WO2011017219A1 - Imidazoquinoxalinones and anti-tumor treatment - Google Patents

Abstract

The present invention provides compounds of Formula I, as well as pharmaceutical compositions including compounds of Formula I. The present invention also provides methods of treating B-cell leukemia and lymphoma, prostate cancer, and osteoporosis. The present invention also provides methods of inhibiting Btk, Etk, Itk and Mer.

Description

IMIDAZOQUINOXALINONES AND ANTI TUMOR TREATMENT

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 61/230,925, filed August 3, 2009, which is incorporated in its/their entirety herein for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with Government support under Grant Nos. ROl- DK052659 and RO 1 -CA098116-01, awarded by the National Institute of Health. The

Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

[0003] Phosphorylation plays a significant role in a wide range of cellular processes.

Kinases, such as the Etk/Btk family of kinases, have been indentified to be important in major human diseases and are intriguing drug targets. Etk (epithelial and endothelial tyrosine kinase, also called BMX) and Btk (Bruton's tyrosine kinase) are members of the Tec family of tyrosine kinases. Etk has been shown as an oncoprotein in prostate cancer cells.

Overexpression of Etk is associated with the development of advanced prostate cancer and transgenic mice bearing this gene developed preneoplastic lesions of prostate cancer (Dai et al, 2006). Etk is also highly expressed in endothelial cells and involved in angiogenesis and metastasis (Zhang et al., 2003; Chang et al, 2007). There is also evidence that Etk plays a role in breast carcinogenesis, hepatocellular carcinoma, and nasopharyngeal cancer (Bagheri et al, 2001 ; Guo et al, 2006, 2007, 2008). Etk inhibitors thus would block growth of epithelial tumors and the processes of angiogenesis and metastasis.

[0004] Btk, another family member, is expressed at high levels in B cells and B cell malignancies. Btk is critical for the maturation and activation of B cells. Btk is important for the survival of many leukemia cells and plays an important role in immune responses.

Therefore, inhibition of Btk would be beneficial in the treatment of auto-immune diseases, graft vs. host rejection disease, leukemia/lymphomas, as well as viral infection (Lindvall et al, 2005; Uckun, 2008)). In addition to Etk and Btk, other tyrosine kinases in Tec family such as Itk and Tec are also implicated in carcinogenesis (Chang et al. , 2007).

[0005] While a number of kinase inhibitors have been approved by the FDA to treat cancer, inflammatory disorders and other human diseases, there are still no effective inhibitors for many kinases. Accordingly, what is needed are new kinase inhibitors for the treatment of human diseases. Surprisingly, the present invention meets this and other needs.

BRIEF SUMMARY OF THE INVENTION

[0006] In one embodiment, the present invention provides compounds of Formula I:

[0007] Radical R¹ of Formula I can be H, Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C]_-6 haloalkyl, OR^la, C_]-6 alkyl-OR^la, -NR^laR^lb, -C_{1 -6} alkyl -NR¹³R^{1 b}, -C(O)R^la, -C(O)OR^la, -OC(O)OR¹³, -C(O)NR¹³R^{1 b}, -NR¹³C(O)R^{1 b}, -OC(O)NR¹³R^{1 b}, -NR¹³C(O)OR^{1 b},

-NR^laC(O)NR^l3R^lb, -CN, -NO₂, -N₃, -SR^la, -S(O)R^la, -S(O)₂R^la, -NR¹³S(O)₂R¹",

-S(O)₂NR^laR^lb, -NR¹³S(O)₂NR¹³R¹", C_3-I0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, C_]-6 alkylaryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents. Radical L¹ of Formula I can be a bond, Ci_-6 alkylene or Ci_-6 heteroalkylene.

[0008] Radical R² of Formula I can be C_1-6 alkyl, -NR^2aR^2b, C_3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R⁵ substituents. Radical L² of Formula I can be a bond, Ci_-6 alkylene, Ci_-6 heteroalkylene or Ci_-6 alkylene-C(O)-.

[0009] Racial R³ of Formula I can be -NR^6aR^6b, C_3-J0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R⁵ substituents. Radical L³ of Formula I can be a bond, C_2-6 alkenylene and C_2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene.

[0010] Radical R⁴ of Formula I can be H or C_]-6 alkyl.

[0011] Each of radical R⁵ of Formula I can separately be Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, Ci_-6 haloalkoxy, OR⁵³, Ci_-6 alkyl-OR^5a, aryl, heteroaryl, -NR^5aR^5b, Ci-βalkylaryl, -C_1-6 alkyl-heteroaryl, -C_{1 -6} alkyl-NR^5aR^5b, -C(0)R^5a, -C(0)0R^5a, -OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b,

-NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R^5a, -NR^5aS(O)₂R^5b, -NR^5aS(O)₂aryl, -S(O)₂NR^5aR^5b, -NR^5aS(O)₂NR^5aR^5b and heteroaryl-oxy. [0012] Each of radicals R^6a and R^6b of Formula I can separately be H or Cj_-6 alkyl, wherein the Ci_-6 alkyl group can optionally be substituted with C_2-6 alkenyl, C_2-6 alkynyl, halogen, Ci- ₆ haloalkyl, OR^5a, -NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a, -OC(O)OR⁵³, -C(O)NR^5aR^5b,

-NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R⁵³, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b or -NR^5aS(O)₂NR^5aR^5b. [0013] Radical X of Formula I can be -O- or -N(R⁷)-. Radical Y of Formula I can be C_{1 -6} alkylene, Ci_-6 heteroalkylene or heterocycloalkyl. Subscript n of Formula I can be 0 or 1.

[0014] Each of radicals R^la, R^{I b}, R^2a, R^2b, R^5a, R^5b and R⁷ of Formula I can separately be H or Ci-₆ alkyl. Alternatively, when attached to the same atom, radicals R^la and R^lb, R^2a and R^2b, R^5a and R^5b, or R⁷ and Y are optionally combined with the atom to which each is attached to form a C_3-8 heterocycloalkyl which can optionally be substituted with Ci_-6 alkyl.

[0015] Alternatively, two R⁵ groups are combined to form a C₃-₈ heterocycloalkyl which can optionally be substituted with Ci_-6 alkyl.

[0016] The salts and isomers of the compounds of Formula I are also included.

[0017] In another embodiment, the present invention provides a pharmaceutical composition of a compound of Formula I and a pharmaceutically acceptable excipient.

[0018] In other embodiments, the present invention provides a method of treating B-cell leukemia or B-cell lymphoma, prostate cancer, or osteoporosis, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I.

[0019] In some other embodiments, the present invention provides a method for the inhibition of Btk, Etk, or Mertk by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 shows a scheme for the preparation of the compounds of the present invention. [0021] Figure 2 shows the viability of LnCaP cells following treatment of compounds at 10 μM was measured using an MTT assay.

[0022] Figures 3A and 3B shows autophagy in CWR22Rvl-LC3 cells. Figure 3A shows autophagosomes as visualized by GFP-LC3 "puncta." Figure 3B shows an immunoblot (CWR22Rvl) of endogenous LC3 isoforms.

[0023] Figure 4 shows inhibition of cell migration of PC3 human prostate cancer cells by compounds of the present invention.

[0024] Figure 5 shows inhibition of Btk kinase activity of compounds of the present invention. [0025] Figure 6 shows inhibition of Etk kinase activity of a compound of the present invention.

[0026] Figure 7 shows percent growth of BCBLl, LnCap and RWPEl (immortalized human prostate cells) for compounds of the present invention at 20 μM. The data was obtained using the MTT assay described within. [0027] Figure 8 shows percent growth of BCBL 1 , LnCap and RWPE 1 (immortalized human prostate cells) for compounds of the present invention at 5 μM. The data was obtained using the MTT assay described within.

[0028] Figure 9 shows percent growth of BCBLl, LnCap and RWPEl (immortalized human prostate cells) for compounds of the present invention at 1 μM. The data was obtained using the MTT assay described within.

[0029] Figure 10 shows inhibition of Mertk kinase activity of compounds of the present invention.

[0030] Figure 11 shows inhibition of Itk kinase activity of compounds of the present invention. CTA06 is a positive control compound. The data was obtained using the TLC kinase inhibition assay described within.

[0031] Figure 12 shows growth inhibition of Jurkat, BCBLl, LnCap and RWPEl cells treated with compounds of the present invention. The data was obtained using the MTT assay described within. DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0032] As used herein, the term "alkyl" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. For example, Ci-C₆ alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Other alkyl groups include, but are not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl can include any number of carbons, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 and 5-6.

[0033] As used herein, the term "alkylene" refers to an alkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene. For instance, a straight chain alkylene can be the bivalent radical of -(CH₂)_n; where n is 1, 2, 3, 4, 5 or 6. Alkylene groups include, but are not limited to, methylene, ethylene, propylene,

isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. [0034] The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines a compound or radical which can be branched or unbranched with up to and including 7, preferably up to and including 4 and (as unbranched) one or two carbon atoms.

[0035] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined above, having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)₂-. For example, heteroalkyl can include ethers, thioethers and alkyl-amines. The heteroalkyl group is typically monovalent, but can be divalent, such as when the heteroalkyl group links two moieties together, i.e., a

"heteroalkylene." The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.

[0036] As used herein, the term "heteroalkylene" refers to a heteroalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene. [0037] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =0, =NR\ =N-0R', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO₂R', -CONR'R", -OC(O)NR⁵R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0)₂R', -NR-C(NR'R"R'")=NR"", -NR-C(NR' R")=NR'", - S(O)R', -S(O)₂R', -S(O)₂NR⁵R", -NRSO₂R', -CN and -NO₂ in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R', R⁵⁵, R⁵'⁵ and R⁵'⁵' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1 -pyrrolidinyl and 4-morpholinyl. [0038] As used herein, the term "alkenyl" refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1 ,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1 ,4-hexadienyl, 1,5-hexadienyl, 2,4- hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons. The alkenyl groups is typically monovalent, but can be divalent, such as when the alkenyl group links two moieties together.

[0039] As used herein, the term "alkenylene" refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene. Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.

[0040] As used herein, the term "alkynyl" refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one triple bond. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4- pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1 ,4-hexadiynyl, 1,5- hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons.

[0041] As used herein, the term "alkynylene" refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene. Alkynylene groups include, but are not limited to, ethynylene, propynylene, isopropynylene, butynylene, sec-butynylene, pentynylene and hexynylene.

[0042] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0043] As used herein, the term "haloalkyl" refers to alkyl group, as defined above, where some or all of the hydrogen atoms are substituted with halogen atoms. Halogen (halo) preferably represents chloro or fluoro, but may also be bromo or iodo. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1, 2,3,4, 5-pentafluoro-phenyl, etc. The term "perfluoro" defines a compound or radical which has at least two available hydrogens substituted with fluorine. For example, perfluorophenyl refers to 1,2,3,4,5- pentafluorophenyl, perfluoromethane refers to 1,1,1 -trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy.

[0044] As used herein, the term "alkoxy" refers to alkyl group having an oxygen atom that either connects the alkoxy group to the point of attachment or is linked to two carbons of the alkoxy group. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. For example, the alkoxy groups can be substituted with halogens to form a "halo-alkoxy" group.

[0045] As used herein, the term "halo-alkoxy" refers to an alkoxy group having at least one halogen. Halo-alkoxy is as defined for alkoxy where some or all of the hydrogen atoms are substituted with halogen atoms. The alkoxy groups can be substituted with 1, 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Halo-alkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

[0046] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic rings include, for example, norbornane, decahydronaphthalene and adamantane. For example, C_3-8cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane. [0047] As used herein, the term "cycloalkylene" refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene. [0048] As used herein, the terms "heterocycle" or "heterocycloalkyl" refer to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)₂-. For example, heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and 1 ,4-dioxa-8- aza-spiro[4.5]dec-8-yl.

[0049] As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group, as defined above, linking at least two other groups. The two moieties linked to the

heterocycloalkylene can be linked to the same atom or different atoms of the

heterocycloalkylene.

[0050] As used herein, the term "aryl" refers to a monocyclic or fused bicyclic, tricyclic or greater, aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, benzyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. Aryl groups can be mono-, di- or tri-substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C₂-C₃-alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2- phenanthrenyl. Alkylenedioxy is a divalent substitute attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C₂-C₃-alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or

oxypropylene. An example for oxy- C₂-C₃-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl. [0051] Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.

[0052] Examples of substituted phenyl groups as R are, e.g. 4-chlorophen-l-yl, 3,4- dichlorophen- 1 -yl, 4-methoxyphen- 1 -yl, 4-methylphen- 1 -yl, 4-aminomethylphen- 1 -yl, A- methoxyethylaminomethylphen- 1 -yl, 4-hydroxyethylaminomethylphen- 1 -yl, 4-hydroxyethyl- (methyl)-aminomethylphen-l-yl, 3-aminomethylphen-l-yl, 4-N-acetylaminomethylphen-l- yl, 4-aminophen-l-yl, 3-aminophen-l-yl, 2-aminophen-l-yl, 4-phenyl-phen-l-yl, A- (imidazol-l-yl)-phen-yl, 4-(imidazol-l-ylmethyl)-phen-l-yl, 4-(morpholin-l-yl)-phen-l-yl, A- (morpholin- 1 -ylmethyl)-phen- 1 -yl, 4-(2-methoxyethylaminomethyl)-phen- 1 -yl and A-

(pyrrolidin-l-ylmethyl)-phen-l-yl, 4-(thiophenyl)-phen-l-yl, 4-(3-thiophenyl)-phen-l-yl, A- (4-methylpiperazin-l-yl)-phen-l-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally substituted in the heterocyclic ring.

[0053] As used herein, the term "aryl-oxy" refers to an aryl group, as defined above, where the aryl group is linked through an oxygen atom. Aryl-oxy groups include, but are not limited to, phenyl-oxy.

[0054] As used herein, the term "arylene" refers to an aryl group, as defined above, linking at least two other groups. The two moieties linked to the arylene are linked to different atoms of the arylene. Arylene groups include, but are not limited to, phenyl ene. [0055] As used herein, the term "arylene-oxy" refers to an arylene group, as defined above, where one of the moieties linked to the arylene is linked through an oxygen atom. Arylene- oxy groups include, but are not limited to, phenylene-oxy.

[0056] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 4 of the ring atoms are a heteroatom each N, O or S. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3- pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl represents preferably 2-, 3- or A- quinolinyl. Isoquinolinyl represents preferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl represents preferably 3 -benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(l,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.

[0057] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted.

[0058] As used herein, the term "heteroaryl-oxy" refers to a heteroaryl group, as defined above, where the heteroaryl group is linked through an oxygen atom. Heteroaryl -oxy groups include, but are not limited to, pyridyl-oxy. [0059] As used herein, the term "heteroarylene" refers to an heteroaryl group, as defined above, linking at least two other groups. The two moieties linked to the heteroarylene are linked to different atoms of the heteroarylene.

[0060] Substituents for the aryl and heteroaryl groups are varied and are selected from: - halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO₂, -CO₂R', -CONR'R", -C(O)R', - OC(O)NR⁵R", -NR"C(O)R', -NR"C(O)₂R', ,-NR'-C(O)NR"R'", -NH-C(NH₂)=NH, - NR'C(NH₂)=NH, -NH-C(NH₂)=NR', -S(O)R', -S(O)₂R', -S(O)₂NR⁵R", -N₃, -CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, and perfluoro(Ci-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, (Ci-C₈)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(Ci-C₄)alkyl, and (unsubstituted aryl)oxy-(Ci-C₄)alkyl.

[0061] As used herein, the term "alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent in order to link to the aryl component to the point of attachment. In some instances, the alkyl component can be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl.

[0062] As used herein, the term "alkyl-heteroaryl" refers to a radical having an alkyl component and an heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent in order to link to the heteroaryl component to the point of attachment. In some instances, the alkyl component can be absent. The heteroaryl component is as defined above.

[0063] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0064] Pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and

tris-(hydroxymethyl)-methyl-ammonium salts.

[0065] As used herein, the term "prodrug" refers to covalently bonded carriers which are capable of releasing the active agent of the methods of the present invention, when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of the active agents of the present invention include active agents wherein a hydroxy, amidino, guanidino, amino, carboxylic or a similar group is modified. [0066] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0067] As used herein, the terms "treat", "treating" and "treatment" refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom or condition. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0068] "Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

II. Compounds [0069] In some embodiments, the compounds of the present invention are those of

Formula I:

[0070] Radical R of Formula I can be H, d_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, Ci_-6 haloalkyl, OR^la, C_-6 alkyl-OR^la, -NR^laR^lb, -C,_₆ alkyl-NR^laR^Ib, -C(O)R^la, -C(O)OR^la, -OC(O)OR¹³, -C(O)NR^laR^lb, -NR^laC(O)R^lb, -OC(O)NR^laR^lb, -NR^laC(O)OR^lb,

-NR^laC(O)NR^laR^lb, -CN, -NO₂, -N₃, -SR^la, -S(O)R^la, -S(O)₂R¹³, -NR¹³S(O)₂R^{1 b},

-S(O)₂NR^laR^lb, -NR^laS(O)₂NR^{l a}R^{l b}, C_3-I0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, C_1-6 alkylaryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents. Radical L¹ of Formula I can be a bond, Ci_-6 alkylene or Ci_-6 heteroalkylene.

[0071] Radical R² of Formula I can be C_{1 -6} alkyl, -NR^2aR^2b, C_3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R⁵ substituents. Radical L² of Formula I can be a bond, Ci_-6 alkylene, Cj_-6 heteroalkylene or Ci_-6 alkylene-C(O)-.

[0072] Racial R³ of Formula I can be -NR^6aR^6b, C_3-I0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R⁵ substituents. Radical L³ of Formula I can be a bond, C_2-6 alkenylene and C_2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroaryl ene. [0073] Radical R⁴ of Formula I can be H or C_1-6 alkyl.

[0074] Each of radical R⁵ of Formula I can separately be Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, Q_-6 haloalkyl, C_1-6 haloalkoxy, OR^5a, C_1-6 alkyl-OR^5a, aryl, heteroaryl, -NR^5aR^5b, C_1-6alkylaryl, -C_1-6 alkyl-heteroaryl, -C_1-6 alkyl-NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a,

-OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b,

-NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R^5a, -NR^5aS(O)₂R^5b, -NR^5aS(O)₂aryl, -S(O)₂NR^5aR^5b, -NR^5aS(O)₂NR^5aR^5b or heteroaryl-oxy.

[0075] Each of radicals R^6a and R ^b of Formula I can separately be H or C_1-6 alkyl, wherein the C_1-6 alkyl group can optionally be substituted with C_2-6 alkenyl, C_2-6 alkynyl, halogen, C₁- ₆ haloalkyl, OR^5a, -NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a, -OC(O)R^5a, -OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R⁵³, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b or -NR^5aS(O)₂NR^5aR^5b.

[0076] Radical X of Formula I can be -O- or -N(R⁷)-. Radical Y of Formula I can be C_1-6 alkylene, C_1-6 heteroalkylene or heterocycloalkyl. Subscript n of Formula I can be 0 or 1. [0077] Each of radicals R^la, R^lb, R^2a, R^2b, R^5a, R^5b and R⁷ of Formula I can separately be H or C_1-6 alkyl. Alternatively, when attached to the same atom, radicals R^la and R^lb, R^2a and R^2b, R^5a and R^5b, or R⁷ and Y are optionally combined with the atom to which each is attached to form a C_3-8 heterocycloalkyl which can optionally be substituted with C_1-6 alkyl.

[0078] Alternatively, two R⁵ groups are combined to form a C₃-₈ heterocycloalkyl which can optionally be substituted with C_1-6 alkyl.

[0079] The salts and isomers of the compounds of Formula I are also included.

[0080] In some embodiments, Radical R¹ of Formula I can be C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, OR^la, C_1-6 alkyl-OR^la, -NR^{l a}R^lb, -C_1-6 alkyl-NR^{l a}R^Ib, -C(O)R^{I a}, -C(O)OR¹³, -OC(O)OR'³, -C(O)NR^l3R^lb, -NR^l3C(0)R^lb, -OC(O)NR^{l a}R^lb, -NR^laC(O)OR^{i b}, -NR^!aC(0)NR^laR^lb, -CN, -NO₂, -N₃, -SR^la, -S(O)R¹³, -S(O)₂R¹³,

-NR¹³S(O)₂R^{1 b}, -S(O)₂NR¹³R^{1 b}, -NR^laS(O)₂NR^laR^Ib, C_3-10 cycloalkyl, C_3-9 heterocycloalkyl, aryl, C_1-6 alkylaryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents. Radical L¹ of Formula I can be a bond, C_{1 -6} alkylene or C_1-6 heteroalkylene. Radical R of Formula I can be C_1-6 alkyl, -NR^2aR^2b, C_3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R⁵ substituents. Radical L of Formula I can be a bond, C_1-6 alkylene, Ci_-6 heteroalkylene or Q_-6 alkylene-C(O)-. Racial R³ of Formula I can be -NR^6aR^6b, C_3-I0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R⁵ substituents. Radical L³ of Formula I can be a bond, C_2-6 alkenylene and C_2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene. Radical R⁴ of Formula I can be H or Ci_-6 alkyl. Each of radical R⁵ of Formula I can separately be Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, Ci_-6 haloalkyl, Ci_-6 haloalkoxy, OR^5a, C_1-6 alkyl-OR^5a, -NR^5aR^5b, -C_]-6 alkyl-NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a, -OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R⁵³, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b,

-NR^5aS(O)₂NR^5aR^5b or heteroaryl-oxy. Each of radicals R^6a and R^6b of Formula I can separately be H or Ci_-6 alkyl, wherein the Ci_-6 alkyl group can optionally be substituted with C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, 0R^5a, -NR^5aR^5b, -C(O)R^5a, -C(0)0R^5a, -OC(O)R⁵³, -OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R^5a, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b or -NR^5aS(O)₂NR^5aR^5b. Radical X of Formula I can be -O- or -N(R⁷)-.

Radical Y of Formula I can be Cj_-6 alkylene, Ci_-6 heteroalkylene or heterocycloalkyl.

Subscript n of Formula I can be O or 1. Each of radicals R^{l a}, R^lb, R^2a, R^2b, R^5a, R^5b and R⁷ of Formula I can separately be H or Ci_-6 alkyl. Alternatively, when attached to the same atom, radicals R^{l a} and R^Ib, R^2a and R^2b, R^5a and R^5b, or R⁷ and Y are optionally combined with the atom to which each is attached to form a C_3-8 heterocycloalkyl.

[0081] In other embodiments, radical R¹ of Formula I can be Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, Ci_-6 haloalkyl, OR^{l a}, C_1-6 alkyl-OR^la, -NR^laR^lb, -C_1-6 alkyl-NR^{l a}R^lb, -C(O)R^la, -C(O)OR^{! a}, -OC(O)OR¹³, -C(0)NR^laR^lb, -NR^laC(O)R^lb, -OC(O)NR¹³R^{1 b}, -NR^laC(0)0R^lb, -NR^laC(O)NR^laR^lb, -CN, -NO₂, -N₃, -SR^la, -S(O)R^la, -S(O)₂R^la,

-NR¹³S(O)₂R^{1 b}, -S(0)₂NR^{l a}R^lb, -NR^laS(O)₂NR^laR^lb, C_3-I0 cycloalkyl, C_3-9 heterocycloalkyl, aryl, C]_-6 alkylaryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents.

[0082] In some other embodiments, the compounds of the present are those of Formula Ia:

[0083] In other embodiments, radical R¹ of Formula Ia can be Ci_-6 alkyl, OR^la, -NR^!aR^ib, -C(O)R^la, -C(O)OR^{l a}, -OC(O)OR¹³, -C(0)NR^laR^lb, -NR^laC(O)R^lb, -0C(0)NR^laR^lb, -NR^laC(O)OR^Ib, -NR^laC(0)NR^laR^lb, -SR^la, -S(O)R^{1 a}, -S(O)₂R¹³, -NR^laS(0)₂R^!b,

-S(O)₂NR^laR^lb, -NR^laS(0)₂NR^laR^lb or aryl. Radical L¹ of Formula Ia can be Cj_-6 alkylene. Radical R² of Formula Ia can be C_3-9 heterocycloalkyl. Radical L² of Formula Ia can be Ci_-6 alkylene. Radical R³ of Formula Ia can be aryl or heteroaryl. Radical L³ of Formula Ia can be a bond or C_2-6 alkenylene.

[0084] In another embodiment, L¹ is a bond or Ci_-6 alkylene.

[0085] In other embodiments, R¹ is aryl. In some other embodiments, R¹ is phenyl. In still other embodiments, R⁵ can be H, halogen, or Ci_-6 haloalkyl. In yet other embodiments, R⁵ is F or Cl. In another embodiment, L¹ is a bond or Ci_-6 alkylene, and R¹ is aryl.

[0086] In other embodiments, L² can be Ci_-6 alkylene.

[0087] In some other embodiments, R² can be heterocycloalkyl. In still other

embodiments, R² can be a nitrogen containing heterocycloalkyl. In yet other embodiments, radical R² can be aziridine, azetidane, 1,3-diazazitidine, pyrolidine, pyrolidin-2-one, piperidine, 1,2-piperazine, 1,3-piperazine, 1 ,4-piperazine, or azocane. In still yet other embodiments, R² can be a C_5-6 heterocycloalkyl containing one nitrogen heteroatom. In another embodiment, L² is Ci_-6 alkylene and R² is a heterocycloalkyl.

[0088] In other embodiments, L³ is a bond, arylene or heteroarylene. In some

embodiments, L³ is a bond. In some other embodiments, L³ is arylene, such as phenylene. In yet other embodiments, L³ is heteroarylene, such as thiophene.

[0089] In some embodiments, R³ is heteroaryl. In other embodiments, radical R³ can be phenyl, pyrrole, pyrazole, imidzaole, pyridine, pyrimidine, pyrazine, pyridazine, 1 ,2,4- triazine, 1,3,5-triazine, pyrrolizine, indole, quinoline, isoquinoline, benzimidazole, indazole, quinolizine, cinnoline, quinazoline, phthalazine, naphthyridine, carboline, or carbazole. IN some other embodiments, L³ is aryl or heteroaryl, and R³ is heteroaryl.

[0090] In another embodiment, at least one of R¹, L³ and R³ is aryl, arylene, heteroaryl or heteroarylene. In some embodiments, at least one of R¹ and R³ is aryl or heteroaryl. In other embodiments, at least one of L³ and R³ is heteroaryl or heteroarylene. [0091] In still other embodiments, R¹ is phenyl, optionally substituted with halogen, L¹ is a bond or Ci_-6 alkylene, R² is piperidine, L² is Ci_-6 alkylene, R³ is a heteroaryl, L³ is selected from the group consisting of a bond, phenylene or thiophene, and R⁴ is hydrogen.

[0092] In still other embodiments, radical R¹ of Formula Ia can be C_]-6 alkyl, -C(O)OR^{l a} or phenyl. Radical L¹ of Formula Ia can be Ci_-6 alkylene. Radical R² of Formula Ia can be pyrolidine or pyrolidin-2-one. Radical L² of Formula Ia can be Ci_-6 alkylene. Radical R^5a of Formula Ia can be Cj_-6 alkyl. Radical R³ of Formula Ia can be phenyl or carbazole. Radical L³ of Formula Ia can be a bond or C_2-6 alkenylene.

[0093] In another embodiment, the compounds of Formula I can be

wherein R is Ci_-6 alkyl.

[0094] In some embodiments, the compounds of Formula I can be

[0095] In other embodiments, the compound can have the formula:

In some other embodiments, L¹ is a bond or Ci_-6 alkylene, and R⁵ is H or halogen. In yet other embodiments, L^! is a bond. In still yet other embodiments, L¹ is Ci_-6 alkylene. In some other embodiments, R⁵ is H. In still other embodiments, R⁵ is halogen. In yet other embodiments, R⁵ is F or Cl. In some other embodiments, L² is Ci_-6 alkylene and R² is a C_5-6 heterocycloalkyl containing 1 N heteroatom. In still other embodiments, L is a bond, arylene or heteroarylene, and R³ is heteroarylene. In other embodiments, L³ is a bond. In some other embodiments, L³ is phenylene. In still other embodiments, L is thiophene. In another embodiment, R³ is pyridyl. In some embodiments, R³ is 4-pyridyl. In some embodiments, the compounds can have the formula:

In other embodiments, the compound can have the formula:

[0096] In some other embodiments, the compounds of Formula I can be

[0097] In still other embodiments, the compounds of Formula I can be

] In another embodiment, the compounds of Formula I can be

[0099] In still other embodiments, the compound can be:

[0100] Compounds of the present invention are also described in Table 1 below. In some embodiments, the compound of the present invention can be CTAOOl, CTA020, CTA033, CTA036, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA065, CTA067, CTA 109, or CTAl 21. In other embodiments, the compound of the present invention can be CTA004, CTA008, CTAOl 3, CTA014, CTAOl 7, CTA038, CTA040, or CTA062. In some other embodiments, the compound of the present invention can be CTAOOl, CTA004, CTA008, CTA013, CTA014, CTA017, CTA020, CTA033, CTA036, CTA038, CTA040, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA065, CTA067, CTA109, or CTA121. In yet other embodiments, the compound can be CTAOOl, CTA020, CTA033, CTA036, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA062, CTA065, CTA067, CTA109, or CTA121. In still other embodiments, the compound is CTA056. In still yet other embodiments, the compound can be CTA056, CTA092, CTA093, CTA095, CTA097 or CTA099. In another embodiment, the compound can be CTA129, CTA151, CTA163 or CTA164. In some embodiments, the compound can be CTAl 51. In another embodiment, the compound can be CTA056 or CTA151.

[0101] Pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and

tris-(hydroxymethyl)-methyl-ammonium salts.

[0102] Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. [0103] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0104] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.

[0105] Prodrug and metabolite forms of the compounds of the present invention are also included in the present invention.

III. Compositions

[0106] The compounds of the present invention can be formulated in a variety of different manners known to one of skill in the art. Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington 's Pharmaceutical Sciences, 20^th ed., 2003, supra). For example, the compounds of the present invention can be prepared and administered in a wide variety of oral, injectible and topical dosage forms. The compounds of the present invention can also be prepared and administered in parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally or topically, e.g., in a liquid or gel form or as a patch.

[0107] Formulations suitable for administration can consist of (a) liquid solutions, such as an effective amount of a compound of the present invention suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets, depots or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; (d) suitable emulsions; and (e) patches. The

pharmaceutical forms can include a pharmaceutically acceptable excipient, such as one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0108] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents. Preferred pharmaceutical preparations can deliver the compounds of the invention in a sustained release formulation.

[0109] The pharmaceutical preparations are typically delivered to a mammal, including humans and non-human mammals. Non-human mammals treated using the present methods include domesticated animals {i.e., canine, feline, murine, rodentia, and lagomorpha) and agricultural animals (bovine, equine, ovine, porcine).

[0110] The compounds of the present invention can be administered as frequently as necessary, including hourly, daily, weekly or monthly. The compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.0001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Doses can be given daily, or on alternate days, as determined by the treating physician. Doses can also be given on a regular or continuous basis over longer periods of time (weeks, months or years), such as through the use of a subdermal capsule, sachet or depot, or via a patch. [0111] The pharmaceutical compositions can be administered to the patient in a variety of ways, including topically, parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally. Preferably, the pharmaceutical compositions are administered parenterally, topically, intravenously, intramuscularly or orally.

[0112] In clinical studies, number of lesions, tumor size, and tumor growth rate can be monitored by radiography, tomography, and, where possible, direct measurement of tumor mass. Anti-tumor effects can also be measured using molecular biology and biochemistry techniques, such as ELISA, PCR, western blotting, or immunocytochemistry.

[0113] The pharmaceutically effective amount of a composition required as a dose will depend on the route of administration, the type of disease being treated, and the physical characteristics of the patient. The dose can be tailored to achieve a desired effect, but will depend on such factors as body surface area, weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0114] The foregoing are general guidelines only that can be expanded or altered based on, for example, disease type and grade, patient age, health status, and sex, the particular drugs used in combination, the route and frequency of administration, and experimental and clinical findings using a multidrug combination.

[0115] In some embodiments, the present invention provides a pharmaceutical composition of a compound of Formula I and a pharmaceutically acceptable excipient. IV. Methods

[0116] The compounds of the present invention can be used to treat a variety of conditions. For example, the compounds can be used to treat B-cell and T-cell malignancies, such as leukemia and lymphoma, cancer, such as prostate cancer, as well as osteoporosis. A. B-cell/T-cell malignancies

[0117] The compounds of the present invention are useful for the treatment of a variety of B-cell and T-cell malignancies. B-cells (Bone-cells in mammals) and T-cells are

lymphocytes that are involved in the humoral immune response and play an important role in the adaptive immune system. B-cells primarily make antibodies (known as plasma B-cells) in response to an antigen, thereby tagging the antigen for destruction. Plasma B-cells are activated in response to an antigen and are formed from memory B-cells. Memory B-cells are long lived B-cells that have been exposed to the antigen previously (exposure of a naϊve B-cell to the antigen), and thus "remember" the antigen and are able to mount a quicker response via the plasma B-cells than would otherwise be possible. [0118] B-cell and T-cell malignancies include, but are not limited to, autoimmune disorders, leukemias such as B-cell acute lymphocytic leukemia and B-cell chronic lymphocytic leukemia, lymphomas such as non-Hodgkin's lymphomas and B-cell lymphoma, or multiple myeloma. Other B-cell and T-cell malignancies can be treated by the compounds of the present invention. [0119] Given the important role of Btk in B-cell malignancies, the activities of these agents to inhibit Btk was used to identify compounds for the treatment of B-cell malignancies. In addition, the effect of these agents on treatment of B-cell malignancies was also identified using BCBLl cells (human lymphoma cells) and MTT growth inhibition assay.

[0120] Similarly, the role of Itk in T-cell proliferation and differentiation was exploited to identify compounds of the present invention useful for the treatment of T-cell malignancies using Jurkat cells.

[0121] In some embodiments, the present invention provides a method of treating leukemia or lymphoma, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of the present invention, thereby treating the leukemia or lymphoma. In some embodiments, the leukemia or lymphoma can be treated by inhibiting Itk. In other embodiments, the leukemia or lymphoma can be treated by inhibiting Btk.

[0122] In some embodiments, the present invention provides a method of treating B-cell leukemia or B-cell lymphoma, by administering to a subject in need thereof, a

pharmaceutically acceptable amount of a compound of Formula I, thereby treating the B-cell leukemia or lymphoma.

B. Treatment of Cancer

[0123] The compounds of the present invention are useful for the treatment of cancer, such as breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, non- small cell lung cancer, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, and kidney cancer, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma,

glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas. In some embodiments, the cancer is prostate cancer.

[0124] Compounds useful for the treatment of cancer can be identified by any number of methods known to one of skill in the art. For example, LnCaP cells can be seeded at 5,000 cells/well in 96-well plate overnight and treated with the compounds of the present invention. The cell viability can then be measured using any means known in the art, such as using an MTT assay. Using the assay described herein, compounds of Formula I were identified as active for the treatment of prostate cancer, see Table 3. Any prostate cancer cell line can be used to test for the efficacy of a compound of the present invention for the treatment of prostate cancer, for example, LnCaP, PC3, DU145 and CWR22Rvl . [0125] In some embodiments, the present invention provides a method of treating prostate cancer, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby treating the prostate cancer.

C. Inhibition of Tyrosine Kinases of the Tec Family [0126] The compounds of the present invention are useful for the inhibition of tyrosine kinases. Tyrosine kinases that can be inhibited by the compounds of the present invention include, but are not limited to, the Tec family and the Axl-Sky-Mer family of tyrosine kinases. Tyrosine kinases of the Tec family are involved in the regulation of immune functions, including T-cell signaling and activation. Tyrosine kinases of the Tec family include epithelial and endothelial tyrosine kinases (Etk), Bruton's tyrosine kinase (Btk), IL2- inducible T-cell kinase (Itk), among others. Tyrosine kinases of the Axl-Sky-Mer family are involved in leukemia, gastric cancer, prostate cancer, as well as immune diseases. Tyrosine kinases of the Axl-Sky-Mer family include the c-mer protooncogene tyrosine kinase, or Mer tyrosine kinase (Mertk). [0127] Compounds useful for the inhibition of tyrosine kinase activity can be identified by any number of methods known to one of skill in the art. For example, compounds can be incubated with Btk and a substrate, such as YIYGSFK, in a kinase reaction using ³³P-ATP. The products of the reaction can be analyzed by any means known to one of skill in the art. For example, the product can be analyzed on a TLC (Thin Layer Chromatography) plate to determine if the compound inhibits Btk. The same assay is useful for the identification of compounds that inhibit other tyrosine kinases, such as Etk, Itk and Mertk. When Mertk is the target, the substrate can be TSFYGRH.

[0128] In some embodiments, the present invention provides a method for the inhibition of Bruton's tyrosine kinase (Btk) by administering to a subject in need thereof, a

pharmaceutically acceptable amount of a compound of Formula I₅ thereby inhibiting Btk.

[0129] In other embodiments, the present invention provides a method for the inhibition of epithelial and endothelial tyrosine kinases (Etk) by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I₅ thereby inhibiting Etk.

[0130] In some other embodiments, the present invention provides a method for the inhibition of Mer tyrosine kinase (Mertk) by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby inhibiting Mertk. [0131] In other embodiments, the present invention provides a method for the inhibition of IL2-inducible T-cell kinase (Itk) by administering to a subject in need thereof, a

pharmaceutically acceptable amount of a compound of Formula I, thereby inhibiting Itk.

[0132] In some other embodiments, the present invention provides a method of inhibiting a tyrosine kinase including epithelial and endothelial tyrosine kinases (Etk), Bruton's tyrosine kinase (Btk), Mer tyrosine kinase (Mertk) or IL2-inducible T-cell kinase (Itk), the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of the present invention, thereby inhibiting the tyrosine kinase.

D. Treatment of Osteoporosis [0133] The compounds of the present invention are useful for the treatment of osteoporosis. Bruton's tyrosine kinase (Btk) and tyrosine kinase (Tec), tyrosine kinases essential for B cell development, have been shown to regulate osteoclast differentiation by linking two essential pathways for osteoclast differentiation: RANKL and ITAM. RANK and ITAM signaling both signal through formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLC- mediated activation of calcium signal (J Immunol 2009, 182(l):329-339). Mice with tyrosine kinases Btk and Tec knockdown developed severe osteoporosis that was associated with a defect in bone resorption.

[0134] Compounds of the present invention useful as small molecule inhibitors of Btk can be used to decrease osteoclast activation and prevent bone loss. Such compounds can be identified using bone marrow cells (BMMs) from 2-month-old C57BL mice. The BMMs can be cultured with the compound (at 0, 10^"10, 10^"8, 10^"6M) supplemented with 20ng/ml mCSF and 100ng/ml RANKL for 7-10 days. TRAP+ cell formation, representing mature osteoclasts, can be monitored. Dentine resorption pit area can also be monitored.

[0135] In some embodiments, the present invention provides a method of treating osteoporosis, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby treating osteoporosis.

V. Examples

Example 1: Preparation of 1,2,7-trisubstituted 6H-Imidazo[4,5-g]quinoxaIin-6-ones

[0136] General Procedure: To a solution of l,5-difluoro-2,4-dinitrobenzene (204.0 mg, 1.0 mmol) in N,N-dimethylformamide (DMF, 0.5ml) was added a solution of an α-amino acid ester hydrochloride (1.0 mmol) and N,N-diisopropylethylamine (DIEA, 383.2μL, 2.2 mmol) in DMF (1.5 ml) dropwise under vigorous stirring. This step was relatively fast and the reaction was usually done after half an hour. Analytical HPLC was used to check reaction for completion. This was followed by the addition of a solution of a primary amine (1.0 mmol) and DIEA (174.2μL, 1.0 mmol) in DMF (1 ml). The resulting mixture was agitated at room temperature overnight. HPLC was used to check completion. Ethanol (12 ml), Pd/C (10%, 200mg), and ammonium formate (1.5Og, 23.8 mmol) were added. The solution was heated to reflux so that there could be a constant ethanol drip. HPLC was used to check reaction every half an hour for completion then cool to room temperature and filter Pd/C. EtOH in filtrate was evaporated the on rotary evaporator. Then, small amount of DMF was added to redissolve the residue. Aldehyde (1 :1) was dissolved in the DMF solution and 5% of HAc (of volume) was added. The solution was allowed to react over night to 2 days. Completion was checked with HPLC. If the HPLC retention time was 13 min or more, the product could be hydrophobic enough to precipitate by adding 4OmL of ice. This could be easily filtered and allowed to dry before storing. In case the product was too hydrophilic for precipitation in ice water, two methods were used for workup. A) Extraction method:

Diluted the product solution in 50 ml of ice water in a 250 ml separatory funnel. 200 ml of ethyl acetate were added to extract the product. The organic layer was collected. This process was repeated two more times. The combined organic layer was washed with brine (100 ml x3), then dried over anhydrous magnesium sulfate overnight. After filtration, the ethyl acetate was evaporated using the rotary evaporator. The crude product was purified by preparative reversed-phase HPLC. The collected fraction was lyophilized to give final product as a powder. The identify of the product was verified by MS (MALDI-TOF or Orbitrap-FTMS) and other spectrometric methods such as ¹HNMR and ¹³CNMR, see Table 1 and Table 2 below.

Table 1. Mass Spectroscopy Data

Table 2. ¹H and ¹³C NMR Data.

Example 2: Treatment of Prostate Cancer

[0137] The activity of the compounds of the present invention were determined by seeding LnCap cells at 5,000 cells/well in 96-well plate overnight and treated with the corresponding compounds. The cell viability was measured using MTT assay after 72 h. Mean±standard deviation of n=3. See Table 3 below.

[0138] Treatment of prostate cancer cells was investigated by using growth inhibition of LnCaP cells using an MTT assay (Figure 2), induction of autophagy in CWR22Rvl-LC3 cells (Figure 3), and inhibition of cell migration of PC3 human prostate cancer cells (Figure 4). Inhibition of LnCaP cells

[0139] Cells were seeded at 5,000 cells/well in 96-well plates overnight and treated with the corresponding compounds (10 μM). The cell viability was measured using MTT assay after 72 h. (See Figure 2, where the column is the mean; the bar is the standard deviation; n=3.)

Autophagy in CWR22Ryl-LC3 cells

[0140] CWR22Rvl and LNCaP cells stably transfected with GFP-LC3 were examined under fluorescence microscopy, 24 hours after treatment with either CTA003 or 6RF3 at 10 μM concentration. The autophagic process started as early as 4 hours post-treatment and lasts for at least 36 hours. Cells treated with different level of CTA003 were further examined for the conversion of endogenous LC3-I to LC3-II forms. (See Figure 3.) Figure 3 A shows autophagosomes as visualized by GFP-LC3 "puncta." Figure 3B shows an immunoblot (CWR22Rvl) of endogenous LC3 isoforms.

Inhibition of cell migration of PC3 human prostate cancer cells

[0141] PC3 cells were grown to the indicated confluence (0 h) and treated with the corresponding agents (5 μM). Cell migration was visualized using "wound-healing" assay (0 h and 24 h). (See Figure 4.)

Example 3: Inhibition of Btk kinase activity

[0142] Inhibition of Btk kinase activity was determined by incubating purified Btk (50 nM) and the corresponding compounds with the substrate (YIYGSFK) in a kinase reaction.

Reactions were started by addition Of³³P-ATP and the resulting product was analyzed on a TLC (Thin Layer Chromatography) plate. LFM-A 13 is a known Btk inhibitor and was used as a control in these experiments (Uckun, 2008). Figure 5 shows the inhibition of Btk using the compounds of the present invention, as well as the concentration-dependent inhibition of Btk by CTA041, CTA008, and CTA013 compared with LFM-A13.

Example 4: Treatment of B-cell leukemia and lymphoma

[0143] Treatment of B-cell leukemia and lymphoma was investigated by growth inhibition of BCBLl cells using an MTT assay (Table 3). Briefly, BCBLl cells were seeded at 5,000 cells/well in 96-well plate overnight and treated with the corresponding compounds. The cell viability was measured using MTT assay after 72 h. See Table 3. Example 5; Treatment of Osteoporosis

[0144] To evaluate the efficacy of CTAO 13 in osteoclatogenesis in vitro, we obtained bone marrow cells (BMMs) from 2-month-old C57BL mice. The BMMs were cultured with CTA013 (at 0, 10^~10, 10^"8, 10^"6M) supplemented with 20ng/ml mCSF and lOOng/ml RANKL for 7-10 days. TRAP+ cells formation, representing mature osteoclasts, were found to decrease by 12% , 30-40% and more than 90%, respectively, in 10^"10, 10^"8, 10^"6M. Dentine resorption pit area was about 40% lower in the 10^"10M concentration and was not detectable in 10^~8and 10^"6M concentrations. CTAO 13 was found to exhibit similar effects on gene expression that associate with osteoclastogenesis. At 10^"8 and 10^"6 M concentration, it down- regulated OSCAR (receptor for Fcγ), Trem2 (receptor for Dap 12), TRAF6 (a key signaling adaptor for RANK), and Trap5b (osteoclast maturation) by 10-50 fold.

Example 6: Inhibition of Mer Tyrosine Kinase (Mertk)

[0145] Inhibition of Mertk kinase activity was determined by incubating purified Mertk (50 nM) and the corresponding compounds with the substrate (p-TSFYGRH) in a kinase reaction. Reactions were started by addition of ³³P-ATP and the resulting product was analyzed on a TLC (Thin Layer Chromatography) plate. Figure 10 shows the inhibition of Mertk using the compounds of the present invention, as well as the concentration-dependent inhibition of Mertk by CTA053.

Table 3. Activity Data

+++, < 1 μM; ++, 1 μM < x < 10 μM; and +, > 10 μM; nd, not determined. ^L +++, < 10 μM; ++, 10 μM < x < 20 μM; and +, > 20 μM; nd, not determined.

[0146] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

wherein

R¹ is selected from the group consisting of H, Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, 0R^la, C_1-6 alkyl-OR^la, -NR^{! a}R^lb, -C_{1 -6} alkyl-NR^{l a}R^lb, -C(O)R ^{! a}, -C(O)OR' \ -OC(O)OR^{1 a}, -C(O)NR¹³R^{1 b}, -NR¹³C(O)R^{1 b},

-0C(0)NR^laR^lb, -NR¹³C(O)OR^{1 b}, -NR^laC(O)NR^laR^lb, -CN, -NO₂, -N₃, -SR^la, -S(O)R¹³, -S(O)₂R¹³, -NR¹³S(O)₂R^{1 b}, -S(O)₂NR¹³R^{1 b}, -NR^laS(O)₂NR^laR^lb, C_3- io cycloalkyl, C₃_₉ heterocycloalkyl, aryl, C_{1 -6} alkylaryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents;

L¹ is selected from the group consisting of a bond, C]_-6 alkylene and C]_-6

heteroalkylene;

R² is a member selected from the group consisting of Ci_-6 alkyl, -NR^2aR^2b, C_3-9

heterocycloalkyl, aryl and heteroaryl, each optionally substituted with 1 to 4 R substituents;

L² is selected from the group consisting of a bond, Ci_-6 alkylene, Ci_-6 heteroalkylene and C_{! -6} alkylene-C(O)-;

R³ is selected from the group consisting of -NR ^aR^6b, C_3-Io cycloalkyl, C_3-9

heterocycloalkyl, aryl, aryl-oxy, heteroaryl and heteroaryl-oxy, each optionally substituted with 1 to 4 R⁵ substituents;

L³ is selected from the group consisting of a bond, C₂.₆ alkenylene and C_2-6

alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene; R⁴ is selected from the group consisting of H and Ci_-6 alkyl;

each R⁵ group is independently selected from the group consisting Of Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_{] -6} haloalkyl, C_]-6 haloalkoxy, 0R^5a, C_{1 -6} alkyl-OR^5a, aryl, heteroaryl, -NR^5aR^5b, Ci_-6alkylaryl, -Ci_-6 alkyl-heteroaryl, -C_-6 alkyl-NR^5aR^5b, -C(O)R⁵³, -C(O)OR⁵³, -OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R⁵³, -NR^5aS(O)₂R^5b, -NR^5aS(O)₂aryl, -S(O)₂NR^5aR^5b, -NR^5aS(O)₂NR^5aR^5b and heteroaryl-oxy;

each of R^6a and R^6b is H or Ci_-6 alkyl, wherein the C_1-6 alkyl group is optionally

substituted with a member selected from the group consisting Of C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, Ci_-6 haloalkoxy, OR^5a, -NR^5aR^5b, -C(0)R^5a, -C(0)0R^5a, -OC(O)R⁵³, -OC(O)OR⁵³, -C(O)NR^5aR^5b,

-NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R⁵³, -S(O)₂R^5a, -NR⁵³S(O)₂R⁵", -S(O)₂NR⁵³R⁵", and -NR^5aS(O)₂NR^5aR^5b;

X is -O- or -N(R⁷)-;

Y is selected from the group consisting of Ci_-6 alkylene, Ci_-6 heteroalkylene and

heterocycloalkyl;

subscript n is O or 1 ;

each of R^la, R^lb, R^2a, R^2b, R^5a, R^5b and R⁷ is independently selected from the group consisting of H and C]_-6 alkyl;

alternatively, when attached to the same atom, R^la and R^!b, R^2a and R^2b, R^5a and R^5b, or R⁷ and Y are optionally combined with the atom to which each is attached to form a C_3-8 heterocycloalkyl which can optionally be substituted with Ci_-6 alkyl;

alternatively, two R⁵ groups are combined to form a C₃-₈ heterocycloalkyl which can optionally be substituted with C]_-6 alkyl;

and salts and isomers thereof.

2. The compound of claim 1 , wherein

R¹ is selected from the group consisting of Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl,

halogen, C_1-6 haloalkyl, 0R^Ia, C,_-6 alkyl-OR^Ia, -NR^laR^lb, -C,_-6 alkyl-NR^{l a}R^lb, -C(O)R¹³, -C(O)OR¹³, -OC(O)OR¹³, -C(0)NR^laR^lb, -NR^l3C(0)R^lb,

-0C(0)NR^{l 3}R^lb, -NR¹³C(O)OR^{1 b}, -NR¹³C(O)NR¹³R^{1 b}, -CN, -NO₂, -N₃, -SR^Ia, -S(O)R^{l a}, -S(O)₂R¹³, -NR^l3S(O)₂R^lb, -S(O)₂NR¹³R^{1 b}, -NR^laS(0)₂NR^laR^lb, C_3- io cycloalkyl, C_3-9 heterocycloalkyl, aryl, C_]-6 alkylaryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl are each optionally substituted with 1 to 4 R⁵ substituents;

L¹ is selected from the group consisting of a bond, Ci_-6 alkylene and Ci_-6

heteroalkylene; R² is a member selected from the group consisting of Ci_-6 alkyl, -NR^2aR^2b, C_3-9 heterocycloalkyl, aryl and heteroaryl, each optionally substituted with 1 to 4 R⁵ substituents;

L² is selected from the group consisting of a bond, Ci_-6 alkyl ene, Ci_-6 heteroalkylene and Ci_-6 alkylene-C(O)-;

R³ is selected from the group consisting of -NR^6aR^6b, C_3-Io cycloalkyl, C_3-9

heterocycloalkyl, aryl, aryl-oxy, heteroaryl and heteroaryl-oxy, each optionally substituted with 1 to 4 R⁵ substituents;

L³ is selected from the group consisting of a bond, C_2-6 alkenylene and C_2-6

alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene; R⁴ is selected from the group consisting of H and Ci_-6 alkyl;

each R⁵ group is independently selected from the group consisting Of Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_]-6 haloalkyl, C_1-6 haloalkoxy, OR^5a, C_{] -6} alkyl-OR^5a, -NR^5aR^5b, -C , _-6 alkyl-NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a,

-OC(O)OR⁵³, -C(O)NR^5aR^5b, -NR^5aC(O)R^5b, -OC(O)NR^5aR^5b,

-NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R^5a, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b, -NR^5aS(O)₂NR^5aR^5b and heteroaryl-oxy;

each of R^6a and R^6b is H or Ci_-6 alkyl, wherein the Ci_-6 alkyl group is optionally

substituted with a member selected from the group consisting of C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_-6 haloalkyl, C_{1 -6} haloalkoxy, OR^5a, -NR^5aR^5b, -C(O)R^5a, -C(O)OR^5a, -OC(O)R⁵³, -OC(O)OR⁵³, -C(O)NR^5aR^5b,

-NR^5aC(O)R^5b, -OC(O)NR^5aR^5b, -NR^5aC(O)OR^5b, -NR^5aC(O)NR^5aR^5b, -CN, -NO₂, -N₃, (=0), -SR^5a, -S(O)R^5a, -S(O)₂R^5a, -NR^5aS(O)₂R^5b, -S(O)₂NR^5aR^5b, and -NR^5aS(O)₂NR^5aR^5b;

X is -O- or -N(R⁷)-;

Y is selected from the group consisting of Ci_-6 alkylene, Ci_-6 heteroalkylene and heterocycloalkyl;

subscript n is 0 or 1 ;

each of R^la, R^lb, R^2a, R^2b, R^5a, R^5b and R⁷ is independently selected from the group consisting of H and Ci_-6 alkyl;

alternatively, when attached to the same atom, R^{l a} and R^lb, R^2a and R^2b, R^5a and R^5b, or R⁷ and Y are optionally combined with the atom to which each is attached to form a C_3-8 heterocycloalkyl; and salts and isomers thereof.

3. The compound of claim 2, wherein the compound has Formula Ia:

4. The compound of claim 3, wherein

R¹ is selected from the group consisting of Ci_-6 alkyl, 0R^la, -NR^laR^lb, -C(O)R^la, -C(O)OR¹³, -OC(O)OR¹³, -C(O)NR^{l a}R^lb, -NR^laC(0)R^lb, -OC(O)NR¹³R^lb, -NR^laC(0)0R^lb, -NR¹³C(O)NR¹³R^{1 b}, -SR^{l a}, -S(O)R¹³, -S(O)₂R¹³,

-NR¹³S(O)₂R^{1 b}, -S(O)₂NR^{l a}R^lb, -NR^l3S(O)₂NR^laR^lb and aryl;

L¹ is Ci_-6 alkyl ene;

R² is C_3-9 heterocycloalkyl;

L² is Ci_-6 alkylene;

R³ is selected from the group consisting of aryl and heteroaryl; and

L³ is selected from the group consisting of a bond and C_2-6 alkenylene.

5. The compound of claim 3, wherein

R¹ is phenyl, optionally substituted with halogen;

L¹ is a bond or Ci_-6 alkylene;

R² is piperidine;

L² is C]_-6 alkylene;

R³ is a heteroaryl;

L³ is selected from the group consisting of a bond, phenylene and thiophene; and R⁴ is hydrogen.

6. The compound of claim 4, wherein

R³ is selected from the group consisting of phenyl, pyrrole, pyrazole, imidzaole, pyridine, pyrimidine, pyrazine, pyridazine, 1 ,2,4-triazine, 1,3,5-triazine, pryyrolizine, indole, quinoline, isoquinoline, benzimidazole, indazole, quinolizine, cinnoline, quinazoline, phthalazine, naphthyridine, carboline, and carbazole.

7. The compound of claim 4, wherein

R is selected from the group consisting of aziridine, azetidane, 1,3-diazazitidine, pyrolidine, pyrolidin-2-one, piperidine, 1 ,2-piperazine, 1,3-piperazine, 1,4- piperazine, and azocane.

8. The compound of claim 6, wherein

R¹ is selected from the group consisting of Ci_-6 alkyl, -C(O)OR^la and phenyl; L¹ is Ci_-6 alkylene;

R² is selected from the group consisting of pyrolidine and pyrolidin-2-one;

L² is Ci_-6 alkylene;

R^5a is C_{1 -6} alkyl;

R³ is selected from the group consisting of phenyl and carbazole; and

L³ is selected from the group consisting of a bond and C_2-6 alkenylene.

9. The compound of claim 2, wherein the compound has the formula:

10. The compound of claim 9, wherein L is C]_-6 alkylene and R is heterocycloalkyl.

11. The compound of claim 9, wherein at least one of L³ and R³ is heteroaryl or heteroarylene.

12. The compound of claim 9, wherein R³ is heteroaryl.

13. The compound of claim 2, wherein the compound has the formula:

14. The compound of claim 2, wherein the compound is selected from the group consisting of:

15. The compound of claim 2, wherein the compound is selected from the group consisting of:

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

17. A method oftreating leukemia or lymphoma, the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of claim 1 , thereby treating the leukemia or lymphoma.

18. A method oftreating prostate cancer, the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of claim 1 , thereby treating cancer.

19. A method of inhibiting a tyrosine kinase selected from the group consisting of endothelial tyrosine kinase (Etk), Bruton's tyrosine kinase (Btk), Mer tyrosine kinase (Mertk) and IL2-inducible T-cell kinase (Itk), the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of claim 1, thereby inhibiting the tyrosine kinase.

20. A method of treating osteoporosis, the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of claim 1 , thereby treating osteoporosis.