Inhibitors of tyrosine kinases and uses thereof

Inhibitors of tyrosine kinases and uses thereof

Related applications

This application claims the benefit of U.S. Provisional Application No. 60/758,617, entitled "Tyrosine Kinase Inhibitors," filed on January 13, 2006, which is incorporated herein by reference.

Described herein are compounds that inhibit the activity of tyrosine kinase, methods of making such compounds, pharmaceutical compositions and drugs containing such compounds, and methods of using such compounds and compositions to inhibit tyrosine kinase activity.

Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays an essential role in the B-cell signaling pathway linking surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

Btk is a key regulator of B-cell development, activation, signaling and survival [Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288]. In addition, Btk is involved in a number of other hematopoietic cell signaling pathways, e.g., Toll-like receptor (TLR) and cytokine receptor mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, B-lineage lymphocytes It plays a role in inhibiting Fas/APO-1 necrotic signaling and collagen-stimulated platelet aggregation in sex cells (CA Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; NJ Horwood, et al., (2003), The Journal of Experimental Medicine 197: 1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3): 1646-1656, and Quek et al. (1998), Current Biology 8(20): 1137-1140].

Summary of the invention

Compounds, compositions, and methods are provided for inhibiting the activity of a subset of tyrosine kinases (eg, Btk). In one embodiment, a compound provided herein is used to inhibit Bruton's tyrosine kinase (Btk), and thus is a Btk inhibitor. Methods of making compounds that inhibit the activity of certain tyrosine kinases, compositions comprising the compounds, and methods of using the same are provided.

Compounds provided herein include compounds having the structures of Formula Ia, Formula Ib, Formula Ic, Formula II, Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IV, Formula V, and/or Formula VI, and their pharmaceutically Acceptable salts, solvates, esters, acids and prodrugs are included. In certain embodiments, isomers and chemically protected Forms are also provided.

In one aspect, provided is a compound of Formula III, and a pharmaceutically acceptable metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

<che id="iii"><img file="KR20080098490A_D0001.tif" /></che>

In the above formula (III),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>haloalkyl, and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is -X<sp>250a</sp>-Y<sp>25O</sp>- or -Y<sp>250</sp>-X<sp>250a</sp>, where X<sp>250a</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is haloalkynyl, and Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NR<sp>45</sp>-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NR<sp>45</sp>C(=O)NR<sp>45</sp>-, -C(=O)NH-, -C(=O)NR<sp>45</sp>-, -OC(=O)-, -C(=O)O-, -NHSO<sb>2</sb>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NH-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>45</sp>)=NO-; -CH=NO-, -ON=CH-, heteroaryl, aryl, -NHC(=O)O-, -OC(=O)NH-, -NR<sp>45</sp>C(=O)O- or -OC(=O)NR<sp>45</sp>- and where R<sp>45</sp>are each independently hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

M is N or CH;

W is <img file="KR20080098490A_D0002.tif" />ego;

E is oxygen or sulfur;

R<sp>100</sp>silver halogen, -OH, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl, C<sb>1</sb>-C<sb>4</sb>Alkyl (heteroaryl), C<sb>1</sb>-C<sb>6</sb>alkoxy, C<sb>1</sb>-C<sb>6</sb>alkenyloxy, C<sb>1</sb>-C<sb>6</sb>alkynyloxy and -NR<sp>102a</sp>R<sp>102b</sp>an optionally substituted group selected from;

R<sp>l02a</sp> and R<sp>l02b</sp>is independently hydrogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>Alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl and C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl) which may be substituted;

R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl, di(C<sb>1</sb>-C<sb>6</sb>Alkyl)aminosulfonyl and C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkylsulfonylamino;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl;

n is 0, 1 or 2.

In any and all aspects, the substituents may be selected from a subset of the listed alternatives. For example, in some embodiments, T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene. In another embodiment, T is 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0003.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0004.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NH-, -NHC(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C (=O)O-, -NHSO<sb>2</sb>-, -SO<sb>2</sb>NH-, -NHC(=O)O- or -OC(=O)NH-; E is O; R<sp>35Oa</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In some embodiments, R<sp>350a</sp>is hydrogen or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, R<sp>350a</sp>is hydrogen or C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, R<sp>350a</sp>is hydrogen.

In some other aspects, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl; n is 1. In other aspects, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is alkenyl.

In some embodiments, a compound provided herein has a structure selected from Formulas IIIa, IIIb, and IIIc.

<che id="iiia"><img file="KR20080098490A_D0005.tif" /></che>

<che id="iiib"><img file="KR20080098490A_D0006.tif" /></che>

<che id="iiic"><img file="KR20080098490A_D0007.tif" /></che>

In certain embodiments, R<sp>100</sp>silver halogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl); R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, R<sp>35Oa</sp>is hydrogen; Y<sp>250</sp>is a bond, -C(=O)-, -NHC(=O)- or -C(=O)NH-.

In other embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0008.tif" />is selected from

In other embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0009.tif" />is selected from

In one embodiment, a compound provided herein has the structure of Formula IIIc. In other embodiments, the compounds provided herein have the structure of Formula IIIa. In other embodiments, the compounds provided herein have the structure of Formula IIIb.

In some embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl or <img file="KR20080098490A_D0010.tif" />ego; R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In other embodiments, R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0011.tif" />is selected from; R<sp>100</sp>silver C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl) ; R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0012.tif" />is substituted with and at position 6 <img file="KR20080098490A_D0013.tif" />1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NH-, -NHC(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C (=O)O-, -NHSO<sb>2</sb>-, -SO<sb>2</sb>NH-, -NHC(=O)O- or -OC(=O)NH-; E is O; R<sp>35Oa</sp>is hydrogen or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl.

In certain embodiments, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl; n is 1.

In certain embodiments, R<sp>100</sp>silver halogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl); R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In other embodiments, R<sp>35Oa</sp>is hydrogen; Y<sp>250</sp>is -C(=O)-; X<sp>250a</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl.

In certain embodiments, L is <img file="KR20080098490A_D0014.tif" />am.

In some embodiments, a compound provided herein has the structure of Formula IIIb. In other embodiments, the compounds provided herein have the structure of Formula IIIa. In other embodiments, the compounds provided herein have the structure of Formula IIIc.

In another aspect, provided is a compound of Formula IV, and a pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

<che id="iv"><img file="KR20080098490A_D0015.tif" /></che>

In the above formula (IV),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene;

R<sp>d</sp>is -OH or -NH-C(O)-R<sp>e</sp>ego;

R<sp>c</sp>is H or C<sb>1</sb>-C<sb>4</sb>Alkyl, halogen or C<sb>1</sb>-C<sb>4</sb>haloalkyl;

R<sp>e</sp>is C<sb>1</sb>-C<sb>6</sb>a substituted or unsubstituted group selected from alkyl, aryl and heteroaryl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0016.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0017.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In certain embodiments, R<sp>c</sp>is H; R<sp>e</sp>is a substituted or unsubstituted group selected from aryl and heteroaryl. In other embodiments, R<sp>e</sp>is a substituted or unsubstituted group selected from phenyl and heteroaryl containing 1 or 2 N atoms.

In another aspect, there is provided a compound of Formula V, and a pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

<che id="v"><img file="KR20080098490A_D0018.tif" /></che>

In the above formula (V),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is -X<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>- or -X<sp>250b</sp>-Y<sp>250</sp>-X<sp>250a</sp>- and where, X<sp>250a</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is haloalkynyl, and Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NR<sp>45</sp>-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NR<sp>45</sp>C(=O)NR<sp>45</sp>-, -C(=O)NH-, -C(=O)NR<sp>45</sp>-, -OC(=O)-, -C(=O)O-, -NHSO<sb>2</sb>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NH-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>45</sp>)=NO-; -CH=NO-, -ON=CH-, heteroaryl, aryl, -NHC(=O)O-, -OC(=O)NH-, -NR<sp>45</sp>C(=O)O- or -OC(=O)NR<sp>45</sp>- and X<sp>250b</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl, wherein R<sp>45</sp>are each independently hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

R<sp>e</sp>Is<sp></sp>C<sb>1</sb>-C<sb>6</sb>a substituted or unsubstituted group selected from alkyl, aryl and heteroaryl;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is haloalkynyl.

In certain embodiments, T is at the 2-position <img file="KR20080098490A_D0019.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0020.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In one aspect, X<sp>250a</sp>is a bond, and X<sp>250b</sp>is a bond

In another aspect, T in position 2 <img file="KR20080098490A_D0021.tif" />is substituted with and at position 6 <img file="KR20080098490A_D0022.tif" />1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In some aspects, X<sp>250a</sp>is a bonded or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>alkyl; Y<sp>250</sp>is a bond, -O-, -C(=O)-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C(=O)O-, -NHC(=O)O- or -OC(=O)NH-; X<sp>250b</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In some embodiments, R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl. In some embodiments, R<sp>350a</sp>is hydrogen.

In other aspects, Y<sp>250</sp>is a bond, -NHC(=O)-, -C(=O)NH-, -OC(=O)- or -C(=O)O-.

In another aspect, provided are compounds of formula VI, and pharmaceutically active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs thereof.

<che id="vi"><img file="KR20080098490A_D0023.tif" /></che>

In the above formula (VI),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Heteroalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl,

R<sp>f</sp>Is<sp></sp>substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

R<sp>g</sp>is H, or C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>alkyl) an optionally substituted group selected from aminosulfonyl;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is haloalkynyl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0024.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0025.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>heteroalkenyl, and R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is heteroalkenyl.

In other embodiments, R<sp>g</sp>is H or C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl and C<sb>1</sb>-C<sb>10</sb>an optionally substituted group selected from alkoxycarbonyl.

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl; R<sp>g</sp>is H or C which may be substituted<sb>1</sb>-C<sb>6</sb>is alkyl.

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkynyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl, <img file="KR20080098490A_D0026.tif" />is selected from

In other embodiments, L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl, <img file="KR20080098490A_D0027.tif" />is selected from

In other embodiments, L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl, <img file="KR20080098490A_D0028.tif" />is selected from

Combinations of any of the above groups for various variables are contemplated herein. Substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art to provide compounds set forth herein and compounds that are chemically stable and can be synthesized by techniques known in the art.

In one aspect, provided herein is a compound selected from:

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 1); 2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 2); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 3); 2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 4); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 5); 2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 6); 2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-{2-[(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-carbonyl]ethenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 7); 2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 8); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 9); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-fluorophenyl)-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 10); 2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-methoxyphenyl)-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 11); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 12); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 13); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 14); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-methyl-1λ<sp>5</sp>-Phosphinan-4-yl)-carbonylamino]propenyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 15); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-trans-phenyl-1λ<sp>5</sp>-Phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 16); 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-cis-phenyl-1λ<sp>5</sp>-Phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 17); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4 ,5-h]isoquinolin-9-one (Compound 18); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (Compound 19); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-chlorophenyl)-piperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 20); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 21); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 22); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-4-yl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 23); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 24); 2-(3-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 25); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-2-yl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 26); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyrimidin-2-yl)-piperazin-1-yl)-propenyl]-1 ,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 27); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(2,6-dichlorophenylmethyl)-piperazin-1-yl)-propenyl]- 1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 28); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 29); 2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-fluorophenyl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 30); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-tert-butyloxycarbonylpiperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 31); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(N,N-dimethylaminosulfonyl)-piperazin-1-yl)-propenyl] -1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 32); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-ethylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 33); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(isopropylsulfonyl)-piperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 34); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(ethylsulfonyl)-piperazin-1-yl)-propenyl]-1,8- dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 35); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-isopropylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro -imidazo[4,5-h]isoquinolin-9-one (Compound 36); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2-(phenylsulfonyl)-ethenyl]-1,8-dihydro-imidazo[4,5-h]iso quinolin-9-one (Compound 37); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-prop-2-enyl]-1,8-dihydro-imidazo[4, 5-h]isoquinolin-9-one (Compound 38); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-2,2-difluorobutynyl]-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (Compound 39); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2,2-difluoro-1-hydroxy-2-(N-phenylmethyl-[1,2,3]tria) zol-4-yl)-ethyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 40); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-(1-hydroxy-3-phenylprop-2-yn-1-yl)-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (Compound 41); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 42); 2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]- 1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 43); 2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde oxime (compound 44); Benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene] -hydrazide (Compound 45); 4-(N,N-dimethylamino)-benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5 -h]Isoquinolin-7-ylmethylene]-hydrazide (Compound 46); Pyridine-2-carboxylic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7 -ylmethylene]-hydrazide (Compound 47); Pyridine-3-carboxylic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7 -ylmethylene]-hydrazide (Compound 48); 2-Methoxy-benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline- 7-ylmethylene]-hydrazide (Compound 49); 2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{2-[4-(4-fluorophenyl)-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl]-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 50); and (S)-2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{N-[1-(phenylsulfonyl)hex-1-en-3-yl]-amino -2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 51).

In a further aspect, any compound of the invention comprises a therapeutically effective amount of one or more, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate. A pharmaceutical composition is provided. In certain embodiments, the compositions provided herein further comprise a pharmaceutically acceptable diluent, excipient, and/or binder.

One provided herein at an effective concentration to deliver an amount effective to treat, prevent, or ameliorate one or more symptoms of a disease, disorder or condition modulated by, affected by, or in which tyrosine kinase activity is involved. A pharmaceutical composition containing the above compound or a pharmaceutically effective derivative thereof is formulated and provided to be administered by an appropriate route and means. An effective amount or concentration is effective to alleviate the symptoms of a disease, disorder or condition described herein.

In certain embodiments, pharmaceutical compositions are provided that contain i) a physiologically acceptable carrier, diluent and/or excipient and ii) one or more compounds provided herein.

In another aspect, there is provided a method of inhibiting Bruton's tyrosine kinase or a cognate thereof comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound as described above.

Packaging materials, compounds or compositions or pharmaceutically acceptable derivatives thereof provided herein effective to inhibit the activity of certain tyrosine kinase(s), e.g., Btk, in the packaging material, and compounds or compositions or pharmaceutically acceptable derivatives thereof A salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate containing a label indicating that it is used to inhibit the activity of the tyrosine kinase(s), e.g., Btk. An article of manufacture is provided.

In a further aspect, administering to a subject in need thereof a composition containing a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described herein, comprising any of the foregoing, is administered to a subject in need thereof, thereby activating the Bruton's tyrosine kinase in the subject. A method of inhibiting is provided. In some embodiments, the subject in need of treatment is an autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Orth thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-myoclonic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease , Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, room temperature autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behcet's disease, chronic fatigue, ataxia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma or vulvovaginitis.

In other embodiments, the subject in need of treatment is a heteroimmune condition or disease, e.g., graft versus host disease, transplantation, transfusion, hypersensitivity, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis. I have dermatitis.

In certain embodiments, the subject in need of treatment is an inflammatory disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, lacrimal glanditis, dermatitis. , dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, gastroarthritis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, hepatitis, suppurative glanditis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, Nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, parapleurisy, phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, uterine tuberitis, sinusitis, stomatitis, synovitis, tendinitis , tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In a further aspect, the subject in need of treatment has cancer. In one embodiment, the cancer is a B-cell proliferative disorder, e.g., giant B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphplasmic cell lymphoma/Walden Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, hematocytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, cover cell lymphoma, mediastinal (chest) giant B-cell lymphoma, intravascular giant B cell lymphoma, primary exudative lymphoma, Burkitt's lymphoma/leukemia or granulomatous lymphomatosis. In some embodiments, if the subject is suffering from cancer, in addition to one of the compounds above, an anticancer agent is administered to the subject. In one embodiment, the anticancer agent is a mitogen activated protein kinase signaling inhibitor, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002; Syk inhibitors; PKC-beta inhibitors; PI3K inhibitors; mTOR inhibitors; or an antibody effective for the treatment of cancer (eg, Rituxan).

In a further aspect, the subject in need of treatment is a thromboembolic disorder, e.g., myocardial infarction, angina pectoris, post-angioplasty reocclusion, post-angioplasty restenosis, post-cardiovascular reocclusion, post-cardiovascular bypass. suffer from restenosis, stroke, transient ischemia, peripheral arterial occlusion disorder, pulmonary embolism, or deep vein thrombosis.

In a further aspect, provided herein is a method of treating an autoimmune disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described above. In one embodiment, the autoimmune disease is arthritis. In another embodiment, the autoimmune disease is lupus. In some embodiments, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute Disseminated encephalomyelitis, Addison's disease, nystagmus-myoclonic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary Liver cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, room temperature autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behcet's disease, chronic fatigue, ataxia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma or is the vulva

In a further aspect, provided herein is a method of treating a heteroimmune condition or disease by administering to a subject in need thereof a composition comprising a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described above. do. In some embodiments, the heteroimmune condition or disease is graft versus host disease, transplantation, transfusion, hypersensitivity, allergy, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

In a further aspect, provided herein is a method of treating an inflammatory disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described above. In some embodiments, the inflammatory disease is asthma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, lacrimal glanditis. , dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, gastroarthritis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, hepatitis, suppurative sweat glands, laryngitis, mastitis, meningitis, myelitis, myocarditis, Myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, parapleurisy, phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, uterine vasculitis, phlebitis, stomatitis, synovitis , tendinitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis.

In another aspect, provided herein is a method of treating cancer by administering to a subject in need thereof a composition containing a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described above. In one embodiment, the cancer is a B-cell proliferative disorder, e.g., giant B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphplasmic cell lymphoma/Walden Stroke's giant globulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, cover cell lymphoma, mediastinal (chest) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, Burkitt's lymphoma/leukemia or granulomatous lymphomatosis. In some embodiments, if the subject is suffering from cancer, in addition to one of the compounds, an anticancer agent is administered to the subject. In one embodiment, the anticancer agent is a mitogen activated protein kinase signaling inhibitor, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

In another aspect, provided herein is a method of treating a thromboembolic disorder by administering to a subject in need thereof a composition comprising a therapeutically effective amount of one or more reversible inhibitors of Btk, including any of the compounds described above. . In some embodiments, the thromboembolic disorder is myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemia, peripheral artery occlusion disorder , is a pulmonary embolism or deep vein thrombosis.

Combinations of any of the above groups for various parameters are contemplated herein.

As used herein, the term "inhibits or inhibits" a kinase or "inhibitor" of a kinase refers to inhibition of the enzyme phosphotransferase activity.

Other objects, features and advantages described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples are provided for illustrative purposes only, while indicating specific embodiments, since various changes and modifications within the spirit and scope of this specification will become apparent to those skilled in the art from the detailed description. do. All references cited herein, including patents, patent applications and publications, are hereby incorporated by reference in their entirety.

reference citation

All publications and patent applications mentioned in this specification are incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

The appended claims specifically point out the features set forth herein. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description, which presents exemplary embodiments in which the principles described herein are employed.

Described herein are compounds that inhibit the activity of a subset of tyrosine kinase(s), compositions comprising such compounds, and uses thereof. The compounds described herein are inhibitors of certain tyrosine kinase(s) (eg, Btk) and are useful for treating diseases, disorders or conditions that would benefit from inhibition of these tyrosine kinase(s). In some embodiments, the compounds provided herein are used to inhibit the activity of Bruton's tyrosine kinase (Btk).

As used herein, the term "Bruton's tyrosine kinase" refers to the Bruton's tyrosine kinase from Homo sapiens, as described, for example, in US Pat. No. 6,326,469 (GenBank Accession No. NP_000052).

As used herein, the term "Bruton's tyrosine kinase homolog" refers to orthologs of Bruton's tyrosine kinase, e.g., mouse (GenBank Acession No. AAB47246), dog (GenBank Acession No. XP_549139.), rat (GenBank Acession No. NP_001007799), orthologs from chicken (GenBank Acession No. NP_989564) or zebrafish (GenBank Acession No. XP_698117), and fusion proteins of the foregoing that exhibit kinase activity against a substrate of one or more Bruton's tyrosine kinases (e.g., peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").

Btk is implicated in abnormal levels of cell proliferation, apoptosis, cell migration and invasion, and angiogenesis associated with tumor growth. Btk is a key regulator of B-cell development, activation, signaling and survival. In addition, Btk plays a role in collagen-stimulated platelet aggregation. The function of Btk both as a modulator of apoptosis and as a modulator of its association in multiple developmental processes makes Btk a desirable target for anticancer, anti-inflammatory and antiviral and antithromboembolic agents, as well as to treat autoimmune diseases and acute inflammatory responses. make it a desirable target for

Btk may play a role in both infectious and non-infectious inflammatory outcomes and in autoimmune and other inflammatory diseases. These autoimmune and inflammatory diseases, disorders and syndromes include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, appendicitis, pancreatitis , cholecystitis, gamma globulinemia- immunodeficiency disease characterized by deficiency of B cell maturation and function, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's syndrome, tissue transplant rejection, hyperacute transplantation organ Rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglottic disease (also known as autoimmune polyglottic syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis , scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, type I diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis , psoriatic arthritis, juvenile arthritis, osteoarthritis, Chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleracierma, mycosis sarcomas, acute inflammatory reactions (eg, acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.

Btk-associated lymphomas include B-cell lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, hairy cell leukemia, acute and chronic myelogenous leukemia, multiple myeloma, EBV lymphoma, acute lymphocytic leukemia and chronic lymphocytic leukemia.

Thus, without being bound by theory, it is believed that inhibiting Btk activity is useful in treating any of the following conditions.

In some embodiments, the methods described herein are for rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ordi's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré Syndrome, acute disseminated encephalomyelitis, Addson's disease, nystagmus-myoclonic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, Primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, room temperature autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behcet's disease, chronic fatigue, ataxia, endometriosis, interstitial cystitis, neuromuscular dystonia, It may be used to treat autoimmune diseases including, but not limited to, scleroderma and vulvovaginalgia.

In some embodiments, the methods described herein treat transplantation versus host disease, transplantation, blood transfusion, anaphylaxis, allergies (eg, plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites, cockroach calyxes). allergy), type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

In a further aspect, the methods described herein can be used for asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, lacrimal glanditis, dermatitis, dermatomyositis , encephalitis, endocarditis, endometritis, enteritis, enterocolitis, gastroarthritis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, hepatitis, pyogenic sweat glanditis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oocystitis , orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, parapleurisy, phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, uterus, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, It may be used to treat inflammatory diseases including, but not limited to, uveitis, vaginitis, vasculitis and vulvitis.

In other embodiments, the methods described herein can be administered to a cancer, e.g., large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom's giant globulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, cover cell lymphoma, mediastinal (chest) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative may be used to treat B-cell proliferative disorders including, but not limited to, lymphoma, Burkitt's lymphoma/leukemia, and granulomatous lymphomatosis.

In a further aspect, the methods described herein can be used for myocardial infarction, angina pectoris (including unstable angina), reocclusion or restenosis after angioplasty or after coronary artery bypass, stroke, transient ischemia, peripheral arterial occlusion disorder, pulmonary embolism and cardiac It may be used to treat thromboembolic disorders including, but not limited to, venous thrombosis.

Symptomatic, diagnostic, and prognostic tests for each of the above conditions are known in the art (Harrison's Principles of Internal Medicine®" 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006) ), Cytojournal 3(24), and the "Revised European American Lymphoma" (REAL) classification system (see the website maintained by the National Cancer Institute).

A number of animal models are useful for establishing a range of therapeutically effective amounts of the compounds described above for the treatment of any of the diseases described above.

For example, the dose of a compound to treat an autoimmune disease can be evaluated in a mouse model of rheumatoid arthritis. In this model, arthritis is induced in Balb/c mice by administration of anti-collagen antibodies and lipopolysaccharides (Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837., L. Svensson, R. Holmdahl, Am. J. Pathol. 2003, 163, 1827)].

In another example, the dose of a compound for treating a B cell proliferative disorder is determined, eg, by human B cell lymphoma cells (eg, Ramos cells), eg, as described in, eg, Pagel et al. (2005), Clin Cancer Res II(13):4857-4866], and can be tested in a human-to-mouse xenograft model transplanted into immunodeficient mice (eg, nude mice).

Animal models for the treatment of thromboembolic disorders are also known.

Without wishing to be bound by theory, phosphate is also a homologue of tyrosine kinases, i.e., tyrosine kinase phosphorylate and phosphatase dephosphorylate, e.g., protein substrates, "diseases, disorders responsive to inhibition of tyrosine kinases. or syndrome". Accordingly, the compounds of the present invention may directly or indirectly modulate phosphatase activity while modulating tyrosine kinase activity as described above. Such additional modulation, if present, may be synergistic (or non-synergistic) with respect to the activity of the compounds of the invention on a related or otherwise interdependent kinase or class of kinases. As already mentioned, the compounds of the present invention are, in part, for the treatment of diseases characterized by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. useful.

The therapeutic efficacy of a compound for treating any of the conditions described above can be optimized during the course of treatment. For example, a diagnostic evaluation of the subject to be treated can relate alleviation of disease symptoms or pathology to in vivo inhibition of the relevant tyrosine kinase by administering predetermined doses of any of the compounds described herein. On-cell assays that measure tyrosine kinase in vivo can be used. For example, as activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), cell populations using phospho-specific immunocytochemical staining of P-Y223 or P-Y551-positive cells Activation of Btk can be detected or quantified (eg by FACS analysis of stained versus unstained cells) [Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226]. Accordingly, the amount of compound administered to a subject can be increased or decreased as needed to maintain a level of inhibition of a target tyrosine kinase (eg, Btk) that is optimal for treating the subject's disease state.

In general, compounds used in the methods described herein are identified or characterized in an in vitro assay, eg, a non-cellular biochemical assay or a cellular functional assay. This assay determines the in vitro IC of the compound.<sb>50</sb>useful for measuring

For example, a cell-free kinase assay can be used to measure Btk activity following kinase incubation, eg, in the absence or presence of a concentration range of representative tyrosine kinase inhibitor compounds. A number of non-cellular kinase assays are available (Kuzmic et al. (2000) Anal. Biochem, 286, 45-50].

Cellular functional assays for tyrosine kinase inhibition are assays for determining one or more cellular endpoints in a response that stimulates a signaling pathway mediated by tyrosine kinase (e.g., BCR activation in Ramos cells) in the absence or presence of a concentration range of representative tyrosine inhibitor compounds. including measuring. For example, in the case of Btk, useful endpoints include, for example, autophosphorylation of Btk in BCR activation reactions, phosphorylation of Btk target proteins (eg PLC-γ), and cytoplasmic calcium flux.

High throughput assays are available for many non-cellular biochemical assays (eg, kinase assays) and cellular functional assays (eg, calcium flux). In addition, high-throughput screening systems are commercially available (Zymark Corp., Hopkinton, MA; Air Technical Industries of Mentor, Ohio; Beckman Instruments, Inc. of Fullerton, CA; Precision Systems, Inc., Natick, Massachusetts, etc.]. These systems typically automate all procedures including all sample and reagent pipetting, liquid dispensing, constant visual incubation and final reading of the microplate in a detector(s) suitable for the assay. The automated system thereby enables the identification and characterization of a large number of tyrosine kinase inhibitor compounds without undue effort.

specific chemical terms

Unless specifically stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications mentioned throughout this specification are incorporated by reference in their entirety unless otherwise indicated. In the event that there are plural definitions of use herein, those in these fields prevail. When reference is made to a URL or other such identifier or address, it is understood that such identifiers may change, and particular information on the Internet may change, but the same information may be found by searching the Internet. References also demonstrate the usefulness and public dissemination of this information.

It is understood that the foregoing general description and the following detailed description are illustrative and descriptive only, and not limiting of the claimed subject matter. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used in the specification and appended claims, the singular forms "a," "an," and "the" include plural referents unless the concept clearly dictates otherwise. As used herein, the use of "or" means "and/or" unless stated otherwise. Also, the term "comprising" as well as other forms such as "comprises" and "includes" are not limiting.

The heading sections used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, manuals, and reports, expressly certify that they have been incorporated by reference in their entirety for any purpose.

Definitions of standard chemical terms are found in Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." VOIS. A (2000) and B (2001), Plenum Press, New York]. Unless otherwise indicated, mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, which are routine methods within the skill in the art, are used. Unless specific definitions are provided, the nomenclature used in connection with, and laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known in the art. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. Standard techniques can be used for synthetic DNA, oligonucleotide synthesis, and tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using kits from the manufacturer's instructions or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can generally be performed in conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification.

An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, meaning that it contains no alkene or alkyne moieties. An alkyl moiety may also be an "unsaturated alkyl" moiety, meaning it contains one or more alkene or alkyne moieties. An "alkene" moiety refers to a group having at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group having at least one carbon-carbon triple bond. Alkyl moieties, saturated or unsaturated, may be branched, straight-chain or cyclic. Depending on the structure, the alkyl group can be a monoradical or a diradical (ie, an alkylene group).

C as used herein<sb>1</sb>-C<sb>x</sb>is C<sb>1</sb>-C<sb>2</sb>, C<sb>1</sb>-C<sb>3</sb> . . . C<sb>1</sb>-C<sb>x</sb>includes

An "alkyl" moiety can have from 1 to 10 carbon atoms (wherever an alkyl moiety is set forth herein, a numerical range, e.g., "1 to 10", means each integer in the range, e.g. For example, "1 to 10 carbon atoms" means that the alkyl group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses numerical ranges. also includes the case of the term "alkyl" where is not specified). The alkyl group of the compounds described herein is "C<sb>1</sb>-C<sb>4</sb> alkyl" or similar designations. By way of example only, "C<sb>1</sb>-C<sb>4</sb> "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. is chosen, so C<sb>1</sb>-C<sb>4</sb> Alkyl is C<sb>1-2</sb> Alkyl and C<sb>1</sb>-C<sb>3</sb> including alkyl. Alkyl groups may be substituted or unsubstituted. Common alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. including, but not limited to.

As used herein, the term "bicyclic alkyl" refers to alkyl that is not cyclic (ie, straight or branched chain containing one or more carbon atoms). Bicyclic alkyls may be fully saturated or contain bicyclic alkenes and/or alkynes. Bicyclic alkyl may be optionally substituted.

The term "alkylamine" refers to -N(alkyl)<sb>x</sb>H<sb>y</sb> group, wherein x and y are selected from x=1, y=1 and x=2, y=0. When x is 2, the alkyl groups together with the N atom to which they are attached may optionally form a cyclic ring system.

The term "alkenyl" refers to a form of an alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C(R)=C(R)-R, where R refers to the remainder of the alkenyl group, which may be the same or different. An alkenyl moiety may be branched, straight-chain, or cyclic (in this case, also known as a "cyclic alkenyl" group). Depending on the structure, an alkenyl group can be a monoradical or a diradical (ie, an alkenylene group). An alkenyl group may be optionally substituted. Non-limiting examples of alkenyl groups include -CH=CH<sb>2</sb>, -C(CH<sb>3</sb>)=CH<sb>2</sb>, -CH=CHCH<sb>3</sb>, -C(CH<sb>3</sb>)=CHCH<sb>3</sb>, -CH=CH-, -C(CH<sb>3</sb>)=CH-, -CH=CHCH<sb>2</sb>-, -CH=CHCH<sb>2</sb>CH<sb>2</sb>- and -C(CH<sb>3</sb>)=CHCH<sb>2</sb>- includes An alkenyl group, unless otherwise stated, can have from 2 to 10 carbon atoms.

The term "alkynyl" refers to a form of an alkyl group in which the first two carbon atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atom -CCR, where R refers to the remainder of the alkynyl group, which may be the same or different. The "R" portion of an alkynyl moiety may be branched, straight chain or cyclic. Depending on the structure, an alkynyl group can be a monoradical or a diradical (ie, an alkynylene group). An alkynyl group may be optionally substituted. Non-limiting examples of alkynyl groups include -CCH, -CCCH<sb>3</sb>, -CCCH<sb>2</sb>CH<sb>3</sb>, -CC- and -CCCH<sb>2</sb>- includes, but is not limited to. An alkynyl group, unless otherwise stated, can have from 2 to 10 carbon atoms.

An "alkoxy" group refers to a (alkyl)O group, where alkyl is as defined herein.

"Hydroxyalkyl" means an alkyl radical, as defined herein, substituted by one or more hydroxy groups. Non-limiting examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3 -Hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxy butyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl, but , but not limited thereto.

"Alkoxyalkyl" means an alkyl radical, as defined herein, substituted with one or more alkoxy groups, as defined herein.

An "alkenyloxy" group refers to a (alkenyl)O group, where alkenyl is as defined herein.

"Amide" is a chemical moiety of the formula -C(O)NHR or -NHC(O)R, wherein R is alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and (bonded through a ring carbon). ) is selected from heteroalicyclic. An amide moiety can form a bond between an amic acid or peptide molecule and a compound described herein to form a prodrug. The carboxyl side chain on any amine, or compound described herein, may be amidated. Procedures and specific groups for preparing such amides are known to those skilled in the art, and are incorporated herein by reference, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3, which is incorporated herein by reference in its entirety.<sp>rd</sp> Ed., John Wiley &amp; Sons, New York, NY, 1999].

The term "aromatic" means a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. An aromatic ring may be formed by 5, 6, 7, 8, 9 or 9 or more atoms. Aromatics may be optionally substituted. The term "aromatic" includes both carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (eg, pyridine). The term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.

As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl rings may be formed by 5, 6, 7, 8, 9 or 9 or more carbon atoms. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (ie, an arylene group).

An "aryloxy" group refers to a (aryl)O group, where aryl is as defined herein.

"Aralkyl" or "arylalkyl" means an alkyl radical, as defined herein, substituted with an aryl group. Non-limiting aralkyl groups include benzyl, phenethyl, and the like.

"Aralkenyl" means an alkenyl radical, as defined herein, substituted with one or more aryl groups, as defined herein.

The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by a bond are considered as part of a larger substructure.

The term "carbocyclic" or "carbocycle" refers to a compound containing one or more covalently closed ring structures and wherein the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains one or more atoms different from carbon. Carbocycles include cycloalkyl and aryl.

The term "cycloalkyl" means a monocyclic or polycyclic radical containing only carbon and hydrogen and which may be saturated, partially unsaturated or fully unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms. Examples of cycloalkyl groups are:

<img file="KR20080098490A_D0029.tif" />

<img file="KR20080098490A_D0030.tif" />

etc. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (eg, a cycloalkylene group).

"Cycloalkylalkyl" is an alkyl radical, as defined herein, substituted with a cycloalkyl group. Non-limiting examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.

The term "ester" is a chemical moiety of the formula COOR, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein may be esterified. Procedures and specific groups for preparing such esters are known to those skilled in the art, and are incorporated herein by reference, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3, which is incorporated herein by reference in its entirety.<sp>rd</sp> Ed., John Wiley &amp; Sons, New York, NY, 1999].

The term "halo" or "halogen" or "halide" means fluoro, chloro, bromo or iodo.

The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures in which one or more hydrogens are replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are substituted with halogen atoms, the halogen atoms are all identical to each other. In other embodiments in which two or more hydrogen atoms are substituted with halogen atoms, the halogen atoms are not all identical to each other. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, wherein halo is fluorine. In certain embodiments, haloalkyl may be optionally substituted.

As used herein, the terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" mean that at least one backbone chain atom is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and combinations thereof. optionally substituted alkyl, alkenyl and alkynyl radicals.

The term "heteroatom" means an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from, but not limited to, oxygen, sulfur, nitrogen, silicon and phosphorus. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may all be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (such as aryl and cycloalkyl), heterocycles (such as heteroaryl and non-aromatic heterocycles), aromatics (such as aryl and heteroaryl) and non-aromatics (such as cycloalkyl). and non-aromatic heterocycles). A ring may be optionally substituted. The ring may be monocyclic or polycyclic.

As used herein, the term "ring system" refers to one or more than one ring.

The term "fused" refers to a structure in which two or more rings share one or more bonds.

The term "heteroaryl" or "heteroaromatic" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group wherein at least one of the ring backbone atoms is a nitrogen atom. Polycyclic heteroaryl groups may be fused or unfused. Examples of heteroaryl groups are:

<img file="KR20080098490A_D0031.tif" />

etc. Depending on the structure, a heteroaryl group may be a monoradical or a diradical (ie, a heteroarylene group).

"Heteroarylalkyl" or "heteroaralkyl" means an alkyl group as described herein substituted with a heteroaryl as described herein.

As used herein, the term "non-aromatic heterocycle", "heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic ring in which one or more atoms forming the ring are heteroatoms. A "non-aromatic heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur. The radical may be fused with aryl or heteroaryl. A heterocycloalkyl ring may be formed of 3, 4, 5, 6, 7, 8, 9 or 9 or more atoms. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups, eg, oxo- and thio-containing groups. Examples of heterocycloalkyl include lactam, lactone, cyclic imide, cyclic thioimide, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxine, 1 , 3-dioxane, 1,4-dioxine, 1,4-dioxane, piperazine, 1,3-oxathian, 1,4-oxatiin, 1,4-oxatian, tetrahydro-1, 4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexa Hydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine , 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-thiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thia zoline, thiazolidine and 1,3-oxathiolane. Examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, are

<img file="KR20080098490A_D0032.tif" />

etc. The term heteroalicyclic also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides and oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (ie, a heterocycloalkylene group).

"Heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with heterocycloalkyl, as defined herein.

The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing 1 to 4 heteroatoms each selected from O, S and N, wherein each heterocyclic group is from 4 to 4 in its ring system. It has 10 atoms, provided that the rings of this group do not contain two adjacent O or S atoms. As used herein, when the number of carbon atoms in the heterocycle is indicated (eg C<sb>1</sb>-C<sb>6</sb> heterocycle), at least one other atom (heteroatom) must be present in the ring. "C<sb>1</sb>-C<sb>6</sb> Designations such as "heterocycle" refer only to the number of carbon atoms in the ring and not the total number of atoms in the ring. It is understood that a heterocyclic ring may have additional heteroatoms in the ring. "4 to 6 membered hetero Names such as "cycle" refer to the total number of atoms contained in the ring (i.e., 4, 5 or 6 members in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining 2 to 4 atoms are carbon atoms or heteroatoms. ring).In the heterocycle with two or more heteroatoms, two or more heteroatoms can be the same or different from each other.Reterocycle can be optionally substituted.The bond to the heterocycle is at the heteroatom or through carbon atoms Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, whereas aromatic heterocyclic groups must have 5 or more atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morphol No, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, Pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexa nyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, furinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl . The groups described above, as derived from the groups listed above, may be C-attached or N-attached where they are possible. For example, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Additionally, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5 - can be one (all C-attached). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-ones. Depending on the structure, a heterocycle group may be a monoradical or a diradical (ie, a heterocyclene group). The phosphorus containing ring is 1-oxo-phospholanyl, 1-methyl-1-oxo-phosphinan-4-yl, 1-phenyl-1-oxo-phosphinan-4-yl, 1-(cyclopropylmethyl)-1 -oxo-phosphinan-4-yl, 4-methyl-4-oxo-[1,4]azaphosphinan-1-yl, 4-phenyl-4-oxo-[1,4]azaphosphinan-1-yl yl and 4-(cyclopropylmethyl)-4-oxo-[1,4]azaphosphinan-1-yl.

As used herein, "1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene" refers to the structure do.

<img file="KR20080098490A_D0033.tif" />

As used herein, "1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene" refers to the structure do.

<img file="KR20080098490A_D0034.tif" />

The term "membered ring" may include any cyclic structure. The term "member" refers to the number of skeletal atoms constituting the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6 membered rings and cyclopentyl, pyrrole, furan and thiophene are 5 membered rings.

An "isocyanato" group refers to a -NCO group.

An "isothiocyanate" group refers to a -NCS group.

The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is often a recognized chemical moiety embedded in or bound to a molecule.

A "sulfinyl" group means -S(=O)-R.

A "sulfonyl" group is -S (=O)<sb>2</sb>-R stands for

A "thioalkoxy" or "alkylthio" group refers to a -S-alkyl group.

As used herein, the term ""O-carboxy" or "acyloxy" refers to a group of the formula RC(=O)O-.

"Alkylcarbonyloxy" means an (alkyl)-C(=O)O- group.

As used herein, the term "alkoxycarbonyl" refers to a group of the formula -C(=O)OR.

"Carboxy" means a -C(O)OH radical.

As used herein, "acetyl" means -C(=O)CH<sb>3</sb>means a group of

"Acyl" refers to the group -C(O)R.

As used herein, the term "trihalomethanesulfonyl" refers to Formula X<sb>3</sb>CS(=O)<sb>2</sb>means a group of -, where X is halogen.

As used herein, the term "cyano" refers to a group of the formula -CN.

"Cyanoalkyl" means an alkyl radical, as defined herein, substituted with one or more cyano groups.

As used herein, "alkylaminosulfonyl" refers to the formula -S(=O)<sb>2</sb>refers to a group of NH (alkyl).

As used herein, the term "dialkylaminosulfonyl" refers to the formula -S(=O)<sb>2</sb>N (alkyl)<sb>2</sb>means a group of

As used herein, the term "aminosulfonyl" refers to the formula -S(=O)<sb>2</sb>NH<sb>2</sb>means a group of

As used herein, the term "N-sulfonamido" or "sulfonylamino" refers to the formula RS(=O)<sb>2</sb>refers to a group of NH-.

As used herein, the term "O-carbamyl" refers to the formula -OC(=O)NR<sb>2</sb>means a group of

As used herein, the term "alkylaminocarbonyloxy" refers to a -OC(O)NH(alkyl) group.

As used herein, the term "dialkylaminocarbonyloxy" refers to -OC(O)N(alkyl)<sb>2</sb> means group.

"Aminocarbonyloxy" means -OC(O)NH<sb>2</sb> means group.

As used herein, the term "N-carbamyl" refers to a group of the formula ROC(=O)NH-.

As used herein, the term "O-thiocarbamyl" refers to the formula -OC(=S)NR<sb>2</sb>- means a group of

As used herein, the term "N-thiocarbamyl" refers to a group of the formula ROC(=S)NH-.

As used herein, the term "C-amido" refers to the formula -C(=0)NR<sb>2</sb>means a group of

As used herein, the term "alkylaminocarbonyl" refers to a group of the formula -C(=O)NH(alkyl).

As used herein, the term "dialkylaminocarbonyl" refers to the formula -C(=O)N(alkyl)<sb>2</sb>means a group of

"Aminocarbonyl" is -CONH<sb>2</sb> means radical.

As used herein, the term "N-amido" refers to a group of the formula RC(=O)NH-.

"Alkylcarbonylamino" means (alkyl)C(=O)NH-.

As used herein, a substituent "R", which appears by itself without designation, is from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon). refers to the selected substituent.

The term "optionally substituted" or "substituted" means that the groups referenced are individually and independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloaliphatic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxy. side, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, fluoroalkyl, silyl and mono- and amino, including disubstituted amino groups, and protected derivatives thereof, which may be substituted with one or more additional group(s). By way of example, any substituent is L<sb>S</sb>R<sb>S</sb>can be, where L<sb>s</sb>is independently a bond, -O-, -C(=O)-, -S-, -S(-O)-, -S(=O)<sb>2</sb>-, -NH-, -NHC(O)-, -C(O)NH-, S(O)<sb>2</sb>NH-, -NHS(=O)<sb>2</sb>, -OC(O)NH-, -NHC(O)O-, - (substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb> alkyl) and -(substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb> alkenyl); R<sb>s</sb>are each independently H, (substituted or unsubstituted C<sb>1</sb>-C<sb>4</sb>alkyl), (substituted or unsubstituted C<sb>3</sb>-C<sb>6</sb>cycloalkyl), heteroaryl and heteroalkyl. Protecting groups capable of forming protective derivatives of the above substituents are known to those skilled in the art and can be found in Greene and Wuts, supra.

The compounds provided herein may contain one or more stereocenters, and each center may exist in the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric and epimeric forms, as well as suitable mixtures thereof. Stereoisomers can optionally be obtained by methods known in the art, for example by separation of stereoisomers by chiral chromatography columns.

The methods and formulations described herein include N-oxides, crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same active form. includes the use of In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be described herein.

Throughout the specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

compound

Compounds that inhibit the activity of tyrosine kinase(s) may serve to restore or promote health. In certain embodiments, the tyrosine kinase inhibitor compounds provided herein are useful for treating various diseases, disorders or conditions. In certain embodiments, the compounds provided herein are Btk inhibitor compounds.

Compounds that inhibit the activity of tyrosine kinase(s), eg, Btk, are described herein. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds are also described herein.

Pharmaceutical compositions comprising one or more such compounds or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites or pharmaceutically acceptable prodrugs of such compounds are provided. In some embodiments, when the compounds described herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.

Compounds provided herein are inhibitors of tyrosine kinase activity, eg, Btk. In one aspect is provided a compound of Formula Ia, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug thereof. The compound of formula Ia is as follows.

<che id="ia"><img file="KR20080098490A_D0035.tif" /></che>

In the above formula (Ia),

J is -O-, -S- or -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl, wherein alkyl, alkenyl, alkynyl and alkylene, alone or as part of another group in J, are 1, 2, 3, 4 optionally substituted independently with 5 or 5 halo;

Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, -OR<sp>1c</sp> or -SR<sp>1d</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, acyl, -C(O)N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-C(O)NR<sp>8a</sp>R<sp>8b</sp>, -SO<sb>2</sb>R<sp>6</sp>, -(A<sp>1</sp>)-SO<sb>2</sb>R<sp>6</sp>, -SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -C(O)OR<sp>6</sp>, -(A<sp>1</sp>)-C(O)OR<sp>33</sp>, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>7</sp>each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, and A<sp>1</sp>is alkylene, alkenylene or alkynylene, R<sp>8a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>8b</sp>is hydrogen or R<sp>8a</sp>and R<sp>6</sp>is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>33</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>1a</sp> as part of another group within, optionally substituted with 1, 2, 3, 4 or 5 halo; R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl or -X<sp>1a</sp>-Y<sp>1</sp>-X<sp>1b</sp>-Q<sp>1</sp>, where X<sp>1a</sp>is a bond, alkylene, alkenylene, alkynylene, cycloalkylene or heterocycloalkylene, wherein alkylene, alkenylene and alkynylene are 1, 2, 3, 4 or 5 halo or 1 or optionally substituted with two hydroxy, Y<sp>1</sp>silver bond, -O-, -S(O)<sb>n1</sb>- (where n1 is 0, 1 or 2), -C(O)-, -NR<sp>18</sp>-, -NR<sp>18</sp>C(O)-, -NR<sp>18</sp>C(O)NR<sp>18</sp>-, -NR<sp>18</sp>C(=NR<sp>18</sp>)NR<sp>18</sp>-, -C(O)NR<sp>18</sp>-, -OC(O)-, -C(O)O-, -C(O)N(R<sp>18</sp>)N=CR<sp>27</sp>-, -NR<sp>18</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NR<sp>18</sp>-, -C(R<sp>27</sp>)(=NO)-, -C(R<sp>27</sp>)=NNR<sp>18</sp>-, -C(R<sp>27</sp>)=NNR<sp>18</sp>C(O)-, -C(R<sp>27</sp>)=NNR<sp>18</sp>C(O)NR<sp>18</sp>-, -NR<sp>18</sp>C(O)O- or -OC(O)NR<sp>18</sp>- and where R<sp>18</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy, R<sp>27</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>1</sp> optionally substituted independently with 1, 2, 3, 4 or 5 halo as part of another group within,

X<sp>1b</sp>is a bond, alkylene, alkenylene, alkynylene, cycloalkylene or heterocycloalkylene, wherein alkylene, alkenylene and alkynylene are 1, 2, 3, 4 or 5 halo or 1 or optionally substituted with two hydroxy;

Q<sp>1</sp>is Z, where Z is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(=E)(Y<sp>10c</sp>R<sp>60a</sp>)(Z<sp>10</sp>R<sp>61</sp>), or one reducing member is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system; E is oxygen or sulfur, Y<sp>1Oa</sp> and Y<sp>10b</sp>is independently a single bond, -O-, -S- or -NR<sp>62a</sp>- and where R<sp>62a</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, R<sp>60a</sp> and R<sp>60b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is -O-, -S- or -NR respectively<sp>62a</sp>-heterocycloalkylalkyl when - R<sp>60a</sp> and R<sp>60b</sp>is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is heterocycloalkylalkyl when each is a single bond, and Y<sp>1Oc</sp>is -O-, -S- or -NR<sp>62a</sp>- and Z<sp>10</sp>is alkylene, alkenylene, alkynylene, -O-, -S- or -NR<sp>62a</sp>- and R<sp>61</sp>is hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; , R<sp>61</sp>is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>) and R<sp>100</sp>X from the silver phosphorus atom<sp>1b</sp>a single bond to, or R<sp>100</sp>is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR<sp>101</sp> or -NR<sp>102a</sp>R<sp>102b</sp>, where R<sp>100 </sp>Alkyl, alkenyl and alkynyl within, alone or as part of another substituent, are independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>101</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R<sp>102a</sp> and R<sp>102b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; , R<sp>1c</sp> and R<sp>1d</sp>is -x<sp>1a</sp>-Z, where X<sp>1a</sp> and Z is as defined above,

R<sp>2a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted phenyl, cyano, optionally substituted phenyl, heteroaryl, -NR<sp>14a</sp>R<sp>14b</sp>, -(A<sp>1</sp>)-NR<sp>12a</sp>R<sp>12b</sp>, -NR<sp>13a</sp>C(O)R<sp>13b</sp>, -(A<sp>1</sp>)-NR<sp>13a</sp>C(O)R<sp>13b</sp>, -C(O)NR<sp>14a</sp>R<sp>14b</sp> or -(A<sp>1</sp>)-C(O)NR<sp>12a</sp>R<sp>12b</sp>wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>2a</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>12a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>12b</sp>is hydrogen or R<sp>12a</sp>and R<sp>14a</sp> and R<sp>14b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>13a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R<sp>13b</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyanoalkyl, alkoxy, alkenyloxy or cycloalkyl;

R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where, X<sp>2a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are optionally substituted with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy; , Y<sp>2</sp>is a bond, -O-, -S(O)<sb>n1</sb>- (where n1 is 0, 1 or 2), -C(O)-, -NR<sp>45</sp>-, -NR<sp>45</sp>C(O)-, -NR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(=NR<sp>45</sp>)NR<sp>45</sp>-, -C(O)NR<sp>45</sp>-, -OC(O)-, -C(O)O-, -C(O)N(R<sp>45</sp>)N=CR<sp>74</sp>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>74</sp>)(=NO)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(O)O- or -OC(O)NR<sp>45</sp>- and where R<sp>45</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy, R<sp>74</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>2</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>2b</sp>is a bond, Q<sp>2</sp>is hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, or R<sp>2a</sp> and R<sp>2b</sp>together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R<sp>3</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, - (A<sp>5</sp>)-S(0)<sb>0-2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-OR<sp>55</sp>, -(A<sp>5</sp>)-OC(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)OR<sp>55</sp>, -(A<sp>5</sp>)-C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)R<sp>53</sp>, -(A<sp>5</sp>)-S(O)<sb>2</sb>N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>S(O)<sb>2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-0C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)OR<sp>55 </sp>or -(A<sp>5</sp>)-NR<sp>54</sp>C(O)N(R)<sp>54</sp>)<sb>2</sb>and A<sp>5</sp>is a bond, alkylene, alkenylene or alkynylene, R<sp>53</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>54</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, Heteroaryl or heteroaralkyl, R<sp>55</sp>is hydrogen or R<sp>53</sp>wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene are alone or R<sp>3</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo.

In one aspect, herein R<sp>3</sp>is hydrogen, and J is -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen or optionally substituted alkyl. In another embodiment, J is -N(methyl)-.

In another aspect, Q<sp>1</sp>One reduction is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system.

In some embodiments, R<sp>1b</sp>is -x<sp>1a</sp>-Y<sp>1</sp>-X<sp>1b</sp>-Q<sp>1</sp>am. In another aspect, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy or acyl, R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl. In other aspects, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen, R<sp>1b</sp>is aryl.

In another aspect, there is provided a compound of Formula Ib, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug thereof. The compound of formula Ib is as follows.

<che id="ib"><img file="KR20080098490A_D0036.tif" /></che>

In the above formula (Ib),

J is -O-, -S- or -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl, wherein alkyl, alkenyl, alkynyl and alkylene, alone or as part of another group in J, are independently 1, 2, 3 , optionally substituted with 4 or 5 halo;

Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, -OR<sp>1c</sp> or -SR<sp>1d</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, acyl, -C(O)N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-C(O)NR<sp>8a</sp>R<sp>8b</sp>, -SO<sb>2</sb>R<sp>6</sp>, -(A<sp>1</sp>)-SO<sb>2</sb>R<sp>6</sp>, -SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -C(O)OR<sp>6</sp>, -(A<sp>1</sp>)-C(O)OR<sp>33</sp>, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>7</sp>each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, and A<sp>1</sp>is alkylene, alkenylene or alkynylene, R<sp>8a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>8b</sp>is hydrogen or R<sp>8a</sp>and R<sp>6</sp>is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>33</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>1a</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo; R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>1a</sp> and R<sp>1b</sp>together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl, and R<sp>1c</sp> and R<sp>1d</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or -(A<sp>18</sp>)-C(O)NR<sp>50a</sp>R<sp>50b</sp>and A<sp>18</sp>is alkylene, alkenylene or alkynylene, R<sp>50a</sp> and R<sp>5Ob</sp>is independently hydrogen, optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl and alkylene are independently or R<sp>1a</sp>, R<sp>1b</sp>, R<sp>1c</sp> and R<sp>1d</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo;

R<sp>2a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted phenyl, cyano, optionally substituted phenyl, heteroaryl, -NR<sp>14a</sp>R<sp>14b</sp>, -(A<sp>1</sp>)-NR<sp>12a</sp>R<sp>12b</sp>, -NR<sp>13a</sp>C(O)R<sp>13b</sp>, -(A<sp>1</sp>)-NR<sp>13a</sp>C(O)R<sp>13b</sp>, -C(O)NR<sp>14a</sp>R<sp>14b</sp> or -(A<sp>1</sp>)-C(O)NR<sp>12a</sp>R<sp>12b</sp>wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>2a</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>12a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>12b</sp>is hydrogen or R<sp>12a</sp>and R<sp>14a</sp> and R<sp>14b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>13a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R<sp>13b</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyanoalkyl, alkoxy, alkenyloxy or cycloalkyl;

R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>3</sp>, where, X<sp>2a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are optionally substituted with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy; , Y<sp>2</sp>is a bond, -O-, -S(O)<sb>n1</sb>- (where n1 is 0, 1 or 2), -C(O)-, -NR<sp>45</sp>-, -NR<sp>45</sp>C(O)-, -NR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(=NR<sp>45</sp>)NR<sp>45</sp>-, -C(O)NR<sp>45</sp>-, -OC(O)-, -C(O)O-, -C(O)N(R<sp>45</sp>)N=CR<sp>74</sp>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>74</sp>)(=NO)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(O)O- or -OC(O)NR<sp>45</sp>- and where R<sp>45</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy, R<sp>74</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>2</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>2b</sp>is a bond, alkylene, alkenylene, alkynylene, cycloalkylene or heterocycloalkylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally substituted with 1 or 2 hydroxy;

Q<sp>3</sp>is Z, where Z is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(=E)(Y<sp>10c</sp>R<sp>60a</sp>)(Z<sp>10</sp>R<sp>61</sp>), or one reducing member is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system; E is oxygen or sulfur, Y<sp>1Oa</sp> and Y<sp>10b</sp>is independently a single bond, -O-, -S- or -NR<sp>62a</sp>- and where R<sp>62a</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, R<sp>60a</sp> and R<sp>60b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is -O-, -S- or -NR respectively<sp>62a</sp>-heterocycloalkylalkyl when - R<sp>60a</sp> and R<sp>60b</sp>is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is heterocycloalkylalkyl when each is a single bond, and Y<sp>1Oc</sp>is -O-, -S- or -NR<sp>62a</sp>- and Z<sp>10</sp>is alkylene, alkenylene, alkynylene, -O-, -S- or -NR<sp>62a</sp>- and R<sp>61</sp>is hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; , R<sp>61</sp>is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>) and R<sp>100</sp>X from the silver phosphorus atom<sp>1b</sp>a single bond to, or R<sp>100</sp>is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR<sp>101</sp> or -NR<sp>102a</sp>R<sp>102b</sp>, where R<sp>100 </sp>Alkyl, alkenyl and alkynyl within, alone or as part of another substituent, are independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>101</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R<sp>102a</sp> and R<sp>102b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; ,

R<sp>3</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, - (A<sp>5</sp>)-S(0)<sb>0-2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-OR<sp>55</sp>, -(A<sp>5</sp>)-OC(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)OR<sp>55</sp>, -(A<sp>5</sp>)-C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)R<sp>53</sp>, -(A<sp>5</sp>)-S(O)<sb>2</sb>N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>S(O)<sb>2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-0C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)OR<sp>55 </sp>or -(A<sp>5</sp>)-NR<sp>54</sp>C(O)N(R)<sp>54</sp>)<sb>2</sb>and A<sp>5</sp>is a bond, alkylene, alkenylene or alkynylene, R<sp>53</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>54</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, Heteroaryl or heteroaralkyl, R<sp>55</sp>is hydrogen or R<sp>53</sp>wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene are alone or R<sp>3</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo.

In another aspect, herein R<sp>3</sp>is hydrogen, and J is -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen or optionally substituted alkyl. In another embodiment, J is -N(methyl)-.

In some other embodiments, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy or acyl, R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl. In another aspect, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen or alkyl, R<sp>1b</sp>is aryl or heteroaryl. In some other embodiments, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen, R<sp>1b</sp>is aryl. In some other embodiments, Y<sp>a</sp>is -NH(aryl). In a further aspect, Y<sp>a</sp>is 4-fluoro-2-methylphenylamino or 2,6-dichlorophenylamino.

In other aspects, Q<sp>3</sp>One reduction is P(=E)(R<sp>100</sp>)- is an optionally substituted ring system.

In other embodiments, R<sp>2a</sp>is optionally substituted alkyl. In some other embodiments, R<sp>2a</sp>is methyl, and R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where X<sp>2a</sp>is alkenylene. In other embodiments, R<sp>2a</sp>is methyl, and R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where X<sp>2a</sp>is -CH<sb>2</sb>CH=CH-. In some other embodiments, Y<sp>2</sp>is a bond, -C(O)NR<sp>45</sp>- or -C(O)NH-. In other aspects, X<sp>2b</sp>is a bond, Q<sp>2</sp>is that one reduction is P(=E)(R<sp>100</sp>)- is an optionally substituted ring system. In some other embodiments, R<sp>2a</sp>is methyl, and R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where X<sp>2a</sp>is -CH<sb>2</sb>CH=CH-, and Y<sp>2</sp>is a bond or -C(O)NH-, and X<sp>2b</sp>is a bond, Q<sp>2</sp>is that one reduction is P(=E)(R<sp>100</sp>)- is an optionally substituted ring system.

In some embodiments, R<sp>2a</sp>is located at position 6, R<sp>2b</sp>is located at position 7.

In some aspects, Y<sp>2</sp>is a bond, Q<sp>2</sp>is one ring atom is nitrogen and one ring atom is P(=E)(R<sp>100</sp>)- is a saturated monocyclic group of 6-membered ring atoms, wherein the nitrogen is X<sp>2b</sp>is the binding point for In other embodiments, R<sp>100</sp>is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl. In a further aspect, Q<sp>2</sp>is 4-methyl-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl; 4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl; 4-(4-fluorophenylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl; 4-(Cyclopropylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl or 4-(cyclopropyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl.

In some other embodiments, Y<sp>2</sp>is -C(O)NH-, Q<sp>2</sp>is that one reduction is -P(=O)(R<sp>100</sp>)- is a saturated monocyclic hydrocarbon radical of 6 membered ring atoms. In other embodiments, R<sp>100</sp>is alkyl or aryl. In other aspects, Y<sp>2</sp>is -C(O)NH-, Q<sp>2</sp>is that one reduction is -P(=O)(R<sp>100</sp>) - is a saturated monocyclic hydrocarbon radical of 6 membered ring atoms, R<sp>100</sp>is alkyl or aryl. In other aspects, Q<sp>2</sp>is 1-oxo-1-methyl-1λ<sp>5</sp>-phosphinan-4-yl, 1-oxo-1-trans-phenyl-1λ<sp>5</sp>-phosphinan-4-yl or 1-oxo-1-cis-phenyl-1λ<sp>5</sp>-phosphinan-4-yl.

In another aspect, J is -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen, R<sp>2a</sp>is optionally substituted alkyl, R<sp>3</sp>is hydrogen, and Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen or alkyl, R<sp>1b</sp>is aryl or heteroaryl, R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>3</sp>, where, X<sp>2a</sp>is alkenylene, and Y<sp>2</sp>is a bond or -C(O)NH-, and X<sp>2b</sp>is a bond, Q<sp>3</sp>One reduction is -P(=E)(R<sp>100</sp>)- and E is oxygen and R<sp>100</sp>an optionally substituted ring system wherein is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl.

In another aspect, R<sp>2a</sp>is optionally substituted alkyl, R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where, X<sp>2a</sp>is alkenylene, and Y<sp>2</sp>is a bond or -C(O)NR<sp>45</sp>- and X<sp>2b</sp>is a bond, Q<sp>2</sp>is that one reduction is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system.

In another aspect, there is provided a compound of Formula Ic, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug thereof. The compound of formula Ic is as follows.

<che id="ic"><img file="KR20080098490A_D0037.tif" /></che>

In the above formula (Ic),

J is -O-, -S- or -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl, wherein alkyl, alkenyl, alkynyl and alkylene, alone or as part of another group in J, are independently 1, 2, 3 , optionally substituted with 4 or 5 halo;

Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, -OR<sp>1c</sp> or -SR<sp>1d</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, acyl, -C(O)N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-C(O)NR<sp>8a</sp>R<sp>8b</sp>, -SO<sb>2</sb>R<sp>6</sp>, -(A<sp>1</sp>)-SO<sb>2</sb>R<sp>6</sp>, -SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -C(O)OR<sp>6</sp>, -(A<sp>1</sp>)-C(O)OR<sp>33</sp>, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>7</sp>each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, and A<sp>1</sp>is alkylene, alkenylene or alkynylene, R<sp>8a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>8b</sp>is hydrogen or R<sp>8a</sp>and R<sp>6</sp>is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl , heterocycloalkyl or heterocycloalkylalkyl, R<sp>33</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>1a</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo; R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>1a</sp> and R<sp>1b</sp>together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl, and R<sp>1c</sp> and R<sp>1d</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or -(A<sp>18</sp>)-C(O)NR<sp>50a</sp>R<sp>50b</sp>and A<sp>18</sp>is alkylene, alkenylene or alkynylene, R<sp>50a</sp> and R<sp>5Ob</sp>is independently hydrogen, optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl and alkylene are independently or R<sp>1a</sp>, R<sp>1b</sp>, R<sp>1c</sp> and R<sp>1d</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo;

R<sp>2a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted phenyl, cyano, optionally substituted phenyl, heteroaryl, -NR<sp>14a</sp>R<sp>14b</sp>, -(A<sp>1</sp>)-NR<sp>12a</sp>R<sp>12b</sp>, -NR<sp>13a</sp>C(O)R<sp>13b</sp>, -(A<sp>1</sp>)-NR<sp>13a</sp>C(O)R<sp>13b</sp>, -C(O)NR<sp>14a</sp>R<sp>14b</sp> or -(A<sp>1</sp>)-C(O)NR<sp>12a</sp>R<sp>12b</sp>wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>2a</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>12a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>12b</sp>is hydrogen or R<sp>12a</sp>and R<sp>14a</sp> and R<sp>14b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>13a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R<sp>13b</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyanoalkyl, alkoxy, alkenyloxy or cycloalkyl;

R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where, X<sp>2a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are optionally substituted with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy; , Y<sp>2</sp>is a bond, -O-, -S(O)<sb>n1</sb>- (where n1 is 0, 1 or 2), -C(O)-, -NR<sp>45</sp>-, -NR<sp>45</sp>C(O)-, -NR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(=NR<sp>45</sp>)NR<sp>45</sp>-, -C(O)NR<sp>45</sp>-, -OC(O)-, -C(O)O-, -C(O)N(R<sp>45</sp>)N=CR<sp>74</sp>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>74</sp>)(=NO)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(O)O- or -OC(O)NR<sp>45</sp>- and where R<sp>45</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy, R<sp>74</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>2</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>2b</sp>is a bond, Q<sp>2</sp>is hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl,

R<sp>3</sp>silver -X<sp>3a</sp>-Y<sp>3</sp>-X<sp>3b</sp>-Q<sp>4</sp>, where, X<sp>3a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently optionally with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy replaced by Y<sp>3</sp>is -C(0)- or -NR<sp>51</sp>- and where R<sp>51</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>3</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>3b</sp>is a bond, alkylene, alkenylene, alkynylene, cycloalkylene or heterocycloalkylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally substituted with 1 or 2 hydroxy;

Q<sp>4</sp>is Z, where Z is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(=E)(Y<sp>10c</sp>R<sp>60a</sp>)(Z<sp>10</sp>R<sp>61</sp>), or one reducing member is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system; E is oxygen or sulfur, Y<sp>1Oa</sp> and Y<sp>10b</sp>is independently a single bond, -O-, -S- or -NR<sp>62a</sp>- and where R<sp>62a</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, R<sp>60a</sp> and R<sp>60b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is -O-, -S- or -NR respectively<sp>62a</sp>-heterocycloalkylalkyl when - R<sp>60a</sp> and R<sp>60b</sp>is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is heterocycloalkylalkyl when each is a single bond, and Y<sp>1Oc</sp>is -O-, -S- or -NR<sp>62a</sp>- and Z<sp>10</sp>is alkylene, alkenylene, alkynylene, -O-, -S- or -NR<sp>62a</sp>- and R<sp>61</sp>is hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; , R<sp>61</sp>is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>) and R<sp>100</sp>X from the silver phosphorus atom<sp>1b</sp>a single bond to, or R<sp>100</sp>is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR<sp>101</sp> or -NR<sp>102a</sp>R<sp>102b</sp>, where R<sp>100 </sp>Alkyl, alkenyl and alkynyl within, alone or as part of another substituent, are independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>101</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R<sp>102a</sp> and R<sp>102b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl .

In some embodiments, herein J is -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen or optionally substituted alkyl. In another embodiment, J is -N(methyl)-.

In another aspect, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy or acyl, R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl. In other aspects, Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, where R<sp>1a</sp>is hydrogen or alkyl, R<sp>1b</sp>is aryl or heteroaryl. In other aspects, Y<sp>a</sp>is -NH(aryl). In some other embodiments, Y<sp>a</sp>is 4-fluoro-2-methylphenylamino or 2,6-dichlorophenylamino.

In another aspect, Q<sp>4</sp>is that one reduction is P(=E)(R<sp>100</sp>)- is an optionally substituted ring system.

In one aspect, provided is a compound having the structure of Formula II, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug thereof. The compound of formula II is:

<che id="ii"><img file="KR20080098490A_D0038.tif" /></che>

In the above formula (II),

R<sp>250a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are independently optionally by 1, 2, 3, 4 or 5 halo replaced,

R<sp>250b</sp>is -CH(=NOH), -C(H)=N-NHC(O)-Q<sp>250</sp> or -X<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>-Q<sp>250</sp>, where X<sp>250a</sp>is alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally by 1 or 2 hydroxy replaced by Y<sp>250</sp>silver bond, -S-, -S(O)-, -S(O)<sb>2</sb>-, -C(O)O- or -OC(O)-, and X<sp>25Ob</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy optionally substituted, Q<sp>250</sp>is aryl or heteroaryl, or Q<sp>250</sp>is aryl, acyl, heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl and -(alkylene )-R<sp>251</sp>heterocycloalkyl substituted by 1 or 2 groups selected from, R<sp>251</sp>is halo, hydroxy, alkoxy, cyano, alkylamino, dialkylamino, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkylsulfonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl phenyl substituted with 1, 2 or 3 groups selected from aminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl and dialkylaminocarbonyl, wherein alkylene, alkyl, alkenyl and alkynyl are alone or R<sp>250</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo,

R<sp>350a</sp>is hydrogen, hydroxy, alkoxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are independently 1, 2, 3, 4 or 5 optionally substituted by halo of

R<sp>350b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl wherein alkyl in aralkyl, cycloalkylalkyl, heteroaralkyl or heterocycloalkylalkyl; ,

R<sp>300</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl Sulfonyl, alkenylsulfonyl, arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, aminosulfonyl, alkyl Aminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino or -A<sp>100</sp>-R<sp>301</sp>and A<sp>100</sp>is alkylene or alkenylene, R<sp>301</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl Sulfonyl, alkenylsulfonyl, arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, aminosulfonyl, alkyl aminosulfonyl, dialkylaminosulfonyl or alkylsulfonylamino, wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene are alone or R<sp>300</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo,

R<sp>400</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy or alkoxy, wherein alkyl, alkenyl and alkynyl are alone or R<sp>400</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo.

In one embodiment, provided herein is a compound of Formula II, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug thereof.

Formula II

<img file="KR20080098490A_D0039.tif" />

In the above formula (II),

R<sp>250a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are independently optionally by 1, 2, 3, 4 or 5 halo replaced,

R<sp>250b</sp>is -x<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>-Q<sp>250</sp>, where X<sp>250a</sp>is alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally by 1 or 2 hydroxy replaced by Y<sp>250</sp>silver bond, -S-, -S(O)-, -S(O)<sb>2</sb>-, -C(O)O- or -OC(O)-, and X<sp>25Ob</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy optionally substituted, Q<sp>250</sp>is aryl or heteroaryl, or Q<sp>250</sp>is one selected from aryl, acyl, heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl and dialkylaminocarbonyl; heterocycloalkyl substituted by two groups, wherein alkylene, alkyl, alkenyl and alkynyl are alone or R<sp>250</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo,

R<sp>350a</sp>is hydrogen, hydroxy, alkoxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are independently 1, 2, 3, 4 or 5 optionally substituted by halo of

R<sp>350b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl wherein alkyl in aralkyl, cycloalkylalkyl, heteroaralkyl or heterocycloalkylalkyl; ,

R<sp>300</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl Sulfonyl, alkenylsulfonyl, arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, aminosulfonyl, alkyl Aminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino or -A<sp>100</sp>-R<sp>301</sp>(here, A<sp>100</sp>is alkylene or alkenylene, R<sp>301</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl Sulfonyl, alkenylsulfonyl, arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, aminosulfonyl, alkyl aminosulfonyl, dialkylaminosulfonyl or alkylsulfonylamino), wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene are alone or R<sp>300</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo,

R<sp>400</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy or alkoxy, wherein alkyl, alkenyl and alkynyl are alone or R<sp>400</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo.

In another aspect, R<sp>25Oa</sp>is optionally substituted alkyl, R<sp>250b</sp>is -CH(=NOH), -C(H)=N-NHC(O)-Q<sp>250</sp> or -X<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>-Q<sp>250</sp>, where X<sp>250a</sp>is alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally by 1 or 2 hydroxy replaced by Y<sp>250</sp>silver bond, -S(O)<sb>2</sb>- or -C(O)O-, and X<sp>25Ob</sp>is a bond, Q<sp>250</sp>is aryl or heteroaryl, or Q<sp>250</sp>is aryl, acyl, heteroaryl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, dialkylaminosulfonyl, alkylaminocarbonyl or -(alkylene)-R<sp>251</sp>(where R<sp>251</sp>is heterocycloalkyl substituted with phenyl substituted with halo, R<sp>350a</sp>is hydrogen, R<sp>350b</sp>is aryl, R<sp>300</sp>is hydrogen, R<sp>400</sp>is optionally substituted alkyl.

In some other embodiments, R<sp>350a</sp>is hydrogen, R<sp>35Ob</sp>is aryl.

In some other embodiments, R<sp>300</sp>is hydrogen, R<sp>250a</sp> and R<sp>400</sp>is optionally substituted alkyl.

In some other embodiments, R<sp>250b</sp>is -x<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>-Q<sp>250</sp>, where X<sp>250a</sp>is -CH<sb>2</sb>CH=CH-, and Y<sp>250</sp>is a bond, and X<sp>25Ob</sp>is a bond, Q<sp>250</sp>is aryl, acyl, heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl and -(alkylene )-R<sp>251</sp>(where R<sp>251</sp>is halo, hydroxy, alkoxy, cyano, alkylamino, dialkylamino, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkylsulfonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl hetero substituted with 1 or 2 groups selected from aminosulfonyl, dialkylaminosulfonyl, phenyl substituted with 1, 2 or 3 groups selected from alkylaminocarbonyl and dialkylaminocarbonyl) cycloalkyl, wherein alkylene, alkyl, alkenyl and alkynyl are alone or R<sp>250</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>250b</sp>is located at position 7. In other aspects, Q<sp>250</sp>is aryl, acyl, heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl and -(alkylene)-R<sp>251</sp>(where R<sp>251</sp>is halo, hydroxy, alkoxy, cyano, alkylamino, dialkylamino, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkylsulfonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl hetero substituted with 1 or 2 groups selected from aminosulfonyl, dialkylaminosulfonyl, phenyl substituted with 1, 2 or 3 groups selected from alkylaminocarbonyl and dialkylaminocarbonyl) cycloalkyl.

In some other embodiments, Q<sp>250</sp>is piperazine-substituted at the 4-position of the piperazin-1-yl ring with one group selected from aryl, acyl, heteroaryl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl and alkylaminosulfonyl- 1-day. In other aspects, Q<sp>250</sp>is piperazin-1-yl substituted at the 4 position of the piperazin-1-yl ring with one group selected from aryl, acyl, heteroaryl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl and alkylaminosulfonyl.

In one aspect, provided herein is a compound of Formula III, and a pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

Formula III

<img file="KR20080098490A_D0040.tif" />

In the above formula (III),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>haloalkyl, and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is -X<sp>250a</sp>-Y<sp>25O</sp>- or -Y<sp>250</sp>-X<sp>250a</sp>, where X<sp>250a</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is haloalkynyl, and Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NR<sp>45</sp>-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NR<sp>45</sp>C(=O)NR<sp>45</sp>-, -C(=O)NH-, -C(=O)NR<sp>45</sp>-, -OC(=O)-, -C(=O)O-, -NHSO<sb>2</sb>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NH-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>45</sp>)=NO-; -CH=NO-, -ON=CH-, heteroaryl, aryl, -NHC(=O)O-, -OC(=O)NH-, -NR<sp>45</sp>C(=O)O- or -OC(=O)NR<sp>45</sp>- and where R<sp>45</sp>are each independently hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

M is N or CH;

W is <img file="KR20080098490A_D0041.tif" />ego; E is oxygen or sulfur; R<sp>100</sp>silver halogen, -OH, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl, C<sb>1</sb>-C<sb>4</sb>Alkyl (heteroaryl), C<sb>1</sb>-C<sb>6</sb>alkoxy, C<sb>1</sb>-C<sb>6</sb>alkenyloxy, C<sb>1</sb>-C<sb>6</sb>alkynyloxy and -NR<sp>102a</sp>R<sp>102b</sp>an optionally substituted group selected from; R<sp>l02a</sp> and R<sp>l02b</sp>is independently hydrogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>Alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl and C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl) which may be substituted; R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl, di(C<sb>1</sb>-C<sb>6</sb>Alkyl)aminosulfonyl and C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkylsulfonylamino;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl;

n is 0, 1 or 2.

In any and all aspects, the substituents may be selected from a subset of the listed alternatives. For example, in some embodiments, T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene. In another embodiment, T is 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0042.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0043.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NH-, -NHC(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C (=O)O-, -NHSO<sb>2</sb>-, -SO<sb>2</sb>NH-, -NHC(=O)O- or -OC(=O)NH-; E is O; R<sp>35Oa</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In some embodiments, R<sp>350a</sp>is hydrogen or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, R<sp>350a</sp>is hydrogen or C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, R<sp>350a</sp>is hydrogen.

In some other aspects, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl; n is 1. In other aspects, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is alkenyl.

In some embodiments, a compound provided herein has a structure selected from Formulas IIIa, IIIb, and IIIc.

Formula IIIa

<img file="KR20080098490A_D0044.tif" />

Formula IIIb

<img file="KR20080098490A_D0045.tif" />

Formula IIIc

<img file="KR20080098490A_D0046.tif" />

In certain embodiments, R<sp>100</sp>silver halogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl); R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, R<sp>35Oa</sp>is hydrogen; Y<sp>250</sp>is a bond, -C(=O)-, -NHC(=O)- or -C(=O)NH-.

In other embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0047.tif" />is selected from

In other embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0048.tif" />is selected from

In one embodiment, a compound provided herein has the structure of Formula IIIc. In other embodiments, the compounds provided herein have the structure of Formula IIIa. In other embodiments, the compounds provided herein have the structure of Formula IIIb.

In some embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl or <img file="KR20080098490A_D0049.tif" />ego; R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In other embodiments, R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, L is C<sb>1</sb>-C<sb>4</sb>alkyl, <img file="KR20080098490A_D0050.tif" />is selected from; R<sp>100</sp>silver C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl); R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>Acyl, aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0051.tif" />is substituted with and at position 6 <img file="KR20080098490A_D0052.tif" />1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NH-, -NHC(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C (=O)O-, -NHSO<sb>2</sb>-, -SO<sb>2</sb>NH-, -NHC(=O)O- or -OC(=O)NH-; E is O; R<sp>35Oa</sp>is hydrogen or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl.

In certain embodiments, X<sp>25Oa</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl; n is 1.

In certain embodiments, R<sp>100</sp>silver halogen, or C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, phenyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (phenyl), C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>8</sb>cycloalkyl), C<sb>2</sb>-C<sb>8</sb>Heterocycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>2</sb>-C<sb>8</sb>heterocycloalkyl), heteroaryl and C<sb>1</sb>-C<sb>4</sb>an optionally substituted group selected from alkyl (heteroaryl); R<sp>200</sp>silver C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>an optionally substituted group selected from alkyl)aminosulfonyl.

In other embodiments, R<sp>35Oa</sp>is hydrogen; Y<sp>250</sp>is -C(=O)-; X<sp>250a</sp>is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl.

In certain embodiments, L is <img file="KR20080098490A_D0053.tif" />am.

In some embodiments, a compound provided herein has the structure of Formula IIIb. In other embodiments, the compounds provided herein have the structure of Formula IIIa. In other embodiments, the compounds provided herein have the structure of Formula IIIc.

In another aspect, provided is a compound of Formula IV, and a pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

Formula IV

<img file="KR20080098490A_D0054.tif" />

In the above formula (IV),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene;

R<sp>d</sp>is -OH or -NH-C(O)-R<sp>e</sp>ego;

R<sp>c</sp>is H or C<sb>1</sb>-C<sb>4</sb>Alkyl, halogen or C<sb>1</sb>-C<sb>4</sb>haloalkyl;

R<sp>e</sp>is C<sb>1</sb>-C<sb>6</sb>a substituted or unsubstituted group selected from alkyl, aryl and heteroaryl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0055.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0056.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In certain embodiments, R<sp>c</sp>is H; R<sp>e</sp>is a substituted or unsubstituted group selected from aryl and heteroaryl. In other embodiments, R<sp>e</sp>is a substituted or unsubstituted group selected from phenyl and heteroaryl containing 1 or 2 N atoms.

In another aspect, there is provided a compound of Formula V, and a pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

Formula V

<img file="KR20080098490A_D0057.tif" />

In the above formula (V),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is -X<sp>250a</sp>-Y<sp>250</sp>-X<sp>250b</sp>- or -X<sp>250b</sp>-Y<sp>250</sp>-X<sp>250a</sp>- and where, X<sp>250a</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is haloalkynyl, and Y<sp>250</sp>is a bond, -O-, -S(=O)-, -S(=O)<sb>2</sb>-, -C(=O)-, -NR<sp>45</sp>-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NR<sp>45</sp>C(=O)NR<sp>45</sp>-, -C(=O)NH-, -C(=O)NR<sp>45</sp>-, -OC(=O)-, -C(=O)O-, -NHSO<sb>2</sb>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NH-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>45</sp>)=NO-, -CH=NO-, -ON=CH-, heteroaryl, aryl, -NHC(=O)O-, -OC(=O)NH-, -NR<sp>45</sp>C(=O)O- or -OC(=O)NR<sp>45</sp>- and X<sp>250b</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl, wherein R<sp>45</sp>are each independently hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

R<sp>e</sp>Is<sp></sp>C<sb>1</sb>-C<sb>6</sb>a substituted or unsubstituted group selected from alkyl, aryl and heteroaryl;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is haloalkynyl.

In certain embodiments, T is at the 2-position <img file="KR20080098490A_D0058.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0059.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In other aspects, Y<sp>250</sp>is a bond, R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In one aspect, X<sp>250a</sp>is a bond, and X<sp>250b</sp>is a bond

In another aspect, T in position 2 <img file="KR20080098490A_D0060.tif" />is substituted with and at position 6 <img file="KR20080098490A_D0061.tif" />1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In some aspects, X<sp>250a</sp>is a bonded or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>alkyl; Y<sp>250</sp>is a bond, -O-, -C(=O)-, -NH-, -NHC(=O)-, -NR<sp>45</sp>C(=O)-, -NHC(=O)NH-, -C(=O)NH-, -OC(=O)-, -C(=O)O-, -NHC(=O)O- or -OC(=O)NH-; X<sp>250b</sp>is a bond, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In some embodiments, R<sp>e</sp>is C<sb>1</sb>-C<sb>6</sb>a substituted or unsubstituted group selected from alkyl, phenyl, heteroaryl containing 1 or 2 N atoms.

In some embodiments, R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>haloalkyl.

In other aspects, Y<sp>250</sp>is a bond, -NHC(=O)-, -C(=O)NH-, -OC(=O)- or -C(=O)O-.

In another aspect, provided are compounds of formula VI, and pharmaceutically active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs thereof.

Formula VI

<img file="KR20080098490A_D0062.tif" />

In the above formula (VI),

R<sp>a</sp> and R<sp>b</sp>are each independently H, halogen, CN, NO<sb>2</sb>, C<sb>1</sb>-C<sb>4</sb>alkyl, C<sb>1</sb>-C<sb>4</sb>Haloalkyl and C<sb>1</sb>-C<sb>4</sb>alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene or 1,7-dimethyl-9-oxo-8 ,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,6-ylene;

L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>3</sb>-C<sb>8</sb>Cycloalkyl, substituted or unsubstituted C<sb>5</sb>-C<sb>8</sb>Cycloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Heteroalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl,

R<sp>f</sp>Is<sp></sp>substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl;

R<sp>g</sp>is H, or C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>3</sb>-C<sb>6</sb>Cycloalkyl, C<sb>1</sb>-C<sb>4</sb>Alkyl (C<sb>3</sb>-C<sb>6</sb>cycloalkyl), aryl, heteroaryl, heteroaralkyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, Arylsulfonyl, Heteroarylsulfonyl, C<sb>1</sb>-C<sb>10</sb>Alkoxycarbonyl, aminosulfonyl, C<sb>1</sb>-C<sb>6</sb>Alkylaminosulfonyl and di(C<sb>1</sb>-C<sb>6</sb>alkyl) an optionally substituted group selected from aminosulfonyl;

R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkynyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>It is haloalkynyl.

In some embodiments, T is at the 2 position <img file="KR20080098490A_D0063.tif" />is substituted with and at position 7 <img file="KR20080098490A_D0064.tif" />1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-2,7-ylene substituted with

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>heteroalkenyl, and R<sp>350a</sp>is hydrogen, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>is alkyl. In other embodiments, L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Heteroalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>is heteroalkenyl.

In other embodiments, R<sp>g</sp>is H or C<sb>2</sb>-C<sb>10</sb>acyl, C<sb>1</sb>-C<sb>6</sb>alkyl, C<sb>2</sb>-C<sb>6</sb>alkenyl, C<sb>2</sb>-C<sb>6</sb>alkynyl, C<sb>1</sb>-C<sb>6</sb>Alkylsulfonyl, C<sb>2</sb>-C<sb>6</sb>Alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl and C<sb>1</sb>-C<sb>10</sb>an optionally substituted group selected from alkoxycarbonyl.

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl or substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl; R<sp>g</sp>is H or C which may be substituted<sb>1</sb>-C<sb>6</sb>is alkyl.

In some embodiments, L is a substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Haloalkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Haloalkenyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>Alkynyl and substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>haloalkynyl, <img file="KR20080098490A_D0065.tif" />is selected from

In other embodiments, L is substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl, <img file="KR20080098490A_D0066.tif" />is selected from

In other embodiments, substituted or unsubstituted C<sb>1</sb>-C<sb>6</sb>Alkyl, substituted or unsubstituted C<sb>2</sb>-C<sb>6</sb>alkenyl, <img file="KR20080098490A_D0067.tif" />is selected from

Combinations of any of the above groups for various variables are contemplated herein. Substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art to provide compounds set forth herein and compounds that are chemically stable and can be synthesized by techniques known in the art.

Additional embodiments of compounds of Formula Ia, Formula Ib, Formula Ic, Formula II, Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IV, Formula V, and Formula VI, include compounds set forth in Tables 1-6 below, but , but not limited thereto.

<tables id="1"><img file="KR20080098490A_D0068.tif" /></tables>

<img file="KR20080098490A_D0069.tif" />

The compounds of Table 1 are named as follows:

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 1);

2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 2);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 3);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 4);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 5);

2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 6);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-{2-[(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-carbonyl]ethenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 7);

2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 8);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 9);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-fluorophenyl)-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 10);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-methoxyphenyl)-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 11);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 12);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 13);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 14);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-methyl-1λ<sp>5</sp>-Phosphinan-4-yl)-carbonylamino]propenyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 15);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-trans-phenyl-1λ<sp>5</sp>-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 16) and

2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-cis-phenyl-1λ<sp>5</sp>-Phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 17).

<tables id="2"><img file="KR20080098490A_D0070.tif" /></tables>

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="6"><colspec colnum="1" align="justify" colname="col1" colwidth="899" /><colspec colnum="2" align="justify" colname="col2" colwidth="3355" /><colspec colnum="3" align="justify" colname="col3" colwidth="1087" /><colspec colnum="4" align="justify" colname="col4" colwidth="1105" /><colspec colnum="5" align="justify" colname="col5" colwidth="1668" /><colspec colnum="6" align="justify" colname="col6" colwidth="2568" /><tbody><row><entry align="justify" colname="col1">compound number</entry><entry align="justify" colname="col2">Q</entry><entry align="justify" colname="col3">X<sp>b</sp></entry><entry align="justify" colname="col4">Y</entry><entry align="justify" colname="col5">X<sp>a</sp></entry><entry align="justify" colname="col6">R<sp>b</sp></entry></row><row><entry align="justify" colname="col1">18</entry><entry align="justify" colname="col2">N-phenylpiperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">19</entry><entry align="justify" colname="col2">N-phenylpiperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">20</entry><entry align="justify" colname="col2">N-(4-chlorophenyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">21</entry><entry align="justify" colname="col2">N-(methylcarbonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">22</entry><entry align="justify" colname="col2">N-(phenylcarbonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">23</entry><entry align="justify" colname="col2">N-(pyridin-4-yl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">24</entry><entry align="justify" colname="col2">N-(methylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">25</entry><entry align="justify" colname="col2">N-(methylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">26</entry><entry align="justify" colname="col2">N-(pyridin-2-yl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">27</entry><entry align="justify" colname="col2">N-(pyrimidin-2-yl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">28</entry><entry align="justify" colname="col2">N-(2,6-dichlorophenylmethyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">29</entry><entry align="justify" colname="col2">N-(phenylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">30</entry><entry align="justify" colname="col2">N-(4-fluorophenyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">31</entry><entry align="justify" colname="col2">N-(tert-Butyloxyaminosulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">32</entry><entry align="justify" colname="col2">N-(N,N-dimethylaminosulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">33</entry><entry align="justify" colname="col2">N-(Ethylcarbonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">34</entry><entry align="justify" colname="col2">N-(Isopropylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">35</entry><entry align="justify" colname="col2">N-(ethylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">36</entry><entry align="justify" colname="col2">N-(isopropylcarbonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">4-Fluoro-2-methyl-phenyl</entry></row><row><entry align="justify" colname="col1">52</entry><entry align="justify" colname="col2">N-(methylsulfonyl)-piperazin-1-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col6">5-Fluoro-2-methyl-phenyl</entry></row></tbody></tgroup></table>

The compounds of Table 2 are named as follows:

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8- dihydro-imidazo[4 ,5-h]isoquinolin-9-one (Compound 18);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (Compound 19);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-chlorophenyl)-piperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 20);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 21);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 22);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-4-yl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 23);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 24);

2-(3-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 25);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-2-yl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 26);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyrimidin-2-yl)-piperazin-1-yl)-propenyl]-1 ,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 27);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(2,6-dichlorophenylmethyl)-piperazin-1-yl)-propenyl]- 1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 28);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 29);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-fluorophenyl)-piperazin-1-yl)-propenyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 30);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-tert-butyloxycarbonylpiperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 31);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(N,N-dimethylaminosulfonyl)-piperazin-1-yl)-propenyl] -1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 32);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-ethylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro- imidazo[4,5-h]isoquinolin-9-one (Compound 33);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(isopropylsulfonyl)-piperazin-1-yl)-propenyl]-1,8 -dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 34);

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(ethylsulfonyl)-piperazin-1-yl)-propenyl]-1,8- dihydro-imidazo[4,5-h]isoquinolin-9-one (compound 35) and

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-isopropylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro -imidazo[4,5-h]isoquinolin-9-one (compound 36).

<tables id="3"><img file="KR20080098490A_D0071.tif" /></tables>

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="6"><colspec colnum="1" align="justify" colname="col1" colwidth="955" /><colspec colnum="2" align="justify" colname="col2" colwidth="2699" /><colspec colnum="3" align="justify" colname="col3" colwidth="1087" /><colspec colnum="4" align="justify" colname="col4" colwidth="1218" /><colspec colnum="5" align="justify" colname="col5" colwidth="2455" /><colspec colnum="6" align="justify" colname="col6" colwidth="2268" /><tbody><row><entry align="justify" colname="col1">compound number</entry><entry align="justify" colname="col2">Q</entry><entry align="justify" colname="col3">X<sp>b</sp></entry><entry align="justify" colname="col4">Y</entry><entry align="justify" colname="col5">X<sp>a</sp></entry><entry align="justify" colname="col6">R<sp>b</sp></entry></row><row><entry align="justify" colname="col1">37</entry><entry align="justify" colname="col2">phenyl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">-S(O)<sb>2</sb>-</entry><entry align="justify" colname="col5">-CH=CH-</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">38</entry><entry align="justify" colname="col2">phenyl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">-C(O)O-</entry><entry align="justify" colname="col5">prop-2-ene-1,1-diyl</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">39</entry><entry align="justify" colname="col2">phenyl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">-C(O)O-</entry><entry align="justify" colname="col5">2,2-difluorobutyne-1,1-diyl</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">40</entry><entry align="justify" colname="col2">N-phenylmethyl-[1,2,3]triazol-4-yl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CF<sb>3</sb>CH(OH)-</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">41</entry><entry align="justify" colname="col2">phenyl</entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">Combination</entry><entry align="justify" colname="col5">-CCCH(OH)-</entry><entry align="justify" colname="col6">2,6-dichlorophenyl</entry></row></tbody></tgroup></table>

The compounds of Table 3 are named as follows:

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2-(phenylsulfonyl)-ethenyl]-1,8-dihydro-imidazo[4,5-h]iso quinolin-9-one (Compound 37);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-prop-2-enyl]-1,8-dihydro-imidazo[4, 5-h]isoquinolin-9-one (Compound 38);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-2,2-difluorobutynyl]-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (Compound 39);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2,2-difluoro-1-hydroxy-2-(N-phenylmethyl-[1,2,3]tria) zol-4-yl)-ethyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (compound 40) and

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-(1-hydroxy-3-phenylprop-2-yn-1-yl)-1,8-dihydro-imidazo [4,5-h]Isoquinolin-9-one (Compound 41).

<tables id="4"><img file="KR20080098490A_D0072.tif" /></tables>

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="5"><colspec colnum="1" align="justify" colname="col1" colwidth="955" /><colspec colnum="2" align="justify" colname="col2" colwidth="2680" /><colspec colnum="3" align="justify" colname="col3" colwidth="1312" /><colspec colnum="4" align="justify" colname="col4" colwidth="2043" /><colspec colnum="5" align="justify" colname="col5" colwidth="3693" /><tbody><row><entry align="justify" colname="col1">compound number</entry><entry align="justify" colname="col2">R<sp>f</sp></entry><entry align="justify" colname="col3">R<sp>g</sp></entry><entry align="justify" colname="col4">L</entry><entry align="justify" colname="col5">R<sp>b</sp></entry></row><row><entry align="justify" colname="col1">42</entry><entry align="justify" colname="col2">prop-1-yn-3-yl</entry><entry align="justify" colname="col3">methyl</entry><entry align="justify" colname="col4">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col5">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">43</entry><entry align="justify" colname="col2">prop-1-yn-3-yl</entry><entry align="justify" colname="col3">methyl</entry><entry align="justify" colname="col4">-CH<sb>2</sb>CH=CH-</entry><entry align="justify" colname="col5">4-fluoro-2-methylphenyl</entry></row></tbody></tgroup></table>

The compounds of Table 4 are named as follows:

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one (compound 42) and

2-(4-Fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]- 1,8-Dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 43).

<tables id="5"><img file="KR20080098490A_D0073.tif" /></tables>

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="3"><colspec colnum="1" align="justify" colname="col1" colwidth="1667" /><colspec colnum="2" align="justify" colname="col2" colwidth="5454" /><colspec colnum="3" align="justify" colname="col3" colwidth="3560" /><tbody><row><entry align="justify" colname="col1">compound number</entry><entry align="justify" colname="col2">R<sp>e</sp></entry><entry align="justify" colname="col3">R<sp>b</sp></entry></row><row><entry align="justify" colname="col1">44</entry><entry align="justify" colname="col2">-OH</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">45</entry><entry align="justify" colname="col2">phenylamido</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">46</entry><entry align="justify" colname="col2">4-(N,N-dimethylamino)-phenylamido</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">47</entry><entry align="justify" colname="col2">(pyridin-2-yl)amido</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">48</entry><entry align="justify" colname="col2">(pyridin-3-yl)amido</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row><row><entry align="justify" colname="col1">49</entry><entry align="justify" colname="col2">2-methoxyphenylamido</entry><entry align="justify" colname="col3">2,6-dichlorophenyl</entry></row></tbody></tgroup></table>

The compounds of Table 5 are named as follows:

2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde oxime (compound 44);

Benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene] -hydrazide (compound 45);

4-(N,N-dimethylamino)-benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5 -h]Isoquinolin-7-ylmethylene]-hydrazide (Compound 46);

Pyridine-2-carboxylic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7 -ylmethylene]-hydrazide (Compound 47);

Pyridine-3-carboxylic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7 -ylmethylene]-hydrazide (compound 48) and

2-Methoxy-benzoic acid [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline- 7-Ylmethylene]-hydrazide (Compound 49).

<tables id="6"><img file="KR20080098490A_D0074.tif" /></tables>

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="6"><colspec colnum="1" align="justify" colname="col1" colwidth="955" /><colspec colnum="2" align="justify" colname="col2" colwidth="2324" /><colspec colnum="3" align="justify" colname="col3" colwidth="2062" /><colspec colnum="4" align="justify" colname="col4" colwidth="1462" /><colspec colnum="5" align="justify" colname="col5" colwidth="1012" /><colspec colnum="6" align="justify" colname="col6" colwidth="2868" /><tbody><row><entry align="justify" colname="col1">compound number</entry><entry align="justify" colname="col2">Q</entry><entry align="justify" colname="col3">X<sp>b</sp></entry><entry align="justify" colname="col4">Y</entry><entry align="justify" colname="col5">X<sp>a</sp></entry><entry align="justify" colname="col6">R<sp>b</sp></entry></row><row><entry align="justify" colname="col1">50</entry><entry align="justify" colname="col2"><img file="KR20080098490A_D0075.tif" /></entry><entry align="justify" colname="col3">Combination</entry><entry align="justify" colname="col4">-C(O)-</entry><entry align="justify" colname="col5">-CH<sb>2</sb>-</entry><entry align="justify" colname="col6">4-fluoro-2-methylphenyl</entry></row><row><entry align="justify" colname="col1">51</entry><entry align="justify" colname="col2"><img file="KR20080098490A_D0076.tif" /></entry><entry align="justify" colname="col3">Butane-1,1-diyl</entry><entry align="justify" colname="col4">-NHC(O)-</entry><entry align="justify" colname="col5">-CH<sb>2</sb>-</entry><entry align="justify" colname="col6">4-fluoro-2-methylphenyl</entry></row></tbody></tgroup></table>

The compounds of Table 6 are named as follows:

2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{2-[4-(4-fluorophenyl)-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl]-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 50) and

(S)-2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{N-[1-(phenylsulfonyl)hex-1-en-3-yl]-amino- 2-Oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 51).

In one embodiment, herein one reducing member is -P(=E)(R<sp>100</sp>)-, optionally substituted ring systems of Formula 34 are provided.

<che id="34"><img file="KR20080098490A_D0077.tif" /></che>

In Formula 34,

E is oxygen;

R<sp>100</sp>is as defined herein,

n is 1, 2 or 3.

In one embodiment, herein one reducing member is -P(=E)(R<sp>100</sp>)-, optionally substituted ring systems of formula (9) are provided.

<che id="9"><img file="KR20080098490A_D0078.tif" /></che>

In Formula 9,

E is oxygen;

R<sp>100</sp>is as defined herein,

n is 1, 2 or 3.

In another embodiment, (a) an optionally substituted ring system of Formula 34 is reacted with (a) a carboxylic acid of Formula Ii (or a salt or activated acid derivative thereof) to obtain a compound of Formula Id, or (b) Formula Ih reacting with an intermediate of or a salt thereof to obtain a compound of formula Ie, or

(b) reacting the intermediate of formula 9 or a salt thereof or an activated acid derivative thereof with an intermediate of formula Ig or a salt thereof to obtain a compound of formula If,

(a) optionally separating the individual isomers of the compound,

(b) optionally forming an acid addition salt of the product formed in step (a) or (b) above;

(c) optionally forming the free base of the product formed in step (a) or (b);

(d) optionally, J, Y in the product formed in step (a), (b), (c), (d) or (e)<sp>a</sp> and modifying the group.

Formula 34

<img file="KR20080098490A_D0079.tif" />

<che id="ii"><img file="KR20080098490A_D0080.tif" /></che>

<che id="id"><img file="KR20080098490A_D0081.tif" /></che>

<che id="ih"><img file="KR20080098490A_D0082.tif" /></che>

<che id="ie"><img file="KR20080098490A_D0083.tif" /></che>

Formula 9

<img file="KR20080098490A_D0084.tif" />

<che id="ig"><img file="KR20080098490A_D0085.tif" /></che>

<che id="if"><img file="KR20080098490A_D0086.tif" /></che>

In Formula 34, Ii, Id, 1h, Ie, 9, Ig and If,

J is -O-, -S- or -NR<sp>5</sp>- and where R<sp>5</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl, wherein alkyl, alkenyl, alkynyl and alkylene, alone or as part of another group in J, are independently 1, 2, 3, optionally substituted with 4 or 5 halo;

Y<sp>a</sp>is -nr<sp>1a</sp>R<sp>1b</sp>, -OR<sp>1c</sp> or -SR<sp>1d</sp>, where R<sp>1a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, acyl, -C(O)N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-C(O)NR<sp>8a</sp>R<sp>8b</sp>, -SO<sb>2</sb>R<sp>6</sp>, -(A<sp>1</sp>)-SO<sb>2</sb>R<sp>6</sp>, -SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -(A<sp>1</sp>)-SO<sb>2</sb>N(R<sp>7</sp>)<sb>2</sb>, -C(O)OR<sp>6</sp>, -(A<sp>1</sp>)-C(O)OR<sp>33</sp>, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>7</sp>each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, and A<sp>1</sp>is alkylene, alkenylene or alkynylene, R<sp>8a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>8b</sp>is hydrogen or R<sp>8a</sp>and R<sp>6</sp>is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>33</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>1a</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo; R<sp>1b</sp>is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>1a</sp> and R<sp>1b</sp>together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl, and R<sp>1c</sp> and R<sp>1d</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or -(A<sp>18</sp>)-C(O)NR<sp>50a</sp>R<sp>50b</sp>and A<sp>18</sp>is alkylene, alkenylene or alkynylene, R<sp>50a</sp> and R<sp>5Ob</sp>is independently hydrogen, optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl and alkylene are independently or R<sp>1a</sp>, R<sp>1b</sp>, R<sp>1c</sp> and R<sp>1d</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo;

R<sp>2a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted phenyl, cyano, optionally substituted phenyl, heteroaryl, -NR<sp>14a</sp>R<sp>14b</sp>, -(A<sp>1</sp>)-NR<sp>12a</sp>R<sp>12b</sp>, -NR<sp>13a</sp>C(O)R<sp>13b</sp>, -(A<sp>1</sp>)-NR<sp>13a</sp>C(O)R<sp>13b</sp>, -C(O)NR<sp>14a</sp>R<sp>14b</sp> or -(A<sp>1</sp>)-C(O)NR<sp>12a</sp>R<sp>12b</sp>wherein alkyl, alkenyl, alkynyl and alkylene are alone or R<sp>2a</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>12a</sp>is substituted alkyl, substituted alkenyl, substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>12b</sp>is hydrogen or R<sp>12a</sp>and R<sp>14a</sp> and R<sp>14b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy or alkenyloxy, R<sp>13a</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R<sp>13b</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyanoalkyl, alkoxy, alkenyloxy or cycloalkyl;

R in Formulas Ii and Id<sp>3</sp>is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, - (A<sp>5</sp>)-S(0)<sb>0-2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-OR<sp>55</sp>, -(A<sp>5</sp>)-OC(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)R<sp>53</sp>, -(A<sp>5</sp>)-C(O)OR<sp>55</sp>, -(A<sp>5</sp>)-C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)R<sp>53</sp>, -(A<sp>5</sp>)-S(O)<sb>2</sb>N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>S(O)<sb>2</sb>R<sp>53</sp>, -(A<sp>5</sp>)-0C(O)N(R<sp>54</sp>)<sb>2</sb>, -(A<sp>5</sp>)-NR<sp>54</sp>C(O)OR<sp>55 </sp>or -(A<sp>5</sp>)-NR<sp>54</sp>C(O)N(R)<sp>54</sp>)<sb>2</sb>and A<sp>5</sp>is a bond, alkylene, alkenylene or alkynylene, R<sp>53</sp>is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, R<sp>54</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, Heteroaryl or heteroaralkyl, R<sp>55</sp>is hydrogen or R<sp>53</sp>wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene are alone or R<sp>3</sp> as part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo,

R' is a leaving group such as halo,

R<sp>150a</sp>is R<sp>2a</sp>and R<sp>150b</sp>is R<sp>2b</sp>this,

R<sp>150a</sp>is R<sp>2b</sp>and R<sp>150b</sp>is R<sp>2a</sp>ego,

R<sp>2b</sp>is -x<sp>2a</sp>-Y<sp>2</sp>-X<sp>2b</sp>-Q<sp>2</sp>, where, X<sp>2a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are optionally substituted with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy; , Y<sp>2</sp>is a bond, -O-, -S(O)<sb>n1</sb>- (where n1 is 0, 1 or 2), -C(O)-, -NR<sp>45</sp>-, -NR<sp>45</sp>C(O)-, -NR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(=NR<sp>45</sp>)NR<sp>45</sp>-, -C(O)NR<sp>45</sp>-, -OC(O)-, -C(O)O-, -C(O)N(R<sp>45</sp>)N=CR<sp>74</sp>-, -NR<sp>45</sp>SO<sb>2</sb>-, -SO<sb>2</sb>NR<sp>45</sp>-, -C(R<sp>74</sp>)(=NO)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)-, -C(R<sp>74</sp>)=NNR<sp>45</sp>C(O)NR<sp>45</sp>-, -NR<sp>45</sp>C(O)O- or -OC(O)NR<sp>45</sp>- and where R<sp>45</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy, R<sp>74</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>2</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>2b</sp>is a bond, Q<sp>2</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl;

n is 1, 2 or 3,

R<sp>100</sp>is as defined above,

R in formula Ig<sp>3</sp>silver -X<sp>3a</sp>-Y<sp>3</sp>-X<sp>3b</sp>-Q<sp>4</sp>, where, X<sp>3a</sp>is a bond, alkylene, alkenylene or alkynylene, wherein alkylene, alkenylene and alkynylene are independently optionally with 1, 2, 3, 4 or 5 halo or 1 or 2 hydroxy replaced by Y<sp>3</sp>is -C(0)- or -NR<sp>51</sp>- and where R<sp>51</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, wherein alkyl, alkenyl and alkynyl are alone or Y<sp>3</sp> As part of another group within, independently optionally substituted with 1, 2, 3, 4 or 5 halo, X<sp>3b</sp>is a bond, alkylene, alkenylene, alkynylene, cycloalkylene or heterocycloalkylene, wherein alkylene, alkenylene and alkynylene are independently 1, 2, 3, 4 or 5 halo or optionally substituted with 1 or 2 hydroxy, Q<sp>4</sp>is Z, where Z is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>), -P(=E)(Y<sp>10c</sp>R<sp>60a</sp>)(Z<sp>10</sp>R<sp>61</sp>), or one reducing member is -P(=E)(R<sp>100</sp>)- is an optionally substituted ring system; E is oxygen or sulfur, Y<sp>1Oa</sp> and Y<sp>10b</sp>is independently a single bond, -O-, -S- or -NR<sp>62a</sp>- and where R<sp>62a</sp>is hydrogen, hydroxy, alkoxy, alkenyloxy, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, R<sp>60a</sp> and R<sp>60b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is -O-, -S- or -NR respectively<sp>62a</sp>-heterocycloalkylalkyl when - R<sp>60a</sp> and R<sp>60b</sp>is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or Y<sp>1Oa</sp> or Y<sp>10b</sp>is heterocycloalkylalkyl when each is a single bond, and Y<sp>1Oc</sp>is -O-, -S- or -NR<sp>62a</sp>- and Z<sp>10</sp>is alkylene, alkenylene, alkynylene, -O-, -S- or -NR<sp>62a</sp>- and R<sp>61</sp>is hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; , R<sp>61</sp>is -P(=E)(Y<sp>10a</sp>R<sp>60a</sp>)(Y<sp>10b</sp>R<sp>60b</sp>) and R<sp>100</sp>X from the silver phosphorus atom<sp>1b</sp>a single bond to, or R<sp>100</sp>is halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, -OR<sp>101</sp> or -NR<sp>102a</sp>R<sp>102b</sp>, where R<sp>100 </sp>Alkyl, alkenyl and alkynyl within, alone or as part of another substituent, are independently optionally substituted with 1, 2, 3, 4 or 5 halo, R<sp>101</sp>is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R<sp>102a</sp> and R<sp>102b</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; ,

Y' is -OH, -NHR<sp>18</sp> or -C(O)NHR<sp>22</sp>, where R<sp>18</sp> and R<sp>22</sp>is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy or alkenyloxy,

Y" is -O-, NR<sp>18</sp>- or NR<sp>22</sp>-am.

Preparation of compounds

Compounds provided herein that inhibit the activity of a tyrosine kinase, such as Bruton's tyrosine kinase (Btk), can be prepared using standard synthetic techniques known to those of skill in the art, or methods known in the art, as described herein. It can be synthesized by using it in conjunction with the method. As a further guide, the following synthetic methods may also be used.

The reactions can be used in a linear sequence to provide the compounds described herein, or they can be used to synthesize fragments that are subsequently linked by methods described herein and/or known in the art.

Use of protection groups

The term "protecting group refers to a chemical moiety that blocks some or all of the reactive moieties so that these groups do not participate in a chemical reaction until the protecting group is removed. It is preferred that each protecting group is removed by a different means. Protecting group cleaved under all individual reaction conditions meets different removal requirements.Protecting group can be removed by acid, base and hydrogenolysis.Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl, which is acid labile and can be removed by hydrogenolysis, can be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups and basic labile Fmoc groups. Carboxylic acid and hydroxy reactive moieties are formed in the presence of acid labile groups, e.g., tert-butyl carbamate or amines blocked with acid and base stable but hydrolytically removable carbamates, base labile groups, e.g. For example, but not limited to, methyl, ethyl and acetyl can be blocked.

Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protecting groups such as benzyl groups, whereas amine groups capable of hydrogen bonding with acids are base labile groups such as Fmoc can be blocked with Carboxylic acid reactive moieties can be protected by conversion to simple ester derivatives as exemplified herein, or they can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl and coexist The amino group may be blocked with a fluoride labile silyl carbamate. In one embodiment, a compound containing both a carboxylic acid reactive moiety and a hydroxy reactive moiety can have one reactive moiety blocked and the other reactive moiety unblocked.

Allyl blocking groups are useful in the presence of acid-protecting groups and base-protecting groups because they are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl blocked carboxylic acids can be deprotected in a Pd°-catalyzed reaction in the presence of acid labile tert-butyl carbamate or base labile acetate amine protecting groups. Another type of protecting group is a resin to which a compound or intermediate can be bound. As long as the moiety is bound to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group can react.

Typical blocking/protection groups can be selected from:

<img file="KR20080098490A_D0087.tif" />

Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999].

synthesis of compounds

In certain embodiments, methods of making and using the tyrosine kinase inhibitor compounds described herein are provided. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds may be synthesized using methodologies analogous to those described below using suitable alternative starting materials.

Described herein are compounds that inhibit the activity of tyrosine kinase(s), eg, Btk, and methods of making them. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds are also described herein. Pharmaceutical compositions comprising one or more of such compounds or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds are provided.

Starting materials used in the synthesis of the compounds described herein may be synthesized or from conventional sources, such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrens, Calif.) or Sigma Chemical Co. (St. Louis, MO). The compounds described herein, and other related compounds having different substituents, are described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4, which is incorporated herein by reference in its entirety.<sp>th</sp> Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4<sp>th</sp> Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3<sp>rd</sp> Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989)]. Other methods for synthesizing the compounds described herein are described in WO 01/25238, US 6,506,769, US 6,770,639 and Snow et al. Tetrahedron Letters, 43 (2002) 7553-7556; Goldberg et al. J. Med. Chem. 2003, 46, 1337-1349; Snow et al. J. Med. Chem. 2002, 45, 3394-3405; and J. Heterocyclic Chem., 1970, 7, 615]. General methods for the preparation of the compounds described herein can be derived from reactions known in the art, which reactions are suitable for incorporating the various moieties found in the formulas provided herein, as will be appreciated by those skilled in the art. It can be modified by the use of reagents and conditions. As a guide, the following synthetic methods can be used.

The reaction product can be isolated and purified, if desired, using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including obtaining physical properties and spectral data.

The compounds described herein can be prepared as a single isomer or a mixture of isomers using the synthetic methods described herein.

<chr id="i"><img file="KR20080098490A_D0088.tif" /></chr>

Ring systems in which one ring member is a phosphine or a phosphine oxide can be prepared according to the procedure outlined in Scheme I. Treatment of a halodialkoxyphosphine oxide such as chlorodiethoxyphosphine oxide (Formula 1) with an alkyl metal salt such as a Grignard reagent provides a compound of Formula 2 Phosphine oxide of Formula 2 is treated with bromotrimethylsilane and then treated with oxalyl chloride to give halo phosphine oxide of Formula 3. Compounds of formula 3 are also commercially available.

Compounds of formula 3 are also of formula P(OR<sp>a</sp>)<sb>2</sb>(OR<sp>b</sp>) of the compound (wherein R<sp>a</sp>is methyl or ethyl, and R<sp>b</sp>is hydrogen, methyl or ethyl), for example trimethyl phosphite or diethyl phosphite with the formula R<sp>100</sp>It can be prepared by reacting with a compound of X (wherein X is halogen). R<sp>100</sp>When this optionally substituted aryl or heteroaryl, the reaction is carried out in the presence of a base, for example triethylamine, of a metal catalyst, for example a palladium catalyst, for example tetrakis(triphenylphosphine)-palladium. carried out in the presence of

The compound of formula 3 is then treated with a vinyl metal salt such as vinylmagnesium bromide to give the compound of formula 4. Treatment of divinyl phosphine oxide of formula 4 with a primary amine such as benzylamine or p-methoxybenzylamine gives the cyclic amine of formula 5. For example, removal of the protecting group on the nitrogen by catalytic hydrogenation provides the cyclic amine of formula (6).

<chr id="ii"><img file="KR20080098490A_D0089.tif" /></chr>

Scheme II describes the synthesis of cyclic phosphine oxides, such as compounds of Formula 9. Reaction of divinyl phosphine oxide of Formula 4 with a malonate such as dibenzylmalonate in the presence of a base such as potassium carbonate provides a heterocycloalkyl of Formula 7. The compound of formula 7 is then deprotected by treatment with hydrogen under reducing conditions, e.g., in the presence of a catalyst, e.g. palladium on carbon, in a suitable solvent, e.g. ethanol, to give the dicarboxylic acid of formula 8 do. Decarboxylation of the dicarboxylic acid of Formula 8 provides the carboxylic acid of Formula 9. In one embodiment, the compound of Formula 8 is decarboxylated under microwave conditions, eg, at a temperature greater than about 200°C. In another embodiment, a compound of formula 8 is decarboxylated under acidic conditions, eg, a solution of formula 8 in the presence of 1N HCl. Other methods of decarboxylation of beta-keto acids are known in the art.

<chr id="iii"><img file="KR20080098490A_D0090.tif" /></chr>

As shown in Scheme III, the synthesis of allyl acetate of formula 21 is selective S using 2,6-dichloro-3-nitrobenzonitrile of formula 10<sb>N</sb>Start by performing the Ar reaction. Reaction of a compound of formula 10 with an amine such as ammonia or an alkylamine such as methylamine provides a compound of formula 12. Subsequent S of a compound of formula 12 and an alkyl acetoacetate derivative<sb>N</sb>The Ar reaction provides a compound of formula 14, which contains the necessary number of atoms to form the isoquinoline core. Reduction of the nitro moiety nitroaromatic of formula 14 followed by reaction of a diamine of formula 15 with an isothiocyanate such as an aryl isothiocyanate in the presence of mercury oxide (HgO) in refluxing THF to form benzimidazole . Alternatively, the diamine of formula 15 is treated with an isothiocyanate and the intermediate thiourea is treated with an activator such as 1,3-dicyclohexylcarbodiimide (DCC) to provide the benzimidazole of formula 17 do.

Then, the benzimidazole of formula 17 is treated with an acid to form a polycycle of formula 18 to form an isoquinoline moiety. Formation of the polycycle of formula 18 involves hydrolysis of a nitrile followed by condensation with a ketone. Depending on the reaction conditions used, isoquinolone formation may or may not involve decarboxylation of the ester moiety. For example, treatment of a benzimidazole of formula 17 with sulfuric acid under mildly acidic reaction conditions, for example at room temperature, yields a compound of formula 18, wherein R<sp>2a</sp>is -C(O)OEt. In other embodiments, treatment of a benzimidazole of formula 17 with sulfuric acid, water and acetic acid at 100° C. provides a compound of formula 18, which in one step hydrolysis of a nitrile, condensation with a ketone, and decarboxylation of an ester moiety in one step includes anger.

Treatment of a compound of formula 18 with selenium dioxide in an ethereal solvent such as dioxane induces selective oxidation at C-7 methyl to provide an aldehyde of formula 19. The aldehyde of formula 19 is then treated with a vinyl metal salt such as vinylmagnesium bromide to provide a compound of formula 20. Treatment of a compound of Formula 20 with an activated carboxylic acid, such as acetic anhydride, provides allyl acetate of Formula 21.

<chr id="iv"><img file="KR20080098490A_D0091.tif" /></chr>

Scheme IV describes the synthesis of benzothiazoles. S of 2-chloro-5-nitrobenzonitrile and alkyl acetoacetate derivatives of formula 22<sb>N</sb>Ar reaction provides the compound of formula 23. The isoquinolone of formula 24 is formed by treatment of a compound of formula 23 with an acid. Reduction of the nitro moiety of Formula 24 followed by treatment of the amine of Formula 25 with an isothiocyanate provides the thiourea intermediate of Formula 26. Reaction of the thiourea intermediate of formula 26 under cyclization conditions, for example, in the presence of bromine in a suitable solvent such as chloroform, provides a benzothiazole. Further functionalization and manipulation of the benzothiazole is then performed as described herein or as known in the art.

<chr id="v"><img file="KR20080098490A_D0092.tif" /></chr>

Scheme V shows the derivatization of the aldehyde of formula 19 using a Homer-Wadsworth-Emmons olefination reaction. Treatment of the aldehyde of formula 19 with trimethyl phosphonoacetate in the presence of a base such as lithium hydroxide provides the α,β-unsaturated ester of formula 28. The compound of formula 28 is then hydrolyzed followed by a coupling agent such as benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), 0-benzotriazole-1- 1-N,N,N,N-tetramethyl-uronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl in the presence of uronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexyl-carbodiimide (DCC) Reaction with an amine provides the amide of formula 29.

<chr id="vi"><img file="KR20080098490A_D0093.tif" /></chr>

Scheme VI shows the synthesis of allyl amines via allyl substitution with an amine nucleophile with an allyl acetate of formula 21. In some embodiments, allyl acetate of Formula 21 is treated with a nucleophile, eg, an amine, in the presence of a metal catalyst, eg, a palladium catalyst, to provide an allyl amine of Formula 30. A suitable palladium catalyst is tris(dibenzylacetone)dipalladium (Pd<sb>2</sb>(dba)<sb>3</sb>), palladium dichloride, bis(acetonitrile)dichloropalladium and tetrakistriphenylphosphine palladium. Suitable ligands for palladium catalysts include, but are not limited to, triphenylphosphine.

In other embodiments, allyl acetate of Formula 21 is treated with an azide, such as sodium azide, in the presence of a metal catalyst, such as a palladium catalyst, followed by Staudinger reaction to yield allylamine of Formula 31 to provide. Allylamines of formula 31 can be coupled with various carboxylic acids to provide amides. Sulfonamide and urea compounds can also be prepared using allylamines of formula (31).

In some embodiments, the alkene moiety of the allyl moiety can be hydrogenated to provide analogous alkyl compounds.

<chr id="vii"><img file="KR20080098490A_D0094.tif" /></chr>

As shown in Scheme VII, an amide of Formula 33 can be prepared by reacting an intermediate of Formula 32 with an amine of Formula 34. The reaction can be carried out in an inert organic solvent such as methylene chloride, acetonitrile, N,N-dimethylformamide, an ethereal solvent such as tetrahydrofuran, dioxane or the like. This reaction is usually carried out with a suitable coupling agent, for example benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), 0-benzotriazol-1-yl-N,N ,N',N'-Tetramethyl-uronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluoro in the presence of rhophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexyl-carbodiimide (DCC) and a base (usually 3 equivalents), for example, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, etc. and optionally in the presence of 1-hydroxy-benzotriazole (HOBT). have.

<chr id="viii"><img file="KR20080098490A_D0095.tif" /></chr>

As shown in Scheme VIII, a diamine of formula 15 can be reacted with bromine in a suitable solvent such as chloroform at ambient temperature to provide a bromine diamine of formula 35. The diamine of formula 35 is then converted to the benzimidazole of formula 36, as described above. Crosslinking chemistry can be used to introduce various groups in place of bromine. In one embodiment, Stille reaction conditions are used, which convert the bromo benzimidazole of formula 36 to a palladium catalyst, e.g., (PPh<sb>3</sb>)<sb>2</sb>PdCl<sb>2</sb>and reacting with an alkyl tributyltin compound in the presence of A solvent such as 1-methyl-2-pyrrolidinone (NMP) is commonly used in the Stille reaction. Alternatively, Sonagashira reaction conditions are used, wherein the bromo bromo benzimidazole of formula 36 is mixed with a palladium catalyst, e.g., (PPh) in a solvent, e.g., THF.<sb>3</sb>)<sb>2</sb>PdCl<sb>2</sb> and CuI, and a terminal alkyne in the presence of a suitable base such as triethylamine. Other crosslinking reactions involving aryl halides are known in the art and include Heck reactions, Suzuki reactions, Negishi reactions, Buchwald- Hartwig cross-coupling reaction), Kumada reactions, and Hiyama cross-coupling reactions.

Alternatively, the bromo benzimidazole of Formula 36 is treated with an acid to form the isoquinolone core. The compound of formula 38 is reacted with triphenylphosphine under an atmosphere of carbon monoxide ((CO), and a base such as tributylamine or N,N-diisopropylethylamine, and optionally a suitable solvent such as N, A palladium catalyst such as Pd(PPh) in the presence of N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), tetrahydrofuran (THF) or dioxane<sb>3</sb>)<sb>4</sb>, PdCl<sb>2</sb>(Ph.<sb>3</sb>P)<sb>2</sb> or Pd(OAc)<sb>2</sb>Treatment with an amine in the presence of

<chr id="ix"><img file="KR20080098490A_D0096.tif" /></chr>

Scheme IX shows a strategy for synthesizing the amide of formula 40. The amide of Formula 40 can be prepared by reacting the carboxylic acid of Formula 9 with the amine of Formula 31. This reaction can be carried out with a coupling agent such as benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), 0-benzotriazol-1-yl-N,N,N ,N'-Tetramethyl-uronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate ( HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexyl-carbodiimide (DCC) and base (usually 3 equivalents) , for example, in the presence of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, etc. and optionally in the presence of 1-hydroxy-benzotriazole (HOBT). Alternatively, the carboxylic acid of formula 9 is first converted to the acid chloride by treatment with thionyl chloride or oxalyl chloride, followed by coupling with the amine of formula 31.

Using the synthetic methods described herein as well as those known in the art, the tyrosine kinase inhibitors described herein are obtained in good yield and purity. The compounds prepared by the methods described herein are purified by conventional methods known in the art, such as filtration, recrystallization, chromatography, distillation, and combinations thereof.

Any combination of the groups described above for various variables is contemplated herein. Substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art to provide those set forth herein, as well as compounds that are chemically stable and can be synthesized by techniques known in the art.

Pharmaceutical composition/formulation

The compounds described herein have a structure selected from Formula Ia, Formula Ib, Formula Ic, Formula II, Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IV, Formula V, and Formula VI. When reference is made to the compounds described herein, unless specifically stated otherwise, Formulas Ia, Ib, Ic, Formula II, Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IV, Formula V and Formula VI It is understood that it is meant to include compounds of

Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of the active compound into preparations which can be used pharmaceutically. Proper formulation depends on the route of administration chosen. Well-known techniques, carriers and excipients are suitable and can be used as understood in the art. For an overview of the pharmaceutical compositions described herein, see, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), which is incorporated herein by reference in its entirety. ); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &amp; Wilkins l999)].

Provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable diluent(s), excipient(s) or carrier(s). The compounds described herein may also be administered as pharmaceutical compositions in which the compounds described herein are admixed with other active ingredients as combination therapy. In some embodiments, the pharmaceutical composition may include other medical or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers. In addition, the pharmaceutical composition may also contain other therapeutically useful substances.

In certain embodiments, the composition also comprises acids, including, but not limited to, acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as, but not limited to, sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylammoniummethane; and buffers such as, but not limited to, one or more pH adjusting agents or buffers including, but not limited to, citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

In other embodiments, the composition may also include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfate anions, suitable salts being sodium chloride, potassium chloride, sodium thiosulfate. , sodium hydrogen sulfite and ammonium sulfate.

As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining one or more active ingredients, and includes both non-volatile and volatile combinations of the active ingredients. The term "fixed combination" means that the active ingredients, eg, a compound described herein and a co-agent, are all administered to a patient simultaneously in a single body or dosage form. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein and a co-agent, are administered to a patient simultaneously, concurrently, or sequentially as separate entities without specific intervening time limits, such administration being administered to the patient's body. to provide effective levels of the two compounds. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical ingredients such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having the disease, disorder or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potential of the compound used, and other factors. The compounds may be used alone or as a component of a mixture in combination with one or more therapeutic agents.

The pharmaceutical formulations described herein may be administered to a patient by a number of routes of administration, including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. may be administered. The pharmaceutical formulations described herein include aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, rapid melt formulations, tablets, capsules, pills , delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Pharmaceutical compositions comprising the compounds described herein may be prepared in a conventional manner, for example, by way of example only, by conventional mixing, dissolving, granulating, dragee preparation, micronizing, emulsifying, encapsulating, encapsulating or compression processes. can

The pharmaceutical composition will comprise, as an active ingredient, one or more of the compounds described herein in free acid or free base form, or in pharmaceutically acceptable salt form. The methods and pharmaceutical compositions described herein also include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same form of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein. Additionally, the compounds described herein may exist in unsolvated form or in solvated form with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be described herein.

specific pharmaceutical terms

As used herein, the terms "treat", "treating" or "treatment" refer to alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing further symptoms, alleviating or preventing the underlying metabolic cause of the symptoms. and inhibiting the disease or condition, e.g., arresting the development of the disease or condition, alleviating the disease or condition, inducing regression of the disease or condition, alleviating the condition causing the disease or condition, or reducing the disease or condition. prophylactically and/or therapeutically arresting the symptoms of the condition.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means not having a lasting adverse effect on the general health of the subject being treated.

As used herein, the term "selective inhibitor compound" refers to a compound that selectively inhibits a specific function/activity of one or more target proteins.

As used herein, the term "selectively inhibits" refers to the ability of a selective inhibitor compound to inhibit a specific function/activity of a target protein (eg, phosphotransferase activity of a kinase) with a potential greater than that of a non-target protein. do. In certain embodiments, selectively inhibiting the IC<sb>50</sb>This means that the target protein activity is inhibited by using a selective inhibitor that is 10, 50, 100, 250, 500, 1000 or more times lower than that of the non-target protein activity.

As used herein, alleviating the symptoms of a particular disease, disorder or condition by administering a particular compound or pharmaceutical composition reduces the severity, slows the onset, slows the progression, is due to, or is due to, administration of the compound or composition. means shortening, whether persistent or temporary, of a continuous or temporary duration that may be associated with it.

The term "modulate," as used herein, is intended to alter the activity of a target, including by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target or prolonging the activity of the target. It means interacting directly or indirectly with the target.

As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, a modulator can increase or decrease a particular activity of a molecule relative to its activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that reduces the extent of one or more molecular activities. In certain embodiments, an inhibitor completely inhibits the activity of one or more molecules. In certain embodiments, a modulator is an activator that increases the activity of one or more molecules. In certain embodiments, the presence of a modulator induces an activity that does not occur in the absence of the modulator.

As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity.

IC as used herein<sb>50</sb>means the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal response, eg, inhibition of tyrosine kinase activity, eg, Btk activity, in an assay that measures this response.

EC as used herein<sb>50</sb>means a dose, concentration or amount of a particular test compound that induces a dose-dependent response at 50% of the maximal expression of a particular response induced, induced or potentiated by the particular test compound.

As used herein, the term "carrier" refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.

As used herein, the term "co-administration" and the like is meant to include administration of the selected therapeutic agent to a single patient and includes treatment regimens in which the agents are administered by the same or different routes of administration or at the same time or at different times.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the agent or compound being administered that alleviates to some extent one or more symptoms of the disease or condition being treated. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease or other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound described herein necessary to provide a clinically significant reduction in disease symptoms without undue side effects. An "effective amount" suitable for an individual case can be determined using techniques, such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound described herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without undue side effects. An "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of the compound being administered, the subject's age, weight, general condition, condition being treated, the severity of the condition being treated, and the judgment of the attending physician.

As used herein, the term "enhance" or "enhancing" means to increase or prolong the potency or duration of a desired effect. Thus, in the context of enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the effect of another therapeutic agent on a system, either in potency or duration. As used herein, "enhancing effective amount" means an amount suitable to enhance the effect of another therapeutic agent in the desired system.

The terms "kit" and "article of manufacture" are used as synonyms.

A "metabolite" of a compound described herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to an overview of the processes by which a particular substance is changed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes such as oxidation reactions. do. Thus, enzymes can produce specific conformational changes to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, whereas uridine diphosphate glucuronyl transferase activates the aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryls of the activated glucuronic acid molecule. Catalyzes the transfer to the drill group. Additional information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds described herein can be identified by administering the compound to the host and analyzing a tissue sample from the host, or by culturing the compound in vitro into hepatic stellate cells and assaying the resulting compound. Both methods are well known in the art. In some embodiments, the compound is metabolized to a pharmacologically active metabolite.

"Prodrug" means an agent that is converted in vivo to the parent drug. In some situations, prodrugs are often useful because they are easier to administer than the parent drug. They may be bioavailable, for example by oral administration, but the parent drug is not. The prodrug may also have improved solubility in the pharmaceutical composition compared to the parent drug. An example of a prodrug can be, without limitation, a compound described herein, which is administered as an ester ("prodrug") that facilitates permeation across cell membranes where water solubility is detrimental to mobility, but once the cell has advantageous water solubility. Internally, it is metabolically hydrolyzed to the active carboxylic acid. An example of a further prodrug may be a short peptide (polyamino acid) linked to an acid group that is metabolized such that the peptide represents an acid residue. In certain embodiments, upon administration in vivo, the prodrug is chemically converted to a more physiologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized to a biologically, pharmaceutically or therapeutically active form of the compound by one or more steps or processes. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound is regenerated upon administration in vivo. Prodrugs can be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the flavor of the drug, or alter other properties or properties of the drug. With knowledge of pharmacodynamic processes and in vivo drug metabolism, those skilled in the art can devise prodrugs of the compounds once a pharmaceutically active compound is known. See Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401].

"Pharmaceutically acceptable," as used herein, does not abrogate the biological activity or properties of the compound, and does not abrogate a relatively non-toxic substance, such as a carrier or diluent, i.e., a composition that does not produce an undesirable biological effect or in which it is contained. It means a substance that can be administered to a subject without interacting in a deleterious manner with any of the ingredients.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that, upon administration to an organism, does not cause significant irritation and does not abrogate the biological activity and properties of the compound. Pharmaceutically acceptable salts can be prepared by reacting a compound described herein with an acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malic acid Ronic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid , 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis- ( 3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. can be obtained by

Pharmaceutically acceptable salts are also prepared by reacting a compound described herein with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as calcium or Forms salts with magnesium salts, organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, etc. or by other methods known in the art.

"Anti-foaming agents" reduce foaming, which can lead to agglomeration of the aqueous dispersion during processing or bubbles in the finished film, or generally impair the processing process. Exemplary defoamers include silicone emulsions or sorbitan sesquoleate.

"Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability, if desired.

In certain embodiments, the compositions provided herein may also include one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances such as muffins and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

The formulations described herein may benefit from antioxidants, metal chelators, thiol containing compounds and other common stabilizers. Examples of such stabilizers include (a) about 0.5 to about 2% w/v glycerol, (b) about 0.1 to about 1% w/v methionine, (c) about 0.1 to about 2% w/v monothioglycerol, (d) about 1 to about 10 mM EDTA, (e) about 0.01 to about 2% w/v ascorbic acid, (f) 0.003 to about 0.02% w/v polysorbate 80, (g) 0.001 to about 0.05% w /v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (1) pentosan polysulfate and other heparinoids, (m) divalent cations, For example, magnesium and zinc; or (n) combinations thereof.

"Binders" impart cohesive properties and include, for example, alginic acid and salts thereof; Cellulose derivatives such as carboxymethylcellulose, methylcellulose (such as Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (such as Klucel®), ethylcellulose (eg, Ethocel®) and microcrystalline cellulose (eg, Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; Tragagant, dextrin, sugars such as sucrose (such as Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (such as Xylitab®) and lactose; natural or synthetic rubbers such as acacia, tragagant, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone such as Polyvidone® CL, coli Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate and the like.

"Bioavailability" means the proportion by weight of a compound described herein administered that is delivered to the general circulation of the animal or human being studied. Total exposure of drug (AUC) when administered intravenously<sb>(0-∞)</sb>) is generally defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which a compound described herein is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous infusion.

"Plasma concentration" means the concentration of a compound provided herein in the plasma component of the blood of a subject. It is understood that the plasma concentrations of the compounds provided herein can vary significantly from subject to subject, due to variability related to metabolism and/or possible interactions with other therapeutic agents. According to one embodiment described herein, the plasma concentration of a compound provided herein may vary from subject to subject. Likewise, the maximum plasma concentration (C<sb>max</sb>) or time to reach maximum plasma concentration (T<sb>max</sb>) or total area under the plasma concentration time curve (AUC)<sb>(0-∞)</sb>) may be different for each subject. Due to such variability, the amount required to constitute a "therapeutically effective amount" of a compound provided herein may vary from subject to subject.

A "carrier material" includes excipients commonly used in pharmaceuticals and should be selected based on compatibility with the compounds described herein and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier substances" include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, Sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dicalcium phosphate, cellulose and cellulose conjugates, sugar sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides , pregelatinous starch, and the like (Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &amp; Wilkins 1999)].

"Dispersant" and/or "viscosity modifier" includes substances that control the diffusion and homogeneity of a drug through a liquid medium or granulation method or compounding method. In some embodiments, these agents also promote the efficacy of the coating or erosion matrix. Exemplary diffusion promoters/dispersants include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; Commonly known as Plasdone®), and carbohydrate-based dispersants such as hydroxypropyl cellulose (such as HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose (such as HPMC KlOO) , HPMC K4M, HPMC K15M and HPMC KlOOM), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), amorphous Cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl with ethylene oxide and formaldehyde) )-phenolic polymers (also known as tyloxapol), poloxamers (such as Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), poloxamers ( Yes: Tetronic 908®, also known as Poloxamine 908®, is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine. BASF Corporation, Parsippany, NJ), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, for example polyethylene glycol, which may have a molecular weight of from about 300 to about 6000 or from about 3350 to about 4000 or from about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate Bate-80, sodium alginate, gums such as gum tragagant, gum acacia, guar gum, xanthan including xanthan gum, sugars, fiber such as sodium carboxymethylcellulose, methylcellulose , sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginate , chitosan and combinations thereof. Plasticizers such as cellulose or triethyl cellulose may also be used as dispersants. Dispersants are particularly useful in liposomal dispersions, where self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.

Combinations of one or more erosion promoters and one or more diffusion promoters may also be used in the present compositions.

The term "diluent" refers to a chemical compound used to dilute the desired compound prior to delivery. Diluents can also be used to stabilize compounds as they can provide a more stable environment. Salts (which can also adjust or maintain pH) dissolved in buffered solutions including, but not limited to, phosphate buffered saline are used as diluents in the art. In certain embodiments, the diluent increases the bulk of the composition to facilitate compression or to produce sufficient bulk for a homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluent, refined sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate; dextrose; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

The term "disintegrate" includes both dissolution and dispersion of the dosage form upon contact with gastrointestinal fluids. A "disintegrant or disintegrant" promotes the breakdown or disintegration of a substance. Examples of disintegrants are starches such as natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycol rate, such as Promogel® or Explotab®, cellulose, such as Wood products, methylcrystalline cellulose, such as Avicel®, Avicel PH10l, Avicel PH 102, Avicel PH 105, Elcema® PlOO, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch, For example, sodium starch glycolate, crosslinked polymers such as Crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum HV (magnesium aluminum silicate), rubbers such as For example, agar, guar gum, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactant, resin such as cation exchange resin, citrus pulp, sodium lauryl sulfate , sodium lauryl sulfate combined with starch, and the like.

"Drug absorption" or "absorption" typically refers to the process of drug transport from the site of administration to a blood vessel or site of action across the barrier, eg, from the gastrointestinal tract into the portal vein or lymphatic system.

An "enteric coating" is a substance that is substantially pure in the stomach but dissolves and releases the drug in the small intestine or colon. In general, the enteric coating contains a polymeric material that inhibits release in the low pH environment of the stomach but ionizes at a high pH, typically pH 6-7, sufficiently soluble in the small intestine or colon to release the active ingredient therein.

"Erosion promoter" includes substances that inhibit the erosion of certain substances in the gastrointestinal fluid. Erosion promoters are generally known to those skilled in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

"Fillers" are compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

"Flavoring agents" and/or "sweetening agents" useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, sagerum, butter scorch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cilamate, Dextrose, Eucalyptus, Eugenol, Fructose, Fruit Punch, Ginger, Glycyretinate, Licorice Syrup, Grape, Grapefruit, Honey, Isomalt, Lemon, Lime, Lemon Cream, Monoammonium Glycyrrhizinate ( MagnaSweet®), Malthol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Prosweet® Powder, raspberry, sarsa root, rum, saccharin, saprole, sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Talin, Silitol, Sucralose, Sorbitol, Swiss Cream, Tagatose , tangerine, thaumatin, tuti fruity, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof.

"Lubricants" and "glidants" are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®). , higher fatty acids and their alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate ate, sodium acetate, sodium chloride, leucine, polyethylene glycol (eg PEG-4000) or methoxypolyethylene glycol such as Carbowax, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol , magnesium or sodium lauryl sulfate, colloidal silica such as Syloid, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

"Measurable serum concentration" or "measurable plasma concentration" describes the blood serum or blood plasma concentration, usually measured in mg, μg or ng of therapeutic agent per mL, dl, or liter of blood plasma absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or μg/ml.

"Plasticizers" are compounds used to soften microencapsulation materials or film coatings, making them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. . In some embodiments, the plasticizer may also act as a dispersing or wetting agent.

A "solubilizer" refers to a compound such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrole Don, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol and dimethyl isosorbide, and the like.

"Stabilizers" include compounds such as antioxidants, buffers, acids, preservatives, and the like.

A "suspending agent" is a compound such as polyvinylpyrrolidone such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, such as polyethylene glycol having a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, sodium carboxymethylcellulose, methyl Cellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragagant, gum acacia, guar gum, xanthan Xanthan, including rubber, sugar, cellulose, such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, poly ethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

"Surfactant" refers to a compound such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate , polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (manufactured by BASF) and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers such as octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to improve physical stability or for other purposes.

"Viscosity enhancers" include, for example, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer , polyvinyl alcohol, alginates, acacia, chitosan and combinations thereof.

"Wetting agent" is a compound, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

dosage form

The compositions described herein are formulated for administration to a subject via conventional means including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. can be pissed off As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

In addition, the pharmaceutical compositions described herein comprising the compounds provided herein may be formulated as aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, etc., solid oral dosage forms, aerosols, modulators for oral ingestion by the patient to be treated. Release formulations, rapid melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate release and controlled release It may be formulated in any suitable dosage form including, but not limited to, formulations.

Pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, optionally adding suitable adjuvants, and then processing the granule mixture to form tablets or dragee cores. It can be obtained by obtaining. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragagant, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, for example polyvinylpyrrolidone ((PVP or povidone) or calcium phosphate. Optionally, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, Agar or alginic acid or a salt thereof, for example sodium alginate, may be added.

Dragee cores have a suitable coating. For this purpose, it is possible to use concentrated sugar solutions, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. can do. It may be added to tablets or dragee coatings to identify dyes or pigments or to characterize different combinations of active compound dosages.

Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. One-touch fitting capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. . In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, for example, fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration should be present in dosages suitable for such administration.

In some embodiments, the solid dosage forms described herein are tablets (including suspension tablets, rapid melt tablets, bite-disintegrating tablets, rapid disintegrating tablets, effervescent tablets, or caplets), pills, powders (sterile packaging) powders, dispersible powders or effervescent powders), capsules (including soft or hard capsules, e.g., animal-derived gelatin or plant-derived HPMC or "spread capsules"), solid dispersions, solid solutions, bioerodible dosage forms, conditioning It may be in the form of a release formulation, a pulsatile release dosage form, a multiparticulate dosage form, pellets, granules or an aerosol. In other embodiments, the pharmaceutical formulation is in powder form. In other embodiments, the pharmaceutical formulation is in tablet form, including, but not limited to, rapid melt tablets. Additionally, the pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in two, three or four capsules or tablets.

In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by admixing particles of a compound provided herein with one or more pharmaceutical excipients to form a bulky blend composition. When these bulky blend compositions are referred to as homogeneous, the compound particles provided herein are uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. means there is The individual unit doses may also include a film coating, which disintegrates upon oral ingestion or contact with a diluent. These formulations can be prepared by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) ) wet granulation or (6) dissolution (Lachman et al., The Theory and Practice of Industrial Pharmacy (1986)). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (eg, wurster coating), tangential coating, top spraying, tableting, extrusion, etc. do.

The pharmaceutical solid dosage forms described herein can be formulated with a compound provided herein and one or more pharmaceutically acceptable additives, for example, compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, interfacial agents. active agents, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or combinations of one or more thereof. In other aspects, a film coating is provided around the formulation of a compound provided herein using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the compound particles provided herein are coated. In other embodiments, some or all of the compound particles provided herein are microencapsulated. In other embodiments, the particles of a compound provided herein are unencapsulated and uncoated.

Suitable carriers for use in the solid dosage forms described herein are acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, Tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystals sex cellulose, lactose, mannitol, and the like.

Fillers suitable for use in the solid dosage forms described herein include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, preparative. Gelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

In order to release the compounds described herein from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, particularly when the dosage form is compressed with a binder. Disintegrants help to swell or rupture the dosage form matrix by capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein are natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amisel, or sodium starch glycolate, such as For example, Promogel or Explotab, cellulose, such as Wood products, methylcrystalline cellulose, such as Avicel, Avicel PH10l, Avicel PH102, Avicel PH105, Elsema PlOO, Amcocell, Vivacel, Ming Thia, and solka-floc, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or alginic acid salts such as sodium alginate, clays such as Veegum HV (magnesium aluminum silicate), rubbers such as agar, guar, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactant, resin, such as cationic exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations, in the case of powder filler capsule formulations, they aid in the formation of plugs that can be filled into soft or hard shell capsules, and in the case of tablet formulations, they remain intact after the tablet is compressed. and helps to ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropylmethylcellulose (eg, Hydromellose USP Pharmacote-603). , hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (such as Klucel®), ethylcellulose (such as Ethocel®) Ethocel®)), and microcrystalline cellulose (such as Avicel), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone , povidone, starch, pregelatinized starch, tragagant, dextrin, sugar, e.g. sucrose (e.g. dipac), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. xylitab), lactose, natural or synthetic rubbers such as acacia, tragagant, gum gatti, isapol blood mucus, starch, polyvinylpyrrolidone (eg polyvidone CL, kollidon CL, polyplas) Don XL-10 and Povidone K-12), larch arabinogalactan, veegum, polyethylene glycol, wax, sodium alginate, and the like.

Generally, binder levels of 20 to 70% are used in powder filled gelatin capsule formulations. The level of binder use in tablet formulations varies with direct compression, wet granulation, roller compaction or the use of other excipients, such as fillers that can themselves act as gentle binders. Formulators skilled in the art can determine binder levels for formulations, and binder usage levels of 70% or less in tablet formulations are typical.

Lubricants or glidants suitable for use in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, Zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearrowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol, for example For example, Carbowax, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, etc. including, but not limited to.

Diluents suitable for use in the solid dosage forms described herein include sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrate and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins and the like.

The term "non-aqueous diluent" refers to mixtures commonly used in pharmaceutical formulations, such as calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose and microcellulose (e.g., having a density of about 0.45 g/cm<sp>3</sp>phosphorus microcellulose such as Avicel, powdered cellulose) and talc.

Wetting agents suitable for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan mono Oleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

Surfactants suitable for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, a copolymer of ethylene oxide and propylene oxide, such as Pluronic (manufactured by BASF) and the like.

Suspending agents suitable for use in the solid dosage forms described herein are polyvinylpyrrolidone, for example polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone. Don K30, polyethylene glycol, for example, a polyethylene glycol, vinyl pyrrolidone/vinyl acetate copolymer (S630), which may have a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, Sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragaganth and gum acacia, guar gum, xanthan gum xanthan, sugars, fiber, including sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxy Sylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

Antioxidants suitable for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

It should be understood that there is significant overlap between the additives used in the solid dosage forms described herein. Accordingly, the excipients listed above should be regarded only as illustrative of the types of excipients that may be included in the solid dosage form of the present invention, and not as limiting. The amount of such additives can be readily determined by one of ordinary skill in the art depending on the particular properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers may be added at about 0.01 to about 50 weight percent (w/w) of the coating composition. Plasticizers include diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate and pima including, but not limited to, freedom.

Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, the compressed tablet comprises a film surrounding the final compressed tablet. In some embodiments, the film coating provides delayed release of a compound described herein from the formulation. In other embodiments, film coatings aid patient compliance (eg, Opadry® coatings or sugar coatings). The film coating comprising Opadry typically ranges from about 1 to about 3% by weight of the tablet. In other embodiments, compressed tablets include one or more excipients.

Capsules can be made, for example, by placing a bulk blend of a formulation of a compound as described above inside the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in standard gelatin capsules or non-gelatin capsules, eg, capsules comprising HPMC. In other embodiments, the dosage form is placed in a sprinkling capsule, wherein the capsule may be fully swollen, or the capsule may be opened and the contents sprung onto food immediately prior to eating. In some embodiments, the therapeutic dose is dispensed in multiple (eg, 2, 3, or 4) capsules. In some embodiments, the entire dosage of the formulation is delivered in capsule form.

In various embodiments, particles of a compound described herein and one or more excipients are dry blended and formed into a mass, e.g., substantially less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes after oral administration. , is compressed into tablets having a hardness sufficient to provide a pharmaceutical composition that disintegrates in less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes to release the dosage form into the gastrointestinal fluid.

In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present as microencapsulation materials. Exemplary materials include, for example, pH modifiers, erosion promoters, defoamers, antioxidants, flavoring agents and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and diluents.

Materials useful for microencapsulation described herein include materials that are compatible with the compounds described herein, which sufficiently separate the compounds described herein from other incompatible excipients. Materials that are compatible with the compounds described herein are those that delay the in vivo release of the compounds described herein.

Exemplary microencapsulation materials useful for delaying release of formulations comprising the compounds described herein are hydroxypropyl cellulose ethers (HPCs) such as Klucel® or Nisso HPC, low-substituted Hydroxypropyl cellulose ether (L-HPC), hydroxypropyl methyl cellulose ether (HPMC), e.g. Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel ( Methocel®)-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as Methocel-A, hydroxypropylmethylcellulose acetate stearate aquat (Aqoat) (HF-LS, HF-LG, HF-MS) and metholose, ethylcellulose (EC) and mixtures thereof, e.g. E461, Ethocel, Aqualon®-EC, Surelis (Surelease®), polyvinyl alcohol (PVA), For example, Opadry AMB, hydroxyethylcellulose such as Natrosol®, carboxymethylcellulose, salts of carboxymethylcellulose (CMC) such as aqualon-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starches, acrylic polymers and acrylic polymers with cellulose. mixtures of ethers, for example Eudragit<sp>R</sp>) EPO, Eudragit L30D-55, Eudragit FS 3OD, Eudragit L100-55, Eudragit L100, Eudragit SlOO, Eudragit RD100, Eudragit ElOO, Eudragit L12.5, Eudragit S12.5, Eudragit NE30D and Eudragit NE 4OD, cellulose acetate phthalate, sephifilm such as HPMC and mixtures of stearic acid, cyclodextrins and mixtures of these substances. does not

In other embodiments, plasticizers such as polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid and triacetin are incorporated into the microencapsulation material. is introduced In other embodiments, microencapsulation materials useful for delaying release of a pharmaceutical composition are described in the USP or National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is methocel.

The microencapsulated compounds described herein can be formulated by methods known to those of skill in the art. These known methods are, for example, spray drying processes, spinning disk-solvent processes, hot melt processes, spray cooling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solids. -polymerization at the gas interface, pressure extrusion or spray solvent extrusion baths. In addition to these, a number of chemical techniques such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, phosphorus-liquid drying and desolvation in liquid medium Painters may also be used. In addition, other methods such as roller compaction, extrusion/spheronization, coacervation or nanoparticle coating may also be used.

In one embodiment, the particles of a compound described herein are microencapsulated prior to being formulated in one of the forms described above. In other embodiments, some or most of the particles are coated prior to further formulation with standard coating procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

In other embodiments, solid dosage forms of the compounds described herein are plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers may be added at about 0.01 to about 50 weight percent (w/w) of the coating composition. Plasticizers include diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate and pima including, but not limited to, freedom.

In other embodiments, powders comprising formulations with compounds described herein may be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders can be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include suspending and/or wetting agents. This bulk blend is uniformly dispensed in single-dose packaging or multi-dose packaging units.

In other embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse medicaments in water for oral administration. Effervescent salts are granules or coarse powders containing the pharmaceutical preparation in anhydrous mixtures, usually consisting of sodium bicarbonate, citric acid and/or tartaric acid. When a salt of the present invention is added to water, the acid and base react to liberate carbon dioxide gas, thereby inducing "boilability". Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate with sodium carbonate, citric acid and/or tartaric acid. An acid-base combination that liberates carbon dioxide can be used in place of the combination of sodium bicarbonate with citric and tartaric acids, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein comprising the compounds described herein are solid dispersions. Methods for preparing such solid dispersions are known in the art and include, for example, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269 and U.S. Published Applications, each specifically incorporated by reference. 2004/0013734, but is not limited thereto. In other embodiments, the formulations described herein are solid solutions. Solid solutions incorporate substances along with the active agent and other excipients to dissolve the drug by heating the mixture, then cooling the resulting composition to provide a solid blend that can be further formulated, added directly to capsules, or compressed into tablets. do. Methods for preparing such solid solutions are known in the art and include, but are not limited to, for example, US Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is specifically incorporated by reference.

Pharmaceutical solid oral dosage forms comprising the compounds described herein can be further formulated to provide controlled release of the compounds described herein. Controlled release means releasing a compound described herein from a dosage form into which it is introduced according to a desired profile for an extended period of time. Controlled release profiles include, for example, sustained release, extended release, pulsatile release and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of the agent to a subject for an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of the agent for an extended period of time, resulting in a longer duration of pharmacological response with minimal side effects compared to conventional rapid release dosage forms. This longer response period provides a number of inherent advantages not achieved with the corresponding short acting immediate release formulations.

In some embodiments, the solid dosage forms described herein are formulated as an enteric-coated delayed-release oral dosage form, i.e., an oral dosage form of a pharmaceutical composition described herein that uses an enteric coating to effect release in the small intestine of the gastrointestinal tract. can be pissed off Enteric-coated dosage forms may be compressed, molded or extruded tablets/moulds (coated or uncoated) containing granules, powders, pellets, beads or particles of the active ingredient and/or other composition ingredients, either coated or uncoated per se. can The enteric-coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of a solid carrier or composition itself coated or uncoated.

As used herein, the term "delayed release" means delivered such that release is achieved at some generally expected location in the intestinal tract more distant than would be achieved in the absence of delayed release alterations. In some embodiments, the delayed release method is coating. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH above about 5. It is expected that any anionic polymer exhibiting a pH dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. In some embodiments, polymers for use in the present invention are anionic carboxylic acid polymers. In other embodiments, polymers and compatible mixtures thereof, and some of these properties, include, but are not limited to:

Shellac, also called purified lac, is a purified product obtained from the dendritic secretions of worms. This coating is soluble in media above pH 7.

acrylic polymer. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary with the degree and type of substitution. Examples of suitable acrylic polymers are methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE from Rohm Pharma are usable when solubilized in organic solvents, aqueous dispersions or dry powders. The Eudragit families RL, NE and RS are insoluble in the gastrointestinal tract, but are permeable and are used primarily for colonic targeting. Eudragit series E dissolves in the stomach. The Eudragit series L, L-30D and S are insoluble in the stomach and soluble in the intestine.

Cellulose derivatives. Examples of suitable cellulose derivatives include ethyl cellulose; It is a reaction mixture of partial acetate esters of cellulose and phthalic anhydride. Performance may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves above pH 6. Aquateric (FMC) is an aqueous-based system and is a spray dried CAP pseudolatex with particles less than 1 μm. Other ingredients in Aquateric include pluronic, tween and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS) and hydroxypropylmethylcellulose acetate succinate (eg, AQOAT manufactured by Shin Etsu). Performance may vary depending on the degree and type of substitution. For example, HPMCP, eg HP-50, HP-55, HP-55S, HP-55F grades are suitable. Performance may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at high pH. ) is included. These polymers are provided as granules or as fine powders for aqueous dispersions.

Poly vinyl acetate phthalate (PVAP). PVAP dissolves above pH 5, which is much less permeable to water vapor and gastric juices.

In some embodiments, the coating may contain generally plasticizers and possible other coating excipients well known in the art, such as colorants, talc and/or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflex A2), carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrates, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxyl acrylic polymers generally contain from 10 to 24% by weight of plasticizers, in particular dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Coatings are applied using conventional coating techniques, such as spraying or pan coating. The coating thickness should be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

Colorants, detackifiers, surfactants, defoamers, lubricants (such as carnauba wax or PEG) may be added to the coating in addition to plasticizers to solubilize or disperse the coating material and improve coating performance and coated article.

In other embodiments, formulations described herein comprising a compound described herein are delivered using a pulsatile dosage form. The pulsatile dosage form may provide one or more immediate release pulses at a specific location or at a predetermined time after a controlled lag time. A pulsatile dosage form comprising a formulation described herein comprising a compound described herein can be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in US Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which is specifically incorporated by reference. Other pulsatile release dosage forms suitable for use in the present formulations are described, for example, in US Pat. 5,837,284; In one embodiment, the controlled release dosage form is a pulsatile release solid oral dosage form comprising two or more groups of particles (ie, multiparticulates) each containing a formulation described herein. The first group of particles provides for substantially immediate administration of the compound described herein upon digestion by the mammal. The first group of particles may be uncoated or may include a coating and/or sealant. A second group of particles comprises coated particles, which in admixture with one or more binders, from about 2 to about 75%, preferably from about 2.5 to about 70%, of the total dose of a compound described herein in the formulation, more preferably from about 40 to about 70%. The coating comprises a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of about 2 to about 7 hours after digestion before releasing the second dose. Suitable coatings include one or more differentially degradable coatings, such as, by way of example only , pH sensitive coatings (enteric coatings), such as acrylic resins, either alone or in combination with cellulose derivatives, such as ethylcellulose (eg : Eudragit EPO, Eudragit L30D-55, Eudragit FS 30D, Eudragit L100-55, Eudragit L1OO, Eudragit S1OO, Eudragit RD1OO, Eudragit E1OO, Eudragit L12 .5, Eudragit S 12.5, Eudragit NE30D and Eudragit NE 40D®), or a non-enteric coating having variable thickness to differentially release formulations comprising the compounds described herein.

Many other controlled release system forms are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include polymer-based systems such as polylactic and polyglycolic acids, polyanhydrides and polycaprolactones; porous matrix non-polymeric systems that are sterols such as cholesterol, lipids including cholesterol esters and fatty acids, or natural fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silastic system; peptide-based systems; wax coatings using conventional binders, bioerodible dosage forms, compressed tablets, and the like [Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et aL, Encyclopedia of Pharmaceutical Technology, 2<sp>nd</sp> Ed., pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175,014; each specifically incorporated by reference].

In some embodiments, a pharmaceutical formulation for oral administration to a subject is provided comprising particles of a compound described herein and one or more dispersing or suspending agents. The formulation may be a powder and/or granules for suspension, and upon mixing with water a substantially homogeneous suspension is obtained.

Liquid formulations for oral administration Dosage forms may be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups [Singh et al. , Encyclopedia of Pharmaceutical Technology, 2<sp>nd</sp> Ed., pp. 754-757 (2002)]. Liquid dosage forms may contain, in addition to the particles of a compound described herein, additives such as (a) a disintegrant; (b) dispersants; (c) wetting agents; (d) one or more preservatives, (e) viscosity enhancing agents, (f) one or more sweetening agents, and (g) one or more flavoring agents. In some embodiments, the aqueous dispersion may further comprise a crystallinity inhibitor.

The aqueous suspensions and dispersions described herein can remain homogeneous for at least 4 hours as described in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905). Homogeneity should be determined by a sampling method that is compatible with the measurement of homogeneity of the entire composition. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than one minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In other embodiments, no agitation is required to maintain a homogeneous aqueous dispersion.

Examples of disintegrants for use in aqueous suspensions and dispersions are starches such as natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amisel, or sodium starch glycolates such as Promogel or Explotab; Cellulose, e.g. Wood Product, methylcrystalline cellulose, e.g. Avicel, Avicel PHlOl, Avicel PH 102, Avicel PH 105, Elsema PlOO, Amcocel, Vivacel, Mingthia and Solka-Floc, methylcellulose , croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose; cross-linked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; cross-linked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as Veegum HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean, karaya, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; Surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate combined with starch; and the like.

In some embodiments, suitable dispersants for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween 60 or 80, PEG, polyvinylpyrrolidone (PVP; typically known as plasmon), and carbohydrate-based dispersants such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers such as HPC, HPC-SL and HPC-L, hydroxypropyl methylcellulose and hydroxypropyl methyl Cellulose ethers (such as HPMC K100, HPMC K4M, HPMC K15M and HPMC KlOOM), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, the secret Qualitative Cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone<sp>R</sp>), e.g. S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamer (e.g. : Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines such as Tetronic 908<sp>R</sp>, Poloxamine 908<sp>R</sp>Also known as , which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine, manufactured by BASF Corporation, Parsippany, NJ. In other embodiments, the dispersant is selected from the group not comprising one of the following agents: hydrophilic polymers; electrolyte; Tween 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers such as HPC, HPC-SL and HPC-L; hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (eg, HPMC K100, HPMC K4M, HPMC K15M, HPMC K10OM and Pharmacoat USP 2910 from Shin-S); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers such as Pluronic F68®, F88® and F108®; It is a block copolymer of ethylene oxide and propylene oxide); and poloxamines such as Tetronic 908<sp>R</sp>, Poloxamine 908<sp>R</sp>Also known as ).

Suitable wetting agents for the aqueous suspensions and dispersions described herein are known in the art and include cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters such as commercially available Tween, such as Tween 20 and Tween. 80 (manufactured by ICI Specialty Chemicals), and polyethylene glycols such as Carbowax 3350® and 1450®, and Carbopol 934® (manufactured by Union Carbide)) , oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium la uryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, porfotidylcholine, and the like.

Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (such as methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid, such as, butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. As used herein, a preservative is incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for aqueous suspensions or dispersions described herein include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, plasmon S-630, carbomer, polyvinyl alcohol, nate, acacia, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent depends on the agent selected and the desired viscosity.

Examples of sweetening agents suitable for use in aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarian cream, berry, sagerum, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cilamate, dextrose, Eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizinate, licorice (licorice) syrup, grapefruit, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (magnasweet) , maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, prosweet powder, raspberry, sarsauri, rum, saccharin, Saffrol, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, taumartin, tuti fruity, vanilla, Walnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring ingredients, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon - lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof. In one embodiment, the aqueous liquid dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.001 to about 1.0 volume percent of the aqueous dispersion. In another aspect, the aqueous liquid dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.005 to about 0.5% by volume of the aqueous dispersion. In another aspect, the aqueous liquid dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.01 to about 1.0 volume percent of the aqueous dispersion.

Liquid formulations may contain, in addition to the additives listed above, inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers. Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, Fatty acids of cholesterol esters, taurocholic acid, phosphotidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, sorbitan esters or mixtures of these substances.

In some embodiments, the pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are generally incompatible dispersions of one phase in the form of droplets. Generally, emulsions are produced by vigorous mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously emulsions when added to excess water without any external mechanical dispersion or agitation. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. In addition, water or an aqueous phase may be added immediately prior to administration, which ensures stability of the unstable or hydrophobic active ingredient. Thus, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can improve the bioavailability of hydrophobic active ingredients. Methods of preparing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

There is an overlap between the additives listed above for use in the aqueous dispersions or suspensions described herein, as certain additives are often classified differently by different practitioners in the art or are commonly used for several different functions. will be understood Accordingly, the additives listed above should only be considered as examples of the types of additives that may be included in the formulations described herein and should not be considered limiting. The amount of such additives can be readily determined by one of ordinary skill in the art depending on the particular properties desired.

nasal formulation

Intranasal formulations are known in the art and are described, for example, in US Pat. Nos. 4,476,116, 5,116,817, and 6,391,452, each of which is specifically incorporated by reference. Formulations comprising the compounds described herein, prepared according to techniques well known in the art and other techniques, may contain benzyl alcohol or other suitable preservatives, fluorocarbons and/or other solubilizing or dispersing agents known in the art. is prepared as a solution in saline using [Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995)]. Preferably, these compositions and formulations are prepared from suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to the skilled person in the formulation of intranasal dosage forms, some of which can be found in the standard reference in the art (REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005). The choice of a suitable carrier depends to a large extent on the precise nature of the desired intranasal dosage form, for example, a solution, suspension, ointment or gel. Non-dosage forms generally contain a large amount of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling or buffering agents and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with the nasal secretions.

For administration by inhalation, the compounds described herein may be in the form of an aerosol, mist or powder. The pharmaceutical compositions described herein may be presented in an aerosol spray presentation form from a press pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. is conveniently delivered to In the case of a compressed aerosol, the dosage unit may be measured by providing a valve to deliver a metered amount. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated for use in an inhaler or insufflator containing, by way of example only, a powder mixture of a compound described herein and a suitable powder base such as lactose or starch.

oral dosage form

Buccal formulations comprising the compounds described herein can be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, US Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is specifically incorporated by reference. In addition, the oral dosage forms described herein may further comprise a bioerodible (hydrolyzable) polymeric carrier that also serves to adhere the dosage form to the oral mucosa. Oral dosage forms are prepared to erode gradually over a period of time, and the compounds described herein deliver essentially universally. As will be understood by those skilled in the art, oral drug delivery has disadvantages experienced with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and/or first passage in the liver. Avoid inactivation. With respect to bioerodible (hydrolysable) polymeric carriers, substantially any of the foregoing carriers may be used, provided that the desired drug release profile is not compromised, the carriers being present in the compounds described herein and in the oral dosage unit. It will be appreciated that other ingredients may be compatible. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the wet surface of the oral mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and noses, such as those known as "carbomers" (Carbopol, obtainable from B.F. Goodrich, is one such polymer). Other ingredients that may be incorporated into the oral dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. Compositions for oral or sublingual administration may take the form of tablets, lozenges or gels formulated in a conventional manner.

transdermal formulation

The transdermal formulations described herein can be administered using a variety of devices described in the art. For example, such devices are described in US Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, and 3,598,122, 3,921,636, each of which is specifically incorporated herein by reference in its entirety. No. 3,972,995, No. 3,993,072, No. 3,993,073, No. 3,996,934, No. 4,031,894, No. 4,060,084, No. 4,069,307 No. , 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, a transdermal formulation described herein comprises three or more components: (1) a formulation of a compound described herein; (2) penetration enhancers; and (3) aqueous adjuvants. In addition, transdermal formulations may include, but are not limited to, additional ingredients such as, but not limited to, gelling agents, cream and ointment bases, and the like. In some embodiments, the transdermal formulation may further include a woven or non-woven backing material that enhances absorption and inhibits removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can remain saturated or supersaturated to promote diffusion into the skin.

Formulations suitable for transdermal administration of the compounds described herein may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and/or dispersed in polymers or adhesives. Such patches may be formulated for continuous, pulsatile or on-demand delivery of pharmaceutical agents. Transdermal delivery of additional compounds described herein can be accomplished by iontophoretic patches and the like. Additionally, transdermal patches may be capable of controlled delivery of the compounds described herein. The rate of absorption can be slowed by using rate controlling membranes or by entrapment of the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers may include absorbable pharmaceutically acceptable solvents to aid passage through the skin. For example, transdermal devices include a retrograde source, a reservoir containing the compound optionally with a carrier, optionally a rate controlling barrier for delivering the compound to the skin of a host at a controlled, predetermined rate for an extended period of time, and anchoring the device to the skin. It is in the form of a bandage including means for

Injectable Formulation

Formulations comprising a compound described herein, suitable for intramuscular, subcutaneous or intravenous injection, include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions for reconstitution. Sex powder may be included. Suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (eg, olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying and dispersing agents. Inhibition of microbial growth can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

For intravenous injection, the compounds described herein may be formulated in an aqueous solution, e.g., a physiologically compatible buffer, e.g., Hank's solution, Ringer's solution, or physiological saline buffer. can For transmucosal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

Parenteral injection solutions may include bulk injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multiple dosage containers with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents, for example, suspending, stabilizing and/or dispersing agents. can do. Pharmaceutical formulations suitable for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active compounds may be prepared as suitable oleaginous injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizing agents or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

other formulations

In certain embodiments, delivery systems for pharmaceutical compounds can be used, such as liposomes and emulsions. In certain embodiments, the compositions provided herein can contain, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium It may also include a mucoadhesive polymer selected from alginates and dextran.

In some embodiments, the compounds described herein may be administered topically and formulated into various topically administrable compositions, for example, solutions, suspensions, lotions, gels, pastes, medicated sticks, perfumes, creams or ointments. . Such pharmaceutical compounds may contain solubilizing agents, stabilizing agents, tonicity enhancing agents, buffering agents and preservatives.

The compounds described herein can also be used in rectal compositions containing conventional suppository bases, such as cocoa butter or other glycerides, as well as synthetic polymers, such as polyvinylpyrrolidone, PEG, and the like, such as enemas, for example. , rectal gel, rectal foam, rectal aerosol, suppository, jelly suppository or retention enema. In the suppository form of the composition, a mixture of fatty acid glycerides optionally combined with a low melting wax such as cocoa butter is first melted.

Method of administration and treatment regimen

The compounds described herein can be used in the manufacture of a medicament for treating a disease or condition that may be beneficial at least in part by inhibiting tyrosine kinase activity, eg, Btk activity, or by inhibiting Btk activity. In addition, methods of treating a disease or condition described herein in a subject in need of such treatment include one or more compounds described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide; and administering to the subject a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate.

Compositions containing the compound(s) described herein may be administered for prophylactic/therapeutic treatment. In therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to treat or at least partially inhibit the symptoms of the disease or condition. Amounts suitable for such use depend on the severity and course of the disease or condition, previous treatments, the patient's health, weight, response to the drug, and the judgment of the attending physician. It is well contemplated for determining such therapeutically effective amounts by routine experimentation in the art (including, but not limited to, dose escalation clinical trials).

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In such use, the exact amount also depends on the patient's state of health, weight, and the like. It is well contemplated to determine such a prophylactically effective amount by routine experimentation in the art (eg, a dose escalation clinical trial). When used in a patient, the amount effective for such use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status, response to the drug, and the judgment of the attending physician.

If the patient's condition does not improve, the compound is administered chronically for an extended period of time, including throughout the patient's life, in the judgment of the physician, i.e., to alleviate, otherwise suppress or limit the symptoms of the patient's disease or condition. can be administered as

When the patient's condition improves, at the physician's discretion, the compound may be administered continuously, or the amount of the administered drug may be temporarily reduced or temporarily stopped for a specific time (i.e., a "drug holiday") ). The drug holiday period is, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days. , 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. Dosage reductions during drug holidays can be, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% , 75%, 80%, 85%, 90%, 95% or 100%, including 10 to 100%.

Once the patient's condition improves, a sustained dose is administered, if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced as a function of symptoms to a level at which the ameliorated disease, disorder or condition is maintained. However, patients may require intermittent treatment on a long-term basis upon relapse of any symptoms.

The amount of a given agent corresponding to this amount will depend on factors such as, for example, the particular compound, disease or condition and its severity, the identity (eg body weight) of the subject or host in need of treatment, but nevertheless. Notwithstanding, it can be routinely determined in a manner known in the art depending on, for example, the particular agent to be administered, the route of administration, the condition to be treated, and the particular circumstances surrounding the case involving the subject or host to be treated. However, in general, dosages used for adult human treatment are usually in the range from 0.02 to 5000 mg/day, preferably from 1 to 1500 mg/day. The desired dosage will conveniently be presented as a single dosage or in divided dosages simultaneously (or over a short period of time) or at appropriate intervals, for example as sub-doses twice, three times, four or more times daily. can

The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise doses. In unit dosage form, the formulation is divided into unit doses containing suitable amounts of one or more compounds. A unit dose may be in the form of a package containing individual quantities of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is customary to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form or multi-dose containers including, but not limited to, ampoules with an added preservative.

A suitable daily dose for the compounds described herein is about 0.01 to 2.5 mg/kg body weight. For large mammals, including but not limited to humans, the indicated daily dose is a drug conveniently administered in divided doses or in extended release form, including, but not limited to, up to 4 times a day. 0.5 to about 300 mg. Unit dosage forms suitable for oral administration contain from about 1 to 200 mg of active ingredient. The above ranges are exemplary only, as the number of variables with respect to individual treatment regimens is large and significant deviations from these recommended values are common. Such dosages may vary depending on a number of variables including, but not limited to, the activity of the compound employed, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the practitioner. have.

Toxicity and therapeutic efficacy of this therapeutic regimen are LD<sb>50</sb>(dose that is lethal to 50% of the population) and ED<sb>50</sb>(dose therapeutically effective in 50% of a population) can be measured by standard pharmaceutical procedures in cell culture or laboratory animals, including but not limited to. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is LD<sb>50</sb> and ED<sb>50</sb>It can be expressed as the ratio of Compounds exhibiting high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of doses for use in humans. Doses of these compounds are preferably administered with minimal toxicity.<sb>50</sb>within a range of circulating concentrations that include The dosage may vary within this range depending upon the dosage form employed and the route of administration employed.

combination therapy

The tyrosine inhibitor compositions described herein may also be used in conjunction with other well known therapeutic agents selected for their therapeutic value for the condition being treated. In general, in embodiments in which the compositions and combination therapies described herein are used, the other agents should be administered in the same pharmaceutical composition and, due to different physicochemical properties, should be administered by different routes. In some cases, it is sufficient within the knowledge of the skilled clinician to determine the mode of administration and suitability of administration in the same pharmaceutical composition. The initial administration is carried out according to established protocols known in the art, and then can be modified by a skilled clinician according to the observed effect, dose, mode of administration and time of administration.

In certain instances, it may be appropriate to administer one or more tyrosine kinase inhibitor compounds described herein in combination with other therapeutic agents. By way of example only, if one of the side effects experienced by a patient administered one of the tyrosine kinase inhibitor compounds described herein is nausea, it may be appropriate to administer an anti-nausea agent in conjunction with the initial therapeutic agent. Or, by way of example only, the therapeutic efficacy of one of the compounds described herein can be improved by administering an adjuvant (ie, the adjuvant may have a mammalian therapeutic benefit on its own, but when combined with other therapeutic agents, the overall therapeutic effect on the patient). benefits are improved) can be improved. Or, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein in combination with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be a mixture of the two therapeutic agents, or the patient may experience a synergistic benefit.

The particular choice of compound used will depend upon the attending physician's diagnosis and their judgment of the patient's condition and the appropriate treatment protocol. The compounds may be administered simultaneously (eg, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the patient, and the actual choice of compound employed. The determination of the order of administration, and the number of repeated administrations of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after assessment of the disease to be treated and the condition of the patient.

It is known to those skilled in the art that when drugs are used in therapeutic formulations, the therapeutically effective dose may vary. Methods for experimentally determining therapeutically effective amounts of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronome dosing to minimize toxic side effects, ie, providing more frequent and lower dosages, has been extensively described in the literature. Combination therapy further includes periodic therapy that is started and stopped at various times to aid clinical management of the patient.

For the combination treatments described herein, the dosage of the co-administered compound will of course vary depending on the form of the co-drug used, the particular drug used, the disease or condition being treated, and the like. In addition, when coadministered with one or more biologically active agents, the compounds provided herein may be administered concurrently or sequentially with the biologically active agent(s). If administered sequentially, the attending physician will determine the appropriate sequence for administering the protein in conjunction with the biologically active agent(s).

In any case, multiple therapeutic agents, one of which is a compound of Formula Ia, Ib, IIa or IIb described herein, may be administered in any order or even simultaneously. When administered concurrently, the multiple therapeutic agents may be provided in a single integrated form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given in multiple doses. When not administered simultaneously, the timing between multiple doses may vary from 0 weeks to less than 4 weeks. Furthermore, the methods of combination, compositions and formulations are not limited to the use of only two agents, and the use of multiple therapeutic combinations is also contemplated.

It is understood that the dosing regimen for treating, preventing or ameliorating the condition(s) to be alleviated may be modified depending on a variety of factors. These factors include the age, weight, sex, diet and medical condition of the subject, as well as the disorder the patient suffers from. Accordingly, the dosing regimen used in practice can vary widely and thus may deviate from the dosing regimen presented herein.

The pharmaceutical agents that make up the combination therapy described herein may be in combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially with the therapeutic compound administered by a regimen called two-step administration. A two-step dosing regimen may be termed for sequential administration of the active agents or for separate administration of individual active agents. The time interval between the multiple administration steps may range from a few minutes to several hours depending on the nature of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Twenty-four hour cycle fluctuations in target molecule concentration can also determine the optimal dosing interval.

In addition, the compounds described herein may also be used in conjunction with procedures that may provide an additional or synergistic benefit to the patient. By way of example only, a patient expects to find a therapeutic and/or prophylactic benefit in the methods described herein, wherein the individual administers a pharmaceutical composition and/or combination of a compound described herein with other therapeutic agents to a particular patient. combined with genetic testing to determine whether the disease or condition of one is carriers of mutated genes known to be correlated.

The compounds and combination therapies described herein may be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compound may vary. Thus, for example, the compound may be used as a prophylactic agent and administered continuously to a subject having a propensity to develop the condition or disorder in order to inhibit the development of the disease or condition. The compounds and compositions may be administered during or as soon as possible after the onset of symptoms. Administration of the compound may be initiated within 48 hours of onset of symptoms, preferably within 48 hours of onset of symptoms, more preferably within 6 hours of onset of symptoms, and most preferably within 3 hours of onset of symptoms. Initial administration may be via any practical route, eg, intravenous infusion, bolus injection, infusion of 5 minutes to about 5 hours, pills, capsule transdermal patches, oral delivery, etc., or a combination thereof. The compound is preferably administered, as is customary, as soon as the onset of a disease or condition is detected or suspected, and for a period of time necessary for treatment of the disease, eg, from about 1 to about 3 months. The duration of treatment may vary from subject to subject, and length may be determined using known criteria. For example, the compound or formulation containing the compound may be administered for at least 2 weeks, preferably from about 1 month to about 5 years, more preferably from about 1 month to about 3 years.

kit/manufactured product

For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits may include a carrier, package, or container compartmentalized to contain one or more containers, e.g., vials, tubes, etc., each container(s) being one of the individual components used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes and test tubes. The container may be formed from a number of materials, such as glass or plastic.

The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art (see US Pat. Nos. 5,323,907, 5,052,558 and 5,033,252). Examples of pharmaceutical packaging materials include blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment; It is not limited thereto. The broad array of formulations of the compounds and compositions provided herein may benefit from inhibition of Bruton's tyrosine kinase activity or are contemplated as a variety of treatments for diseases, disorders or conditions in which Bruton's tyrosine kinase activity is a modulator or inducer for a symptom or cause. do.

For example, the container(s) may contain one or more compounds described herein, optionally in a composition or in combination with other agents described herein. The container(s) may optionally have a sterile access port (eg, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection bed). Such kits optionally include identification instructions or labels or instructions for their use in the methods described herein.

The kit will include one or more additional containers, each having one or more of a variety of materials (eg, reagents, and/or devices, optionally in concentrated form) desirable from the customary and user perspectives for the use of the compounds described herein. can Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials and/or tube labels listing the contents and/or package inserts comprising instructions for use and instructions for use. A set of instructions is also typically included.

The label is present on or associated with the container. A label may be present on a container when the letters, numbers or symbols forming the label are affixed, molded, and etched into the container itself; The label is associated with the container, for example, as a package insert, when present in a carrier that also holds the gut or container. A label can be used to indicate that the contents are to be used for a particular therapeutic use. The label may also indicate instructions for use of the contents, eg, as in the methods described herein.

In certain embodiments, pharmaceutical compositions that may contain one or more unit dosage forms containing a compound provided herein may be presented in a pack or dispensing device. The pack may contain, for example, metal or plastic foil, such as a blister pack. A pack or dispensing device may be achieved by means of a dosing guide. The pack or dispenser may also be accompanied by instructions in combination with the container in a form prescribed by a governmental agency controlling the manufacture, use, or sale of a medicament, which instructions may indicate that the agency has approved the form of a medicament for human or veterinary administration. reflects that Such instructions may be, for example, labels or approved product inserts approved by the US Food and Drug Administration for drug prescribing. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier may also be provided, placed in a suitable container, and labeled for treatment of the condition indicated.

<u>Exemplary Therapeutics for Use with Tyrosine Kinase Inhibitor Compounds</u>

Agents for the treatment of autoimmune, inflammatory or allergic diseases

If the subject is suffering from or at risk of suffering from an autoimmune disease, inflammatory disease, or allergic disease, the tyrosine kinase inhibitor compound may be used in any combination with one or more of the following therapeutic agents: Immunosuppressants (eg, tacrolimus, cyclosporine, rapamycin) , methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate or FTY720), glucocorticoids such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, flud Locortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g. salicylate, arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, oxicam, coxib or sulfonanilide) , Cox-2-specific inhibitors such as valdecoxib, celecoxib or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, orophine, sulfasalazine, hydroxychloroquinine, minocycline, TNF-α binding protein (eg inflixi) mab, etanercept or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-antagonists, theophylline or anticholinergics.

anticancer drugs

If the subject is suffering from or at risk of suffering from a B-cell proliferative disorder (eg, plasma cell myeloma), the subject may be treated with a tyrosine kinase inhibitor compound in combination with one or more other anticancer agents. In a preferred embodiment, the at least one anti-cancer agent is a pro-apoptotic agent. Examples of anticancer agents include, but are not limited to: gosipol, genasense, polyphenol E, chlorofuscin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis inducing ligand (TRAIL) , 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino - 17-demethoxygeldamycin (17-AAG), flavopyridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412 or PD184352, anticancer acting by enhancing and stabilizing microtubule formation Taxol, also referred to as the drug "paclitaxel," and taxol analogs, such as Taxotere. Compounds having a basic taxane backbone as a common structural feature have also been shown to have the ability to inhibit cells on G2-M phase due to stabilized microtubules, and may be useful in cancer treatment together with the compounds of the present invention.

Additional examples of anticancer agents for use with tyrosine kinase inhibitor compounds include inhibitors of mitogen activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

Other anticancer agents that may be used in combination with a tyrosine kinase inhibitor compound include adriamycin, dactinomycin, bleomycin, vinblastine, cisplastin, axibicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; amethantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperine; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnapide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropyrimine; laying plate; cactinomycin; calusterone; carasemide; carvetimer; carboplatin; carmustine; carubicin hydrochloride; caselecin; sedefimgol; chlorambucil; sirolemycin; cladribine; Crisnathol mesylate; cyclophosphamide; cytarabine; Dacarbazine; daurorubicin hydrochloride; decitabine; dexormaplatin; dejaguanine; dejaguanine mesylate; diagequoon; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; Duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enroplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etophrine; fadrozole hydrochloride; pajarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; posttriesin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imophosine; interleukin II (including recombinant interleukin II or rlL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; rometrexol sodium; lomustine; rosoxantrone hydrochloride; Masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; methotrexate sodium; methoprine; Meturedepa; mitindomide; mitocasin; mitochromin; Mitogiline; mitomalcin; mitomycin; Mitospur; Mitotan; mitoxantrone hydrochloride; mycophenolic acid; Nokodajoie; nogalamicin; ormaplatin; oxysuran; Pegaspargase; pelomycin; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; flomestane; porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazopulin; Riboprine; rogletimide; saffingol; safingol hydrochloride; Seustine; simtragen; sodium sparphosate; spasomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; thalisomycin; Tecogalan sodium; tegapur; teloxantrone hydrochloride; temophorfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazopurine; tyrapazamine; toremifene citrate; trestolone acetate; tricyribine phosphate; trimetrexate; trimetrexate glucuronate; tryptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzollidine sulfate; vorozol; geniplatin; ginostatin; Zorubicin hydrochloride.

Other anticancer agents that may be used in combination with tyrosine kinase inhibitor compounds include 20-epi-1, 25 dihydroxyvitarine D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecaiphenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; Amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-embryonic osteogenic protein-1; anti-androgen prostate carcinoma; antiestrogens; anti-neoplaston; antisense oligonucleotides; apidicoline glycinate; apoptosis gene modulators; apoptosis modulators; apuric acid; Ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorine; benzoylstaurosporine; beta-lactam derivatives; beta-alletin; betaclamycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnapide; Bistraten A; bizelesin; breplate; bropyrimine; butotitanium; butionine sulfoximine; calcipotriol; Calpostin C; camptothecin derivatives; canaryfox IL-2; capexitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitors; caselecin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; Chlorine; chloroquinoxaline sulfonamide; cicafrost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin homologues; konagenin; crambescidin 816; Crisnathol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopent anthraquinone; cycloplatam; cyphemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslaurelin; dexamethasone; dexiphosphamide; dexrazoxic acid; dexverapamil; diagequoon; didemnin B; dedog; diethylnorspermine; dihydro-5-azacitidine; 9-dioxamicin; diphenyl spiromustine; docosanol; dolacetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; evselen; ecomustine; edelfosine; edrecolomab; eflornithine; element; Ettepur; epirubicin; epristeride; estramustine homologues; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; pajarabine; fenretinide; filgrastim; finasteride; flavopyridol; plegelastine; fluasterone; fludarabine; fluorodaurolunicin hydrochloride; porphenimex; formestane; posttrisin; Potemustine; gadolinium texapyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; Idramanton; ilmoposine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukins; iovenguan; iododoxorubicin; ipomeanol, 4-; Irofloat; Irsogladin; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; Kahalalid F; lamellarine-N triacetate; lanreotide; linamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lysoclinamide 7; lovaplitan; Lombricin; rometrexol; ronidamine; rosoxantrone; lovastatin; Loxoribin; rurtotecan; lutetium texapyrin; lysophylline; cytolytic peptide; maytansine; mannostatin A; marimastat; Masoprocol; maspin; Matrilysine inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; metrelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosin; Myrimosteam; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonapid; mitotoxin fibroblast growth factor-saporin; mitoxantrone; moparotene; Molgamostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+mycobacterium cell wall sk; fur damol; multiple drug resistance gene inhibitors; multiple tumor suppressor 1-line therapies; mustard anticancer drugs; mycopperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; naparelin; Nagrestip; naloxone + pentazoxine; napabine; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; natural endopeptidase; nilutamide; nisamycin; nitrate modifiers; nitroxide antioxidants; nitrulline; O6-benzylguanine; octreotide; oxynon; oligonucleotide; Onapristone; ondansetron; ondansetron; aurasin; oral cytokine inducers; ormaplatin; Osateron; oxaliplatin; oxaunomycin; Palauamine; palmitoylzoxin; palmidronic acid; panaxitriol; panomifen; parabactin; pazeliptin; Pegaspargase; feldesin; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphate inhibitors; fish vanil; pilocarpine hydrochloride; pyrarubicin; pyritrexime; placetin A; placetin B; plasminogen activator inhibitors; platinum complex; platinum compounds; platinum-triamine complexes; porfimer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulators; protein kinase C inhibitors; protein kinase C inhibitor, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; Purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated reteliptin; rhenium Re 186 etidronate; lyzoxine; ribozyme; RII retinamide; rogletimide; Rohitukin; Romurtide; roquinimex; rubiginone B1; luboxyl; saffingol; sinetophins; SarCNU; sarcopitol A; Sargramostim; Sdi 1 analogs; Seustine; senescence induction inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sijopiran; Sodium acid; sodium boroceptate; sodium phenyllactate; solverol; somatomedin binding protein; sonermin; sparphosic acid; spicamycin D; spiromustine; Splenopentin; spongestatin 1; squalamine; stem cell inhibitors; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonists; Suradista; suramin; swinesonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; Tecogalan sodium; tegapur; tellurapyrylium; telomerase inhibitors; temophorfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomine; Taliblastine; thiocoralin; thrombopoietin; thrombopoietin analogs; thymalfacin; thymopoietin receptor agonists; thymotrinan; thyroid stimulating hormone; tin ethyl ethiopurpurine; tyrapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; tricyribine; trimetrexate; tryptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; UBC inhibitors; Ubenimex; urogenital co-induced growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; belarezol; veramine; Verdin; verteporfin; vinorelbine; vinsaltine; vitaxin; vorozol; zanoterone; geniplatin; zilascorb; and ginostatin stimalamer.

Other anticancer agents that may be used in conjunction with tyrosine kinase inhibitors include alkylating agents, antimetabolites, natural products or hormones, such as nitrogen mustard (eg, mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfo nates (eg, busulfan), nitrosoureas (eg, carmustine, lomucitin, etc.), or triazenes (eg, decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogues (eg methotrexate) or pyrimidine analogues (eg cytarabine), purine analogues (eg mercaptopurine, thioguanine, pentostatin). does not

Examples of natural products useful with tyrosine kinase inhibitor compounds include vinca alkaloids (eg vinblastine, vincristine), epipodophyllotoxins (eg etoposide), antibiotics (eg daunorubicin, doxorubicin, bleomycin), enzymes (eg, L-asparaginase) or biological response modifiers (eg, interferon alpha).

Examples of alkylating agents that can be used in conjunction with the tyrosine kinase inhibitor compound include nitrogen mustard (eg, mechloroethamine, cyclophosphamide, chlorambucil, maypalan, etc.), ethylenimine and methylmelamine (eg, hexamethylmelamine, thio tepa), alkyl sulfonates (such as busulfan), nitrosoureas (such as carmustine, lomusitin, semustine, streptozoxine, etc.), or triazenes (such as decarbazine) . Examples of antimetabolites include folic acid analogues (eg methotrexate) or pyrimidine analogues (eg fluorouracil, floxouridine, cytarabine), purine analogues (eg mercaptopurine, thioguanine, pentopurine). statins), but are not limited thereto.

Examples of hormones and antagonists useful in conjunction with tyrosine kinase inhibitors include adrenocorticosteroids (eg, prednisone), progestins (eg, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogen (eg, diethylstyl) bestrol, ethinyl estradiol), antiestrogens (eg tamoxifen), androgens (eg testosterone propionate, fluoxymesterone), antiandrogens (eg flutamide), gonadotropin-releasing hormone analogues (eg, leuprolide). Other agents that may be used in the methods and compositions of the present invention for treating or preventing cancer include platinum coordination complexes (eg cisplatin, carboblatin), anthracendions (eg mitoxantrone), substituted ureas (eg, hydroxyurea), methyl hydrazine derivatives (eg procarbazine), adrenocortical inhibitors (eg mitotane, aminoglutethimide). Examples of anticancer agents that act by inhibiting cells during the G2-M phase due to the stabilized microtubules and that can be used in combination with tyrosine kinase inhibitor compounds include, but are not limited to, the following commercially available drugs and drugs under development: Erbulo Zol (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin isethionate (also known as CI-980), vincristine, NSC-639829, Discordermolide (also known as NVP-XX-A-296), ABT-751 (also known as Abbott, E-7010), altoritin (eg, altoritin A and altoritin C) ), spongestatins (e.g. spongestatin 1, spongestatin 2, spongestatin 3, spongestatin 4, spongestatin 5, spongestatin 6, spongestatin 7, spongestatin 8 and spongestatin 9), semadotin hydrochloride ( Also known as LU-103793 and NSC-D-669356), epothilone (e.g. Epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxy Pothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), soblidotin (also known as TZT-1027) ), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS- 4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences) )), BSF-223651 (also known as BASF, ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (are Med/Kyowa Hakko), AM-132 (Armed), AM-138 (Armed/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (LY-) 355703), AC-7739 (also known as Ajinomoto, AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, AVE-8062, AVE-8062A, CS-39-L-Ser.HCI and also known as RPR-258062A), vitilebuamide, tubulin A, canadensole, centauridin (also known as NSC-106969), T-138067 (tularic) (Tularik), also known as T-67, TL-138067 and TI-138067), COBRA-1 (also known as Parker Hughes Institute, DDE-261 and WHI-261), HO ( Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Physianolid B, Laurimal Reed, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mountain Sinai School of Medicine (Cytoskeleton/Mt. Sinai School of Medicine), also known as MF-569), Narcosine (also known as NSC-5366), Nascarpine, D-24851 (Asta Medica), A-105972 (Abbott), Hemi Asterine, 3-BAABU (Cytoskeleton/Mountain Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene Acetylacetonate, T-138026 ( Tularic), Monsatrol, Elanosine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mountain Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik) ), also known as T-900607), RPR-115781 (Aventis), eroiterobine (e.g., Desmethyleloiterobin, Desaethyleloiterobin, Isoeloiterobin A and 2-Eloyterobin), Carivaeoside, Carivaeolin, Halicondrin B, D-64131 (Asta Medica) , D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Tacalonolid A, TUB-245 (Aventis), A-259754 (Abbott) ), iozostatin, (-)-phenylahistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverine B, D-43411 (gentaris ( Zentaris), also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth) ), D-82317 (gentaris), D-82318 (gentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi).

Treatment for thromboembolic disorders

If the subject is suffering from or at risk of suffering from a thromboembolic disorder (eg, stroke), the subject may be treated with a tyrosine kinase inhibitor compound in combination with one or more other antithromboembolic agents. Examples of antithromboembolic agents include, but are not limited to: thrombolytic agents (eg, alteplase anistreplase, streptokinase, urokinase or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (eg dabigatran etexilate), factor Xa inhibitors (eg fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717 or YM150), ticlopidine, Clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran or BIBR 1048.

In some embodiments, a compound provided herein may be administered in combination with one or more compound(s) selected from azathioprine, plaquenil, prednisone, sulfasalazine, methotrexate, arabah, remicad and enbrel.

In other embodiments, the compounds provided herein are estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, other antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcription and one or more compound(s) selected from enzyme inhibitors and angiogenesis inhibitors.

In other embodiments, the compounds provided herein are selected from Taxol, Taxotere, Epothilone A, Epothilone B, desoxyepothilone A, desoxyepothilone B or derivatives thereof; epidophyllotoxin; procarbazine; mitoxantrone; Mitomycin, Dystodermolide, Podophyllotoxin, Doxorubicin, Caminomycin, Daunorubicin, Aminopterin, Methotrexate, Methopterin, Dichloromethotrexate, Mitomycin C, Porphyromycin, Herceptin®, Rituxan ( Rituxan®), 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, colchicine, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, vinorel Vine, leurocidin, vindesine, leurocin, paclitaxel, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cyta Ravine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-1l, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzo indole derivatives, interferon, interleukin, and one or more chemotherapeutic compound(s) selected from capexitabine and gefitinib.

In other embodiments, the compounds provided herein may be administered in combination with a β-2 adrenergic receptor agonist, a corticosteroid, a leukotriene antagonist, a phosphodiesterase 4 inhibitor, and/or an antihistamine. In a further aspect, a compound provided herein may be administered in combination with one or more compound(s) selected from salmeterol, fluticasone, budesonide, montelukast, levalbuterol and roflumilast.

Example

Those skilled in the art may further appreciate various aspects and advantages of the present disclosure upon observation of the following illustrative, non-limiting examples.

synthesis of compounds

Intermediate 1: 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride

<img file="KR20080098490A_D0097.tif" />

Step 1

A solution of methylphosphonic acid dichloride (9.92 g, 74.6 mmol) in THF (75 mL) at -78 °C was treated with vinylmagnesium bromide in THF (175 mL, 1.0 M), which was added via dropping funnel for 4 h. The solution was warmed to 0 °C and saturated NH<sb>4</sb>Quenched with Cl. The solvent was evaporated under reduced pressure, and the residue was triturated several times with 1:1 THF/ethyl acetate to extract the divinyl methyl phosphine oxide product, which was used directly without further purification.

Step 2

A solution of methyl divinyl phosphine oxide (10.73 g, 92.4 mmol) and benzylamine (11.6 mL, 106.3 mmol) in 1:1 THF/water (250 mL) was heated to reflux for 16 h. The solvent was removed under reduced pressure. CH residue<sb>2</sb>Cl<sb>2</sb>Crystallization from /ether gave 1-benzyl-4-methyl-[1,4]azaphosphinane 4-oxide as a white solid (13.24 g, 64%). <sp>1</sp>H NMR (400 MHz, DMSO) δ 7.13-3.37 (5H, m); 3.6 (2H, s); 2.81 (2H, m); 2.59 (2H, m); 1.7-1.9 (4H, m); 1.42 (3H, d, JH-CP = 13.6 Hz).<sp>31</sp>P NMR δ 32 ppm.

Step 3

1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1M HCl (100 mL) was added along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker at 50 psi for 4 hours. The mixture was filtered through celite and all solvents were removed under reduced pressure. The product was triturated with hot ethanol (50 mL), cooled and the solution diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2x50 mL) and hexanes (2x50 mL) and dried under vacuum to yield 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride as a white crystalline solid (9.46 g). , 94%).<sp>1</sp>H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, SH-CP = 13.6 Hz.);<sp>31</sp>P NMR: δ 29 ppm; ESMS (m/z): (M+1)<sp>+</sp> found, 134.

Intermediate 2: 4-methyl-[1,4]azaphosphinane 4-oxide

<img file="KR20080098490A_D0098.tif" />

Step 1

In a scintillation vial, 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride (0.2 g, 1.18 mmol), carbonate resin (1.0 g, MP-carbonate, Argonaute, 2.5-3 mmol/g, manufactured by Argonaut Technologies) , Argonaut Technologies, Inc., 220 Saginaw Drive, Redwood City, CA 94063, USA), methanol (2 mL) and THF (2 mL) were added. The mixture was stirred at room temperature for 1 h, then filtered and concentrated in vacuo.

Intermediate 3: 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride

<img file="KR20080098490A_D0099.tif" />

Step 1

A solution of phenylphosphonic acid dichloride (29 mL, 200 mmol) dissolved in anhydrous THF (600 mL) was cooled to -78 °C and mechanically stirred under an atmosphere of dry nitrogen. Vinylmagnesium bromide (1M in THF, 500 mL) is added slowly so that the reaction mixture temperature does not exceed -70°C. The addition took 2 hours. After stirring for an additional 1 h at -78 °C, the cold reaction mixture was stirred with cold saturated NH<sb>4</sb>Directly poured into Cl (1 L). mixture to CH<sb>2</sb>Cl<sb>2</sb>extracted twice, and the combined organic phases were washed with 1M NaOH, brine, then Mg<sb>2</sb>SO<sb>4</sb>dried with Filtration and solvent evaporation gave divinyl-phenyl-phosphine oxide (26.8 g, 75%) as a viscous yellow oil that solidified on standing.<sp>1</sp>H NMR (400 MHz, DMSO-d6); δ 7.8-7.4 (m, 5H), 6.7 (m, 2H), 6.4-6.1 (m, 4H).<sp>31</sp>P NMR (DMSO-d6); δ 17.0 (s).

Step 2

Divinyl-phenyl-phosphine oxide (26.5 g, 149 mmol) and benzylamine (17.9 mL, 164 mmol) were dissolved in 50% aqueous THF (400 mL) and heated to reflux under nitrogen for 38 hours. The cooled reaction mixture was stirred with saturated aqueous NaHCO<sb>3</sb> and CH<sb>2</sb>Cl<sb>2</sb> distributed between them. aqueous phase CH<sb>2</sb>Cl<sb>2</sb>washed once more with , and the combined organic phases were washed with brine, MgSO<sb>4</sb>dried with Filtration and solvent evaporation gave 29 g of a yellow oil, which was purified by flash chromatography on silica gel eluting with 0-10% MeOH in EtOAc. 1-Benzyl-4-phenyl-[1,4]azaphosphinane 4-oxide was obtained as a yellow solid (25.5 g, 60%).<sp>1</sp>H NMR (400 MHz, DMSO-d6); δ 7.8 (m, 2H), 7.55 (m, 3H), 7.3 (m, 5H), 3.65 (s, 2H), 2.8 (m, 4H), 2.25 (m, 2H), 1.9 (broad t, 2H) .<sp>31</sp>P NMR (DMSO-d6); δ 27.0 (s).

Step 3

1-Benzyl-4-phenyl-[1,4]azaphosphinane 4-oxide (14.2 g, 49.8 mmol) was dissolved in anhydrous EtOH (65 mL) and 1N HCl (50 mL). Palladium on carbon (10%, 2.0 g) was added and the mixture was hydrogenated on a Parr shaker at 50 psi for 60 hours. After filtration through celite, the filtrate was rotary evaporated and the residue was triturated with ether to afford 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride as an off-white solid (11.40 g, 99%). .<sp>1</sp>H NMR (400 MHz, DMSO-d6) δ 7.85 (m, 2H), 7.65 (m, 3H), 3.5 (m, 4H), 2.7 (m, 2H), 2.2 (broad t, 2H). <sp>31</sp>P NMR (DMSO-d6); δ 24.0 (s).

4-Phenyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained using a procedure analogous to that described in Intermediate 2 and Step 6 of Example 3.

Intermediate 4: 4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide hydrochloride

<img file="KR20080098490A_D0100.tif" />

Step 1

4-Fluorobenzyl bromide (25 mL, 0.20 mol) was added to a stirred solution of trimethyl phosphite (35.9 mL, 0.30 mol) at ambient temperature under a nitrogen atmosphere. The resulting solution was heated at 110° C. for 6 hours and then at 90° C. overnight. The reaction mixture was cooled to ambient temperature, then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) followed by saturated brine (2 x 350 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The resulting crude product was purified by flash silica chromatography using 0-35% acetonitrile in ethyl acetate as eluent (4-fluoro-benzyl)-phosphonic acid dimethyl ester (29.44 g, 135 mmol, 66% yield) was obtained as a colorless oil.<sp>1</sp>H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 2H); 7.17-7.12 (dd, 2H); 3.61-3.58 (d, 6H); 3.31-3.24 (d, 2H); ESMS (m/z): (M+1)<sp>+</sp> Found, 219.

Step 2

Bromotrimethylsilane (6.0 mL, 45.4 mmol) was added dropwise to (4-fluoro-benzyl)-phosphonic acid dimethyl ester (4.57 g, 20.95 mmol) and stirred in a reaction flask cooled to 0°C. The resulting solution was warmed to ambient temperature, stirred for an additional 1 h and then concentrated by rotary evaporation to remove volatiles to afford crude (4-fluoro-benzyl)phosphonic acid bis(trimethylsilyl) ester, which was It was used without further purification.

Step 3

To (4-fluoro-benzyl) phosphonic acid bis(trimethylsilyl) ester was added 25 mL of anhydrous methylene chloride, 12 drops of anhydrous DMF, followed by dropwise addition of 6 mL of oxalyl chloride (68.3 mmol). The resulting solution was stirred overnight at ambient temperature until gas evolution. The reaction was concentrated by rotary evaporation to give 5.2 g of a yellow waxy solid, which was purified by distillation under reduced pressure to give 1.71 g (37%) of 4-fluorobenzyl phosphonic acid dichloride as a white solid.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 7.37-7.31 (m, 2H); 7.11-7.05 (m, 2H); 3.93-3.87 (d, 2H).

Step 4

4-Fluorobenzyl phosphonic acid dichloride (1.71 g, 7.82 mmol) was dissolved in 10 mL of anhydrous THF under a nitrogen atmosphere and cooled to -70°C. To this stirred solution was added dropwise vinyl magnesium bromide (18.3 mL, 1M) in THF. The resulting solution was stirred at -70 °C for 30 min. Aqueous ammonium chloride solution (100 mL, 2M) was cooled to 0° C. and the cold reaction mixture was added with rapid stirring. The product was extracted in dichloromethane and washed with saturated aqueous sodium bicarbonate followed by water. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation to give 1.375 g of (4-fluorophenylmethyl) divinyl phosphine oxide (6.55 mmol, 84%) as a white solid.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) 7.20-7.14 (m, 2H); 7.01-6.95 (m 2H); 6.29-6.08 (m, 6H); 3.20-3.15 (d, 2H); ESMS (m/z): (M+1)<sp>+</sp> found, 211.

Step 5

Divinyl-(4-fluorophenylmethyl)-phosphine oxide (0.719 g, 3.42 mmol) and benzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15 mL) and deionized water (15 mL). The reaction mixture was heated at 82° C. for 22 hours. The reaction was not complete, so an additional 0.04 mL of benzylamine was added and the reaction mixture was heated at 90° C. for an additional 6 hours. The reaction mixture was concentrated by rotary evaporation and the product was extracted with dichloromethane and washed with saturated brine. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was dissolved in 1:1 ethyl acetate:dichloromethane and passed through a plug of silica. The product was then eluted from the silica using a solution of 10% methanol in ethyl acetate. The solvent was removed by rotary evaporation to give 0.84 g of 1-benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide (2.65 mmol, 77%).<sp>1</sp>H MMR (400 MHz, CDCl<sb>3</sb>) δ 7.34-7.25 (m, 5H); 7.25-7.20 (m, 2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m, 2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H).

Step 6

1-Benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). Aqueous HCl (5.2 mL, 1M) and water (20 mL) were added. The solution was degassed with a stream of nitrogen, then palladium on carbon (10%, 0.5 g) was added. The mixture was hydrogenated overnight at 60 psi on a Parr shaker. The mixture was filtered through celite and all solvents were removed under reduced pressure. The product was recrystallized from methanol/diethyl ether to yield 0.659 g (2.50 mmol, 93%) of 4-(4-fluorophenylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride as a white crystalline solid. obtained.<sp>1</sp>H NMR (400 MHz, DMSO) δ 7.38-7.32 (m, 2H); 7.23-7.18 (m, 2H) 3.46-3.36 (m, 6H); 2.10-1.96 (m, 4H); ESMS (m/z): (M+1)<sp>+</sp> found, 228; (M+23)<sp>+</sp> Found, 250.

A procedure analogous to Intermediate 2 and Example 3, Step 6 was used to obtain the free base of 4-(4-fluorophenylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride).

Intermediate 5: 4-(cyclopropylmethyl)-[1,4]azaphosphinane 4-oxide hydrochloride

<img file="KR20080098490A_D0101.tif" />

Step 1

Bromomethyl-cyclopropane (26.0Og, 0.193mol) was added to triisopropyl phosphite (35.9mL, 0.30mol) at ambient temperature under a nitrogen atmosphere. The resulting solution was stirred and heated to reflux overnight (bath temperature: 144° C.). The reaction mixture was cooled to ambient temperature, then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) followed by saturated brine (2 x 350 mL). The organic phase was dried over magnesium sulfate, filtered, concentrated by rotary evaporation and concentrated under high vacuum to afford 39.96 g of cyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94% yield) as a colorless oil.<sp>1</sp>H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H); 1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H); 0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): (M+1)<sp>+</sp> found, 221; (M+23)<sp>+</sp> Found, 243.

Step 2

Bromotrimethylsilane (43 mL, 0.326 mol) was added dropwise to the stirred cyclopropylmethyl-phosphonic acid diisopropyl ester (18.00 g, 81.8 mmol) in a reaction flask cooled to 5°C. The resulting solution was warmed to ambient temperature, stirred for 3 h, and then concentrated by rotary evaporation to afford the crude cyclopropylmethyl-phosphonic acid bis(trimethylsilyl) ester, which was used without further purification.

Step 3

To the cyclopropylmethyl-phosphonic acid bis(trimethylsilyl) ester from step 2 was added anhydrous methylene chloride (100 mL), anhydrous DMF (2 mL) followed by dropwise addition of oxalyl chloride (23.3 mL, 267 mmol). The resulting solution was stirred overnight at ambient temperature. The reaction was concentrated by rotary evaporation to give 16.03 g of a yellow waxy solid, which was purified by distillation under reduced pressure to give 8.50 g of cyclopropylmethyl-phosphonic acid dichloride (49.1 mmol, 60%) as a white solid.<sp>1</sp>H NMR (400 MHz, DMSO) δ 1.57-1.45 (m, 2H); 0.95-0.75 (m, 1H) 0.53-0.43 (m, 2H); 0.24-0.12 (m, 2H).

Step 4

Cyclopropylmethyl-phosphonic acid dichloride (8.43 g, 48.7 mmol) was dissolved in anhydrous THF (70 mL), placed under a nitrogen atmosphere and cooled to -70°C. To this stirred solution was added dropwise vinyl magnesium bromide (122 mL, 1M) in THF. The resulting solution was stirred at -70 °C for 90 min. An aqueous solution of ammonium chloride (500 mL, 2M) was cooled to 0° C. and the cold reaction mixture was added with rapid stirring. The product was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by water. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation to give 3.56 g of (cyclopropylmethyl)-divinyl-phosphine oxide (22.8 mmol, 47%) as a white solid.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 6.44-6.14 (m, 6H); 1.84-1.78 (d, d, 2H) 0.98-0.86 (m, 1H); 0.66-0.60 (m, 2H); 0.25-0.19 (m, 2H); ESMS (m/z): (M+1)<sp>+</sp> found, 157; (M-1)<sp>- </sp>found, 155.

Step 5

(Cyclopropylmethyl)-divinyl-phosphine oxide (3.56, 22.8 mmol) and benzylamine (3.0 mL, 27.4 mmol) were dissolved in a mixture of THF (100 mL) and deionized water (100 mL). The reaction mixture was heated at 90° C. for 24 hours. The reaction was not complete so more benzylamine (1.0 mL, 9.1 mmol) was added and the reaction mixture was heated at 90° C. for an additional 6 hours. The reaction mixture was concentrated by rotary evaporation and the product was extracted with dichloromethane and washed with saturated brine. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was dissolved in ethyl acetate and passed through a plug of silica. The product was then eluted from the silica using ethanol. The solvent was removed by rotary evaporation to give 4.835 g of 1-benzyl-4-(cyclopropylmethyl)-[1,4]azaphosphinane 4-oxide (18.38 mmol, 81%) as an off-white crystalline solid.<sp>1</sp>H NMR (400 MHz, DMSO) δ 7.38-7.30 (m, 4H); 7.30-7.24 (m, 1H); 3.59 (s, 2H); 2.81-2.63 (m, 4H); 1.94-1.83 (m, 2H); 1.82-1.71 (m, 2H); 1.74-1.68 (d of d, 2H); 0.96-0.83 (m, 1H); 0.56-0.49 (m, 2H); 0.22-0.14 (m, 2H); ESMS (m/z): (M+1)<sp>+</sp> found, 264; (M+23)<sp>+</sp> Found, 286.

Step 6

The material from step 5 was dissolved in ethanol (80 mL) and aqueous HCl (40 mL, 1M) was added. The solution was degassed with a stream of nitrogen and palladium on carbon (10%, 1.0 g) was added. The mixture was hydrogenated on a Parr shaker overnight at 20 psi. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The product was dissolved in methanol and benzene was added. The solvent was removed by rotary evaporation. The product was recrystallized from ethanol/diethyl ether to give 3.526 g of 4-(cyclopropylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride (16.83 mmol, 92%) as a white crystalline solid.<sp>1</sp>H NMR (400 MHz, DMSO) 9.60-9.30 (d, 2H); 3.42-3.29 (m, 4H); 2.32-2.21 (m, 2H); 2.16-2.03 (m, 2H); 1.91-1.85 (d of d, 2H); 0.95-0.85 (m, 1H); 0.59-0.51 (m, 2H); 0.26-0.20 (m, 2H); ESMS (m/z): (M+1)<sp>+</sp> found, 174; (M+23)<sp>+</sp> Found values, 196.

4-(Cyclopropylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained using a procedure analogous to Intermediate 2).

Intermediate 6: 4-cyclopropyl-[1,4]azaphosphinane 4-oxide HBF<sb>4</sb>

<img file="KR20080098490A_D0102.tif" />

Step 1

To a 200 mL round bottom flask equipped with a magnetic stir-bar was added chlorophosphoric acid diethyl ester (17.25 mL, 120 mmol) and THF (200 mL). The mixture was cooled to 78° C. and a solution of cyclopropylmagnesium bromide (200 mL, 0.5M in THF, 100 mmol) was added dropwise using a dropping funnel over 30 minutes. The reaction was slowly warmed to room temperature overnight. The resulting clear reaction mixture was stirred with saturated NH<sb>4</sb>Poured into Cl (200 mL) and partitioned. The product was extracted from the aqueous layer using diethyl ether (1 x 100 mL). The organic fractions were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was further purified by vacuum distillation (65-75° C. at 500 mTorr) to afford cyclopropylphosphonic acid diethyl ester (9,025 g, 51%) as a colorless oil.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 4.11 - 4.03 (m, 4H), 1.32 - 1.29 (m, 6H), 0.90 - 0.77 (m, 5H); <sp>13</sp>C NMR (100 MHz, CDCl<sb>3</sb>) δ ppm 61.7 (d, J = 5.3 Hz), 16.4 (d, J = 6.1 Hz), 3.3 (d, J = 196.3 Hz), 3.0 (d, J = 4.6 Hz).

Step 2

To a 250 mL round bottom flask equipped with a stir bar was added cyclopropyl phosphonic acid diethyl ester (9.03 g, 51 mmol). The pure solution was cooled to 4° C. by immersion in an ice-water bath. Trimethylsilyl bromide (20.1 mL, 152 mmol) was then slowly added via syringe to the rapidly stirred solution. The addition was exothermic and the reaction mixture was gently auto-refluxed for several minutes. After addition the ice bath was allowed to warm to room temperature and the reaction was stirred for an additional 1.5 hours. All volatile reaction components were then removed in vacuo to afford trimethylsilyl ester as a pale yellow oil, which was used in the next step without further purification.

Step 3

Methylene chloride (75 mL) and DMF (200 μL) were added to the product of step 2 (in the same flask). Oxalyl chloride (12.8 mL, 152 mmol) was added dropwise to the stirred reaction mixture, which was vented to air. Vigorous gas evolution was observed upon addition, which continued for several hours. The resulting reaction mixture was stirred overnight and then all volatile components were removed in vacuo, resulting in a dark brown syrup. The crude reaction mixture was further purified by bulb-to-bulb distillation to afford cyclopropyl phosphinic acid dichloride (3.7 g, 45%) as a pale yellow free flowing oil.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 1.80 - 1.65 (m, 1H), 1.40 - 1.08 (m, 4H); <sp>13</sp>C NMR (100 MHz, CDCl<sb>3</sb>) δ 20.7 (d, J = 151.8 Hz), 6.9 (d, J = 5.3 Hz).

Step 4

To a 250 mL round bottom flask equipped with a magnetic stir bar was added cyclopropyl phosphonic acid dichloride (2.33 g, 14.7 mmol) and THF (100 mL). The solution was cooled to 78° C. and vinylmagnesium bromide (58.8 mmol, 1.0 M solution in THF) was added dropwise over 15 min. The solution was stirred at 78° C. for 7 h, then with cooling saturated aqueous NH<sb>4</sb>It was poured into Cl (200 mL). The resulting solution was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo to afford cyclopropyl-divinyl phosphine oxide (0.811 g, 39%) as a light brown free flowing oil, which was further purified used without<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 6.40 - 6.00 (m, 6H), 0.98 - 0.80 (m, 5H); GC-CIMS (m/z): (M+1)<sp>+</sp> found, 142.

Step 5

To a 100 mL round bottom flask equipped with a magnetic stir bar was added cyclopropyl-divinyl-phosphine oxide (0.81 g, 5.7 mmol), THF (20 mL), water (20 mL) and benzylamine (0.73 g, 6.8 mmol). The flask was equipped with a reflux condenser and heated to 85° C. for 16 hours. THF was removed in vacuo and the resulting cloudy aqueous solution was extracted with DCM. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated to give a yellow oil. The product was converted to MeOH/HCl<sb>3</sb>Further purification by column chromatography eluting with (0-10%) gave 1-benzyl-4-cyclopropyl-[1,4]azaphosphinane 4-oxide (0.77 g, 54%) as a pale yellow oil. obtained. <sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 7.37 - 7.26 (m, 5H), 3.35 (s, 2H), 2.82 - 2.73 (m, 4H), 1.89 - 1.73 (m, 4H), 1.09 - 1.01 (m, 1H), 0.83 - 0.61 (m) , 4H); ESMS (m/z): found, 250.

Step 6

To a 500 mL Parr pressure flask was added 1-benzyl-4-cyclopropyl-[1,4]azaphosphinane 4-oxide (0.77 g, 3.1 mmol), ethanol (50 mL), and 1N aqueous HCl (50 mL). To this solution was then added palladium on carbon (10% w/w, 0.4 g) and squeezed at 30 psi while shaking the flask. After 48 hours, the catalyst was filtered off and the reaction concentrated in vacuo to give a waxy solid. The crude product was converted to methanolic HBF<sb>4</sb> It was redissolved in solution (5% v/v) and crystallized by vapor diffusion of diethyl ether for 24 h. The resulting crystals were separated by filtration and 4-cyclopropyl-[1,4]azaphosphinane 4-oxide HBF<sb>4</sb> The salt (0.12 g, 16%) was obtained as white needles. <sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ ppm 8.61 (s, 2H), 3.46 - 3.39 (m, 4H), 2.10 - 1.99 (m, 4H), 1.26 - 1.18 (m, 1H), 0.86 - 0.70 (m, 4H); ESMS (m/z): found, 160.

4-cyclopropyl-[1,4]azaphosphinane 4-oxide HBF using a procedure similar to Intermediate 2<sb>4</sb> The organic base of the salt was obtained.

Intermediate 7: 4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide hydrochloride

<img file="KR20080098490A_D0103.tif" />

Step 1

4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethyl phosphite (8.86 mL, 68.8 mmol) at ambient temperature followed by triethylamine (9.6 mL, 68.8 mmol). The resulting solution was degassed with nitrogen, and tetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol) was added. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) followed by saturated brine (2 x 350 mL). The crude product was purified by vacuum distillation (ca. 98° C., 0.6 Torr) to give 8.956 g of 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield) as a colorless oil.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 7.88-7.80 (m, 2H); 7.20-7.14 (m, 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z): (M+1)<sp>+</sp> Found, 233.

Step 2

Bromotrimethylsilane (15.3 mL, 0.116 mol) was added dropwise to the stirred 4-fluorophenyl-phosphonic acid diethyl ester (8.95 g, 38.58 mmol) in a reaction flask cooled to 0°C. The resulting solution was warmed to ambient temperature and stirred for an additional hour. The mixture was then concentrated by rotary evaporation to give crude 4-fluorophenyl-phosphonic acid bis(trimethylsilyl) ester, which was used in the next step without further purification.

Step 3

To the 4-fluorophenyl-phosphonic acid bis(trimethylsilyl) ester from step 2 was added anhydrous methylene chloride (50 mL) and anhydrous DMF (1 mL) followed by oxalyl chloride (11.0 mL, 126 mmol) dropwise. The resulting solution was stirred overnight at ambient temperature. The reaction was concentrated by rotary evaporation to give 10.02 g of a yellow waxy solid, which was purified by distillation under reduced pressure to give 6.86 g of 4-fluorophenyl-phosphonic acid dichloride (32.2 mmol, 83%) as a yellow oil. did.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 8.08-7.98 (m, 2H); 7.35-7.26 (m 2H).

Step 4

4-Fluorophenyl-phosphonic acid dichloride (6.86 g, 32.2 mmol) was dissolved in anhydrous THF (50 mL), placed under a nitrogen atmosphere and cooled to -70°C. To this stirred solution was added dropwise a solution of vinyl magnesium bromide in THF (80.5 mL, 1M). The resulting solution was stirred at -70 °C for 90 min. Aqueous ammonium chloride solution (500 mL, 2M) was cooled to 0° C. and the cold reaction mixture was added with rapid stirring. The product was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by water. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation to give 5.214 g of 4-fluoro-phenyl-divinyl-phosphine oxide (26.6 mmol, 83%) as a white solid.<sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) 7.80-7.71 (m, 2H); 7.25-7.18 (m, 2H); 6.56-6.22 (m, 6H); ESMS (m/z): (M+1)<sp>+</sp> Found values, 197.

Step 5

(4-fluorophenyl) divinyl phosphine oxide (1.50 g, 7.65 mmol) and benzylamine (1.05 mL, 9.57 mmol) were dissolved in a mixture of 100 mL of THF and 100 mL of deionized water. The reaction mixture was heated at 90° C. overnight. The reaction mixture was concentrated by rotary evaporation and the product was extracted with dichloromethane and washed with saturated brine. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation to give 2.52 g of crude product. Impurities were removed by passing a solution of the crude product in ethyl acetate through a plug of silica. The product was then eluted from the silica using 10% methanol in ethyl acetate. The solvent was removed by rotary evaporation to give 1.89 g (6.24 mmol, 82%) of 1-benzyl-4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide as a colorless oil. ESMS {m/z): (M+1)<sp>+</sp> Found, 304.

Step 6

1-Benzyl-4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide (from step 5) was dissolved in ethanol (80 mL) and 40 mL of 1N aqueous HCl was added. After the solution was degassed with a stream of nitrogen, palladium on carbon (10%, 1.0 g) was added. The mixture was hydrogenated on a Parr shaker overnight at 50 psi. The mixture was filtered through celite, washed with 2:1 ethanol:1N HCl and all solvents were removed under reduced pressure. The product was dissolved in ethanol, benzene was added and the solvent was removed by rotary evaporation. The product was recrystallized from ethanol to give 1.158 g (4.64 mmol, 61%) of 4-(4-fluorophenyl-[1,4]azaphosphinane 4-oxide hydrochloride as a white crystalline solid.<sp>1</sp>H NMR (400 MHz, DMSO) δ 9.10-10.10 (d, 2H); 7.88-7.98 (m, 2H); 7.44-7.54 (m, 2H); 3.38-3.57 (m, 4H), 2.65-2.80 (m, 2H); 2.49-2.52 (m, 2H); ESMS (m/z): (M+1)<sp>+</sp> Found values, 214.

A procedure analogous to that described in Intermediate 2 and Example 3, Step 6 was used to obtain the free base of 4-(4-fluorophenyl-[1,4]azaphosphinane 4-oxide hydrochloride).

Intermediate 8: l-methyl-l-oxo-1λ<sp>5</sp>-phosphinane-4-carboxylic acid

<img file="KR20080098490A_D0104.tif" />

Step 1

Divinyl-methyl-phosphine oxide (10 g, 86 mmol), O,O-dibenzylmalonate (27 g, 95 mmol), DMSO (400 mL) and potassium carbonate (18 g, 130 mmol) in a 1 L round bottom flask equipped with a magnetic stir bar. was added The heterogeneous mixture was heated to 75°C. After 22 hours, the reaction was complete as determined by analytical HPLC. The reaction was cooled to room temperature, poured onto ice (500 mL) and extracted with EtOAc (3 x 100 mL). The organic fractions were collected and washed with 1N aqueous HCl (2×125 mL), saturated sodium bicarbonate (1×100 mL), then brine (3×125 mL). The organic layer was finally washed briefly with aqueous citric acid solution (1N, 50 mL), dried over sodium sulfate and concentrated to a light brown syrup. The crude product was further purified by silica gel chromatography eluting with MeOH/EtOAc (5% to 10%) to 1-methyl-1-oxo-1λ<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid dibenzyl ester (12 g, 35%) was obtained as a clear amber syrup. <sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ ppm 7.33 - 7.29 (m, 6H), 7.27 - 7.22 (m, 4H), 5.13 - 5.11 (m, 2H), 2.61 - 2.50 (m, 2H), 2.33 - 2.23 (m, 2H), 2.02 - 1.95 (m, 2H), 1.92 - 1.73 (m, 2H), 1.45 (d, J= 13 Hz, 3H); ESMS m/z: found, 423 (M+Na)<sp>+</sp>.

Step 2

1-methyl-1-oxo-1λ in a 500 mL Parr flask<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid dibenzyl ester (23.0 g, 59.7 mmol) was added. The solid was completely dissolved in ethanol (200 mL). To the solution was added palladium on carbon (10%, 1.15 g) and the flask was charged with hydrogen gas (48 psi). The flask was shaken with a mechanical shaker for 2.5 hours, after which time the starting material was completely consumed as determined by LC-MS. A large amount of white precipitate was present in the reaction mixture. Water (100 mL) and methanol (100 mL) were added to dissolve the precipitate and the palladium on carbon was filtered off through celite and washed with water/methanol (1:1). The resulting filtrate was concentrated in vacuo to remove most of the methanol and ethanol. Residual water was removed by lyophilization to 1-methyl-1-oxo-1λ<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid (12.68 g, 96%) was provided as a white free flowing powder. <sp>1</sp>H NMR (400 MHz, D<sb>2</sb>O) δ 2.40 - 2.20 (m, 4H), 1.95 - 1.85 (m, 4H), 1.49 (d, J= 13.3 Hz, 3H); ESMS m/z: found, 423 (221 (M+1)<sp>+</sp>, 441 (2M+1)<sp>+</sp>.

Step 3

1-Methyl-1-oxo-1λ in a 50 mL microwave pressure flask equipped with a stir bar<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid (0.25 g, 5.7 mmol) and water (20 mL) were added to give a suspension. The flask was sealed and heated to 215° C. for 60 seconds, at which time a pressure spike was observed. The flask was cooled to room temperature and then vented to dissolve the CO<sb>2</sb>pressure was released from The resulting clear colorless solution was concentrated by lyophilization to 1-methyl-1-oxo-1λ<sp>5</sp>A mixture of cis/trans isomers in quantitative yield of -phosphinane-4-carboxylic acid (about 2:1; no body of the preferred isomer was determined). <sp>1</sp>H NMR (400 MHz, D<sb>2</sb>O) δ ppm 2.6 - 2.4 (m, 1H), 2.2 - 1.6 (m, 8H), 1.48 (d, J= 12.9 Hz, least isomer, 1H), 1.44 (d, J = 13.7 Hz, major isomer, 2H) ); ESMS m/z: found, 177 (M+1)<sp>+</sp>, 353 (2M+1)<sp>+</sp>.

Intermediate 9: 1-oxo-1-phenyl-1λ<sp>5</sp>-phosphinane-4,4-dicarboxylic acid dibenzyl ester

<img file="KR20080098490A_D0105.tif" />

Step 1

Divinyl-phenyl-phosphine oxide (8.34 g, 46.8 mmol), DMSO (240 mL), dibenzylmalonate (13.31 g, 46.8 mmol) and K<sb>2</sb>CO<sb>3</sb>(9.7 g, 70 mmol) was added. The flask was sealed with a plastic stopper and heated to 75° C. for 2 hours, then cooled to 70° C. and heated for an additional 14 hours. The reaction mixture was then cooled to room temperature, then poured into 1N aqueous HCl (300 mL) and extracted with EtOAc (3×100 mL). The organic layer was collected, washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated to a dark brown syrup. The crude product was purified by flash chromatography eluting with MeOH:DCM (0-20%) to 1-oxo-1-phenyl-1λ<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5 g, 39%) was obtained as a light brown syrup. <sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 7.48 - 7.43 (m, 3H), 7.39 - 7.37 (m, 2H), 7.28 - 7.19 (m, 10H), 5.12 (s, 3H), 5.09 (s, 3H), 2.56 - 2.49 (m, 4H) ), 1.97 - 1.90 (m, 4H); ESMS m/z: found, 464 (M+1)<sp>+</sp>.

Step 2

1-oxo-1-phenyl-1λ in a 500 mL Parr flask<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5 g, 18 mmol), ethanol (250 mL) and palladium on carbon (10%, 1.1 g) were added. The flask was charged with hydrogen (51 psi) and shaken on a mechanical shaker. After 1 hour, the ballast was recharged to 50 psi (from 40 psi) and shaking was continued overnight (14 hours). The reaction mixture was filtered and the solvent was removed in vacuo to 1-oxo-1-phenyl-1λ<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid (1.8 g, 35%) was provided as a white solid. <sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ 7.9 - 7.4 (m, 5H), 2.6 - 1.4 (m, 8H); ESMS m/z: found, 283 (M+1)<sp>+</sp>.

Step 3

1-oxo-1-phenyl-1λ in a 250 mL round bottom flask equipped with a magnetic stir bar<sp>5</sp>-Phosphinane-4,4-dicarboxylic acid was added followed by 4N HCl (100 mL). The flask was equipped with a condenser and heated to vigorous reflux for 32 hours. The mixture was frozen and lyophilized to give an off-white solid, which was redissolved in 1:1 water:MeCN (100 mL), filtered and lyophilized twice to give crude 1-oxo-1-phenyl-1λ<sp>5</sp>-Phosphinane-4,4-carboxylic acid was provided, which was used without further purification. <sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ 7.9 - 7.4 (m, 5H), 2.6 - 1.4 (m, 9H); ESMS m/z: found, 239 (M+1)<sp>+</sp>.

Intermediate 10: 2-(4-Amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester

<img file="KR20080098490A_D0106.tif" />

Step 1

To a 1 L two-necked round bottom flask was added 2,6-dichloro-3-nitrobenzonitrile (11.1 g, 51.1 mmol) followed by ethyl acetate (102 mL). The flask was equipped with an internal thermometer and magnetic stir bar and cooled to 5° C. by immersion in an ice bath. Methylamine was added dropwise to the cooled reaction mixture as a 40% aqueous solution (8.9 mL, 115 mmol) with vigorous stirring. The reaction mixture was stirred for an additional 3 h with cooling, then additional methylamine (1.8 mL, 23 mmol) was added. The reaction vessel was removed from the ice bath and stirred for an additional 1.5 hours. To the reaction mixture was added water (30 mL), followed by hexane (45 mL), and the resulting slurry was stirred for 15 hours. The solid was recovered by filtration and washed with water followed by methanol to give 6-chloro-2-methylamino-3-nitro-benzonitrile (10.49 g, 96%) as a pale yellow solid which was directly without further purification. used<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb>) δ 8.55 - 8.53 (m, 1H), 8.28 (d, 1H, J = 9.0 Hz), 6.95 (d, 1H), J = 9.0 Hz), 3.30 (d, 1H, 7 = 5.5 Hz).

Step 2

Potassium tert-butoxide (5.0 g, 45 mmol) and dimethylsulfoxide (100 mL) were added to a 1 L two-necked round bottom flask equipped with a magnetic stir bar and internal thermometer. To the rapidly stirred suspension was added 2-methylacetoacetate (7.13 g, 49.5 mmol) dropwise over 5 minutes. After the addition was complete, the mixture was clear and slightly yellow. To the reaction mixture was then added 6-chloro-2-methylamino-3-nitro-benzonitrile from step 1 (8.6 g, 41 mmol) in portions over 15 minutes. The reaction mixture immediately turned deep red in color and the temperature was raised to 40°C. The reaction mixture was stirred for 1.5 h, then saturated NH<sb>4</sb>It was poured into Cl solution (100 mL). The mixture was extracted with EtOAc (3 x 150 mL). The organic layers were combined and washed with brine (3 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a dark red oil. Methanol (40 mL) was added and the mixture was stirred for 1.5 h with cooling in an ice bath. The resulting precipitate was collected by filtration, washed with cold methanol and 2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (7.13 g, 40.6) %) as a yellow solid, which was used without further purification.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb>) δ 8.23 (d, 1H, J = 9.0 Hz), 8.10 - 8.05 (m, 1H), 6.64 (d, 1H, J = 9.0 Hz), 4.28 - 4.19 (m, 2H), 3.17 (d, 3H, J = 5.5 Hz), 2.36 (s, 3H), 1.81 (s, 3H), 1.22 (t, 3H, J = 7.0 Hz).

Step 3

To a 500 mL Parr pressure flask was added 2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (7.13 g, 16.5 mmol) in EtOAc (50 mL). It was added as a solution, followed by 10% palladium on carbon (1.0 g). The flask was purged under vacuum and then charged with hydrogen gas (50 psi). The flask is shaken at room temperature, with the ballast open (Caution: strong exotherm). After 8 hours, TLC analysis indicated that all starting material was consumed. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The resulting solution was concentrated to give 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (5.11 g, 77%) as a gray solid , it was used without further purification.<sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ 6.70 (d, J= 8.2 Hz, 1H), 6.33 (d, J= 8.2 Hz, 1H), 6.17 (s, 2H), 4.90 (q, J)<sb>1</sb> = 5.1 Hz, J<sb>2</sb> = 10.6 Hz, 1H), 4.21 -4.15 (m, 2H), 2.95 (d, J= 5.5 Hz, 2H), 2.22 (s, 3H), 1.66 (s, 3H), 1.2 (t, J= 7.0 Hz) , 3H).

Intermediate 11: Acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline -7-yl]-allyl ester

<img file="KR20080098490A_D0107.tif" />

Step 1

2,6-dichlorophenyl isothiocyanate (3.46 g, 17.0 mmol), THF (100 mL) and 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo -Butyric acid ethyl ester (4.91 g, 17.0 mmol) was added to a 250 mL round bottom flask equipped with a magnetic stir bar, and the reaction was stirred at room temperature. After 2 h, mercuric oxide (4.04 g, 18.7 mmol) was added and the reaction stirred for an additional 14 h. The resulting brown slurry was filtered through celite and washed with THF. The filtrate was concentrated and the residue was triturated with diethyl ether to 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2 -Methyl-3-oxo-butyric acid ethyl ester (4.2 g, 54%) was provided as a gray solid, which was used without further purification.

Step 2

2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid in a 25 mL round bottom flask Ethyl ester (0.258 g, 0.562 mmol) and a stir bar were charged. Water (3 mL), glacial acetic acid (3 mL) and concentrated sulfuric acid (3 mL) were combined and added to a round bottom flask while kept warm (60° C.). The flask was sealed with a plastic stopper and heated at 100° C. in an oil bath. After 2 h, the flask was removed from the oil bath and stirred at room temperature overnight. The clear solution was then poured onto ice and neutralized with concentrated ammonium hydroxide. The resulting precipitate was collected by filtration, resuspended in methanol and filtered. The resulting solid was washed with methanol until the filtrate became colorless, and 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h ]Isoquinolin-9-one (0.106 g, 46%) was provided as a light gray solid, which was used without purification.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.47 (s, 1H), 7.78 - 7.68 (m, 4H), 7.59 (t, 1H, J = 8.6 Hz), 4.28 (2, 3H), 2.31 (s, 3H), 2.22 (s, 3H); ESMS (m/z): found, 387.

Step 3

2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9 in a 200 mL round bottom flask equipped with a stir bar -one (2.4 g, 6.2 mmol), selenium dioxide (2.0 g, 18 mmol) and dioxane (150 mL) were added. A condenser was attached to the flask and heated to reflux for 4.5 hours. Heat was then removed from the reaction and cooled to room temperature. The slightly opaque solution was filtered through celite and washed with dichloromethane:methanol (9:1). The solution was concentrated and the resulting residue was triturated with dichloromethane to 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4 ,5-h]isoquinoline-7-carbaldehyde (1.8 g, 72%) was obtained as a brownish yellow solid, which was used without further purification.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.65 (s, 1H), 10.24 (s, 1H), 7.96 (d, 1H, J= 8.6 Hz), 7.78 (d, 1H, J= 8.6 Hz), 7.70 (d, 2H, J = 7.8 Hz), 7.49 (d, 2H, J=7.8 Hz), 4.15 (s, 3H), 2.70 (s, 3H); ESMS (m/z): found, 401.

Step 4

2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h] in a 50 mL round bottom flask equipped with a stir bar Isoquinoline-7-carbaldehyde (0.415 g, 1.03 mmol) and THF (12 mL) were added. The reaction mixture was cooled to -78 °C. To the stirred suspension was added vinylmagnesium bromide (5 mL, 1M in THF, 5 mmol) in one portion. The solution was gradually warmed to -30°C for 1 h. Additional vinylmagnesium bromide (3 mL, 1M in THF, 3 mmol) was added and the reaction mixture was warmed to 0° C. for an additional 1.5 h. The cold reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 x 50 mL). The organic fractions were collected, washed with brine (3 x 25 mL) and concentrated. The resulting solid was further purified by flash chromatography eluting with EtOAc:hexanes (0-100%) to 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1, Obtained 6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 40%) as a pale yellow solid. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.43 (s, 1H), 7.77 - 7.75 (m, 4H), 7.59 (t, 1H, J= 8.6 Hz), 6.06 - 5.98 (m, 1H) 5.42 (app d, 1H, J= 5.5 Hz), 5.32 (app d, 1H, J = 17.2 Hz), 5.16 (app d, 1H, J= 10.2 Hz), 4.26 (s, 3H), 2.27 (s, 3H); ESMS (m/z): found, 429.

Step 5

2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo [ 4,5-h]isoquinolin-9-one (0.175 g, 0.409 mmol), THF (5 mL), triethylamine (60 μL, 0.43 mmol) and acetic anhydride (1 mL) were added. Then, to the stirred suspension was added N,N-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixture became clear within 1 minute and TLC analysis showed all starting material was consumed. The reaction mixture was concentrated in vacuo and the residue was further purified by silica gel chromatography eluting with methanol:dichloromethane (0-10%) to acetic acid 1-[2-(2,6-dichloro-phenylamino)-1 gave ,6-Dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.168 g, 87%) as a pale yellow solid .<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.42 (s, 1H), 7.80 - 7.76 (m, 4H), 7.57 (t, 1H, J= 8.2 Hz), 6.34 (d, 1H, J= 6.3 Hz), 6.21 - 6.13 (m, 1H), 5.41 (d, 1H, J = 17.2 Hz), 5.33 (d, 1H, J = 10.2 Hz), 4.25 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); ESMS (m/z): found, 471.

Intermediate 12: 7-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5- h]isoquinolin-9-one

<img file="KR20080098490A_D0108.tif" />

Step 1

Pd in a 50 mL round bottom flask equipped with a magnetic stir bar<sb>2</sb>(dba)<sb>3</sb>(38 mg, 42 μmol), triphenylphosphine (52 mg, 200 μmol) and THF (6.6 mL) were added. The resulting solution was stirred under nitrogen for 20 min and then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro- 1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.288 mg, 0.664 mmol) was added. The resulting red solution was stirred for 20 min, then sodium azide (47 mg, 0.72 mmol) was added as an aqueous solution (0.6 mL). The flask was sealed with a plastic cap and heated to 60° C. for 3 hours. The reaction mixture was cooled to room temperature and triphenylphosphine (165 mg, 0.63 mmol) was added. After stirring at room temperature for 7 hours, ammonium hydroxide was added (0.7 mL) and the reaction was stirred for an additional 12 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and the solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was converted to MeOH:HCCl<sb>3</sb>7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1, purified by flash chromatography eluting with (10-40%), 8-dihydro-imidazo[4,5-h]isoquinolin-9-one was obtained. <sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ 11.24 (s, 1H), 10.62 (s, 1H), 8.1 - 8.0 (m, 2H), 7.77 (d, J= 9 Hz, 1H), 7.71 (d, J= 9 Hz, 1H) , 7.6 - 7.5 (m, 1H), 6.6 - 6.45 (m, 2H), 4.18 (s, 3H), 3.75 - 3.65 (m, 2H), 2.36 (s, 3H), 2.30 (s, 3H); ESMS m/z: found, 392 (M+1)<sp>+</sp>.

Example 1: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 1)

<img file="KR20080098490A_D0109.tif" />

Step 1

2-(4-Amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (0.247 g, 0.854 mmol) followed by THF (5 mL) and A magnetic stir bar was added. To the resulting solution was added 4-fluoro-1-isothiocyanate-2-methyl-benzene (0.191 g, 1.14 mmol), and the solution was stirred at room temperature for 48 hours. To the solution was then added mercuric oxide (0.222 g, 1.02 mmol) and stirring was continued at room temperature for 24 hours. The brown suspension was then filtered through a 1/2 inch thick pad of silica, washed with THF and concentrated to dryness. The resulting dark red solid was further purified by silica gel chromatography eluting with ethyl acetate:hexanes (0-100%) to 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino) )-3-Methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.204 g, 56%) was provided as a dark red solid. ESMS (m/z): (M+1)<sp>+</sp> found, 423.

Step 2

2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2- in a glass scintillation vial equipped with a magnetic stir bar Methyl-3-oxo-butyric acid ethyl ester (0.204 g, 0.483 mmol) was added. Freshly prepared H at 60 °C<sb>2</sb>A mixture of O (3.3 mL), glacial acetic acid (3.3 mL) and concentrated sulfuric acid (3.3 mL) was added to a vial. The vial was closed with a screw cap and heated to 100° C. in a heating block. After 2.5 h, the vial was cooled to room temperature and stirred for an additional 12 h. The reaction mixture was then poured onto ice and neutralized by addition of concentrated ammonium hydroxide. The resulting precipitate was collected by filtration and further purified by trituration with methanol to 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (0.1188 g, 70%) was provided as a light gray solid.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.43 (br s, 1H), 10.49 (br s, 1H), 7.70 - 7.65 (m, 2H), 7.57 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.37 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.27 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb>= 11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): found, 351.

Step 3

2-(4-Fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h] in a 200 mL round bottom flask equipped with a magnetic stir bar Isoquinolin-9-one (1.3 g, 3.7 mmol) selenium dioxide (1.23 g, 11.0 mmol) and dioxane (100 mL) were added. The flask was fitted with a reflux condenser and heated to 100° C. in an oil bath for 5 hours. The flask was then cooled to room temperature and the mixture was filtered through a plug of celite and washed with 10% MeOH/DCM. The filtrate was concentrated to dryness and the resulting brown solid was further purified by trituration with cold DCM to 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9- Dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (1.11 g, 82%) was obtained as a red-yellow solid.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.80 (d, 1H, J= 8.8 Hz) , 7.57 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.26 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): found, 365.

Step 4

2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4, 5-h]isoquinoline-7-carbaldehyde (0.750 g, 2.06 mmol) was added followed by THF (20 mL). The suspension was cooled to 78° C., then vinylmagnesium bromide (16.5 mmol, 1.0 M in THF) was added over 5 min. The reaction mixture was warmed to 10° C. for 2.5 h, after which time all material was completely dissolved. The cold reaction mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3 x 30 mL). The organic fractions were recovered, washed with brine (1 x 50 mL), dried over sodium sulfate and concentrated in vacuo to 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl). )-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.680 g, 84%) was provided as an orange-yellow solid, which was further purified used without <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.52 (br s, 1H), 10.38 (br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.24 (td, 1H, J<sb>1</sb> = 9.1 Hz, J<sb>2</sb> = 11.7 Hz), 6.02 (ddd, 1H, J<sb>1</sb>= 5.9 Hz, J<sb>2</sb> = 10.6 Hz, J<sb>3</sb> = 17.2 Hz), 5.41 (app d, 1H, J= 5.5 Hz), 5.33 (dt, 1H, J)<sb>1</sb> = 1.6 Hz, J<sb>2</sb> = 17.2 Hz), 5.17 (dt, 1H, J<sb>1</sb> = 1.2 Hz, J<sb>2</sb> = 10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z): found, 393.

Step 5

2-(4-Fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro- in a 25 mL round bottom flask equipped with a magnetic stir bar. Add imidazo[4,5-h]isoquinolin-9-one (0.65 g, 1.7 mmol), THF (5 mL), triethylamine (0.52 g, 5.1 mmol) and acetic anhydride (0.22 g, 2.2 mmol) did. DMAP (0.002 g, 0.02 mmol) was then added to the stirred suspension. After 1 hour, all reaction components were completely dissolved and the reaction was complete as determined by TLC analysis. To the reaction mixture was added saturated aqueous ammonium chloride (20 mL) and the solution was extracted with ethyl acetate (2 x 20 mL). The organic fractions were collected, washed with brine (1 x 20 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was further purified by silica gel chromatography eluting with 2% methanol:DCM to acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo- Provided 8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.404 g, 55%) as a yellow solid. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ ppm 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J= 9.0 Hz), 7.70 (d, 1H, J= 8.6 Hz), 7.56 (dd, 1H) , J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.37 - 7.34 (m, 3H), 7.25 (td, 1H, J)<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 8.2 Hz), 6.34 (app d, 1H, J = 6.3 Hz), 6.17 (ddd, 1H, J)<sb>1</sb> = 6.3 Hz, J<sb>2</sb> = 10.2 Hz, J<sb>3</sb> = 16.8 Hz), 5.41 (app d, 1H, J = 17.2 Hz), 5.33 (app d, 1H, J= 10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H) ); ESMS (m/z): found, 435.

Step 6

To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxide (100 mg, 0.75 mmol). To a separate glass vial was added tris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine (30 mg, 0.12 mmol) and THF (2.5 mL). The resulting solution was stirred for 20 min and then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H- Imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL) followed by TEA (0.90 mL, 12.2 mmol) . Of the resulting solution, 2.4 mL (0.15 mmol total allylic acid acetate) was transferred to a vial containing 4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at room temperature for 20 h. The solvent was removed in vacuo and the resulting solid was redissolved in MeCN (2 mL) and DMSO (2 mL). The solution was filtered, followed by preparative reverse-phase HPLC (0% to 100% MeCN:H<sb>2</sb>O + 0.1% formic acid) to 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ<sp>5</sp>[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (32mg, 42%) as a pale yellow solid obtained. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J = 8.6 Hz), 7.72 (d, 1H, J = 8.6 Hz), 7.56 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 3.9 Hz, J<sb>2</sb> = 9.8 Hz), 7.25 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz), 7.19 - 7.15 (m, 2H), 6.54 - 6.48 (m, 1H), 4.18 (s, 3H), 4.10 -4.00 (br s, 2H), 3.80 - 3.30 (br m, 4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30 - 2.10 (br m, 4H), 1.7 - 1.6 (br m, 3H); ESMS (m/z): found, 508.

Example 2: 2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (compound 5)

<img file="KR20080098490A_D0110.tif" />

2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one to acetic acid 1-[2-(2) ,6-Dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester and 4- It was prepared according to the procedure of Example 1 from phenyl-[1,4]azaphosphinane 4-oxide. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.38 (br s, 1H), 10.71 (br s, 1H), 7.90 - 7.60 (m, 9H), 7.56 (t, 1H, J= 7.8 Hz), 7.22 (br d, 1H, J = 15.3 Hz), 7.70 - 6.40 (br m, 1H), 4.23 (s, 3H), 4.18 (br m, 2H), 4.00 - 4.15 (br m, 4H), 2.60 - 2.40 (br n, 4H), 2.39 (s, 1H); ESMS (m/z): found, 606 (M+1)<sp>+</sp>.

Example 3: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one HCl (compound 3)

<img file="KR20080098490A_D0111.tif" />

Step 1

In a 250 mL round-bottom flask, 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmol) ) and THF (80 mL) were added. The solution was stirred with gentle heating until all material was completely dissolved. The reaction mixture was then concentrated in vacuo to a final solution of about 20 mL. After cooling to room temperature, 4-fluoro-1-isothiocyanate-2-methyl-benzene (9.36 g, 56.0 mmol) was added in one portion, stirring was continued at room temperature for 12 hours, after which time TLC analysis All diamines were converted to the corresponding thioureas as determined by To the reaction mixture was then added mercuric oxide (12.15 g, 56 mmol) and the resulting slurry was stirred at room temperature. The slurry quickly turned black, indicating the formation of mercuric sulfide. After 1 hour, the reaction was complete as determined by TLC analysis. Silica gel was added to the mixture and the resulting viscous slurry was filtered through a pad of celite and washed with an aqueous volume of EtOAc. The clear filtrate was concentrated to give a dark gray solid. Diethyl ether was added to the solid, and the insoluble material was separated by filtration and 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5 -yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 52%) was obtained as a white solid.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb>) δ 8.71 (s, 1H), 7.46 - 7.42 (m, 2H), 7.14 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.06 (td, 1H, J<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 8.6 Hz), 6.87 (d, 1H, J= 8.6 Hz), 4.28 - 4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s) , 3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)<sp>+</sp>.

Step 2

2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2 in a 500 mL round bottom flask equipped with a magnetic stir bar -Methyl-3-oxo-butyric acid ethyl ester (8.25 g, 1.95 mmol) was added followed by a mixture of freshly prepared water (25 mL), acetic acid (25 mL) and concentrated sulfuric acid (25 mL) at 60°C. A reflux condenser was attached to the flask and heated to a bath temperature of 100° C. under a nitrogen atmosphere. After 5 h, the reaction was cooled to room temperature and stirred for an additional 14 h. The mixture was then poured onto ice and concentrated ammonium hydroxide was carefully added to bring the pH to slightly basic, while maintaining the temperature below 15°C. The resulting precipitate was filtered off and washed with several volumes of water. The solid was then slurried in methanol for 1 hour and filtered. The isolated solid was washed with cold methanol until the filtrate became colorless and washed with 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[ 4,5-H]isoquinolin-9-one (6.11 g, 89%) was obtained as a light gray solid. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.43 (br s, 1H), 10.49 (br s, 1H), 7.70 - 7.65 (m, 2H), 7.57 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.37 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.27 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): 351 (M+1)<sp>+</sp>.

Step 3

To a 1 L round bottom flask equipped with a magnetic stir bar was added dioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C. and selenium dioxide (8.6 g, 77 mmol) was added. The mixture was stirred at 55° C. for 1 hour, during which time all selenium dioxide was dissolved. Then in solution 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was added A reflux condenser was attached to the flask and the resulting slurry was heated to a bath temperature of 115°C. After 18 h, additional selenium dioxide (4.0 g, 36 mmol) was added and stirring was continued for 6 h. The reaction mixture was black-red with gray metallic selenium lining the sides of the flask. After the reaction mixture was cooled to room temperature, it was filtered through a pad of celite and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo to give a sticky red solid. Methanol (50 mL) was added and the mixture was stirred in an ice bath, at which time a hairy yellow precipitate formed. The solid is isolated by filtration and washed sparingly with cold methanol. 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo [4,5-h]isoquinoline-7-carbaldehyde (3.90 g, 61%) was obtained as a pale yellow solid.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J= 8.8 Hz), 7.80 (d, 1H, J= 8.8 Hz) , 7.57 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.26 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)<sp>+</sp>.

Step 4

2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo [ 4,5-h]isoquinoline-7-carbaldehyde (7.96 g, 21.9 mmol) and THF (260 mL) were added. The resulting slurry was cooled to 78° C. and vinylmagnesium bromide (175 mL, 1.0 M in THF) was added dropwise over 30 min. The mixture was stirred at 78° C. for 2 h, then warmed to 10° C. for 30 min and held at 10° C. for an additional 2 h. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was collected, washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated in vacuo to 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl). )-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 91%) was obtained as an orange-yellow solid. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 10.52 (br s,l H), 10.38 (br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.8 Hz), 7.24 (td, 1H, J<sb>1</sb> = 9.1 Hz, J<sb>2</sb> = 11.7 Hz), 6.02 (ddd, 1H, J<sb>1</sb> = 5.9 Hz, J<sb>2</sb> = 10.6 Hz, J<sb>3</sb> = 17.2 Hz), 5.41 (app d, 1H, J = 5.5 Hz), 5.33 (dt, 1H, J)<sb>1</sb> = 1.6 Hz, J<sb>2</sb> = 17.2 Hz), 5.17 (dt, 1H, J<sb>1</sb> = 1.2 Hz, J<sb>2</sb> = 10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z): 393 (M+1)<sp>+</sp>.

Step 5

2-(4-Fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro- in a 500 mL round bottom flask equipped with a magnetic stir bar. Imidazo[4,5-h]isoquinolin-9-one (7.8 g, 20 mmol), DCM (100 mL), TEA (3.0 g, 30 mmol) and DMAP (25 mg, 0.2 mmol) were added. At room temperature, to the rapidly stirred suspension was added acetic anhydride (2.3 g, 23 mmol). The reaction was completed after 10 minutes as determined by TLC analysis. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous ammonium chloride. The aqueous layer was back extracted with additional DCM (100 mL). The combined organic fractions were washed with brine (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo to give an amorphous orange solid. The crude product was redissolved in 5% MeOH/DCM (65 mL). To the stirred solution was added diethyl ether (200 mL), which formed a pale yellow precipitate. The stirred suspension was cooled to -5[deg.] C. in a salt/ice bath and then filtered to recover a solid. The solid is washed sparingly with diethyl ether and collected acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H -imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (6.94 g, 80.4%) was obtained as a yellow powder.<sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J = 9.0 Hz), 7.70 (d, 1H, J = 8.6 Hz), 7.56 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.37 - 7.34 (m, 3H), 7.25 (td, 1H, J)<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 8.2 Hz), 6.34 (app d, 1H, J= 6.3 Hz), 6.17 (ddd, 1H, J)<sb>1</sb> = 6.3 Hz, J<sb>2</sb> = 10.2 Hz, J<sb>3</sb> = 16.8 Hz), 5.41 (app d, 1H, J= 17.2 Hz), 5.33 (app d, 1H, J= 10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H) ); ESMS (m/z): 435 (M+1)<sp>+</sp>.

Step 6

To a 500 mL round bottom flask were added 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride salt (5.91 g, 25.6 mmol), MP-carbonate resin (20 g, 2.9 mmol/g) and water (200 mL). did. The flask was sealed with a plastic stopper and placed on a rotary shaker for 12 hours. The resin was then removed by filtration through a glass frit and washed with water (40 mL) to afford 4-phenyl-[1,4]azaphosphinane 4-oxide free base as an aqueous solution.

Step 7

Pd in a 500 mL 3-necked round-bottom flask equipped with a magnetic stir bar.<sb>2</sb>(dba)<sb>3</sb>HCl<sb>3</sb>(0.476 g, 0.46 mmol), triphenylphosphine (0.383 g, 1.5 mmol) and THF (100 mL) were added. The resulting wine-red solution was stirred for 30 minutes under a nitrogen atmosphere. Then, solid acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[[ 4,5-h]isoquinolin-7-yl]-allyl ester (4.0 g, 9.2 mmol) was added in one portion. Then, 4-phenyl-[1,4]azaphosphinane 4-oxide free base aqueous solution (200 mL, 0.106 M) was added to the stirred solution via dropping funnel over 3 minutes. The reaction temperature was immediately raised to 24° C. to 29.5° C. and held at this temperature for about 20 minutes. After 1 h, the reaction mixture was cooled to room temperature and a yellow precipitate formed. The precipitate was isolated by filtration and washed with water followed by diethyl ether. The filter cake was redissolved in methanol (150 mL) and cooled in an ice bath. To the cooled solution was added anhydrous HCl (10 mL, 1.25M in methanol) with rapid stirring. The solution was then poured into a flask containing diethyl ether (600 mL) with stirring. Pentane (100 mL) was added followed by additional anhydrous HCl (20 mL, 1.25M in methanol). The resulting solution was decanted leaving the crude product as a rubber on the side of the flask. This material was redissolved in methanol (100 mL). Diethyl ether was poured into the stirred solution to give a yellow hairy precipitate. It was recovered by filtration and washed with diethyl ether to 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ).<sp>5</sp>-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one HCl salt (2.9 g, 52%) was obtained. <sp>1</sp>H NMR (400 MHz, CD<sb>3</sb>OD) δ 7.96- 7.89 (m, 2H), 7.89 (d, 1H, J= 9.0 Hz), 7.73 (d, 1H, J= 9.0 Hz), 7.71 - 7.65 (m, 1H), 7.66 - 7.61 (m) , 2H), 7.51 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.32 (d, 1H, J= 15.7 Hz), 7.26 (dd, 1H, J)<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 9.4 Hz), 7.16 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz), 6.56 - 6.48 (m, 1H), 4.26 (s, 3H), 4.19 (d, 2H, J= 7.0 Hz), 4.2 - 3.8 (br m, 2H), 3.8 - 3.6 (br m, 2H), 3.0 - 2.9 (br m, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 2.5 - 2.3 (br m, 2H); ESMS m/z 569.7 (MH+).

Example 4: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 12)

<img file="KR20080098490A_D0112.tif" />

Treated as described above for Example 3 to convert 4-methyl-[1,4]azaphosphinane 4-oxide to 4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.32 (br s, 1H), 10.62 (br s, 1H), 7.79 (d, 1H, J= 9.2 Hz), 7.72 (d, 1H, J= 9.2 Hz), 7.56 (dd, 1H, J<sb>1</sb> = 6.0 Hz, J<sb>2</sb> = 8.8 Hz), 7.37 - 7.28 (m, 3H), 7.25 (dt, 1H, J)<sb>1</sb> = 2.8 Hz, J<sb>2</sb> = 8.8 Hz), 7.23 - 7.14 (m, 3H), 6.48 (dt, 1H, J)<sb>1</sb> = 7.2 Hz, J<sb>2</sb> = 14.8 Hz), 4.17 (s, 3H), 4.07 (d, 2H, J= 6.8 Hz), 3.8 - 3.6 (br m, 2H), 3.6 - 3.4 (br m, 4H), 2.36 (s, 3H) , 2.30 (s, 3H), 2.4 - 2.0 (br m, 4H); ESMS (m/z): found, 602.1 (M+1)<sp>+</sp>.

Example 5: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 13)

<img file="KR20080098490A_D0113.tif" />

Treatment as described above for Example 3, replacing 4-methyl-[1,4]azaphosphinane 4-oxide with 4-cyclopropylmethyl-[1,4]azaphosphinane 4-oxide (4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>5</sb> + TFA) δ 11.08 (br s, 1H), 10.70 (s, 1H), 7.79 (d, 1H, J= 8.8 Hz), 7.72 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J)<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.35 (dd, 1H, J<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 9.8 Hz), 7.25 (td, 1H, J<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz), 7.30 - 7.10 (br m, 1H), 6.6 - 6.45 (br m, 1H), 4.18 (s, 3H), 4.10 - 4.00 (br m, 2H), 3.80 - 3.65 (br m, 2H) ), 3.60 - 3.45 (br m, 1H), 3.45 - 3.30 (br m, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.50 - 1.70 (m, 6H), 1.0-0.70 (br m, 1H), 0.56 (d, 2H, J=7.4 Hz), 0.23 (s, 2H); ESMS (m/z): found, 548 (M+1)<sp>+</sp>.

Example 6: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 14)

<img file="KR20080098490A_D0114.tif" />

Treated as described above for Example 3, replacing 4-methyl-[1,4]azaphosphinane 4-oxide with 4-cyclopropyl-[1,4]azaphosphinane 4-oxide to 2-( 4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ<sp>5</sp>-[1,4]azaphosphinan-1-yl]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb> + TFA) δ 11.37 (br s, 1H), 10.63 (s, 1H), 10.49 (br s, 1H), 7.80 (d, 1H, J = 8.8 Hz), 7.72 (d, 1H, J = 8.8 Hz) , 7.56 (dd, 1H, J<sb>1</sb> = 5.5 Hz, J<sb>2</sb> = 8.6 Hz), 7.36 (dd, 1H, J<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 7.8 Hz), 7.26 (td, 1H, J<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 8.2 Hz), 7.18 (br d, 1H, J= 15.3 Hz), 6.60 - 6.50 (br m, 1H), 4.18 (s, 3H), 4.15 - 4.05 (br m, 2H), 4.00 - 3.40 (br m, 4H), 2.37 (s, 3H), 2.30 (s, 3H), 2.50 - 2.10 (br m, 4H), 1.50 - 1.00 (br m, 1H), 0.90 - 0.82 (br m, 2H), 0.81 - 0.70 (br m, 2H); ESMS (m/z): found, 534 (M+1)<sp>+</sp>.

Example 7: 2-(4-Fluoro-2-methyl-phenylamino)-7-(3-(4-methanesulfonyl-piperazin-1-yl)-propenyl]-1,6-dimethyl- 1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 24)

<img file="KR20080098490A_D0115.tif" />

Treated as above for Example 3, replacing 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride with methanesulfonylpiperazine 2-(4-fluoro-2-methyl- Phenylamino)-7-[3-(4-methanesulfonyl-piperazin-1-yl)-propenyl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h] Isoquinolin-9-one was prepared. <sp>1</sp>H NMR (400 MHz, DMSO-d<sb>6</sb>) (free base) δ 10.78 (1H s); 8.41 (1H m); 7.69 (d, 1H, J=9.0 Hz); 7.7-7.66 (1H, m); 7.5 (1H, J = 9 Hz); 7.07 (1H, m); 7.02 (1H, m); 6.82 (1H, d); 6.5 (1H, m)l 4.08 (3H, s); 3.26 (2H, m); 3.19 (4H, m); 2.92 (3H, s); 2.59 (4H, m); 2.37 (3H, s); 2.26 (3H, s). ESMS m/z 539 (MH+).

Example 8: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonyl Amino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 15)

<img file="KR20080098490A_D0116.tif" />

Step 1

7-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo in a scintillation vial equipped with a magnetic stir bar. [4,5-h]isoquinolin-9-one (68 mg, 173 μmol) was added followed by dimethylformamide (DMF) (1.0 mL) and triethylamine (TEA) (0.25 mL). 1-methyl-1-oxo-1λ in a separate scintillation vial<sp>5</sp>-Phosphinane-4-carboxylic acid (130 mg, 0.74 mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol) and DMF (2.0 mL) were added followed by TEA (0.25 mL). The solution was sonicated until most of the solids were dissolved. The active ester solution (1.0 mL or about 1/2) was transferred to the amine solution and stirred at room temperature for 2.5 hours, after which time the starting material was completely consumed as determined by LC-MS. The reaction mixture was quenched by addition of water (0.5 mL) and then acidified with TFA. The mixture was filtered (syringe membrane filter) and purified directly by reverse phase HPLC to 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1). -oxo-phosphinan-4-yl) carbonylamino] -propenyl} -1,8-dihydro-imidazo [4,5-h] isoquinolin-9-one (24.9 mg, 26%) cis Obtained as a mixture of /trans isomers.<sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21 - 8.17 (m, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H) , 7.55 (dd, J<sb>1</sb> = 5.9 Hz, J<sb>2</sb> = 9.0 Hz, 1H), 7.27 (td, J)<sb>1</sb> = 2.7 Hz, J<sb>2</sb> = 8.6 Hz, 1H), 6.66 (d, J= 15 Hz, 1H), 6.55 - 6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.35 -2.30 (m, 1H), 2.08 - 1.90 (m, 6H), 1.78 - 1.65 (m, 2H), 1.52 - 1.47 (m, 3H); ESMS m/z: found, 550 (M+1)<sp>+</sp>.

Example 9: 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(trans-1-phenyl-1-oxo-phosphinan-4-yl) Carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (compound 16) and 2-(4-fluoro-2-methyl-phenylamino )-1,6-dimethyl-7-{3-[(cis-1-phenyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo [4,5-h]isoquinolin-9-one (compound 17)

<img file="KR20080098490A_D0117.tif" /><img file="KR20080098490A_D0118.tif" />

compound 16 compound 17

7-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5- in a scintillation vial h]Isoquinolin-9-one (70 mg, 180 μmol), DMF (2.0 mL) and TEA (110 mg, 1.1 mmol) were added. Crude 1-oxo-1-phenyl-1λ in a separate vial<sp>5</sp>-Phosphinane-4,4-carboxylic acid (64 mg, 270 μmol), HATU (108 mg, 284 μmol) and DMF (2.0 mL) were added. After the active ester solution was completely dissolved, the entire volume was transferred to the amine solution. The reaction mixture was stirred at room temperature for 2 hours, then quenched by addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with EtOAc (3 x 10 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuo.

The crude material was further purified by flash chromatography eluting with MeOH:DCM (5-25%) to 1-oxo-1-phenyl-1λ<sp>5</sp>-Phosphinane-4-carboxylic acid {3-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4 ,5-h]isoquinolin-7-yl]-allyl}-amide was obtained as two chromatographically distinct geometric isomers (12.7 mg of the first eluting isomer and 10.5 mg of the second eluting isomer, 21%). combined yield). First eluted isomer:<sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO+TFA) δ 11.09 (s, 1H), 10.56 (s, 1H), 8.21 (t, J = 6.3 Hz, 1H), 7.83 - 7.81 (m, 2H), 7.73 (d, J= 8.6 Hz, 1H), 7.66 (d, J= 8.6 Hz, 1H), 7.61 - 7.53 (m, 4H), 7.36 - 7.33 (m, 1H), 7.25 (td, J)<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.2 Hz, 1H), 6.63 (d, J= 16 Hz, 1H), 6.47 (dt, J)<sb>1</sb> = 5.1 Hz, J<sb>2</sb> = 16 Hz, 1H), 4.18 (s, 3H), 3.9 - 3.86 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.7 - 1.9 (m, 7H), 1.7 - 1.6 ( 2H); ESMS m/z: found, 612 (M+1)<sp>+</sp>. Second eluted isomer:<sp>1</sp>H NMR (400 MHz, d<sb>6</sb>-DMSO+TFA) δ 11.16 (s, 1H), 10.57 (s, 1H), 8.25 (t, J = 5.8 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.77 (d, J = 9 Hz, 1H), 7.71 (d, J = 9 Hz, 1H), 7.62 - 7.5 (m, 4H), 7.38 - 7.32 (m, 2H), 7.28 (td, J)<sb>1</sb> = 3.1 Hz, J<sb>2</sb> = 8.6 Hz, 1H), 6.76 (d, J = 16 Hz, 1H), 6.6 - 6.5 (m, 1H), 4.20 (s, 3H), 4.0 - 3.9 (m, 2H), 2.35 (s, 3H) , 2.33 (s, 3H), 2.37 - 2.29 (m, 1H), 2.11 - 2.00 (m, 8H); ESMS m/z: found, 612 (M+1)<sp>+</sp>.

Example 10: 2-(4-Fluoro-2-methylphenylamino)-7-{3-[4-(4-fluorophenyl)-piperazin-1-yl]-propenyl}-1,6- Dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 30)

<img file="KR20080098490A_D0119.tif" />

2-(4-fluoro-2-methylphenylamino)-7-{3-[4-(4-fluorophenyl)-piperazin-1-yl]-propenyl}-1,6-dimethyl-1, 8-dihydro-imidazo[4,5-h]isoquinolin-9-one replaced with 4-phenyl-[1,4]azaphosphinane 4-oxide with 4-fluorophenylpiperazine It was prepared according to the procedure of Example 3. <sp>1</sp>H NMR (400 MHz DMSO-d<sb>6</sb>) (free base) δ ppm 10.78 (1H, s); 8.4 (1H, s); 7.67 (1H, d); 7.58 (1H, dd); 7.45 (1H, d); 7,07 (1H, m); 7.02 (2H, m); 6.95 (2H, m); 6.9 (1H, d); 6.56 (1H, td); 4.05 (3H, s): 3.23 (2H, d); 3.1 (4H, br. s); 2.61 (4H, br. s); 2.36 (3H, s); 2.23 (3H, s). ESMS m/z 539 (MH+).555.2.

Example 11: Inhibitory Activity on Kinases: Enzyme Assay and Cytoplasmic Assay

Suitable in vitro assays for determining kinase activity and its rate of inhibition by compounds are known (Kuzmic et al. Anal. Biochem. 2000, 286, 45-50].

The following protocol represents an assay for determining the rate of inhibition of a kinase under physiological conditions (pH 7.4). Kinase activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) methodology. Measurements were performed in a reaction volume of 50 μl using 96-well assay plates. Kinase Enzyme, Inhibitor, ATP (K for Kinase<sb>m</sb>in) and 1 μM peptide substrate (Biotin-AVLESEEELYSSARQ-NH<sb>2</sb>) with 20 mM Tris, 50 mM NaCl, MgCl<sb>2</sb>(5-25 mM depending on kinase), 1 mM DTT, 0.1 mM EDTA, 0.01% bovine serum albumin, 0.005% Tuwin-20 and 10% DMSO in reaction buffer, pH 7.4 for 1 hour. The reaction was mixed with 1.2 equivalents of EDTA (Mg) in 25 μl of 1x Lance buffer (Perkin-Elmer).<sp>2+</sp>for) was added and quenched. Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-TyrlOO antibody (Perkin-Elmer) in lx lance buffer were added in 25 μl volumes to obtain final concentrations of 100 nM and 2.5 nM, respectively, and the mixture was mixed with 1 incubated for hours. TR-FRET signals were measured on a multimode plate reader with excitation wavelengths of 330 nm and detection wavelengths of 615 nm and 665 nm. Activity was measured as the ratio of fluorescence at 665 nm to fluorescence at 615 nm. For each compound, enzyme activity was measured at various compound concentrations. Negative control reactions were performed with 6 replicates in the absence of inhibitors, and basal fluorescence levels were measured using 2 enzyme-free controls. Inhibition constants were obtained using the program batch Ki [Kuzmic et al. Anal. Biochem. 2000, 286, 45-50]. IC<sb>50</sb>was obtained using the following equation.

IC<sb>50</sb> = {Ki(app)/(1+[ATP]/K<sb>m</sb><sp>ATP</sp>)} + [E]<sb>total</sb>/2

For all kinases, [ATP] = K<sb>m</sb><sp>ATP</sp>, [Btk]<sb>total</sb> = 0.5 nM, [Lck]<sb>total</sb> = 6 nM.

Cytoplasmic calcium flux assays were performed according to the manufacturer's instructions (Molecular Devices). Briefly, wash actively growing Ramos B-cells (ATCC) in RPM1 medium supplemented with 10% FBS (Invitrogen), and approximately 5×10 per well in 96 well plates with low serum medium.<sp>5</sp> Cells/100 μl were re-cultured. The compound to be assayed is dissolved in DMSO, diluted to the appropriate concentration (final concentration of 0-10 μM at a dilution of 0.3) in low serum medium and added to each well (final DMSO concentration was 0.01% in each well), 5% CO at 37°<sb>2</sb> It was incubated for 1 hour in an incubator. Then 100 μl calcium assay dye (calcium 3 assay kit, molecular device) was added to each well and incubated for an additional 1 hour. Compound treated cells were stimulated with goat anti-human IgM antibody (80 ug/ml; Jackson ImmunoResearch) and Flexstation II384 (molecular device) at Ex=485 nm and Em=538 nm for 200 sec. was read as Relative fluorescence units (RFU) and 50% inhibition (IC50%) were recorded and analyzed using the built-in Softmax program (Molecular Instruments).

Data for both kinase and cytoplasmic calcium flux assays are presented in Table 7. All values are presented in μM.

<tables id="7"><img file="KR20080098490A_D0120.tif" /></tables>

A = less than 100 nM; B = greater than 100 nM, less than 1000 nM; C=&gt;1000 Nm; nd = not measured

Example 12: Pharmaceutical composition

Example 12a: Parenteral Composition

To prepare parenteral pharmaceutical compositions suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein was dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated in dosage unit form suitable for administration by injection.

In another embodiment, the following ingredients are mixed to form an injectable formulation.

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="2"><colspec colnum="1" align="justify" colname="col1" colwidth="5340" /><colspec colnum="2" align="justify" colname="col2" colwidth="5340" /><tbody><row><entry align="justify" colname="col1">ingredient</entry><entry align="justify" colname="col2">sheep</entry></row><row><entry align="justify" colname="col1">Compounds described herein</entry><entry align="justify" colname="col2">1.2g</entry></row><row><entry align="justify" colname="col1">sodium acetate buffer solution</entry><entry align="justify" colname="col2">0.4M 2.0mL</entry></row><row><entry align="justify" colname="col1">HCl (1N) or NaOH (1M)</entry><entry align="justify" colname="col2">Appropriate amount to achieve a suitable pH</entry></row><row><entry align="justify" colname="col1">Water (distilled, sterile)</entry><entry align="justify" colname="col2">Appropriate amount to make 20mL</entry></row></tbody></tgroup></table>

All the above ingredients except water were combined and heated to 60-70°C with stirring. A sufficient amount of water was then added with vigorous stirring at 60 DEG C to emulsify the ingredients, and then water was added in an appropriate amount to make 100 g.

Example 12b: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein was mixed with 750 mg of starch. The mixture is introduced into an oral dosage unit such as a hard gelatin capsule suitable for oral administration.

In another embodiment, the following ingredients are intimately mixed and compressed into single graded tablets.

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="2"><colspec colnum="1" align="justify" colname="col1" colwidth="5340" /><colspec colnum="2" align="justify" colname="col2" colwidth="5340" /><tbody><row><entry align="justify" colname="col1">ingredient</entry><entry align="justify" colname="col2">Amount per tablet (mg)</entry></row><row><entry align="justify" colname="col1">Compounds described herein</entry><entry align="justify" colname="col2">400</entry></row><row><entry align="justify" colname="col1">corn starch</entry><entry align="justify" colname="col2">50</entry></row><row><entry align="justify" colname="col1">Croscarmellose Sodium</entry><entry align="justify" colname="col2">25</entry></row><row><entry align="justify" colname="col1">lactose</entry><entry align="justify" colname="col2">120</entry></row><row><entry align="justify" colname="col1">magnesium stearate</entry><entry align="justify" colname="col2">5</entry></row></tbody></tgroup></table>

In another embodiment, the following ingredients are intimately mixed and loaded into hard shell gelatin capsules.

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="2"><colspec colnum="1" align="justify" colname="col1" colwidth="5340" /><colspec colnum="2" align="justify" colname="col2" colwidth="5340" /><tbody><row><entry align="justify" colname="col1">ingredient</entry><entry align="justify" colname="col2">Amount per tablet (mg)</entry></row><row><entry align="justify" colname="col1">Compounds described herein</entry><entry align="justify" colname="col2">200</entry></row><row><entry align="justify" colname="col1">Lactose, spray dried</entry><entry align="justify" colname="col2">148</entry></row><row><entry align="justify" colname="col1">magnesium stearate</entry><entry align="justify" colname="col2">2</entry></row></tbody></tgroup></table>

In some other embodiments, the following ingredients are admixed to form a suspension for oral administration.

<table><tgroup xmlns="http://www.oasis-open.org/tables/exchange/1.0" cols="2"><colspec colnum="1" align="justify" colname="col1" colwidth="5340" /><colspec colnum="2" align="justify" colname="col2" colwidth="5340" /><tbody><row><entry align="justify" colname="col1">ingredient</entry><entry align="justify" colname="col2">sheep</entry></row><row><entry align="justify" colname="col1">Compounds described herein</entry><entry align="justify" colname="col2">1.0g</entry></row><row><entry align="justify" colname="col1">fumaric acid</entry><entry align="justify" colname="col2">0.5g</entry></row><row><entry align="justify" colname="col1">sodium chloride</entry><entry align="justify" colname="col2">2.0g</entry></row><row><entry align="justify" colname="col1">methyl paraben</entry><entry align="justify" colname="col2">0.15g</entry></row><row><entry align="justify" colname="col1">propyl paraben</entry><entry align="justify" colname="col2">0.05g</entry></row><row><entry align="justify" colname="col1">granulated sugar</entry><entry align="justify" colname="col2">25.5g</entry></row><row><entry align="justify" colname="col1">Sorbitol (70% solution)</entry><entry align="justify" colname="col2">12.85g</entry></row><row><entry align="justify" colname="col1">Vegan K (Vanderbilt Co.)</entry><entry align="justify" colname="col2">1.0g</entry></row><row><entry align="justify" colname="col1">flavoring agent</entry><entry align="justify" colname="col2">0.035mL</entry></row><row><entry align="justify" colname="col1">coloring agent</entry><entry align="justify" colname="col2">0.5mg</entry></row><row><entry align="justify" colname="col1">Distilled water</entry><entry align="justify" colname="col2">Appropriate amount to make 100mL </entry></row></tbody></tgroup></table>

Example 12c: Sublingual (hard lozenge) composition

To prepare a pharmaceutical composition for oral delivery, such as a hard lozenge, 100 mg of a compound described herein is mixed with 420 mg of powdered sugar, 16 mL of hard corn syrup, 2.4 mL of distilled water and 0.42 mL of mint extract. do. The mixture is gently blended and poured into molds to form lozenges suitable for oral administration.

Example 12d: Inhalation Composition

To prepare a pharmaceutical composition for delivery by inhalation, 20 mg of a compound described herein was mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is introduced into an inhalation delivery device, such as a nebulizer suitable for inhalation administration.

Example 12e: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound described herein was mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparafen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then introduced into a rectal delivery device, such as a syringe suitable for rectal administration.

suppository formulation

A suppository of 2.5 g total weight contains a compound described herein (500 mg) with 2000 mg of Witepsol® H-15 (a triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc. (Riches-Nelson, Inc.) Inc.), located in New York).

Example 12f: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound described herein was mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then introduced into a container, such as a tube suitable for topical administration.

Example 12g: Ophthalmic Solution Composition

To prepare the pharmaceutical ophthalmic solution composition, 100 mg of a compound described herein was mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 μm filter. The resulting isotonic solution is then introduced into an ophthalmic delivery device, such as an eye drop container suitable for ophthalmic administration.

The examples and embodiments described herein are for the purpose of illustration only, and various modifications and variations suggested to those skilled in the art are intended to be included within the scope of this application and the spirit and scope and appended claims. All publications, patents and patent applications cited herein are all incorporated by reference.