitumor effect was not observed in the immunocompromised mice, suggesting that the once daily dosing regimen with compound 76 allows the generation of an effective immune response that contributes to long-term cure.

3. Examples

Example 1: Penetration into brain tissue

Compound 76 shows penetration into brain tissue, as reported in Table 4.

Table 4: Brain and plasma pharmacokinetic parameters of compound 76 in male CD-1 mice after a single oral dose of 10 mg / kg

<td>Sample ID</td><td>Tmax (hr)</td><td>Cmax (ng / mL)</td><td>AUClast (ng-hr / mL)</td>

<td>Brain</td><td> 1.00</td><td> 279</td><td> 656</td>

<td>Plasma</td><td> 1.00</td><td> 426</td><td> 863</td>

Cmax and AUClast of the brain are in ng / g and ng-hr / g, respectively. Compound 76 has 76% brain penetration of plasma.

To determine the ability of compound 76 to penetrate brain tissue, mice received a single oral dose of 10 mg / kg. The concentration of compound 76 was measured in plasma and brain tissue homogenates. This analysis indicates that 76% of the drug that enters the plasma is divided into brain tissue.

Example 2: inhibition of cell growth

The drug concentration required to block net cell growth by 50% relative to a control sample is measured as the GI50. The GI50's for several of the compounds of the invention were tested as described herein.

The HT29 cell line is an NCI standard human colon carcinoma cell line. HT29 cells were obtained from ATCC at passage 125 and used for inhibition studies between passage 126-151. HT29 cells were routinely cultured in McCoy's 5A medium supplemented with fetal calf serum (1.5% v / v) and L-glutamine (2 mM).

C-Src 3T3 is a normal mouse fibroblast NIH 3T3 cell line that has been transfected with a human c-Src mutant point in which tyrosine 527 has been converted to a phenylalanine. This mutation results in "constitutively active" c-Src because phosphorylation of tyrosine 527 results in self-inhibition of Src causing it to fold into its own SH2 domain. With a Phe there, this phosphorylation cannot occur and therefore automatic inhibition cannot occur. In this way, the always fully active mutant Src then converts normal mouse fibroblasts into rapidly growing tumor cells. Since hyperactive Src is the main factor driving growth in these cells (particularly when grown under low-growth serum conditions), compounds active to block this growth are believed to work by blocking Src signaling (for example, as a direct inhibitor of Src kinase or as an inhibitor acting elsewhere in the Src signaling cascade). Cells were routinely cultured in DMEM supplemented with fetal calf serum (2.0% v / v), L-glutamine (2 mM), and sodium pyruvate (1 mM).

In the BrdU assay for cell growth inhibition, quantification of cell proliferation was based on measurement of BrdU incorporation during DNA synthesis. The BrdU Cell Proliferation ELISA Assay Kit (Colorimetric) was obtained from Roche Applied Science and performed according to the supplier's instructions.

Growth inhibition was expressed as a GI50 where the GI50 is the sample dose that inhibits 50% of cell growth. Growth inhibition (GI) is determined from the formula GI = (Tü-Tn x100 / Tü-CONn) where T0 is the BrdU growth of the untreated cells at time 0, Tn is the BrdU growth of the cells treated on day n and CONn is the BrdU growth control of control cells on day n. The GI50 was extrapolated and the data was plotted using XL-Fit 4.0 software.

ES 2 645 367 T3

The actively growing cultures were trypsinized and the cells were resuspended in 190 gL of appropriate culture medium supplemented with 1.05% FBS in each well of a 96-well culture plate (1000 HT-29 cells; 2500 c- Src 3T3). For the 96-well culture plate experiments, c-Src 3T3 medium was supplemented with 10 mM HEPES buffer. HT-29 cells were seeded in standard tissue culture 96-well plates and c-Src 3T3 cells were seeded in Poly-Dlysine coated 96-well plates (BIOCOAT ™). To increase CO2 diffusion, 96-well c-Src 3T3 plates were incubated with their lids raised by ~ 2mm using sterile rubber lids.

Plates with 96 seeded wells were allowed to bind and bind overnight, for 18-24 hours, either at 37 ° C and 5% CO2 for HT-29 or at 37 ° C and 10% CO2 for c- Src 3T3. Approximately 18-24 hours after seeding, initial cell growth (T0) was determined for untreated cells using the BrdU assay. Samples were reconstituted in 20 mM DMSO and intermediate dilutions were made using DMEM containing 10% FBS. Final assay concentrations were 1.5% for FBS and 0.05% for DMSO. Samples were added as 10 µl aliquots in triplicate and plates were incubated as before for ~ 72 hours. Negative (vehicle) and positive (eg, AZ (KX2-328)) controls were included. Plates were tested for BrdU and data analyzed as above for GI50.

The results are shown in Table 5. In this table, the data is listed as% control growth, such that a lower number at an indicated concentration indicates a greater potency of the compound to block the growth of that tumor cell line. . All compounds were initially prepared as 20 mM DMSO stock solutions and then diluted in buffer for in vitro tumor growth assays. NG means that there is no cell growth beyond the control and T means that the number of cells in the drug-treated wells was lower than in the control (that is, loss of net cells). NT indicates that the test was not performed. Compound AZ (KX2-328) is a competitive ATP tyrosine kinase inhibitor, as described in Plé et al., J. Med. Chem, 47: 871-887 (2004).

As shown in Table 5, GI50's were obtained for various compounds in other cell lines. These GI50's were determined using standard tumor growth inhibition assays, similar to those described in detail for the HT29 cell line above, and the following cell lines: KM12 colon tumor cell lines, H460 lung cancer cell line and A549 lung cancer cell (all are NCI standard tumor cell lines).

Table 5:

<td></td><td colspan="3">HT-29 growth, Mean% of control, n = 3</td><td></td><td colspan="3">C-Src 3T3 growth, Mean% of control, n = 3</td>

ES 2 645 367 T3

ES 2 645 367 T3

<td> 64</td><td></td><td></td><td></td><td>1,430 nM (c-Src 3T3); inactive (HT-29)</td><td></td><td></td><td></td>

<td> 37</td><td></td><td></td><td></td><td>897 nM (c-Src 3T3); inactive (HT- 29)</td><td></td><td></td><td></td>

<td> 38</td><td></td><td></td><td></td><td>Inactive (c-Src 3T3); 1,860 nM (HT-29)</td><td></td><td></td><td></td>

<td> 60</td><td></td><td></td><td></td><td>Inactive (c-Src 3T3); inactive (HT-29)</td><td></td><td></td><td></td>

<td> 135</td><td></td><td></td><td></td><td>inactive (c-Src 3T3); inactive (HT-29)</td><td></td><td></td><td></td>

<td colspan="8">NG = No growth, total inhibition of growth; T = Cytotoxic effect on cells, negative growth; NT = not tested</td>

Table 6 shows the inhibition of compound 134 and compound 76 in brain tumor cell lines. These GI50's were determined using standard tumor growth inhibition assays.

Table 6. GI50 of Compound 76, Compound 134, and Dasatinib in Brain Tumor Cell Lines:

<td>Line mobile</td><td>IC50 Compound 76</td><td>IC50 Compound 134</td><td>IC50 Dasatinib</td><td>Organism</td><td>Disease</td><td>Morphology</td><td>Tumorigenic</td>

<td>Daoy</td><td>54.9 nM</td><td>13.6 nM</td><td>2927 nM</td><td>Human</td><td>Medulloblastoma cerebellar desmoplastic</td><td>Polygonal</td><td>Yes</td>

<td>SK-N- MC</td><td>0.13 nM</td><td>5.8 nM</td><td>5114 nM</td><td>Human</td><td>Neuroepithelioma</td><td>Epithelial</td><td>Yes</td>

<td>SW1088</td><td>22.1 nM</td><td>76.1 nM</td><td>897.3 nM</td><td>Human</td><td>Astrocytoma</td><td>Fibroblast</td><td>Yes</td>

ES 2 645 367 T3

<td>LN-18</td><td>2.9 nM</td><td>14.5 nM</td><td>565.3 nM</td><td>Human</td><td>Glioblastoma; glioma</td><td>Epithelial</td><td>Yes</td>

<td>SK-N-FI</td><td>0.46 nM</td><td>1.7 nM</td><td>12.6 nM</td><td>Human</td><td>Neuroblastoma</td><td>Epithelial</td><td>Yes</td>

<td>U87</td><td>9.7 nM</td><td>33.1 nM</td><td>1586 nM</td><td>Human</td><td>Glioblastoma; astrocytoma</td><td>Epithelial</td><td>Yes</td>

<td>GL261</td><td>8.8 nM</td><td>13.7 nM</td><td>17.7 nM</td><td>Mouse</td><td>Glioblastoma</td><td>Epithelial</td><td>Yes</td>

Example 3: Exposure to plasma and brain

The compounds of the invention demonstrate good plasma / brain exposure. For example, plasma and brain exposure of compound 134 (also referred to as compound 134 and compound 134) and compound

76 (also referred to as compound 76) are described below. Plasma concentrations were measured in mice after oral administration. All doses were formulated in purified water. Four groups of male CD-1 mice were dosed after an overnight fast and fed 4 hours after dosing. The dosage was as follows:

<td>Group number</td><td>Route</td><td>Compound</td><td>Dose (mg / kg) *</td><td>Dose Vol. (ML / kg)</td>

<td> 1</td><td>PO</td><td>Compound 134 Mesylate</td><td> 10</td><td> 10</td>

<td> 2</td><td>PO</td><td>Compound 134 Mesylate</td><td> 50</td><td> 10</td>

<td> 3</td><td>PO</td><td>Compound 76 2HCl</td><td> 10</td><td> 10</td>

<td> 4</td><td>PO</td><td>Compound 76 2HCl</td><td> 50</td><td> 10</td>

<td colspan="5">* Note: the doses administered were mg of free base / kg</td>

The protein was precipitated with 0.25 mL of acetonitrile for plasma, 0.25 mL for brain. After centrifugation, the supernatant was injected directly into an LC / MS system. The limit of quantification was 1 ng / mL using a 50 pL aliquot for plasma and a 50 pL aliquot for brain. The standard curve was 1 to 1,000 ng / mL for both plasma and brain.

The HPLC conditions were as follows:

HPLC system: Shimadzu SCL-10 system

Analytical column: Aquasil C18 column 5 pm 100x2 mm.

Column temperature: Room temperature

Autosampler Temperature: Room Temperature

Mobile phase A) 10 mM ammonium formate in water (pH 4)

B) Acetonitrile.

Flow rate: 0.6 mL / min

Injection volume: 2 pL

Gradient:

<td>Time (minute)</td><td> 0.0</td><td> 1.6</td><td> 2.6</td><td> 3.8</td><td> 3.9</td><td> 4.1</td><td> 4.4</td><td> 4.6</td><td> 4.65</td><td> 7.0</td>

The mass spectrometry conditions were as follows:

ES 2 645 367 T3

Instrument: ABI Sciex API 4000

Mode: ESI +

Experiment: MRM (Multiple Reaction Monitoring)

Transitions: Compound 134: m / z 432.4 114.2 (Rt = 3.11 minute)

Compound 76: m / z 406.1 253.2 (Rt = 3.33 minute)

Tables 7-10 below show plasma and brain concentrations after administration of a single oral dose of compound 76 at 10 mg / kg and 50 mg / kg.

Table 7. Plasma concentrations (ng / mL) of compound 76 in male CD-1 mice after a single PO dose of 10 mg / kg (Group 3)

<td>Time (hr)</td><td>Group A</td><td>B Group</td><td>Group C</td><td>Half</td><td>SD</td><td>% CV</td>

NA: not applicable

BLQ: below the limit of quantification (1 ng / mL) BLQ = 0 when calculating the mean, SD and% CV

Table 8. Brain concentrations (ng / g) of compound 76 in male CD-1 mice after a single PO dose of 10 mg / kg (Group 3)

<td>Time (hr)</td><td>Group A</td><td>B Group</td><td>Group C</td><td>Half</td><td>SD</td><td>% CV</td>

Table 9. Plasma concentrations (ng / mL) of compound 76 in male CD-1 mice after a single PO dose of 50 mg / kg (Group 4)

<td>Time (hr)</td><td>Group A</td><td>B Group</td><td>Group C</td><td>Half</td><td>SD</td><td>% CV</td>

ES 2 645 367 T3

Table 10. Brain concentrations (ng / g) of compound 76 in male CD-1 mice after a single PO dose of 50 mg / kg (Group 4)

<td>Time (hr)</td><td>Group A</td><td>B Group</td><td>Group C</td><td>Half</td><td>SD</td><td>% CV</td>

The brain and plasma pharmacokinetic parameters of compound 76 in mice after a single dose of 10 mg / kg (Group 3) are as follows:

<td>Sample ID</td><td>Tmax (hr)</td><td>Cmax (ng / mL)</td><td>AUClast (ng-hr / mL)</td>

<td>Brain</td><td> 1.00</td><td> 279</td><td> 656</td>

<td>Plasma</td><td> 1.00</td><td> 426</td><td> 863</td>

<td colspan="4">Note: Brain Cmax and AUClast are in ng / g and ng-hr / g, respectively.</td>

The ratio of AUClast brain / AUClast plasma is 0.76.

The brain and plasma pharmacokinetic parameters of compound 76 in mice after a single dose of 50 mg / kg (Group 4) are as follows:

<td>Sample ID</td><td>Tmax (hr)</td><td>Cmax (ng / mL)</td><td>AUClast (ng-hr / mL)</td>

<td>Brain</td><td> 0.5</td><td> 1379</td><td> 3338</td>

<td>Plasma</td><td> 1.00</td><td> 2137</td><td> 5443</td>

<td colspan="4">Note: Brain Cmax and AUClast are in ng / g and ng-hr / g, respectively.</td>

The AUClast brain / AUClast plasma ratio is 0.61.

Example 4: glioma survival studies

A mouse brain tumor xenograft study was performed, comparing compound 76 and compound 134 (compound 134) with Temodar®. The studies were conducted in C57BL / 6 mice. GL261 glioma cells (1 x

105 in 5 pL of DMEM) were implanted in intracranial coordinates: bregma, lateral 2.0 mm, anterior 1.2 mm,

3.0mm deep hard. Treatment started 3 days after implantation. The groups were as follows (all doses in 100 ml H2O):

Vehicle (H2O)

Compound 134 2.5 mg / kg orally twice daily Compound 134 5 mg / kg orally twice daily Compound 76 15 mg / kg

Compound 76 30 mg / kg Temodar® 5 mg / kg oral twice daily oral twice daily oral once weekly

Table 11 below shows a summary of the results. Median survival interval and results of log-rank (Mantel-Cox) statistical tests comparing survival distributions of

ES 2 645 367 T3 the samples. Compound 76 showed the best results when administered orally at 15 mg / kg / dose twice daily 7 hours apart.

Table 11

<td></td><td>Vehicle</td><td>Compound 134 2.5mg / kg oral two times a day</td><td>Compound 134 5mg / kg oral twice up to date</td><td>Compound 76 15 mg / kg oral twice daily day</td><td>Compound 76 30 mg / kg oral twice daily day</td><td>Temodar® 5mg / kg once a week xl oral</td>

<td>Median survival interval:</td><td> 22 21-25</td><td> 25 22-36</td><td> 23 22-29</td><td> 30.5 25-34</td><td> 29 23-32</td><td> 29 26-29</td>

<td colspan="7">(Mantel-Cox) Log-Rank Test</td>

<td>vs. Vehicle</td><td></td><td>P = 0.1062</td><td>P = 0.1762</td><td>P = 0.0106</td><td>P = 0.0425</td><td>P = 0.0017</td>

<td>vs. Compound 134 2.5 mg / kg</td><td></td><td></td><td></td><td>P = 0.7559</td><td>P = 0.6530</td><td>P = 0.8901</td>

<td>vs. Compound 134 5mg / kg</td><td></td><td></td><td></td><td>P = 0.0605</td><td>P = 0.1166</td><td>P = 0.1366</td>

Figures 2A-F show the weight gain in each of the C57BL / 6 mice in the different treatment groups. The average weight at the end point for each of the treatment groups is shown below in Table 12. Figure 3 is a graph showing the average weights over a 40 day period for each of the treatment groups.

Table 12

Average weight at end point

<td>Vehicle =</td><td>19.2g</td>

<td>Compound 76 15 mg / kg =</td><td>16.9 g</td>

<td>Compound 76 30 mg / kg =</td><td>15.0 g</td>

<td>Compound 134 2.5 mg / kg =</td><td>16.0 g</td>

<td>Compound 134 5 mg / kg =</td><td>14.3 g</td>

<td>Temodar® 5 mg / kg =</td><td>13.3 g</td>

Example 5. Evaluation in the orthotropic GL261 glioma model

Compound 76 was evaluated in the orthotropic GL261 glioma model in immunocompetent, syngeneic C57BL / 6 mice. Compound 76 is shown in Table 1. Mice implanted intracerebrally with 1x105 GL261 cells treated with carrier alone (saline) have a median survival time (MeST) of 21 days (range 18-28). Mice treated with oral compound 76 (30 mg / kg, bid) have a MeST of

30.5 days that varies between 23 and 32 days. In contrast, when compound 76 is administered orally (30 mg / kg,

sid) MeST increases to more than 120 days, with more than 60% of the treatment group still alive 12 months later (p <0.0001). Samples from these mice also showed lymphocytic infiltration of the tumor site. Further experiments were performed using a SCID version of C57BL / 6 mice (B6.CB17-Prkdcscid/ SzJ), a B6 reference mouse model, but it is immunocompromised. In this SCID model, mice with GL261 intracerebral tumors and treated with carrier alone had similar survival to the immunocompetent C57BL / 6 counterpart, however, mice treated with compound 76 now only had a MeST of 40 days (interval 29- 75). SCID mice that survived longer than 45 days all proceeded to develop lethal GL261 gliomas (seen by MRI) shortly after the drug was discontinued. C57BL / 6 mice

ES 2 645 367 T3 cured in the above group (immunocompetent) also subsequently rejected a second GL261 tumor implant challenge. Additional molecular studies show that compound 76 increased the expression and altered the localization of intracellular survivin, a molecule that can be targeted by immunotherapy.

The results of five independent studies indicate that compound 76 slows the growth rate of intracerebral GL261 glioma relative to control groups. When administered in a single daily dose (sid), compound 76 led to complete tumor regression in up to 60% of treated mice without further progression. Subsequent rejection of a second tumor in these mice is indicative of immune memory. This magnitude of the antitumor effect was not observed in the SCID models leading to the possibility that compound 76 could be involved in an antitumor immune response.

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