WO2011150201A2

WO2011150201A2 - Azolyl amide compounds and methods of use thereof

Info

Publication number: WO2011150201A2
Application number: PCT/US2011/038129
Authority: WO
Inventors: Gang Liu
Original assignee: Ambit Biosciences Corporation
Priority date: 2010-05-27
Filing date: 2011-05-26
Publication date: 2011-12-01
Also published as: WO2011150201A3

Abstract

Provided herein are azolyl amide compounds for treatment of CSF-1R kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.

Description

AZOLYL AMIDE COMPOUNDS AND METHODS OF USE THEREOF RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application no.

61/349,128, filed May 27, 2010. The disclosure of the above referenced application is incorporated by reference herein in its entirety.

FIELD

[0002] Provided herein are azolyl amide compounds. In certain embodiments, the compounds are modulators of type III receptor tyrosine kinase family. In other embodiments, the compounds are modulators of FLT3, KIT or CSF-1R. Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention, or amelioration of a disease or disorder related to FLT3, KIT or CSF-1R kinase activity or one or more symptoms associated with such diseases or disorders.

BACKGROUND

[0003] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Receptor tyrosine kinases (RTKs) are a sub-family of protein kinases that play a critical role in cell signaling and are involved in the process of tumorigenesis including cell proliferation, survival, angiogenesis, invasion and metastasis. A class of RTK known as the type III receptor tyrosine kinase family, which includes the receptors

PDGFR a, PDGFR β, FLT3, KIT, VEGFR and CSF-1R, has been implicated in various proliferative and inflammatory diseases.

[0004] CSF-1R (also known as macrophage colony stimulating factor receptor

(M-CSFR) or fms) is a receptor for the macrophage colony stimulating factor (M-CSF or CSF-1). Binding of the CSF-1 ligand to its receptor results in dimerization and auto-phosphorylation of the receptor and leads to activation of downstream signal transduction pathways including the PI3K/Akt and the mitogen activating protein kinase MAPK pathways. Activation of CSF-1R leads to the proliferation, survival, motility and differentiation of cells of the monocyte/macrophage lineage and hence plays a role in normal tissue development and immune defense. Activation of CSF- 1R also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone resorption. [0001] Because of its role in osteoclast biology, CSF-IR is believed to be an important therapeutic target for osteoporosis and inflammatory arthritis. For example, elevated M-CFS signaling leads to elevated osteoclast activity, which leads to bone loss attending arthritis and other inflammatory bone erosion. (See Scott et al.

Rheumatology 2000, 39: 122-132, Ritchlin et al. J. Clin. Invest. 2003, 111 :821-831). Inhibition of CSF-IR therefore represents a promising therapeutic approach for arthritis and other inflammatory bone erosion which is further supported by the efficacy data of known CSF-IR inhibitors such as ΚΪ20227 and GW2580 in arthritic animal models (See Conwat et al. JP£T2008, 326:41-50 and Ohno et al. Eur. J. Immunol. 2008, 38:283-291). Dysregulation of osteoclast development and disruption in the balance of bone resorption and bone formation that underlie osteoporosis might also be treated with a modulator of CSF-IR.

[0002] Elevated expression or activation of CSF-IR and/or its ligand have been found in patients with acute myeloid leukemia, prostate, breast, ovarian, endometrial, colorectal, pancreatic and a variety of other cancers, and elevated levels of M-CSF is associated with poor prognosis in certain cancers (See, Muller-Tidow et al. Clin Cancer Res, 2004, 10:1241-1249, Bauknecht et al. Cancer Detect. Prev., 1994, 18: 231-239; Baiocchi G et al. Cancer 1991, 67:990-996; Kirma et al Cancer Res. 2007; Sapi et al. Exp. Biol. Med., 2004, 229: 1-11; Kluger et al. Clin. Cane. Res. 2004 10:173-177; Mroczko et al, Clin. Chem. Lab. Med. 2005 43: 146-50 and Mroczko et al, Clin. Chim. Acta 2007, 380:208-212). The data suggests that CSF-IR may be a valuable therapeutic target for these solid tumors.

[0001] Early studies have associated elevated expression of M-CSF with increased leukocyte infiltration of solid tumors in human breast and ovarian cancers (Scholl et al. J. Natl. Cancer Inst. 1994, 86: 120-126, Tang et al. J. Cell. Biochem. 1990, 44: 189-198). Further studies have shown that M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis, and more recently, that the preclinical inhibitor GW2580 inhibits tumor metastasis and angiogenesis in mice tumor xenograft experiments (Priceman et al. Blood 2010 115(7): 1461-1471). Stimulated osteoclast activity is also believed to underlie the pathophysiology of bone metastases. (Lipton, J. Support. Oncol. 2004 2:205-220). Metastatic bone lesions results in significant localized bone loss and lead to skeletal morbidity, symptoms which include bone pain, bone fractures and hypercalcemia. Inhibition of CSF-1R therefore may therefore provide therapy for solid tumors and metastatic cancer including metastases to the bone.

[0002] Another member of the PDGFR family, Flt3 (also called Flk2), plays an important role in the proliferation and differentiation of hematopoietic stem cells and activating mutation or overexpression of this receptor is found in AML (See, Heinrich Mini-Reviews in Medicinal Chemistry 2004, 4(3):255-271, Kiyoi et al. IntJ Hematol, 2005 82:85-92). More than a dozen known Flt3 inhibitors are being developed and some have shown promising clinical effects against AML (See Levis et al. Int J Hematol. 2005 82:100-107). The Flt3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC). Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, Flt3 inhibition is a mechanism for downregulating DC-mediated inflammatory and autoimmune responses. One study shows the Flt3 inhibtor CEP-701 to be effective in reducing myelin loss in

experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (See Whartenby et al. PNAS 2005 102: 16741-16746). A high level of the Flt3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates Flt3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (See Rolland et al. J. Immunol. 2005 174:3067-3071).

[0003] KIT (or stem cell factor receptor, or SCFR) is another member of the

RTK family, and the presence of kit mutations is a key diagnostic marker for gastrointestinal stromal tumors (GIST) (Duensing et al. Cancer Investigation 2004, 22(1): 106-116). Gleevec® (imatinib mesylate or STI571), the first FDA-approved RTK inhibitor originally approved for c-Abl-mediated chronic myeloid leukemia, gained FDA-approval for KIT-mediated GIST in 2002 and has validated the molecular-based approach of Kit inhibition for the treatment of GIST. (Giorgi and Verweij, Mol. Cancer Ther. 2005 4(3):495-501). Gain of function mutations of the Kit receptor are also associated with mast cell/myeloid leukemia and

seminomas/dysgerminomas (Blume -Jensen Nature 2001 411(17): 355-365. KIT mutations have been also identified in certain melanomas and is recognized as a potential therapeutic target for melanoma (Curtain et al. J Clin. Oncol. 2006

24(26):4340-4346). [0004] There continues to be a need for the identification of small molecules that inhibit RTKs, particularly compounds useful for the treatment of FLT3-, CSF-IR and/or KIT- mediated diseases.

SUMMARY

[0005] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof. In certain embodiments, the compounds have activity as CSF-IR kinase modulators. The compounds are useful in medical treatments, pharmaceutical compositions and methods for modulating the activity of CSF-IR kinase, including wildtype and/or mutated forms of CSF-IR kinase. In certain embodiments, the compounds provided herein have activity as CSF-IR kinase modulators. In one embodiment, the compounds for use in the compositions and methods provided herein have formula (I).

[0006] In certain embodiments, provided herein are compounds of Formula I:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

B is 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; Z is phenyl, cyclohexenyl or cyclohexyl;

each R¹ is independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, hydroxyalkyl, haloalkyl,

alkylaminosulfonyl, alkylaminocarbonyl, aryl, arylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, cycloalkyl,

cycloalkylalkyl, cycloalkenyl, hydroxyalkyl, haloalkyl, alkylaminosulfonyl, alkylaminocarbonyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, c S(0),R^w;

L^J is

R⁵ is O, S, N-CN, or N-N0₂;

R⁶ and R⁷ are each independently selected from hydrogen and optionally substituted alkyl; where the substituents, when present are each independently selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy;

L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; each R² is independently selected from halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, cyano, amino, hydroxy, alkoxy, -R^uN(R^y)(R^z), -R^uS(0)_tR^w, aryl, heterocyclyl, and heteroaryl;

each R⁴ is independently selected from halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, cyano, amino, hydroxy, alkoxy, hydroxyalkoxyalkyl,

-R^uN(R^y)(R^z), -R^uS(0),R^w, aryl, heterocyclyl, and heteroaryl;

2 8 9 8 9

L is direct bond, alkylene, alkenylene, alkynylene, -R OR -, -R S(0)_tR -, -R⁸N(R¹⁰)R⁹-, -R⁸C(0)R⁹-, -R⁸C(O)N(R¹⁰)R⁹-,-R⁸S(O),N(R¹⁰)R⁹-, -R⁸ N(R¹⁰)C(O)R⁹- or -R⁸N(R¹⁰)S(O)_tR⁹-, where alkylene, alkenylene and alkynylene are optionally substituted with -R⁸OR¹⁰, -R⁸SR¹⁰, or -R⁸NR¹⁰R¹⁰;

R⁸ and R⁹ are each independently direct bond, alkylene, alkenylene, alkynylene, -R^uOR^u-, -R^uN(R^y)R^u- or -R^uS(0)_tR^u-;

each R¹⁰ is independently hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, and 0 to 1 additional heteroatom selected from O, N or S, wherein the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups;

R^3a and R^3b are each independently selected from (i) or (ii) below:

(i) R^3a and R^3b are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^3a and R^3b, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q¹ groups;

each Q¹ is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,

cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,

heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x,

-R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, or -R^uN(R^x)S(0)_tR^w; where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q² groups; each Q² is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x,

-R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, or -R^uN(R^x)S(0)_tR^w;

each R^u is independently alkylene or a direct bond;

R^w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

each R^x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,

cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^y and R^z are each independently selected from (i) or (ii) below: (i) R^y and R^z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q groups; each Q is independently selected from halo, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^X or S;

each t is independently an integer from 0-2;

m and n are each independently an integer from 0-4; and

p is an integer from 1-4,

wherein the compound is selected such that

i) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, B is pyrimidinyl, m is 1, and R⁴ is morpholinyl, then L² is not direct bond;

ii) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is 3-pyridyl, then R^3a and R^3b are not both methyl; and iii) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is

-NH-C(0)-CH₂-, m is 0, and B is 2-pyridyl, then then R³ is not pyrimidinyl.

[0007] In one embodiment, the compound provided herein is a compound of formula (I). In one embodiment, the compound provided herein is a pharmaceutically acceptable salt of the compound of formula (I). In one embodiment, the compound provided herein is a solvate of the compound of formula (I). In one embodiment, the compound provided herein is a hydrate of compound of formula (I). In one embodiment, the compound provided herein is a prodrug of the compound of formula (I). In one embodiment, the compound provided herein is a clathrate of the compound of formula (I).

[0008] Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof, and optionally comprising at least one pharmaceutical carrier.

[0009] In one embodiment, the pharmaceutical compositions deliver amounts effective for the treatment, prevention, or amelioration of diseases or disorders that are modulated or otherwise affected by CSF-IR kinase, or one or more symptoms or causes thereof. Such diseases or disorders include without limitation, cancers, nonmalignant proliferation diseases, atherosclerosis, restenosis following vascular angioplasty, fibroproliferative disorders, inflammatory diseases or disorders related to immune dysfunction, infectious diseases, and/or diseases or disorders that can be treated, prevented or managed by modulating the activity, binding or sub-cellular distribution of kinases, wherein such methods comprise administering to a subject, e.g., a human, in need of such treatment, prevention or management a therapeutically and prophylactically effective amount of a compound provided herein. Such diseases or disorders are further described herein.

[0010] Also provided herein are combination therapies using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents for the treatment of the diseases and disorders described herein.

[0011] In one embodiment, such additional pharmaceutical agents include one or more chemotherapeutic agents, anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents.

[0012] The compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above agents. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.

[0013] In certain embodiments, provided herein are methods of treating, preventing or ameliorating a disease or disorder that is modulated or otherwise affected by CSF-IR kinase such as wild type and/or mutant CSF-IR kinase, or one or more symptoms or causes thereof.

[0014] In certain embodiments, provided herein are methods of treating, preventing or ameliorating a disease or disorder that is modulated or otherwise affected by FLT3 kinase such as wild type and/or mutant FLT3 kinase, or one or more symptoms or causes thereof. In certain embodiments, the mutant FLT3 kinase is a FLT3 kinase having a D835 mutation or an ITD mutation. In certain

embodiments, the mutant FLT3 kinase is a FLT3 kinase having an ITD mutation.

[0015] In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for systemic delivery, including parenteral, oral, or intravenous delivery, or for local or topical application are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

[0016] Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like.

[0017] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description.

DETAILED DESCRIPTION

[0018] Provided herein are compounds of formula I that have activity as CSF-

1R kinase modulators. Further provided are methods of treating, preventing or ameliorating diseases that are modulated by CSF-1R, and pharmaceutical

compositions and dosage forms useful for such methods. The methods and compositions are described in detail in the sections below.

A. DEFINITIONS

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are

incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (z^'so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.

[0021] The term "branched alkyl" refers to hydrocarbon chain containing at least one forked carbon in the chain, with the smallest branched alkyl being an isopropyl group. Examples of branched alkyl groups include but is not limited to - CH(CH₃)₂, C(CH₃)₃, -CH(CH₃)(CH₂CH₃), -CH(CH₂CH₃)₂, -C(CH₃)(CH₂CH₃)₂, - C(CH₃)₂(CH₂CH₃), -C(CH₂CH₃)₃, -C(CH₃)₂(CH(CH₃)₂) and -C(CH₃)₂(C(CH₃) ₃).

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g., ethynyl, prop-l-ynyl, but-l-ynyl, pent-l-ynyl, pent-3-ynyl and the like.

[0024] "Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-l-enylene, but-2-enylene and the like. The alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as triple bonds and wherein the triple bond can exist between any two carbon atoms in the chain, e.g., ethynylene, prop-l-ynylene, but-2-ynylene, pent-l-ynylene, pent-3-ynylene and the like. The alkynylene chain may be attached to the rest of the molecule through any two carbons within the chain. [0027] "Alkoxy" refers to the group having the formula -OR wherein R is alkyl or haloalkyl. An "optionally substituted alkoxy" refers to the group having the formula -OR wherein R is an optionally substituted alkyl as defined herein.

[0028] "Amino" refers to a radical having the formula -NR'R" wherein R' and R' ' are each independently hydrogen, alkyl or haloalkyl. An "optionally substituted amino" refers to a radical having the formula -NR'R" wherein one or both of R' and R" are optionally substituted alkyl as defined herein.

[0029] "Aryl" refers to a group of carbocylic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic C₆-Ci8 ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and fluorene.

[0030] "Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl,

bicyclo[2.2.2]octane and the like.

[0031] "Cycloalkenyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, which is partially unsaturated. Examples of cycloalkenyl include cyclopropene, cyclobutylene, cyclopentene and cyclohexene.

[0032] "Halo, "halogen" or "halide" refers to F, CI, Br or I.

[0033] "Haloalkyl" refers to an alkyl group, in certain embodiments, Ci_₆alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl

l-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2- trifluoroethyl, 1,1-difluoroethyl, l,3-difluoro-2-methylpropyl, 2,2- difluorocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and 2,2,2- trifluoro- 1 , 1 -dimethyl-ethyl.

[0034] "Heterocyclyl" refers to a stable 3- to 15-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one embodiment, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Exemplary heterocylic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1 Joctanyl,

azabicyclo[2.2.2]octanyl and others.

[0035] "Heteroaryl" refers to a heterocyclyl group as defined above which is aromatic. The heteroaryl group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.

Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl and others.

[0036] "Heterocyclylalkyl" refers to a group of the formula -R_aR_e wherein R_a is an alkyl group as defined above and R_e is a heterocyclyl group as defined herein, where the alkyl group R_a may attach at either the carbon atom or the heteroatom of the heterocyclyl group R_e. The alkyl group and the heterocyclyl group may be optionally substituted as defined herein.

[0037] "IC₅₀" refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as cell growth or proliferation measured via any the in vitro or cell based assay described herein.

[0038] "Oxo" refers to the group =0 attached to a carbon atom.

[0039] Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine,

l-/?ara-chlorobenzyl-2-pyrrolidin '-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

[0040] As used herein and unless otherwise indicated, the term "hydrate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces.

[0041] As used herein and unless otherwise indicated, the term "solvate" means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term "solvate" includes hydrates (e.g., mono- hydrate, dihydrate, trihydrate, tetrahydrate and the like).

[0042] As used herein, "substantially pure" means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.

[0043] Unless stated otherwise specifically described in the specification, it is understood that the substitution can occur on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

[0044] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound is described as having one of two tautomeric forms, it is intended that the both tautomers be encompassed herein.

[0045] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.

[0046] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0047] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0048] As used herein, "isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non- enriched" atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural isotopic composition.

[0049] As used herein, "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.

"Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0050] As used herein, "isotopic enrichment" refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0051] Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens. [0052] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.

[0053] "Anti-cancer agents" refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as

bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g. cisplatin,

[0054] carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines

(e.g., doxrubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.

[0055] "Anti-inflammatory agents" refers to matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNF molecules, TNF soluble receptors, and ILl) non-steroidal anti-inflammatory drugs (NSAIDs) such as prostaglandin synthase inhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid), COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such as corticosteroids, methylprednisone, prednisone, or cortisone.

[0056] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, 77 :942-944).

B. COMPOUNDS

[0057] In certain embodiments, provided herein are compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms; Z is phenyl, cyclohexenyl or cyclohexyl;

each R¹ is independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, alkylthio, alkylsulfonyl, alkylsulfmyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, hydroxyalkyl, haloalkyl,

alkylaminosulfonyl, alkylaminocarbonyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylsulfonyl, alkylsulfmyl, cycloalkyl,

cycloalkylalkyl, cycloalkenyl, hydroxyalkyl, haloalkyl, alkylaminosulfonyl, alkylaminocarbonyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, alkyl, hydroxy, alkoxy, cycloalkyl, cycloalkenyl,

L¹

;

R⁵ is O or S;

R⁶ and R⁷ are each independently selected from hydrogen and optionally substituted lower alkyl; where the substituents, when present are each independently selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy;

and L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy;

each R² is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, hydroxy, and alkoxy;

each R⁴ is independently selected from alkyl, cycloalkyl, amino, hydroxy, and alkoxy;

2 8 9 8 9

L is direct bond, alkylene, alkenylene, alkynylene, -R OR -, -R SR -, or -R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond, alkylene, alkenylene, or alkynylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, and 0 to 1 additional heteroatom selected from O, N or S, wherein the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups; R^3a and R^3b are each independently selected from (i) or (ii) below:

(i) R^3a and R^3b are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or

each R^u is independently alkylene or a direct bond;

R^w is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

each R^x is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^y and R^z are each independently selected from (i) and (ii) below:

(i) R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl; or

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q groups; each Q is independently selected from halo, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

each Q¹ is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), - R^uN(R^y)(R^z), -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X, - R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, and -R^uN(R^x)S(0),R^w; where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one, two or three Q² groups; each Q² is independently selected from is halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z),

-R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x,

-R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, or -R^uN(R^x)S(0),R^w;

J is O, NR^X or S;

each t is independently 0-2;

m and n are each independently 0-4; and

p is 1-4.

[0058] In certain embodiments, the compounds provided herein are selected such that

i) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, B is pyrimidinyl, m is 1, and R⁴ is morpholinyl, then R³ is not morpholinyl;

ii) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, B is 3-pyridyl and m is 0, then R^3a and R^3b are not both alkyl; and iii) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is

-NH-C(0)-CH₂-, m is 0, and B is pyridyl, then then R³ is not pyrimidinyl.

[0059] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is

-NH-C(0)-CH₂- and B is pyrimidinyl, L² is direct bond, then R³ is not morpholinyl.

[0060] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is

-NH-C(0)-CH₂-, and R⁴ is morpholinyl, L² is direct bond, then R³ is not morpholinyl.

[0061] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is 3-pyridyl, then R^3a and R^3b are not both alkyl.

[0062] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is pyridyl, then R^3a and R^3b are not both methyl.

[0063] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is pyridyl, then R^3a and R^3b are not both alkyl.

[0064] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, and B is 3-pyridyl, then R³ is not NR^3aR^3b. [0065] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is pyridyl, then R³ is not pyrimidinyl.

[0066] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is pyridyl, then V is not -0-.

[0067] In certain embodiments, the compound provided herein is selected such that when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is -NH-C(0)-CH₂-, m is 0, and B is 2-pyridyl, V is -0-, then R³ is not pyrimidinyl.

[0068] In certain embodiments, provided herein are compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

each R¹ is inde endentl selected from alk l, halo and haloalkyl;

R⁵ is O;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl;

L³ and V are each independently a direct bond or alkylene;

each R² is independently selected from alkyl and alkoxy; each R⁴ is alkyl;

2 8 9 8 9

R⁸ and R⁹ are each independently direct bond or alkylene; R¹⁰ is hdrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to V on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in another embodiment, 1-7, in another embodiment, 1-5 or in another embodiment, one, two or three Q¹ groups, each independently selected from oxo, alkyl, cycloalkyl, haloalkyl, hetrocyclyl, R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), and -R^uS(0),R^w; where the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with one, two or three Q² groups; each Q² is independently selected from is halo, oxo, thioxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z),

R^3a and R^3b are each independently selected from (i) or (ii) below:

heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each independently selected from (i) and (ii) below:

(i) R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl; and

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, where heterocyclyl and heteroaryl are each optionally substituted with an alkyl;

J is O;

each t is independently 0-2;

m and n are each independently 0, 1 or 2; and

p is 1, 2 or 3.

[0069] In certain embodiments, A is optionally substituted azolyl, wherein substituents when present are selected from one, two or three R¹ groups each independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, hydroxy, alkoxy, cycloalkyl, cyano, and -R^uN(R^y)(R^z), where R^u is independently alkylene or a direct bond, R^y, and R^z are each

independently hydrogen or alkyl.

[0070] In certain embodiments, A is optionally substituted azolyl, wherein substituents when present are selected from one, two or three R¹ groups. In certain embodiments, A is optionally substituted isoxazolyl or optionally substituted pyrazolyl, wherein substituents when present are selected from one, two or three R¹ groups.

[0071] In certain embodiments, each R¹ is independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, hydroxy, alkoxy, cycloalkyl, cyano, and -R^uN(R^y)(R^z), where R^u is independently alkylene or a direct bond, R^y, and R^z are each independently hydrogen or alkyl.

[0072] In certain embodiments, each R¹ is independently selected from hydrogen, halo, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, and haloalkyl, where the alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, and haloalkyl groups are optionally substituted with 1 to 5 groups selected from halo, hydroxy, alkoxy, cycloalkyl, cyano, and -R^uN(R^y)(R^z), where R^u is independently alkylene or a direct bond, R^y, and R^z are each independently hydrogen or alkyl.

[0073] In certain embodiments, A is selected from:

where each R¹ is independently selected from hydrogen, halo, haloalkyl, and alkyl, where the alkyl group is optionally substituted with, in one embodiment, 1 to 5, in another embodiment, 1 or 2 groups selected from halo, cyano, hydroxy, alkoxy, and cycloalkyl.

[0074] In one embodiment, A is

where R¹ is as described elsewhere herein. In one embodiment, each R¹ is independently hydrogen, alkyl, hydroxyalkyl, cycloalkyl, haloalkyl, cyanoalkyl, alkoxyalkyl, aryl or heteroaryl. In one embodiment, each R¹ is independently hydrogen, alkyl or haloalkyl. In one embodiment, each R¹ is t-butyl, -CF₃,

-CF(CH₃)₂, -C(CH₃)(CH₂F)₂ or -C(CH₃)₂CF₃. In one embodiment, each R¹ is independently hydrogen, alkyl or haloalkyl. In one embodiment, each R¹ is independently t-butyl, -CF₃, -CF(CH₃)₂, -C(CH₃)(CH₂F)₂, -C(CH₃)₂CF₃ or

.

[0075] In one embodiment, A is

where R¹ is as described elsewhere herein. In one embodiment, R¹ is hydrogen, alkyl or haloalkyl. In one embodiment, R¹ is t-butyl, -CF₃, -CF(CH₃)₂, -C(CH₃)(CH₂F)₂ or -C(CH₃)₂CF₃. odiment, R¹ is t-butyl, -CF₃, -CF(CH₃)₂

-C(CH₃)(CH₂F)₂, -C(CH₃)₂CF₃ or

[0076]

[0077]

[0078] In one embodiment, A is

where R¹ is hydrogen, alkyl, aryl or cycloalkyl. In one embodiment, where R¹ is hydrogen, or alkyl. In one embodiment, where R¹ is hydrogen, or methyl.

[0079] In certain embodiments, compounds provided herein have formula I, where B is

where m is 0 or 1; Z¹ and Z² are selected from (i), (ii) and (iii) as follows:

(i) Z¹ and Z² are both CR^4a,

(ii) Z¹ is N, and Z² is CR^4a, and

(iii) Z¹ is CR^4a, and Z² is N;

each R^4a is independently hydrogen, -L²-R³ or R⁴ provided there is only one -L²-R³ on the B ring, and R³, R⁴, and L² are as described elsewhere herein. In certain embodiments, m is 0. In certain embodiments, L² is direct bond, alkylene, or -R⁸OR⁹, where R⁸ is direct bond and R⁹ is direct bond or alkylene. In certain embodiments, L² is direct bond, alkylene, or -O-(CH₂)₀_₃. In certain embodiments, L² is direct bond, methylene, -0-, -0-CH₂-, -0-CH₂-CH₂-, or -0-CH₂-CH₂-CH₂-. In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b, where R^3aand R^3b are alkyl; or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is

independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0080] In certain embodiments, B is

(i) Z¹ and Z² are both CR^4a,

(ii) Z¹ is N, and Z² is CR^4a, and

(iii) Z¹ is CR^4a, and Z² is N;

each R^4a is independently hydrogen or R⁴, and R³, R⁴, and L² are as described elsewhere herein. [0081] In certain embodiments, B is

(i) Z¹ and Z² are both CR^4a,

(ii) Z¹ is N, and Z² is CR^4a, and

(iii) Z¹ is CR^4a, and Z² is N;

each R^4a is independently hydrogen or R⁴ ; and R³, R⁴, and L² are as described elsewhere herein.

[0082] In certain embodiments, B is pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl. In certain embodiments, B is pyridinyl.

[0083] In certain embodiments, B is

where m is O or 1, R³, R⁴, and L² are as described elsewhere herein. In certain embodiments, m is 0. In certain embodiments, L² is direct bond, alkylene, or - R⁸OR⁹, where R⁸ is direct bond and R⁹ is direct bond or alkylene. In certain embodiments, L² is direct bond, alkylene, or -O-(CH₂)₀_3. In certain embodiments, L² is direct bond, methylene, -0-, -0-CH₂-, -0-CH₂-CH₂-, or -0-CH₂-CH₂-CH₂-. In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b,

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups,

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are alkyl; or

ii) R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups, each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, - (CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0084] In certain embodiments, B is

where m is O or 1, R³, R⁴, and L² are as described elsewhere herein. In certain embodiments, m is 0.

[0085] In certain embodiments, L² is direct bond, alkylene, or -R⁸OR⁹, where

R⁸ is direct bond and R⁹ is direct bond or alkylene. In certain embodiments, L² is direct bond, alkylene, or -O-(CH₂)₀_₃. In certain embodiments, L² is direct bond, methylene, -0-, -0-CH₂-, -0-CH₂-CH₂-, or -0-CH₂-CH₂-CH₂-.

[0086] In certain embodiments, L² is direct bond, alkylene, alkenylene, alkynylene, -R⁸OR⁹-, -R⁸S(0),R⁹- -R⁸N(R¹⁰)R⁹-, where R⁸ and R⁹ are each independently direct bond, alkylene, alkenylene, alkynylene, -R^uOR^u-, -R^uN(R^y)R^u- or -R^uS(0)_tR^u- and the other variables are as described elsewhere herein.

[0087] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b,

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are alkyl or haloalkyl; or

ii) R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups,

each Q¹ is independently selected from alkyl, haloalkyl, aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), heterocyclyl and heterocyclylalkyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is independently selected from -CH₃, - CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0088] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b,

where R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups, each Q¹ is independently selected from alkyl, haloalkyl, aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, -R^uC(J)OR^x, -R^uS(0)_tR^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one

embodiment, each Q¹ group is independently selected from -CH₃, -CH₂-CH₃, - CH₂CF₃, -CH-(CH₃)₂, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0089] In one embodiment, each Q¹ is independently selected from alkyl, haloalkyl, aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, -R^uC(J)OR^x, -R^uS(0),R^w -R^uC(J)N(R^y)(R^z) and heterocyclyl where R^u is alkylene and the other variables are as described elsewhere herein.

[0090 tain embodiments, B is

where m is O or 1, R³, R⁴, and L² are as described elsewhere herein. In certain embodiments, m is 0. In certain embodiments, L² is direct bond, alkylene, or - R⁸OR⁹, where R⁸ is direct bond and R⁹ is direct bond or alkylene. In certain embodiments, L² is direct bond, alkylene, -O-(CH₂)₀_₃. In certain embodiments, L² is direct bond, methylene, -0-, -0-CH₂-, -0-CH₂-CH₂-, or -0-CH₂-CH₂-CH₂-. In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are alkyl or haloalkyl; or

each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl, - R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, - (CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0091] In certain embodiments, B is

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl or haloalkyl; or

[0092] In certain embodiments, B is

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl or haloalkyl; or

ii) R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups, each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂,

(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl.

[0093] In certain embodiments, B is

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl or haloalkyl; or

each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl, - R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2. In one embodiment, each Q¹ group is independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, - (CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cycloalkyl, and oxetanyl. [0094] In certain embodiments, L² is direct bond, alkylene, -R⁸OR⁹-, or

-R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups,

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl; or ii) R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups,

each Q¹ is independently selected from is halo, oxo, thioxo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X,

-R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, -R^uN(R^x)S(0)_tR^w, each R^u is independently alkylene or a direct bond;

each R^x is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and

R^y and R^z are each independently selected from (i) or (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, where heterocyclyl and heteroaryl are each optionally substituted with an alkyl. [0095] In certain embodiments, L² is direct bond, alkylene, or -R⁸OR⁹-, where

R⁸ is direct bond and R⁹ is direct bond or alkylene. In certain embodiments, L² is direct bond, alkylene, -0-(CH₂)o-3-. In certain embodiments, L² is direct bond, methylene, -0-, -0-CH₂-, -0-CH₂-CH₂-, or -0-CH₂-CH₂-CH₂-.

[0096] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² of the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups,

where R^3a and R^3b are selected as follows:

each Q¹ is independently selected from is halo, oxo, thioxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z),

-R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, -R^uN(R^x)S(0),R^w,

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) or (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, where heterocyclyl and heteroaryl are each optionally substituted with an alkyl. [0097] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b where R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q¹ groups, or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² of the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups,

-R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x, -R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, -R^uN(R^x)S(0)_tR^w,

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) or (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, where heterocyclyl and heteroaryl are each optionally substituted with an alkyl.

[0098] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl or haloalkyl; or

each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl, - R^uC(J)OR^x, -R^uS(0)_tR^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where the alkyl and cycloalkyl groups are optionally substituted with one, two or three Q² groups; each Q² is independently selected from is halo, hydroxy, cycloalkyl and aryl;

each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2.

[0099] In certain embodiments, R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

where R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each alkyl or haloalkyl; or

each Q¹ is independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl, and oxetanyl.

[00100] In certain embodiments, R³ is optionally substituted 5-7 membered heterocyclyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, R³ is optionally substituted 5- 6 membered heterocyclyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, R³ is optionally substituted 5-6 membered heterocyclyl containing one nitrogen atom, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups.

[00101] In certain embodiments, R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine,

octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl.

[00102] In certain embodiments, Q¹ is selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl, where the alkyl and cycloalkyl groups are optionally substituted with one, two or three Q² groups; each Q² is independently selected from is halo, hydroxy, cycloalkyl and aryl; each R^u is independently alkylene or a direct bond, R^w and R^x are each alkyl; R^y and R^z are each hydrogen or alkyl; J is O; and t is 2.

[00103] In certain embodiments, L¹ is

, where R⁵ is selected from O and S; R⁶ and R⁷ are each independently selected from hydrogen and optionally substituted lower alkyl; where the substituents, when present are each independently selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; and L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy.

[00104] In certain embodiments, L¹ is

where R⁵ is O; R⁶ and R⁷ are each hydrogen; and L³ and L⁴ are each independently a bond, or alkylene, where the alkylene is optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy.

[00105] In certain embodiments, compounds provided herein are of Formula II

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, R³ is optionally substituted 5-7 membered heterocyclyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, R³ is optionally substituted 5-6 membered heterocyclyl containing one nitrogen atom, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups.

[00106] In certain embodiments, compounds provided herein are of Formula II or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

each R¹ is independently selected from alkyl, halo and haloalkyl;

L s

R⁵ is O or S;

L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; each R² is independently selected from alkyl and alkoxy;

each R⁴ is alkyl;

2 8 9 8 9

L is direct bond, alkylene, alkenylene, alkynylene, -R OR -, -R SR -, or - R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R⁹ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to V on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in another embodiment, 1-7, in another embodiment, 1-5 or in another embodiment, one, two or three Q¹ groups, each independently selected from oxo, alkyl, cycloalkyl, haloalkyl, hetrocyclyl, R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), and -R^uS(0),R^w;

R^3a and R^3b are selected as follows:

i) R^3a and R^3b are each independently alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl; or

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each independently selected from (i) and (ii) below:

J is O;

t is 0-2;

m and n are each independently 0, 1 or 2; and

p is 1, 2 or 3.

[00107] In certain embodiments, compounds provided herein are of Formula II or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

each R¹ is independently selected from alkyl and haloalkyl;

R⁵ is O or S;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; L³ and L⁴ are each independently a bond, or alkylene, where the alkylene is optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy. each R² is independently selected from alkyl and alkoxy;

each R⁴ is alkyl;

L² is a direct bond, alkylene, -R⁸OR⁹-, -R⁸SR⁹-, or -R⁸N(R¹⁰)R⁹-; R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in another embodiment, 1-7, in another embodiment, 1-5 or in another embodiment, one, two or three Q¹ groups, each independently selected from oxo, alkyl, cycloalkyl, haloalkyl, hetrocyclyl, R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), and -R^uS(0)_tR^w;

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each independently selected from (i) and (ii) below:

J is O;

t is 0-2;

m and n are each independently 0, 1 or 2; and

p is 1, 2 or 3. [00108] In certain embodiments, compounds provided herein are of Formula III

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula III , wherein

A is azolyl;

B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms; each R¹ is inde endentl selected from alk l, halo and haloalkyl;

R⁵ is O or S;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl;

each R² is independently selected from alkyl and alkoxy;

each R⁴ is alkyl;

L² is direct bond, alkylene, -R⁸OR⁹-, or -R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl,

R^3a and R^3b are selected as follows: i) R^3a and R^3b are each independently alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl; or

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each hydrogen or alkyl;

J is O; and

P is 0, 1 or 2;

t is 0-2.

[00109] In certain embodiments, compounds provided herein are of Formula

III, wherein R¹ is tert-butyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine, octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, - CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, - CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00110] In certain embodiments, compounds provided herein are of Formula

IVa or IVb:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein.

[00111] In certain embodiments, compounds provided herein are of Formula

IVa or IVb, wherein Z is phenyl and all the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula IVa or IVb, wherein L² is a direct bond, alkylene, alkenylene, alkynylene or -R⁸OR⁹- wherein R⁸ and R⁹ are each independently a direct bond , alkylene or alkynylene, and all the other variables are as described elsewhere herein.

[00112] In certain embodiments, the compounds provided herein are of

Formula IVc or IVd:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, provided

R⁷ herein are compounds of Formula IVc or IVd, wherein L¹ is R or

, R⁵ is O; R⁶ and R⁷ are each hydrogen; L³ and L⁴ are each independently a bond, or alkylene, where the alkylene is optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R² is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, hydroxyl and alkoxy; and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula IVc or IVd wherein R² is alkyl, haloalkyl, halo or alkoxy and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula IVc or IVd wherein R² is alkyl or alkoxy and the other variables are as described elsewhere herein.

[00113] In certain embodiments, compounds provided herein are of Formula

Va or Vb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula Va or Vb, wherein R¹ is tert-butyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, morpholinyl, pyrrolidinyl, quinuclidine, octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00114] In certain embodiments, compounds provided herein are of Formula

Via or VIb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, R³ is optionally substituted 5-7 membered heterocyclyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, R³ is optionally substituted 5-6 membered heterocyclyl containing one nitrogen atom, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, compounds provided herein are of Formula Via or VIb, wherein R¹ is tert-butyl; B is

where m is 0 or 1; n is 0 or 1; Z¹ and Z² are selected from (i), (ii) and (iii) as follows:

((i) Z¹ and Z² are both CR^4a,

(ii) Z¹ is N, and Z² is CR^4a, and

(iii) Z¹ is CR^4a, and Z² is N;

each CR^4a is independently hydrogen or R⁴; R⁶ and R⁷ are each independently hydrogen or alkyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R² is alkyl; and R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine,

octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00115] In certain embodiments, compounds provided herein are of Formula

Vila or Vllb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, R³ is optionally substituted 5-7 membered heterocyclyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another

embodiment, 1-5, in another embodiment, one, two or three alkyl groups. In certain embodiments, R³ is optionally substituted 5-6 membered heterocyclyl containing one nitrogen atom, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three alkyl groups.

[00116] In certain embodiments, compounds provided herein are of Formula

Vila or Vllb, wherein

B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms;

R¹ is selected from alkyl, halo and haloalkyl;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl;

L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; each R² is independently selected from alkyl and alkoxy; each R⁴ is alkyl;

L² is direct bond, alkylene, -R⁸OR⁹- or -R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0)_tR^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl,

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each hydrogen or alkyl;

J is O; and

t is 0-2.

[00117] In certain embodiments, compounds provided herein are of Formula

Vila or Vllb, wherein R¹ is tert-butyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine,

[00118] In certain embodiments, compounds provided herein are of Formula

Villa or VHIb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms;

R¹ is alkyl, halo or haloalkyl;

R^la is hydrogen or alkyl;

each R⁴ is alkyl;

L² is direct bond, alkylene, -R⁸OR⁹- or -R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from alkyl, haloalkyl, cycloalkyl, -R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl;

ii) R^3a and R^3b together form optionally substituted heterocyclyl, wherein the substituents when present are selected from one, two or three Q groups,

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each hydrogen or alkyl;

J is O; and

t is 0-2.

[00119] In certain embodiments, compounds provided herein are of Formula

Villa or VHIb wherein R¹ is te

(i) Z¹ and Z² are both CR^4a;

(ii) Z¹ is N, and Z² is CR^4a; and

(iii) Z¹ is CR^4a, and Z² is N;

each CR^4a is independently hydrogen or R⁴; R⁶ and R⁷ are each independently hydrogen or alkyl; R² is alkyl; and R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine,

[00120] In certain embodiments, compounds provided herein are of Formula

IXa or IXb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula IXa or IXb, wherein R¹ is tert-butyl; R^la is hydrogen or alkyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, morpholinyl, pyrrolidinyl, quinuclidine, octahydroquinolizinyl, and

azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃,

-CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00121] In certain embodiments, compounds provided herein are of Formula

Xa or Xb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula Xa or Xb, wherein R¹ is tert-butyl; R^la is hydrogen or alkyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; B is

(i) Z¹ and Z² are both CR^4a;

(ii) Z¹ is N, and Z² is CR^4a; and

(iii) Z¹ is CR^4a, and Z² is N;

[00122] In certain embodiments, compounds are of Formula XIa or Xlb

XIa or

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula XIa or Xlb, wherein

R¹ is selected from alkyl, halo and haloalkyl;

R^la is hydrogen or alkyl;

each R⁴ is alkyl;

L² is direct bond, alkylene, -R⁸OR⁹-, or -R⁸N(R¹⁰)R⁹-;

R⁸ and R⁹ are each independently direct bond or alkylene;

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond; R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each hydrogen or alkyl;

J is O; and

t is 0-2.

[00123] In certain embodiments, compounds provided herein are of Formula

XIa or Xlb, wherein R¹ is tert-butyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, morpholinyl, quinuclidine,

[00124] In certain embodiments, compounds provided herein are of Formula

Xlla or Xll

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, the compounds provided herein are of Formula Xlla or Xllb wherein L² is a direct bond, -CH₂-, -0(CH₂)o-₃- and the other variables are as described elsewhere herein. In certain embodiments, n is 0.

[00125] In certain embodiments, compounds provided herein are of Formula

XIIc or Xlld:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula Xlla, Xllb, XIIc or Xlld, wherein R¹ is tert-butyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, morpholinyl, pyrrolidinyl,

quinuclidine, octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00126] In certain embodiments, compounds provided herein are of Formula

XHIa or XHIb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula Xllla or Xlllb, wherein R¹ is tert-butyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, quinuclidine,

[00127] In certain embodiments, compounds provided herein are of Formula

XlVa, XlVb, XIVc

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula XlVa, XlVb, XIVc or XlVd, wherein R¹ is ierf-butyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, quinuclidine,

[00128] In certain embodiments, compounds provided herein are of Formula

XVa or XVb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula XVa or XVb, wherein R¹ is tert-butyl; R^la is hydrogen or alkyl; L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, quinuclidine, octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH- (CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00129] In certain embodiments, compounds provided herein are of Formula

XVIa or XVIb

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as described elsewhere herein. In certain embodiments, compounds provided herein are of Formula XVIa or XVIb, wherein R¹ is tert-butyl; R^la is hydrogen or alkyl, L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl; R³ is optionally substituted piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, quinuclidine, octahydroquinolizinyl, and azabicyclo[3.2.1]octanyl, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-7, in another embodiment, 1-5, in another embodiment, one, two or three Q¹ groups, each independently selected from -CH₃, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, -CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl; and other variables are as described herein.

[00130] In certain embodiments, provided herein are compounds of Formula

XVII:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as decribed elsewhere herein.

[00131] In certain embodiments, provided herein are compounds of Formula

XVIIIa or XVII

XVIIIa or

XVIIIb or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as decribed elsewhere herein. In certain embodiments, provided herein are compounds of Formula XVIIIa or XVIIIb or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

each R¹ is independently selected from halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, hydroxy, alkoxy, cycloalkyl, cyano, and -R^uN(R^y)(R^z);

L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; each R⁴ is independently selected from alkyl, cycloalkyl, amino, hydroxy, and alkoxy;

2 8 9 8 9

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more, in one embodiment, 1-9, in another embodiment, 1-7, in another embodiment, 1-5, in another embodiment, 1-3, or in another embodiment, one, two or three Q¹ groups;

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) and (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one, two or three Q groups selected from halo, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; each Q¹ is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0)_tR^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x,

-R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, and -R^uN(R^x)S(0),R^w;

J is O, NR^X or S;

t is 0-2;

m is 0-4; and

p is 1-4.

[00132] In certain embodiments, provided herein are compounds of Formula

XlXa or XIXb:

or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein the variables are as decribed elsewhere herein. In certain embodiments, provided herein are compounds of Formula XlXa or XlXb or pharmaceutically acceptable salts, solvates, hydrates or clathrates thereof, wherein:

A is azolyl;

2 8 9 8 9

R¹⁰ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) and (ii) below:

-R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, and -R^uN(R^x)S(0),R^w;

J is O, NR^X or S;

t is 0-2;

p is 1-4.

[00133] In another embodiment, a compound provided herein is selected from

Table 1 or Table 2.

[00134] Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al, Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al, Mutation Res. 308: 33 (1994); Gordon et. al, Drug Metab. Dispos., 15: 589 (1987); Zello et. al.,

Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. I ll: 191 (1999).

[00135] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[00136] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For example, if a C-H bond is broken during a rate- determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect ("DKIE"). (See, e.g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al, Can. J. Physiol. Pharmacol, vol. 77, pp. 79- 88 (1999)).

[00137] Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T₂0. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium ("T") for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷0 or ¹⁸0 for oxygen, will provide a similar kinetic isotope effects.

[00138] In another embodiment, provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, or hydrates thereof, for the local or systemic treatment or prophylaxis of human and veterinary diseases, disorders and conditions modulated or otherwise affected mediated via CSF-1R kinase activity.

C. FORMULATION OF PHARMACEUTICAL COMPOSITIONS

[00139] The pharmaceutical compositions provided herein contain

therapeutically effective amounts of one or more of compounds provided herein that are useful in the prevention, treatment, or amelioration of CSF-1R kinase mediated diseases or one or more of the symptoms thereof.

[00140] The compositions contain one or more compounds provided herein.

The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art. [00141] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salt, solvate, hydrate or prodrug is (are) mixed with a suitable pharmaceutical carrier or vehicle. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of CSF-1R kinase mediated diseases.

[00142] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[00143] In addition, the compounds may be formulated as the sole

pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art.

Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[00144] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans.

[00145] The concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of CSF-1R kinase mediated diseases.

[00146] Typically a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 1 ng/ml to about 50-100 μg/ml. The pharmaceutical compositions typically should provide a dosage of from about 10 mg to about 4000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 10 mg to about 1000 mg and in certain embodiments, from about 10 mg to about 500 mg, from about 20 mg to about 250 mg or from about 25 mg to about 100 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. In certain embodiments, the pharmaceutical dosage unit forms are prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the essential active ingredient.

[00147] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the

administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[00148] Pharmaceutically acceptable derivatives include acids, bases, enol ethers and esters, salts, esters, hydrates, solvates and prodrug forms. The derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.

[00149] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating or preventing CSF-1R kinase mediated diseases. The concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

[00150] The compositions are intended to be administered by a suitable route, including, but not limited to, orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[00151] Solutions or suspensions used for parenteral, intradermal,

subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as

ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

[00152] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[00153] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. In one embodiment, the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[00154] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. The pharmaceutically

therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a

predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

[00155] Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene -vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D- (-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 °C, resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions

[00156] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others.

Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001%- 100% active ingredient, in certain embodiments, about 0.1-85%), typically about 75-95%).

[00157] The active compounds or pharmaceutically acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[00158] The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or

pharmaceutically acceptable derivatives thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as CSF- 1R kinase mediated diseases. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

1. Compositions for oral administration

[00159] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be

enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[00160] In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.

[00161] Examples of binders include microcrystalline cellulose, gum

tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[00162] If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[00163] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[00164] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[00165] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets are compressed tablets to which different layers of

pharmaceutically acceptable substances are applied. Film-coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[00166] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in- water or water-in-oil.

[00167] Elixirs are clear, sweetened, hydroalcoholic preparations.

Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[00168] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[00169] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. , water, to be easily measured for administration.

[00170] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters {e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[00171] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[00172] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, solutions and emulsions

[00173] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.

Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be

administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. In one embodiment, the composition is administered as an aqueous solution with hydroxypropyl-beta- cyclodextrin (HPBCD) as an excipient. In one embodiment, the aqueous solution contains about 1% to about 50% HPBCD. In one embodiment, the aqueous solution contains about 1%, 3%, 5%, 10% or about 20% HPBCD.

[00174] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g.,

polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene - vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers,

polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[00175] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[00176] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. [00177] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[00178] Examples of aqueous vehicles include Sodium Chloride Injection,

Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate.

Antioxidants include sodium bisulfate. Local anesthetics include procaine

hydrochloride. Suspending and dispersing agents include sodium

carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[00179] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired

pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.

[00180] The unit-dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[00181] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration.

Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[00182] Injectables are designed for local and systemic administration.

Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90%> w/w or more, such as more than 1% w/w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[00183] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for

ameliorating the symptoms of the condition and may be empirically determined.

3. Lyophilized powders

[00184] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.

[00185] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, hydroxypropyl-beta- cyclodextrin (HPBCD) or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (10- 1000 mg, 100-500 mg, 10-500 mg, 50-250 mg or 25-100 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[00186] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.

4. Topical administration

[00187] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays,

suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

[00188] The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation. These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfme powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will typically have diameters of less than 50 microns or less than 10 microns.

[00189] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[00190] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic solutions, pH about 5-7, with appropriate salts. 5. Compositions for other routes of administration

[00191] Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein.

[00192] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm.

[00193] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

6. Sustained Release Compositions

[00194] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981,

6,376,461,6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[00195] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[00196] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[00197] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose. In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized

polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene,

polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,

ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and

ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.

7. Targeted Formulations

[00198] The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[00199] In one embodiment, liposomal suspensions, including tissue -targeted liposomes, such as tumor-targeted liposomes, may also be suitable as

pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. D. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS

[00200] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activities that modulate the activity of CSF-IR kinase.

[00201] Such assays include, for example, biochemical assays such as binding assays, radioactivity incorporation assays, as well as a variety of cell based assays.

[00202] In certain embodiments, the compounds disclosed herein are tested in an M-NFS-60 cell proliferation assay to determine their cellular potency against CSF- IR. M-NFS-60s are mouse monocytic cells that depend on the binding of the ligand M-CSF to its receptor, CSF-IR, to proliferate. Inhibition of CSF-IR kinase activity will cause reduced growth and/or cell death. This assay assesses the potency of compounds as CSF-IR inhibitors by measuring the reduction of Alamar Blue reagent by viable cells. An exemplary assay is described in the Examples section.

[00203] In certain embodiments, competition binding assays were performed as described in Fabian et ah, Nature Biotechnology 2005, 23,329-336.

[00204] In one embodiment, the compounds provided herein were found to have Kds of about or less than about 150 nM against FLT3 kinase. In one

embodiment, the compounds provided herein have Kds of about 1 nM or less, 3 nM or less, 5 nM or less, 0.1-2 nM, 2-5 nM, 5-10nM, 10-25nM, 25-50 nM, or 50-150 nM, against FLT3 kinase. In one embodiment, the compounds provided herein have Kds of less than about 50, 25, 10, 5, 4, 3, 2, or 1 nM against FLT3 kinase. In another embodiment, the compounds provided herein have Kds of about or less than about 5 nM, 3 nM or 1 nM against FLT3 kinase.

[00205] In one embodiment, the compounds provided herein were found to have Kds of about or less than about 50 nM against KIT kinase. In one embodiment, the compounds provided herein have Kds of about 1 nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-10nM, or 10-25 M, against KIT kinase. In one embodiment, the compounds provided herein have Kds of less than about 10, 5, 4, 3, 2 or 1 nM against KIT kinase. In another embodiment, the compounds provided herein have Kds of about or less than about 5 nM, 3 nM or 1 nM against KIT kinase.

[00206] In one embodiment, the compounds provided herein were found to have Kds of about or less than about 100 nM or 50 nM against PDGFRB kinase. In one embodiment, the compounds provided herein have Kds of about about 1 nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-10nM, or 10-25 M, against PDGFRB kinase. In one embodiment, the compounds provided herein have Kds of less than about 10, 5, 4, 3, 2 or 1 nM against PDGFRB kinase. In another embodiment, the compounds provided herein have Kds of about or less than about 5 nM, 3 nM or 1 nM against PDGFRB kinase.

[00207] In one embodiment, the compounds provided herein were found to have Kds of about or less than about 100 nM or 50 nM against PDGFRA kinase. In one embodiment, the compounds provided herein have Kds of about about 1 nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-10nM, or 10-25 M, against PDGFRA kinase. In one embodiment, the compounds provided herein have Kds of less than about 10, 5, 4, 3, 2 or 1 nM against PDGFRA kinase. In another embodiment, the compounds provided herein have Kds of about or less than about 5 nM, 3 nM or 1 nM against PDGFRA kinase.

[00208] In one embodiment, the compounds provided herein were found to have Kds of about or less than about 1 μΜ against CSF-1R kinase. In one

embodiment, the compounds provided herein were found to have Kds of less than about 1, 0.5, 0.1 or 0.01 μΜ against CSF-lR kinase. In one embodiment, the compounds provided herein were found to have Kds of less than about 300, 200, 100, 50, 10, 5, 4, 3, 2, or 1 nM against CSF-lR kinase. In another embodiment, the compounds provided herein were found to have Kds of about or less than about 5 nM, 3 nM or 1 nM against CSF-1R kinase.

E. METHODS OF USE OF THE COMPOUNDS AND COMPOSITIONS

[00209] Also provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, for the treatment, prevention, or amelioration of a disease or disorder that is mediated or otherwise affected via protein kinase activiy or one or more symptoms of diseases or disorders that are mediated or otherwise affected via protein kinase activity (see, Krause and Van Etten, N EnglJ Med (2005) 353(2): 172- 187, Blume- Jensen and Hunter, Nature (2001) 411(17): 355-365 and Plowman et al, DN&P, 7:334-339 (1994)).

[00210] In certain embodiments, provided herein are methods of treating the following diseases or disorders:

[00211] 1) carcinomas include Kit-mediated and/or CSF-lR-mediated carcinomas, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, teratocarcinoma, head and neck cancer, brain cancer, intracranial carcinoma, glioblastoma including PDGFR-mediated glioblastoma, glioblastoma multiforme including PDGFR-mediated glioblastoma multiforme, neuroblastoma, cancer of the larynx, multiple endocrine neoplasias 2A and 2B (MENS 2A and MENS 2B) including RET-mediated MENS, thyroid cancer, including sporadic and familial medullary thyroid carcinoma, papillary thyroid carcinoma, parathyroid carcinoma including any RET-mediated thyroid carcinoma, follicular thyroid cancer, anaplastic thyroid cancer, bronchial carcinoid, oat cell carcinoma, lung cancer, small-cell lung cancer including flt-3 and/or Kit-mediated small cell lung cancer, stomach/ gastric cancer, gastrointestinal cancer, gastrointestinal stromal tumors (GIST) including Kit- mediated GIST and PDGFRa -mediated GIST, colon cancer, colorectal cancer, pancreatic cancer, islet cell carcinoma, hepatic/liver cancer, metastases to the liver, bladder cancer, renal cell cancer including PDGFR-mediated renal cell cancer, cancers of the genitourinary tract, ovarian cancer including Kit-mediated and/or PDGFR-mediated and/or CSF-lR-mediated ovarian cancer, endometrial cancer including CSF-lR-mediated endometrial cancer, cervical cancer, breast cancer including Flt-3 -mediated and/or PDGFR-mediated and/or CSF-lR-mediated breast cancer, prostate cancer including Kit-mediated prostate cancer, germ cell tumors including Kit-mediated germ cell tumors, seminomas including Kit-mediated seminomas, dysgerminomas, including Kit-mediated dysgerminomas, melanoma including PDGFR-mediated melanoma, metastases to the bone including CSF-lR- mediated bone metastases, metastatic tumors including VEGFR-mediated and/or CSF-IR metastatic tumors, stromal tumors, neuroendocrine tumors, tumor

angiogenesis including VEGFR-mediated and/or CSF-lR-mediated tumor

angiogenesis, mixed mesodermal tumors;

[00212] 2) sarcomas including PDGFR-mediated sarcomas, osteosarcoma, osteogenic sarcoma, bone cancer, glioma including PDGFR-mediated and/or CSF-lR- mediated glioma, astrocytoma, vascular tumors including VEGFR-mediated vascular tumors, Kaposi's sarcoma, carcinosarcoma, hemangiosarcomas including VEGFR3- mediated hemangiosarcomas, lymphangiosarcoma including VEGFR3 -mediated lymphangiosarcoma;

[00213] 3) myeloma, leukemia, myeloproliferative diseases (MPD), acute myeloid leukemia (AML) including flt-3 mediated and/or KIT-mediated and/or CSFlR-mediated acute myeloid leukemia, chronic myeloid leukemias (CML) including Flt-3 -mediated and/or PDGFR-mediated chronic myeloid leukemia, myelodysplasia leukemias including Flt-3 -mediated myelodysplasia leukemia, acute megakaryoblastic leukemia CSFlR-mediated acute megakaryoblastic leukemia, myelodysplasia syndrome (MDS), including Flt-3 mediated and/or Kit-mediated myelodysplasia syndrome, idiopathic hypereosinophilic syndrome (HES) including PDGFR-mediated HES, chronic eosinophilic leukemia (CEL) including PDGFR- mediated CEL, chronic myelomonocytic leukemia (CMML), mast cell leukemia including Kit-mediated mast cell leukemia, or systemic mastocytosis including Kit- mediated systemic mastocytosis; and

[00214] 4) lymphoma, Hodgkin's lymphoma, lymphoproliferative diseases, acute lymphoblastic leukemia (ALL), B- cell acute lymphoblastic leukemias, T-cell acute lymphoblastic leukemias, natural killer (NK) cell leukemia, B-cell lymphoma, T-cell lymphoma, and natural killer (NK) cell lymphoma, any of which may be Flt-3 mediated and/or PDGFR-mediated, Langerhans cell histiocytosis including CSF-1R- mediated and flt-3 -mediated Langerhans cell histiocytosis, mast cell tumors and mastocytosis;

[00215] 2) Nonmalignant proliferation diseases; atherosclerosis including CSF-

1R mediated atherosclerosis or PDGFR-mediated atherosclerosis, restenosis following vascular angioplasty including PDGFR-mediated restenosis, and fibroproliferative disorders such as obliterative bronchiolitis and idiopathic myelofibrosis, both of which may be PDGFR-mediated, pulmonary fibrosis and obesity;

[00216] 5) Inflammatory diseases or immune disorders including autoimmune diseases, which include, but is not limited to, tissue transplant rejection, graft-versus- host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic rhinitis, nephritis, Alzheimer's disease, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), including any of the aforementioned diseases which are flt-3- mediated and/or CSF-lR-mediated and/or KIT-mediated;

[00217] 6) Bone diseases including disorders relating to the mineralization, formation and resorption of the bone, including but not limited to osteoporosis, glucocorticoid-induced osteoporosis, periodontitis, bone loss due to cancer therapy, periprosthetic osteolysis, Paget's disease, hypercalcemia, osteomyelitis, and bone pain; and [00218] 7) Infectious diseases mediated either via viral or bacterial pathogens and sepsis, including KIT -mediated and/or CSF-lR-mediated sepsis.

[00219] Also provided are methods of modulating the activity, or subcellular distribution, of kinases in a cell, tissue or whole organism, using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof. In one embodiment, provided herein are methods of modulating the activity of Flt3 activity in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof. In one embodiment, provided herein are methods of modulating the activity of CSF-1R activity in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof. In one embodiment, provided herein are methods of modulating the activity of KIT activity in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof.

[00220] In one embodiment, the methods provided herein are for treating tumor-associated osteolysis, osteoporosis including ovariectomy-induced bone loss, orthopedic implant failure, renal inflammation and glomerulonephritis, transplant rejection including renal and bone marrow allografts and skin xenograft, obesity, Alzheimer's Disease and Langerhans cell histiocytosis. In one embodiment, the methods provided herein are for treating chronic skin disorders including psoriasis.

[00221] In another embodiment, a method for treating periodontitis,

Langerhans cell histiocytosis, osteoporosis, Paget's disease of bone (PDB), bone loss due to cancer therapy, periprosthetic osteolysis, glucocorticoid-induced osteoporosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and/or inflammatory arthritis is provided herein.

[00222] In one embodiment, the methods provided herein are for treating bone diseases including disorders relating to the mineralization, formation and resorption of the bone, including but not limited to osteoporosis, Paget's disease, hypercalcemia, osteolysis, osteomyelitis, and bone pain.

[00223] In one embodiment, the methods provided herein are for treating cancers, including, but not limited to head and neck cancer, (originating in lip, oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, nasal cavity and paranasal sinuses or salivary glands); lung cancer, including small cell lung cancer, non-small cell lung cancer; gastrointestinal tract cancers, including esophageal cancer, gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, gallbladder cancer, extrahepatic bile duct cancer, cancer of the ampulla of vater; breast cancer; gynecologic cancers, including, cancer of uterine cervix, cancer of the uterine body, vaginal cancer, vulvar cancer, ovarian cancer, gestational trophoblastic cancer neoplasia; testicular cancer; urinary tract cancers, including, renal cancer, urinary bladder cancer, prostate cancer, penile cancer, urethral cancer; neurologic tumors; endocrine neoplasms, including carcinoid and islet cell tumors, pheochromocytoma, adrenal cortical carcinoma, parathyroid carcinoma and metastases to endocrine glands. In another embodiment, the methods provided herein are for treating carcinoma, breast cancer, ovarian cancer, bone metastases, osteoporosis, Paget' s disease, hypercalcemia, osteolysis, osteomyelitis, bone pain, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis and multiple sclerosis. In another embodiment, provided herein are methods for treating inflammatory diseases of the eye including conjunctivitis, uveitis, iritis, scleritis, blepheritis, meibomitis and optical neuritis. In yet another embodiment, provided herein are methods for treating glaucoma, diabetic retinopathy and macular degeneration.

[00224] Further examples of cancers are basal cell carcinoma; squamous cell carcinoma; chondrosarcoma (a cancer arising in cartilage cells); mesenchymal- chondrosarcoma; soft tissue sarcomas, including, malignant tumours that may arise in any of the mesodermal tissues (muscles, tendons, vessels that carry blood or lymph, joints and fat); soft tissue sarcomas include; alveolar soft-part sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheral neuroectodermal tumours, rhabdomyosarcoma, synovial sarcoma; gestational trophoblastic

tumour(malignancy in which the tissues formed in the uterus following conception become cancerous); Hodgkin's lymphoma and laryngeal cancer.

[00225] In one embodiment, the cancer is a leukemia. In one embodiment, the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia.

[00226] In another embodiment, the leukemia is acute leukemia. In one embodiment, the acute leukemia is acute myeloid leukemia (AML). In one embodiment, acute myeloid leukemia is undifferentiated AML (M0), myeloblastic leukemia (Ml), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7). In another embodiment, the acute myeloid leukemia is

undifferentiated AML (MO). In yet another embodiment, the acute myeloid leukemia is myeloblastic leukemia (Ml). In yet another embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In yet another embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In yet another embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In yet another embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In yet another embodiment, the acute myeloid leukemia is erythroleukemia (M6). In yet another embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). In yet another embodiment, the acute myeloid leukemia is promyelocytic leukemia

[00227] In another embodiment, the acute leukemia is acute lymphocytic leukemia (ALL). In one embodiment, the acute lymphocytic leukemia is leukemia that originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), or lymph nodes. The acute lymphocytic leukemia is categorized according to the French- American-British (FAB) Morphological Classification Scheme as LI - Mature-appearing lymphoblasts (T-cells or pre-B-cells), L2 - Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3 - Lymphoblasts (B-cells; Burkitt's cells). In another embodiment, the acute

lymphocytic leukemia originates in the blast cells of the bone marrow (B-cells). In yet another embodiment, the acute lymphocytic leukemia originates in the thymus (T- cells). In yet another embodiment, the acute lymphocytic leukemia originates in the lymph nodes. In yet another embodiment, the acute lymphocytic leukemia is LI type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In yet another embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In yet another embodiment, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells; Burkitt's cells).

[00228] In yet another embodiment, the leukemia is T-cell leukemia. In one embodiment, the T-cell leukemia is peripheral T-cell leukemia, T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia. In another embodiment, the T-cell leukemia is peripheral T-cell leukemia. In yet another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In yet another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In still another embodiment, the T-cell leukemia is adult T-cell leukemia.

[00229] In yet another embodiment, the leukemia is Philadelphia positive. In one embodiment, the Philadelphia positive leukemia is Philadelphia positive AML, including, but not limited to, undifferentiated AML (M0), myeloblasts leukemia (Ml), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant

[M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7). In another embodiment, the Philadelphia positive leukemia is Philadelphia positive ALL.

[00230] In still another embodiment, the leukemia is drug resistant. In still another embodiment, the gastrointestinal stromal tumor (GIST) is drug resistant. In still another embodiment, the melanoma is drug resistant. In one embodiment, the subject has developed drug resistance to the anticancer therapy.

[00231] The cancers to be treated herein may be primary or metastatic. In one embodiment, the cancer is a solid or blood born metastatic tumor. In another embodiment, the cancer is metastatic cancer of bone.

[00232] Also provided are methods of modulating the activity, or subcellular distribution, of CSF-1R kinase in a cell, tissue or whole organism, using the compounds and compositions provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof thereof.

[00233] The active ingredient(s) in one embodiment are administered in an amount sufficient to deliver to a patient a therapeutically effective amount of the active compound in order to e.g., treat the diseases described herein, without causing serious toxic effects in a treated subject.

[00234] A typical dose of the compound may be in the range of from about 1 to about 50 mg/kg, from about 1 to about 20 mg/kg, from about 0.1 to about 10 mg/kg, from about 0.5 mg/kg to about 10 mg/kg, of body weight per day, more generally from about 0.1 to about 100 mg/kg body weight of the recipient per day.

Alternatively, a typical dose of the compound may be in the range of from about 50 mg to about 500 mg. Lower dosages may be used, for example, doses of about 0.5- 100 mg, 0.5-10 mg, or 0.5-5 mg per kilogram body weight per day. Even lower doses may be useful, and thus ranges can include from about 0.1-0.5 mg/kg body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable derivatives is calculated based on the weight of the parent derivative compound to be delivered. If the derivative compound itself exhibits activity, then the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those of skill in the art.

[00235] The compounds are conveniently administered in units of any suitable dosage form, including but not limited to one containing from about 1 to 2000 mg, from about 10 to 1000 mg, or from about 25 to 700 mg of active ingredient per unit dosage form. In one embodiment, the unit dose is selected from 12, 18, 25, 27, 40, 50, 60, 90,100, 135, 200, 250, 300, 400, 450, 500, 600, 675, 700, 800, 900 and 1000 mgs. For example, an oral dosage of from about 25 to 1000 mg is usually convenient, including in one or multiple dosage forms of 10, 12, 18, 25, 27, 40, 50, 60, 90,100, 135, 200, 250, 300, 400, 450, 500, 600, 675, 700, 800, 900 or 1000 mgs. In certain embodiments, lower dosages may be used, for example, from about 10-100 or 1-50 mgs. Also contemplated are doses of 0.1-50 mg, 0.1-20 mgs., or 0.1-10 mgs.

Furthermore, lower doses may be utilized in the case of administration by a non-oral route, as for example, by injection or inhalation.

[00236] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the compositions provided herein.

[00237] In certain embodiments, the compound or composition provided herein can be administered as a single once-a-day dose (QD) or as divided doses throughout a day. In particular embodiments, the compound or composition is administered four times per day (QID). In particular embodiments, the compound or composition is administered three times per day (TID). In particular embodiments, the compound or composition is administered two times per day (BID). In particular embodiments, the compound or composition is administered once per day (QD).

[00238] The administration can also be continuous (i.e., daily for consecutive days or every day) or intermittent . The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound of Formula I may be administration for one to six days per week or administration on alternate days.

[00239] In one embodiment, the compound or composition provided herein is administered intermittently. In yet another embodiment, the compound or

composition provided herein is administered intermittently once weekly, twice weekly or three times weekly. In yet another embodiment, the compound or composition provided herein is administered once weekly. In yet another embodiment, the compound or composition provided herein is administered twice weekly. In yet another embodiment, the compound or composition provided herein is administered three times weekly. In one embodiment, the compound or composition provided herein is administered QD intermittently once weekly, twice weekly or three times weekly. In yet another embodiment, the compound or composition provided herein is administered QD once weekly. In another embodiment, the compound or

composition provided herein is administered QD twice weekly. In another

embodiment, the compound or composition provided herein is administered QD three times weekly.

[00240] In one embodiment, the active ingredient is administered to achieve peak plasma concentrations of the active compound of from about 0.02 to 20 μΜ, from about 0.2 to about 5 μ M or from about 0.5 to 10 μΜ. For example, this can be achieved by intravenous injection of a 0.1 to 5% solution of active ingredient, optionally in saline, or administered as a bolus of active ingredient. It is to be understood that for any particular subject, specific dosage regimens should be adjusted over time to meet individual needs, and will vary depending upon absorption, inactivation and excretion rates of the drug. The concentrations set forth here are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered all at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. [00241] The subject matter has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Thus, it will be appreciated by those of skill in the art that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, one of skill in the art will also appreciate that many of the reagents provided in the examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 5^th ed. (2001).

F. COMBINATION THERAPY

[00242] Furthermore, it will be understood by those skilled in the art that the compounds, isomers, and pharmaceutically acceptable salts provided herein, including pharmaceutical compositions and formulations containing these

compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, also contemplated herein is the use of compounds, and pharmaceutically acceptable salts provided herein in combination with other active pharmaceutical agents for the treatment of the disease/conditions described herein.

[00243] In one embodiment, such additional pharmaceutical agents include without limitation anti-cancer agents (including chemotherapeutic agents and antiproliferative agents), anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents.

[00244] In certain embodiments, the anti-cancer agents include anti-metabolites

(e.g., 5-fluoro-uracil, cytarabine, clofarabine, methotrexate, fludarabine and others), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel and docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and

hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, satraplatin and CI-973), anthracyclines (e.g., doxrubicin and daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin and daunomycin), topoisomerase inhibitors (e.g., etoposide and camptothecins), anti-angiogenesis agents (e.g. Sutent®, sorafenib and Bevacizumab) or any other cytotoxic agents, (e.g. estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors (such as imatinib), and radiation treatment. [00245] In certain embodiments, the anti-inflammatory agents include matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNF molecules, TNF soluble receptors, and IL1) non-steroidal anti-inflammatory drugs (NSAIDs) such as prostaglandin synthase inhibitors (e.g., choline magnesium salicylate and salicylsalicyclic acid), COX-1 or COX-2 inhibitors, glucocorticoid receptor agonists (e.g., corticosteroids, methylprednisone, prednisone, and cortisone) or antifolates such as methotrexate.

[00246] The compound or composition provided herein, or pharmaceutically acceptable salt of the compound, may be administered simultaneously with, prior to, or after administration of one or more of the above agents.

[00247] Pharmaceutical compositions containing a compound provided herein or pharmaceutically acceptable salt thereof, and one or more of the above agents are also provided.

[00248] Also provided, in one embodiment, is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of cancer and related diseases and disorders, said therapy comprising the administration to a subject in need thereof, one of the compounds or compositions disclosed herein, or pharmaceutically acceptable salts thereof, with one or more anti-cancer agents. Also provided, in another embodiment, is a combination therapy that treats or prevents the onset of the symptom of osteoporosis and related diseases and disorders, said therapy comprising the administration to a subject in need thereof, one of the compounds or compositions disclosed herein, or pharmaceutically acceptable salts thereof, with one or more anti-inflammatory or immunomodulatory agents. Also provided, in yet another embodiment, is a combination therapy that treats or prevents the onset of the symptom of rheumatoid arthritis and related diseases and disorders, said therapy comprising the administration to a subject in need thereof, one of the compounds or compositions disclosed herein, or pharmaceutically acceptable salts thereof, with one or more anti-inflammatory or immunomodulatory agents.

G. PREPARATION OF COMPOUNDS

[00249] Starting materials in the synthesis examples provided herein are either available from commercial sources or via literature procedures (e.g. , March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (1992) 4th Ed.; Wiley Interscience, New York). All commercially available compounds were used without further purification unless otherwise indicated. 300 MHz Proton (1H) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 300 NMR spectrometer. Significant peaks are tabulated and typically include: number of protons, and multiplicity (s, singlet; d, double; t, triplet; q, quartet; m, multiplet; br s, broad singlet). Chemical shifts are reported as parts per million (δ) relative to tetramethylsilane. Low resolution mass spectra (MS) were obtained as electrospray ionization (ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% acetic acid). Preparative reverse phase HPLC was typically performed using a Varian HPLC system equipped with a Phenomenex phenylhexyl, a Phenomenex Luna CI 8, or a Varian Pursuit diphenyl reverse phase column; typical elution conditions utilized a gradient containing an increasing composition of organic cosolvent (0.05%

HOAc/CH₃CN or 0.05% HOAc/MeOH) to aqueous cosolvent (0.05% aq HO Ac). Silica gel chromatography was either performed manually, typically following the published procedure for flash chromatography (Still et al. (1978) J. Org. Chem.

43:2923), or on an automated system (for example, Biotage SP instrument) using prepacked silica gel columns.

[00250] It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds under standard conditions.

[00251] It will also be appreciated by those skilled in the art that in the process described below, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl {e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(0)-R (where R is alkyl, aryl or aralkyl), /?-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.

[00252] Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience. [00253] One of ordinary skill in the art could easily ascertain which choices for each substituent are possible for the reaction conditions of each Scheme. Moreover, the substituents are selected from components as indicated in the specification heretofore, and may be attached to starting materials, intermediates, and/or final products according to schemes known to those of ordinary skill in the art.

[00254] Also it will be apparent that the compounds provided herein could exist as one or more isomers, that is, E/Z isomers, enantiomers and/or diastereomers.

[00255] Compounds of formula (I) may be generally prepared as depicted in the following schemes, unless otherwise noted, the various substituents are as defined elsewhere herein.

[00256] Standard abbreviations and acronyms as defined in J. Org. Chem. 2007

72(1): 23A-24A are used herein. Other abbreviations and acronyms used herein are as follows:

[00257] In the schemes below, R , R , R^/a, R , R , and R^1Ua are each independently selected from hydrogen and optionally substituted alkyl; where the substituents, when present are each independently selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy.

Scheme 1: General synthesis of azolyl amides.

leaving group)

8 9

In an illustrative method, azolyl amide compounds of formula (I) may be routinely prepared according to the synthetic routes outlined in Scheme 1. The commercially available nucleophiles 1 (H-L²-R³, in which L² may represent -OR⁹-, -SR⁹-, or -N(R¹⁰)R⁹-) and cyano-substituted heteroaryl compound 2 with a leaving group, such as, but not limited to, chloride or fluoride, are condensed under nucleophilic substitution conditions to give compounds 3. The reaction is promoted by bases such as, but not limited to, NaH or t-BuOK in solvents such as, but not limited to, DMF and THF. The reaction can be promoted using heating in a conventional oil bath or in a microwave reactor. The cyano group of compounds 3 is hydrolyzed under basic conditions, such as, but not limited to, aqueous NaOH in EtOH to give the carboxylic acids 4. The reaction is promoted using heating in a conventional oil bath. The azolyl amides 7 can be prepared by coupling of the carboxylic acid derivatives 6 with aminoazole derivatives 5 using coupling reagents, such as, but not limited to, EDCI or HATU. The reaction is promoted with bases such as DIEA or DMAP and in solvents such as DCM or DMF. The nitro group of 7 is reduced to anilines 8, using reducing agents, such as, but not limited to, zinc/AcOH or SnCl in EtOH. The reaction can be promoted using heating in a conventional oil bath. The anilines 8 are then coupled with acids 4 using, such as, but not limited to, EDCI or HATU, to give the amide derivates 9. [00258] In an illustrative method, azolyl amide compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 2. In cases when R³ (either acylic or cyclic) contains a protected amino group, such as, but not limited to, the tert-butyloxy carbonyl group, the protecting group within the amide derivatives 10 can be deprotected to give amines 11, using various conditions, such as, but not limited to, TFA in DCM or 4N HC1 in 1,4-dioxane. Amines 11 can undergo reductive amination with various aldehydes and ketones, using reducing agents, such as, but not limited to NaCNBH₃, Na(OAc)₃BH, or NaBH₄. The reaction can be conducted in a pH~4 NaOAc/AcOH buffer in MeOH, or promoted by addition of AcOH in dichloroethane. The reaction can be run at ambient temperature for reaction with aldehydes to give amines 12a, or be promoted using heating in a conventional oil bath for reaction with ketones to give amines 12b. The amines 11 can also undergo Michael addition with electron-withdrawing group (EWG)-activated vinyl derivatives to give amines 12c. The reaction may be promoted with the addition of bases, such as, but not limited to, DIEA, at elevated temperature if necessary. The amines 11 can also be alkylated with appropriate electrophiles, such as, but not limited to, alkyl halides or alkyl sulfonates, to give amines 12d. The reaction may be promoted with the addition of bases, such as, but not limited to, DIEA or TEA, at elevated temperature if necessary.

Scheme 2: General synthesis of azolyl amides.

e erocyc y , cycoa y ;

EWG is electron withdrawing group

[00259] In an illustrative method, azolyl amide compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 3. In cases when R³ contains a primary alcohol (13a) or secondary alcohol (13b), such as, but not limited to, the hydroxymethyl group, the hydroxy 1 group within the amide derivatives 13 can be oxidized to give aldehydes 14a or ketones 14b, using oxidizing agents, such as, but not limited to, Dess-Martin periodinane. Aldehydes 14a or ketones 14b can undergo reductive amination with various amines, using reducing agents, such as, but not limited to NaCNBH₃, Na(OAc)₃BH, or NaBH₄. The reaction can be done in a pH~4 NaOAc/AcOH buffer in MeOH, or promoted by addition of AcOH in dichloroethane. The reaction can be run at ambient temperature for aldehydes to give amines 15a, or be promoted using heating in a conventional oil bath for ketones to give amines 15b. Scheme 3: General synthesis of azolyl amides.

Q³, Q⁴ = H, alkyl, aryl, 15a (R = H)

cycloalkyl, heterocyclyl, 15b (R = alkyl, aryl,

cycloalkyl, heterocyclyl,

heteroaryl, etc

heteroaryl, etc)

[00260] In an illustrative method, azolyl amide compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 4. The amide derivatives 16 containing a heteroaryl moiety B substituted with a reactive halogen atom, such as, but not limited to, bromide or iodide, or in some cases sulfonate and phosphonate can undergo a variety of transition metal-mediated catalyzed reactions with various organometallic reagents or nucleophiles. For example, the halogen-containing amide derivatives 16 can undergo Negishi coupling with organozinc reagents to give compounds 17a, in which L² is such as, but not limited to, an alkylene or a direct bond. Such coupling reactions are catalyzed using transition metal catalysts, such as, but not limited to, θ₂Νί(Ρ1ΐ₂Ρ ¾ ¾ΡΡ1ΐ₂).

[00261] In another example, the halogen-containing amide derivatives 16 can also undergo Suzuki coupling with reagents, such as, but not limited to, boronic acids, boronate esters, or trifluoroborates, to give compounds 17b, in which L² may be, but is not limited to, a direct bond to R³ = aryl or heteroaryl, an alkylene, an alkenylene. Such coupling reactions are catalyzed using transition metal catalysts, such as, but not limited to, Pd(Ph₃P)₄, and are promoted by bases, such as, but not limited to, Na₂C0₃, and using heating in a conventional oil bath or in a microwave reactor. The addition of ligands, such as, but not limited to, Xphos, may be necessary to facilitate the transformations . [00262] In yet another example, the halogen-containing amide derivatives 16 can also undergo Buchwald-Hartwig coupling with various nucleophiles, such as, but not limited to, amines, mercaptans, alcohols, and carbon nucleophiles, to give compounds 17c, in which L² is -OR⁹-, -SR⁹-, or -N(R¹⁰)R⁹-, or an appropriately activated alkylene. Such coupling reactions are catalyzed using transition metal catalysts, such as, but not limited to, Pd₂(dba)₃, and are promoted by the addition of ligands, such as, but not limited to, Xantphos, by the addition of bases, such as, but not limited to NaOt-Bu or K₃P0₄, and using heating in a conventional oil bath or in a microwave reactor, in solvents, such as, but not limited to toluene or 1,4-dioxane.

[00263] In yet another example, the halogen-containing amide derivatives 16 can also undergo Sonogashira coupling with various alkynylenes, to give compounds 17d, in which L² is -an alkynylene. Such coupling reactions are catalyzed using transition metal catalysts, such as, but not limited to, PdCl₂(PPh₃)₂ and copper (I) iodide, by the addition of bases, such as, but not limited to DIEA, and using heating in a conventional oil bath or in a microwave reactor.

Scheme 4: General synthesis of azolyl amides.

17d

[00264] In an illustrative method, azolyl amide compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 5. The transition-metal mediated couplings as detailed for Scheme 4, such as, but not limited to, Negishi coupling, Suzuki coupling, Buchwald-Hartwig coupling, and Sonogashira coupling, can be performed with bromo/iodo-containing heteroaryl carboxylates 18, to give compounds 19. The carboxylate of 19 can be hydro lyzed under basic conditions, such as, but not limited to, aqueous NaOH in EtOH to give the carboxylic acids 4. The carboxylic acids 4 can then be converted to mixed anhydrides by reacting with an alkyl chloroformate, such as, but not limited to, ethyl chloroformate, with the addition of a base, such as, but not limited to, TEA. The mixed anhydride can then be condensed with the anilines 8 to give the amide derivatives 9. The condensation may be promoted using heating in a conventional oil bath.

Scheme 5: General synthesis of azolyl amides.

solvent, heat

18 (R^x = alkyl, X = Br, I) 19 4

* as detailed in Scheme 4

1 ) Chloroformate, base

solvent

2) 8, solvent, base, heat

[00265] In an illustrative method, azolyl amide compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 6. The readily available phenyleneamine derivatives 20 can couple with the carboxylic acids 4 using appropriate coupling reagents, such as, but not limited to, EDCI or HATU, promoted by bases such as DIE A, TEA, or DMAP to give the amide derivates 21. The carboxylate group of 21 is hydrolyzed under basic conditions, such as, but not limited to, NaOH or KOH in 1,4-dioxane or MeOH to give the carboxylic acid 22. The diaryl amides 9 can be prepared by the reaction of the acids 22 with azole amine derivatives, such as 5, using coupling reagents, such as, but not limited to, EDCI or HATU. The reaction is promoted with bases such as DIEA or DMAP and in solvents such as DCM or DMF.

Scheme 6: General synthesis of azolyl amides.

[00266] Heteroaryl carboxylic acid derivatives 26 may also be prepared in an illustrative method as outlined in Scheme 7. Carboxylic acid-containing heteroaryls or heterocycles (23) can be reduced to the corresponding alcohols 24 using a reducing agent, such as, but not limited to, diborane in THF, at elevated temperature if necessary. The alcohols 24 are condensed under nucleophilic substitution conditions with compounds 2 to give compounds 25. The reaction is promoted by bases such as, but not limited to, NaH or t-BuOK in solvents such as, but not limited to, DMF and THF, at elevated temperature. The cyano group of compounds 25 is hydrolyzed under basic conditions, such as, but not limited to, aqueous NaOH in EtOH to give the carboxylic acids 26.

Scheme 7: General synthesis of carboxylic acids.

ssoollvveenntt,, hheeaatt base

23 24 solvent, heat

(X = leaving group)

[00267] Heteroaryl carboxylic acid derivatives 29 may also be prepared in an illustrative method as outlined in Scheme 8. Ketone-containing heterocycles (27) can react with a Grignard reagent (e.g. R-Mg-Cl) to give the corresponding alcohols 28. The alcohols 28 can then be converted to compounds 29 as described in Scheme 7.

Scheme 8: General synthesis of carboxylic acids.

^Q3

27

Q³ = al

aryl, heteroaryl, etc haloalkyl, aryl, heteroaryl, etc

[00268] Heteroaryl carboxylic acid derivatives 32 may also be prepared in an illustrative method as outlined in Scheme 9. The a-proton of ketone-containing heterocycles 30 can be deprotonated with bases, such as, but not limited to, NaH or LDA. The enolate formed can then undergo nucleophilic substitution upon halo- substituted heteroaryl ring B (2) to give compounds 31. The reaction can be promoted by heating in a conventional oil bath. The cyano group of compounds 31 is hydrolyzed under basic conditions, such as, but not limited to, aqueous NaOH in EtOH to give the carboxylic acids 32. The reaction is promoted using heating in a conventional oil bath.

Scheme 9: General synthesis of carboxylic acids.

₃₁ 32

n = 0, 1 , 2

[00269] Azole amine derivatives (R¹)_p-A-NH₂, wherein the heteroaryl ring A is a 5-membered isoxazole ring, may be prepared by condensation of appropriate fragments and precursors by methods well known in the art and described in texts such as Gilchrist, T.L., Heterocyclic Chemistry (1992), 2nd Ed., Longman Scientific & Technical and John Wiley & Sons. Scheme 10 shows one example where (R^_p-A- NH₂ is 5-substituted-3-aminoisoxazole, whereby an appropriate 3-oxonitrile (35) is treated with hydroxylamine under appropriate conditions of pH and temperature which are described, for example, in Takase et al. Heterocycles 1991 32(6), 1153- 1158, to afford the desired azole amine product (36). This method is particularly applicable for cases in which the atom of R¹ directly attached to the aromatic ring is highly substituted, for example, is an α,α-dialkyl substituent (See Takase et al.

Heterocycles 1991 32(6), 1153-1158). The requisite 3-oxonitriles (35) can be prepared by reaction of an R¹ -containing carboxylic ester (33) with an akali metal salt of acetonitrile (34) (See, for example, US 4,728,743).

Scheme 10: General synthesis of 3-aminoisoxazole derivatives.

33 34 35 36

[00270] Scheme 11 shows an example for the synthesis of azole amine derivatives (R¹)_P-A-NH₂, wherein the heteroaryl ring A is 3-substituted-5- aminoisoxazole, whereby an appropriate 3-oxonitrile 35, prepared as described in Scheme 10, is treated with hydroxylamine under appropriate conditions of pH and temperature, as described again in Takase et al. Heterocycles 1991 32(6), 1153-1158, to afford the desired aryl amine product (37). This method is particularly applicable for cases in which the atom of R¹ directly attached to the aromatic ring is not highly substituted, for example, is not an α,α-dialkyl substituent (See Eddington et al. Eur. J. Med. Chem. 2002 37, 635-648), or when R¹ contains one or more highly electron- withdrawing groups, for example fluorine, or under special conditions of pH and solvent, such as an ethanol and water mixture as described in EP 0220947.

Scheme 11: General synthesis of 5-aminoisoxazole derivatives.

NH OH _n.

^R _N —

Q¹ Solvent, hea►t " N-0 ™^,

pH control

35 37

[00271] Azole amine derivatives (39) (R¹)_P-A-NH₂, wherein the NH₂ group is directly attached to a nitrogen atom of the azole ring, may be prepared by amination of the corresponding azoles using methods well known in the art. Scheme 12 shows one example where

is 4-substituted-pyrazole 38, whereby the amination can be realized by treating with a base, such as, but not limited to, NaH, and using amination reagents, such as, but not limited to, hydroxylamine-O-sulfonic acid or chloroamine. The reaction can be conducted in solvents such as, but not limited to, DMF and THF. The reaction can be promoted using heating in a conventional oil bath.

Scheme 12: General synthesis of 1-amino azole derivatives.

amination reagent . _^

^« base, solvent, hea^►t ^R- <— N

NH₂

38 39

[00272] In an illustrative method, aryl acetic acid derivatives may be routinely prepared according to the synthetic route outlined in Scheme 13. The readily available benzyl bromide 40 can be treated with a cyanide, such as, but not limited to, NaCN or KCN, in a solvent such as, but not limited to EtOH, to give the phenyl acetonitrile derivatives 41. The cyano group of 41 can be converted to carboxylate 42 under acidic conditions, using acids, such as, but not limited to, HC1 or sulfuric acid, in a solvent, such as, but not limited to, EtOH. The reaction can be promoted by heating in a conventional oil bath. The nitro group of 42 can be reduced to an amino group to give aniline derivatives 43 by hydrogenation in the presence of a catalyst, such as, but not limited to, Pd on carbon, or with alternative nitro reducing systems such Sn or Fe metal in the presence of acid. The amino group of 43 can be protected as its t-butyl carbamate to give derivatives 44 by reacting with di-tert-butyl dicarbonate and a base, such as, but not limited to triethylamine. The carboxylate group of 44 can be hydrolyzed under basic conditions, such as, but not limited to, NaOH or KOH in 1,4- dioxane or MeOH to give the carboxylic acid 45.

Scheme 13: General synthesis of aryl acetic acid derivatives.

[00273] In an illustrative method, cyclohexane amide compounds of formula

(I) may be routinely prepared according to the synthetic routes outlined in Scheme 14. The cyclohexane aryl amides 47 can be prepared by coupling of the carboxylic acid derivatives 46 with aminoazole derivatives 5 using coupling reagents, such as, but not limited to, EDCI or HATU. The reaction is promoted with bases such as DIEA or DMAP and in solvents such as DCM or DMF. The tert-butyloxy carbonyl group of 47 is cleaved under acidic conditions, such as, but not limited to, TFA in DCM or 4N HC1 in 1,4-dioxane, to give the cyclohexaneamines 48. The amines 48 are then coupled with acids 4 using coupling agents, such as, but not limited to, EDCI or HATU, to give the cyclohexane amide derivatives 49.

Scheme 14: General synthesis of cyclohexane azolyl amides.

48 49

[00274] In an illustrative method, cyclohexane amide compounds of formula

(I) may also be routinely prepared according to the synthetic route outlined in Scheme 15. In cases when R³ (either acylic or cyclic) contains a protected amino group, such as, but not limited to, the tert-butoxycarbonylamino group, the protecting group within the amide derivatives 50 can be deprotected to give amines 51, using various conditions, such as, but not limited to, TFA in DCM or 4N HC1 in 1,4-dioxane.

Amines 51 can undergo reductive alkylation with various aldehydes and ketones, using reducing agents, such as, but not limited to NaCNBH₃, Na(OAc)₃BH, or NaBH₄. The reaction can be conducted in a pH~4 NaOAc/AcOH buffer in MeOH, or promoted by addition of AcOH in dichloroethane. The reaction can be run at ambient temperature for reaction with aldehydes to give amines 52a, or be promoted using heating in a conventional oil bath for reaction with ketones to give amines 52b.

Scheme 15: General synthesis of cyclohexane azolyl amides.

52b [00275] In an illustrative method, the azole acetamide compounds of formula

(I) may be routinely prepared according to the synthetic routes outlined in Scheme 16. The phenylenediamine derivatives 53 can couple with acids 4 using appropriate coupling reagents, such as, but not limited to, EDCI or HATU, promoted by bases such as DIE A, TEA, or DMAP to give amide derivatives 54. The tert-butyloxy carbonyl group of 54 is cleaved under acidic conditions, such as, but not limited to, TFA in DCM or 4N HC1 in 1,4-dioxane, to give the anilines 55. The anilines 55 can then couple with azole acetic acids 56 using appropriate coupling reagents, such as, but not limited to, EDCI or HATU, promoted by bases such as DIEA or TEA, to give the azole acetamide derivates 57. Alternatively, the anilines 55 can condense with azole acetyl chlorides 58 in solvents such as DCM or THF, promoted by bases such as DIEA or aq. NaHC0₃, to give the azole acetamide derivates 57.

Scheme 16: General synthesis of azole acetamides.

58

base, solvent

[00276] Azole N-acetic acid derivatives (62), wherein the acetic acid group is directly attached to a nitrogen atom of the azole ring, may be prepared by alkylation of the corresponding azoles using methods well known in the art. Scheme 17 shows one example where

is a substituted azole 59, whereby the alkylation can be effected by treating with a base, such as, but not limited to, NaH, and electrophiles 60 to give the azole acetates 61. The reaction can be conducted in solvents such as, but not limited to, DMF or THF. The reaction can be promoted using heating in a conventional oil bath. The acetates 61 can then be hydro lyzed under basic conditions, such as, but not limited to, aqueous NaOH in EtOH to give the azole acetic acids 62.

Scheme 17: General synthesis of azole N-acetic acids.

_R1

59 X = CH, N 61 X = CH N 62 X = CH, N

[00277] In an illustrative method, azole C-acetic acid derivatives, wherein the acetic acid group is directly attached to a carbon atom of the azole ring, may be routinely prepared according to the synthetic route outlined in Scheme 18. The readily available azole carboxylic acids 63 can be reduced with a reducing agent, such as, but not limited to, borane in THF, in a solvent such as, but not limited to THF, to give the azole methanols 64. The reaction can be promoted by heating in a conventional oil bath. The hydroxyl group of 64 can be converted to bromides 65 using a bromination reagent, such as, but not limited to, phosphorus tribromide. The bromide of azoles 65 can be displaced with cyanide using a reagent such as, but not limited to, NaCN or KCN, in solvent such as, but not limited to EtOH, to give the azole acetonitrile derivatives 66. The cyano group of 66 can be hydro lyzed to give the carboxylic acid 67 under basic conditions, such as, but not limited to, NaOH or KOH in 1,4-dioxane or MeOH. The reaction can be promoted by heating in a conventional oil bath.

Scheme 18: General synthesis of azole C-acetic acids.

^,R'

^{λ Y}

63 X = N, Y = O, NR¹ 64 X = N, Y = O, NR¹ 65 X = N, Y = O, NR¹

NR¹ [00278] The subject matter has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Thus, it will be appreciated by those of skill in the art that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, one of skill in the art will also appreciate that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 5 ^th ed. (2001). Such changes and

modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use provided herein, may be made without departing from the spirit and scope thereof. U.S. patents and publications referenced herein are incorporated by reference.

EXAMPLES

Example 1

Preparation of N-(4-(2-(5-tei"i-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5- (pyrrolidin-3-yloxy)picolinamide hydrochloride

[00279] Step 1 : NaH (60% in mineral oil, 393 mg, 9.8 mmol) in 15 mL of DMF was stirred at rt in a round-bottom flask. tert-Butyl 3-hydroxypyrrolidine-l- carboxylate (1.84 g, 9.8 mmol) was added in portions and the resulting mixture was stirred at rt for 30 min. 5-Fluoro picolinonitrile (1.0 g, 8.2 mmol) in 5 mL of DMF was added dropwise. After stirring at rt for 2 h, LC-MS indicated that the reaction was complete. The reaction mixture was then partitioned between EtOAc (30 mL) and water (25 mL). The organic layer was washed with brine (10 mL), dried over MgS0₄, filtered, and concentrated under reduced pressure, and dried under high vacuum to give crude tert- vXy\ 3 -((6-cyanopyridin-3-yl)oxy)pyrrolidine-l -carboxylate (2.37 g) as an oil. LC-MS (ESI) m/z 290 (M +H)⁺.

[00280] Step 2: Crude tert- vXy\ 3 -((6-cyanopyridin-3-yl)oxy pyrrolidine- 1- carboxylate from Step 1 (2.37 g, 8.0 mmol) was stirred in 30 mL of EtOH. Aq. NaOH (2N, 12.3 mL) was added. The resulting mixture was heated at 85 °C for over night. LC-MS indicated that the hydrolysis was complete. The reaction mixture was then cooled to rt, most of the volatile solvent was evaporated under reduced pressure. The residue was acidified with 3N aq. HC1 to pH~5. The solid formed was collected via filtration and washed with cold water, and dried in a vacuum oven at 50 °C for over night to give 5-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid (738 mg, 30%). LC-MS (ESI) m/z 309 (M +H)⁺.

[00281] Step 3: N-(5-tert-Butylisoxazol-3-yl)-2-(4-nitrophenyl)acetamide was prepared using a procedure analogous to that described in Step 5 of Example 1, substituting 5-fert-butylisoxazol-3-amine for 2-(4-aminophenyl)-N-(5-tert- butylisoxazol-3-yl)acetamide, and 2-(4-nitrophenyl)acetic acid for 5- \- tert- butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid used. LC-MS (ESI) m/z 304 (M + H)⁺.

[00282] Step 4: To a stirred solution of N-(5-tert-butylisoxazol-3-yl)-2-(4- nitrophenyl)acetamide (500 mg, 1.65 mmol) from Step 3 of this example in DCM (10 mL) was added AcOH (0.95 mL, 16.5 mmol), followed by zinc (0.54 g, 8.25 mmol) in small portions. The resulting mixture was stirred at rt for 3h. LC-MS indicated that the reaction was complete. The reaction mixture was carefully quenched with sat. NaHC0₃ (50 mL) at rt, and the resulting biphasic mixture was extracted with DCM (30 mL) and EtOAc (30 mL) sequentially. The organic layers were washed with brine (20 mL) sequentially, dried over MgS0₄, filtered, and concentrated under reduced pressure to give 2-(4-aminophenyl)-N-(5-fert-butylisoxazol-3-yl)acetamide (450 mg, 100%). LC-MS (ESI) m/z 274 (M + H)⁺.

[00283] Step 5: 5-((l-(tert-Butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid from Step 2 of this example (135 mg, 0.44 mmol) was stirred in 3 mL of DMF.

HATU (217 mg, 0.57 mmol) was added, followed by TEA (62 μί, 0.44 mmol). After 10 min, 2-(4-aminophenyl)-N-(5-tert-butylisoxazol-3-yl)acetamide from Step 4 of this example (120 mg, 0.44 mmol) was added, followed by TEA (62 μί, 0.44 mmol). The resulting mixture was stirred at rt for 3h. LC-MS indicated that the reaction was complete. Water (20 mL) was then added, the precipitates were collected by filtration, washed with cold water, and dried in a vacuum oven to give tert-butyl 3-((6-((4-(2- ((5 -(tert-butyl)isoxazol-3 -yl)amino)-2-oxoethyl)phenyl)carbamoyl)pyridin-3 - yl)oxy)pyrrolidine-l-carboxylate as a light yellow solid (215 mg, 87%>). LC-MS (ESI) m/z 564 (M + H)⁺. [00284] Step 6: tert-Butyl 3-((6-((4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2- oxoethyl)phenyl)carbamoyl)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate from Step 5 of this example (215 mg, 0.38 mmol) was suspended in 3 mL of EtOAc and 4N HCl/l,4-Dioxane (5 mL) was added. The resulting mixture was stirred at rt for 3d. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with CH₃CN (20 mL) and evaporated under reduced pressure. The residue was taken up in CH₃CN/Et₂0 (1 :5, v/v), sonicated at rt for 15 min, filtered, and dried in a vacuum oven to give N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5- (pyrrolidin-3-yloxy)picolinamide hydrochloride (185 mg, 97%) as a yellow solid. LC- MS (ESI) m/z 464 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.18 (s, 1H), 10.45 (s, 1H), 9.44 (d, J= 4.52 Hz, 2H), 8.39 (br. s., 1H), 8.14 (d, J= 8.29 Hz, 1H), 7.81 (d, J= 8.29 Hz, 2H), 7.69 (d, J= 8.48 Hz, 1H), 7.28 (d, J= 7.91 Hz, 2H), 6.56 (s, 1H), 5.37 (br. s., 1H), 3.21 - 3.60 (m, 5H), 2.25 (d, J= 15.45 Hz, 2H), 1.27 (s, 9H).

Example 2

Preparation of 3-(6-(4-(2-(5-terf-butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l-isopropylpyrrolidinium

methanesulfonate

[00285] Step 1 : To a stirred solution of N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5 -(pyrrolidin-3 -yloxy)picolinamide hydrochloride from Step 6 of Example 1 (125 mg, 0.25 mmol) in 3 mL of pH~4 MeOH/NaOAc buffer (21 grams of NaOAc 3H₂0 and 48 mL of AcOH, diluted to 1.0 L with methanol) was added acetone (0.3 mL, excess) and NaCNBH₃ (25 mg, excess). The resulting mixture was reflux at 85 °C for 1 h. LC-MS indicated that the reaction was complete. The reaction was cooled to rt and the crude product was purified by reverse phase HPLC to give N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l- isopropylpyrrolidin-3-yloxy)picolinamide (120 mg, 95% yield). LC-MS (ESI) m/z 506 (M + H)⁺.

[00286] Step 2: N-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(l-isopropylpyrrolidin-3-yloxy)picolinamide (120 mg, 0.24 mmol) from Step 1 of this example was stirred in 5 mL of anhydrous EtOH, and methanesulfonic acid (15.5 μί, 0.24 mmol) was added. The resulting mixture was heated at 60 °C for 1 h. The organic solvent was removed under reduced pressure and the residue was dissolved in 20 mL of water. The solution was frozen in an acetone/dry ice bath and lyophilized to give 3-(6-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3 -yloxy)- 1 -isopropylpyrrolidinium

methanesulfonate (120 mg, 90% yield) as a light yellow powder. LC-MS (ESI) m/z 506 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.17 (s, 1H), 10.45 (br. s., 1H), 8.39 (br. s., 1H), 8.15 (d, J= 8.48 Hz, 1H), 7.81 (d, J= 7.72 Hz, 2H), 7.68 (d, J= 9.04 Hz, 1H), 7.28 (d, J= 7.72 Hz, 2H), 6.56 (s, 1H), 5.26 - 5.48 (m, 1H), 3.64 (br. s., 4H), 3.60 - 3.41 (m, 6H), 2.31 (s, 4H), 1.27 (s, 15H).

Example 3

Preparation of 5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)-N-(4-(2-(4- (trifluoromethyl)-lH-pyrazol-l-yl)acetamido)phenyl)picolinamide

[00287] Step 1 : To a stirred mixture of 2-(4-(trifluoromethyl)-lH-pyrazole

(1.68 g, 12.4 mmol) and K₂C0₃ (2.45 g, 17.7 mmol) in DMF (30 mL) at rt was added ethyl 2-bromoacetate (2.69 g, 16.1 mmol). The resulting mixture was heated at 60 °C for 12 h. The reaction mixture was cooled to rt, quenched with water, and extracted with DCM twice. The combined organic layers were dried over MgS0₄, and concentrated under reduced pressure. The residue was purified on a silica gel column, eluting with a mixture of EtOAc-hexanes, to afford ethyl 2-(4-(trifluoromethyl)-lH- pyrazol-l-yl)acetate (2.64 g, 96%) as an oil. LC-MS (ESI) m/z 223 (M+H)⁺; 1H NMR (300 MHz, CDC1₃) δ 7.80 (s, 1H), 7.05 (s, 1H), 4.93 (s, 2H), 4.25 (q, 2H), 1.30 (t, 3H).

[00288] Step 2 : A mixture of ethyl 2-(4-(trifluoromethyl)- 1 H-pyrazol- 1 - yl)acetate from Step 1 of this example (2.64 g, 11.9 mmol) and LiOH monohydrate (2.50 g, 59.5 mmol) in 1,4-dioxane (45 mL) and water (45 mL) was stirred at room temperature for 5 h. Organic solvent was then evaporated under reduced pressure, the residue was neutralized with 10%> aq. HC1 solution to pH ~ 6. The resuling mixture was extracted with EtOAc twice. The combined organic layers were dried over MgS0₄ and concentrated under reduced pressure to give 2-(4-(trifluoromethyl)-lH- pyrazol-l-yl)acetic acid (1.13 g, 49% yield). LC-MS (ESI) m/z 195 (M+H)⁺; 1H NMR (300 MHz, CDCls) δ 13.2 (br. s., 1H), 8.38 (s, 1H), 7.91 (s, 1H), 5.04 (s, 2H).

[00289] Step 3: 5-(l,2,2,6,6-Pentamethylpiperidin-4-yloxy)picolinic acid was prepared using procedures analogous to those described in Steps 1-2 of Example 1, substituting 1, 2,2,6, 6-pentamethylpiperidin-4-ol for tert-butyl 3-hydroxypyrrolidine- 1-carboxylate used in Example 1. LC-MS (ESI) m/z 293 (M + H)⁺.

[00290] Step 4: To a stirred solution of 5-(l, 2,2,6, 6-pentamethylpiperidin-4- yloxy)picolinic acid from Step 3 of this example (250 mg, 0.86 mmol) in DCM/THF (6 mL, 2: 1, v/v) at rt was added TEA (144 uL, 1.03 mmol) and ethyl chloro formate (82 μΕ, 0.86 mmol). The resulting mixture was stirred at rt for 20 min before tert- butyl 4-aminophenylcarbamate (178 mg, 0.86 mmol) was added. The resulting mixture was heated at 50 °C for lh. LC-MS indicated the reaction was complete. Solvents were then removed under reduced pressure and the residue was partitioned between EtOAc (30 mL) and brine (20 mL). The organic layer was dried over MgSO- 4, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-(5- (1, 2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamido)phenylcarbamate (500 mg) as an off-white foam. LC-MS (ESI) m/z 483 (M + H)⁺.

[00291] Step 5 : N-(4-Aminophenyl)-5-(l ,2,2,6,6-pentamethylpiperidin-4- yloxy)picolinamide dihydrochloride (350 mg) was prepared using a procedure analogous to that described in Step 6 of Example 1, substituting tert-butyl 4-(5- (1, 2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamido)phenylcarbamate from Step 4 of this Example for tert-butyl 3-((6-((4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2- oxoethyl)phenyl)carbamoyl)pyridin-3-yl)oxy)pyrrolidine- 1 -carboxylate used in Example 1. LC-MS (ESI) m/z 383 (M + H)⁺.

[00292] Step 5: 5-(l,2,2,6,6-Pentamethylpiperidin-4-yloxy)-N-(4-(2-(4-

(trifluoromethyl)-lH-pyrazol-l-yl)acetamido)phenyl)picolinamide (40 mg, 38%) was prepared as a white powder using a procedure analogous to that described in Step 5 of Example 1, substituting 2-(4-(trifluoromethyl)-lH-pyrazol-l-yl)acetic acid from Step 2 of this example for 5-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid, and N-(4-aminophenyl)-5-(l, 2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamide dihydrochloride from Step 5 of this example for 2-(4-aminophenyl)-N-(5-tert- butylisoxazol-3-yl)acetamide used in Example 1. LC-MS (ESI) m/z 559 (M+H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.40 (br. s., 1H), 8.43 (s, 1H), 8.37 (br. s., 1H), 8.11 (d, J= 8.85 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J= 8.29 Hz, 2H), 7.60 - 7.71 (m, 1H), 7.55 (d, J= 8.29 Hz, 2H), 5.10 (s, 2H), 4.95 (br. s., 1H), 2.35 (br. s., 2H), 2.11 (br. s., 2H), 1.91 (s, 2H), 1.46 (br. s., 2H), 1.23 (br. s., 12H).

Example 4

Preparation of 4-(6-(4-(2-(5-terf-butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l,2,2,6,6-pentamethylpiperidinium methanesulfonate

[00293] Step 1 : N-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide (114 mg, 81%) was prepared as a yellow solid using a procedure analogous to that described in Step 5 of Example 1, substituting 5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinic acid from Step 3 of Example 3 for 5-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid used in Example 1. LC-MS (ESI) m/z 548 (M + H)⁺.

[00294] Step 2: 4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l,2,2,6,6-pentamethylpiperidinium methanesulfonate (120 mg, 95%) was prepared using a procedure analogous to that described in Step 2 of Example 2, substituting N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide from Step 1 of this example for N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-isopropylpyrrolidin-3-yloxy)picolinamide used in Example 2. LC-MS (ESI) m/z 548 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.17 (s, 1H), 10.44 (s, 1H), 8.42 (br. s., 1H), 8.08 - 8.20 (m, 1H), 7.81 (d, J= 7.91 Hz, 2H), 7.73 (d, J= 8.67 Hz, 1H), 7.28 (d, J= 7.72 Hz, 2H), 6.56 (s, 1H), 3.64 (s, 2H), 2.77 (d, J = 3.96 Hz, 3H), 2.35 - 2.45 (m, 2H), 2.33 (s, 4H), 1.74 - 1.90 (m, 2H), 1.47 (d, J= 10.36 Hz, 12H), 1.27 (s, 9H).

Example 5

Preparation of 4-(6-(4-(2-(5-terf-butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l-ethyl-2,2,6,6- tetramethylpiperidinium methanesulfonate

[00295] Step 1 : 5-(l-Ethyl-2,2,6,6-tetramethylpiperidin-4-yloxy)picolinic acid was prepared using procedures analogous to those described in Steps 1-2 of Example 1, substituting l-ethyl-2,2,6,6-tetramethylpiperidin-4-ol (Reference: Gan, H.; Whitten, D. G.; J. Amer. Chem. Soc. 115, 1993, 8031-8037) for tert-butyl 3- hydroxypyrrolidine-l-carboxylate used in Example 1. LC-MS (ESI) m/z 293 (M +

H)⁺.

[00296] Step 2: N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(l-ethyl-2,2,6,6-tetramethylpiperidin-4-yloxy)picolinamide (129 mg, 80%) was prepared as a yellow solid using a procedure analogous to that described in Step 5 of Example 1, substituting 5-(l-ethyl-2,2,6,6-tetramethylpiperidin-4-yloxy)picolinic acid from Step 1 of this example for 5-((l-(fert-butoxycarbonyl)pyrrolidin-3- yl)oxy)picolinic acid used in Example 1. LC-MS (ESI) m/z 562 (M + H)⁺.

[00297] Step 2: 4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l-ethyl-2,2,6,6-tetramethylpiperidinium methanesulfonate (142 mg, 100%) was prepared using a procedure analogous to that described in Step 2 of Example 2, substituting N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5-(l-ethyl-2,2,6,6-tetramethylpiperidin-4- yloxy)picolinamide from Step 1 of this example for N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5-(l-isopropylpyrrolidin-3-yloxy)picolinamide used in Example 2. LC-MS (ESI) m/z 562 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) 5 11.16 (s, 1H), 10.42 (s, 1H), 8.41 (d, J= 2.83 Hz, 1H), 8.13 (d, J= 8.67 Hz, 1H), 7.81 (d, J = 8.67 Hz, 2H), 7.72 (dd, J= 2.83, 8.85 Hz, 1H), 7.28 (d, J= 8.48 Hz, 2H), 6.56 (s, 1H), 5.07 - 5.24 (m, 1H), 3.64 (s, 2H), 3.32 (d, J= 7.35 Hz, 2H), 2.22 - 2.37 (m, 5H), 1.95 (t, J= 12.34 Hz, 2H), 1.48 (d, J= 11.11 Hz, 12H), 1.34 (t, J = 7.25 Hz, 3H), 1.27 (s, 9H).

Example 6

Preparation of 4-(6-(4-(2-(5-terf-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-2,2,6,6-tetramethylpiperidinium methanesulfonate H /S.₅

[00298] Step 1 : 5-(2,2,6,6-Tetramethylpiperidin-4-yloxy)picolinic acid was prepared as a white solid using procedure analogous to those described in Steps 1-2 of Example 1, substituting 2,2,6, 6-tetramethylpiperidin-4-ol for tert-butyl 3- hydroxypyrrolidine-l-carboxylate used in Example 1. LC-MS (ESI) m/z 279 (M + H)⁺.

[00299] Step 2: N-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(2,2,6,6-tetramethylpiperidin-4-yloxy)picolinamide (28 mg, 22%) was prepared as a yellow solid using a procedure analogous to that described in Step 5 of Example 1, substituting 5-(2,2,6,6-tetramethylpiperidin-4-yloxy)picolinic acid from Step 1 of this example for 5-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid used in Example 1. LC-MS (ESI) m/z 534 (M + H)⁺.

[00300] Step 3: 4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-2,2,6,6-tetramethylpiperidinium methanesulfonate (33 mg, 97%) was prepared using a procedure analogous to that described in Step 2 of Example 2, substituting N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yloxy)picolinamide from Step 2 of this example for N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-isopropylpyrrolidin-3-yloxy)picolinamide used in Example 2. LC-MS (ESI) m/z 534 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.15 (s, 1H), 10.41 (s, 1H), 8.35 (d, J= 2.64 Hz, 1H), 8.10 (d, J= 8.67 Hz, 1H), 7.81 (d, J= 8.48 Hz, 2H), 7.63 (dd, J= 2.73, 8.76 Hz, 1H), 7.27 (d, J= 8.48 Hz, 2H), 6.56 (s, 1H), 4.93 - 5.10 (m, 1H), 3.31 (br. s., 2H), 2.02 (dd, J= 3.39, 12.06 Hz, 2H), 1.90 (s, 2H), 1.27 (s, 19H), 1.14 (s, 6H).

Example 7

Preparation of 4-(6-(4-(2-(5-tef"f-butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l-ethylpiperidinium

methanesulfonate

[00301] Step 1 : 5-(l-(fert-Butoxycarbonyl)piperidin-4-yloxy)picolinic acid

(1.50 g, 76% over two steps) was prepared using procedures analogous to those described in the Steps 1-2 of Example 1, substituting tert-butyl 4-hydroxypiperidine- 1-carboxylate for tert-butyl 3-hydroxypyrrolidine-l-carboxylate used in Example 1. LC-MS (ESI) m/z 323 (M + H)⁺.

[00302] Step 2: N-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(piperidin-4-yloxy)picolinamide hydrochloride (200 mg, 80%) was prepared as a yellow solid using procedures analogous to those described in Steps 5-6 of Example 1, substituting 5-(l-(fert-butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Step 1 of this example for 5-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinic acid used in Example 1. LC-MS (ESI) m/z 478 (M + H)⁺.

[00303] Step 3 : To a stirred solution of N-(4-(2-(5-tert-butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5 -(piperidin-4-yloxy)picolinamide hydrochloride from Step 2 of this example (100 mg, 0.19 mmol) in 2 mL of pH~4 MeOH/NaOAc buffer at 0 °C was added acetaldehyde (0.2 mL, excess) and NaCNBH₃ (25 mg, excess). The resulting mixture was stirred at rt for 1 h. LC-MS indicated that the reaction was complete. The crude product was purified by reverse phase HPLC to afford N-(4-(2- (5-fert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-ethylpiperidin-4- yloxy)picolinamide (54 mg, 55%) as a white powder. LC-MS (ESI) m/z 506 (M + H)⁺.

[00304] Step 4: 4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3 -yloxy)- 1 -ethylpiperidinium methanesulfonate (60 mg, 100%)) was prepared using a procedure analogous to that described in Step 2 of Example 2, substituting N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-ethylpiperidin-4-yloxy)picolinamide from Step 3 of this example for N-(4-(2-(5-fert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l- isopropylpyrrolidin-3-yloxy)picolinamide used in Example 2. LC-MS (ESI) m/z 506 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.15 (s, 1H), 10.42 (d, J= 4.14 Hz, 1H), 8.43 (dd, J= 2.73, 9.89 Hz, 1H), 8.13 (dd, J= 3.20, 8.67 Hz, 1H), 7.81 (d, J = 8.10 Hz, 2H), 7.72 (dt, J= 2.83, 8.48 Hz, 1H), 7.28 (d, J= 8.48 Hz, 2H), 6.56 (s, 1H), 4.69 - 5.05 (m, 1H), 3.58 (br. s., 1H), 3.42 (d, J= 11.87 Hz, 1H), 2.98 - 3.26 (m, 4H), 2.35 (s, 5H), 1.97 - 2.21 (m, 2H), 1.72 - 1.93 (m, 1H), 1.27 (s, 10H), 1.24 (t, J= 1.00 Hz, 3H).

Example 8

Preparation of 4-(6-(4-(2-(5-tef"f-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3-yloxy)-l-isopropylpiperidinium

methanesulfonate

H ^¾

[00305] Step 1 : N-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-

5-(l-isopropylpiperidin-4-yloxy)picolinamide (67 mg, 55%) was prepared as a white powder using a procedure analogous to that described in Step 1 of Example 2, substituting N-(4-(2-(5-fert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5- (piperidin-4-yloxy)picolinamide hydrochloride from Step 2 of Example 7 for N-(4-(2- (5-fert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(pyrrolidin-3- yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 520 (M + H)⁺.

[00306] Step 2: 4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2- oxoethyl)phenylcarbamoyl)pyridin-3 -yloxy)- 1 -isopropylpiperidinium

methanesulfonate (75 mg, 96%) was prepared using a procedure analogous to that described in Step 2 of Example 2, substituting N-(4-(2-(5-tert-Butylisoxazol-3- ylamino)-2-oxoethyl)phenyl)-5-(l-isopropylpiperidin-4-yloxy)picolinamide from Step 1 of this example for N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5- (l-isopropylpyrrolidin-3 -yloxy )picolinamide used in Example 2. LC-MS (ESI) m/z 520 (M + H)⁺; 1H NMR (300 MHz, DMSO-d₆) δ 11.15 (s, 1H), 10.42 (d, J= 3.20 Hz, 1H), 8.43 (dd, J= 2.83, 15.07 Hz, 1H), 8.14 (d, J= 8.85 Hz, 1H), 7.81 (d, J= 8.29 Hz, 2H), 7.65 - 7.75 (m, 1H), 7.28 (d, J= 8.48 Hz, 2H), 6.56 (s, 1H), 4.73 - 5.07 (m, 1H), 3.42 - 3.57 (m, 3H), 3.27 - 3.40 (m, 1H), 3.04 - 3.26 (m, 2H), 2.24 - 2.41 (m, 5H), 2.04 - 2.22 (m, 2H), 1.76 - 1.96 (m, 1H), 1.15 - 1.37 (m, 15H).

Example 9 [00307] The following compounds can be prepared by the methods described herein and/or routine modifications thereof:

Table 1

Example 10

M-NFS-60 Cell proliferation assay

[00308] The compounds disclosed herein were tested in an M-NFS-60 cell proliferation assay to determine their cellular potency against CSFIR. M-NFS-60s are mouse monocytic cells that depend on the binding of the ligand M-CSF to its receptor, CSFIR, to proliferate. Inhibition of CSFIR kinase activity will cause reduced growth and/or cell death. This assay assesses the potency of compounds as CSFIR inhibitors by measuring the reduction of Alamar Blue reagent by viable cells.

[00309] On day one of the experiment, M-NFS-60 cells were maintained in

RPMI complete medium (Omega Scientific) plus 10% FBS supplemented with 20 ng/mL of M-CSF (R&D Systems). 96-well TC- treated, flat bottom plates were seeded at 10,000 cell/well at a volume of 100 μΐ, per well. The cells were cultured overnight at 37°C under 5% C0₂.

[00310] On day two, compounds were added to the cells at 9 different concentrations, with half-log intervals alongside a control reference compound serving as a positive control. Final DMSO concentration was kept at 0.5% for a final volume of 200 μί. The compounds were allowed to incubate with the cells for 72 hours at 37°C under 5% C0₂.

[00311] On day five of the experiment, 40 μΐ of Alamar Blue reagent was added to each well and allowed to incubate for 3 hours. Alamar Blue fluorescence was read using SoftMax Pro software at 560nm (excitation) and 590nm (emission). IC50S were generated as an average of duplicates and represents the concentration of test compound that achieves 50% inhibition of cellular proliferation compared to control.

[00312] In one embodiment, the compounds provided herein were found to have IC₅₀ of about or less than about 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 μΜ. In another embodiment, the compounds provided herein were found to have activity IC50 of about or less than about 2000, 1000, 500, 300, 100, 50, 40, 30 or 20 nM. In another embodiment, the compounds provided herein were found to have activity IC50 of less than about 200 or 100 nM.

Example 11

Competition binding assay to determine selectivity scores and binding constants

(Kd) of the compounds against a panel of kinases

[00313] Competition binding assays used herein were developed, validated and performed as described in Fabian et al, Nature Biotechnology 2005, 25,329-336. Kinases were produced as fusions to T7 phage {See, Fabian et al. or WO04/015142) or alternatively, the kinases were expressed in HEK-293 cells and subsequently tagged with DNA for PCR detection (See, WO08/005310). For the binding assays, streptavidin-coated magnetic beads were treated with biotinylated affinity ligands for 30 min at room temperature to generate affinity resins. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1 %> BSA, 0.05 %> Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining kinase, liganded affinity beads, and test compounds in 1 x binding buffer (20 %> SeaBlock, 0.17x PBS, 0.05 %> Tween 20, 6 mM DTT). Test compounds were prepared as 100 x stocks in DMSO and diluted into the aqueous environment. K s were determined using an eleven point threefold serial dilutions. DMSO or control compounds were was added to control assays lacking a test compound. Primary screen assays were performed in polypropylene 384-well plates in a final volume of 20-40 μί, while Kd determinations were performed in polystyrene 96-well plates in a final volume of 135 μί. The assay plates were incubated at room temperature with shaking for 1 hour to allow the binding reactions to reach equilibrium, and the affinity beads were washed

extensively with wash buffer (lx PBS, 0.05 % Tween 20) to remove unbound protein. The beads were then resuspended in elution buffer (lx PBS, 0.05 % Tween 20, 0.5 μΜ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 min. The kinase concentration in the eluates was measured by quantitative PCR.

[00314] A selectivity score (S 10) is a quantitative measure of selectivity of a compound against a panel of kinases. An S10 was calculated for a compound by dividing the number of kinases found to have a percent of control (DMSO) less than 10 by the total number of distinct kinases tested (excluding mutant variants). Percent of control (POC) is calculated by subtracting the signal of the control compound (POC = 0) from the signal of the test compound and dividing the outcome by the signal of DMSO (POC = 100) minus the signal of the control compound. For the compounds disclosed herein, S10 scores were obtained by testing the compounds at 10 μΜ concentration in a kinase panel containing either 359 or 386 distinct kinases.

[00315] In one embodiment, the compounds provided herein were found to have S 10 score of about or less than about 0.1 , 0.08, 0.06, 0.04, 0.03, or 0.02.

Example 12

MV4-11 cell proliferation assay

[00316] The compounds disclosed herein were tested in an MV4-1 1 cell proliferation assay to determine their cellular potency against Flt3. MV4-1 1 cells carry ITD mutation within juxtamembrane domain of Flt3 kinase which renders the kinase constitutive ly active. The growth and/or survival of MV4-1 1 cells are greatly reduced in the presence of Flt3 inhibitors. This assay measures the potency of compounds as Flt3 inhibitors by measuring the reduction of Alamar Blue reagent by viable cells.

[00317] MV4-1 1 cells were grown in an incubator at 37°C under 5% C0₂ in

Iscove's media (Celgro) with 10% FBS. The cell density was kept between le5 and 8e5 cells/mL. [00318] On day one of the experiment, cells were harvested and spun at 500g for 5 min at 4°C, the supernatant aspirated and the cells resuspended in Iscove's media with 0.5% FBS. Cell density was maintained at 7.5e5 to achieve maximum viability of the cells. The resuspended cells were incubated at 37°C in 5% C0₂ overnight.

[00319] On day two of the experiment, cells were diluted to 6.4e5/mL with

Iscove's media with 0.5% FBS. ΙΟΟμί of the cell suspension (64,000 cells) were aliquoted into each well of a 96-well TC-treated plate. Compounds were added at 9 different concentrations, with half-log intervals alongside a control reference compound serving as a positive control. Final DMSO concentration was kept at 0.5% and final volume at 200 μί. The cells were then incubated at 37°C under 5% C0₂ for 3 days.

[00320] On day five of the experiment, 40 of Alamar Blue reagent was added to each well and the mixture was allowed to incubate for 3 hours. Alamar Blue fluorescence was measured using SoftMax Pro software at 560nm (excitation) and 590nm (emission). IC₅₀s were generated as an average of duplicates and represents the concentration of test compound that achieves 50% inhibition of cellular proliferation compared to negative control.

[00321] In one embodiment, the compounds provided herein were found to have IC₅₀ of about or less than about 1, 5, 10, 25, 100 or 250 nM. In another embodiment, the compounds provided herein were found to have activity IC₅₀ of less than about 250 nM.

[00322] The compounds provided herein were found to have the following activity shown in Table 2:

Table 2

In Table 2, CSF1R (human) Kd (nM): A <3, 3<B<10, C>10; and ND= no data; Flt3(human)_Kd (nM): A<10, B>10; and ND= no data;

CSF1R Cell Proliferation Assay (M-NSF-60) IC₅₀ (nM): A <100, 100<B<250,

250<C<1000, D>1000; and ND= no data; and

S score: A <0.03, 0.03<B<0.05, C > 0.08; and ND= no data.

[00323] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims.

[00324] Since modifications will be apparent to those of skill in the art, it is intended that the claimed subject matter be limited only by the scope of the appended claims.

Claims

What is claimed is:

1. A compound having formula I:

or a pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof, wherein:

A is azolyl;

alkylaminosulfonyl, alkylaminocarbonyl, aryl, arylalkyl, heterocyclyl,

cycloalkylalkyl, cycloalkenyl, hydroxyalkyl, haloalkyl, alkylaminosulfonyl, alkylaminocarbonyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, c S(0)_tR^w;

L¹ is

R⁵ is O, S, N-CN, or N-N0₂;

each R⁴ is independently selected from halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, cyano, amino, hydroxy, alkoxy, hydroxyalkoxyalkyl, - R^uN(R^y)(R^z), -R^uS(0),R^w, aryl, heterocyclyl, and heteroaryl;

2 8 9 8 9

each R¹⁰ is independently hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, and 0 to 1 additional heteroatom selected from O, N or S, wherein the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more Q¹ groups;

R^3a and R^3b are each independently selected from (i) or (ii) below:

(i) R^3a and R^3b are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,

cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^3a and R^3b, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more Q¹ groups; each Q¹ is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,

cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,

heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, - R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, - R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x, - R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, or -R^uN(R^x)S(0),R^w; where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q² groups; each Q² is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^USR^X, -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x,

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) or (ii) below:

(i) R^y and R^z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more Q groups; each Q is independently selected from halo, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^X or S;

each t is independently an integer from 0-2;

m and n are each independently an integer from 0-4; and

p is an integer from 1-4,

wherein the compound is selected such that i) when A is isoxazolyl, R¹ is tert-butyl, Z is phenyl, L¹ is

-NH-C(0)-CH₂-, B is pyrimidinyl, m is 1, and R⁴ is morpholinyl, then L² is not direct bond;

-NH-C(0)-CH₂-, m is 0, and B is 2-pyridyl, then then R³ is not pyrimidinyl.

2. The compound of claim 1 having formula I A or IB:

or a pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof.

3. The compound of claims 1 or 2, wherein A is optionally substituted isoxazolyl or optionally substituted pyrazolyl, wherein substituents when present are selected from one, two or three R¹ groups, each independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, and heteroarylalkyl, where the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 to 5 groups selected from halo, hydroxy, alkoxy, cycloalkyl, cyano, and -R^uN(R^y)(R^z), where R^u is independently alkylene or a direct bond, R^y, and R^z are each independently hydrogen or alkyl. The compound of any of claims 1-3, wherein A

where each R¹ is independently hydrogen, alkyl or haloalkyl.

5. The compound of any of claims 1-4, where A is:

R¹ is alkyl or haloalkyl.

The compound of any of claims 1-5, where B

(i) Z¹ and Z² are both CR^4a,

(ii) Z¹ is N, and Z² is CR^4a, and

(iii) Z¹ is CR^4a, and Z² is N; and each CR^4a is independently hydrogen or R⁴.

7. The compound of any of claims 1-6, where

L¹ is

;

R⁵ is O, S, N-CN, or N-N0₂;

8. The compound of claim 1, where

R⁵ is O or S;

R⁶ and R⁷ are each independently selected from hydrogen and alkyl; and L³ and L⁴ are each independently a bond, alkylene or alkenylene.

9. The compound of of any of claims 1-8, where R⁶ is hydrogen, alkyl or alkoxy.

10. The compound of any of claims 1-9, where R⁸ is hydrogen, cycloalkyl, heterocyclyl or heterocyclylalkyl, where the cycloalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or two alkyl groups.

11. The compound of claim 1 , where the compound has formula II

(^Rl

A is azolyl;

each R¹ is independently selected from alkyl, halo and haloalkyl;

R⁵ is O or S;

R⁶ and R⁷ are each independently selected from hydrogen and lower alkyl;

L³ and L⁴ are each independently a bond, alkylene, alkenylene, or alkynylene, where the alkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy; each R² is independently selected from alkyl and alkoxy;

each R⁴ is alkyl; 2 8 9 8 9

R⁸ and R⁹ are each independently direct bond or alkylene;

R⁹ is hydrogen or alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more Q¹ groups, each independently selected from oxo, alkyl, cycloalkyl, haloalkyl, hetrocyclyl, R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), and - R^uS(0)_tR^w;

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each independently selected from (i) and (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with an alkyl;

J is O;

t is 0-2;

m and n are each independently 0, 1 or 2; and

p is 1, 2 or 3.

12. The compound of claim 1, where the compound has formula Xlla or

Xllb

or a pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof, wherein R¹ is tert-butyl; A is azolyl,

R⁶ and R⁷ are each independently hydrogen or alkyl;

L³ and L⁴ are each independently a bond, alkylene, or alkenylene, where the alkylene and alkenylene are each optionally substituted with one or more substituents selected from alkyl, haloalkyl, amino, hydroxyl and alkoxy;

R² is alkyl;

R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl containing at least one nitrogen atom, such that the heterocyclyl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more Q¹ groups, R^3a and R^3b are selected as follows:

each Q¹ is independently selected from alkyl, haloalkyl, cycloalkyl,

-R^uC(J)OR^x, -R^uS(0),R^w, -R^uC(J)N(R^y)(R^z), and heterocyclyl,

each R^u is independently alkylene or a direct bond;

R^w is alkyl;

each R^x is alkyl;

R^y and R^z are each hydrogen or alkyl;

J is O; and

p is 0, 1 or 2; n is 0 or 1 ; and

t is 0-2.

13. The compound of claim 1, wherein each Q¹ is independently selected from -CHs, -CH₂-CH₃, -CH₂CF₃, -CH-(CH₃)₂, -C(0)0(CH₃)₃, -(CH₂)₂S(0)₂CH₃, - CH₂C(0)N(CH₃)₂, -C(CH₃)₃, cyclopropyl and oxetanyl.

14. The compound of claim 1, wherein the compound has formula XlXa or

XlXb:

or a pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof, wherein

A is azolyl;

2 8 9 8 9

R¹⁰ is hydrogen or alkyl; R³ is selected as follows:

i) R³ is -NR^3aR^3b, or

ii) R³ is optionally substituted heterocyclyl or optionally substituted heteroaryl containing at least one nitrogen atom, such that the heterocyclyl or heteroaryl ring is connected to L² on the carbon atom of the ring, and wherein the substituents, when present are selected from one or more Q¹ groups;

R^3a and R^3b are selected as follows:

each R^u is independently alkylene or a direct bond;

R^y and R^z are each independently selected from (i) and (ii) below:

(ii) R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one, two or three Q¹ groups;

each Q¹ is independently selected from halo, oxo, thioxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R^uOR^x, -R^uOR^uN(R^y)(R^z), -R^uN(R^y)(R^z), -R^UC(J)R^X, -R^uC(J)OR^x, -R^uC(J)N(R^y)(R^z), -R^UC(J)SR^X, -R^uS(0),R^w, -R^uOC(J)R^x, -R^uOC(J)OR^x, -R^uOC(J)N(R^y)(R^z), -R^uOC(J)SR^x, -R^UN(R^X)C(J)R^X, -R^uN(R^x)C(J)OR^x,

-R^uN(R^x)C(J)N(R^y)(R^z), -R^UN(R^X)C(J)SR^X, and -R^uN(R^x)S(0)_tR^w;

J is O, NR^X or S;

each t is independently 0-2; and

p is 1-4.

15. The compound of claim 1, wherein the compound is selected from N- (4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(pyrrolidin-3- yloxy)picolinamide hydrochloride;

3- (6-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)- 1 -isopropylpyrrolidinium methanesulfonate;

5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)-N-(4-(2-(4-(trifluoromethyl)-lH-pyrazol- l-yl)acetamido)phenyl)picolinamide;

4- (6-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)-l ,2,2,6,6-pentamethylpiperidinium methanesulfonate;

4-(6-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)- 1 -ethyl-2,2,6,6-tetramethylpiperidinium methanesulfonate;

4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)-2,2,6,6-tetramethylpiperidinium methanesulfonate;

4-(6-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)- 1 -ethylpiperidinium methanesulfonate;

4-(6-(4-(2-(5-tert-Butylisoxazol-3-ylamino)-2-oxoethyl)phenylcarbamoyl)pyridin-3- yloxy)- 1 -isopropylpiperidinium methanesulfonate;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4-(piperidin-4- yloxy)picolinamide hydrochloride;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4-(l-ethylpiperidin-4- yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4-(4-methylpiperazin-l- yl)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4-(l-methylpiperidin-4- yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4-(2- morpholinoethoxy)picolinamide;

4-(aminomethyl)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenyl)picolinamide hydrochloride;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-4- ((diethylamino)methyl)picolinamide;

N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5 -( 1 -methylpiperidin-4-yloxy)picolinamide; N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide;

N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-isopropylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-ethylazetidin-3- yloxy)picolinamide;

5-(azetidin-3-yloxy)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2- oxoethyl)phenyl)picolinamide hydrochloride;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-isopropylazetidin- 3-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-(oxetan-3- yl)azetidin-3-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-(oxetan-3- yl)pyrrolidin-3-yloxy)picolinamide;

5-(l -ethylpiperidin-4-yloxy)-N-(4-(2-oxo-2-(5-(l , 1 , 1 -trifluoro-2-methylpropan-2- yl)isoxazol-3-ylamino)ethyl)phenyl)picolinamide;

(R)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l- isopropylpyrrolidin-3-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-6-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)pyridazine-3-carboxamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)-2-methylphenyl)-5-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)-3-methylphenyl)-5-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)picolinamide;

(S)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(pyrrolidin-3- yloxy)picolinamide hydrochloride;

(S)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l- isopropylpyrrolidin-3-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)-3-methoxyphenyl)-5-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)pyrazine-2-carboxamide;

N-(4-(2-(3-(2-fluoropropan-2-yl)isoxazol-5-ylamino)-2-oxoethyl)phenyl)-5- ( 1 ,2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamide; (R)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-((l- isopropylpyrrolidin-3-yl)methoxy)picolinamide;

N-(4-(2-(3-tert-butylisoxazol-5-ylamino)-2-oxoethyl)phenyl)-5-(l-ethyl-2,2,6,6- tetramethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(3-tert-butylisoxazol-5-ylamino)-2-oxoethyl)phenyl)-5-(l-ethylpiperidin-4- yloxy)picolinamide;

(R)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-((l- ethylpyrrolidin-3-yl)methoxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(piperidin-4- y lmethy l)pico linamide hydrochloride ;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-((l-ethylpiperidin-4- yl)methyl)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(piperidin-4- yl)picolinamide hydrochloride;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-ethylpiperidin-4- yl)picolinamide;

N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride;

N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l-ethylpiperidin-4-yloxy)pico linamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l -(2,2,2- trifluoroethyl)piperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-ethylpyrrolidin-3- yloxy)picolinamide;

5-(l-ethylpiperidin-4-yloxy)-N-(4-(2-(3-(2-fluoropropan-2-yl)isoxazol-5-ylamino)-2- oxoethyl)phenyl)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-(2- (methylsulfonyl)ethyl)pyrrolidin-3-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-(2- (dimethylamino)-2-oxoethyl)pyrrolidin-3-yloxy)picolinamide; N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l- cyclopropylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-tert-butylpiperidin-

4- yloxy)picolinamide;

N-(4-(2-oxo-2-(5-(l , 1 , 1 -trifluoro-2-methylpropan-2-yl)isoxazol-3- ylamino)ethyl)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride;

5- (l -ethylpiperidin-4-yloxy)-N-(4-(2-oxo-2-(5-(l , 1 , 1 -trifluoro-2-methylpropan-2- yl)isoxazol-3-ylamino)ethyl)phenyl)picolinamide;

N-(4-(2-(5-(l,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylamino)-2- oxoethyl)phenyl)-5-(l,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-oxo-2-(5-(l , 1 , 1 -trifluoro-2-methylpropan-2-yl)isoxazol-3- ylamino)ethyl)phenyl)-5-(l, 2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamide; (S)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-((l,5,5-trimethylpyrrolidin-2- yl)methoxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l-ethyl-2,2,6,6- tetramethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(3-tert-butylisoxazol-5-ylamino)-2-oxoethyl)phenyl)-5-(l,2,2,6,6- pentamethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(3-tert-butylisoxazol-5-ylamino)-2-oxoethyl)phenyl)-5-(piperidin-4- yloxy)picolinamide hydrochloride;

N-(4-(2-(3-tert-butylisoxazol-5-ylamino)-2-oxoethyl)phenyl)-5-(l-isopropylpiperidin- 4-yloxy)picolinamide;

(R)-N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(pyrrolidin-3- ylmethoxy)picolinamide hydrochloride;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(((lS,9aS)-octahydro- 1 H-quinolizin- 1 -yl)methoxy)picolinamide;

N-(4-(2-(3 -tert-butyl- 1 -methyl- 1 H-pyrazol-5 -ylamino)-2-oxoethyl)phenyl)-5- ( 1 ,2,2,6, 6-pentamethylpiperidin-4-yloxy)picolinamide;

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(quinuclidin-3- yloxy)picolinamide; and

N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5-(l, 2,2,4, 6,6- hexamethylpiperidin-4-yloxy)picolinamide.

16. A pharmaceutical composition comprising a compound of any of claims 1-15 and a pharmaceutically acceptable carrier.

17. A method for treatment of a disease selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and cancer comprising administering a therapeutically effective amount of a compound of any of claims 1- 15.

18. The method of claim 17, wherein the disease is modulated by FLT3 kinase.

19. The method of claim 18, wherein the disease is modulated by wild type or mutant FLT3 kinase.

20. The method of claim 18 wherein the mutant FLT3 kinase is a FLT3 kinase having an ITD mutation.

21. A method for the treatment of a disease comprising administering a therapeutically effective amount of a compound of any of claims 1-15, wherein the disease is selected from myeloproliferative disorder (MPD), myelodysplasia syndrome (MDS), polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), myeloid leukemia, chronic myeloid leukemia (CML), imatinib- resistant CML, acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), lymphoma, lymphoblastic leukemia, myeloma, cancer of the head and neck, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, melanoma, lung cancer, brain cancer, thyroid cancer, stomach cancer, gastrointestinal stromal tumor, colorectal cancer, pancreatic cancer, renal cancer, non-small cell lung cancer, idiopathic hypereosinophilic syndrome, chronic eosinophilic syndrome, systemic mastocytosis, Langerhans cell histiocytosis, Kaposi's sarcoma, multiple endocrine neoplasia, immunodeficiency, autoimmune diseases, tissue transplant rejection, graft- versus-host disease, wound, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD).

22. The method of claim 20 further comprising administering a second pharmaceutical agent selected from anti-proliferative agent, anti-inflammatory agent, immunomodulatory agent and immunosuppressive agent.

23. A method of modulating FLT3 kinase by administering a compound of any of claims 1-15.

24. A compound of any of claims 1-15 for use in a method of treating a disease selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and cancer.