MX2007007910A

MX2007007910A - Compositions and methods of treating cell proliferation disorders

Info

Publication number: MX2007007910A
Application number: MXMX/A/2007/007910A
Authority: MX
Inventors: David G Hangauer
Original assignee: David G Hangauer; Kinex Pharmaceuticals Llc
Priority date: 2004-12-28
Filing date: 2007-06-27
Publication date: 2008-10-03

Abstract

The invention relates to compounds and methods for treating cell proliferation disorders.

Description

COMPOSITIONS AND METHODS OF TREATMENT OF CELLULAR PROLIFERATION DISORDERS BACKGROUND OF THE INVENTION With more than 563,000 deaths in the United States annually, cancer is the second leading cause of death behind heart dse (UBS Warburg "Dse Dynamics: The Cancer arket", Nov. 8, 2000). Surgery and radiotherapy can be curative if the dse is discovered early, but current therapies with drugs for metastatic dse are mainly palliative and rarely offer a long-term cure. Even with the new chemotherapies that enter the market, the improvement in patient survival is measured in months instead of years, and the need for new drugs persists, effective in combination with existing agents as first-line therapy and as second and third line therapies in the treatment of resistant tumors. The need in the art for improved treatments for cell proliferation and cancer disorders persists.

SUMMARY OF THE INVENTION The invention relates to compounds and methods of using the compounds to treat cell proliferation disorders. The compounds of the present invention are useful as pharmaceutical agents. For example, the compounds may be useful as antiproliferative agents, for the treatment of mammals, as for the treatment of humans and animals. The compounds can be used without limitation, for example, as anticancer, anti-angiogenesis, antimetastatic, antimicrobial, antibacterial, antifungal, antiparasitic and / or antiviral agents. The compounds of the invention are useful, for example, in the treatment of lung cancer. The compounds of the invention are also useful, for example, in the treatment of colon cancer. The compounds of the invention are also useful, for example, in the treatment of breast cancer. The compounds of the invention are useful in the treatment of dses and disorders that are modulated by the inhibition of tyrosine kinase. For example, the compounds of the invention are useful in the treatment of dses and disorders that are modulated by the Src kinase. The compounds of the invention may also be useful in the treatment of dses and disorders that are modulated by focal adhesion kinase (FAK).

The compounds of the invention include compounds of Formula I, and salts, solvates, hydrates or prodrugs thereof: Formula I where: T is absent (ie the rings are connected by a link), CR12R13, C (0), 0, S, S (0), S (0) 2, NR14, C (Ri5Ri6) C (Ri7Ri8 ), CH20 or 0CH2; Xy is CZ, CY, N or N-0; Xz is CZ, CY, N or N-0; at least one of Xy and Xz is CZ; Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5 or Ce), alkoxy Ci, C2, C3, C4, C5 or C6, 0-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, and 0-benzyl; Xa is CRa, N or N-0; Xb is CRb, N or N-0; Xc is CRC, N or N-0; Xd is CRd, N or N-0; Xe is CRe, N or N-0; Ra, Rb, RC Rdf Re, R 4, R 5, and Re are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or C6, alkoxy Ci, C2, C3, C4, C5 or C ^ , 0-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, 0-benzyl, alkyl Ci, C2, C3, C4, C5 or C6-0H, alkyl Ci, C2, C3, C4, C5 or C6-0-lower alkyl (Ci, C2, C3, C4, C5 or C6), COOH, C00-lower alkyl (Ci, C2, C3, C4, C5 or C6), S02H, S02-lower alkyl (Ci, C2, C3, C4, C5 or C6), or V or V- N I N- W wherein W is H or alkyl Ci, C2, C3, C, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6) -aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-; R12, Ri3 Ri Ri5 Rie, 17, and Rie, are, independently, H or alkyl Ci, C2, C3, C4, C5 or 0β; Z is: (CHRi) n-C (0) -NR2 (CHR3) m-Ar, where Ar is a heteroaryl group containing nitrogen or substituted or unsubstituted aryl, such as benzene, pyridine or pyrimidine. For example, Z is: wherein Rir R2, and R3 are independently H or alkyl Ci, C2, C3, C4, C5 or Ce; n and m are, independently 0, 1 or 2; R7, R8, Rg, Rio, and R11 are, independently, hydrogen, hydroxyl, halogen, Ci, C2, C3, C4, C5, or C6 alkyloxy, Ci, C2, C3, C, C5 or C6 alkoxy, O-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, O-benzyl, alkyl Ci, C2, C3, C4, C5 or C6-OH, alkyl Ci, C2, C3, C4, C5 or C6-0- alkyl Cx, C2, C3, C4, C5 or C6, wherein W is H or alkyl Ci, C2, C3, C, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0- CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of the invention, Z is Certain compounds of the invention are selected from Compounds 1-136 and 137. For example, the compound of the invention is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 or 137. The compounds of the invention include Compounds 33, 38, 40, 76, 133, 134, 136 and 137. In certain Compounds of Formula I, at least one of Xa, Xb, Xc, Xd and Xe is N. For example, in the compound of the Formula I, Xa is N and each of Xb, Xc, Xd and e is CR. In certain compounds of Formula I, Xy is CY, and Xz is CZ. For example, in certain compounds of Formula I, Y is hydrogen. In certain compounds of Formula I, Rb is Ci, C2, C3, C4, C5 or C6 alkoxy. For example, Rb is methoxy or ethoxy. In certain compounds of Formula I, Rb is hydrogen. In other compounds of Formula I, Rb is selected from F, Cl, Br, and I. to Formula I, Rb is wherein W is H or alkyl Ci, C2, C3, C4, C5 or alkyl Ci, C2, C3, C4, C5 or C6 ~ aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, V is a link. In certain compounds of Formula I, W is hydrogen. In other compounds of Formula I, W is alkyl Ci, C2, C3, C4, C5 or C In certain compounds of Formula I, Rc is Ci, C2, C3, C4, C5 or C6 alkoxy. For example, Rc is methoxy or ethoxy. In other compounds of Formula I, Rc is hydrogen, F, Cl, Br or I. In other compounds of Formula I, Rc is wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Cx, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, V is a link. In certain compounds of Formula I, W is hydrogen. In other compounds of Formula I, W is alkyl Ci, C2, C3, C4, C5 or c6. In certain compounds of Formula I, Rd is C1, C2, C3, C4, C5 or C6 alkoxy. For example, Rd is methoxy or ethoxy. In other compounds of Formula I, Rd is hydrogen, F, Cl, Br or I. In other compounds of Formula I, Rd is wherein is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, V is a link. In certain compounds of Formula I, W is hydrogen. In other compounds of Formula I, W is alkyl Ci, C2, C3, C4, C5 or C6 · The invention includes a solvate of a compound according to Formula I. The invention also includes a hydrate of a compound according to Formula I. The invention also includes a salt by acid addition of a compound according to Formula I. For example, a hydrochloride salt. The invention also includes a prodrug of a compound according to Formula I. The invention also includes a pharmaceutically acceptable salt of a compound of Formula I. The invention also includes a composition of a compound according to Formula I and at least one pharmaceutically acceptable excipient. The invention relates to a compound of Formula I, which has a structure according to one of Formulas II-XIII: Formula II: Formula III Formula IV: Formula V: 10 Formula XII Formula XIII: or a salt, solvate, hydrate or prodrug thereof, wherein: Rb, R, R5, Re, and Rio are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or C6 , alkoxy Ci, C2, C3, C4, C5 or Ce, O-lower alkyl (Ci, C2, C3, C4, C5 or Ce) -aryl, O-benzyl, alkyl Ci, C2, C3, C4, C5 or C6 ) -OH, alkyl Ci, C2, C3, C, C5 or C6-0-lower alkyl (Ci, C2, C3, C4, C5 or C6), COOH, COO-lower alkyl (Ci, C2, C3, C4, C5 or C6), S02H, S02-lower alkyl (Ci, C2, C3, C4, C5 or ~ w. Ce), where W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3 C4, C5 or C6-aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0- CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, in the compound of Formulas II-XIII, R8 is hydrogen, F, Cl, Br or I. For example, R8 is F. In certain compounds, Re is H. In certain compounds of Formulas II-XIII, Rb is Ci, C2, C3, C4, C5 or e alkoxy. For example, Rb is methoxy or ethoxy. In certain compounds of Formulas II-XIII, Rb is hydrogen, Cl, Br or I. In other compounds, in II-XIII, Rb is wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2 -, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formulas II-XIII, R4 is hydrogen, C1, C2, C3, C4, C5 or C6 alkoxy, F, Cl, Br or I. In other compounds, in the compound of Formulas II- where W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formulas II-XIII, R5 is hydrogen, alkoxy Ci, C2, C3, C4, C5 or C6, F, Cl, Br or I. In other compounds, in the compound of Formulas II- XIII, R5 is where is H or alkyl Cx, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formulas II-XIII, Ri0 is hydrogen, Ci, C2, C3, C4, C5 or C6 alkoxy, F, Cl, Br or I. For example, Rio is methoxy, ethoxy or isobutoxy. In other compounds of Formulas II-XIII, Ri0 is on whether w is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, in the compound of Formulas II-XIII, W is hydrogen or alkyl Ci, C2, C3, C4, C5 or C6. Certain compounds of the invention include compounds according to Formula II. The invention relates to a solvate of a compound according to one of Formulas II-XIII. The invention also relates to a hydrate of a compound according to one of Formulas II-XIII. The invention also relates to a salt by acid addition of a compound according to one of Formulas II-XIII. For example, a hydrochloride salt. In addition, the invention relates to a prodrug of a compound according to one of Formulas II-XIII. The invention also relates to a pharmaceutically acceptable salt of a compound of one of Formulas II-XIIII. The invention includes compositions comprising a compound according to one of Formulas I-XIII and at least one pharmaceutically acceptable excipient. Certain compounds of the invention are kinase inhibitors non-competitive with ATP. The invention also includes a method of preventing or treating a cell proliferation disorder by administering a pharmaceutical composition that includes a compound according to one of Formulas I-XIII or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient, to a subject in need thereof. For example, the cell proliferation disorder is pre-cancer or cancer. The cell proliferation disorder treated or prevented by the compounds of the invention can be a cancer, such as, for example, colon cancer or lung cancer. The cell proliferation disorder treated or prevented by the compounds of the invention can be a hyperproliferative disorder. The cell proliferation disorder treated or prevented by the compounds of the invention can be psoriasis. For example, the treatment or prevention of proliferative disorder can occur through the inhibition of a tyrosine kinase. For example, the tyrosine kinase can be a Src kinase or focal adhesion kinase (FAK). The invention relates to a method of treating or preventing a disease or disorder that is modulated by the inhibition of tyrosine kinase, by administration of a pharmaceutical composition that includes a compound according to Formula I or one of Formulas II-XIII or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient. For example, the disease or disorder that is modulated by tyrosine kinase inhibition is cancer, pre-cancer, a hyperproliferative disorder or a microbial infection. For example, the compound is a compound according to Formula I or II. The pharmaceutical composition of the invention can modulate a kinase path. For example, the kinase pathway is a Src kinase pathway or a focal adhesion kinase pathway. The pharmaceutical composition of the invention can modulate a kinase directly. For example, the kinase is Src kinase or focal adhesion kinase. Certain pharmaceutical compositions of the invention are kinase inhibitors non-competitive with ATP.

The compounds of the invention are also useful for treating or preventing a microbial infection, such as a bacterial, fungal, parasitic or viral infection. Certain pharmaceutical compositions of the invention include a compound selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 , 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 , 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137. For example, the pharmaceutical composition includes Compound 33, 38 , 40, 76, 133, 134, 136 or 137. Certain pharmaceutical compositions of the invention include a compound selected from the compounds listed in Table 2. A compound of the invention can be used as a pharmaceutical agent ico For example, a compound of the invention is used as an antiproliferative agent, for the treatment of humans and / or animals, such as for the treatment of humans and / or other mammals. The compounds can be used without limitation, for example, as anticancer, antiangiogenesis, antimicrobial, antibacterial, antifungal, antiparasitic and / or antiviral agents. Additionally, the compounds can be used for other disorders related to cell proliferation such as diabetic retinopathy, macular degeneration and psoriasis. Anticancer agents include anti-metastatic agents. The compound of the invention used as a pharmaceutical agent can be selected from Compounds 1-136 and 137. For example, the compound of the invention used as a pharmaceutical agent is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 or 137. For example, the compound of the invention used as a pharmaceutical agent is selected from Compounds 33, 38, 40, 76, 133, 134, 136 and 137. certain pharmaceutical agents include a sele compound of the compounds listed in Table 2. In one aspect of the invention, a compound of the invention, for example, a compound of Formula I or one of Formulas II-XIII, is used to treat or prevent a disorder of cell proliferation in a subject. In one aspect of the modality, the cell proliferation disorder is pre-cancer or cancer. In another aspect of the embodiment, the cell proliferation disorder is a hyperproliferative disorder. In another embodiment, the prevention or treatment of cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a kinase. In another embodiment, the prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a tyrosine kinase. In another embodiment, the prevention or treatment of cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of Src kinase or focal adhesion kinase (FAK). In another embodiment, the subject is a mammal. Preferably, the subject is human. The invention is also written for a method of treating or preventing cancer or a cell proliferation disorder in a subject, which comprises administering an effective amount of a compound of the invention, for example, a compound of Formula I or one of Formulas II-XIII. For example, the compound of the invention can be a kinase inhibitor. The compound of the invention can be a kinase inhibitor non-competitive with ATP. The compound of the invention can inhibit a kinase directly or can affect the kinase path. The above description more broadly establishes the most important features of the present invention in order that its following description can be understood, and in order that the present contributions to the art can be better appreciated. Other objects and features of the present invention will be apparent from the following detaidescription, considered in conjunction with the examples.

DETAILED DESCRIPTION OF THE INVENTION The details of one or more embodiments of the invention are set forth in the following appended description.

Although methods and materials similar or equivalent to those described herein can be used, in the practice or testing of the present invention, preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification, singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, this specification will take over. The invention relates to compounds and methods of using the compounds to treat cell proliferation disorders. The compounds of the present invention are useful as pharmaceutical agents, particularly as antiproliferative agents, for the treatment of humans and animals, particularly for the treatment of humans and other mammals. The compounds can be used without limitation, for example, as anticancer, antiangiogenesis, antimetastatic, antimicrobial, antibacterial, antifungal, antiparasitic and / or antiviral agents. The compounds can be used for other disorders related to cell proliferation such as psoriasis. Compounds of the invention include compounds of Formula I, and salts thereof:, wherein: T is absent (i.e., the rings are connected by a bond), CR12R13, C (0), 0, S, S (0), S (0) 2, NR14, C (RisRie) C (R17R18), CH20 or 0CH2; Xy is CZ, CY, N or N-0; Xz is CZ, CY, N or N-0; at least one of Xy and Xz is CZ; Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5 or C6, alkoxy Ci, C2, C3, C4, C5 or C6, 0-lower alkyl Ci, C2, C3, C4, C5 or C6) -aryl, and 0-benzyl; Xa is CRa or N or N-0; Xb is CRb, N or N-0; Xc is CRC or N or N-0; Xd is CRd or N or N-0; Xe is CRe, N or N-0; Ra, b, Rc, d, Re, R4, R5, and Re are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or C6, alkoxy Cx, C2, C3, C4, C5 or C6, 0-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, 0-benzyl, alkyl (Ci, C2, C3, C4, C5 or C6) -0H, alkyl (Ci, C2, C3) , C4, C5 or C6) -0-lower alkyl (Ci, C2, C3, C4, C5 or C6), COOH, C00-lower alkyl (Ci, C2, C3, C4, C5 or C6), S02H, S02- lower alkyl (Ci, C2, C3, C4, C5 or C6), wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-; R12, Ri3 Ri f Ri5 i6 / Ri7 and Ri8 are, independently, H or alkyl Ci, C2, C3, C4, C5 or C6; Z is (CHRi) n-C (0) -NR2 (CHR3) m-Ar, where Ar is a heteroaryl group containing aryl or substituted or unsubstituted nitrogen, such as benzene, pyridine or pyrimidine. For example, Z is: wherein Ri, R2, and R3 are independently H or alkyl Ci, C2, C3, C, C5 or CQ; n and m are, independently 0, 1 or 2; R7, R8, R9 / Rio / and R11 are, independently, hydrogen, hydroxyl, halogen, Ci, C2, C3, C4, C5 or C6 alkyl, Ci, C2, C3, C4, C5 or C6 alkoxy, O-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, O-benzyl, alkyl Ci, C2, C3, C4, C5 or C6-OH, alkyl Ci, C2, C3, C4, C5 or C6 ~ 0- alkyl Ci, C2, C3, C, C5 oe, V N-W. V-N, V- O O V-N N-W. - '-' ^ - '^ -' where W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of the invention, Z is Certain compounds of the invention are selected from Compounds 1-136 and 137. For example, the compound of the invention is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 , 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 , 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 , 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117 , 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 or 137. The compounds of the invention include Compounds 33 , 38, 40, 76, 133, 134, 136 and 137. In certain Compounds of Formula I, at least one of Xa, Xb, XC and Xe is N. For example, in the compound of Formula I, Xa is N and each of Xb, Xc, a and Xe is CR. In certain compounds of Formula I, Xy is CY, and Xz is CZ. For example, in certain compounds of the Formula I, Y is hydrogen. The compounds of the invention can tolerate a wide range of functional groups, therefore several substituted initial materials can be used to synthesize them. The syntheses described herein generally provide the final desired bi-aryl compound at or near the end of the entire process, although it may be desirable in certain cases to then convert the compound to a pharmaceutically acceptable salt, ester or prodrug thereof. In certain compounds of Formula I, Rb is Ci, C2, C3, C4, C5 or C6 alkoxy. For example, Rb is methoxy or ethoxy. In certain compounds of Formula I, Rb is hydrogen. In other compounds of Formula I, Rb is selected from F, Cl, Br, and I. For example, Rb is F. In other compounds of Formula I, Rb is wherein W is H or alkyl Ci, C2, C3, C4, C5 or Ce, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, V is a link. In certain compounds of Formula I, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formula I, W is hydrogen. In other compounds, W is alkyl Ci, C2, C3, C, C5 or C6. In some compounds, W is methyl. In certain compounds of Formula I, Rc is halogen, for example, Rc is F, Cl, Br or I. In some compounds, Rc is F. In other compounds, Rc is Cl. In some compounds, R c is C 1, C 2, C 3, C 4, C 5 or C 6 alkoxy. In some compounds, Rc is methoxy or ethoxy. In some modalities, Rc is ethoxy. In other compounds of Formula I, Rc is hydrogen. In other compounds of Formula I, Rc is where it is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In some compounds, V is a bond. In other compounds, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In some compounds of Formula I, W is hydrogen. In other compounds, W is alkyl Clf C2, C3, C4, C5 or C6. In certain compounds, W is methyl. In certain compounds of Formula I, Rb is Ci, C2, C3, C4, C5 or C6 alkoxy. For example, Rb is methoxy or ethoxy. In certain compounds of Formula I, Rb is hydrogen. In other compounds of Formula I, Rb is selected from F, Cl, Br, and I. For example, Rb is F. In other compounds of Formula I, Rb is / where is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6 ~ aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, V is a link. In certain compounds of Formula I, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formula I, it is hydrogen. In other compounds, W is alkyl Ci, C2, C3, C4, C5 or C6- In some compounds, W is methyl. In certain compounds of Formula I, Ra is halogen, for example, Rd is F, Cl, Br or I. In some compounds, Rd is F. In other compounds, Rd is Cl. In some compounds, Rd is alkoxy Ci, C2, C3, C, C5 or C6- In some compounds, Rd is methoxy or ethoxy. In some modalities, Rd is ethoxy. In other compounds of Formula I, Rd is hydrogen. In other compounds of Formula I, Rd is wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6 ~ aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In some compounds, V is a bond. In other compounds, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In some compounds of Formula I, W is hydrogen. In other compounds, W is alkyl Ci, C2, C3, C4, C5 or C6. In certain compounds, it is methyl. The invention relates to a compound of Formula I, which has a structure according to one of Formulas II-XIII: hydrate or prodrug thereof, wherein R < w R5, Re »Y Rio are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or C6, alkoxy Ci, C2, C3, C4, C5 or C6, O-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, O-benzyl, alkyl Ci, C2, C3, C4, C5 or C6-0H, alkyl Ci, C2, C3, C4, C5 or C6-0-lower alkyl ( Ci, C2, C3, C, C5 or C6), COOH, COO-lower alkyl (Ci, C2, C3, C4, C5 or C6), S02H, S02-lower alkyl (Ci, C2, C3, C4, C5 or C6), wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C, C5 or C6-aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2 -, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, in the compound of Formulas II-XIII, R8 is hydrogen, F, Cl, Br or I. For example, R8 is F. In certain compounds, R8 is H. In certain compounds of Formulas II-XIII, Rb is Ci, C2, C3, C4, C5 or C6 alkoxy. For example, Rb is methoxy or ethoxy. In certain compounds, Rb is ethoxy. In certain compounds, R is hydrogen. In certain compounds of Formulas II-XIII, Rb is Cl, Br or I. For example, Rb is F or Cl. In other compounds, in the compound of Formulas II-XIII, Rb is wherein W is H alkyl, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6 aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In some compounds, V is -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds W is H. In other compounds, W is alkyl Ci, C2, C3, C4, C5 or C6. For example, W is methyl. In certain compounds of Formulas II-XIII, R4 is hydrogen, Ci, C2, C3, C4, C5 alkoxy or Ce, F, Cl, Br or I. In some compounds, R 4 is C 1, C 2, C 3, C 4, C 5 or C 6 alkoxy. For example, R 4 is methoxy or ethoxy. In certain compounds, R4 is ethoxy. In other compounds, in the compound of Formulas II-XIII, R4 is V- H-, V-N i. V- O, O V- Nd-- w, wherein W is H or alkyl Ci, C2, C3, C4, C5 or Ce, alkyl Cx, C2, C3, C4, C5 or C6 ~ aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds, V is a bond. In other compounds, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formulas II-XIII, R5 is hydrogen, alkoxy Ci, C2, C3, C4, C5 or C6, F, Cl, Br or I. For example, R5 is hydrogen. In some compounds, R5 is ethoxy. In certain compounds R5 is F. In other compounds, in the compound of Formulas II-XIII, wherein is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds, V is a bond. In other compounds, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds of Formulas II-XIII, Rio is hydrogen, alkoxy Ci, C2, C3, C4, C5 or C6, F, Cl, Br or I. In some compounds Rio is alkoxy Ci, C2, C3, C, C5 or C6. For example, Rio is methoxy or ethoxy. In some compounds, Rio is isobutoxy. In some compounds, Rio is hydrogen. In certain compounds, Rio is halogen. For example, Rio is F or Cl. In other compounds of Formulas II-XIII, Rio wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6) -aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-. In certain compounds, V is a bond. In other compounds, V is -CH2-, -CH2CH2- or -CH2CH2CH2-. In other compounds, V is -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. For example, in the compound of Formulas II-XIII, W is hydrogen or alkyl Ci, C2, C3, C4, C5 or < Z In some compounds, W is methyl.

Certain compounds of the invention include compounds according to Formula II. The compounds of the invention include those listed in Table 1: Table 1 Other compounds are listed in Table 2.

?? ?? ?? The invention relates to a solvate of a compound according to one of Formulas I-XIII. The invention also relates to a hydrate of a compound according to one of Formulas I-XIII. The invention also relates to a salt by acid addition of a compound according to one of Formulas I-XIII. For example, a hydrochloride salt. In addition, the invention relates to a prodrug of a compound according to one of Formulas I-XIII. The invention also relates to a pharmaceutically salt acceptable of a compound of one of Formulas I-XIIII. The invention includes compositions comprising a compound according to one of Formulas I-XIII and at least one pharmaceutically acceptable excipient. Certain compounds of the invention are kinase inhibitors non-competitive with ATP. The invention also includes a method of preventing or treating a cell proliferation disorder by administering a pharmaceutical composition which includes a compound according to one of Formulas I-XIII or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient, to a subject in need thereof. For example, the cell proliferation disorder is pre-cancer or cancer. The cell proliferation disorder treated or prevented by the compounds of the invention can be cancer, such as, for example, colon cancer or lung cancer. The cell proliferation disorder treated or prevented by the compounds of the invention can be a hyperproliferative disorder. The cell proliferation disorder treated or prevented by the compounds of the invention can be psoriasis. For example, the treatment or prevention of proliferative disorder can occur through the inhibition of a tyrosine kinase. For example, tyrosine kinase can be, a Src kinase or focal adhesion kinase (FAK). The invention relates to a method of treating or preventing a disease or disorder that is modulated by the inhibition of tyrosine kinase, by administration of a pharmaceutical composition that includes a compound according to Formula I or one of Formulas II -XIII or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient. For example, the disease or disorder that is modulated by tyrosine kinase inhibition is cancer, pre-cancer, a hyperproliferative disorder or a microbial infection. For example, the compound is a compound according to Formula I or II. The pharmaceutical composition of the invention can modulate a kinase path. For example, the kinase pathway is a Src kinase pathway or focal adhesion kinase pathway. The pharmaceutical composition of the invention can modulate a kinase directly. For example, the kinase is Src kinase or focal adhesion kinase. Certain pharmaceutical compositions of the invention are kinase inhibitors non-competitive with ATP. For example, the compounds of the invention are useful for treating or preventing a microbial infection, such as a bacterial, fungal, parasitic or viral infection. Certain pharmaceutical compositions of the invention include a compound selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 ,. 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137. For example, the pharmaceutical composition includes Compound 33, 38, 40, 76, 133, 134, 136 or 137. Certain pharmaceutical compositions of the invention include a compound selected from the compounds listed in Table 2. A compound of the invention can be used as a pharmaceutical agent. For example, a compound of the invention is used as an antiproliferative agent, for the treatment of humans and / or animals, such as for the treatment of humans and / or other mammals. The compounds can be used without limitation, for example, as anticancer, antiangiogenesis, antimicrobial, antibacterial, antifungal, antiparasitic and / or antiviral agents. Additionally, the compounds can be used for other disorders related to cell proliferation such as diabetic retinopathy, macular degeneration and psoriasis. Anticancer agents include anti-metastatic agents. The compound of the invention used as a pharmaceutical agent can be selected from Compounds 1-136 and 137. For example, the compound of the invention used as a pharmaceutical agent is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 , 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 or 137. For example, the compound of the invention used as a pharmaceutical agent is selected between Compounds 33, 38, 40, 76, 133, 134, 136 and 137. Certain pharmaceutical agents include a compound selected from the compounds listed in Table 2. In one aspect of the invention, a compound of the invention, for example , a compound of Formula I or one of Formulas II-XIII, is used to treat or prevent a cell proliferation disorder in a subject. In one aspect of the modality, the cell proliferation disorder is pre-cancer or cancer. In another aspect of the embodiment, the cell proliferation disorder is a hyperproliferative disorder. In another embodiment, the prevention or treatment of cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a kinase. In another embodiment, the prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a tyrosine kinase. In another embodiment, the prevention or treatment of cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of Src kinase or focal adhesion kinase (FAK). In another embodiment, the subject is a mammal. Preferably, the subject is human. The invention is also written for a method of treating or preventing cancer or a cell proliferation disorder in a subject, comprising administering an effective amount of a compound of the invention, for example, a compound of Formula I or one of Formulas II-XIII. For example, the compound of the invention can be a kinase inhibitor. The compound of the invention can be a kinase inhibitor non-competitive with ATP. The compound of the invention can inhibit a kinase directly or can affect the kinase path.

Definitions For convenience, here are some terms used in the specification, the examples and the appended claims. Protein kinases are a large class of enzymes that catalyze the transfer of ATP? -phosphate to the hydroxyl group in the side chain of Ser / Thr or Tyr in proteins and peptides and are intimately involved in the control of several important cellular functions, such 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 these phosphorylates particular protein / peptide substrates, they all bind to the same second ATP substrate in a highly conserved pocket. Approximately 50% of the known oncogenic products are tyrosine kinase (PTK) proteins, and their kinase activity has been shown to lead to cell transformation. PTKs can be classified into two categories, PTKs of the membrane receptor (for example PTK of the growth factor receptor) and non-receptor PTKs (for example the Src family of proto-oncogenic products and focal adhesion kinase (FAK)). Src hyperactivation has been reported in several human cancers, including cancer of the colon, breast, lung, bladder, and skin, as well as gastric cancer, hairy cell leukemia, and neuroblastoma. "Treatment" includes any effect, for example, reduction, reduction, modulation or elimination, which results in the improvement of the condition, disease, disorder, etc. "Treating" or "Treatment" of a disease state includes: (1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject who may be exposed to or predisposed to the disease state , but still does not experience or show symptoms of the disease state; (2) inhibit the disease state, for example, stop the development of the disease state or its clinical symptoms; or (3) alleviate the disease state, that is, causing temporary or permanent regression of the disease state or its clinical symptoms. "Sickness status" means any disease, disorder, condition, symptom or indication. As used herein, the term "cell proliferative disorder" refers to conditions in which the deregulated and / or abnormal growth of cells can lead to the development of an unwanted condition or disease, which may be cancerous or non-cancerous, for example, a psoriatic condition. As used herein, the terms "psoriatic condition" or "psoriasis" refer to disorders that involve hyperproliferation of keratinocytes, infiltration of inflammatory cells, and alteration of cytosine. In a preferred embodiment, the cell proliferation disorder is cancer. As used herein, the term "cancer" includes solid tumors, such as lung, breast, colon, ovarian, brain, liver, pancreas, prostate, malignant melanoma, skin cancers that do not they are melanoma, as well as tumors and / or hematological malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic leukemia, acute myelocytic or chronic myelocytic leukemia, cell neoplasm Plasma, lymphoid neoplasm and cancers associated with AIDS. In addition to psoriatic conditions, the types of proliferative diseases that can be treated using the compositions of the present invention are epidermal and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevus lesions, teratomas, nephromas, myofibromatosis, tumors. osteoplastic, and other dysplastic masses and the like. Proliferative diseases may include dysplasias and similar disorders. An "effective amount" of a compound of the invention described is the amount that, when administered to a subject having a disease or disorder, results in the regression of the disease or disorder in the subject. Thus, an effective amount of a compound of the invention described is the amount that, when administered to a subject having a cell proliferation disorder, results in the regression of cell growth in the subject. The amount of the described compound to be administered to the subject will depend on the particular disorder, the mode of administration, the co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex. , genotype, body weight and tolerance to drugs. The person skilled in the art will be able to determine the appropriate dosages, depending on these and other factors. As used herein, the term "effective amount" refers to an amount of a compound or combination of compounds, of the present invention, effective when administered alone or in combination as an antiproliferative agent. For example, an "effective amount" refers to an amount of the compound, present in a formulation or in a medical device, given to a patient or recipient subject, sufficient to promote biological activity, for example, antiproliferative activity, such as, for example, anticancer activity or antineoplastic activity. The combination of compounds is optionally a synergistic combination. Synergy, as described for example, by Chou and Talalay, Adv. Enzyme Regul. Vol. 22, pages 27-55 (1984), occurs when the effect of the compounds, when administered in combination, is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is demonstrated more clearly at suboptimal concentrations of the compounds. The synergy may be in terms of minor cytotoxicity or increased antiproliferative effect or some other beneficial effect of the combination, compared with the individual components. "A therapeutically effective amount" means the amount of a compound that, when administered to a mammal for the treatment of a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. A therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a human or animal. Accordingly, the compounds or formulations can be administered, for example, through the oral, parenteral or topical routes, to provide an effective amount of the compound. In alternative embodiments, the compounds prepared according to the present invention can be used to cover or impregnate a medical device, for example, a stent. The term "prophylactically effective amount" means an effective amount of a compound or compounds, of the present invention, that is administered to prevent or reduce the risk of unwanted cell proliferation. "Pharmacological effect" as used herein, encompasses effects produced in the subject that achieve the intended purpose of a therapy. In a preferred embodiment, a pharmacological effect means that the primary indications of the subject to be treated are prevented, alleviated or reduced. For example, a pharmacological effect would be one that would result in the prevention, alleviation or reduction of primary indications in a treated subject. In another preferred embodiment, a pharmacological effect means that the disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated or reduced. For example, a pharmacological effect would be one that would result in the prevention or reduction of primary indications in a treated subject. With respect to chemical compounds, useful in the present invention, the following terms may be applied: The term "substituted", as used herein, means that one or more hydrogens on the designated atom, is replaced with a selection of the indicated group, with the proviso that it does not exceed the normal valence of the designated atom, and that the substitution results in a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens are replaced on the atom. Keto substituents are not present in the aromatic portions. The double bonds in the ring, as used herein, are double bonds that are formed between two adjacent ring atoms (eg, C = C, C = N or N = N). It is intended that the present invention include all isotopes of atoms that appear in the present compounds. Isotopes include those atoms that have the same atomic number, but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and carbon isotopes include C-13 and C-14. The compounds described herein may have asymmetric centers. The compounds of the present invention which contain an asymmetrically substituted atom can be isolated in optimally active or racemic forms. It is well known in the art how to prepare the optically active forms, such as by resolution of racemic forms or by synthesis from the optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like, may also be present in the compounds described or herein, and all stable isomers of this type are considered in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. It is intended to include all chiral, diastereoisomeric, racemic, and geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated. All tautomers of compounds shown or described are also considered to be part of the present invention. When some variable (for example, Ri) appears more than once in some constituent or formula for a compound, its definition in each occurrence is independent of its definition in each other occurrence. Therefore, for example, if it is shown that a group is to be substituted with 0-2 Ri portions, then the group can optionally be substituted with up to two Ri portions and R1 at each occurrence is selected independently of the definition of Ri. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds. When it is shown that a bond to a substituent crosses a bond connecting two atoms in a ring, then such a substituent may be attached to any atom in the ring. When a substituent is listed without indicating the atom through which such a substituent is linked to the rest of the compound of a given formula, then such a substituent may be linked through any atom in such a substituent. Substitute and / or variable combinations are permissible, but only if such combinations result in stable compounds. The compounds of the present invention containing nitrogens can be converted to N-oxides by treatment with an oxidizing agent (for example, 3-chloroperoxybenzoic acid (zn-CPBA) and / or hydrogen peroxides) to provide other compounds of the present invention . Therefore, all nitrogen-containing compounds, shown and claimed, are considered, when they allow by valence and structure, to include both the compound shown and its N-oxide derivative (which can be designated as N? 0 or N + -0 ~) In addition, in other cases, the nitrogens in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds. For example, the N-hydroxy compounds can be prepared by oxidation of the progenitor amine by an oxidizing agent such as m-CPBA. All nitrogen-containing compounds, shown and claimed, are also considered, when they allow by valence and structure, to cover both the compound shown and its derivatives of N-hydroxy (e.g., N-OH) and N-alkoxy (e.g. , N-OR, wherein R is substituted or unsubstituted Ci_6 alkyl, Ci_6 alkenyl, Ci-6 alkynyl, C3-14 carbocycle or 3-14 membered heterocycle). When an atom or chemical portion is followed by a subscribed numerical range (for example, Ci-6), it means that the invention encompasses each number within the range, as well as all intermediate intervals. For example, "Ci-6 alkyl" means that it includes alkyl groups With 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6 , 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons. As used herein, "alkyl" is intended to include both the straight chain and branched chain saturated, aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, alkyl Ci-6 is intended to include the alkyl Ci, C2, C3, C4, C5, and C ^ groups. Examples of alkyl include, without restriction, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl. "Alkyl" also includes alkyl groups having oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbon atoms of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (eg, Ci-C6 for the straight chain, C3-C6 for the branched chain), and most preferably four or more. less. Similarly, preferred cycloalkyls have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. Unless the carbon number is otherwise specified, "lower alkyl" includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. The term "alkyl" also includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl portions having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl , sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic portion. The cycloalkyls may also be substituted, for example, with the substituents described above. A portion "Alkylaryl" or an "aralkyl" is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). "Alkenyl" includes unsaturated aliphatic groups, analogous in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes alkenyl groups chain (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), alkenyl branched chain groups, cycloalkenyl groups (e.g., alicyclic ) (for example, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), cycloalkenyl groups substituted with alkyl or alkenyl, and alkenyl groups substituted with cycloalkyl or cycloalkenyl. The term "alkenyl" also includes alkenyl groups, which include oxygen, nitrogen, sulfur or phosphorus atoms by replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight-chain or branched-chain alkenyl group has six or fewer carbon atoms in its backbone (eg, C2-C6 for the straight chain, C3-C6 for the branched chain). Similarly, cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. The term "C2-C6" includes alkenyl groups containing from two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing from three to six carbon atoms. The term "alkenyl" also includes both "alkenyls unsubstituted" as the "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbon atoms in the backbone of hydrocarbon. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfaraoilo , sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic portion. "Alkynyl" includes unsaturated aliphatic groups, analogous in length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes alkynyl groups straight chain (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), alkynyl branched chain groups, and alkynyl groups substituted with cycloalkyl or cycloalkenyl. The term "alkynyl" also includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (eg, C2-C6 for the straight chain, C3-C6 for the branched chain). The term "C2-Ce" includes alkynyl groups containing from two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing from three to six carbon atoms. The term "alkynyl" also includes both "alkynyl unsubstituted" as the "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbon atoms of the backbone of hydrocarbon . Such substituents may includeFor example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino ( including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl , cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. "Aryl" includes groups with aromaticity, which include aromatic groups of 5- and 6-membered "unconjugated" or single-ring, which may include from zero to four heteroatoms, as well as "conjugated" or multiciclic systems, with at least an aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naptiridina, indole, benzofuran, purine, benzofuran, deazapurine or indolizine. Those aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles", "heterocycles", "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino , sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic portion. The aryl groups may also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic to form a multiciclic system (for example, tetralin, methylenedioxyphenyl). As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "perhalogenated" generally refers to a portion wherein all hydrogens are replaced by halogen atoms. "Contraión" is used to represent a small, negatively charged species, such as chloride, bromide, hydroxide, acetate, and sulfate. The term "non-hydrogen substituent" refers to substituents other than hydrogen. Non-limiting examples include alkyl groups, alkoxy groups, halogen groups, hydroxyl groups, aryl groups, etc. As used herein, "carbocycle" or "carbocyclic ring" is intended to include any stable, monocyclic, bicyclic or tricyclic ring having the specified number of carbons, either of which may be saturated, unsaturated or aromatic. For example, it is intended that a C3-14 carbocycle represents a mono-, bi- or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, without restriction, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. Bridge rings are also included in the definition of carbocycle, including, for example, [3.3.0] bicyclooctane, [4.3.0] biciclononane, [4.4.0] bicyclodecane, and [2.2.2] bicyclooctane. A bridge ring appears when one or more carbon atoms are bonded to two non-adjacent carbon atoms. The preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents indicated for the ring may also be present on the bridge. Fused rings (eg, naphthyl and tetrahydronaphthyl) and spiro are also included. As used herein, the term "heterocycle" or "heterocycle" is intended to include any stable monocyclic, bicyclic or tricyclic ring that is saturated, unsaturated or aromatic and comprising carbon atoms and one or more heteroatoms in the ring , for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur. A bicyclic or tricyclic heterocycle may have one or more heteroatoms located in a ring or the heteroatoms may be located in more than one ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (for example, N-? 0 and S (0) p, where p = 1 or 2). When a nitrogen atom is included in the ring, it is N or NH, depending on whether or not it is coupled to a double bond in the ring (for example, a hydrogen is present if it is necessary to maintain the trivalency of the nitrogen atom) . The nitrogen atom may be substituted or unsubstituted (for example, N or NR, where R is H or another substituent, as defined). The heterocyclic ring can be coupled to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on a carbon or a nitrogen atom, if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S atoms and 0 in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Bridge rings are also included in the definition of heterocycle. A bridge ring occurs when one or several atoms (eg, C, 0, N or S) are bonded to two non-adjacent carbon or nitrogen atoms. Preferred bridges include, without restriction, a carbon atom, two carbon atoms, a nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents indicated for the ring may also be present in the bridge. Spiro and fused rings are also included. As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable aromatic heterocyclic ring of 5, 6 or 7 members, monocyclic or bicyclic or bicyclic aromatic heterocyclic ring of 7, 8, 9, 10 , 11 or 12 members, consisting of carbon atoms and one or more heteroatoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur. In the case of heterocyclic, bicyclic aromatic rings, only one of the two rings needs to be aromatic (for example, 2, 3-dihydroindole), although both can be (eg, quinoline). The second ring can also be fused or bridged as previously defined for heterocycles. The nitrogen atom may be substituted or unsubstituted (for example, N or NR where R is H or another substituent, as defined). Nitrogen and sulfur heteroatoms may optionally be oxidized (eg, N? 0 and S (0) p, where p = 1 or 2). It should be noted that the total number of S and 0 atoms in the aromatic heterocycle is not greater than 1. Examples of heterocycles include, without restriction, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl , benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl , imidazolidinyl, imidazolidyl, imidazolyl, lido-indazolyl, indolenyl, indolinyl, indolizinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl , 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, fenoxatinilo, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1, 2, 5- thiadiazinyl, 1. 2,3-thiadiazolyl, 1,2-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1. 3.-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1. 2.5-triazolyl, 1,3-triazolyl, and xanthenyl. "Acyl" includes compounds and portions that contain the acyl radical (CH3CO-) or a carbonyl group. "Substituted acyl" includes acyl groups in which one or more of the nitrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio , arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic portion. "Acylamino" includes portions wherein an acyl portion is linked to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. "Aroyl" includes compounds and portions with an aryl or heteroaromatic moiety linked to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which additionally include oxygen, nitrogen or sulfur atoms by replacing one or more carbon atoms of the hydrocarbon backbone, for example, carbon atoms. oxygen, nitrogen or sulfur. The term "alkoxy" or "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups, covalently bonded to an oxygen atom. Examples of alkoxy groups (or alkoxy radicals) include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano , amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido , nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, without restriction, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy. "The term" thiocarbonyl "or" thiocarboxy "includes compounds and portions containing a carbon connected with a double bond to a sulfur atom.The term" ether "includes compounds or portions containing an oxygen bonded to two different carbon atoms or heteroatoms For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl or alkynyl group, covalently bonded to an oxygen atom that is covalently linked to another alkyl group.The term "ester" includes compounds and portions containing a carbon or a hetero atom bound to an oxygen atom, which is bonded to the carbon of a carbonyl group The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl or alkynyl groups are as defined above. The term "thioether" includes compounds and portions that contain a sulfur atom bonded to two different carbons or heteroatoms. Examples of thioethers include, without restriction, alkali alkyl, alkoxy alkyls, and alkyoalkynyls. The term "alkali alkyl" includes compounds with an alkyl, alkenyl or alkynyl group linked to a sulfur atom that is linked to an alkyl group. Similarly, the terms "alkaryl alkyls" and "alkaryalkynyls" refer to compounds or portions wherein an alkyl, alkenyl or alkynyl group is linked to a sulfur atom that is covalently bonded to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -0. "" Polycyclyl "or" polycyclic radical "refers to two or more cyclic rings (eg, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls) in which two or more carbons are common to two adjacent rings.The rings that are bonded through non-adjacent atoms are called "bridged" rings.Each of the rings of the polycycle may be substituted with substituents such as described above, such as, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, a: rylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate , phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl or an aromatic or heteroaromatic portion. An "anionic group," as used herein, refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate or phosphorothioate or functional equivalents thereof. "Functional equivalents" of anionic groups are intended to include bioisosteres, for example, bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisostic equivalents and non-classical bioisostic equivalents. Classical and non-classical bioisosteres are known in the art (see, for example, Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc .: San Diego, Calif., 1992, pages 19-23). A particularly preferred anionic group is a carboxylate. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers as geometric isomer, optical isomer based on an asymmetric carbon, stereoisomer, tautomer and the like, which are structurally presented and an isomeric mixture, and is not limited to the description of the formula for convenience, and may be any isomer or mixture. Therefore, an asymmetric carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the present compound, but the present invention is not limited thereto and includes any. In addition, a crystalline polymorphism may be present but is not limited, but any crystalline form may be simple or a mixture of crystalline form or an anhydrate or hydrate. In addition, the so-called metabolite that is produced by degradation of the present compound in vivo, is included in the scope of the present invention. "Isomerism" means compounds that have identical molecular formulas, but that differ in the nature or in the bonding sequence of their atoms or in the arrangement of their atoms in space. The isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are mirror images of another are termed "diastereomers," and stereoisomers that are not superimposed mirror images are referred to as "enantiomers" or sometimes optical isomers. A carbon atom bonded to four substituents that are not identical is termed a "chiral center". "Chiral isomer" means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist either as a single enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture". A compound that has more than one chiral center has 2n_1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist either as a single diastereomer or as a mixture of diastereoisomers, called a "diastereoisomeric mixture". When a chiral center is present, a stereoisomer may be characterized by an absolute configuration (R or S) of that chiral center. The absolute configuration refers to the arrangement in the space of the substituents coupled to the chiral center. The substituents coupled to the chiral center under consideration are classified according to the Seguence Rule of Cahn, Ingold and Prelog. (Cahn et al, Angew, Chem., Inter .: Edit, 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem.

Educ. 1964, 41, 116). "Geometric isomers" means the diastereomers that owe their existence to the hidden rotation around double bonds. These configurations differ in their names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite side of the double bond, in the molecule according to the rules of Cahn-Ingold-Prelog . In addition, the structures and other compounds described in this application include all the atropic isomers thereof. "Atropic isomers" are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The atropic isomers owe their existence to a restricted rotation, caused by the obstruction of rotation of large groups around a central link. Such atropic isomers commonly exist as a mixture, however as a result of recent advances in chromatographic techniques, it has been possible to separate mixtures of two atropic isomers in selected cases. The terms "crystalline polymorphs" or "polymorphs" or "crystalline forms" mean crystalline structures in which a compound (or salt or solvate thereof) can be crystallized in different crystal packing arrangements, all of which have the same elemental composition. The different crystalline forms usually have different X-ray diffraction patterns, infrared spectrum, melting points, density hardness, crystalline form, optical and electrical properties, stability and solubility. The recrystallization solvent, the rate of crystallization, the storage temperature, and other factors can cause a crystalline form to dominate. The crystalline polymorphs of the compounds can be prepared by crystallization under different conditions. Additionally, the compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or dehydrated form (the anhydrous) or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. "Solvates" represent solvent addition forms that contain any stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or several water molecules, with one of the substances in which water retains its molecular status as H20, such combination is able to form one or more hydrates. "Tautomers" refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It should be understood that the compounds of the formula I can be described as different tautomers. It should also be understood that when the compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and in naming the compounds some tautomeric form is not excluded. Some compounds of the present invention may exist in a tautomeric form, which is also intended to be encompassed within the scope of the present invention. The compounds, salts and prodrugs of the present invention can exist in various tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric group in solution. In solid form, usually a tautomer predominates. Although a tautomer can be described, the present invention includes all the tautomers of the present compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and that are easily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom, accompanied by a change in adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be achieved. The exact ratio of tautomers depends on several factors, which include temperature, solvent, and PH. The concept of tautomeros that are interconvertible by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In the tautomerism of keto-enol a simultaneous displacement of electrons and a hydrogen atom occurs. Ring chain tautomerism is shown by glucose. This arises as a result of the aldehyde group (-CHO) in a sugar chain molecule that reacts with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic form (ring shape).

The tautomerizations are catalyzed by: base: 1. deprotonation; 2. formation of a delocalized anion (for example an enolate); 3. protonation in a different position of the anion; acid: 1. protonation; 2. formation of a delocalised cation; 3. deprotonation in a different position, adjacent to the cation. Common tautomeric pairs are: tautomerism of ketone-enol, amide-nitrile, lactam-lactimate, amide-imidic acid, in heterocyclic rings (for example in the nucleobases guanine, thymine and cytosine), amine-enamine and enamine-enamine. Examples include: It will be noted that some compounds of the invention include asymmetric carbon atoms. It should therefore be understood that isomers arising from such asymmetry (e.g., all enantiomers and diastereoisomers) are included within the scope of the invention, unless otherwise indicated. Such isomers can be obtained practically in pure form by classical separation techniques and by stereochemically controlled synthesis. In addition, the structures and other compounds and portions described in this application also include all tautomers thereof. Alkenes can include geometry E or Z, where appropriate. The compounds of this invention can exist in stereoisomeric form, therefore they can be produced as individual stereoisomers or as mixtures. As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another, but differs slightly in its composition (as in the replacement of one atom by another atom of a different element or in the presence of a particular functional group or the replacement of a functional group by another functional group). Therefore, an analogue is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. As defined herein, the term "derivative" refers to compounds that have a common core structure, and are substituted in various groups as described herein. For example, all compounds represented by formula I are indole derivatives, and have formula I as a common core. The term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another, broadly similar, atom or group of atoms. The goal of a bioisostomeric replacement is to create a new compound with biological properties similar to the parent compound. The bioisostic replacement can be based physicochemically or topologically. Examples of carboxylic acid bioisosteres include acyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and La Voie, Chem. Rev. 96, 3147-3176 (1996). A "pharmaceutical composition" is a formulation that contains the described compounds in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a simple pump in an aerosol inhaler or a bottle. The amount of active ingredient (eg, a formulation of the described compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition, is an effective amount and varies according to the particular treatment involved. One of skill in the art will appreciate that it is sometimes necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration. A range of routes are considered including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required. The term "instantaneous dose" refers to formulations of compounds which are fast dispersing dosage forms. The term "immediate release" is defined as a release of compound from a dosage form in a relatively short period of time, generally up to about 60 minutes. The term "modified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsed release" is defined as a series of drug releases from a dosage form. The term "sustained release" or "extended release" is defined as continuous release of a compound from a dosage form over a prolonged period. A "subject" includes mammals, for example humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, poultry and the like) and laboratory animals (for example, rats, mice, guinea pigs, birds and the like). More preferably, the subject is human. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, in accordance with a reasonable benefit / risk ratio. "Pharmaceutically acceptable excipient" means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as for human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims, includes one and more than one excipient of this type. The compounds of the invention are capable of additionally forming salts. All these forms are also considered within the scope of the claimed invention. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the parent compound is modified by producing acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, without restriction, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the non-toxic, conventional salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, such non-toxic, conventional salts include, without restriction, those derived from organic and inorganic acids selected from 2-acetoxybenzoic, 2-hydroxyethane-sulphonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, emetic, disulphonic, 1,2-ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycolylanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroximic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl-sulphonic, maleic, malic, mandelic, methane-sulphonic, napsilic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polyractic, propionic, salicylic, stearic, subacic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the amino acids that commonly appear, for example, glycine, alanine, phenylalanine, arginine, etc. Other examples include hexanoic acid, cyclopentan-propionic acid, pyruvic acid, malonic acid, 3- (-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo- [2.2.2. ] -oct-2-en-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The invention also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion or an aluminum ion; or is coordinated 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 pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic portion, by conventional chemical methods. Generally, such salts can be prepared by reacting the acidic or basic free forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For example, the salts may include, without restriction, the hydrochloride and acetate salts of the aliphatic amine-containing compounds, which contain hydroxyl amine, and imine-containing compounds, of the present invention. The compounds of the present invention can 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, for example 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, for example, pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active progenitor drug in vivo. Since it is known that prodrugs increase the numerous desirable qualities of pharmaceutical products (eg, solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be delivered in the form of a prodrug. It is therefore intended that the present invention cover prodrugs of the compounds, methods of distribution thereof and compositions containing them, claimed herein. It is intended that "prodrugs" include any covalently linked carriers that release an active parent drug of the present invention, in vivo when such a prodrug is administered to a subject. The prodrugs of the present invention are prepared (by modifying the functional groups present in the compound, such that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.) Prodrugs include compounds of the present invention. wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group is linked to any group which can be cleaved in vivo to form a free hydroxyl group, free amino, free sulfhydryl, free carboxy or free carbonyl, respectively. include, without restriction, esters (e.g., acetate, dialkylaminoacetate, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups, ester groups (e.g., ethyl esters, morpholinoethanol) of carboxyl functional groups, N-acyl derivatives (for example N-acetyl) N-Mannich bases, Schi bases ff and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of formula I, and the like. See Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York Oxford (1985). "Protective group" refers to a group of atoms that when coupled to a reactive group in a molecule, masks, reduces or prevents reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2nd ed., 1991); Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996); and Kocienski, Protecting Groups, (Verlag, 3rd ed., 2003). The term "amine protecting group" is intended to mean a functional group that converts an amine, amide, or other nitrogen-containing portion to a different chemical group that is practically inert to the conditions of a particular chemical reaction. Amine protecting groups are preferably easily and selectively removed in good yield, under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, without restriction, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), flourenyl-methyloxycarbonyl, 2-trimethylsilyl-ethoxycarbonyl, 1-methyl-1- (4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted groups of trityl, 9-flourenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Other suitable amine protecting groups are directly identified by those skilled in the art. Representative hydroxy protecting groups include those wherein the hydroxy groups are acylated or alkylated as benzyl, and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers. "Stable compound" and "stable structure" indicate a compound that is sufficiently robust to survive isolation, to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent. In the specification, singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, it will control the present specification.

All percentages and proportions used herein, unless otherwise indicated, are by weight. "Combination Therapy" (or "therapy") includes the administration of a compound of the invention and at least one second agent as part of a specific treatment regimen, designed to provide the beneficial effect of the coercion of these therapeutic agents. The beneficial effect of the combination includes, without restriction, pharmacokinetic or pharmacodynamic coercion resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out for a defined period of time (usually minutes, hours, days or weeks, depending on the combination selected). "Combination therapy" may, but generally does not, purport to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in combinations of the present invention. "Combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents or at least two of the agents therapeutic, practically simultaneously. Virtually simultaneous administration can be achieved, for example, by administration to the subject, of a single capsule having a fixed ratio of each therapeutic agent or in single, multiple capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, without restriction, oral routes, intravenous routes, intramuscular routes, and direct absorption through the mucosal membrane tissues. The 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 narrowly critical. "Combination Therapy" also encompasses the administration of the therapeutic agents, as described above, in additional combination with other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-pharmacological treatment, the non-pharmacological treatment can be conducted at any suitable time, as long as a beneficial effect of the coercion of the combination of the therapeutic agents and the non-pharmacological treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-pharmacological treatment is temporarily withdrawn from the administration of the therapeutic agents, perhaps for days or weeks. Throughout the description, where compositions having, including or comprising specific components are described, it is considered that the compositions also consist essentially of or consist of the indicated components. Similarly, where the processes are described as having, including or comprising specific process steps, the processes also consist essentially of or consist of the indicated processing steps. In addition, it must be understood that the order of stages or the order to perform certain actions are not important as long as the invention remains operable. In addition, two or more stages or actions can be conducted simultaneously. The compounds or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonarily, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In a preferred embodiment, the compound is administered orally. One of skill in the art will recognize the advantages of certain administration routes. The dosage regimen used by the compounds is selected according to a range of factors including type, species, age, weight, sex, patient's medical condition; the severity of the condition to be treated; the administration route; the liver and kidney function of the patient; and the particular compound or salt thereof, employed. An expert physician or veterinarian can ordinarily easily determine and prescribe the effective amount of the drug required to prevent, combat or stop the progress of the condition. Techniques for formulation and administration of the described 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. In one embodiment, the compound is prepared for oral administration, wherein the described compounds or salts thereof are combined with a solid or liquid carrier or diluent, suitable for forming capsules, tablets, pills, powders, syrups, solutions, suspensions and the like. Tablets, pills, capsules and the like contain from about 1 to about 99% by weight of the active ingredient and a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and / or a sweetening agent such as sucrose, lactose, saccharin, xylitol, and the like. When a unit dosage form is a capsule, it frequently contains, in addition to the materials of the above type, a liquid carrier such as a fatty oil. In some embodiments, several different materials are present, such as coatings or to modify the physical form of the dosage unit. For example, in some embodiments, the tablets are coated with shellac, sugar or both. In some embodiments, a syrup or elixir contains, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like. For some embodiments that relate to parenteral administration, the disclosed compounds or salts, solvates, tautomers or polymorphs thereof, may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable compositions are preferably aqueous isotonic solutions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, promoters of the solution, salts for regulating the osmotic and / or regulatory pressure. In addition, these may contain therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1 to 75%, preferably from about 1 to 50%, of the active ingredient. For example, injectable solutions are produced using solvents such as sesame or peanut oil or aqueous propylene glycol, as well as aqueous solutions of salts of the pharmaceutically acceptable, water-soluble compounds. In some embodiments, the dispersions are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms. The terms "parenteral administration" and "parenterally administered" as used herein, means modes of administration other than enteral and topical administration, usually by injection, and include without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular injection , subarachnoid, intraspinal, and intrasternal and infusion. For rectal administration, suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas. Suppositories are advantageously prepared from fat emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1 to 75%, preferably from about 1 to 50%, of the active ingredient. In some embodiments, the compounds are formulated to deliver the active agent by pulmonary administration, for example, administration of an aerosol formulation containing the active agent, for example, from a manual pump spray, inhaler with nebulizer or metered dose pressurized In some embodiments, suitable formulations of this type also include other agents, such as antistatic agents, to keep the described compounds as effective aerosols. A device for distributing the drug, for distributing aerosols, comprises a suitable aerosol can, with a metering valve containing an aerosol pharmaceutical formulation as described and an actuator housing, adapted to hold the can and allow the distribution of the drug. The can in the drug delivery device has a top space that represents more than about 15% of the total volume of the can. Frequently, the polymer designed for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is kept under pressure in a can that has been sealed with a metering valve. For nasal administration, a solid or a liquid carrier can be used. The solid carrier includes a coarse powder having a particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nostrils. In some embodiments where the liquid carrier is used, the formulation is administered as a nasal spray or drops and includes aqueous or oily solutions of the active ingredients. Also considered are formulations which are fast dispersing dosage forms, also known as "instant dose" forms. In particular, some embodiments of the present invention are formulated as compositions that release their active ingredients within a short period of time, for example, typically less than about 5 minutes, preferably less than about 19 seconds, more preferably less than about 30 seconds and more preferably in less than about 10 or 15 seconds. Such formulations are suitable for administration to a subject through a range of routes, for example by insertion into a body cavity or application to a moist body surface or open wound. Typically, an "instant dosing" is a solid dosage form that is orally administered, that disperses rapidly in the mouth, and therefore requires no greater effort in swallowing and allows the compound to be swallowed or absorbed rapidly through of oral mucous membranes. In some modalities, suitable rapid dispersion dosage forms are also used in other applications, which include the treatment of wounds and other bodily injuries and disease states in which it is not possible to release the medicament by moisture supplied externally.

The forms of "instant dose" are known in the art; see, for example, effervescent dosage forms and fast release coatings of insoluble microparticles in U.S. Patent Nos. 5,578, 322, and 5, 607, 697; foams and lyophilized liquids in U.S. Patent Nos. 4,642,903 and 5,631,023; spun yarn of dosage forms in U.S. Patent Nos. 4,855,326, 5,380,473 and 5,518,730; solid-form manufacturing, in U.S. Patent No. 6,471,992; saccharide-based carrier matrix and a liquid binder in U.S. Patent Nos. 5,587,172, 5,616,344, 6,277,406, and 5,622,719; and other forms known in the art. The compounds of the invention are also formulated as "pulsed release" formulations, in which the compound is released from the pharmaceutical compositions in a series of releases (ie pulses). The compounds are also formulated as "sustained release" formulations in which the compound is continuously released from the pharmaceutical composition for a prolonged period. Also considered are formulations, e.g., liquid formulations, including cyclic or acyclic encapsulation or solvating agents, e.g., cyclodextrins, polyethers or polyscarbons (e.g., methylcellulose) or more preferably, polyanionic β-cyclodextrin derivatives with a group of sodium sulfonate salt, separated from the lipophilic cavity by an alkyl ether spacer group or polysaccharides. In a preferred embodiment, the agent is methylcellulose. In another preferred embodiment, the agent is a polyanionic β-cyclodextrin derivative with a sodium sulfonate salt, separated from the lipophilic cavity by a butyl ether spacer group, for example CAPTISOL® (CyDex, Overland, K.S.). One skilled in the art can evaluate the proportions of suitable agent / compound formulation described by preparing a solution of the agent in water, for example, a 40% by weight solution; prepare serial dilutions, for example to produce solutions of 20%, 10.5%, 2.5%, 0% (control), and the like; adding an excess (compared to the amount that can be solubilized by the agent) of the described compound; mix under appropriate conditions, for example, heating, stirring, sonication and the like; centrifuge or filter the resulting mixtures to obtain clear solutions; and analyzing the solutions for the concentration of the described compound. All publications and patent documents cited herein are incorporated by reference, as if such publication or document was specifically and individually indicated as being incorporated herein by reference. It is not intended that the citation of publications and patent documents be an admission that any is prior relevant technique, nor constitutes any admission as to the content and date thereof. The invention has now been described by means of the written description, those of skill in the art will recognize that the invention can be practiced in a range of modalities and that the foregoing description and the following examples are for purposes of illustration and not limitation of the following claims.

EXAMPLES Example 1: Synthesis Representative syntheses of the compounds of the invention are described herein. Synthesis of Compounds 1 and 2 (KX1-136 and KX1-305) 3-benzyloxybenzonitrile To a solution of 3-cyanophenol (5.00 g, 42.00 mmol) in acetone (100 mL), potassium carbonate (5.79 g, 42.0 mmol) potassium iodide (335 mg, 21.0 mmol) and benzyl bromide (4.20 ml) were added. , 42.00 mmol) and the reaction mixture was heated to reflux for 12 hours. (TLC, ethyl acetate: hexane 1: 1, Rf = 0.6), then the solvent was removed in vacuo and the residue was partitioned between water (50 ml), and ethyl acetate (50 ml), the organic layer was washed twice with water and dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the objective ether as a yellow oil (8.46 g) 96% yield; X H NMR (DMSO (dimethyl sulfoxide), 400 MHz): d 7.51-7.33 (m, 9H), 5.16 (s, 2H). 3-benzyloxybenzylamine hydrochloride To a suspension of lithium aluminum hydride, LAH (4.314 g, 113.684 mmol) in anhydrous ether (200 ml), a solution of 3-benzyloxybenzonitrile in ether (7.92 g, 37.894 mmol) was added dropwise over 10 minutes at room temperature. The reaction was quenched with 10 ml of ethyl acetate and 10 ml of water and filtered. The organic layer was washed with water, dried over Na2SC > 4 and treated with 10 ml of concentrated HC1 to instantaneously form a white precipitate (6 g) 68% yield. 1 H-NMR (DMSO, 400 MHz): d 8.33 (s, 3 H), 7.45-7.37 (m, 4 H), 7.34-7.30 (m, 2 H), 7.19 (s, 1 H), 7.02 (t, J = 10 Hz , 2H), 5.10 (s, 2H), 3.97 (s, 2H).

N- (3-benzyloxy-benzyl) -4-biphenylacetamide To a solution of 4-biphenylacetic acid (2.29 g, 10.45 mmol) in dimethylformamide, DMF (30 mL), diisopropylethylamine, DIEA, (5.47 mL, 31.35 mmol) was added and stirred at room temperature for 15 minutes, then added benzotriazolyloxy-tris [pyrrolidino] -phosphonium hexafluorophostat, PyBOPMR (5.43 g, 10.45 mmol) and stirring was continued for another 30 minutes, then 3-benzyloxybenzylamine hydrochloride (2.6 g, 10.45 mmol) was added and stirring was continued for 24 hours. The reaction mixture was poured into ice water, acidified with 1N HCl (10 mL) and extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated NaHCO3 solution, water and brine, dried Na2SO4 and the solvent was removed in vacuo to give a yellowish-white powder of the desired compound (2.65 g) 62% yield. Another method involves the use of the amide formation using the acid chloride as shown in the next reaction.

To 4-biphenylacetic acid (2.5 g) in a flask, thionyl chloride (20 ml) was added and heated to reflux for 1 hour, cooled, and the thionyl chloride was removed in vacuo to dryness, then the acid chloride crude oil (2.8 g) was dissolved in DCM (dichloromethane) (30 ml), and added dropwise at 0 ° C to the equimolar amount of the solution of 3-benzyloxybenzylamine in DCM (10 ml) with (1.5 mol) of triethylamine (TEA) and stirred for 5 hours, then it was emptied into cold acidified water, the organic layer was washed with water, brine, and the solvent was removed under reduced pressure to give the objective amide in 80% yield. 1 H NMR (DMSO, 500 MHz): d 8.58 (t, J = 12 Hz 1H), 7.60-7.57 (m, 4H), 7.44-7.29 (m, 10H), d 7.21 (t, J = 16.5 Hz, 2H ), 6.85 (d, J = 6.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.00 (s, 2H), 4.24 Hz, 2H), 3.51 (s, 2H) Compound 1: N (3-hydroxy-benzyl) -4-biphenylacetamide To remove the benzyl group from this ether (5.00 g, 13. 35 mmol) was dissolved in methanol (20 ml), to this solution was added a catalytic amount of 10% Pd / C (355 mg, 2.21 mmol) in a Hydrogenator Parr (3.8 kg / cm2 (55 psi)) for 5 hours, was filtered through celite and the solvent was removed in vacuo to give the objective phenol as a yellowish powder (3.20 g) 84% yield, which crystallized at from methanol to give (1. 5 g) of white crystalline material, mp = 169-170 ° C. NMR * H (SO, 400 MHZ): d 9.34 (s, 1H), 8. 53 (s, 1H), 7.63 (d, J = 8 HZ, 2H), 7.58 (d, J = 8.4 Hz, 2H ), 7.44 (t, J = 7.6 Hz, 2H), 7. 35 (d, J = 8 Hz, 3 H), 7.07 (t, J = 8 Hz, 1H), 6.65-6.60 (m, 3H), 4.17 (d, J = 5.6 Hz, 2H), 3. 5 (s, 2H). FAB (fast atomic bombardment) HRMS m / e calculated for (M + H) C21H20 O2: 318.1449; found: 318.1484.

Compound 2: N- (3-fluoro-benzyl) -4-biphenylacetamide To a solution of 4-biphenyl-acetic acid (2.00 g, 9.42 mmol) in DMF (20 mL) was added DIEA (3.29 mL, 18.84 mmol) and stirred at room temperature for 15 minutes, then PyBOP (4.90 g) was added. , 9.42 mmol) and stirring was continued for another 30 minutes, 3-fluorobenzylamine (1.18 g, 9.42 mmol) was added and stirring was continued for 24 hours, then the reaction mixture was poured into ice-cooled water, acidified with HC1 1 N (10 mL) and extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4 and the solvent was removed in vacuo to give a white powder. of the desired compound (1.00 g) with 33% yield. Another method involves the acid chloride coupling method described below. 4-biphenylacetic acid (2.5 g, 11.78 mmol) was charged into a flask, then thionyl chloride (15 mL) was added and it was heated to reflux for 1 hour, cooled, and the excess thionyl chloride was removed in vacuo. to dryness, then the crude acid chloride produced (2.8 g, 12.13 mmol) was dissolved in anhydrous DCM (30 mL), and added dropwise at 0 ° C to 3-fluorobenzylamine solution (1.38 mL, 12.13 mmol) in DCM (10 ml) together with TEA (1.69 ml, 12.13 mmol) and stirred for 5 hours, then it was emptied into cold acidified water, the organic layer was washed with water, brine and the solvent was removed under reduced pressure to give the amide target (3.1 g) with 80% performance. Recrystallized from methanol, mp = 170-172 ° C. X H NMR (DMSO, 500 MHz): d 8.62 (t, J = 11 Hz, 1H), 7.63 (d, J = 8 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.37-7.31 (m, 4H), 7.08-7.01 (m, 3H), 4.28 (d, J = 5.5 Hz, 2H), 3.52 (s, 2H). FAB HRMS m / e calculated for (M + H) C2iHi8FNO: 320.1406; found: 320.2, and the base peak found: 342.1262 for (M + Na); calculated 342.1372.

Synthesis of Compound 3, KX1-306 The synthesis, indicated in Scheme 1, began with the formation of acid chloride of biphenylacetic acid, then with the coupling of amide with 3,5-dibenzyloxybenzylamine. A large amount of impurities was introduced by the formation of acid chloride. However, other methods of amide coupling, such as, for example, PyBOP or carbodiimides, can be used in this reaction. Cleavage of one of the benzyl groups was achieved under high hydrogen pressure (3.5-4.2 kg / cm2 (50-60 psi)) for 15 hours. The reaction was monitored by TLC. Silica gel chromatography was used to separate the product from the starting material as well as the dihydroxy byproduct. Biphenyl-acetic acid (220 mg, 1.00 mmol) was dissolved in DCM, 5 eq. (0.38 ml) of thionyl chloride and the reaction was heated to reflux for 4 hours. The solvents were removed in vacuo and the residue was dissolved in DCM. 3, 5-Dibenzyloxybenzylamine (1.1 eq.) Was added followed by TEA (1 eq.). The reaction was stirred at room temperature overnight. The reaction was diluted to 45 mL (with DCM) and washed with 1N HC1 (3X20 L), saturated sodium bicarbonate (3X20 mL), and brine (3X20 mL). . The reaction was dried with sodium sulfate and removed in vacuo to give 330 mg of crude product. Chromatography on silica gel (1: 1 DCM: EtOAc (ethyl acetate)) gave 220 mg of pure product. TLC Rf = 0.2 (single spot, 7: 3 hexanes: EtOAc). LCMS 514.2 (m + H) 536.2 (m + Na). 1N-NMR (300 MHz, CDC13) d (ppm) 3.65 (s, 2H), 4.50 (d, 5.7 Hz, 2H), 4.96 (s, 4H), 5.71 (s, 1H), 6.43 (s, 2H), 6.49 (s, 1H), 7.58-7.26 (m, 19H).

The dibenzyloxyamide (1) was dissolved in 15 ral of EtOAc (ethyl acetate) with gentle heating in a Parr bottle. This was placed in the hydrogenator at 3.5 kg / cm2 (50 psi) of hydrogen for 15 hours. The reaction was filtered through celite and the solvent was removed in vacuo to give a crude mixture of starting material and product. Chromatography on silica gel gave 50 mg of 1 and 41 mg of the desired product KX1-306; LCMS 424.1 (m + H), 446.2 (m + Na), 847.0 (2m + H), 868.9 (2m + Na). NMR XH (400 MHz, CDC13) d (ppm) 3.66 (s, 2H), 4.38 (d, 5.6 Hz, 2H), 4.98 (s, 2H), 5.71 (s, 1H), 6.43 (s, 2H), 6.49 (s, 1H), 7.30-7.45 (m, 10H), 7.54-7.57 (m, 4H).

Scheme 1 Reagents: i) S0C12, DC. ii) 3,5-dibenzyloxybenzylamine (1.0 eq.), TEA (2.0 eq.) 20% yield (two steps, with chromatography), iii) 10% Pd / C (10 mol%), H2, 3.8 kg / cm2 (55 psi), EtOAc 24 hours (53%, then chromatography, BORMS.

Synthesis of Compound 4, KX1-307 synthesis is outlined in Scheme 2. In one synthesis, the reaction began with the formation of the amide bond to give 2, followed by a Suzuki coupling with phenylboronic acid to give the meta-biphenyl product, Compound 4, KX1-307. In the Suzuki reaction, the biphenyl product was formed, but the reaction did not reach completion (by NMR and LCMS) despite the time, additional heat, and extra catalyst. Using chromatography on silica gel, the product could not be separated from the initial bromine material 2. By reversing the Suzuki coupling and the amide, the problem of separation was solved and the metabiphenyl-amide KX1-307 was successfully produced as well as the catalyst. '-fluorobiphenyl-4-acetamide KX1-309 (Compound 6, Scheme 3). 3-Bromophenylacetic acid (250 mg, 1163 mmol) and 156 mg (1.1 eq.) Of phenylboronic acid were dissolved in 6 ml of water: isopropanol (6: 1). Sodium carbonate (160 mg, 1.3 eq.) Was dissolved in 0.5 ml of distilled water and added to the reaction followed by Pd (OH) 2 / C (74 mg, 3 mol%). This was stirred in a water bath at 65 ° C for 5 hours. The reaction was filtered through filter paper. The filter paper was washed with 25 ml of isopropanol: water: 1 N NaOH (35: 5: 1). The washings were combined and acidified to pH 2 with 1 N sulfuric acid. The isopropanol was removed in vacuo and water (10 mL) was added. This aqueous layer was washed with dichloromethane (3 × 20 ml). The organic washes were combined, dried with sodium sulfate, and removed in vacuo to give 215 mg (87% yield) of the biphenyl product 3. TLC Rf = 0.7 (long line, 1: 1 EtOAc: DCM). 1 H NMR (300 MHz, CDC13) d (ppm) 3.72 (s, 2H), 7.26-7.60 (m, 9H). 3-biphenylacetic acid (3) (100 mg, 0.472 mmol), 3-fluorobenzylamine (1.1 eq.), L- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, EDCI (1.1 eq.), And HOBT (1- hydroxybenzotriazole, 1.0 eq.) were dissolved in 10 ml of anhydrous DCM. After 10 minutes, DIEA (1.1 eq.) Was added and the reaction was allowed to evolve overnight. The reaction was diluted to 25 mL and washed with 1N HC1 (3X10 L), saturated sodium bicarbonate (3X10 mL), and brine (2X20 mL). The reaction was dried with sodium sulfate and removed in vacuo to give 124 mg of pure KX1-307 (83% yield). TLC Rf = 0.7 (single spot, 1: 1 EtOAc: DCM). RMN ?? (300 Hz, CDC13) d (ppm) 3.69 (s, 2H) 4.40 (d, 6.0 Hz) 5.77 (s, 1H) 6.86-6.96 (m, 3H) 7.10-7.26 (m, 2H) 7.32 (m, 8H ).

Scheme 2 Reagents: i) S0C12, DCM. ii) 3-fluorobenzylamine (1.1 eq.), DIEA (2.2 eq.) (20% after chromatography). iii) phenylboronic acid (1.2 eq.), 2 M sodium carbonate, Pd (PPh3) 4 (3 mol%), toluene (inseparable mixture). iv) phenylboronic acid (1.1 eq.), Na2CO3 (1.3 eq.), Pd (OH) 2 / C (3 mol%), 1: 6 isopropanol: water (87% yield). v) 3-fluorobenzylamine (1.1 eq.), EDCI (1.1 eq.), HOBT (1.0 eq.), DIEA (l., l eq.) (83% yield).

Synthesis of Compound 6, KX-309 The synthesis is indicated in Scheme 3. 4-Bromophenylacetic acid (500 mg, 2.33 mmol) and 358 mg of 2-fluorophenylboronic acid (1.1 eq.) Were dissolved in 12 ml, 6: 1 water: isopropanol. Sodium carbonate (320 mg, 1.3 eq.) Was dissolved in 1 ml of distilled water and added to the reaction, followed by Pd (OH) 2 / C (148 mg, 3 mol%). This was stirred in a water bath at 65 ° C for 5 hours. The reaction was filtered through filter paper. The filter paper was washed with 50 ml of isopropanol: water: 1 N NaOH (35: 5: 1). The washings were combined and acidified to pH 2 with 1N sulfuric acid. The isopropanol was removed in vacuo, water (20 ml) was added and washed with dichloromethane (3X30 ml). The organic washings were combined, dried with sodium sulfate, and removed in vacuo to yield 177 mg (35% yield) of the biphenyl product 4. TLC Rf = 0.7 (long line, 1: 1 EtOAc: DCM). 1 H NMR (500 MHz, CDCl 3) d (ppm) 3.73 (s, 2 H), 7.16 (t, 10.5 Hz, 1 H), 7.22 (t, 7.5 Hz, 1 H), 7.32 (qd, 1.5 Hz, 7.5 Hz, 1 H ), 7.38 (d, 8.0 Hz, 2H), 7.44 (td, 1.5 Hz, 7.5 Hz, 1H), 7.54 (d, 8.0 Hz, 2H). 2'-Fluorobiphenylacetic acid (4) (103 mg, 0.448 mmol), 3-fluorobenzylamine (1.1 eq.), EDCI (1.1 eq.), And HOBT (1.0 eq.) Were dissolved in 6 mL of anhydrous DCM. After 10 minutes, DIEA (1.1 eq.) Was added and the reaction was allowed to evolve overnight. The reaction was diluted to 25 mL and washed with 1N HC1 (3X10 L), saturated sodium bicarbonate (3X10 mL), and brine (2X20 mL). The reaction was dried with sodium sulfate and removed in vacuo to give 126 mg of pure Compound 6, KX1-309 (83% yield). LCMS 360.1 (m + Na) 696.8 (2m + Na). 1 H NMR (300 MHz, CDCl 3) d (ppm) 3.67 (s, 2 H) 4.21 (d, 6.0 Hz, 2 H) 5.79 (s, 1 H) 6.87-6.98 (m, 3 H) 7.10-7.44 (m, 7 H) 7.53 (dd, 1.5 Hz, 7.5 Hz, 2H).

Scheme 3 Reagents: i) phenylboronic acid (1.1 eq.), Na2CC > 3 (1.3 eq.), Pd (OH) 2 / C (3 mol%), 1: 6 isopropanol: water (35% yield), ii) 3-fluorobenzylamine (1.1 eq.), EDCI (1.1 eq. ), HOBT (1.0 eq.), DIEA (1.1 eq.), 83% yield.

Synthesis of Compound 5: N- (3-fluorophenyl) -4-biphenylacetamide, KX1-308.

Thionyl chloride (0.38 mL, 5.0 mmol) was added to a solution cooled in ice water of 4-biphenylacetic acid (0.2 g, 0.9 mmol) in 5 mL of dichloromethane, the solution was allowed to warm to room temperature, then heated to room temperature. refluxing for 1 hour, the solvent and excess thionyl chloride were evaporated in vacuo, the oil formed was redissolved in 5 ml of dichloromethane followed by the addition of 4-dimethylaminopyridine (0.12 g, 1.0 mmol) and 3-fluoroaniline (0.11 g. g, 1.0 mmol), was stirred at room temperature overnight, then the reaction mixture was diluted with 10 ml of dichloromethane and 20 ml of water, the organic layer was washed with 1N HC1, saturated solution of NaHCO3, and NaCl saturated, dried using Na2SO4 and evaporated to dryness (0.2 g, 72%), 1H INOVA-500 NMR (CDC13) d 3.805 (s, 2H), 6.815 (t, J = 8.5 Hz, 1H), 7.068 (d, J = 8.0 Hz, 1H), 7.218-7.284 (m, 2H), 7.380-7.499 (m, 6H) 7.620-7.664 (m, 4H). MS (m / z) 306.2 (M + H) +.

Synthesis of Compound 7: N- (3-fluorobenzyl) -4- (3-fluorophenyl) -phenylacetamide, KX1-310 Synthesis of (4'-fluoro-biphenyl-4-yl) -acetic acid: 4-bromo-phenylacetic acid (0.5 g, 2.3 mmol), 3-fluorophenylboronic acid (0.36 g, 2.4 mmol) and 10% palladium-carbon moistened with 50% water (0.16 g, 0.075 mmol of Pd) were added to 10 ml of water mixture. and isopropanol 5: 1, then Na2C03 (0.32 g, 3 mmol) dissolved in 3 ml of water was added to the previous mixture, the reaction was heated to 65-70 ° C overnight, the reaction was cooled to room temperature, diluted with 20 ml of i-PrOH / H2O / 10% NaOH, 70: 15: 1, filtered, the catalyst was washed with 20 ml X 3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and the acid was dried (31 -fluoro -biphenyl-4-yl) -acetic: (0.4 g, 75%) XH INOVA-500 NMR (DMSO d6) d 3.623 (s, 2H), 7.192 (m, 1H), 7.358 (d, J = 8.0 Hz, 2H), 7.474-7.515 (m, 3H), 7.652 (d, J = 8.0 Hz, 2H), 12.316 (s, 1H). 3-fluorobenzylamine (0.14 ml, 1.1 mmol), PyBOP (0.57 g, 1.1 mmol), and DIEA (0.36 ml, 2.2 mmol) were dissolved in DMF and stirred overnight, the reaction mixture was poured into water, collected a solid by filtration, recrystallized using water-methanol. (0.22 g, 76%); NMR H1 INOVA-500 (DMSO d6) d 3.550 (s, 2H), 4.303 (d, J = 6.5 Hz, 2H), 7.027-7.097 (m, 3H), 7.197 (m, 1H), 7.350 (m, 1H) ), 7.389 (d, J = 8.0 Hz, 2H), 7.477-7.518 (m, 3H), 7.657 (d, J = 8.0 Hz, 2H), 8.652 (t, J = 5.5 Hz, 1H). S (m / z) 338.1 (M + H) +.Synthesis of Compound 8, N- (3-fluorobenzyl) -4- (4-fluorophenyl) -phenylacetamide, KX1-311 Synthesis of (4'-fluoro-biphenyl-4-yl) -acetic acid: 4-bromo-phenylacetic acid (0.5 g, 2.3 mmol), 4-fluorophenylboronic acid (0.36 g, 2.4 mmol) and palladium-carbon were added to the 10% moistened with 50% water (0.16 g, 0.075 mmol Pd) to 10 ml of water and 5: 1 isopropanol mixture, then Na2CC > 3 (0.32 g, 3 mmol) dissolved in 3 ml of water, the reaction was heated to 65-70 ° C overnight, the reaction was cooled to room temperature, diluted with 20 ml of i-PrOH / H20. 10% NaOH, 70: 15: 1, filtered, the catalyst was washed with 20 ml X 3 using the above mixture, the filtrate was acidified using 20% H2SO, filtered and dried (0.4 g, 75%) NMR H1 INOVA-500 (DMSO d6) d 3.621 (s, 2H), 7.290 (t, J = 8.5 Hz, 2H), 7.351 (d, J = 7.5 Hz, 2H), 7.593 (d, J = 7.5 Hz, 2H), 7.695 (t, J = 7 Hz, 2H), 12.386 (s, 1H). (4'-Fluoro-biphenyl-4-yl) -acetic acid (0.2 g, 0.9 mmol), 3-fluorobenzylamine (0.14 mL, 1.1 mmol), PyBOP (0.57 g, 1.1 mmol), and DIEA (0.36 mL) were dissolved. , 2.2 mmol) in DMF, were stirred overnight, the reaction mixture was then poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.26 g, 90%); NMR 1ti INOVA-500 (D SO d6) d 3,541 (s, 2H), 4,304 (d, J = 5.5 Hz, 2H), 7,027-7,098 (m, 3H), 7,273-7,382 (m, 5H), 7,582 ( d, J = 8.0, 2H), 7.694 (m, 2H), 8.641 (t, J = 5.5 Hz, 2H) MS (m / z) 338.1 (M + H) +.

Synthesis of Compound 9, N- (3-fluorobenzyl) -N-methyl-4-biphenylacetamide, KX1-312 4-biphenylacetic acid (0.25 g, 1. 2 mmol), N-methyl-3-fluorobenzylamine (0.16 g, 1.2 mmol), EDCI (0.23 g, 1.2 mmol), and DIEA (0.42 mL, 2.4 mmol) in 10 mL of DC and were stirred overnight. The reaction mixture was diluted with 10 ml of DCM, washed with 10% HC1, saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated to yield a clear viscous oil (160 mg, 43% ), the 1H NMR INOVA-500 (DMSO de) indicated the presence of a mixture of the cis and trans isomers in a ratio of 1: 2, running the NMR, the experiment was run at 50 ° C slightly changing the value by the chemical shift, but had almost no effect on the proportion. The protons were labeled Ha or Hb to indicate that they belong to one isomer or the other. NMR INOVA-500 (DMSO d6) 2,813 (s, 3Ha), 3,000 (s, 3 Hb), 3,784 (s, 2Ha), 3,841 (s, 2Hb), 4,543 (s, 2Hb), 4,681 (s, 2Ha) ), 6,931-7,649 (m, 13 Ha + 13 Hb). S (m / z) 334.2 (M + H) +.

Synthesis of Compound 10, N- (3-fluorobenzyl) -4-phenyl-2-fluorophenylacetamide, KX1-313 Synthesis of 4-bromo-2-fluoro-phenylacetamide: 4-bromo-2-fluorobenzyl bromide (5 g, 18.7 mmol) was dissolved in 30 mL of ethanol, to which was added aqueous solution (10 mL) of KCN ( 2.43 g, 37.4 mmol), was heated to reflux overnight, then cooled to room temperature, poured into 200 ml of crushed ice, filtered, chromatographed using ethyl acetate 1: 1 followed by ethyl acetate (the cyano compound was hydrolyzed on the silica gel to produce the carboxamide), which was evaporated to yield a white solid (1.3 g, 32%). H1 INOVA-500 (DMSO d6) NMR d 3.436 (s, 2H), 7.005 (s, 1H), 7.289 (t, J = 8.0 Hz, 1H), 7.361 (d, J = 8.0 Hz, 1H), 7.478 (m, 1H), 7.517 (s, 1H). Synthesis of 4-bromo-2-fluoro-phenylacetic acid: 4-bromo-2-fluoro-phenylacetamide (1.3 g) was suspended in 100 ml of 30% NaOH, heated to reflux temperature for 24 hours, cooled to Room temperature was washed with DCM and ethyl acetate. The aqueous layer was acidified with concentrated HC1, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give crystals in the form of needles (0.5 g, 38%) H1-NMR INOVA-500 (DMSO d6) d 3.619 (s, 2H), 7,316 (t, J = 8.0 Hz, 1H), 7.379 (dd, J = 8.0, 1.5 Hz, 1H), 7.516 (dd, J = 8.0, 1.5 Hz, 1H), 12.555 (s, 1H). Synthesis of 4-phenyl-2-fluorophenylacetic acid: 4-bromo-2-fluoro-phenylacetic acid (0.25 g, 1.1 mmol), phenylboronic acid (0.15 g, 1.2 mmol) and 10% palladium-carbon moistened with 50% water (0.07 g, 0.033 mmol of Pd) were added to 10 ml of 5: 1 water and isopropanol mixture, then Na2CC >was added to the previous mixture.; 3 (0.14 g, 1.3 mmol) dissolved in 3 ml of water, the reaction was heated to 65-70 ° C overnight, the reaction was cooled to room temperature, diluted with 20 ml of i-PrOH / H20 / 10% NaOH, 70: 15: 1, filtered, the catalyst was washed with 20 ml X 3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and dried (0.2 g, 83%) 1H NMR INOVA-500 (DMSO d6) d 3.675 (s, 2H), 7.382-7.518 (m, 6H), 7.707 (d, J = 7.5 Hz, 2H), 12.498 (s, 1H). Synthesis of N- (3-fluorobenzyl) -4-phenyl-2-fluorophenylacetamide acid: 4-phenyl-2-fluorophenylacetic acid (0.2 g, 0.9 mmol), 3-fluorobenzylamine (0.14 ml, 1.1 mmol), PyBOP ( 0.57 g, 1.1 mmol), and DIEA (0.36 mL, 2.2 mmol) in DMF, were stirred overnight, the reaction mixture was then poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.20 g, 70%); RMN 1H INOVA-500 (DMSO d6) d 3.612 (s, 2H), 4318 (d, J = 6 Hz, 2H), 7.064-7.117 (m, 3H), 7.345-7.503 (m, 7H), 7.695 (d, J = 7.5 Hz, 2H), 8.660 ( t, J = 6 Hz, 1H). MS (m / z) 338.1 (M + H) +.

Synthesis of Compound 11, N- (3-fluorobenzyl) -2- phenylpyridin-5-acetamide, KX1-314 Synthesis of 2-phenylpyridin-5-acetic acid: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), phenylboronic acid (0.16 g, 1.3 mmol) and 10% palladium-carbon moistened with 50% water ( 0.08 g, 0.036 mmol Pd) were added to 10 ml of water and 5: 1 isopropanol mixture, then Na2C03 (0.15 g, 1.4 mmol) dissolved in 3 ml of water was added to the above mixture, the reaction was heated to 65 -70 ° C overnight, the reaction was cooled to room temperature, diluted with 20 ml of i-PrOH / H20 / 10% NaOH 70: 15: 1, filtered, the catalyst was washed with 20 ml X 3 using the above mixture, the filtrate was dried under vacuum and the crude mixture was used without any purification in the next step. Synthesis of N- (3-fluorobenzyl) -2-phenylpyridin-5-acetaraide: To the crude product of the previous reaction, 3-fluorobenzylamine (0.15 g, 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA were added. (0.32 g, 2.6 mmol) and stirred in DMF overnight. The reaction mixture was poured into water; a solid was collected by filtration, recrystallized using water-methanol (0.06 g, 18% in two steps). 1H NMR INOVA-500 (CDC13) d 3,645 (s, 2H), 4,438 (d, J = 5.5 Hz, 2H), 5,867 (s, 1H), 6,925-7,009 (m, 3H), 7,268 (m, 1H) , 7.408-7.493 (m, 3H), 7.735 (m, 2H), 7.965-7.982 (m, 2H), 8.582 (s, 1H). MS (m / z) 321.2 (M + H) +.

Synthesis of Compound 12, N- (3-fluoro-benzyl) -2- (4-pyridin-2-yl-phenyl) -acetamide, KXI-315 Synthesis of 4- (2-pyridinyl) benzyl alcohol: 4- (2-pyridinyl) benzaldehyde (2 g, 11 mmol), and NaBH 4 (0.42 g, 11 mmol) were stirred at room temperature for 2 hours, the ethanol was evaporated The residue was dissolved in ethyl acetate washed with saturated NaHCO 3 solution and saturated NaCl solution, dried using Na 2 SO 4 and evaporated to yield a white solid (1.5 g, 75%). Synthesis of (4-pyridin-2-yl-phenyl) -acetic acid: The crude product of the 4- (2-pyridinyl) benzyl alcohol was dissolved in 20 ml of DCM, cooled using ice / methanol, triethylamine (1.25 g) was added. mi, 8.9 mmol) followed by methanesulfonyl chloride (0.7 ml, 8.9 mmol) added dropwise over 5 minutes. The reaction was continued stirring at room temperature until TLC indicated the initial material consumption (3 hours), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCO 3 solution, and saturated NaCl solution. , dried using Na2SO4 and evaporated to yield a yellow oil, the oil produced was dissolved in 25 ml of 90% ethanol, then KCN (1.05 g, 16.2 mmol) was added and it was heated to reflux overnight. The ethanol was evaporated; the solid was washed with 50 ml of water and filtered. The solid was dissolved in 30 ml of concentrated HC1, heated to reflux for 48 hours; Charcoal was added, heated to reflux for 1 hour, filtered. The HC1 was evaporated, the solid formed was dissolved in 5 ml of water, 1N NaOH was added dropwise while it was extracted with ethyl acetate, the ethyl acetate extract was dried with Na2SO4 and evaporated to yield a white solid ( 0.6 g, 35% in 3 stages) RMN ?? INOVA-500 (DMSO d6) d 3.641 (s, 2H), 7.345 (t, J = 6.0 Hz, 1H), 7.381 (d, J = 8.5 Hz, 2H), 7.879 (t, J = 8.0 Hz, 1H) , 7.951 (d, J = 8.0 Hz, 1H), 8.034 (d, J = 8.0 Hz, 2H), 8.662 (d, J = 4.0 Hz, 1H), 12.390 (s, 1H). Synthesis of N- (3-fluoro-benzyl) -2- (-pyridin-2-yl-phenyl) -acetamide: (4-pyridin-2-yl-phenyl) -acetic acid (0.2 g, 0.9 mmol), 3 -fluorobenzylamine (0.14 ml, 1.1 mmol), PyBOP (0.57 g, 1.1 mmol), and DIEA (0.36 ml, 2.2 mmol) were dissolved in DMF, stirred overnight, the reaction mixture was poured into water, collected by filtration a solid, recrystallized using water-methanol (0.13 g, 45%); NMR lti INOVA-500 (DMSO d6) d 3.563 (s, 2H), 4.305 (d, J = 6.0 Hz, 2H), 7.032-7.095 (m, 3H), 7.332-7.360 (m, 2H), 7.404 (d , J = 8.0 Hz, 2H), 7.874 (t, J-7.0 Hz, 1H), 7.948 (d, J = 8.0 Hz, 1H), 8.034 (d, J = 8.0 Hz, 2H), 8.659 (d, J = 4. Hz, 2H). MS (m / z) 321.2 (M + H) +.

Synthesis of Compounds 13 and 24 Synthesis of the pyridyl derivatives, Compound 13, KX1-316, and Compound 24, KXI-327, are shown in Scheme 4. First the amide was produced with an EDCI coupling to give the amide 5. Thereafter, performed the Suzuki reaction with 3- or 4-pyridylboronic acids. The basic nature of the pyridine ring was used to purify the product and to keep the initial material. The product in the aqueous phase was separated from the initial material using HC1 1 N.

After several organic washes, the aqueous layer was basified and the product was extracted with ethyl acetate. This purification procedure worked well and eliminated the need for chromatography.

KX1-316 (Compound 13) A 50 ml round bottom flask, dried to the flame, with two condensers, was charged with argon. 15 ml of dimethoxyethane, and 1 ml of 2 M potassium carbonate were heated to 45 ° C while argon was bubbled through the solution. After 1 hour, bromo-amide (240 mg, 0.7475 mmol) and 3-pyridylboronic acid (92 mg, 1.1 eq.) Were added. After one hour, pure Pd (PPh3) 4 (43 mg, 5 mol%) was added. The reaction was heated to 65-75 ° C for 48 hours. The solvent was emptied into a round bottom flask, the remaining residue was washed with ethyl acetate. The solvents were combined and removed in vacuo. The residue was taken up in 20 ml of 1 N HCl and washed with ethyl acetate (3 × 10 ml). The acid layer was then made alkaline with a combination of 2 N NaOH and saturated sodium bicarbonate at pH 8-9. The aqueous layer was then washed with ethyl acetate (3X20 mL). The solvent extracts were combined, dried with sodium sulfate and removed in vacuo. The residue was purified on a column of silica gel (DCM: EtOAc 1: 1) to give 90 mg of the desired product (38% yield). TLC, Rf 0.2 (DCM: EtOAc 1: 1). LCMS 321.3 (m + H) 640.8 (2m + Na) 662.9 (2M + Na). NMR XH (500 MHz, DMSO) 3.54 (s, 2H) 4.29 (d, 6.0 Hz, 2H) 7.00-7.08 (m, 3H) 7.34 (q, 8.0 Hz, 1H) 7.40 (d, 10.0 Hz, 2H) 7.47 (dd, 6.0 Hz, 10.0 Hz, 1H) 7.66 (d, 10.0 Hz, 2H) 8.05 (dt, 2.5 Hz, 10.0 Hz, 1H) 8.55 (dd, 2.0 Hz, 6.0 Hz, 1H) 6.40 (t, 7.0 Hz , 1H) 8.78 (d, 2.5Hz, 1H).

KX1-327 (Compound 24) A 50 ml round bottom flask, dried to the flame, with two condensers, was charged with argon. 15 ml of dimethoxyethane and 1 ml of 2 M potassium carbonate were heated to 45 ° C while argon was bubbled through the solution. After 1 hour, bromo-amide (150 mg, 0.4672 mmol) and 4-pyridylboronic acid (57 mg, 1 eq.) Were added.

After one hour, pure Pd (PPh3) 4 (27 mg, 5 mol%) was added. The reaction was heated to 65-75 ° C for 72 hours. The solvent was emptied into a round bottom flask, the remaining residue was washed with ethyl acetate. The solvents were combined and removed in vacuo. The residue was taken up in 20 ml 1 N HCl and washed with ethyl acetate (3 × 10 ml). The acid layer was then made alkaline with a combination of 2 N NaOH and saturated sodium bicarbonate at pH 8-9. The aqueous layer was then washed with ethyl acetate (3X20 mL). The solvent extracts were combined, dried with sodium sulfate and removed in vacuo to give 71 mg of the desired product (48% yield). TLC, Rf 0.2 (DCM: EtOAc 1: 1). LCMS 321.3 (m + H). 1 H NMR (500 Hz, DMSO) 3.56 (s, 2 H) 4.29 (d, 6.0 Hz, 2 H) 7.04 (m, 3 H) 7.34 (q, 6.5 Hz, 1 H) 7.42 (d, 8.0 Hz, 2 H) 7.69 (d , 6.0 Hz, 2H) 7.75 (d, 8.5Hz, 2H) 8.61 (d, 6.0 Hz, 2H) 8.64 (t, 5.5Hz, 1H).

Scheme 4 Reagents: i) 3-fluorobenzylamine (1.1 eq.), EDCI (1.1 eq.), HOBT (1.0 eq.), DIEA (1.1 eq.), 88% yield. ii) 3 (or 4) -pyridylboronic acid (1.1 eq.), Na2CO3 (1.3 eq.), Pd (PPh3) 4 (5 mol%), dimethoxyethane, 2N Na2CO3 (2 eq.). X1-316 (Xi = N, X2 = C) 38%, KX1-327 (Xi = C, X2 = N) 47%.

Synthesis of Compound 14, 2 [6- (3-chloro-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide. KX1-317 Synthesis of 2- (3-chloro-phenyl) -pyridin-5-acetic acid: 2-chloropyridine-5-acetic acid (0.2 g) was added, 1.21 mmol), 3-chlorophenylboronic acid (0.2 g, 1.3 mmol) and 10% palladium-carbon moistened with 50% water (0.08 g, 0.036 mmol Pd) to 10 ml of water and 5: 1 isopropanol mixture, Na2CO3 (0.15 g, 1.4 mmol) dissolved in 3 mL of water was then added to the above mixture, the reaction was heated to 65-70 ° C overnight, the reaction was cooled to room temperature, diluted with 20 mL of i-PrOH / H20 / 10% NaOH 70: 15: 1, filtered, the catalyst was washed with 20 ml X 3 using the above mixture, the filtrate was dried in vacuo and the crude mixture was used without any purification in the next stage. Synthesis of 2- [6- (3-chloro-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide: To the crude product of the previous reaction, 3-fluorobenzylamine (0.15) was added. g, 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.32 g, 2.6 mmol) and shaken in DF overnight. The reaction mixture was emptied in water; a solid was collected by filtration, recrystallized using water-methanol (0.02 g, 6% in two steps). XH INOVA-500 NMR (DMSO d6) d 3,611 (s, 2H), 4,314 (d, J = 6.0 Hz, 2H), 7,048-7,106 (m, 3H), 7,364 (m, 1H), 7,500-7,545 (m , 2H), 7.808 (dd, J = 8.0, 2.0 Hz, 1H), 7.997 (d, J = 8.0 Hz, 1H), 8.046 (d, J = 8.0 Hz, 1H), 8.126 (d, J = 2.0 Hz, 1H), 8.578 (s, 1H), 8.699 (bs, 1H). MS (m / z) 355.2 (+ H) +.

Synthesis of Compound 14, 2- [6- (4-ethyl-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide, KX1-318 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine ( 0.15 mL, 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) in DMF and stirred overnight, the reaction mixture was poured into water, a solid was collected by filtration, it was recrystallized using water-methanol. (0.3 g, 85%); NMR H1 INOVA-500 (CDCI3) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (ra, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of 2- [6- (4-ethyl-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide, (0.125 g, 0.5 mmol), and 4-ethylbenzeneboronic acid (0.083 g, 0.55 mmol) were dissolved in dimethoxymethane (DME), Na 2 CO 3 (0.11 g, 1 mmol) was added in 5 ml. ml of water to the DME solution, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.029 g, 0.025 mmol) was added, it was degassed for another 15 minutes. minutes, it was heated to reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 3: 2. The product is a white solid (0.08 g, 47%). 1 INOVA-500 NMR (DMSO d6) d 1.228 (t, J = 7.5 Hz, 3H), 2669 (q, J = 7.5 Hz, 2H), 3.590 (s, 2H), 4.321 (d, J = 6Hz, 2H ), 7.053-7.113 (m, 3H), 7.324-7.375 (m, 3H), 7.766 (dd, J = 9.0, 2.0 Hz, 1H), 7.887 (d, J = 8.5 Hz, 1H), 7.994 (d, J = 8.0 Hz, 2H), 8.548 (s, 1H), 8.696 (t, J = 5.5Hz, 1H). S (m / z) 349.3 (M + H) +.

Synthesis of Compound 16, N- (3-Fluoro-benzyl) -2- (2-fluoro-biphenyl-4-yl) -acetamide, KX1-319 Synthesis of 2-fluoro-biphenyl-4-carbaldehyde: 4-bromo-2-fluoro-biphenyl (2 g, 8 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran, THF, cooled to -78 ° C under an argon atmosphere (Ar), 2.5 M n-Butyllithium (3.5 ml, 8.8 mmol) was added dropwise over the course of 10 minutes and stirred for an additional 1 hour, then anhydrous DMF (0.68 ml, 8.8 mmol) was added, it was stirred for a further 1 hour, then it was warmed to room temperature for 4 hours, quenched with water, extracted with ether, the ether was dried, evaporated, the produced compound was purified using hexane / ethyl acetate 9: 1, to produce a white solid (1 g, 62.5%); 1H NMR INOVA-500 (CDC13) d 7.416-7.495 (m, 3H), 7.581-7.661 (m, 4H), 7.723 (d, J = 8.0 Hz, 1H), 9.991 (s, 1H). Synthesis of (2-fluoro-biphenyl-4-yl) -methanol: 2-fluoro-biphenyl-4-carbaldehyde (1 g, 5 mmol) and NaBH 4 were dissolved in ethanol, stirred for 2 hours, 10% NaOH was added. %, the ethanol was evaporated, the reaction mixture was extracted with ethyl acetate, the ethyl acetate extract was dried with Na 2 SO 4 and evaporated to yield a white solid (0.8 g, 80%). RMN ?? INOVA-500 (CDC13) d 2.266 (s, 1H), 4.683 (s, 2H), 7.142-7.168 (m, 2H), 7.339-7.442 (m, 4H), 7.519-7.535 (m, 2H). Synthesis of (2-fluoro-biphenyl-4-yl) -acetic acid: (2-fluoro-biphenyl-4-yl) -methanol (0.75 g, 3.7 mmol) was dissolved in 20 mL of DCM, cooled using ice / methanol, added triethylamine (0.55 ml, 4.0 mmol) followed by methanesulfonyl chloride (0.3 ml, 4.0 mmol) added dropwise for 5 minutes. The reaction was continued stirring at room temperature until the TLC indicated the consumption of the starting material (2 hours), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCC solution > 3, and saturated NaCl solution, dried using Na 2 SO 4 and evaporated to yield a yellow oil, the oil produced was dissolved in 25 ml of 70% ethanol, KCN (0.4 g, 6 mmol) was added and heated to reflux. all night. Ethanol evaporated; the solid was washed with 50 ml of water and filtered. The solid was dissolved in 20 ml of ethanol, 20 ml of concentrated H2SO4 was added, and it was heated to reflux overnight; the solution was allowed to cool to room temperature, was emptied into 200 ml of crushed ice, the solid was collected by vacuum filtration, suspended in 25 ml of 30% NaOH, heated at reflux temperature for 24 hours, cooled at room temperature, it was washed with DCM and ethyl acetate. The aqueous layer was acidified with concentrated HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give a white solid (0.15 g, 18% in 3 steps) H1 NMR INOVA-500 (DMSO d6) d 3.672 (s, 2H), 7.191-7.254 (ra, 2H) , 7.389-7.560 (m, 6H), 12.494 (s, 1H). Synthesis of N- (3-fluoro-benzyl) -2- (2-fluoro-biphenyl-4-yl) -acetamide: (2-fluoro-biphenyl-4-yl) -acetic acid (0.12 g, 0.5 mmol), 3-fluorobenzylamine (0.08 ml, 0.6 mmol), PyBOP (0.34 g, 0.6 mmol), and DIEA (0.22 ml, 1.3 mmol) were dissolved in DMF, stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol. (0.140 g, 83%); 1N INOVA-500 NMR (DMSO d6) d 3,580 (s, 2H), 4,316 (d, J = 5.5 Hz, 2H), 7,037-7,110 (m, 3H), 7,210-7,247 (m, 2H), 7,343-7,372 (m, 2H), 7.457-7.501 (m, 3H), 7.544 (d, J = 8.0 Hz, 2H), 8.660 (t, J = 6.0 Hz, 1H). MS (m / z) 338.1 (MH-H) +.

Synthesis of Compound 17, N- (3-fluoro-benzyl) -2- [6- (4-fluoro-phenyl) -pyridin-3-yl] -acetamide, KX1-320 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) was dissolved in DMF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol. (0.3 g, 85%); NMR 1H INOVA-500 (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of N- (3-fluoro-benzyl) -2- [6- (4-fluoro-phenyl) -pyridin-3-yl] -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide and (0.093 g, 0.33 mmol), 4-fluorobenzeneboronic acid (0.052 g, 0.37 mmol) was dissolved in DME, Na2CC was added. 3 (0.07 g, 0.66 mmol) in 5 ml of water to the DME solution, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.016 g) was added. , 0.015 mmol), degassed for another 15 minutes, heated to reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 3: 2, then crystallized from methanol-water to yield a white solid (0.013 g, 12%). 1H NMR INOVA-500 (DMSO dd 3.587 (s, 2H), 4.306 (d, J = 5.0 Hz, 2H), 7.041-7.099 (m, 3H), 7.295-7.363 (m, 3H), 7.777 (d, J = 7.5, 1H), 7.913 (d, J = 8.0 Hz, 1H), 8.119 (s, 2H), 8.546 (s, 1H), 8.702 (s, 1H) MS (m / z) 339.2 (M + H ) + Synthesis of Compound 18, N- (3-fluoro-benzyl) -2- [6- (3-fluoro-phenyl-pyridin-3-yl] -acetamide, KX1-321 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DMF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol. (0.3 g, 85%); NMR H1 INOVA-500 (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of N- (3-fluoro-benzyl) -2- [6- (3-fluoro-phenyl) -pyridin-3-yl] -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide and (0.125 g, 0.5 mmol), 3-fluorobenzeneboronic acid (0.08 g, 0.55 mmol) were dissolved in DME, to the DME solution was added Na2C03 (0.11 g, 1.0 mmol) in 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.029 g, 0.025 ramol) was added, degassed for another 15 minutes, heated at reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 3: 2, then crystallized from methanol-water to yield a white solid (0.075 g, 45%). NMR 1 INOVA-500 (DMSO d6) d 3,614 (s, 2H), 4,318 (d, J = 6.0 Hz, 2H), 7,053-7,099 (m, 3H), 7,273 (t, J = 9.0 Hz, 1H), 7.367 (q, J = 7.0 Hz, 1H), 7.542 (q, J = 7.0 Hz, 1H), 7.812 (d, J = 8.0 Hz, 1H), 7.891 (d, J = 10.0 Hz, 1H), 7.942 ( d, J = 7.5 Hz, 1 H), 7,992 (d, J = 8.0 Hz, 1 H), 8,583 (s, 1 H), 8,717 (s, 1 H). MS 339.2 (M + H) +.

Synthesis of Compound 19, 2- [6- (3-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide, KX1-322 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol. (0.3 g, 85%); NMR H1 INOVA-500 (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of N- (3-fluoro-benzyl) -2- [6- (3-fluoro-phenyl) -pyridin-3-yl] -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide (0.15 g, 0.54 mmol), and 3-ethoxybenzeneboronic acid (0.096 g, 0.6 mmol) were dissolved in DME, to the DME solution was added Na2C03 (0.11 g, 1.08 mmol) in 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.031 g, 0.027 mmol) was added, degassed for another 15 minutes, heated at reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 3: 2, then crystallized from methanol-water to yield a white solid (0.03 g, 17%). 1N INOVA-500 NMR (DMSO d6) d 1.366 (t, J = 7.0 Hz, 3H), 3.591 (s, 2H), 4.110 (q, J = 7.0 Hz, 2H), 4.312 (d, J = 5.5 Hz, 2H), 6,985 (d, J = 7.5 Hz, 1H), 7.048-7.105 (m, 3H), 7.342-7.402 (m, 2H), 7.621 (m, 2H), 7.770 (d, J = 7.0 Hz, 1H ), 7.826 (d, J = 8.0 Hz, 1H), 7.942 (d, J = 7.5 Hz, 1H), 8.550 (s, 1H), 8.701 (s, 1H). MS (m / z) 365.2 (M + H) +.

Synthesis of Compound 20, 4-. { 5- [(3-Fluorobenzylcarbamoyl) -methyl] -pyridin-2-yl} -benzoic, KX1-323 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.3 g, 85%); XH INOVA-500 NMR (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of N- (3-fluoro-benzyl) -2- [6- (3-fluoro-phenyl) -pyridin-3-yl] -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide (0.15 g, 0.54 mmol), and 4-carboxybenzanboronic acid (0.096 g, 0.6 mmol) were dissolved in DME, to the DME solution was added Na2C03 (0.11 g, 1.08 mmol) in 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.031 g, 0.027 mmol) was added, degassed for another 15 minutes, heated at reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate, 10% NaOH, the aqueous layer was washed several times with ethyl acetate, neutralized by the dropwise addition of 1% HC1. , having the ethyl acetate in the medium with stirring after each addition of HC1, the ethyl acetate was evaporated and the solid formed was crystallized from methanol-water to yield a white solid (0.07 g, 40%). , XH INOVA-500 NMR (DMSO d6) d 3.625 (s, 2H), 4.318 (d, J = 5.5 Hz, 2H), 7.053-7.111 (m, 3H), 7.376 (q, J = 7.0 Hz, 1H) , 7.8341 (d, J = 8.0, 1H), 8.015-8.063 (m, 3H), 8.206 (d, J = 8.0 Hz, 1H), 8.613 (s, 1H), 8.724 (t, J = 5.5, 1H) . S [m / z) 365.3 (M + H) +.

Synthesis of Compound 21, 2- [6- (2-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide, KX1-324 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DMF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.3 g, 85%); XH INOVA-500 NMR (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H).

Synthesis of 2- [6- (2-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetaraide and (0.15 g, 0.54 mmol), 2-ethoxybenzeneboronic acid (0.096 g, 0.6 mmol) were dissolved in DME, to the DME solution was added Na2C03 (0.11 g, 1.08 mmol) in 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.031 g, 0.027 mmol) was added, degassed for another 15 minutes, heated at reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 2: 1, then crystallized from methanol-water to yield a white solid (0.075 g, 40%). NMR 1H INOVA-500 (DMSOi d6) d 1339 (t, J = 7.0 Hz, 3H), 3.581 (s, 2H), 4.112 (q, J = 7.0 Hz, 2H), 4.322 (d, J = 5.5 Hz, 2H), 7.032-7.135 (m, 5H), 7.358-7.387 (m, 2H), 7.703 (d, J = 7.0, 1H), 7.748 (d, J = 7.0 Hz, 1H), 7.871 (d, J = 7.0 Hz, 1H), 8.548 (s, 1H), 8.725 (s, 1H). MS (m / z) 365.2 (M + H) +.

Synthesis of Compound 22, 2- [6- (4-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide, KX1-325 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DMF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.3 g, 85%); XH INOVA-500 NMR (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H). Synthesis of 2- [6- (4-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide and (0.15 g, 0.54 mmol), 4-ethoxybenzeneboronic acid (0.096 g, 0.6 mmol) was dissolved in DME, Na2C03 (0.11 g, 1.08 mmol) was added to the DME solution. 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.031 g, 0.027 mmol) was added, degassed for another 15 minutes, heated at reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 2: 1, then crystallized from methanol-water to yield a white solid (0.08 g, 42%). XH INOVA-500 NMR (DMSO d6) d 1357 (t, J = 7.0 Hz, 3H), 3.564, (s, 2H), 4090, (q, J = 7.0 Hz, 2H), 4.309 (d, J = 6.0) Hz, 2H), 7.012-7.103 (m, 5H), 7.361 (q, J = 7.0 Hz, 1H), 7.726 (d, J = 8.0 Hz, 1H), 7.842 (d, J = 8.0 Hz, 1H), 8.012 (d, J = 8.5 Hz, 2H), 8.503 (s, 1H), 8.686 (s, 1H). MS (m / z) 365.2 (M + H) +.

Scale synthesis of Compound 22 HCl, 2- [6- (4-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide-HCl, KX1-325 HCl Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide HCl: 2-chloropyridine-5-acetic acid (6.0 g, 34 mmol), 3-fluorobenzylamine (4.5 mi, 34 mmol), PyBOP (18 g, 36 mmol), and DIEA (12.5 mL, 75 mmol) were dissolved in DMF stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol (6.3 g, 70%); NMR 1H INOVA-500 (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6'929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5 Hz, 1H).

Synthesis of 2- [6- (4-ethoxy-phenyl) -pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide (4.8 g, 17.2 mmol), and 4-ethoxybenzeneboronic acid (3.14 g, 18.9 mmol) were suspended in DME (100 mL), to the DME solution was added Na2CO3 (3.6 g, 34.4 mmol) in 15 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and vacuum for the first 5 minutes), paladiotetrakistriphenylphosphine (0.99 g, 0.86 mmol) was added, degassed for another 15 minutes. minutes, it heated to reflux all night. The reaction was allowed to cool to room temperature, filtered, the solid was washed with cold ethyl acetate and saturated NaHCO 3 solution, the solid was recrystallized from methanol to yield a white solid (4.8 g). 4.6 g of the free amine was dissolved in 50 ml ethanol with gentle heating, 25 ml of 4N HC1 in ethyl acetate was added, the solution was concentrated to 20 ml, diluted with 100 ml of cold ethyl acetate, the solid filtered was filtered, washed with more ethyl acetate (50x2) and dried (4.3 g, 65%); NMR * H INOVA-500 (DMSO d6) d 1386 (t, J = 7.0 Hz, 3H), 3,822 (s, 2H), 4,179 (q, J = 7.0 Hz, 2H), 4,339 (d, J = 6.0 Hz) , 2H), 7,074-7,182 (m, 5H), 7,374 (m, 1H), 8,106 (d, J = 8.0 Hz, 1H), 8,263 (d, J = 8.0 Hz, 1H), 8,312 (s, 2H) , 8.718 (s, 1H), 8.981 (s, 1H). MS (m / z) 365.2 (+ H) +. Melting point of the free base: 0.1 g of the hydrochloride salt was stirred in 10 ml of 20% NaOH for 10 minutes, filtered; the solid was crystallized from ethanol water, dried in the oven at 100 ° C for 2 hours. It was found that the melting point was 173-176 ° C.

Synthesis of Compound 23, N- (3-fluoro-benzyl) -2- [6- (4-methanesulfonyl-phenyl) -pyridin-3-yl] -acetamide, KX1-326 Synthesis of 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide: 2-chloropyridine-5-acetic acid (0.2 g, 1.21 mmol), 3-fluorobenzylamine (0.15 ml) , 1.2 mmol), PyBOP (0.67 g, 1.3 mmol), and DIEA (0.43 mL, 2.6 mmol) were dissolved in DMF, stirring overnight, the reaction mixture was poured into water, a solid was collected by filtration, recrystallized using water-methanol (0.3 g, 85%); XH INOVA-500 NMR (CDC13) d 3,562 (s, 2H), 4,429 (d, J = 6.5 Hz, 2H), 5,868 (s, 1H), 6,929-7,015 (m, 3H), 7,300-7,333 (m, 2H), 7.668 (dd, J = 8, 2.5 Hz, 1H), 8.280 (d, J = 2.5Hz, 1H). Synthesis of N- (3-fluoro-benzyl) -2- [6- (4-methanesulfonyl-phenyl) -pyridin-3-yl] -acetamide: 2- (6-chloro-pyridin-3-yl) -N- (3-fluoro-benzyl) -acetamide (0.15 g, 0.54 mmol) and 4-methanesulfonyl-benzeneboronic acid (0.12 g, 0.6 mmol) were dissolved in DME, to the solution of DE was added Na2C03 (0.11 g, 1.08 mraol) in 5 ml of water, the solution was degassed for 30 minutes (through the solution Ar was applied and empty for the first 5 minutes), paladiotetrakistriphenylphosphine (0.031 g, 0.027 mmol) was added, degassed for another 15 minutes, heated to reflux for 24 hours. The reaction was allowed to cool to room temperature, filtered, the solid was washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate / hexane 2: 1, crystallized from methanol-water to yield a white solid (0.02 g, 10%); XH NMR INOVA-500 (DMSO d6) d 3.341 (s, 3H), 3.635 (s, 2H), 4.315 (d, J = 7.0 Hz, 2H), 7.047-7.110 (m, 3H), 7.366 (q, J = 9.0 Hz, 1H), 7.857 (d, J = 8.5 Hz, 1H), 8.027-8.081 (m, 3H), 8.343 (d, J = 10.5 Hz, 2H), 8.631 (s, 1H), 8.731 (s) , 1 HOUR) . MS (m / z) 399.2 (M + H) +.

Synthesis of Compound 24, KXI-327, and Compound 26, KX1-357 The syntheses are shown in Scheme 5. Compound 24, KXl-327 HC1 A solution of 75 ml of 1,2-dimethoxyethane and 16 ml of 2 M sodium carbonate was perfectly degassed by heating at 50 ° C with a stream of argon through the solvent. 5.00 g of 4-bromophenyl acetamide (5.15.6 mmol) and 1.95 grams of 4-pyridylboronic acid (1.00 eq.) Were added and degassing continued for 1 hour. Tetrakis (triphenylphosphine) palladium (5 mol%) was added neat and the reaction was heated to reflux for 24 hours. The reaction was cooled and evacuated in 300 ml of distilled water and filtered to give 5.014 g of crude product. This crude product was taken up in 1 L of a 1 to 1 mixture of 1 N HC1 and ethyl acetate. The organic layer was removed and the aqueous layer was washed twice more with EtOAc. The aqueous layer was basified with solid sodium bicarbonate at pH 7.5. This was extracted 3X 300 ml EtOAc to give approximately 3.25 g of semi-hard product. Pure crystals of the free base were produced by dissolving 200 mg in a minimum amount of ethyl acetate with gentle heating and sonication. To this solution hexanes were added until it became turbid. It warmed up until it was clear. The addition of more hexanes followed by heating was repeated twice more. This clear solution was left to sit overnight in a sealed container. The white crystals were washed with hexanes and dried to give approximately 50 mg (melting point 145-146 ° C). The remainder of the product was dissolved in ethanol and two equivalents of hydrochloric acid (1.1 M in EtOAc) were added. After 1 hour, the ethanol was removed and redissolved in the lowest amount of ethanol at 40 ° C. EtOAc was added until the solution became turbid. The solution was allowed to stand and the desired product crystallized as pure white crystals. The crystals were filtered, washed with EtOAc and dried to give 2.4 grams (48% total yield); LCMS 321.3 (m + H). 1N NMR (500 MHz, DMSO) 3.61 (s, 2H) 4.29 (d, 7.5 Hz, 2H) 7.04 (m, 3H) 7.34 (q, 9.5 Hz, 1H) 7.50 (d, 10.5 Hz, 2H) 7.95 (d , 10.5 Hz, 2H) 8.24 (d, 8.0 Hz, 2H) 8.70 (s, 1H) 8.87 (d, 8.0 Hz, 2H).

Compound 26, KX1-357 47. 0 mg of KX1-327 was dissolved in 5 ml of DCM. Meta-chloroperoxybenzoic acid (35.0 mg, 1.4 eq.) Was added and the reaction was continued stirring for 13 hours. The reaction was washed 3X 5 mL of saturated sodium bicarbonate, dried with sodium sulfate and concentrated to give 45 mg of a yellow solid. The NMR revealed that the product contained approximately 15% impurities, which could have been m-chlorobenzoic acid (or the peroxide). The solid was redissolved in 5 ml of DCM and 3X 5 ml of saturated sodium bicarbonate was washed, dried with sodium sulfate and concentrated to give 26 mg of the desired product as a yellow solid; LCMS 337.2 (M + H), 672.9 (2M + H), 694.8 (2M + Na). NMR XH (400 MHz, DMSO) 3.54 (s, 2H), 4.28 (d, 6.0 Hz, 2H), 7.00-7.08 (m, 3H), 7.34 (q, 8.0 Hz, 1H), 7.40 (d, 8.4Hz) , 2H), 7.72 (d, 8.4 Hz, 2H), 7.75 (d, 7.2 Hz, 2H), 8.24 (d, 8.4 Hz, 2H), 8.63 (t, 5.6 Hz, 1H).

Scheme 5 4-Broraophenylacetic acid (6.00 g, 47.9 mrnol) was dissolved in 40 ml of anhydrous dichloromethane under an argon atmosphere and cooled in an ice bath. 3-Fluorobenzylamine (1.00 eq.) Was added and the acetic acid / benzylamine salt precipitation was not intended to occur. More dichloromethane (20 ml) was added followed by DIEA (2.2 eq.), HOBT (1.0 eq.), And EDCI (1.1 eq.). After about 2 hours, the solid broke, 4 hours later, the reaction was terminated by TLC. The reaction was diluted with 200 ml of dichloromethane and 200 ml of 1 N hydrochloric acid. After stirring in a separatory funnel, an emulsion was formed. This emulsion was divided in half and the dichloromethane was removed. To each half were added 500 ml of ethyl acetate and another 300 ml of 1 N HCl. The organic layer was washed 2 times more with 1N HC1, 3X 300 ml of saturated sodium bicarbonate, and 3X200 ml with saturated sodium chloride. The organic layers from each extraction were combined and dried with sodium sulfate, and the solvent was removed to give 13.12 g (85% yield) of the desired product; 1N-NMR (500 MHz, CDC13) d (ppm) 3.58 (s, 2H), 4.45 (d, 6.0 Hz, 2H), 5.70 (bs, 1H) 6.93 (m, 3H), 7.16 (d, 8.1 Hz, 2H ), 7.26 (m, 1H) 7.48 (d, 8.1 Hz, 2H).

Synthesis of Compound 25, KXl-329 As shown in Scheme 6, 5-Hydroxy-2-methylpyridine was converted to triflate, 6, followed by the Suzuki Reaction to give 5-phenyl-2-methylpyridine. Methyl pyridine, 7, was deprotonated with n-butyl lithium and added to a solution of ethyl carbonate. Saponification followed by amide coupling with PyBOP gave the desired product. 5-hydroxy-2-methylpyridine (3.00 g, 27.5 mmol) was dissolved in 15 ml of anhydrous pyridine and cooled to 0 ° C. Triflic anhydride (7.76 g, 1.1 eq.) Was added dropwise over 3 minutes. After the addition, the reaction was removed from the ice bath and stirring continued for 6 hours. The volume was reduced to 8 ml under vacuum, diluted with 50 ml of distilled water, and then extracted with 75 ml of EtOAc. The organic layer was washed with 1 N HC1 (3X50 mL), dried with sodium sulfate, and removed in vacuo to give 2.78 g (42%) of an amber oil (6); LCMS 242.1 (m + H). NMR * H (400 MHz, CDC13) 2.58 (s, 3H) 7.26 (d, 8.4 Hz, 1H) 7.52 (dd, 2.8 Hz, 8.4 Hz, 1H) 8.47 (d, 2.8 Hz, 1H). A 50 ml round bottom flask, dried to the flame, with two condensers, was charged with argon. 25 ml of dimethoxyethane and 6 ml of 2 M sodium carbonate was heated to 45 ° C while argon was bubbled through the solution. After 1 hour, pyridyl triflate (6) (1.538 g, 6.382 mmol) and phenylboronic acid (856 mg, 1.1 eq.) Were added. After one hour, Pd (PPh3) 4 (370 mg, 5 mol%) was added, the reaction was heated at 65-75 ° C for 48 hours. The solvent was emptied into a round bottom flask, the remaining residue was washed with ethyl acetate. The solvents were combined and removed in vacuo. The residue was purified by chromatography on silica gel (hexanes: EtOAc) to give 702 mg of the desired product 7 (65% yield); LCMS 170.2 (m + H). XH NMR (400 MHz, CDC13) 3.60 (s, 3H) 7.22 (d, 8.0 Hz, 1H) 7.38 (t, 7.2 Hz, 1H) 7.46 (t, 7.2 Hz, 2H) 7.56 (d, 8.0 Hz, 2H) 7.77 (dd, 2.4 Hz, 8.0 Hz, 1H) 8.73 (d, 2.4 Hz, 1H). 5-phenyl-2-methylpyridine (7, 205 mg, 1.223 mmol) was dissolved in freshly distilled THF, in flame-dried glassware under argon atmosphere. It was cooled to -78 ° C in a dry ice / acetone bath for 20 minutes. N-butyl lithium (0.485 ml, 1.0 eq.) Was added dropwise for 5 minutes. This solution was added to a solution of THF and ethyl carbonate (1.5 eq.) Through a cannula. The solution was stirred for 2 hours before it was quenched with added methanol by dripping. 1 N sodium hydroxide (1 ml) was added before removing the organic solvents in vacuo. The remaining aqueous solution was extracted with ether (3X15 ml). The organic layers were combined and dried with sodium sulfate and removed in vacuo to give 208 mg of 8 (71% yield) 1 H-NMR (500 MHz, CDC13) 1.30 (m, 3 H) 2.61 (s, 2 H) 4.20 (m, 3H) 7.22 (d, 8.0 Hz, 1H) 7.38 (t, 7.5 Hz, 1H) 7.48 (t, 7.5 Hz, 2H) 7.58 (m, 2H) 7.78 (dd, 2.5 Hz, 8.0 Hz, 1H) 8.73 (d, 2.5 Hz, 1H). The ethyl ester 8 (208 mg, 0.86 mmol) was dissolved in 5 ml of THF. 1 N NaOH was added (approximately 1 ml) and the reaction was placed in a water bath at 35 ° C overnight. The volume of the reaction was reduced to about 1 ml and then acidified with 1 N HC1 to precipitate the desired product. The precipitate was isolated by decantation and dried in vacuo to give 54 mg (30% yield) of 9; LCMS 214.1 (m + H) 236.0 (ra + Na). NMR XH (400 MHz, CD3OD) 3.64 (s, 2H) 7.24-7.28 (m, 4H) 7.25 (t, 8.4 Hz, 2H) 7.52 (d, 8.4 Hz, 2H) 7.87 (dd, 2.0 Hz, 8.0 Hz, 1H) 8.53 (d, 2.0 Hz, 1H).

The carboxylic acid 9 (54 mg, 0.232 mmol), 3-fluorobenzylamine (1.1 eq.), And PyBOP (1.1 eq.) Were dissolved in 3 ml of anhydrous DMF. After 10 minutes, DIEA (1.1 eq.) Was added and the reaction was continued stirring overnight. The DMF was removed in vacuo and the residue was taken up in methanol and crystallized from methanol / water to give 44 mg of Compound 25, KX1-329 (55%) as clear crystals in the form of needles; TLC, Rf 0.2 (DCM: EtOAc 1: 1). LCMS 321.2 (m + H), 343.1 (m + Na), 662.9 (2m + Na). 1 H NMR (400 MHz, CDC13) 3.82 (s, 2H), 4.46 (d, 8.8 Hz, 2H), 6.91 (t, 9.2 Hz, 2H) 6.99 (d, 7.6 Hz, 1H), 7.25 (t, 8.4 Hz , 2H), 7.34 (d, 8.0 Hz, 2H) 7.40 (tt, 1.2 Hz, 7.2 Hz, 2H) 7.55 (d, 7.6 Hz, 2H) 7.80 (b, 1H) 7.86 (dd, 2.0 Hz, 7.6 Hz, 1H) 8.73 (d, 2.0 Hz, 1H).

Scheme 6 Reagents: i) Tf20, pyridine (43%). ii) phenylboronic acid (1.1 eq.), Na2CO3 (1.3 eq.), Pd (PPh3) 4 (5 mol%), dimethoxyethane, 2N Na2CO3 (2 eq.) (65% after chromatography), iii) n- butyl lithium (1.0 eq.), diethyl carbonate (1.5 eq.), anhydrous THF. iv) LiOH, THF 30C (18% after crystallization). v) 3-fluorobenzylamine (1.1 eq.), PyBOP (1.1 eq.), DIEA (1.1 eq.), DMF (55% yield).

Synthesis of Compound 27, 2- [6- (-ethoxy-phenyl) -1-oxo-pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide, KX1-358 To 0.2 g of an ice-cooled solution of 2- [6- (-ethoxy-phenyl) pyridin-3-yl] -N- (3-fluoro-benzyl) -acetamide in 80 ml of DCM was added as solid 0.13 g of m-chloroperbenzoic acid. After stirring overnight, the reaction was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, evaporated to dryness in vacuo, then subjected to chromatography (silica gel) using ethyl acetate followed by drying. % methanol in ethyl acetate to yield 0.16 g (78%); NMR lti INOVA-400 (DMSO d6) d 1357 (t, J = 7.0 Hz, 3H), 3.564 (s, 2H), 4090 (q, J = 6.8 Hz, 2H), 4.309 (d, J = 5.60 Hz, 2H), 7.012-7.103 (m, 5H), 7.245 (d, J = 8.0 Hz, 1H), 7.729 (m, 1H), 7.529 (d, J - 8.0 Hz, 1H), 7.800 (d, J = 8.5 Hz, 2H), 8.225 (s, 1H), 8.663 (t, J = 5.6 Hz, 1H). S (m / z) 380 (+ H) +. For the following syntheses, unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. Carbon and proton nuclear magnetic resonance spectra were obtained in a Bruker AC 300 or a Bruker AV 300 spectrometer at 300 MHz for protons and 75 MHz for carbon. The spectra are given in ppm (d) and the coupling constants, J, are reported in Hertz. Tetramethylsilane was used as an internal standard for the proton spectra and the peak of the solvent was used as the reference peak for the carbon spectra. The mass spectra and the mass data by liquid chromatography-mass spectrometry or LC-MS were obtained in an Perkin Elmer Sciex 100 ionization mass spectrometer at atmospheric pressure (APCI). The LC-MS analyzes were obtained using a column Luna C8 (2) (100 x 4.6 mm, Phenomenex) with UV detection at 254 nm using a standard gradient solvent program (Method B). Thin layer chromatography (TLC) was carried out using Analtech silica gel plates and visualized by ultraviolet light (UV), iodine or 20% by weight of phosphomolybdic acid in ethanol. HPLC analyzes were obtained using a Prevail C 18 column (53 x 7 mm, Alltech) with UV detection at 254 nm using a standard gradient solvent program (Method A).

Method A: A = Water with 0.1 v / v of trifluoroacetic acid B = Acetonitrile with 0.1 v / v of trifluoroacetic acid Method B: A = Water with 0.02 v / v of trifluoroacetic acid B = Acetonitrile with 0.02 v / v of trifluoroacetic acid Synthesis of N-benzyl-2- (5-bromopyridin-2-yl) acetamide: A flask was charged with 5- (5-bromopyridin-2 (1H) -ylidene) -2,2-dimethyl-1,3-dioxan-4,6-dione (1039 g, 3.46 mmol), benzylamine (0.50 ml, 4.58 mmol), and toluene (20 mL). The reaction was refluxed under nitrogen atmosphere for 18 hours, then cooled and placed in a freezer until cooled. The product was collected by filtration and washed with hexanes to yield a mass of bright white crystals (1.018 g, 96%).

Synthesis of 4- (2- (4- (4, 4, 5, 5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) -phenoxy) ethyl) morpholine: To a stirred solution of 4- (4, 4,5,5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) -phenol (2.55 g, 11.58 mmol), 2-morpholin-4-ylethanol (1.60 ml) , 1.73 g, 13.2 mmol) and triphenylphosphine (3.64 g, 13.9 mmol) in methylene chloride (60 ml) at 0 ° C, DIAD (2.82 g, 13.9 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. After 18 hours, additional portions of triphenylphosphine (1.51 g, 5.8 mmol), 2-morpholin-4-ylethanol (0.70 ml, 5.8 mmol), and DIAD (1.17 g, 5.8 mmol) were added. After stirring an additional 2 hours at room temperature, the reaction was concentrated and the residue was purified by flash chromatography (5% to 25% EtOAc in CHC13) to give the product as a white solid (2.855 g, 74%).

Synthesis of Compound 134, KX2-391: A 10 ml reaction tube, equipped with a septum closure and stir bar, was charged with N-benzyl-2- (5-bromopyridin-2-yl) acetamide (123 mg, 0.403 mmol), 4- (2- (4- (4, 4, 5, 5-tetramethyl [1,3,2] dioxaborolan-2-yl) -phenoxy) -ethyl) morpholine (171 mg, 0.513 mmol), and FibreCat 10071 (30 mg, 0.015 mmol ). Ethanol (3 mL) was added, followed by aqueous potassium carbonate solution (0.60 mL, 1.0, 0.60 mmol). The tube was sealed and heated under microwave conditions at 150 ° C for 10 minutes. The reaction was cooled and concentrated to remove most of the ethanol, and then taken up in 10 mL of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO 4, filtered and concentrated to a white solid. This white solid was triturated with ethyl ether to give ALB 30349 as a white solid (137 mg, 79%): mp 135-137 ° C; 1 H NMR (300 MHz, CDC13) d 8.70 (d, 1H, J = 2.0 Hz), 7.81 (dd, 1H, J = 2.4 Hz, J = 8.0 Hz), 7.65 (br, 1H), 7.49 (d, 2H , J = 8.8 Polymeric linkage of di (acetate) dicyclohexylphenylphosphinepalladium (II), manufactured by Johnson Matthey, Inc. and available from Aldrich (catalog # 590231) Hz), 7.37-7.20 (m, 6H), 7.01 (d, 2H, J = 8.8 Hz ), 4.49 (d, 2H, J = 5.8 Hz), 4.16 (t, 2H, J = 5.7 Hz, 3.82 (s, 2H), 3.78-3.72 (m, 4H), 2.84 (t, 2H, J = 5.7 Hz), 2.62-2.58 (m, 4H), HPLC (Method B) 98.0% (AUC), tR = 1834 min, APCI MS m / z 432 [M + H] +. (4-bromo-3-fluorophenyl) (morpholino) methanone: A 500 ml flask was charged with 4-bromo-3-fluorobenzoic acid (5.00 g, 22.83 mmol), 100 ml of DMF, morpholine (2.4 ml, 27.5 mmol), and 4-ethylmorpholine (8.6 ml, 67.9 mmol). HOBt (4.32 g, 32.0 mmol) was added followed by EDC (5.25 g, 27.4 mmol) and the reaction was allowed to stir at room temperature for 18 hours. The reaction was concentrated and the resulting orange syrup was taken up in 100 mL of EtOAc and 100 mL of water. The organic layer was washed with 100 ml of 2N HCl, 100 ml of saturated sodium bicarbonate, and 100 ml of saturated sodium chloride. The organic material was dried with MgSO ,} , filtered, and concentrated to give 6.476 g (98%) of a viscous yellow oil. This material was used without further purification. 4- (4-bromo-3-fluorobenzyl) morpholine: A 250 ml flask was charged with (4-bromo-3-fluorophenyl) (morpholino) methanone (4569 g15.86 mmol) and dissolved in 16 ml of THF. Diphenylsilane (6.2 ml, 33.4 mmol) was added followed by carbonyltris (triphenylphosphine) rhodium (I) hydride (100 mg, 0.109 mmol) and the reaction was stirred at room temperature for 20 hours. The reaction was diluted with 200 ml of ether and extracted with 1 N HC1 (2 x 150 ml). This resulted in the formation of a white precipitate in the separatory funnel. The acid layer and the resulting white precipitate were washed with ether (2 x 100 mL), and then made alkaline with solid NaOH pellets (23 g). The aqueous layer was extracted with ether (3 x 125 mL), dried over MgSO4, filtered, and concentrated to give 1.35 g (31%) of a colorless oil. This material was used without further purification. 4- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzylmorpholine: A 10 ml microwave reaction tube with septum closure was charged with 4- (4-bromo-3-fluorobenzyl) morpholine (405 mg, 1.48 mmol), Bis (pinacolato) diboro (516 mg, 2.03 mmol), Pd (dppf) C12 »CH2C12 (62 mg, 0.076 mmol), potassium acetate (659 mg, 6.72 mmol), and DMF (3.6 mL). The flask was placed under nitrogen atmosphere by evacuation / filling (5 cycles) and stirred at 80 ° C for 8 hours. The reaction was cooled, diluted with ethyl acetate (25 mL) and filtered. The organic materials were washed with water (25 ml) and saturated sodium chloride (25 ml). The organic layer was dried over MgSO4 and concentrated to a dark oil. The product was purified by chromatography on silica gel eluting with 2% MeOH in CHC13 to give 310 mg (65%) of an off-white solid.

Synthesis of Compound 136, KX2-393: A 10 ml microwave reaction tube with septum closure was charged with 4- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-1,2,3-dioxaborolan-2-yl) benzyl) morpholine (307 mg, 0.96 mmol), 2- (5-bromopyridin-2-yl) -N- (3-fluorobenzyl) acetamide (247 mg, 0.77 mmol), and FibreCat 1007 (60 mg, 0.03 mmol). Ethanol (3 mL) was added followed by aqueous potassium carbonate solution (1.2 mL, 1.0 M, 1.2 mmol). The tube was sealed and heated under microwave conditions at 150 ° C for 10 minutes. The reaction was cooled and concentrated to remove most of the ethanol, and then taken up in 10 mL of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO 4, filtered, and concentrated. The material was purified by column chromatography (silica gel, 100: 0 CHCl 3 / MeOH to 95: 5 CHCl 3 / MeOH) to provide ALB 30351 as a white solid (240 mg, 74%): mp 91-92 ° C NMR 1ti (300 MHz, CDC13) d 8.71 (broad s, 1H), 7.86-7.84 (m, 1H), 7.78 (br, 1 H), 7.37 (t, 2H, J = 7.5 Hz), 7.28-7.21 (m , 3H), 7.02 (dd, 1H, J = 0.6 Hz, J = 7.7 Hz), 6.98-6.90 (m, 2H), 4.49 (d, 2H, J = 5.9 Hz), 3.84 (s, 2H), 372 -3.75 (m, 4H), 3.52 (s, 2H), 2.47-2.50 (m, 4H); HPLC (Method A) 98.7% (AUC), t R = 3.866 min; APCI MS m / z 438 [M + H] +. 4- (2- (4-bromo-3-fluorophenoxy) ethyl) morpholine: A flask was charged with 4-bromo-3-fluorophenol (4999 g, 26.2 mmol) and triphenylphosphine (10298 g, 39.3 mmol). Methylene chloride (120 ml) was added followed by 2-morpholinoethanol (4 ml, 33.0 mmol) and the solution was stirred in an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added for 6 to 8 minutes. The reaction was continued by stirring in the cold bath until warmed slowly to room temperature overnight. The reaction was concentrated and the residue was purified by flash chromatography (25% to 100% EtOAc in hexanes) to give the product as a colorless oil (2621 g, 33%). 4- (2- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) morpholine: A 40 ml microwave reaction tube with a septum closure and stir bar was charged with 4- (2- (4-bromo-3-fluorophenoxy) ethyl) morpholine (307 mg, 1.0 mmol), Bis (pinacolato) diboro (318 mg, 1.25 mmol), Pd (dppf) Cl2-CH2C12 (68 mg, 83 μp), and potassium acetate (316 mg, 3.22 mmol). DME (20 ml) was added and the tube was sealed. The tube was evacuated / refilled with N2 (5 cycles) and subjected to microwave at 125 ° C for 30 minutes. The reaction was cooled to room temperature, concentrated and the residue was purified by column chromatography (silica gel, 2% MeOH in CHC13) to give the product as a colorless oil (356 mg,> 99¾). The 1 H NMR spectrum shows that the product contains a small amount of impurity such as pinacol. The material was used like this.

Synthesis of Compound 133, KX2-392: A 10 ml microwave reaction tube with septum closure was charged with 4- (2- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-1,2,3-dioxaborolan-2-yl) phenoxy) ethyl) morpholine (175 mg, 0.50 mmol), 2- (5-bromopyridin-2-yl) -N- (3 -fluorobenzyl) acetamide (121 mg, 0.37 mmol), and FibreCat 1007 (30 mg, 0.03 mmol). Ethanol (3 mL) was added followed by aqueous potassium carbonate solution (0.600 mL, 1.0 M, 0.60 mmol). The tube was sealed and heated under microwave conditions at 150 ° C for 10 minutes. The reaction was cooled, filtered, and concentrated to remove most of the ethanol. The residue was then taken up in 10 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO 4, filtered, and concentrated. The material was purified by column chromatography (silica gel, 100: 0 CHCl 3 / MeOH to 95: 5 CHCl 3 / MeOH) to provide ALB 30350 as a white solid (70 mg, 40%): mp 126-127 ° C; NMR XH (500 MHz, CDC13) d 8.67 (br, 1H), 7.77-7.85 (m, 2H), 7.21-7.37 (m, 3H), 7.02 (d, 1H, J = 7.7 Hz), 6.90-6.97 ( m, 2H), 6.82 (dd, 1H, J = 2.5 Hz, J = 8.6 Hz), 6.76 (dd, 1H, J = 2.4 Hz, J = 12.4 Hz), 4.49 (d, 2H, J = 5.9 Hz) , 4.15 (t, 2H, J = 5.7 Hz), 3.83 (s, 2H), 3.71-3.78 (m, 4H), 2.83 (t, 2H, J = 5.7 Hz), 2.56-2.63 (m, 4H); HPLC (Method A) > 99% (AUC), tR = 4,026 min; APCI MS m / z 468 [M + A] +. 1- (2- (4-Bromo-3-fluorophenoxy) ethyl) -4-methylpiperazine: A flask was charged with 4-bromo-3-fluorophenol (5.00 g, 26 mmol) and triphenylphosphine (10.30 g, 39 mmol). Methylene chloride (120 ml) was added followed by 2- (4-methylpiperazin-1-yl) ethanol (4.61 g, 32 mmol) and the solution was stirred in an ice water bath to cool.

After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added for 6 to 8 minutes. The reaction was continued stirring in the cold bath until warmed slowly to room temperature overnight. The reaction was concentrated and the residue was purified by flash chromatography (25% to 100% EtOAc in hexanes) to give the product as a colorless oil (2.62). 1- (2- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) -4-methylpiperazine: A 40 ml microwave reaction tube with a septum closure and stir bar was charged with l- (2- (4-bromo-3-fluorophenoxy) ethyl) -4-methylpiperazine (428 mg, 1.35 mmol), bis (pinacolato) diboro (375 mg, 1.48 mmol), Pd (dppf) Cl2-CH2Cl2 (63 mg, 77 ymol), and potassium acetate (410 mg, 4.18 mmol). DME (10 ml) was added and the tube was sealed. The tube was evacuated / refilled with N2 (5 cycles) and microwaved at 100 ° C for 30 minutes. More Pd (dppf) CI2-CH2Cl2 (63 mg, 77 μp) was added and the reaction was microwaved at 100 ° C for 60 minutes. The reaction was cooled to room temperature, concentrated and the residue was purified by column chromatography (silica gel, 1% to 2% MeOH in CHC13) to give the product as a dark oil (354 mg, 72%).

Synthesis of Compound 137, KX2-394 A 10 ml microwave reaction tube with septum closure was loaded with 1- (2- (3-fluoro-4- (4, 4, 5, 5-tetramethyl-1,2,3-dioxaborolan-2- il) phenoxy) ethyl) -4-methylpiperazine (340 mg, 0.93 mmol), 2- (5-bromopyridin-2-yl) -N- (3-fluorobenzyl) acetamide (201 mg, 0.62 mmol), and FibreCat 1007 ( 125 mg, 0.06 mmol). Ethanol (3 mL) was added followed by aqueous potassium carbonate solution (1.00 mL, 1.0 M, 1.00 mmol). The tube was sealed and heated under microwave conditions at 150 ° C for 10 minutes. The reaction was cooled, filtered, and concentrated to remove most of the ethanol. The residue was then taken up in 10 ml of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO 4, filtered, and concentrated. The material was purified by column chromatography (silica gel, 98: 2 CHCl 3 / MeOH to 90:10 of CHCl 3 / MeOH) to give ALB 30352-2 as a tan gum (28 mg, 9%): 1 H NMR ( 300 MHz, CDC13) d 8.6.6 (br, 1H), 7.78-7.94 (m, 2H), 7.20- 7.40 (m, 3H), 6.88-7.06 (m, 3H), 6.70-6.85 (m, 2H) , 4.47 (d, 2H, J = 5.9 Hz), 4.14 (t, 2H, J = 5.7 Hz), 3.83 (s, 2H), 2.85 (t, 2H, J = 5.7 Hz), 2.41-2.77 (m, 8H), 2.34 (s, 3H); HPLC (Method A) > 99% (AUC), tR = 3778 min .; APCI MS m / z 481 [ÍV1 + H] +.

Example 2: Inhibition of Cell Growth The concentration of drug required to block net cell growth by 50% relative to a control sample is measured as the GI50. The GI50 for several of the compounds of the invention were evaluated as described herein. The HT29 cell line is a standard human colon carcinoma cell line from the NCI (National Cancer Institute). HT-29 cells were obtained from the ATCC at passage 125 and used for inhibition studies between the passage 126-151. HT29 cells were routinely cultured in McCoy's 5A medium supplemented with fetal bovine serum (1.5% v / v) and L-glutamine (2 mM). C-Src 3T3 is a normal NIH 3T3 cell line from mouse fibroblasts that has been transfected with the point mutant of human c-Src where tyrosine 527 has been converted to a phenylalanine. This mutation results in "constitutively active" c-Src because phosphorylation in tyrosine 527 results in self-inhibition of folded Src on its own SH2 domain. With a Phe there, this phosphorylation can occur and therefore self-inhibition can not occur. In this way, the fully active mutant Src always converts normal mouse fibroblasts into rapidly growing tumor cells. Since overactive Src is the main factor that activates growth in these cells (particularly when grown under low growth serum conditions), it is thought that the compounds active in blocking this growth function by blocking Src signaling. (for example as a direct inhibitor of Src-kinase or as an inhibitor that acts somewhere in the Src signaling cascade). The cells were routinely cultured in DME supplemented with bovine fetal serum (2.0% v / V), L-glutamine (2 mM) and sodium pyruvate (1 mM). In the BrdU assay for inhibition of cell growth, the quantification of cell proliferation was based on the measurement of BrdU incorporation during DNA synthesis. The ELISA BrdU assay kit for cell proliferation (colorimetric) was obtained from Roche Applied Science and performed according to the vendor's instructions.

Growth inhibition was expressed as a GI50 wherein the GI50 is the sample dose that inhibits 50% of cell growth. Growth inhibition (GI) is determined from the formula GI = (T0-Tn x 100 / T0-CONn) where T0 is the growth of BrdU of untreated cells at time "0", Tn is Growth of BrdU from cells treated on day "n" and CONn is the growth of BrdU control cells on day "n". The GI50 was extrapolated and the data was plotted using XL-Fit 4.0 software. The cultures with active growth were trypsinized and the cells were resuspended in 190 μ? of appropriate culture medium, supplemented with 1.05% FBS in each well of a 96-well plate (1000 HT-29 cells, 2500 c-Src 3T3 cells). For experiments in 96-well culture plates, the medium for c-Src 3T3 is supplemented with 10 mM HEPES buffer. HT-29 cells were seeded in standard 96-well tissue culture plates and c-Src 3T3 cells were seeded in 96-well plates covered with Poly-D-lysine (BIOCOAM). To increase the diffusion of C02, the 96 well plates with c-Src 3T3 were incubated with their lids raised ~ 2 mm using sterile rubber plugs. The 96-well plates, seeded, were allowed to adhere overnight for 18-24 hours, either at 37 ° C and 5% C02 for HT-29 or at 37 ° C and 10% C02 for c-Src 3T3. Approximately 18-24 hours after sowing, the initial growth of the cells (T0) was determined for the untreated cells using the BrdU assay. Samples were reconstituted in DMSO at 20 mM and intermediate dilutions made using 10% FBS containing DMEM. The final assay concentrations were 1.5% for FBS and 0.05% for DMSO. The samples were added as aliquots of 10 μ? in triplicate and plates were incubated as indicated above for ~ 72 hours. Negative (vehicle) and positive controls (for example, AZ (KX-328)) were included. The plates were tested for BrdU and the data analyzed as indicated above for GI50. The results are shown in Table 3. In this table, the data is listed as Control Growth%, such that a lower number in a indicated concentration indicates a higher potency of the compound in blocking the growth of that cell line tumor. All compounds were initially prepared as stock solutions of 20 mM DMSO and diluted in buffer for in vitro tumor growth assays. NG means no cell growth beyond the control and T means that the number of cells in the wells treated with the drug was lower than in the control (ie net cell loss). NT indicates that the test was not performed. Compound AZ (KX-328) is a non-competitive tyrosine kinase inhibitor for ATP, as described in Pié et al, J. Med. Chem, 47: 871-887 (2004). As shown in Table 3, the GI50 were obtained for a number of the compounds in other cell lines. These GI50 were determined using standard assays for tumor growth inhibition, similar to those described in detail for the HT29 cell line above, and the following cell lines: colon tumor cell lines KM12, lung cancer cell line H460 and line lung cancer A549 (all are standard NCI tumor cell lines).

Table 3: Table 3: Table 3: Other embodiments While the invention has been described in conjunction with its detailed description, it is intended that the foregoing description should illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Those skilled in the art will understand that various changes in form and details may be made herein without departing from the scope of the invention, encompassed by the appended claims.

Claims

CLAIMS:

1. A compound according to Formula I Formula I solvate, prodrug hydrate thereof, wherein: T is absent, CR12R13, C (0), 0, S, S (0), S (0) 2, NR14, C (R15R16) C (Ri7R18), CH20 or 0CH2; Xy is CZ, CY, N or N-0; Xz is CZ, CY, N or N-0; at least one of Xy and Xz is CZ; Y is selected from hydrogen, hydroxyl, halogen, lower alkyl (Ci, C2, C3, C4, C5 or C6), alkoxy Ci, C2, C3, C4, C5 or C6, 0-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, and 0-benzyl; Xa is CRa or N or N-0; Xb is CRb, N or N-0; Xc is CRC or N or N-0; Xd is CRd, N or N-0; Xe is CRe, N or N-0; Ra, Rb / RCi Ra, Rei R4, R5 / and 6 are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or Ce, alkoxy Ci, C2, C3, C4, C5 or C, 0-lower alkyl (Ci, C2, C3, C4, C5 or C6) -aryl, 0-benzyl, alkyl (Ci, C2, C3, C, C5 or C6) -OH, alkyl Ci, C2, C3, C4, C5 or C6) -0-lower alkyl (Ci, C2, C3, C4, C5 or C6), COOH, C00-lower alkyl (Ci, C2, C3, C4, C5 or C6), S02H, S02-lower alkyl ( Ci, C2, C3, C4 C5 or C6), wherein W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl (Ci, C2, C3, C4, C5 or C6) -aryl; V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-; Ri2, R13i R14 R15, R16, R17, and R18, are, independently, H or alkyl Ci, C2, C3, C4, C5 or Ce; and Z is: (CHRi) nC (0) -NR2 (CHR3) m-Ar, wherein Ar is a heteroaryl group containing nitrogen or substituted or unsubstituted aryl, Ri, R2, and R3 are independently H or Cx alkyl, C2, C3, C, C5 or C6; ynym are, independently 0, 1 or

2. The compound according to claim 1, wherein at least one of Xa, b, Xcr Xd and Xe is N,

3. The compound according to claim 1, wherein Xy is CY , and Xz is CZ.

4. The compound according to claim 1, wherein Y is hydrogen. The compound according to claim 1, wherein Z is 6. The compound according to claim 1, wherein Rb is Ci, C2, C3, C4, C5 or C6 alkoxy. 7. The compound according to claim 1, wherein Rb is hydrogen. 8. The compound according to claim 1, in V N N-, V-N, V- O, or V- N-W, where Rb is - ^ ^ ^ '' V where W is H or Ci alkyl. , C2, C3, C4, C5 or alkyl Ci, C2, C3, C4, C5 or C6 ~ aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -QCH2CH2- or -OCH2CH2CH2-. 9. The compound according to claim 8, wherein V is a bond. 10. The compound according to claim 1, wherein Xa is N and each of Xb, Cf d and Xe is CR. 11. The compound according to claim 1, wherein the compound is a solvate. 12. The compound according to claim 1, wherein the compound is a hydrate. The compound according to claim 1, wherein the compound is a pharmaceutically acceptable salt. 14. A composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient. 1

5. The compound according to claim 1, wherein the compound is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 or 137. 1

6. A compound according to Formula II : Formula II: or a salt, solvate, hydrate or prodrug thereof, wherein: Rb, R4, R5, R8, and R10 are, independently, hydrogen, hydroxyl, halogen, alkyl Ci, C2, C3, C4, C5 or C6 , alkoxy Ci, C2, C3, C4, C5 or Ce, O-lower alkyl (Cx, C2, C3, C4, C5 or C6) -aryl, O-benzyl, alkyl Ci, C2, C3, C4, C5 or C6 -OH, alkyl Ci, C2, C3, C, C5 or C6-0-lower alkyl (Ci, C2, C3, C, C5 or C6), COOH, COO-lower alkyl (Ci, C2, C3, C, C5) or C6), S02H, S02-lower alkyl (Ci, C2, C3, C4, C5 or C6), wherein W is H alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C, C5 or C6-aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2- , -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. 1

7. The compound according to claim 16, wherein R8 is hydrogen, F, Cl, Br or I. 1

8. The compound according to claim 16, wherein Rb is C1, C2, C3, C4, C5 or 0e-19 alkoxy. The compound according to claim 16, in where is H or Cif alkyl C2, C3, C4, C5 or C ^, alkyl Ci, C2, C3, C4, C5 or C6-aryl, and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. The compound according to claim 16, wherein R 4 is hydrogen, C 1, C 2, C 3, C 4, C 5 alkoxy or e, F, Cl, Br or I. 21. The compound according to claim 16, in where R4 is where is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-. 22. The compound according to claim 16, wherein R5 is hydrogen, alkoxy Ci, C2, C3, C4, C5 or C6, F, Cl, Br or I. 23. The compound according to claim 16, in where R5 is where W is H or alkyl Ci, C2, C3, C4, C5 or Ce, alkyl Ci, C2, C3, C, C5 or C6) -aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-, -OCH2CH2- or -OCH2CH2CH2-. The compound according to claim 16, wherein Rio is hydrogen, C 1, C 2, C 3, C 4, C 5 or C alkoxy, F, Cl, Br or I alkoxy. 25. The compound according to claim 16, in where Ri0 is where W is H or alkyl Ci, C2, C3, C4, C5 or C6, alkyl Ci, C2, C3, C4, C5 or C6-aryl; and V is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -0-CH2-, -OCH2CH2- or -OCH2CH2CH2-. 26. A method of preventing or treating a cell proliferation disorder comprising administering a pharmaceutical composition comprising a compound according to Formula I or one of Formulas II-XIII or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient, to a subject in need thereof. The method according to claim 26, wherein the compound is selected from Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137. 28. A method of treatment or prevention of a disease or disorder that is modulated by the inhibition of tyrosine kinase, which comprises administering a pharmaceutical composition comprising a compound according to Formula I or one of Formulas II-XIII or a salt, solvate, hydrate or prodrug of the same, and at least one pharmaceutically acceptable excipient. The method according to claim 28, wherein the compound is selected from Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137.