Processes and intermediates for preparing fused heterocyclic kinase inhibitors

Abstract

This invention relates to processes and intermediates for manufacturing fused heterocyclic-type kinase inhibitor compounds, such as thienopyridine-based compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type kinase inhibitor compounds, such as thienopyridine-based compounds, particularly at an industrial level.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to processes and intermediates for manufacturing fused heterocyclic-type compounds, such as thienopyridine-based kinase inhibitor compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type compounds, such as thienopyridine-based kinase inhibitor compounds, particularly at an industrial level. Fused heterocyclic-type compounds have been found to be useful to inhibit protein tyrosine kinase activity. In particular, fused heterocyclic-type compounds, such as thienopyridine-based compounds, have been found useful to inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling; for example, the inhibition of VEGF receptor signaling and HGF receptor signaling. Fused heterocyclic-type compounds have been found to be useful in the treatment of cancer by inhibiting protein tyrosine kinase activity. The pharmaceutical compositions that comprise these compounds are also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factor and anti-angiogenesis receptors such as c-Met.

2. Summary of the Related Art

Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. The receptor type tyrosine kinases make up about 20 different subfamilies. The non-receptor type tyrosine kinases make up numerous subfamilies. These tyrosine kinases have diverse biological activity. Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and hence to influence cell proliferation. Aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity.

Angiogenesis is an important component of certain normal physiological processes such as embryogenesis and wound healing, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. VEGF-A (vascular endothelial growth factor A) is a key factor promoting neovascularization (angiogenesis) of tumors. VEGF induces endothelial cell proliferation and migration by signaling through two high affinity receptors, the fms-like tyrosine kinase receptor, Flt-1, and the kinase insert domain-containing receptor, KDR. These signaling responses are critically dependent upon receptor dimerization and activation of intrinsic receptor tyrosine kinase (RTK) activity. The binding of VEGF as a disulfide-linked homodimer stimulates receptor dimerization and activation of the RTK domain. The kinase activity autophosphorylates cytoplasmic receptor tyrosine residues, which then serve as binding sites for molecules involved in the propagation of a signaling cascade. Although multiple pathways are likely to be elucidated for both receptors, KDR signaling is most extensively studied, with a mitogenic response suggested to involve ERK-1 and ERK-2 mitogen-activated protein kinases.

Disruption of VEGF receptor signaling is a highly attractive therapeutic target in cancer, as angiogenesis is a prerequisite for all solid tumor growth, and that the mature endothelium remains relatively quiescent (with the exception of the female reproductive system and wound healing). A number of experimental approaches to inhibiting VEGF signaling have been examined, including use of neutralizing antibodies, receptor antagonists, soluble receptors, antisense constructs and dominant-negative strategies.

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can themselves be elevated by numerous diverse stimuli and perhaps most importantly, the hypoxic state of tumors resulting from VEGFr inhibition, can lead to the induction of factors that themselves promote tumor invasion and metastasis thus, potentially undermining the impact of VEGF inhibitors as cancer therapeutics.

The HGF (hepatocyte growth factor) and the HGF receptor, c-Met, are implicated in the ability of tumor cells to undermine the activity of VEGF inhibition. HGF derived from either stromal fibroblasts surrounding tumor cells or expressed from the tumor itself has been suggested to play a critical role in tumor angiogenesis, invasion and metastasis. For example, invasive growth of certain cancer cells is drastically enhanced by tumor-stromal interactions involving the HGF/c-Met (HGF receptor) pathway. HGF, which was originally identified as a potent mitogen for hepatocytes, is primarily secreted from stromal cells, and the secreted HGF can promote motility and invasion of various cancer cells that express c-Met in a paracrine manner. Binding of HGF to c-Met leads to receptor phosphorylation and activation of Ras/mitogen-activated protein kinase (MAPK) signaling pathway, thereby enhancing malignant behaviors of cancer cells. Moreover, stimulation of the HGF/c-Met pathway itself can lead to the induction of VEGF expression, itself contributing directly to angiogenic activity.

Biological agents, such as ribozymes, antibodies and antisense RNA targeting either HGF or Met have been shown to inhibit tumorogenesis (Stabile et al., (2004) Gene Therapy, 11:325-335; Jiang et al., (2003) Clin. Cancer Res., 9:4274-4281; and Genentech U.S. Pat. No. 6,214,344).

Thus, anti-tumor and/or anti-angiogenic strategies or approaches that target either or both VEGF/VEGFr signaling and HGF/c-Met signaling may circumvent the ability of tumor cells to overcome VEGF inhibition alone and may represent improved cancer therapeutics.

BRIEF SUMMARY OF THE INVENTION

This invention is directed to processes and intermediates for manufacturing fused heterocyclic-type compounds, such as thienopyridine-based kinase inhibitor compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type compounds, such as thienopyridMe-based kinase inhibitor compounds.

In one embodiment of the present invention, processes and intermediates are provided for preparing compounds having the formula (A):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof, wherein D, M, Z, Ar and G are as defined herein.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.

DETAILED DESCRIPTION

This invention relates to processes and intermediates for manufacturing fused heterocyclic-type compounds, such as thienopyridine-based kinase inhibitor compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type compounds, such as thienopyridine-based kinase inhibitor compounds. Fused heterocyclic-type compounds have been found to be useful to inhibit protein tyrosine kinase activity. In particular, fused heterocyclic-type compounds, such as thienopyridine-based compounds, have been found useful to inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling and HGF receptor signaling. Fused heterocyclic-type compounds have been found to be useful in the treatment of cancer by inhibiting protein tyrosine kinase activity. The pharmaceutical compositions that comprise these compounds are also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factor and anti-angiogenesis receptors such as c-Met.

The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.

For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise):

For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH₃—CH₂—), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)_a-B—, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B— and when a is 1 the moiety is A-B—.

For simplicity, reference to a “C_n-C_m” heterocyclyl or “C_n-C_m” heteroaryl means a heterocyclyl or heteroaryl having from “n” to “m” annular atoms, where “n” and “m” are integers. Thus, for example, a C₅-C₆-heterocyclyl is a 5- or 6-membered ring having at least one heteroatom, and includes pyrrolidinyl (C₅) and piperazinyl and piperidinyl (C₆); C₆-heteroaryl includes, for example, pyridyl and pyrimidyl.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is used to refer to a covalent bond. Thus, “C₀-C₃ hydrocarbyl” includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.

The term “alkyl” is intended to mean a straight chain or branched aliphatic group having from 1 to 12 carbon atoms, alternatively 1-8 carbon atoms, and alternatively 1-6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. A “C₀” alkyl (as in “C₀-C₃alkyl”) is a covalent bond.

The term “alkenyl” is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The terms “alkylene,” “alkenylene,” or “alkynylene” as used herein are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

The term “carbocycle” as employed herein is intended to mean a cycloalkyl or aryl moiety.

The term “cycloalkyl” is intended to mean a saturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, alternatively having 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons. In certain embodiments, the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group. Examples of cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

The term “heteroalkyl” is intended to mean a saturated or unsaturated, straight chain or branched aliphatic group, wherein one or more carbon atoms in the group are independently replaced by a heteroatom selected from the group consisting of O, S, and N.

The term “aryl” is intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example a C₆-C₁₄aromatic moiety, for example comprising one to three aromatic rings. Alternatively, the aryl group is a C₀-C₁₀aryl group, alternatively a C₆aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

The terms “aralkyl” or “arylalkyl” are intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as “optionally substituted”, it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. Alternatively, the aralkyl group is (C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as “arylalkyl” this term, and terms related thereto, is intended to indicate the order of groups in a compound as “aryl-alkyl”. Similarly, “alkyl-aryl” is intended to indicate the order of the groups in a compound as “alkyl-aryl”.

The terms “heterocyclyl”, “heterocyclic” or “heterocycle” are intended to mean a group which is a mono-, bi-, or polycyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are independently selected from the group consisting of N, O, and S. The ring structure may be saturated, unsaturated or partially unsaturated. In certain embodiments, the heterocyclic group is non-aromatic, in which case the group is also known as a heterocycloalkyl. In a bicyclic or polycyclic structure, one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro anthracene. Examples of heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.

In certain embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term “heteroaryl” is intended to mean a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms independently selected from the group consisting of N, O, and S. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Examples of heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.

The terms “arylene,” “heteroarylene,” or “heterocyclylene” are intended to mean an aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

Examples of heterocyclyls and heteroaryls include, but are not limited to, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzothienyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzoxazolyl, benzoxadiazolyl, benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, 1,3-dioxolane, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such as fuor[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl), furyl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro-1,1-dioxothienyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholuiyl sulfone, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazinylazepinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), and xanthenyl.

The term “azolyl” as employed herein is intended to mean a five-membered saturated or unsaturated heterocyclic group containing two or more hetero-atoms, as ring atoms, selected from the group consisting of nitrogen, sulfur and oxygen, wherein at least one of the hetero-atoms is a nitrogen atom. Examples of azolyl groups include, but are not limited to, optionally substituted imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

As employed herein, and unless stated otherwise, when a moiety (e.g., alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as “optionally substituted” it is meant that the group optionally has from one to four, alternatively from one to three, alternatively one or two, independently selected non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Examples of substituents, which are themselves not further substituted (unless expressly stated otherwise) are:

• • (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, C₁-C₅alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C₁-C₈alkyl, C₁-C₈alkenyl, C₁-C₈alkoxy, C₁-C₈alkyamino, C₁-C₈alkoxycarbonyl, aryloxycarbonyl, C₂-C₈acyl, C₂-C₈acylamino, C₁-C₈alkylthio, arylalkylthio, arylthio, C₁-C₈alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C₁-C₈alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C₀-C₆N-alkyl carbamoyl, C₂-C₁₅N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C₃-C₇heterocycle, C₅-C₁₅heteroaryl or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and
  • (b) —(CR³²R³³)_s—NR³⁰R³¹, wherein
    • s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6,
    • R³² and R³³ are each independently hydrogen, halo, hydroxyl or C₁-C₄alkyl, and
    • R³⁰ and R³¹ are each independently hydrogen, cyano, oxo, hydroxyl, C₁-C₈alkyl, C₁-C₈heteroalkyl, C₁-C₈alkenyl, carboxamido, C₁-C₃alkyl-carboxamido, carboxamido-C₁-C₃alkyl, amidino, C₂-C₈hydroxyalkyl, C₁-C₃alkylaryl, aryl-C₁-C₃alkyl, C₁-C₃alkylheteroaryl, heteroaryl-C₁-C₃alkyl, C₁-C₃alkylheterocyclyl, heterocyclyl-C₁-C₃alkyl C₁-C₃alkylcycloalkyl, cycloalkyl-C₁-C₃alkyl, C₂-C₈alkoxy, C₂-C₈alkoxy-C₁-C₄alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃alkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-C₁-C₃alkoxycarbonyl, C₁-C₈acyl, C₀-C₈alkyl-carbonyl, aryl-C₀-C₈alkyl-carbonyl, heteroaryl-C₀-C₈alkyl-carbonyl, cycloalkyl-C₀-C₈alkyl-carbonyl, C₀-C₈alkyl-NH-carbonyl, aryl-C₀-C₈alkyl-NH-carbonyl, heteroaryl-C₀-C₈alkyl-NH-carbonyl, cycloalkyl-C₀-C₈alkyl-NH-carbonyl, C₀-C₈alkyl-O-carbonyl, aryl-C₀-C₈alkyl-O-carbonyl, heteroaryl-C₀-C₈alkyl-O-carbonyl, cycloalkyl-C₀-C₈alkyl-O-carbonyl, C₁-C₈alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C₁-C₈alkyl-NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl, heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C₁-C₃alkyl-, cycloalkyl-C₁-C₃alkyl-, heterocyclyl-C₁-C₃alkyl-, heteroaryl-C₁-C₃alkyl-, or protecting group, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or
    • R³⁰ and R³¹ taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X³⁰—Y³¹—), wherein said heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge); wherein
    • X³⁰ is selected from the group consisting of C₁-C₈alkyl, C₂-C₈alkenyl-, C₂-C₈alkynyl-, —C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl, C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl, C₀-C₃alkyl-O—C₀-C₃alkyl-, HO—C₀-C₃alkyl-, C₀-C₄alkyl-N(R³⁰)—C₀-C₃alkyl-, N(R³⁰)(R³¹)—C₀-C₃alkyl-, N(R³⁰)(R³¹)—C₀-C₃alkenyl-, N(R³⁰)(R³¹)—C₀-C₃alkynyl-, (N(R³⁰)(R³¹))₂—C═N—, C₀-C₃alkyl-S(O)_0-2—C₀-C₃alkyl-, CF₃—C₀-C₃alkyl-, C₁-C₈heteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C₁-C₃alkyl-, cycloalkyl-C₁-C₃alkyl-, heterocyclyl-C₁-C₃alkyl-, heteroaryl-C₁-C₃alkyl-, N(R³⁰)(R³¹)-heterocyclyl-C₁-C₃alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 substituents from (a); and
    • Y³¹ is selected from the group consisting of a direct bond, —O—, —N(R³⁰)—, —C(O)—, —O—C(O)—, —C(O)—O—, —N(R³⁰)—C(O)—, —C(O)—N(R³⁰)—, —N(R³⁰)—C(S)—, —C(S)—N(R³⁰)—, —N(R³⁰)—C(O)—N(R³¹)—, —N(R³⁰)—C(NR³⁰)—N(R³¹)—, —N(R³⁰)—C(NR³¹)—, —C(NR³¹)—N(R³⁰)—, —N(R³⁰)—C(S)—N(R³¹)—, —N(R³⁰)—C(O)—O—, —O—C(O)—N(R³¹)—, —N(R³⁰)—C(S)—O—, —O—C(S)—N(R³¹)—, —S(O)_0-2—, —SO₂N(R³¹)—, —N(R³¹)—SO₂— and —N(R³⁰)—SO₂N(R³¹)—.

A moiety that is substituted is one in which one or more (for example one to four, alternatively from one to three and alternatively one or two), hydrogens have been independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (—CH₂—) substituted with oxygen to form carbonyl —CO—.

When there are two optional substituents bonded to adjacent atoms of a ring structure, such as for example a phenyl, thiophenyl, or pyridinyl, the substituents, together with the atoms to which they are bonded, optionally form a 5- or 6-membered cycloalkyl or heterocycle having 1, 2, or 3 annular heteroatoms.

In one embodiment, a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group is unsubstituted.

In another embodiment, a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group is substituted with from 1 to 3 independently selected substituents.

Examples of substituents on alkyl groups include, but are not limited to hydroxyl, halogen (e.g., a single halogen substituent or multiple halo substituents; in the latter case, groups such as CF₃ or an alkyl group bearing Cl₃), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, —OR^a, —SR^a, —S(═O)R^e, —S(═O)₂R^e, —P(═O)₂R^e, —S(═O)₂OR^e, —P(═O)₂OR^e, —NR^bR^c, —NR^bS(═O)₂R^e, —NR^bP(═O)₂R^e, —S(═O)₂NR^bR^c, —P(═O)₂NR^bR^c, —C(═O)OR^e, —C(═O)R^a, —C(═O)NR^bR^c, —OC(═O)R^a, —OC(═O)NR^bR^c, —NR^bC(═O)OR^e, —NR^dC(═O)NR^bR^c, —NR^dS(═O)₂NR^bR^c, —NR^dP(═O)₂NR^bR^c, —NR^bC(═O)R^a or —NR^bP(═O)₂R^e, wherein R^a is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R^b, R^c and R^d are independently hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R^b and R^c together with the N to which they are bonded optionally form a heterocycle; and R^e is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

Examples of substituents on alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents.

Examples of substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-attached or fused cyclic substituents, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

Examples of substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

Examples of substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cylcoalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Still other examples of substituents on aryl groups (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents.

Examples of substituents on heterocylic groups include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., ═O), cyano, alkyl, substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of substituents on heterocyclic groups include, but are not limited to, spiro-attached or fused cylic substituents at any available point or points of attachment, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl, fused heterocycle and fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

In certain embodiments, a heterocyclic group is substituted on carbon, nitrogen and/or sulfur at one or more positions. Examples of substituents on nitrogen include, but are not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfur include, but are not limited to, oxo and C_1-6alkyl. In certain embodiments, nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.

In other embodiments, substituents on ring groups, such as aryl, heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and alkyl.

In other embodiments, substituents on alkyl groups include halogen and hydroxy.

A “halohydrocarbyl” as employed herein is a hydrocarbyl moiety, in which from one to all hydrogens have been replaced with halo.

The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino” refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—). The term “carbamoyl” refers to an amide group attached at the carbonyl carbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted. The term “sulfonamido” refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term “amino” is meant to include NH₂, alkylamino, dialkylamino (wherein the alkyl groups are independently selected) arylamino, and cyclic amino groups. The term “ureido” as employed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising one or more unpaired electrons.

Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system. Substituents on cyclic moieties also include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties attached to the parent cyclic moiety by a covalent bond to form a bi- or tri-cyclic bi-ring system. For example, an optionally substituted phenyl includes, but is not limited to, the following:

An “unsubstituted” moiety (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means a moiety as defined above that does not have any optional substituents.

A saturated or unsaturated three- to eight-membered carbocyclic ring is for example a four- to seven-membered, alternatively five- or six-membered, saturated or unsaturated carbocyclic ring. Examples of saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

A saturated or unsaturated three- to eight-membered heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, and sulfur atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring for example contains one or two heteroatoms with the remaining ring-constituting atoms being carbon atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring is for example a saturated or unsaturated four- to seven-membered heterocyclic ring, alternatively a saturated or unsaturated five- or six-membered heterocyclic ring. Examples of saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

A saturated or unsaturated carboxylic and heterocyclic group may condense with another saturated or heterocyclic group to form a bicyclic group, for example a saturated or unsaturated nine- to twelve-membered bicyclic carbocyclic or heterocyclic group. Bicyclic groups include naphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl, and 1,2,3,4-tetrahydronaphthyl.

When a carbocyclic or heterocyclic group is substituted by two alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C_1-3 alkylene chain. Carbocyclic or heterocyclic groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.

Throughout the specification, particular embodiments of one or more chemical substituents are identified. Also encompassed are combinations of particular embodiments. For example, the invention describes particular embodiments of D in the compounds and describes particular embodiments of group G. Thus, as an example, also contemplated as within the scope of the invention are compounds in which particular examples of D are as described and in which particular examples of group G are as described.

In one embodiment, the invention provides a process and intermediates for preparing a compound having the Formula (A)

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof, wherein,

D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, each of which is optionally substituted with 1 to 5 independently selected R³⁸;

M is an optionally substituted fused heterocyclic moiety;

Z is selected from the group consisting of covalent bond, —O—, —O—CH₂—, —CH₂—O—, —S(O)_0-2—, —CH₂—, —N(R⁵)—, —N(R⁵)—CH₂— and —CH₂—N(R⁵)—;

Ar is a 5 to 7 membered cycloalkyl, aromatic, heterocyclic or heteroaromatic ring system, any of which is optionally substituted with 0 to 4 R² groups; and

G is a group B-L-T, wherein

B is selected from the group consisting of absent, —N(R¹³)—, —N(SO₂R¹³)—, —O—, —S(O)_0-2 and

L is selected from the group consisting of absent, —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—, —SO₂N(R¹³)—, —SO₂—, —C(═O)N(R¹³)—, —N(R¹³)—, —C(═O)C_1-2alkyl-N(R¹³)—, —N(R¹³)C_1-2alkyl-C(═O)—, —C(═O)C_0-1alkyl-C(═O)N(R¹³)—, —C_0-4alkylene, —C(═O)C_0-1alkyl-C(═O)OR³—, —C(═NR¹⁴)—C_0-1alkyl-C(═O)—, —C(═O)—, —C(═O)C_0-1alkyl-C(═O)— and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen, wherein an alkyl group of the aforementioned L group is optionally substituted; and

T is selected from the group consisting of —H, —R¹³, —C_0-5alkyl, —C_0-5alkyl-Q, —O—C_0-5alkyl-Q, —C_0-5alkyl-O-Q, —N(R¹³)—C_0-5alkyl-Q, —C_0-5alkyl-SO₂—C_0-5alkyl-Q, —C(═O)—C_0-5alkyl-Q, —C(═S)—C_0-5-alkyl-Q, —C(═NR¹⁴)—C_0-5-alkyl-Q, —C_0-5alkyl-N(R¹³)-Q, —C(═O)—N(R¹³)—C_0-5alkyl-Q, —C(═S)—N(R¹³)—C_0-5alkyl-Q, —C(═NR¹⁴)—N(R¹³)—C_0-5alkyl-Q, —(C_0-5alkyl-C(O))_0-1—C_0-5alkyl-Q wherein each C_0-5alkyl is optionally substituted;

or G is a group

or G is selected from the group consisting of:

wherein

each R³⁸ is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷, —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, (C₃-C₁₀)cycloalkyl, —(CH₂)_jO(CH₂)_iNR³⁶R³⁹, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nOR³⁷, —S(O)_j(C₁-C₆ alkyl), —(CH₂)_n(C₆-C₁₀ aryl), —(CH₂)_n(5-10 membered heterocyclyl), —C(O)(CH₂)_n(C₆-C₁₀ aryl), —(CH₂)_nO(CH₂)_j(C₆-C₁₀ aryl), —(CH₂)_nO(CH₂)_j(5-10 membered heterocyclyl), —C(O)(CH₂)_n(5-10 membered heterocyclyl), —(CH₂)_jNR³⁹(CH₂)_iNR³⁶R³⁹, —(CH₂)_jNR³⁹CH₂C(O)NR³⁶R³⁹, —(CH₂)_jNR³⁹(CH₂)_iNR³⁷C(O)R⁴⁰, —(CH₂)_jNR³⁹(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_jNR³⁹(CH₂)_iS(O)_j(C₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_iNHSO₂(C₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_iSO₂NH(C₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_nR³⁶, —SO₂(CH₂)_n(C₆-C₁₀ aryl), —SO₂(CH₂)_n(5-10 membered heterocyclyl), —(CH₂)_nNR³⁶R³⁹, —NR³⁷SO₂NR³⁶R³⁹, SO₂R³⁶, C₂-C₆alkenyl, C₃-C₁₀cycloalkyl and C₁-C₆alkylamino, wherein each j is an integer independently ranging from 0 to 4, n is an integer ranging from 0 to 6, i is an integer ranging from 2 to 6, the —(CH₂)_i—, —(CH₂)_j— and —(CH₂)_n-moieties of the foregoing R³⁸ groups optionally include a carbon-carbon double or triple bond where i, j, and n are an integer between 2 and 6, and the alkyl, aryl and heterocyclyl moieties of the foregoing R³⁸ groups are optionally substituted by one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_nNR³⁶R³⁹, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_n(C₆-C₁₀aryl), —(CH₂)_n(5-10 membered heterocyclyl), —(CH₂)_nO(CH₂)_iOR³⁷, and —(CH₂)_nOR³⁷;

R³⁶ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_n(C₆-C₁₀aryl), —(CH₂)_n(5-10 membered heterocyclyl), —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷ and —(CH₂)_nA⁴R³⁷, wherein each n is an integer independently ranging from 0 to 6, i is an integer ranging from 2 to 6, A⁴ is selected from the group consisting of O, S, SO, SO₂, NH and N(optionally substituted C₁-C₄alkyl), and the alkyl, aryl and heterocyclyl moieties of the foregoing R³⁶ groups are optionally substituted by one or more substituents independently selected from —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —NR³⁷R⁴¹, —NR³⁷R⁴¹, —C₁-C₆alkyl, —(CH₂)_n(C₆-C₁₀aryl), —(CH₂)_n(5 to 10 membered heterocyclyl), —(CH₂)_nO(CH₂)_iOR³⁷, and —(CH₂)_nOR³⁷, with the proviso that when R³⁶ and R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogen directly through an oxygen;

each R³⁷ and R⁴¹ is independently selected from H, —O—C₁-C₆alkyl, —O—C₃-C₁₀cycloalkyl, —O—(CH₂)_n(C₆-C₁₀aryl), —O—(CH₂)_n(5-10 membered heterocyclyl), optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally substituted C₃-C₁₀cycloalkyl, optionally substituted —O—(CH₂)_nA⁴-C₁-C₆alkyl, optionally substituted —O—(CH₂)_nA⁴-C₂-C₆alkenyl, optionally substituted —O—(CH₂)_nA⁴-C₂-C₆alkynyl and optionally substituted —O—(CH₂)_nA⁴-C₃-C₁₀cycloalkyl;

R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_n(C₆-C₁₀aryl), —(CH₂)_n(5-10 membered heterocyclyl), —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, —(CH₂)_nOR³⁷, —NMe₂, —NHMe, —NEt₂, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups, wherein n is an integer ranging from 0 to 6, and the alkyl, aryl and heterocyclyl moieties of the foregoing R³⁹ groups are optionally substituted by one or more substituents independently selected from —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰, —CO(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹, —NR³⁷R⁴¹, —C₁-C₆alkyl, —(CH₂)_n(C₆-C₁₀aryl), —(CH₂)_n(5 to 10 membered heterocyclyl), —(CH₂)_n—O—(CH₂)_iOR³⁷, and —(CH₂)_nOR³⁷, with the proviso that when R³⁶ and R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogen directly through an oxygen;

R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocycle);

each R⁴⁰ is independently selected from H, C₁-C₁₀alkyl, —(CH₂)_n(C₆-C₁₀aryl), C₃-C₁₀cycloalkyl, and —(CH₂)_n(5-10 membered heterocyclyl), wherein n is an integer ranging from 0 to 6;

R⁵ is selected from the group consisting of H, an optionally substituted (C₁-C₅)acyl and C₁-C₆alkyl-O—C(O), wherein C₁-C₆alkyl is optionally substituted;

R² at each occurrence is independently selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)_0-2R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, C₁-C₄alkoxy, C₁-C₄alkylthio, —O(CH₂)_0-6aryl, —O(CH₂)_0-6heteroaryl, 4-CH₂)_0-5(aryl), —(CH₂)_0-5(heteroaryl), C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CH₂(CH₂)_0-4-T², wherein the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl are optionally substituted;

T² is selected from the group consisting of —OH, —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂;

each R³ is independently selected from the group consisting of —H and R⁴;

R⁴ is selected from the group consisting of a (C₁-C₆)alkyl, an aryl, a lower arylalkyl, a heterocyclyl and a lower heterocyclylalkyl, each of which is optionally substituted, or

R³ and R⁴, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;

each R¹³ is independently selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)_0-2R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —C(O)SR³, C₁-C₄alkoxy, C₁-C₄alkylthio, —O(CH₂)_0-6aryl, —O(CH₂)_0-6heteroaryl, —(CH₂)_0-5(aryl), —(CH₂)_0-5(heteroaryl), —(CH₂)_0-5(cycloalkyl), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CH₂(CH₂)_0-4-T², an optionally substituted C_1-4alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl are optionally substituted; or

two R¹³, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R⁶⁰, wherein the heteroalicyclic can have up to four annular heteroatoms, and the heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case the aryl or heteroaryl is optionally substituted with an additional one to four of R⁶⁰;

R¹⁴ is selected from the group —H, —NO₂, —NH₂, —N(R³)R⁴, —CN, —OR³, an optionally substituted (C₁-C₆)alkyl, an optionally substituted heteroalicyclylalkyl, an optionally substituted aryl, an optionally substituted arylalkyl and an optionally substituted heteroalicyclic,

R⁶⁰ is selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)_0-2R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, an optionally substituted (C₁-C₆)alkyl, an optionally substituted aryl, an optionally substituted heteroarylalkyl and an optionally substituted arylalkyl; or

two R⁶⁰, when attached to a non-aromatic carbon, can be oxo;

Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R²⁰;

each R²⁰ is independently selected from the group consisting of —H, halogen, trihalomethyl, —O-trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —OCF₃, —NR³R⁴, —S(O)_0-2R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)C(O)OR³, —C(O)R³, —C(O)SR³, —C₄alkoxy, C₁-C₄alkylthio, —O(CH₂)_0-6aryl, —O(CH₂)_0-6heteroaryl, —(CH₂)_0-5(aryl), —(CH₂)_0-5(heteroaryl), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CH₂(CH₂)_0-4-T², an optionally substituted C_1-4alkylcarbonyl, C_1-4alkoxy, an amino optionally substituted by C_1-4alkyl optionally substituted by C_1-4alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group and wherein the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl are optionally substituted, wherein the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl are optionally substituted;

L¹ is selected from the group consisting of O, S and N(R¹⁴);

L² is selected from the group consisting of —C(O)—, —C(S)—, —C(NH)—, >C═N(C₁-C₆ alkyl) and —CH₂—;

L³ is selected from the group consisting of —CH—, —C(C₁-C₆alkyl)- and N;

L⁴ is selected from the group consisting of —CH— and N;

n1 is an integer from 0 to 5;

each X is independently selected from the group consisting of O, S, NH, N-alkyl, N—OH, N—O— alkyl and NCN;

R¹¹ and R¹² are independently selected from the group consisting of H, C₁-C₆alkyl, halo, cyano and nitro, wherein the alkyl is optionally substituted; or

R¹¹ and R¹², taken together with the atom to which they are attached, form a C₃-C₇cycloalkyl;

E is selected from the group consisting of O, S, —CH₂—, —CH(C₁-C₆alkyl), —N(H)—, —N(C₁-C₆alkyl)-, —CH₂N(H)— and —N(H)CH₂—;

R^11a and R^12a are independently selected from the group consisting of H, halogen, —OH, unsubstituted —O—(C₁-C₆alkyl), substituted —O—(C₁-C₆alkyl), unsubstituted —O-(cycloalkyl), substituted —O-(cycloalkyl), unsubstituted —NH(C₁-C₆alkyl), substituted —NH(C₁-C₆alkyl), —NH₂, —SH, unsubstituted —S—(C₁-C₆alkyl), substituted —S—(C₁-C₆alkyl), unsubstituted C₁-C₆alkyl and substituted C₁-C₆alkyl; or

R^11a and R^12a taken together with the atom to which they are attached form a C₃-C₇ ring system, wherein said ring system is optionally substituted;

each R^13a is independently selected from the group consisting of H, C₁-C₆alkyl, substituted C₁-C₆alkyl, cycloalkyl, substituted cycloalkyl, OH, unsubstituted —O—(C₁-C₆alkyl), substituted —O—(C₁-C₆alkyl); or

R^12a and R^13a taken together with the atoms to which they are attached optionally form a 4 to 8 membered cycloalkyl or heterocyclic ring system, which ring system is optionally substituted;

R^14a, R^15a, R^16a and R^17a are independently selected from the group consisting of —H, halogen, trihalomethyl, —O-trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)_0-2R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)C(O)OR³, —C(O)R³, —C(O)SR³, C₁-C₄alkoxy, C₁-C₄alkylthio, —O(CH₂)_naryl, —O(CH₂)_nheteroaryl, —(CH₂)_0-5(aryl), —(CH₂)_0-5(heteroaryl), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CH₂(CH₂)_0-4-T², an optionally substituted C_1-4alkylcarbonyl, C_1-4alkoxy, an amino optionally substituted by C_1-4alkyl optionally substituted by C_1-4alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein n is an integer ranging from 0 to 6, and the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl are optionally substituted; or

R^13a and R^14a taken together with the atoms to which they are attached optionally form a 4 to 8 membered cycloalkyl or heterocyclic ring system, which ring system is optionally substituted;

R^18a and R^19a are independently selected from the group consisting of H, OH, halogen, NO₂, unsubstituted —O—(C₁-C₆alkyl), substituted —O—(C₁-C₆alkyl), CH₃, CH₂F, CHF₂, CF₃, CN, C₁-C₆alkyl, substituted C₁-C₆alkyl, partially fluorinated C₁-C₆alkyl, per-fluorinated C₁-C₆alkyl, heteroalkyl, substituted heteroalkyl and —SO₂(C₁-C₆alkyl); or

R^18a and R^19a together with the atom to which they are attached form a 3 to 6 membered cycloalkyl or heterocycle, each of which is optionally substituted with 1 to 4 halo, for example F;

W is selected from the group consisting of H, alkyl, alkenyl, alkynyl, —(CH₂)_0-5(five- to ten-membered cycloalkyl), —(CH₂)_0-5(aryl), —(CH₂)_0-5(heterocylic) and —(CH₂)_0-5(heteroaryl), each of which is optionally substituted; and

is a single or double bond;

X¹ is selected from the group consisting of O, S, CH₂, N—CN, N—O-alkyl, NH and N(C₁-C₆alkyl) when is a double bond, or

X¹ is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, CN, alkoxy, NH(alkyl) and alkyl-thio, when is a single bond;

L^a and L^1a are independently selected from the group consisting of —CH—, —N—, —C(halogen)- and —C(C₁-C₆alkyl)-;

L^2a and L^3a are independently selected from the group consisting of CH, CH₂, N, O and S;

L^4a is selected from the group consisting of absent, CH, CH₂, N, O and S; and

the group

is aromatic or non-aromatic, provided that two O are not adjacent to each other;

K and K¹ are independently selected from the group consisting of —C(O)—, —C(NH)—, —C(NCN)— and —C(R^18aR^19a)—;

U is selected from the group consisting of O, S, SO₂, NH, and N(C₁-C₆alkyl), wherein the C₁-C₆alkyl is optionally substituted with a substituent selected from the group consisting of —OH, -alkoxy, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,

U¹ is a ring system selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

E¹ is selected from the group consisting of —N(H)—, —N(C₁-C₆alkyl)-, —CH₂N(H)— and —N(H)CH₂—;

E² is selected from the group consisting of —N(H)—, —N(C₁-C₆alkyl)-, —CH₂N(H)— and —N(H)CH₂—:

X² is selected from the group consisting of O, S, NH, NOH, NOMe, NOEt and NCN; and

n is 0, 1, 2, 3 or 4;

the process comprising

reacting a compound represented by the Formula (A-1)

wherein

RG¹ is a reactive group (for example, selected from the group consisting of nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂, and —CH₂NHMe);

with a compound represented by the Formula (A-2):RG²-G¹  (A-2),

wherein RG² is a functional group reactive with —RG¹, and RG²-G¹ is a precursor of group G, such that the reaction of —RG¹ with RG²-G¹ forms -G; and

if R³⁸ comprises a protecting group, removing the protecting group.

In an example of the compounds according to Formula (A) D is an aromatic or heteroaromatic ring system, each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is substituted with one R³⁸ group.

In another example of the compounds according to Formula (A), D is a 5- or 6-membered aromatic or 5- or 6-membered heteroaromatic ring system, each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is a 6-membered aromatic or 6-membered heteroaromatic ring system, each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is a 6-membered aromatic ring system, optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is a 6-membered heteroaromatic ring system, optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is phenyl or pryidinyl, each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is phenyl, optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is pyridine, optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another example of the compounds according to Formula (A), D is phenyl, optionally substituted with one R³⁸.

In another example of the compounds according to Formula (A), D is pyridine, optionally substituted with one R³⁸.

In another example of the compounds according to Formula (A), D is phenyl, substituted with one R³⁸.

In another example of the compounds according to Formula (A), D is pyridine, substituted with one R³⁸.

In another example of the compounds according to Formula (A), each R³⁸ is independently selected from the group consisting of —(CH₂)_jO(CH₂)_jNR³⁶R³⁹, —(CH₂)_nO(CH₂)_jOR³⁷, —(CH₂)_nOR³⁷, —(CH₂)_nO(CH₂)_j(C₆-C₁₀ aryl), —(CH₂)_nO(CH₂)_i(5-10 membered heterocyclyl), —(CH₂)_jNR³⁹(CH₂)_iNR³⁶R³⁹, —(CH₂)_jNR³⁹CH₂C(O)NR³⁶R³⁹, —(CH₂)_jNR³⁹(CH₂)_iNR³⁷C(O)R⁴⁰, —(CH₂)_jNR³⁹(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_jNR³⁹(CH₂)_iS(O)_jC₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_iNHSO₂(C₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_iSO₂NH(C₁-C₆ alkyl), —(CH₂)_jNR³⁹(CH₂)_nR³⁶, —(CH₂)_nNR³⁶R³⁹ and —NR³⁷SO₂NR³⁶R³⁹, alternatively —(CH₂)_jO(CH₂)_iNR³⁶R³⁹, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_jNR³⁹(CH₂)_iNR³⁶R³⁹, —(CH₂)_jNR³⁹CH₂C(O)NR³⁶R³⁹, —(CH₂)_jNR³⁹(CH₂)_iNR³⁷C(O)R⁴⁰, —(CH₂)_jNR³⁹(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_jNR³⁹(CH₂)_iS(O)_j(C₁-C₆ alkyl) and —(CH₂)_jNR³⁹(CH₂)_nR³⁶, and alternatively —(CH₂)_jNR³⁹(CH₂)_nR³⁶.

In another example of the compounds according to Formula (A), R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an integer independently ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), and i is an integer ranging from 2 to 6.

In another example of the compounds according to Formula (A), each R³⁸ is independently C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹.

In another example of the compounds according to Formula (A), each R³⁸ is independently —(CH₂)_jNR³⁹(CH₂)_nR³⁶, wherein j is 1 and n is 2.

In another example of the compounds according to Formula (A), R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the compounds according to Formula (A), R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

In another example of the compounds according to Formula (A), R³⁹ is H or C₁-C₆alkyl, alternatively H.

In another example of the compounds according to Formula (A), R³⁹ is selected from the group consisting of

In another embodiment of the present invention. ID is optionally substituted with one or two (alternatively one) R³⁸, wherein each said R³⁸ is independently selected from C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocycle).

In another example of the compounds according to Formula (A), D is phenyl or pryidinyl (for example pyridinyl), optionally substituted with one or two (for example one) R³⁸, wherein each said R³⁸ is independently selected from C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moe, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocycle).

In another example of the compounds according to Formula (A) A⁴ is O.

In another example of the compounds according to Formula (A), M is a structure selected from the group consisting of

wherein

* represents the point of attachment to D;

† represents the point of attachment to Z;

A¹ is selected from the group consisting of —CH₂—, —O—, —S—, —N(H)—, —N(C₁-C₆alkyl)-, —N—(Y-aryl)-, —N-OMe, —NCH₂OMe and N-Bn;

Y is a bond or —(C(R^x)(H))₁—, wherein t is an integer from 1 to 6; and

R^x at each occurrence is independently selected from the group consisting of H and C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted;

A² is selected from the group consisting of N and CR, wherein R is selected from the group consisting of —H, halogen, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —COOH and —C(O)Oalkyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and —C(O)Oalkyl are optionally substituted;

A³ is selected from the group consisting of CH, C-D and N, alternatively CH and N;

each R⁸⁰ is independently selected from the group consisting of H, halogen, NO₂, cyano, OR⁸³, N(R⁸³)₂, CO₂R⁸³, C(O)N(R⁸³)₂, SO₂R⁸³, SO₂N(R⁸³)₂, NR⁸³SO₂R⁸³, NR⁸³C(O)R⁸³, NR⁸³CO₂R⁸³, —CO(CH₂)₁R⁸³, —CONH(CH₂)₁R⁸³, alkylaminoalkyl, alkylaminoalkynyl, C₁-C₆alkyl, substituted C₁-C₆alkyl, C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and

each R⁸³ is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; or

two R⁸³ taken together with the N atom to which they are attached form a heterocyclic ring.

In another example of the compounds according to Formula (A), M is a structure selected from the group consisting of

wherein

J is CR⁸⁰ or N;

R⁸² is selected from the group consisting of H, C₁-C₆alkyl or substituted C₁-C₆alkyl, —Y-(aryl), —Y-(heteroaryl), -alkoxy and —CH₂OMe;

wherein *, †, R⁸⁰ and Y are as defined above.

In another example of the compounds according to Formula (A), M is a structure selected from the group consisting of

wherein

* and † are as defined above;

D is selected and as defined above; and

R²² is selected from the group consisting of —H, —C₁-C₆alkyl, —Y-aryl, alkoxy, —CH₂—O-Me and —Bn.

In another example of the compounds according to Formula (A), M is

In another example of the compounds according to Formula (A), A¹ is S.

In another example of the compounds according to Formula (A), A² is —CH— or —C(CN)—.

In another example of the compounds according to Formula (A), A³ is —C(R^q)— or N, wherein R^q is selected from the group consisting of H, halogen, NO₂, cyano, OR^r, NR^rR^r, CO₂R^r, C(O)NR^rR^r, SO₂R^r, SO₂NR^rR^r, NR^rSO₂R^r, NR^rC(O)R^r, NR^rCO₂R^r, —CO(CH₂)_0-4R^r, —CONH(CH₂)_0-4R^r, alkylaminoalkyl, alkylaminoalkynyl, C₁-C₆alkyl, substituted C₁-C₆alkyl, C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heterocycloalkyl and substituted heterocycloalkyl; wherein each R^r is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl.

In another example of the compounds according to Formula (A), Z is selected from the group consisting of —O—, —S— and wherein R⁵ is selected from the group consisting of H, an optionally substituted (C₁-C₅)acyl and C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl is optionally substituted.

In another example of the compounds according to Formula (A), Z is —O—.

In another example of the compounds according to Formula (A), Ar is selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pryimidine and pyridine is optionally substituted with 0 to 4 R² groups.

In another example of the compounds according to Formula (A), Ar is phenyl, optionally substituted with 0 to 4 R² groups, alternatively with between zero and four halo.

In another example of the compounds according to Formula (A), G is selected from the group consisting of

wherein R¹³, R¹⁴, Q, R⁶⁰ and R³ are as defined above;

any methylene group is independently optionally substituted with R²⁵, wherein

R²⁵ is selected from the group consisting of halogen, trihalomethyl, —CN, —OR³, —NR³, R⁴, —S(O)_0-2R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, and an optionally substituted (C₁-C₆)alkyl, or

two R²⁵, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic, or

two R²⁵, on a single carbon can be oxo;

R⁹ is selected from the group consisting of a C_1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R²⁴, -T¹-R¹⁵, or —NR¹⁶R¹⁷, a —N(R¹⁸)(R¹⁹) moiety and a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring wherein, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

wherein

T¹ is selected from the group consisting of —O—, —S— and —NH—;

R²⁴ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;

R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent a C_1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; wherein the three- to eight-membered carbocyclic or heterocyclic group represented by R²⁴, R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, a cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring; and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and wherein the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; and

R¹⁸ and R¹⁹, which may be the same or different, represent (1) a hydrogen atom, (2) a C_1-6 alkyl which is optionally substituted by a C_1-6 alkoxy, a C_1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or (3) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and in which, when the three to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;

X³ and X⁴ are each independently selected from the group consisting of —H, halogen, cyano, nitro, C₁-C₆ alkyl, or

X³ and X⁴ together with the atom to which they are attached form a C₃-C₄ cycloalkyl;

each E³ is independently selected from the group consisting of —O—, —N(R¹³)—, —CH₂— and —S(O)_0-2;

J² is selected from the group consisting of —O—, —N(R¹³)—, —CH₂— and —C(═O)N(R¹³);

J³ represents —C(R²⁶)(R²⁷)—, wherein

R²⁶ and R²⁷ are independently selected from the group consisting of a hydrogen atom, a C_1-4alkyl, a C_1-4 alkoxy and —N(R^12b), wherein

R^12b is a hydrogen atom or a C_1-4 alkyl;

each V is independently selected from the group consisting of ═N— and ═C(H)—;

R²¹ and R²³ are independently selected from the group consisting of H, halogen, —OH, unsubstituted —O—(C₁-C₆alkyl), substituted —O—(C₁-C₆alkyl), unsubstituted —O-(cycloalkyl), substituted —O-(cycloalkyl), unsubstituted —NH(C₁-C₆alkyl), substituted —NH(C₁-C₆alkyl), —NH₂, —SH, unsubstituted —S—(C₁-C₆alkyl), substituted —S—(C₁-C₆alkyl), unsubstituted C₁-C₆alkyl and substituted C₁-C₆alkyl; or

R²¹ and R²³ taken together with the atom to which they are attached form a C₃-C₇ ring system, wherein said ring system is optionally substituted;

d is 0, 1, 2 or 3;

e is 0, 1, 2 or 3; and

f is 0 or 1.

In another example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), G is selected from the group consisting of

wherein each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R²⁵;

R^5a is —H or an optionally substituted (C₁-C₆)alkyl;

R¹⁰ is an azolyl, wherein one or more hydrogen atoms are optionally substituted by a moiety selected from the group consisting of a halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, trihalomethyl, nitro, amino optionally independently substituted by one or two of C_1-4 alkyl, a alkoxycarbonyl C_1-4 alkyl, a C_1-4 alkylcarbonyl and a C_3-5 cyclic alkyl.

In another example of the compounds according to Formula (A), a methylene group between two carbonyl groups is mono- or di-substituted with either an optionally substituted (C₁-C₆)alkyl or an optionally substituted spirocycle.

In another example of the compounds according to Formula (A), R¹⁰ is selected from the group consisting of

wherein A⁸ is selected from the group consisting of —O—, —S— and —NH—; and

R^22a and R^23a are independently selected from the group consisting of —H, halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, trihalomethyl, nitro, amino optionally independently substituted by one or two of C_1-4 alkyl, a C_1-4 alkoxycarbonyl C_1-4 alkyl, a C_1-4 alkylcarbonyl and a C_3-5 cyclic alkyl.

In another example of the compounds according to Formula (A) example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), G is selected from the group consisting of

In another example of the compounds according to Formula (A), any of E, E¹, E² or E³ are independently —NH—.

In another example of the compounds according to Formula (A), one of R^18a and R^19a is —CF₃ and the other is —H.

In another example of the compounds according to Formula (A), R¹¹ and R¹² are each —H.

In another example of the compounds according to Formula (A), X is S or O.

In another example of the compounds according to Formula (A), X is S.

In another example of the compounds according to Formula (A), R¹³ is H.

In another example of the compounds according to Formula (A), R¹¹, R¹² and R¹³ are each —H.

In another example of the compounds according to Formula (A), X is O, one of R^18a and R^19a is —CF₃ and the other is —H, and R¹¹, R¹² and R¹³ are each —H.

In another example of the compounds according to Formula (A), W is selected from the group consisting of

wherein P¹ is a five- to seven-membered ring, including the two shared carbon atoms of the aromatic ring to which P¹ is fused, and wherein P¹ optionally contains between one and three heteroatoms.

In another example of the compounds according to Formula (A), W is selected from the group consisting of phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted.

In another example of the compounds according to Formula (A), W is selected from the group consisting of phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with one or more of R^14a, R^15a, R^16a and R^17a.

In another example of the compounds according to Formula (A), W is phenyl, optionally substituted.

In another example of the compounds according to Formula (A), W is phenyl, optionally substituted with one or more of R^14a, R^15a, R^16a and R^17a.

In another example of the compounds according to Formula (A), W is substituted by a halogen and either an alkenyl or alkynyl.

In another example of the compounds according to Formula (A), W is phenyl substituted by a halogen and either an alkenyl or alkynyl.

In another example of the compounds according to Formula (A), Q is selected from the group consisting of

wherein P¹ is a five- to seven-membered ring, including the two shared carbon atoms of the aromatic ring to which P¹ is fused, and wherein P¹ optionally contains between one and three heteroatoms.

In another example of the compounds according to Formula (A), Q is selected from the group consisting of phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R²⁰, wherein

In another example of the compounds according to Formula (A), Q is phenyl, optionally substituted.

In another example of the compounds according to Formula (A), Q is phenyl, optionally substituted with one or more of R²⁰.

In another example of the compounds according to Formula (A), Q is substituted by a halogen and either an alkenyl or alkynyl.

In another example of the compounds according to Formula (A), Q is phenyl substituted by a halogen and either au alkenyl or alkynyl.

In another example of the compounds according to Formula (A), R^14a and R^15a are both H, R^16a is C₂-C₇ alkenyl or C₂-C₆ alkynyl and R^17a is halogen, for example fluorine.

In another example of the compounds according to Formula (A), L³ and L⁴ are independently —CH— or N.

In another example of the compounds according to Formula (A), R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the compounds according to Formula (A), R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

In an alternate embodiment of the compounds according to Formula (A), D is -(aryl), -(heterocycle) or -(heteroaryl), each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ group;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, for example —O—;

Ar is aryl or heteroaryl, for example selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, for example phenyl, each of which is optionally substituted with 0 to 4 R² groups, alternatively with between zero and four halo; and

G is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰, wherein said R²⁰ are for example halogen, trihalomethyl, alkoxy, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkenyl or optionally substituted C₂-C₆alkynyl, for example halogen.

For example, in such embodiment, D is optionally substituted with one or two (alternatively one) R³⁸, wherein each said R³⁸ is independently C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocycle).

In an example of the compounds according to this alternate embodiment, D is phenyl or pyridinyl (for example pyridinyl), optionally substituted with one or two (alternatively one) R³⁸, wherein each said R³⁸ is independently selected from C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the compounds according to this alternate embodiment, R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the compounds according to this alternate embodiment, R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is for example selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moe, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

In another alternate embodiment of the compounds according to Formula (A), D is -(aryl), -(heterocycle) or -(heteroaryl), each of which is optionally substituted with 1 to 5 independently selected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸ group;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, for example —O—;

Ar is aryl or heteroaryl, for example selected from the group consisting of phenyl, pyrazine, pyridazine, pyrimidine and pyridine, for example phenyl, each of which is optionally substituted with 0 to 4 R² groups, alternatively with between zero and four halo; and

G is

wherein said phenyl groups of G are optionally substituted with from 0 to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰, wherein said R²⁰ are for example halogen, trihalomethyl, alkoxy, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl, for example halogen.

In an example of the compounds according to this alternate embodiment, D is optionally substituted with one or two (alternatively one) R³⁸, wherein each said R³⁸ is independently selected from C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z (alternatively H or C₁-C₆alkyl, alternatively H), —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z, —C(O)O—R⁷), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_n—O—(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the compounds according to this alternate embodiment, D is phenyl or pyridinyl (for example pyridinyl), optionally substituted with one or two (alternatively one) R³⁸, wherein each said R³⁸ is independently selected from C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z (alternatively H or C₁-C₆alkyl, alternatively H), —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z, —C(O)O—R^z), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the compounds according to this alternate embodiment, R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the compounds according to this alternate embodiment, R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

In another example of the compounds according to this alternate embodiment, D is phenyl or pryidinyl, substituted with one R³⁸, wherein R³⁸ is —(CH₂)_jR³⁹(CH₂)_nR³⁶, wherein j is an integer from 0 to 4, n is an integer from 0 to 6, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is —(CH₂)_nOR³⁷, wherein n is an integer ranging from 0 to 6, and R³⁷ is H or C₁-C₆alkyl.

In another example of the compounds according to this alternate embodiment, RG² is SCN— or HO—.

In another example of the compounds according to this alternate embodiment, RG¹ is —NH₂.

In another embodiment of the present invention, a process and intermediates are provided for preparing compounds having Formula (D):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof,

wherein

R³⁸, D, M, Z and Ar are as defined above for any previous embodiment or alternative embodiment thereof or example thereof; and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ or —CH₂NHMe;

the processes comprising

providing an intermediate group R³⁸-D-LG¹, wherein R³⁸ comprises zero or more protected reactive moities therein, and wherein LG¹ is a leaving group;

reacting said intermediate group R³⁸-D-LG¹ or protected intermediate group R³⁸-D-LG¹ with

wherein LG² is a leaving group, * represents the point of attachment of group R³⁸-D-, and † represents the point of attachment of group Z,

to form intermediate (D-1)

and reacting (D-1) with intermediate (D-2) via moiety Z^x

wherein

Z^x is selected from the group consisting of H, —OH, —CH₂—OH, —SH, —N(R⁵)H, and —CH₂—N(R⁵)H, wherein R⁵ is selected from the group consisting of H, C₁-C₆-alkyl, an optionally substituted (C₁-C₅)acyl and C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl is optionally substituted.

In an example of the compounds according Formula (D),

D is -(aryl) or -(heteroaryl);

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂— or —N(R⁵)—; and

Ar is aryl or heteroaryl, each of which is optionally substituted with 0 to 4 R² groups.

In another example of the compounds according to Formula (D), D is optionally substituted phenyl or optionally substituted pyridinyl.

In another example of the compounds according to Formula (D), Z is O.

In another example of the compounds according to Formula (D), Ar is phenyl, pyrazine, pyridazine, pyrimidine or pyridine, each of which is optionally substituted.

In another example of the compounds according to Formula (D), Ar is optionally substituted phenyl.

In another example of the compounds according to Formula (D), M is

In another example of the compounds according to Formula (D), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹, wherein j is an integer from 0 to 4, n is an integer from 0 to 6, R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z, —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Loc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6, i is an integer from 2 to 6, R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl.

In another example of the compounds according to Formula (D), D is phenyl or pyridinyl, and R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹, wherein j is an integer from 0 to 4, n is an integer from 0 to 6, R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z, —C(O)—O—R^z, —SO₂—C₁-C₆alkyl and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6, i is an integer from 2 to 6, R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl.

In another example of the compounds according to Formula (D), LG¹ and LG² are independently selected from the group consisting of halo, alkoxy, triflate, mesylate, tosylate, acetate, trifluoroacetate, SO₂Me, nosylate, p-nitrophenolate and the like.

In another example of the compounds according to Formula (D), RG¹ is nitro, and said nitro is subsequently reduced to amino.

In another example of the compounds according to Formula (D):

R³⁸ is as defined above, or alternatively is —(CH₂)_nNR³⁹(CH₂)_mA⁴R³⁷;

D is -(aryl), -(heterocyclyl) or -(heteroaryl), for example phenyl or pyridinyl (for example pyridinyl);

M is an optionally substituted fused heterocyclic moiety,

for example selected from the group consisting of

for example

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, for example —O—;

Ar is aryl or heteroaryl, for example selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, for example phenyl, each of which is optionally substituted with 0 to 4 R² groups, for example with between zero and four halo; and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ or —CH₂NHMe.

In another example of the compounds according to Formula (D), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z, —C(O)—O—R^z and —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_n—O—(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the compounds according to Formula (D), D is phenyl or pyridinyl (for example pyridinyl), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z, —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the compounds according to Formula (D), R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the compounds according to Formula (D), R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moe, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

According to another embodiment of the present invention, the invention provides a process for preparing an intermediate compound R³⁸-D-LG¹, wherein R³⁸ comprises zero or protected reactive moieties therein, and LG¹ is a leaving group, the process comprising (a) reacting a compound

with a pre-R³⁸ group, and wherein the reaction of the aldehyde moiety of D with the pre-R³⁸ group gives the compound R³⁸-D-LG¹; and (b) protecting a reactive moiety of R³⁸.

In an example of this embodiment for preparing an intermediate compound R³⁸-D-LG¹, R³⁸ is —(CH₂)_nNR³⁹(CH₂)_mA⁴R³⁷.

In another example of the embodiment for preparing an intermediate compound R³⁸-D-LG¹, a pre-R³⁸ compound is an amino derivative of R³⁸.

In another example of the embodiment for preparing an intermediate compound R³⁸-D-LG¹, the amine precursor of —(CH₂)_nNR³⁹(CH₂)_mA⁴R³⁷ is H₂N(R³⁹)(CH₂)_mA⁴R³⁷.

In another example of the embodiment for preparing an intermediate compound R³⁸-D-LG¹, D is -(aryl)-, -(heterocycle)- or -(heteroaryl)-, for example phenyl or pyridinyl, each of which is optionally substituted.

In another example of the embodiment for preparing an intermediate compound R³⁸-D-LG¹, R³⁸ is C₁-C₆alkyl, —(CH₂)_nNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the embodiment for preparing an intermediate compound R³⁸-D-LG¹, D is phenyl or pryidinyl (for example pyridinyl), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z and —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In an alternate embodiment of the process and intermediates for preparing compounds having the Formula (D):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof,

wherein

R³⁸, D, M, Z and Ar are as defined above, wherein R³⁸ comprises zero or more reactive moieties therein, and RG¹ is a reactive group selected from the group consisting of nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ and —CH₂NHMe;

the process comprises:

reacting an intermediate

wherein LG² is a leaving group, * represents the point of attachment of group R³⁸-D-, and † represents the point of attachment of group Z with intermediate (D-2)

wherein Ar is optionally substituted with O to 4 R²,

to form intermediate (D-5)

wherein

Z^x is selected from the group consisting of —OH, —CH₂—OH, —SH, —N(R⁵)H, and —CH₂—N(R⁵)H, wherein R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, an optionally substituted (C₁-C₅)acyl and C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl is optionally substituted;

reacting intermediate (D-5) with intermediate (D-6)

• • wherein LG¹ is a leaving group, and RG² is a reactive group for constructing R³⁸, to form intermediate (D-7)

reacting the RG² moiety of intermediate (D-7) with a pre-R³⁸ compound, wherein the reaction of RG² with the pre-R³⁸ compound gives the substituent R³⁸; and

if present, protecting a reactive moiety of R³⁸.

In an example of this alternate embodiment of the process and intermediates for preparing compounds having the Formula (D), RG² is —CHO or —CH₂Hal; pre-R³⁸ is NH₂(CH₂)_mA⁴R³⁷ and R³⁸ is —(CH₂)_nNH(CH₂)_mA⁴R³⁷.

In another embodiment of the processes and intermediates for preparing compounds having the Formula (D),

R³⁸ is —(CH₂)_nNR³⁹(CH₂)_mA⁴R³⁷;

D is -(aryl) or -(heteroaryl);

RG² is —CHO;

M is selected from the group consisting of

wherein represents the point of attachment to group D and † represents the point of attachment of the group Z;

Z is —O—;

Ar is aryl or heteroaryl, each of which is optionally substituted with 0 to 4 R² groups;

and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ or —CH₂NHMe.

In another example of this alternate embodiment of the process and intermediates for preparing compounds having Formula (D), M is

In another example of this alternate embodiment of the process and intermediates for preparing compounds having Formula (D), RG¹ is nitro, and said nitro is subsequently reduced to amino.

In another embodiment of the present invention there is provided, a process and intermediates for preparing a compound having the formula (E):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof,

wherein

D, M, Z and Ar are as defined above,

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ or —CH₂NHMe;

R^k is selected from the group consisting of H, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₄ alkenyl and C₂-C₄ alkynyl,

each R^f is independently —O—C₁-C₇alkyl, or both R^f taken together with the atom to which there are attached may form a cyclic acetal (a 5 to 8 member ring system), or a carbonyl group;

the process comprising

reacting an intermediate compound of Formula (E-1)

wherein

LG¹ is a leaving group,

with

wherein LG² is a leaving group, * represents the point of attachment of group R³⁸-D-, and † represents the point of attachment of group Z, to form intermediate compound (E-2)

and reacting (E-2) with

via said Z^x moiety,

wherein

Z^x is selected from the group consisting of H, —OH, —SH, —N(R⁵)H, —NH—CH₃ and —CH₂—N(R⁵)H, wherein R⁵ is selected from the group consisting of H, an optionally substituted (C₁-C₅)acyl and C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl is optionally substituted.

In an example of the embodiment of the process and intermediates for preparing a compound having the Formula (E):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof, wherein

R^k is selected from the group consisting of H, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₄ alkenyl and C₂-C₄ alkynyl;

each R^f is independently —O—C₁-C₇alkyl, or both R^f taken together with the atom to which they are attached may form a cyclic acetal (a 5 to 8 member ring system), or a carbonyl group;

D is -(aryl), -(heterocyclyl) or -(heteroaryl), for example phenyl or pryidinyl (for example pyridinyl);

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, for example —O—;

Ar is aryl or heteroaryl, for example selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, for example phenyl, each of which is optionally substituted with 0 to 4 R² groups, alternatively with between zero and four halo; and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ and —CH₂NHMe;

In another example of this embodiment of the process and intermediates for preparing a compound having the Formula (E)

D is -(aryl) or -(heteroaryl);

M is selected from the group consisting of

wherein * represents the point of attachment to group D and † represents the point of group Z;

Z is —O—;

Ar is aryl or heteroaryl, each of which is optionally substituted with 0 to 4 R² groups;

and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂ or —CH₂NHMe.

In another example of this embodiment of the process and intermediates for preparing a compound having Formula (E), M is

In another example of this embodiment of the process and intermediates for preparing a compound having Formula (E), RG¹ is nitro, wherein said nitro is subsequently reduced to —NH₂.

In another example of this embodiment of the process and intermediates for preparing a compound having Formula (E), compound (E-1) is prepared by protection of an aldehyde of Formula (E-3):OHC-D-LG¹  (E-3).

In another example of this embodiment of the process and intermediates for preparing a compound having Formula (E), D is phenyl or pyridinyl (for example pyridinyl).

In another embodiment the present invention provides a process and intermediates for preparing a compound having Formula (F):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof and racemic and scalemic mixtures, diastereomers, tautomers and enantiomers thereof,

wherein

R³⁸, D, M, Z, Ar and G are as defined herein, the process comprising:

reacting a compound of Formula (E)

wherein

R^k is selected from the group consisting of H, C₃-C₆cycloalkyl, C₂-C₄ alkenyl and C₂-C₄ alkynyl;

each R^f is independently —O—C₁-C₇alkyl, or both R^f taken together with the atom to which they are attached may form a cyclic acetal (a 5 to 8 member ring system), or a carbonyl group; and

RG¹ is nitro, —NH₂, —NH—C₁-C₄alkyl-, —NH—C₂-C₄alkenyl, —NH—C₂-C₄alkynyl, —NH—C₃-C₆cycloalkyl, —OH, —SH, —NH—NH₂, —NHOH, —N(Me)OH, —N(Me)NH₂, —N(Me)-NHMe, —CH₂NH₂, or —CH₂NHMe;

with a compound of Formula (A-2)RG²-G¹  (A-2),

wherein RG² is a functional group reacting with —RG¹, and RG²-G¹ is a precursor of group G, such that the reaction of —RG¹ with RG²-G¹ forms -G;

deprotecting

to yield

and

reacting the

with a pre-R³⁸ group to provide the moiety R³⁸-D- to yield a compound having Formula (F).

In an example of this embodiment of the process and intermediates for preparing a compound having Formula (F), deprotecting

forms the aldehyde

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), D is aryl or heteroaryl, each of which is optionally substituted.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), D is phenyl or pyridinyl, each of which is optionally substituted.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), M is selected from the group consisting of

wherein * represents the point of attachment to group D and † represents the point of group Z.

In another example of the embodiment of the process and intermediates for preparing compounds having Formula (F), M is

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), Z is O.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), Ar is phenyl, optionally substituted with 0 to 4 R².

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is a group B-L-T.

In another example of this embodiment of the process and intermediates for preparing a compound having Formula (F), G is a group

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

wherein

any methylene group is independently optionally substituted with R²⁵, wherein

R²⁵ is selected from the group consisting of halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³, R⁴, —S(O)_0-2R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, and an optionally substituted (C₁-C₆)alkyl, or

two R²⁵, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic, or two R²⁵, on a single carbon can be oxo;

R⁹ is selected from the group consisting of a C_1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R²⁴, -T¹-R¹⁵, or a —NR¹⁶R¹⁷, a —N(R¹⁸)(R¹⁹) moiety and a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring wherein, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein

T¹ is selected from the group consisting of —O—, —S— and —NH—;

R²⁴ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;

R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent a C_1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; wherein the three- to eight-membered carbocyclic or heterocyclic group represented by R²⁴, R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, a cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring; and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and wherein the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; and

R¹⁸ and R¹⁹, which may be the same or different, represent (1) a hydrogen atom, (2) a C_1-6 alkyl which is optionally substituted by a C_1-6 alkoxy, a C_1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or (3) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C_1-6 alkyl, a C_1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C_1-6 alkoxy carbonyl, cyano, a cyano C_1-6 alkyl, a C_1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and in which, when the three to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;

X³ and X⁴ are each independently selected from the group consisting of —H, halogen, cyano, nitro, C₁-C₆ alkyl, or

X³ and X⁴ together with the atom to which they are attached form a C₃-C₄ cycloalkyl;

each E³ is independently selected from the group consisting of —O—, —N(R¹³)—, —CH₂— and —S(O)_0-2;

J² is selected from the group consisting of —O—, —N(R¹³)—, —CH₂— and —C(═O)N(R¹³);

J³ represents —C(R²⁶)(R²⁷)—, wherein

R²⁶ and R²⁷ are independently selected from the group consisting of a hydrogen atom, a C_1-4 alkyl, a C_1-4 alkoxy and —N(R^12b), wherein

R^12b is a hydrogen atom or a C_1-4 alkyl;

each V is independently selected from the group consisting of ═N— and ═C(H)—;

R²¹ and R²³ are independently selected from the group consisting of H, halogen, —OH, unsubstituted —O—(C₁-C₆alkyl), substituted —O—(C₁-C₆alkyl), unsubstituted —O-(cycloalkyl), substituted —O-(cycloalkyl), unsubstituted —NH(C₁-C₆alkyl), substituted —NH(C₁-C₆alkyl), —NH₂, —SH, unsubstituted —S—(C₁-C₆alkyl), substituted —S—(C₁-C₆alkyl), unsubstituted C₁-C₆alkyl and substituted C₁-C₆alkyl; or

R²¹ and R²³ taken together with the atom to which they are attached form a C₃-C₇ ring system, wherein said ring system is optionally substituted;

d is 0, 1, 2 or 3;

e is 0, 1, 2 or 3; and

f is 0 or 1.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

wherein each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R²⁵;

R^5a is —H or an optionally substituted (C₁-C₆)alkyl;

R¹⁰ is an azolyl, wherein one or more hydrogen atoms are optionally substituted by a moiety selected from the group consisting of a halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, trihalomethyl, nitro, amino optionally independently substituted by one or two of C_1-4 alkyl, a C_1-4 alkoxycarbonyl C_1-4 alkyl, a C_1-4 alkylcarbonyl and a C_3-5 cyclic alkyl.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), G is selected from the group consisting of

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), R³⁸ is —(CH₂)_nNH(CH₂)_mA⁴R³⁷ or —(CH₂)_nNR³⁶R³⁹.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (F), RG¹, RG²-G¹ and G are selected from the following combinations:

RG1	RG2—G1	G
—NH2
—NH2
—NH2
—NH2
—NH2
—NH2
—NH2
—NH2
—NH2

In another embodiment the present invention provides a process and intermediates for preparing a compound having Formula (D-1):

the process comprising

providing an intermediate compound R³⁸-D-LG¹, wherein R³⁸ comprises zero or more protected reactive moities therein, and LG^A is a leaving group; and

reacting said intermediate compound R³⁸-D-LG¹ or protected intermediate group R³⁸-D-LG¹ with

wherein LG² is a leaving group, * represents the point of attachment of group R³⁸-D-, and † represents the point of attachment of group Z.

In an example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), D is optionally substituted -(aryl), optionally substituted -(heterocyclyl) or optionally substituted -(heteroaryl), for example optionally substituted phenyl or optionally substituted pryidinyl (for example optionally substituted pyridinyl).

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), M is

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R⁷, —C(O)—O—R^z, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z) (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl).

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), D is phenyl or pryidinyl (for example pyridinyl), R³⁸ is C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)_nNR³⁶R³⁹ wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —C(O)—R^z, —C(O)—O—R^z, —SO₂—C₁-C₆alkyl (alternatively H or C₁-C₆alkyl, alternatively H), and a protecting group used to protect secondary amino groups (for example tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z or —C(O)O—R^z), (alternatively R³⁹ is H or C₁-C₆alkyl, alternatively H), and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_nCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nOR³⁷, alternatively —(CH₂)_nOR³⁷, wherein each n is an independently selected integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl, alternatively C₁-C₆alkyl, alternatively C₁-C₂alkyl) and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocycle).

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), R³⁹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, —OMe, —C(O)—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, and a protecting group used to protect secondary amino groups.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (D-1), R³⁹ is a protecting group used to protect secondary amino groups, wherein said protecting group is selected from the group consisting of tert-butoxycarbonyl (Boc), benzylocycarbonyl (Cbz), F-Moc, —CH₂Ph, —COCF₃, —C(O)—R^z and —C(O)O—R^z.

In another embodiment the present invention provides a process and intermediates for preparing a compound having the Formula (E-2):

wherein

R^k is selected from the group consisting of H, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkenyl and C₂-C₄ alkynyl;

each R^f is independently —O—C₁-C₇alkyl, or both R^f taken together with the atom to which there are attached may form a cyclic acetal (a 5 to 8 member ring system), or a carbonyl group;

LG² is a leaving group; and

D and M are as defined above,

the process comprising

reacting an intermediate compound of Formula (E-1):

wherein

LG¹ is a leaving group,

with

wherein, * represents the point of attachment of group R³⁸-D-, and † represents the point of attachment of group Z.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (E-2), D is -(aryl), -(heterocyclyl) or -(heteroaryl), each of which is optionally substituted.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (E-2), M is

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (E-2), LG¹ and LG² are independently selected from the group consisting of halo, alkoxy, triflate, mesylate, tosylate, acetate, trifluoroacetate, SO₂Me, nosylate and p-nitrophenolate and the like.

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (E-2), D is phenyl or pryidinyl (for example pyridinyl).

In another example of the embodiment of the process and intermediates for preparing a compound having Formula (E-2), R³⁹ is selected from the group consisting of

In another embodiment of the present invention, compounds having a Formula as described herein are provided.

In accordance with the present invention, compounds having a Formula (A), (A-1), (A-2), (A-3), (D), (D-1), (D-2), (D-3), (D-4), (D-5), (D-6), (D-7), (E), (E-1) or (E-2) are provided.

In accordance with the present invention, compounds prepared according to a process as described herein are provided.

Certain compounds of above formulas may generally be prepared according to the following Schemes. Tautomers and solvates (e.g., hydrates) of the compounds of above formulas are also within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds of the present invention may be in the free, hydrate or salt form, and may be obtained by methods exemplified by the following schemes below.

In certain embodiments of the processes provided for preparing compounds having a formula as described herein, steps involved in the processes optionally do not include chromatography, such as column chromatograph.

The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.

Examples of compounds according to the invention include those described in the examples below. Compounds were named using Chemdraw Ultra version 10.0 or version 8.0.3, which are available through Cambridgesoft.com, 100 Cambridge Park Drive, Cambridge, Mass. 02140, or were derived therefrom.

Synthetic Schemes and Experimental Procedures

wherein

each R² is independently selected from the group consisting of halo, cyano, CF₃, C₁-C₄alkyl, C₂-C₄alkynyl and C₃-C₆cycloalkyl, C₁-C₄alkoxy, C₃-C₆cycloalkoxy;

each R²⁸ is independently selected from R²⁰, R^14a, R^15a, R^16a and R^17a (alternatively halo, cyano, CF₃, C₁-C₄alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl and C₃-C₆cycloalkyl)

R³⁸ is for example C₁-C₆alkyl, —(CH₂)_jNR³⁹(CH₂)_nR³⁶ or —(CH₂)₆NR³⁶R³⁹, wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4, alternatively still, 2), R³⁹ is selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, —NHMe, NEt₂, —SO₂—C₁-C₆alkyl, tert-butoxycarbonyl (Boc), F-Moc, benzylocycarbonyl (Cbz), —COCF₃, —CH₂Ph, —C(O)—R⁷, —C(O)O—R^z or other protecting groups used to protect secondary amino groups (examples of such protective groups could be found e.g. in “Protective Groups in Organic Synthesis” T. W. Greene, Wiley, N.Y.). Alternatively R³⁹ is selected from H, C₁-C₆alkyl, —C(O)—R^z and —C(O)—O—R^z, alternatively H, and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, —(CH₂)_nO(CH₂)_iOR³⁷, —(CH₂)_iCN(CH₂)_nOR³⁷, —(CH₂)_nCN(CH₂)_nR³⁷, and —(CH₂)_nA⁴R³⁷, (alternatively —(CFE)_nA⁴R³⁷), wherein n is an integer ranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0), i is an integer ranging from 2 to 6, R³⁷ is H, C₁-C₆alkyl or C₃-C₁₀cycloalkyl (alternatively H or C₁-C₆alkyl and C₃-C₆cycloalkyl), A⁴ is O, S, SO, SO₂, NH or N(optionally substituted C₁-C₄alkyl) (alternatively O, S or N(C₁-C₄alkyl)), and R^z is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆heterocyclyl and aryl (for example benzyl and C₅-C₆heterocyclyl); provided that if R³⁹ is H then no deprotection is required.

In an example, R³⁹ is a cyclic moiety selected from the structures below:

Compounds of the first embodiment (exemplified in the scheme A as chemical entities II, III and IV) prepared from the Boc-protected anilino derivatives I in two steps according to the scheme A. Thus, compounds I reacting with a substituted 2-arylacetyl isothiocyanates (a1) in a variety of solvents such as THF, acetone, toluene, DCM, CHCl₃, MeCN, DMF, DMSO, alcohols (MeOH, EtOH, iso-PrOH etc.) (for example in THF), or in a mixtures of the listed solvents (e.g. toluene -EtOH, THF-acetone, IPA-MeCN) (for example in toluene-EtOH or in IPA-MeCN) in the temperature range from −10° to +120° C. (for example 15-100° C.), followed by deprotection of the Boc-protecting group in the intermediate V, are converted into the kinase inhibitors II [WO 2006/019264 A1, U.S. 2006/0287343 A1].

Boc-Deprotection is carried out in acidic media such as TFA, AcOH, TFA/DCM, HCl/DCM, HCl/dioxane, AcOH/HCl, AcOH/HCl/H₂O and the like (for example in TFA, HCl/dioxane, AcOH/HCl or AcOH/HCl/H₂O).

Same compounds I reacting either with substituted 1-(phenylcarbamoyl)cyclopropane-carboxylic acids (a2) or with substituted 3-oxo-3-(phenylamino)propanoic acids (a3), followed by deprotection of the Boc-protecting groups of the intermediates VI and VII, are converted into the kinase inhibitors III and IV [U.S. 2007/0004675 A1]. The reactions proceed in aprotic solvents such as DMF, THF, DMSO, pyridine (etc.) (for example in DMF), at ambient temperatures in the presence of amide coupling reagents known in the art (EDC, HATU, HBTU, BOP, DCC, DIC, CIP, PyBOP, HNTU, AOP, PPAA, PFTU, etc.) (for example EDC and HATU) and tertiary amines (e.g. Et₃N, DIPEA, N-methylmorpholine, N-methylpiperidine, DMAP, N,N-dimethylaniline, N,N-diethylaniline, DBU, DABCO, etc.) (for example DIPEA). Boc-Deprotection is carried out in the same way as in the case of compounds II—in acidic media such as TFA, AcOH, TFA/DCM, HCl/DCM, HCl/dioxane, AcOH/HCl, AcOH/HCl/H₂O and the like

To an ordinary person skilled in the art it should be understood that compounds III and IV may be prepared by a slightly different way from the compounds I using malonate derivatives such as aa2, aa3, aa4, and aa5, and anilines b as synthetic building blocks. It should also be understood that the alternative syntheses would involve hydrolysis of the alkyl ester functionalities as well as the Boc-deprotection steps.

Protected anilino derivatives I prepared according to the general Scheme B. A variety of aromatic or heteroaromatic aldehydes VIII undergo reductive amination by reacting with primary amines a4. The procedure is carried out under standard conditions (Abdel-Magid A. F. et al, J. Org. Chem., 1996, 61, 3849-3862), at temperatures between −20 and +60° C. in the presence of borohydride agents such as NaBH(OAc)₃, NaBH₃CN, NaBH₄, in solvents such as DCE, DCM, AcOH or THF (or mixtures thereof). The reductive amination products IX are then protected by a variety of protecting groups known in the art (e.g.“Protective Groups in Organic Synthesis” T. W. Greene, Wiley, N.Y.); to form compounds X. Examples of protecting groups include but are not limited to acetyl-, trifluoroacetyl-, benzoyl-, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, etc.

Attaching the building blocks X to the thienopyridine scaffold is achieved under Negishi reaction conditions (Scott R. W., et al, Org. process Research & Development, 2006, 10, 296-303; Ragan J. A., et al, Org. process Research & Development, 2003, 7, 676-683). Thus, metallation of 7-chlorothieno[3,2-b]pyridine (XI) (Klemm, L. H. et al. J. Heterocyclic Chem., 22, 1985, 1249-1252) using reagents such as n-BuLi, sec-BuLi LDA and like in the temperature range from −78° C. to 15° C., for example from −15 to −5° C., followed by transmetallation with zinc chloride with a subsequent coupling to compounds X in the presence of a transition metal catalyst in the temperature range from 25 to 150° C., for example from 60 to 90° C. to form chlorides XII. The reactions are performed in aprotic solvents such as ether, THF, dioxane, benzene, toluene, xylenes, hexane, heptane. Alternative coupling reactions include but are not limited to Suzuki and Stille reactions. In these cases 7-chloro-2-iodothieno[3,2-b]pyridine (XIV, scheme C) (or its bromo-analogue 7-chloro-2-bromothieno[3,2-b]pyridine) could be used.

Compounds XII lead to the compounds I either directly by replacing the chlorine atom in XII by 4-amino-2-fluorophenol at elevated temperatures from 60 to 200° C., for example from 80 to 120° C.) in solvents such as DMF, DMA, DMSO, diphenyl ether, mono- and dichlorobenzenes, xylenes, etc. in the presence of bases such as NaH, NaHCO₃, NaHMDS, KH, K₂CO₃, tert-BuOK, etc., or via the intermediate nitro compounds XIII. Nitro compounds XIII are obtained, for example, by replacing the chlorine atom in XII with 2-fluoro-4-nitrophenol. The reaction proceeds at elevated temperatures (100-200° C.) in solvents such as DMF, DMA, DMSO, diphenyl ether, etc., in the presence of bases such as KH, K₂CO₃, NaH, Na₂CO₃, NaHCO₃, tert-BuOK, etc. Reduction of the nitro group in XIII is achieved using standard procedures known in art. Examples of such procedures include but are not limited to catalytic hydrogenation, iron-ammonium chloride, zinc-ammonium chloride, nickel chloride-sodium borohydride, etc. in organic solvents (alcohols, AcOEt, DMA, DMF) or aqueous solutions or mixtures MeOH/water, EtOH/water or like.

An alternative way of preparing nitro compounds XIII is shown in the Scheme C. Thus, 7-chloro-2-iodothieno[3,2-b]pyridine (XIV) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) is reacted with 2-fluoro-4-nitrophenol (120-200° C.) in solvents such as DMF, DMA, DMSO, diphenyl ether, etc. in the presence of bases such as KH, K₂CO₃, NaH, Na₂CO₃, NaHCO₃, tert-BuOK, etc., to form 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (XV). This material undergoes Stille coupling reaction (e.g. Zhang N., et al; J. Org. Chem., 2001, 66, 1500-1502 or references therein) with a variety of aldehydes VIII, to form the nitro aldehydes XVI. The nitro aldehydes XVI undergo reductive amination by reacting with primary amines a4, to form the reductive amination products XVII. The procedure is carried out under standard conditions (Abdel-Magid A. F. et al, J. Org. Chem., 1996, 61, 3849-3862), at temperatures between −20 and +60° C. in the presence of borohydride agents such as NaBH(OAc)₃, NaBH₃CN, NaBH₄, in solvents such as DCE, DCM, AcOH or THF (or mixtures thereof). The reductive amination products XVII are then protected by a variety of protecting groups known in the art (e.g.“Protective Groups in Organic Synthesis” T. W. Greene, Wiley, N.Y.) to form compounds XIII. Protecting groups include but are not limited to acetyl-, trifluoroacetyl-, benzoyl-, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), etc.

Heterocyclic kinase inhibitors II [WO 2006/019264 A1, U.S. 2006/0287343 A1] can also be prepared from the anilino-compounds XVIII via a three-step reaction sequence shown in the scheme D.

Thus, compounds XVIII reacting with substituted 2-arylacetyl isothiocyanates (a1) in a variety of solvents such as THF, acetone, toluene, DCM, CHCl₃, MeCN, DMF, DMSO, alcohols (MeOH, EtOH, iso-PrOH etc.) (for example in THF), or in the mixtures of the listed solvents (e.g. toluene-EtOH, THF-acetone, IPA-MeCN) (for example in toluene-EtOH of in IPA-MeCN) in the temperature range from −10° to +120° C. are converted into the compounds XIX. Deprotection of the protected carbonyl group in XIX yields compounds XX; it is for example carried out in aqueous acidic media such as AcOH/water, TFA/water, TFA/acetone/water, HCl/acetone/water, HCl/THF/water HCl/dioxane/water and like. Compounds XX undergo reductive amination by reacting with primary amines a4. The procedure is carried out under standard conditions (Abdel-Magid A. F. et al, J. Org. Chem., 1996, 61, 3849-3862), at temperatures between −20 and +60° C. in the presence of borohydride agents such as NaBH(OAc)₃, NaBH₃CN, NaBH₄, in solvents such as DCE, DCM, AcOH or THF (or mixtures thereof).

Similarly to the heterocyclic kinase inhibitors II the kinase inhibitors III and IV [U.S. 2007/0004675 A1] can be prepared from the anilino-compounds XVIII. These transformations are shown in the schemes E and F. Thus, anilines XVIII reacting either with a variety of substituted 1-(arylcarbamoyl)cyclopropanecarboxylic acids (a2, scheme E) or with a variety of substituted 3-oxo-3-(arylamino)propanoic acids (a3 scheme F) form compounds XXI and XXIII, respectively.

The reactions for example proceed in aprotic solvents such as DMF, THF, DMSO, pyridine (etc.) at ambient temperatures in the presence of amide coupling reagents known in the art (EDC, HATU, HBTU, BOP, DCC, DIC, CIP, PyBOP, HNTU, AOP, PPAA, PFTU, etc.) and tertiary amines (e.g. Et₃N, DIPEA, N-methylmorpholine, N-methylpiperidine, DMAP, N,N-dimethylaniline, N,N-diethylaniline, etc.). Deprotection of the protected carbonyl groups in XXI and XXIII yields compounds XXII (scheme E) and XXIV (scheme F). Similarly to the deprotection of XIX (scheme D) it is for example carried out in aqueous acidic media: AcOH/water, TFA/water, TFA/acetone/water, HCl/acetone/water, HCl/THF/water HCl/dioxane/water and like.

Compounds XXII (scheme E) and XXIV (scheme F) undergo reductive amination by reacting with primary amines a4. The procedure is carried out under standard conditions (Abdel-Magid A. F. et al., J. Org. Chem., 1996, 61, 3849-3862), at temperatures between −20 and +60° C. in the presence of borohydride agents such as NaBH(OAc)₃, NaBH₃CN, NaBH₄, in solvents such as DCE, DCM, AcOH or THF (or mixtures thereof).

To an ordinary person skilled in the art it should be understood that compounds III and IV may also be prepared from the compounds XVIII using malonate derivatives such as aa2, aa3, aa4, and aa5, and anilines b as synthetic building blocks. It should also be understood that the alternative syntheses would involve hydrolysis of the alkyl ester functionalities and acetal protecting groups.

Protected anilino derivatives XVIII can be prepared according to the general scheme G. A variety of aromatic or heteroaromatic aldehydes VIII undergo reactions with alcohols to form protected species XXV (e.g.“Protective Groups in Organic Synthesis” T. W. Greene, Wiley, N.Y.). The reactions are carried out under anhydrous conditions in solvents such as toluene, benzene, CHCl₃ at reflux in the presence of acids such as PTSA, CSA and like. Amberlyst or Dowex 50 can be used for such a purpose as well. Azeotropic removal of water facilitates the reactions.

Attaching the building blocks XXV to the thienopyridine scaffold is achieved under Negishi reaction conditions (Scott R. W., et al, Org. process Research & Development, 2006, 10, 296-303; Ragan 3.A., et al, Org. process Research & Development, 2003, 7, 676-683). Thus, metallation of 7-chlorothieno[3,2-b]pyridine (XI) (Klemm, L. H. et al. J. Heterocyclic Chem., 22, 1985, 1249-1252)) using reagents such as n-BuLi, sec-BuLi, LDA and like in the temperature range from −78° C. to 15° C., followed by transmetallation with zinc chloride with a subsequent coupling to compounds XXV in the presence of a transition metal catalyst in the temperature range from 25 to 150° C. (for example 60 to 90° C.)., to form chlorides XXVI. The reactions are performed in aprotic solvents such as ether, THE, dioxane, benzene, toluene, xylenes, hexane, heptane. Alternative coupling reactions include Suzuki and Stille reactions. In these cases 7-chloro-2-iodothieno[3,2-b]pyridine (XIV, Scheme C) (or its bromo-analogue 7-chloro-2-bromothieno[3,2-b]pyridine) can be used.

Compounds XXVI can lead to the compounds XVIII either directly by replacing the chlorine atom in XXVI by 4-amino-2-fluorophenol at elevated temperatures (90-180° C.) (for example 80 to 110° C.) in solvents such as DMF, DMA, DMSO, diphenyl ether, etc. in the presence of bases such as KH, K₂CO₃, NaH, Na₂CO₃, NaHCO₃, NaHMDS, tert-BuOK, etc., or via the intermediate nitro compounds XXVII. Nitro compounds XXVII can be obtained by replacing the chlorine atom in XXVI with 2-fluoro-4-nitrophenol. The reaction proceeds at elevated temperatures (120-200° C.) in solvents such as DMF, DMA, DMSO, diphenyl ether, etc. in the presence of bases such as KH, K₂CO₃, NaH, Na₂CO₃, NaHCO₃, tert-BuOK etc. Reduction of the nitro group in XVIII can be achieved using standard procedures known in art. Examples of such procedures include iron-ammonium chloride, zinc-ammonium chloride, nickel chloride-sodium hydride, etc. in aqueous solutions or mixtures MeOH/water, EtOH/water or like, as well as the catalytic hydrogenation.

INTERMEDIATES AND EXAMPLES

2-(4-Fluorophenyl)acetyl isothiocyanate (2)

Method A (For the Method B see Scheme 20)

To a solution of 4-fluorophenylacetic acid (1) (25 g, 162 mmol) in DCM (75 mL) was added oxalyl chloride (28.4 mL. 324 mmol) and 3-4 drops of DMF. The mixture was stirred at r.t. for 1 h-2 h and concentrated to produce 2-(4-fluorophenyl)acetyl chloride (1a) (yellow oil) that was re-dissolved in toluene (100 mL). To this solution was added lead(II) thiocyanate (55.0 g, 170 mmol). The mixture was heated to reflux for 1.5 h-2 h, cooled down, filtered and the filtrate was concentrated. The residue was applied onto a silica gel pad (20 cm) and eluted with EtOAc/hexanes (1/9), to afford after evaporation of the solvents title compound 2 (31 g, 98% yield) as a yellow oil. MS (m/z): 228.1 (M+H+MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.26-7.22 (m, 2H), 7.09-7.07 (m, 2H), 3.84 (s, 2H).

4-Amino-2-fluorophenol (4)

To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10%) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3 h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et₂O (50 mL) to afford compound 4 (11.264 g, 87% yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.57 (s, 1H), 6.62 (dd, J=10.0, 8.4 Hz, 1H), 6.34 (dd, J=13.4, 2.6 Hz, 1H), 6.20 (ddd, J=8.6, 2.6, 1.2 Hz, 1H), 4.67 (s, 2H).

7-Chlorothieno[3,2-b]pyridine (6)

To neat POCl₃ (200 mL, 2146 mmol) at 60° C. in a 500 mL round-bottom flask was added thieno[3,2-b]pyridin-7-ol (1 eq., 200 g, 1323 mmol) in small portions over 1.5 h. The reaction mixture was heated at 60° C. for 1 h and at 100° C. for an additional hour. After cooling down to 0° C., the reaction mixture was poured onto crushed ice (1 L) over a period of 30 min. After 15 min, NH₄OH (1.5 L) was added to the mixture to form a grey precipitate that was collected by filtration, washed with water (50 mL) and air dried. The dry solid was suspended in EtOAc (1 L). The slurry was stirred at r.t. for 15 min, filtered and the filter was washed with EA (2×100 mL). The organic phase was collected, dried over MgSO₄ and concentrated. The residue was passed through a short silica gel pad (300 g, eluent—a gradient hexane/EtOAc, 8/2 to 5/5) and dried in the vacuum oven (35° C.) for 2 h to afford 6 as a off-white solid (214.8 g, 1266 mmol, 96% yield). MS (m/z): 170.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.64 (d, J=5.1 Hz, 1H) 8.25 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.5 Hz, 1H), 7.54 (d, J=5.1 Hz, 1H).

N-((6-Bromopyridin-3-yl)methyl)-2-methoxyethanamine (9)

To a solution of 6-bromonicotinaldehyde (7) (5 g, 26.9 mmol) in DCM (40 mL) was added 2-methoxyethylamine (8) (2.80 mL, 32.3 mmol). After 10 min, sodium triacetoxyborohydride (7.98 g, 37.6 mmol) was added to the mixture and the mixture was stirred at r.t. for 17 h Additional amounts of DCM (100 mL), water (50 mL) and NH₄Cl (50 mL) were added to the reaction mixture, which turned into a biphasic system. The organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solution were washed with brine, dried over anhydrous MgSO₄ and concentrated under reduce pressure. The residue was purified by flash column chromatography (eluent a gradient DCM/MeOH from 98/2 to 95/5), to afford intermediate 9 (2.958 g, 45% yield) as a brown oil. MS (m/z): 245.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.31 (dd, J=2.6, 0.6 Hz, 1H), 7.70 (dd, J=8.2, 2.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 3.69 (s, 2H), 3.37 (t, J=5.8 Hz, 2H), 3.22 (s, 3H), 2.60 (t, J=5.8 Hz, 2H).

tert-Butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl) carbamate (10)

To a solution of intermediate 9 (13.072 g, 53.3 mmol) in THF (40 mL) was added di-tert-butyl dicarbonate (14.86 mL, 64.0 mmol). The mixture was stirred at r.t. for 16 h and concentrated under reduce pressure. The residue was purified by flash column chromatography (eluent a gradient of hexane/EtOAc:7/3, 6/4, 5/5), to intermediate 10 (16.196 g, 88% yield) as a yellow oil. MS (m/z): 345.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.26 (dd, J=2.4, 0.8 Hz, 1H), 7.64-7.58 (m, 2H), 4.39 (s, 2H), 3.40-3.33 (m, 4H), 3.20 (s, 3H), 1.41-1.31 (m, 9H).

tert-Butyl (6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11)

To a solution of 7-chlorothieno[3,2-b]pyridine (6) (8.84 g, 52.1 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was allowed to warm to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and tert-butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl) carbamate (10) (6 g, 17.38 mmol) in THF (25.00 mL) were added and the mixture was heated to reflux for 1 h and cooled to room temperature. To the cooled reaction mixture were added NaHCO₃ (sat. aq.) (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic solutions were washed with brine, dried over anhydrous Na₂SO₄ and evaporated under reduce pressure. The residue was purified by flash column chromatography (eluent hexane/EtOAc:5/5, 3/7, 0/100), to afford intermediate 11 (5.41 g, 72% yield). MS (m/z): 434.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H).

tert-Butyl (6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (12)

Method A (For the Method B see Scheme 7)

To a suspension of intermediate 11 (2 g, 4.61 mmol) in phenyl ether (5 mL) were added potassium carbonate (0.764 g, 5.53 mmol) and 2-fluoro-4-nitrophenol (3) (1.448 g, 9.22 mmol). The mixture was heated at 160° C. for 5 h, cooled to room temperature and partitioned between water and EtOAc. The organic phase was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic solutions were washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduce pressure and suspended in THF (20.00 mL). Di-tert-butyl dicarbonate (1.070 mL, 4.61 mmol) was added to this suspension and the mixture was stirred at r.t. for 30 min, and concentrated. The residue was purified by flash column chromatography (eluent hexane/EtOAc:5/5, 3/7, 0/100), to afford intermediate 12 (1.695 g, 66% yield) as a yellow gum. MS (m/z): 555.3 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.61 (d, J=5.2 Hz, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.46 (dd, J=10.4, 2.8 Hz, 1H), 8.37 (s, 1H), 8.26 (d, J=7.6 Hz, 1H), 8.20 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 7.79 (dd, J=8.4, 2.0 Hz, 1H), 7.70 (t, J=8.6 Hz, 1H), 6.96 (d, J=5.6 Hz, 1H), 4.47 (s, 2H), 3.43-3.33 (m, 4H), 3.22 (s, 3H), 1.42-1.33 (m, 9H).

tert-Butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (13)

Method A

To a suspension of intermediate 12 (5.853 g, 10.55 mmol) in EtOH (50 mL) and water (25 mL) were added ammonium chloride (0.480 g, 8.97 mmol) and iron powder (3 mL, 90 mmol). The mixture was heated to reflux for 1 h and filtered while hot. The filtrate was collected and concentrated to afford intermediate 13 (6.04 g, quantitative yield) as a yellow solid. MS (m/z): 525.3 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.51 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.13 (t, J=9.2 Hz, 1H), 6.60 (dd, J=5.4, 0.6 Hz, 1H), 6.64 (dd, J=13.0, 2.6 Hz, 1H), 6.46 (ddd, J=8.8, 2.5, 0.7 Hz, 1H), 5.56 (s, 2H), 4.48 (s, 2H), 3.43-3.34 (m, 4H), 3.23 (s, 3H), 1.44-1.34 (m, 9H).

Method B

To a solution of 4-amino-2-fluorophenol (4) (1.933 g, 15.21 mmol) in DMSO (30 mL) was added potassium tert-butoxide (2.017 g, 17.97 mmol). After 30 min, intermediate 11 (6 g, 13.83 mmol) was added and the reaction mixture was heated at 100° C. for 45 min. The reaction mixture was then cooled down, poured in water (250 mL) at 40-45° C. and the resultant suspension was stirred for 30 min. The precipitate was collected by filtration, washed with water (2×30 mL) and dried overnight. The dry solid was triturated with Et₂O (50 mL), to afford intermediate 13 (4.18 g, 58% yield) as a brown solid. MS (m/z): 525.2 (M+H).

Example 1

(Version A)

tert-Butyl (6-(7-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (14)

To a suspension of intermediate 13 (5.53 g, 10.55 mmol) in toluene (80 mL) and EtOH (80 mL) was added 2-(4-fluorophenyl)acetyl isothiocyanate (2) (3.09 g, 15.83 mmol) in a minimum of toluene-EtOH mixture (1:1). The reaction mixture was stirred at r.t. for 45 min then concentrated. The residue was purified by flash column chromatography (eluent EtOAc), followed by two triturations: first one in a mixture Et₂O-EtOAc-hexanes and second one in Et₂O, to afford intermediate 14 (4.68 g, 62% yield) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 11.84 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.04 (d, J=11.6 Hz, 1H), 7.79 (dd, J=8.2, 2.2 Hz, 1H), 7.55-7.54 (m, 2H), 7.38 (dd, J=8.6, 5.8 Hz, 2H), 7.18 (t, J=8.8 Hz, 2H), 6.69 (d, J=5.6 Hz, 1H), 4.48 (s, 2H), 3.84 (s, 2H), 3.43-3.34 (m, 4H), 3.23 (s, 3H), 1.44-1.34 (m, 9H). MS (m/z): 720.3 (M+H).

N-(3-Fluoro-4-(2-(5-((2-methoxyethoxy)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (15, Example 1))

To a solution of intermediate 14 (8.41 g, 11.68 mmol) in DCM (100 mL) was added HCl in dioxane (5.84 mL, 23.37 mmol) (4M HCl in dioxane). After 10 min, a precipitate was formed and more HCl in dioxane (5.84 mL, 23.37 mmol) was added. The reaction mixture was stirred at r.t. for an additional 1 h, diluted with a mixture of 5% MeOH in DCM and neutralized to pH=7 with aqueous NaHCO₃. The layers were separated, the organic phase was collected and the aqueous layer was extracted with another portion of the mixture of 5% MeOH in DCM. The combined organic solutions were washed with brine, dried over anhydrous Na₂SO₄ and evaporated. The residue was triturated with MeOH, to afford compound 15 (4.96 g, 58% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.56(d, J=1.2 Hz, 1H), 8.53(d, J=5.2 Hz, 1H), 8.32(s, 1H), 8.22(d, J=8.0 Hz, 1H), 8.04(dd, J=2.0 and 11.2 Hz, 1H), 7.89(dd, J=2.0 and 8.0 Hz, 1H), 7.58-7.50(m, 2H), 7.42-7.35(m, 2H), 7.23-7.15(m, 2H), 6.67(d, J=5.2 Hz, 1H), 3.83(s, 2H), 3.77(s, 2H), 3.40(t, J=6.0 H1z, 2H), 3.23(s, 3H), 2.65(t, J=6.0 Hz, 2H). MS (m/z): 620.1 (M+H).

Example 2

tert-Butyl (6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno [3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (17)

To intermediate 13 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF (20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (16) [U.S. 2007/0004675 A1] (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol). The mixture was stirred at r.t. for 18 h and partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, brine, dried (anhydrous MgSO₄), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded intermediate 17 (0.60 g, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J=8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.65 (d, J=5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).

N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (18, Example 2)

To the intermediate 17 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h, then concentrated. The residue was partitioned between dichloromethane and 1M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with 1M NaOH, brine, dried (MgSO₄), filtered, and concentrated to afford compound 18 (0.35 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H). 10.01 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J=5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).

Example 3

tert-Butyl (6-(7-(4-amino-3-fluorophenoxy)thieno[3,2-]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (20)

To a solution of 4-amino-3-fluorophenol (19) in DMSO (12 mL) was added potassium tert-butoxide (0.824 g, 7.34 mmol). After 30 min, intermediate 11 (2.451 g, 5.65 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h, cooled to room temperature, poured in water (50 mL) at 40-45° C. and stirred for 30 min. EtOAc (40 mL), DCM (40 mL) and water (40 ml) were added and the pH was adjusted to 7 by addition of HCl. Solids were removed by filtration through a paper filter and the two phases were separated. The organic layer was collected, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (eluent DCM/MeOH:99/1, 98/2, 95/5), to afford intermediate 20 (0.952 g, 32% yield). MS (m/z): 525.2 (M+H).

tert-Butyl (6-(7-(3-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido) phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (21)

Following the procedure described above for the synthesis of compound 14 (scheme 4) but substituting compound 13 for compound 20 intermediate 21 was obtained (55% yield) MS (m/z): 720.3 (M+H).

N-(2-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (22, Example 3)

HCl gas was bubbled into a solution of the intermediate 21 (150 mg, 0.209 mmol) in DCM (5 ml). The flask was capped and the mixture was stirred at r.t. for 2 hours, concentrated and the resultant yellow solid was triturated with Et₂O to afford compound 22 (126 mg, 98% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 11.94 (s, 1H), 9.50 (s, 1H), 8.78 (s, 1H), 8.47 (d, J=1.0 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.12 (t, J=8.7 Hz, 1H), 7.53 (dd, J=11.9, 2.3 Hz, 1H), 7.38 (dd, J=8.5, 5.6 Hz, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (t, J=8.8 Hz, 2H), 6.95 (dd, J=5.7, 2.3 Hz, 1H), 4.26-4.24 (m, 2H), 3.84 (s, 2H), 3.64 (t, J=5.1 Hz, 2H), 3.30 (s, 3H), 3.13 (m, 2H) (presumably tri-hydrochloride salt). MS (m/z): 620.1 (M+H).

7-(2-Fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24)

A mixture of the 7-chloro-2-iodothieno[3,2-b]pyridine (23) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), 2-fluoro-4-nitrophenol (3) (11.15 g, 71.1 mmol), K₂CO₃ (13.08 g, 94.8 mmol) in Ph₂O (30 ml) was heated at 200° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with DCM and filtered; the filtrate was collected and then concentrated. The resultant solid was triturated with diethyl ether, to afford intermediate 24 (7.3 g, 74% yield), which was used directly in the next step with no additional purification. MS (m/z): 417.0 (M+H).

6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinaldehyde (25)

To a solution of intermediate 24 (6 g, 14.42 mmol) in dioxane (40 mL) were added 6-bromopyridine-3-carbaldehyde (7) (3.22 g, 17.30 mmol), palladium tetrakistriphenylphosphine (0.500 g, 0.433 mmol), and hexamethyldistannane (3.29 mL, 15.86 mmol). The mixture was heated at 100° C. for 20 h, concentrated, adsorbed on silica gel, placed onto a silica gel column and subjected to flash chromatography purification (eluent DCM/MeOH: 100/0, 99/1, 98/2, 97/3), to afford intermediate 25 (2.864 g, 50% yield). MS (m/z): 396.1 (M+H).

N-((6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-2-methoxyethanamine (26)

To a solution of 25 (2.864 g, 7.24 mmol) in DCM (30 mL) was added 2-methoxyethylamine (8) (0.756 mL, 8.69 mmol). After 45 min, sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. More sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was quenched with saturated aqueous NaHCO₃ and the phases were separated. Organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solutions were concentrated and the residue was purified by flash column chromatography (eluent DCM/MeOH) to afford, intermediate 26 (1.742 g, 53% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.62 (d, J=5.6 Hz, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.48 (dd, J=10.2, 2.6 Hz, 1H), 8.37 (s, 1H), 8.26-8.23 (m, 1H). 8.21 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (dd, J=9.0, 8.2 Hz, 1H), 6.97 (dd, J=5.6, 0.4 Hz, 1H), 3.78 (s, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H). MS (m/z): 455.2 (M+H).

tert-Butyl (6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (12)

Method B

To a suspension of 26 (1.742 g, 3.83 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (1.335 mL, 5.75 mmol). The mixture was stirred at r.t. for 15 h and concentrated under reduce pressure. The residue was purified by flash column chromatography (eluent EtOAc), to afford intermediate 12 (1.657 g, 78% yield) as a yellow pale solid. MS (m/z): 555.3 (M+H).

2-Bromo-5-(1,3-dioxan-2-yl)pyridine (28)

To a solution of 6-bromopyridine-3-carbaldehyde (7) (25 g, 134 mmol) in toluene (130 mL) were added 1,3-propanediol (27) (20.45 g, 269 mmol) and 10-camphorsulfonic acid (3.12 g, 13.44 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 50 minutes, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO₃ solution (100 mL). Organic phase was collected and the aqueous phase was extracted with EtOAc (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated to yield a brown solid which was triturated with Et₂O and hexane (10/200 mL), to afford intermediate 28 (27.7 g, 84% yield) as a beige solid. MS (m/z): 244.1, 246.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.40 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.0, 0.4 Hz, 1H), 5.61 (s, 1H), 4.15 (ddd, J=11.8, 5.0, 1.2 Hz, 2H), 3.98-3.91 (m, 2H), 2.028-1.95 (m, 1H), 1.46 (d quint, J=13.2, 1.2 Hz, 1H).

2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine (29)

To a solution of 7-chlorothieno[3,2-b]pyridine (6) (13.33 g, 79 mmol) in THF (204 mL) at −5° C./−10° C. was added n-BuLi (2.5 M in hexanes, 31.6 mL, 79 mmol) over 50 min. After 30 min, a solution of zinc chloride in ether (1M, 79 mL, 79 mmol) was added at −5° C./−10° C. over 50 min and the reaction mixture was allowed to warm-up to r.t. After 45 min, 2-bromo-5-(1,3-dioxan-2-yl)pyridine (28) (15.98 g, 65.5 mmol) and palladium tetrakistriphenylphosphine (2.27 g, 1.964 mmol) in THF (28 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t., and concentrated. The residue was diluted with DCM (600 mL), H₂O (500 mL) and NH₄OH (100 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL); the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was triturated with MTBE (150 mL), to afford intermediate 29 (12.796 g, 59% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.66-8.65 (m, 2H), 8.43 (d, J=0.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=5.0, 0.6 Hz, 1H), 5.68 (s, 1H), 4.19 (dd, J=11.6, 4.8 Hz, 2H), 3.99 (t, J=11.4 Hz, 2H), 2.07-2.01 (m, 1H), 1.49 (d, J=13.2 Hz, 1H). MS (m/z): 333.1 (M+H).

2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (30)

To a suspension of 29 (22.48 g, 67.5 mmol) in phenyl ether (65 mL) was added sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol (3) (15.92 g, 101 mmol). The reaction mixture was heated at 180° C. for 2 h, cooled down to 40° C., diluted with DCM (300 mL), stirred at r.t. for 15 min and filtered. The filtrate was collected and concentrated to a minimal volume; Et₂O (200 mL) was added and the formed suspension was stirred for 30 min. The solid material was collected by filtration, to afford intermediate 30 (25.20 g, 55.6 mmol, 82% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.63-8.62 (m, 2H), 8.48 (dd, J=10.6, 2.6 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (dt, J=8.8, 1.2 Hz, 1H), 7.94 (dd, 0.1=8.4, 2.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.19 (dd, J=10.8, 5.2 Hz, 2H), 3.98 (td, J=12.0, 2.0 Hz, 2H), 2.08-1.99 (m, 1H), 1.46 (d, J=13.6 Hz, 1H). MS (m/z): 454.2 (M+H).

4-(2-(5-(1,3-dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (31)

Method A

To a suspension of 30 (10 g, 22.05 mmol) in EtOH (216 ml) and water (108 ml) was added iron powder (10.47 g, 187 mmol) and ammonium chloride (1.015 g, 18.97 mmol). The mixture was heated to reflux for 30 min, filtered while hot and the solids were washed with ether (200 mL). The filtrate and washings were combined and concentrated to afford intermediate 31 (9.62 g, 99% yield) as a beige solid. This material was used in the next step (Scheme 9) without additional purification. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.64 (d, J=2.0 Hz, 1H), 8.51 (dd, J=5.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.0, 0.8 Hz, 1H), 7.93 (dd, J=8.4, 2.0 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 6.61 (dd, J=5.4, 0.6 Hz, 1H), 6.54 (dd, J=13.2, 2.4 Hz, 1H), 6.46 (ddd, J=8.8, 2.8, 0.6 Hz, 1H), 5.67 (s, 1H), 5.56 (s, 2H), 4.19 (dd, J=10.6, 5.0 Hz, 2H), 3.98 (td, J=12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1H), 1.49 (dt, J=13.2, 1.3 Hz, 1H). MS (m/z): 424.1 (M+H).

Method B

To a solution of 4-amino-2-fluorophenol (4) (7.42 g, 58.4 mmol) in DMSO (65 mL) was added potassium tert-butoxide (7.75 g, 69.0 mmol)). After 30 min, intermediate 29 (17.67 g, 53.1 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h, cooled down to room temperature, poured in water (300 mL) at 40-45° C. and stirred for 30 min. The solid was collected by filtration, washed with water (2×30 mL) and dried for 2 h. This material was triturated with ether (60 mL), to afford intermediate 31 (19.80 g, 88% yield) as a brown solid. MS (m/z): 424.1 (M+H).

Example 1

Version B

N-(4-(2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (32)

To a solution of 2 (2.69 g, 13.80 mmol) in toluene (16.5 mL) and ethanol (16.5 mL) was added a suspension of 31 (4.87 g, 11.50 mmol) in toluene (41 mL) and ethanol (41 mL). The mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent EtOAc/MeOH, 98/2) to afford intermediate 32 (5.31 g, 8.58 mmol, 74% yield) as a beige solid. MS (m/z): 619.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.2 Hz, H), 8.38 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.02 (dd, J=12.4, 1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.37 (dd, J=8.6, 5.8 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.66 (s, 1H), 4.18 (dd, J=10.6, 5.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.82 (s, 2H), 2.10-1.98 (m, 1H), 1.47 (dd, J=14.0, 1.6 Hz, 1H).

N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (33)

Method A:

To a solution of 80% acetic acid (104 mL AcOH/26 mL water) was added 32 (4.01 g, 6.48 mmol). The reaction mixture was heated at 90° C. overnight, cooled to r.t., to form a precipitate which was collected by filtration to afford intermediate 33 (2.4 g, 66% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.51 (s, 1H), 11.86 (s, 1H), 10.14 (s, 1H), 9.14 (s, 1H), 8.66 (d, J=5.6 Hz, 1H) 8.59 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.07 (d, J=12.8 Hz, 1H), 7.58 (s, 2H), 7.38 (t, J=7.2 Hz, 2H), 7.19 (t, J=8.6 Hz. 2H), 6.83 (d, J=5.6 Hz, 1H), 3.84 (s, 2H). MS (m/z): 560.9 (M+H).

Method B:

To a solution of 2 (5.27 g, 27.0 mmol) in toluene (50.0 mL) and ethanol (50.0 mL) was added a suspension of intermediate 31 (9.52 g, 22.5 mmol) in toluene (20 mL) and ethanol (20 mL) over 30 min. After few minutes, more of isothiocyanate (1 g) in ethanol/toluene (5 mL/5 mL) mixture was added over 1 min. The reaction mixture was stirred at r.t. for an additional 30 min and concentrated under reduced pressure. The residue was triturated with toluene (70 mL), filtered and washed with toluene (20 mL) to afford a beige solid material that was suspended in 80% acetic acid (204 mL) and heated at 90° C. overnight. The reaction mixture was cooled down to r.t., and the precipitate was collected by filtration, washed with 80% AcOH (2×30 mL) to afford compound 33 (8.24 g, 72% yield) as a yellow solid.

N-(3-Fluoro-4-(2-(5-((2-methoxyethoxy)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (15, Example 1)

To a yellow suspension of 33 (5.05 g, 9.01 mmol) in THF (90 ml) was added 2-methoxyethylamine (3.93 ml, 45.0 mmol) and acetic acid (2.58 ml, 45.0 mmol). After 1 hour, sodium triacetoxyborohydride (9.55 g, 45.0 mmol) was added to the reaction mixture that was stirred at r.t. overnight. The reaction mixture was then quenched with 2N HCl (100 mL), stirred at r.t. for an additional 15 minutes and basified to pH 9 with 2N NaOH. Most of the THF was removed under reduced pressure and a solid material precipitated. The material was collected by filtration, washed with water (3×100 mL), dried in the vacuum oven at 40° C. for 60 h, to afford compound 15 (3.52 g, 63% yield) as a light beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 11.85 (s, 1H), 9.35 (bs, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.45 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.16 (dd, J=2.0 and 8.0 Hz, 1H). 8.04 (dd, J=1.6 and 11.6 Hz, 1H), 7.60-7.52 (m, 2H), 7.42-7.35 (m, 2H), 7.23-7.15 (m, 2H), 6.74 (d, J=5.2 Hz, 1H), 4.29-4.23 (m, 2H), 3.83 (s, 2H), 3.63 (t, J=4.8 Hz, 2H), 3.31 (s, 3H), 3.18-3.12 (m, 2H). MS (m/z): 620.1 (M+H).

2-Bromo-5-(1,3-dioxolan-2-yl)pyridine (35)

Following the procedure described above for the synthesis of compound 28 (Scheme 8) but substituting 1,3-propanediol (27) for 1,2-ethanediol (34), title compound 35 was obtained in 61% yield [Romero-Salguero, F. J.; Lehn, J-M.; Tetrahedron Letters, 40, 1999, 859-862]. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.45 (d, J=2.3 Hz, 1H), 7.79 (ddd, J=8.2, 2.5, 0.4 Hz, 1H), 7.69 (dd, J=8.2, 0.8 Hz, 1H), 5.83 (s, 1H), 4.10-3.93 (m, 4H). MS (m/z): 230.0 (M+H).

2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine (36)

Following the procedure described above for the synthesis of compound 29 (Scheme 8) but substituting compound 28 for compound 35, title compound 36 was obtained in 79% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.70 (d, J=1.8 Hz, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.00 (dd, J=8.2, 2.1 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 5.90 (s, 1H), 4.13-4.07 (m, 2H), 4.05-3.99 (m, 2H). MS (m/z): 319.2 (M+H).

2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (37)

Following the procedure described above for the synthesis of compound 30 (Scheme 8) but substituting compound 29 for compound 36, title compound 37 was obtained in 72% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.49 (dd, J=10.4, 2.5 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (t, J=8.5 Hz, 1H), 6.99 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H). MS (m/z): 440.1 (M+H).

4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (38)

Following the procedure described above for the synthesis of compound 31 (Scheme 8) but substituting compound 30 for compound 37, title compound 38 was obtained in 95% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.29 (d, J=8.2 Hz, 1H), 7.96 (dd, J=8.2, 2.0 Hz, 1H), 7.11 (t, J=9.0 Hz, 1H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=13.1, 2.5 Hz, 1H), 6.44 (dd, J=8.7, 1.9 Hz, 1H), 5.87 (s, 1H), 5.55 (s, 2H), 4.11-4.07 (m, 2H), 4.00-3.97 (m, 2H). MS (m/z): 410.2 (M+H).

N-(4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (39)

Following the procedure described above for the synthesis of compound 32 (Scheme 9) but substituting compound 31 for compound 38, title compound 39 was obtained in 60% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 12.48 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.56 (d, J=5.5 Hz. 1H), 8.42 (s, 1H), 8.33 (dd, J=8.2, 0.8 Hz, 1H), 8.07-8.03 (m, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.56-7.55 (m, 2H), 7.38 (dd, J=8.7, 5.6 Hz, 2H), 7.19 (t, J=9.0 Hz, 2H), 6.70 (d, J=5.5 Hz, 1H), 5.90 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H), 3.84 (s, 2H). MS (m/z): 605.1 (M+H).

N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (33)

Method C (Methods A and B Described within the SCHEME 9):

To a solution of 39 (0.32 g, 0.529 mmol) in acetone (50 mL) was added water (20 mL) and TFA (2 mL). The mixture was then heated to reflux for 3 h, cooled to r.t. and left stirred overnight. Finally the mixture was cooled on ice and the white solid precipitate was isolated by suction filtration then dried in vacuum to afford compound 33 (0.32 g, quantitative yield, presumably as di-trifluoroacetate salt) as a colorless solid that could be used directly for the synthesis of compound 15, Example 1 (scheme 9). MS (m/z): 561.2 (M+H).

Example 4

N-(4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (41)

To intermediate 38 (0.46 g, 1.1 mmol) in dry DMF (20 mL) was added 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (40) (0.46 g, 2.2 mmol) [U.S. 2007/0004675 A1], DIPEA (0.98 mL, 5.6 mmol) and HATU (1.07 g, 2.81 mmol) and the mixture was stirred at r.t. for 18 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, 1M NaOH, saturated NH₄Cl, and brine, dried (anhydrous MgSO₄), filtered and concentrated. Silica gel chromatography (2% methanol in ethyl acetate) afforded intermediate 41 (0.23 g, 34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1H), 9.98 (s, 1H), 8.68 (s, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.97 (dd, J=8.2, 2.0 Hz, 1H). 7.90 (dd, J=13.1, 2.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.53-7.46 (m, 2H), 7.30 (t, J=7.4 Hz, 2H), 7.06 (t, J=7.4 Hz, 1H), 6.66 (d, J=5.3 Hz, 1H), 5.88 (s, 1H), 4.11-3.97 (m, 4H), 1.47 (br s, 4H). MS (m/z): 597.2 (M+H).

N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (42)

Intermediate 41 (0.22 g, 0.37 mmol) was dissolved in acetone (50 mL) to give a colorless solution. The reaction mixture was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 2 h, then cooled and concentrated. The precipitated product was isolated by suction filtration. A small amount of toluene (5 mL) was added to the wet solid, the mixture was concentrated to remove water azeotropically, and dried in vacuum to afford intermediate 42 (0.21 g, 103% yield, presumably as tri-fluoroacetate salt). MS (m/z): 553.2 (M+H).

N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide, (43, Example 4)

Intermediate 42 (0.20 g, 0.362 mmol) and 2-methoxyethylamine (8) (0.158 mL, 1.810 mmol) were dissolved in THF (50 mL) to give a colorless solution. Sodium triacetoxyborohydride (0.384 g, 1.810 mmol) was added and the mixture was stirred at r.t. for 20 h. Additional 2-methoxyethylamine (8) (0.158 mL, 1.810 mmol) and sodium triacetoxyborohydride (0.384 g, 1.810 mmol) were added, and the mixture was stirred for a further 20 h. The mixture was then concentrated, partitioned between water and dichloromethane; organic phase was collected, washed with H₂O, 1M NaOH, and brine, dried (anhydrous MgSO₄), filtered and concentrated. The residue was purified by Gilson Reverse Phase HPLC (Aquasil C₁₈, 40-90% MeOH/water, 30 min, elutes ˜20 min), and the product was lyophilized. Starting material 42 (50 mg) was also isolated.

The recovered starting material was re-subjected to the reaction conditions except in acetic acid (5 ml), with 2-methoxyethylamine (8) (1 mL) and sodium trisacetoxyborohydride (0.030 g). After stirring for 5 min the mixture was concentrated. The residue was purified by Gilson Reverse Phase HPLC as before. The isolated product was combined with that above to produce compound 43 (0.13 g, 59% yield) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1H), 9.98 (s, 1H), 8.68 (s, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.0 Hz, 1H), 7.62 (d, J=7.6, 2H), 7.53-7.46 (m, 2H), 7.30 (t, J=7.4 Hz, 2H), 7.06 (t, J=7.4 Hz, 1H), 6.66 (d, J=5.3 Hz, 1H), 5.88 (s, 1H), 4.11-3.97 (m, 4H), 1.47 (br s, 4H). MS (m/z): 597.2 (M+H).

Example 5

N¹-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)-N3-methylmalonamide (45)

To intermediate 38 (0.35 g, 0.86 mmol) in dry DMF (25 mL) was added 3-((4-fluorophenyl)(methyl)amino)-3-oxopropanoic acid (44) [U.S. 2007/0004675 A1] (0.36 g, 1.7 mmol) [Met-036], and EDCHCl (0.33 g, 1.7 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, saturated NaHCO₃, and brine, dried (anhydrous MgSO₄), filtered and concentrated. The crude product was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), and heated to reflux for 3 h. It was then cooled and concentrated. The residue was then partitioned between ethyl acetate and water, the organic phase was collected, washed with water, saturated NaHCO₃, and brine, dried (anhydrous MgSO₄), filtered and concentrated to produce intermediate 45 (0.27 g, 57% yield). MS (m/z): 559.2 (M+H).

N¹-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)-N³-methylmalonamide (46, Example 5)

Intermediate 45 (0.25 g, 0.45 mmol) and 2-methoxyethylamine (8) (0.67 g, 9.0 mmol) were dissolved in AcOH (10 mL) to give a colorless solution, which was allowed to stir for 30 min. Sodium trisacetoxyborohydride (0.29 g, 1.3 mmol) was added and the mixture was stirred at r.t. for 1 h, poured into conc. NH₄OH and dichloromethane. The organic phase was washed with water, saturated NaHCO₃, and brine, dried (anhydrous MgSO₄), filtered and concentrated. The residue was purified by Gilson Reverse Phase HPLC (Aquasil C₁₈, 25-80% MeOH/water, 30 min) and lyophilized providing compound 46 (132 mg, 48% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.28 (s, 1H), 8.58 (s, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.15 (s, 1H), 7.91 (dd, J=8.0, 2.0 Hz, 1H), 7.79 (dd, J=12.9, 2.0 Hz, 1H), 7.49-7.43 (m, 3H), 7.33-7.27 (m, 3H), 6.66 (d, J=5.3 Hz, 1H), 3.92 (s, 2H), 3.42 (t, J=5.7 Hz, 2H), 3.25 (s, 3H), 3.23 (s, 2H), 3.19 (s, 3H), 2.69 (t, J=5.5 Hz, 2H). MS (m/z): 618.3 (M+H).

Example 6

N¹-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide (48)

To intermediate 38 (0.40 g, 0.98 mmol) in dry DMF (20 mL) was added 3-(4-fluorophenylamino)-3-oxopropanoic acid (47) (0.39 g, 2.0 mmol) [U.S. 2007/0004675 A 1], and EDC.HCl (0.38 g, 2.0 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water resulting in precipitate. The precipitate was isolated by suction filtration and combined with the organic phase from the filtrate, concentrated, and dried in vacuum. The residue was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 3 h, then cooled and concentrated. The precipitated product was isolated by suction filtration, and dried in vacuum to afford intermediate 48 (0.35 g, 66%, presumably as the trifluoroacetate salt). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.59 (s, 1H), 10.29 (s, 1H), 10.14 (s, 1H), 9.15 (s, 1H). 8.59 (s, 1H), 8.58 (m, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.39 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 6.75 (d, J=5.5 Hz, 1H), ˜3.50 (s, 2H, obscured by water peak). MS (m/z): 545.2 (M+H).

N¹-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide (49, Example 6)

Intermediate 48 (0.35 g, 0.64 mmol) and 2-methoxyethylamine (8) (1.2 g, 16 mmol) were dissolved in AcOH (10 mL) to give a yellow suspension, and stirred for 30 min. Sodium trisacetoxyborohydride (0.27 g, 1.3 mmol) was added and the mixture was stirred at r.t. for 18 h. The reaction mixture was poured into conc. NH₄OH and dichloromethane. The resulting suspension was collected by filtration and rinsed with water to provide a solid material. The material was triturated with diethyl ether and ethyl acetate, and dried in vacuum to afford compound 49 (166 mg, 43%). ¹H NMR (400 MHz. DMSO-d₆) δ (ppm): 10.61 (s, 1H). 10.32 (s. 1H), 8.57 (s, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.89-7.86 (m, 1H), 7.66-7.60 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.44 (dd, J=9.0, 2.0 Hz, 1H), 7.20-7.14 (m, 2H), 6.68 (d, J=5.5 Hz, 1H), 3.78 (s, 2H), 3.51 (s, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.7 Hz, 2H). MS (m/z): 604.2 (M+H).

6-(7-Chlorothieno[3,2-b]pyridin-2-yl)nicotinaldehyde (50)

7-Chlorothieno[3,2-b]pyridine (6) (4.02 g, 23.70 mmol) was dissolved in THF (150 mL) to give a colorless solution. The solution was cooled to −40° C. in an acetonitrile/dry ice bath. n-BuLi (9.95 mL, 24.88 mmol, 2.5M in hexanes) was added dropwise. The dark mixture was then stirred for 15 min followed by an addition of zinc chloride (24.88 mL, 24.88 mmol, 1M in ether). The mixture was warmed to 0° C., then tetrakistriphenylphosphine palladium (1.095 g, 0.948 mmol) was added. The mixture was then stirred for 10 min and 6-bromonicotinaldehyde (7) (4.41 g, 23.70 mmol) was added. The mixture was heated to reflux and a precipitate formed rapidly. After 3 h, the reaction mixture was cooled down to r.t., quenched with 2 mL NH₄Cl and left overnight. The solid was isolated by suction filtration, rinsed with small amount of THF and triturated with a mixture of water (200 mL) and EtOAc (100 mL) followed by an additional trituration with acetic acid (1×100 mL), to afford intermediate 50 (4.95 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.13 (s, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.39 (dd, J=2.1, 8.4 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H). MS (m/z): 275.1 (M+H).

Step 2: 6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinaldehyde (25)

Method B (Method A is Provided within the Scheme 7)

Following the procedure described above for the synthesis of compound 30 (Scheme 8) but substituting compound 29 for compound 50 and sodium carbonate for potassium carbonate, title compound 25 was obtained in 55% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.13 (s, 1H), 9.13 (dd, J=2.2, 0.8 Hz, 1H), 8.67 (d, J=5.5 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=8.6 Hz, 1H), 8.50 (dd, J=10.5, 2.6 Hz, 1H), 8.40 (dd, J=8.3, 2.1 Hz, 1H), 8.23 (ddd, J=9.1, 2.7, 1.5 Hz, 1H), 7.75 (dd, J=8.9, 8.1 Hz, 1H), 7.03 (dd, J=5.3, 0.6 Hz, 1H). MS (m/z): 396.1 (M+H).

2-(5-(Diethoxymethyl)pyridin-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (51)

The Dowex-50 resin (0.75 g) and intermediate 25 (0.95 g, 2.4 mmol) were suspended in EtOH (100 mL). The reaction mixture was heated to reflux for 2 hours. More Dowex-50 resin (0.30 g) was then added and the mixture was heated to reflux for another 3 hours. It was then cooled down to r.t. and filtered through a celite pad. The filtrate was concentrated under reduce pressure. The residue was purified by flash column chromatography eluting with 50-75% EtOAc in hexanes, to afford intermediate 54 (0.35 g, 31% yield) as a colorless crystalline solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.63-8.61 (m, 2H), 8.48 (dd, J=10.5, 2.6 Hz, 1H), 8.42 (s, 1H), 8.30 (dd, J=8.2, 0.8 Hz, 1H), 8.20 (ddd, J=9.0, 2.7, 1.4 Hz, 1H), 7.92 (ddd, J=8.2, 2.2, 0.4 Hz, 1H), 7.71 (dd, J=9.0, 8.0 Hz, 1H), 6.97 (dd, J=5.4, 0.5 Hz, 1H), 5.62 (s, 1H), 3.64-3.50 (m, 4H), 1.17 (t, J=7.0 Hz, 6H). MS (m/z): 470.1 (M+H).

4-(2-(5-(Diethoxymethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (52)

The intermediate 51 (0.29 g, 0.62 mmol) was solubilized in EtOH (100 mL) and palladium on charcoal 10% (0.075 g) was added. The reaction mixture was stirred overnight under hydrogen atmosphere, filtered through a celite pad and the filtrate was concentrated under reduce pressure. The residue was purified by column chromatography with 60-80% EtOAc in hexanes to afford intermediate 52 (0.14 g, 52% yield) as a colorless solid. MS (m/z): 440.1 (M+H).

N-(4-(2-(5-(Diethoxymethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl) acetamide (53)

Following the procedure described above for the synthesis of compound 32 (Scheme 9) but substituting compound 31 for compound 52, title compound 53 was obtained in 31% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.46 (s, 1H), 11.82 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 8.29 (dd, J=8.2, 0.8 Hz, 1H), 8.02 (d, J=11.9 Hz, 1H), 7.91 (dd, J=8.1, 1.7 Hz, 1H), 7.53-7.52 (m, 2H), 7.37 (dd, J=8.8, 5.7 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (dd, J=5.4, 0.9 Hz, 1H), 5.63 (s, 1H), 3.82 (s, 2H), 3.64-3.50 (m, 4H), 1.17 (t, J=7.0 Hz, 6H). MS (m/z): 635.1 (M+H).

N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (33)

Method D (Methods B and C Described within the Scheme 9):

Intermediate 53 (0.050 g, 0.078 mmol) was dissolved in a mixture of acetone and water 4:1 (20 mL). Trifluoroacetic acid (2.1 mL) was added and the mixture was heated to reflux for 2 hours, cooled down to r.t.; and the solid was isolated by suction filtration. The material was rinsed with a mixture of acetone and water (1:1) then dried in vacuum to afford compound 33 (0.030 g, 68% yield), which could be used in the synthesis of compound 15 (Example 1). MS (m/z): 561.1 (M+H).

2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine (36)

Method B (Method A was Described within the Scheme 10):

A suspension of intermediate 50 (2.69 g, 9.79 mmol), ethylene glycol (34) (2.184 mL, 39.2 mmol), and (1R)-(+10-camphorsulfonic acid (0.227 g, 0.979 mmol) in toluene (150 mL) was heated to reflux with a Dean-Stark trap. After 3 h, the mixture was cooled down and filtered through a celite pad (while warm). The filtrate was washed with water, saturated aqueous NaHCO₃, NaOH (aq) and brine. It was then dried over MgSO₄ and concentrated to afford intermediate 36 (2.77 g, 89% yield) as an off-white solid. MS (m/z): 319.1 (M+H).

N-((6-Bromopyridin-2-yl)methyl)-2-methoxyethanamine (55)

A mixture of 6-bromo-2-pyridinecarboxaldehyde (54) (20 g, 108 mmol) and 2-methoxy ethanamine (10.3 mL, 8.88 g, 118 mmol) in DCM (1.3 L) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)₃ (25 g, 118 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (400 mL) and acidified to pH=4 with 1M HCl (−140 mL). The two phases were separated and the organic layer was extracted with 0.25M HCl (2×500 mL). The aqueous layers were combined, basified to pH=9 with 4N NaOH, extracted with DCM (1×500 mL), dried over Na₂SO₄, filtered and concentrated yielding 25.2 g of 55 (96%). MS (m/z): 245.1 (M+1).

tert-Butyl (6-bromopyridin-2-yl)methyl(2-methoxyethyl)carbamate (56)

To a solution of 55 (25.19 g, 103 mmol) in THF (32.1 ml) Boc₂O (23.86 ml, 103 mmol) was added in small portions (solid). The reaction mixture was stirred for 2 hours. It was then concentrated yielding 56 (37.6 g, 100% yield) which was used without further purification. MS (m/z): 345.1 (M+1).

tert-Butyl (6-(7-chlorobenzo[b]thiophen-2-yl)pyridin-2-yl)methyl(2-methoxyethyl)carbamate (57)

A solution of 7-chlorothieno[3,2-b]pyridine (6) (4.49 g, 26.6 mmol) in THF (20 ml) was treated with 2.5 M hexane solution of n-BuLi (11.1 mL, 27.9 mmol) at −78° C. and allowed to stir at the same temperature for 45 min. The reaction mixture was then treated with 1M ether solution of ZnCl₂ (28 mL, 28 mmol) and stirred at room temperature for an additional 1 h. The reaction mixture was then treated with 56 (2.3 g, 6.7 mmol) and Pd(PPh₃)₄ and was heated to reflux for 2 hrs. It was quenched with saturated NaHCO₃ (50 mL) and extracted with EtOAc (2×50 mL). The extract was dried over anhydrous Na₂SO₄, filtered and evaporated. Obtained crude product was purified by flash chromatography (using the gradient 60-80% EtOAc/hexanes as an eluent), yielding 57 (1.43 g, 50% yield). MS (m/z): 434.2 (M+1).

tert-Butyl (6-(7-(2-fluoro-4-nitrophenoxy)benzo[b]thiophen-2-yl)pyridin-2-yl)methyl(2-methoxyethyl)carbamate (58)

A solution of 57 (1.43 g, 3.3 mmol) and 2-fluoro-4-nitrophenol (3) (1.03 g, 6.61 mmol) in diphenyl ether (30 mL) were stirred overnight at 160° C. The reaction mixture was cooled down to room temperature, diluted with THF (30 mL), treated with Et₃N (1.38 mL, 9.9 mmol) and Boc-anhydride (1.08 g, 4.95 mmol) and stirred at room temperature for 2 h. It was then diluted with EtOAc (100 mL) and washed with saturated NaHCO₃ (100 mL). The organic phase was collected, dried over Na₂SO₄, filtered and concentrated. Obtained crude product was purified by flash chromatography (using the gradient 70-100% EtOAc in hexanes as an eluent), yielding 58 (850 mg, 47% yield). MS (m/z): 555.2 (M+1).

tert-butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-2-yl)methyl(2-methoxyethyl)carbamate (59)

A solution of 58 (1 g, 1.81 mmol) and NH₄Cl (97 mg, 1.8 mmol) in a 2:1 mixture of EtOH and water (30 mL) was treated with iron powder (605 mg, 10.8 mmol) and stirred at reflux for 1 hour. The reaction mixture was then filtered through a celite pad and concentrated yielding title compound 59 (980 mg, 100% yield) that was used in the next step (scheme 18) without further purification. MS (m/z): 525.2 (M+1).

Example 7

Step 1. tert-Butyl (6-(7-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropane carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-2-yl)methyl(2-methoxyethyl) carbamate (61)

A solution of 60 (800 mg, 1.53 mmol), 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (16) [U.S. 2007/0004675 A1] (512 mg, 2.3 mmol) and DIPEA (1.1 mL, 6.1 mmol) in DMF (10 mL) was treated with HATU (1162 mg, 3.06 mmol) at 0° C. The mixture was then stirred at room temperature overnight, diluted with EtOAc, washed sequentially with H₂O, 1M NaOH and saturated NaCl, dried over Na₂SO₄, filtered and concentrated. The obtained crude product was purified by flash chromatography (using 75-85-100% EtOAc/hexanes as an eluent) yielding 61 (495 mg, 45%). MS (m/z): 730.3 (M+1).

Step 2: N-(3-Fluoro-4-(2-(6-(2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (62)

HCl gas was bubbled into a solution of 61 (280 mg, 0.38 mmol) in DCM (150 mL). The flask was capped and the mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with 1M NaOH (2×100 mL) and saturated NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated.yielding title compound 62 (215 mg 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.51 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J=7.7 Hz, 1H), 7.90 (m, 2H), 7.62 (m, 2H), 7.45 (m, 3H), 7.13 (t, J=8.8 Hz, 2H), 6.61 (d, J=5.1 Hz, 1H), 3.86 (s, 2H), 3.40 (m, 2H), 3.22 (s, 3H), 2.72 (m, 2H), 1.41 (br.s, 4H). MS (m/z): 630.3 (M+1).

Example 8

1-(Chlorocarbonyl)cyclopropanecarboxylic acid (63)

To 1,1-cyclopropanedicarboxylic acid (1.70 g, 13.1 mmol) in dry THF (50 mL) was added triethylamine (1.9 mL, 1.4 g, 13.7 mmol) and the mixture was cooled to 0° C. Thionyl chloride (0.95 mL, 1.6 g, 13.1 mmol) was added and the resulting suspension was allowed to warm to room temperature and stirred for 2 h. This suspension of 63 (−0.26 M) was used without further purification in the following reaction.

tert-Butyl (6-(7-(3-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate, (64)

To aniline 20 (40 mg, 0.076 mmol, Scheme 6) and triethylamine (0.20 mL, 1.4 mmol) in THF (10 mL) at r.t. was added a solution of 63 (1.0 mL, 0.26 mmol) in THF and the resulting mixture was stirred for 3 h. The reaction mixture was then quenched with water (1.0 mL) and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with water and brine, dried (MgSO₄), filtered and concentrated. The residue was dissolved in DMF (10 mL) and diisopropylethylamine (0.2 mL, 0.14 g, 1.1 mmol), 4-fluoroaniline (50 mg, 0.45 mmol), and HATU (75 mg, 0.20 mmol) were sequentially added. The mixture was stirred for 4 h at r.t. and partitioned between ethyl acetate and water. The organic phase was separated, washed with water, sat. NaHCO₃, and brine, dried (MgSO₄), filtered and concentrated. Silica gel chromatography of the residue (eluent ethyl acetate) provided 64 (34 mg, 61%). MS (m/z)=730.5 (M+H).

N-(2-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (65)

To 64 (52 mg g, 0.071 mmol) in dichloromethane (25 mL) was added TFA (3 mL). The solution was stirred for 24 h, then concentrated. The residue was purified by reverse phase HPLC (Aquasil C-18 column, 45-90% MeOH/H₂O+HCO₂H, 30 min. linear gradient elution). The eluate was evaporated and lyophilized. The obtained solid was triturated with diethyl ether to afford the title compound 65 (27 mg, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.66 (s, 1H); 9.95 (s, 1H); 8.55-8.53 (m, 2H); 8.32 (s, 1H); 8.23-8.21 (m, 1H); 7.99 (t, J=8.8, 1H); 7.88 (dd, J=8.0, 2.2, 1H); 7.61-7.58 (m, 2H); 7.43-7.40 (m, 1H); 7.19-7.13 (m, 3H); 6.75 (d, J=5.3, 1H); 3.77 (s, 2H); 3.40 (t, J=5.7, 2H); 3.23 (s, 3H); 2.64 (t, J=5.3, 2H); 1.60-1.55 (m, 4H). MS (m/z)=630.3 (M+H).

Example 1

Version C

Step 1: 2-Bromo-5-(1,3-dioxan-2-yl)pyridine (28)

To a solution of 6-bromopyridine-3-carbaldehyde 7 (47.2 g, 254 mmol) in toluene (130 mL) in a 250 mL round-bottom flask was added 1,3-propanediol (38.6 g, 508 mmol) and 10-camphorsulfonic acid (2.95 g, 12.69 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 1 h, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and NaHCO₃ soln (100 mL). Organic phase was collected and the aqueous phase was extracted with EA (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated to yield a brown solid which was triturated with Et₂O/Hex (10/150 mL) for 1 h, filtered to give 28 (53.98 g, 221 mmol, 87% yield) as a beige solid. MS (m/z): 243.1 (M+1)

Step 2: 2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine (29)

To a solution of chlorothienopyridine 6 (22.93 g, 135 mmol) in THF (325 mL) at −5° C./−10° C. in a 1 L round-bottom flask was added n-BuLi (2.5 M in hexanes, 54.1 mL, 135 mmol) over 20 min. After 30 min, a solution of zinc chloride in ether (1M, 135 mL, 135 mmol) was added at −5° C./−10° C. over 20 min and the reaction mixture was allowed to warm-up to r.t. After 1 h, the bromide 28 (27.5 g, 113 mmol) and Pd(PPh₃)₄ (1.953 g, 1.169 mmol) in THF (48.8 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t. and concentrated. The residue was diluted with DCM (1000 mL)/H₂O (800 mL)/NH₄OH (200 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL), the organic phase and the extracts were combined, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was triturated with MTBE (100 mL) and collected by filtration (washed with MTBE, 2×20 mL) to give 29 (23.73 g, 71.3 mmol, 63.3% yield) as a beige solid. MS (m/z): 333.1 (M+1)

Step 3: 2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-yloxy)-3-fluoroaniline (31)

To a solution of aminophenol 4 (8.40 g, 66.1 mmol) in DMSO (75 ml) in a 250 mL round-bottom flask was added potassium tert-butoxide (8.77 g, 78 mmol). After 30 min, chloride 29 (20 g, 60.1 mmol) was added and the mixture was heated at 100° C. for 1.5 h. After cooling to r.t., the mixture was poured into water (300 mL) at 40° C. and the formed suspension was stirred for 30 min. The solid was collected by filtration, washed with water (2×30 mL) and dried under vacuum for 2 h. It was then triturated with Et₂O (60 mL) for 2 h and collected by filtration to give a brown solid of 31 (23.8 g, 56.2 mmol, 94% yield). MS (m/z): 424.1 (M+1)

Step 4: N-(4-(2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl) acetamide (32)

To a solution of isothiocyanate 2 (13.17 g, 67.4 mmol) in a mixture of toluene (100 ml)/EtOH (100 ml) in a 500 mL round-bottom flask was added aniline 31 (23.8 g, 56.2 mmol). The mixture was stirred for 1 h at room temperature and concentrated. The solid was triturated with toluene (100 mL) for 1 h, collected by filtration, washed with toluene (20 ml). The solid was dried under vacuum for 2 h to give crude 32 (35.10 g) which was used in the next step without any further purification. MS (m/z): 619.1 (M+1)

Step 5: N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (33)

A suspension of crude 32 (35.10 g) in AcOH 80% (576 mL) in a 1 L round-bottom flask was heated at 90° C. for 18 h, cooled to r.t. to form a precipitate which was collected by filtration to give 33 (18.41 g, 32.8 mmol, 58% yield over two steps) as a beige solid. MS (m/z): 561.1 (M+1)

Step 6: N-(3-Fluoro-4-(2-(5-((2-methoxyethoxy)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (15)

To a suspension of aldehyde 33 (17.06 g, 30.04 mmol) and 2-methoxyethylamine (13.25 ml, 152 mmol) in THF (300 ml) in a 1 L round-bottom flask was added AcOH (8.71 ml, 152 mmol)). After 1 h, NaBH(OAc)₃ (32.2 g, 152 mmol) was added and the reaction mixture was stirred for 20 h at r.t. and was then quenched with HCl 2M (300 mL) After 1 h, NaOH 2N (350 mL) was added until pH 11 and the mixture was concentrated. The solid was subjected to chromatographic purification through a pad of silica gel, eluent 2%-10% MeOH/DCM, to give 15 (8.59 g, 13.86 mmol, 81% yield) as a white solid. MS (m/z): 620.2 (M+1)

Example 1

Version D

Step 1: N-((6-bromopyridin-3-yl)methyl)-2-methoxyethanamine (9)

To a dark-yellow solution of 6-bromopyridine-3-carbaldehyde 7 (30 g, 161 mmol) in DCM (300 ml) and 2-methoxyethylamine 8 (1.05 eq, 14.72 ml, 169 mmol) in a 1 L round-bottom flask was added acetic acid (1 eq, 9.23 mL, 161 mmol). After 15 min, sodium triacetoxyborohydride (1.05 eq, 35.9 g, 169 mmol) was added over 10 min and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was then quenched with 10% HCl (200 mL). The two layers were separated and the organic layer was extracted with 10% HCl (2×100 mL). The aqueous layers were combined, basified to pH=9 with 4M NaOH (450 mL), extracted with EA (3×150 mL) and combined organic extracts were washed with brine (150 mL), dried over Na₂SO₄, filtered and evaporated to afford 9 as brown oil that could be used crude for next step (31.1 g, 127 mmol, 79% yield). MS (m/z): 245.1 (M+1)

Step 2: tert-butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate (10)

Amine 9 (36.64 g, 149 mmol) was dissolved in THF (60 mL) in a 250 mL round-bottom flask, to give a brown solution. To this solution, solid Boc-anhydride (1.03 eq, 33.6 g, 154 mmol) was added in small portions. The reaction mixture was stirred at r.t. for 1.5 hours, evaporated to dryness and the residue was dried on the vacuum pump for a few minutes to afford 10 (as brown oil) that was used crude for next step (55.12 g, 160 mmol, quant). MS (m/z): 345.1 (M+1)

Step 3: N-((6-(7-chlorobenzo[b]thiophen-2-yl)pyridin-3-yl)methyl)-2-methoxy ethanamine (11)

To a solution of 7-chlorothieno[3,2-b]pyridine 6 (7.37 g, 43.4 mmol, 1.5 eq) in THF (70 mL) at −10° C. in a 250 mL round-bottom flask was added n-BuLi (17.38 mL, 43.4 mmol, 1.5 eq). After 1 h, ZnCl₂ (1M in ether) (43.4 mL, 43.4 mmol, 1.5 eq) was added at −10° C. and the reaction mixture was allowed to warm up to r.t. After 1 h, Pd(PPh₃)₄ (0.669 g, 0.579 mmol, 0.02 eq) and bromide 10 (10 g, 29 mmol, 1 eq) in THF (10.5 mL) were added and the mixture was heated to reflux for 1 h. After cooling to room temperature the reaction mixture was concentrated to dryness. DCM (200 mL)/water (160 mL)/NH₄OH (40 mL) were added to the solid and the resultant mixture (an emulsion) was stirred for 1 h. Brine (50 ml) was added to the emulsion and the stirring was continued for an additional 10 min. The mixture was then filtered through a paper filter and phases were separated. The aqueous phase was extracted with DCM (2×50 mL). The organic phases were combined, dried over Na₂SO₄ and concentrated to dryness. MTBE (30 mL) was added to the solid and the suspension was stirred for 30 min. The solid was collected by filtration, washed with MTBE (2×5 mL) and dried to afford of 11 as a beige solid (8.02 g, 64% yield). MS (m/z): 434.2 (M+1).

Step 4: tert-butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (13)

To a solution of 4-amino-2-fluorophenol (10.55 g, 83 mmol, 1.2 eq) in DMSO (150 mL) in a 100 mL round-bottom flask was added potassium tert-butoxide 95% (10.08 g, 90 mmol, 1.3 eq). After 30 min, 11 (30 g, 69.1 mmol) was added and the reaction mixture and was heated at 100° C. for 2 h, cooled to room temperature, poured into water (400 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water (2×50 mL) and dried under vacuum overnight. The solid was triturated with MTBE (200 mL) for 3 h and filtered to give 13 as beige solid (28.00 g, 77% yield). MS (m/z): 525.3 (M+1).

Step 5: tert-butyl (6-(7-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (14)

To a suspension of isothiocyanate 2 (5.50 g, 28.2 mmol) in a mixture of toluene (20 mL)/EtOH (20 mL) in a 500 mL round-bottom flask was added aniline 13 (10 g, 19.06 mmol) in a mixture of toluene (50 mL)/EtOH (50 mL). After 30 min, additional amount of isothiocyanate 2 (1 g, 5.12 mmol) in a mixture toluene (5 mL)/EtOH (5 mL) was added to the reaction mixture which was stirred at r.t. for an additional 45 min. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with MeOH (40 mL) to dryness. Finally MeOH (80 mL) was added to the dry residue to produce a precipitate that was stirred at room temperature for 14 h, collected by filtration, dried for 2 h under vacuum to afford 14 as beige solid (7 g, 51% yield). MS (m/z): 720.3 (M+1)

Step 7: N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (15)

To solid 14 (7.00 g, 9.72 mmol) in a 250 mL round-bottom flask was added TFA (20 mL). The addition was a little bit exothermic. The mixture was stirred at r.t. for 2 h then concentrated and co-evaporated with MTBE (2×100 mL) to obtain a solid that was triturated with MTBE (80 mL) for 2 h. The solid was collected by filtration, washed with MTBE (2×10 mL) and dried in vacuum for 1 h. The dry solid was partitioned between the mixture of DCM/MeOH: (9/1, 300 mL) and NaHCO₃ (200 mL). The phases were separated. The organic phase was collected and the aqueous phase was extracted with DCM/MeOH: 9/1 (2×150 mL). Organic phases were combined, washed with brine (100 mL), dried over Na₂SO₄ and concentrated. The solid residue was triturated with EA (40 mL) for 1 h, collected by filtration, washed with EA (2×5 mL), dried in vacuum for 1 h to afford 15 as beige solid (3.77 g, 63% yield). MS (m/z): 620.6 (M+1).

Example 1

Version E

Steps 1-3 (combined): tert-Butyl (6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11)

To a solution of 6-bromopyridine-3-carboxaldehyde (7) (20 g, 113 mmol) in DCM (240 mL) cooled to 0-5° C. was added 2-methoxyethylamine (8) (24.23 g, 323 mmol, 3 eq.) over 5 min followed by AcOH (1.05 eq., 6.46 mL, 113 mmol) over 10 min. The reaction mixture was stirred for 15 min at 0-5° C. then for 30 min at r.t. NaBH(OAc); was added portion wise and the reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was quenched by addition of 10% aqueous HCl (160 mL). The layers were separated. The organic phase was collected and extracted with 10% aqueous HCl (2×100 mL). The original aqueous phase (also acidic) and the acidic extracts were combined and basified to pH 9 with NaOH 4M (500 mL). The basic solution was extracted with DCM (3×200 mL). The organic phase was collected, washed with water (3×250 mL) and brine (400 mL) then concentrated to a volume of 100-120 mL. THF (250 mL) was added and the resultant solution was concentrated to a volume of 100-120 mL. A second portion of THF (250 mL) was added and the resultant solution containing crude N-((6-bromopyridin-3-yl)methyl)-2-methoxyethanamine (9) was concentrated again to a volume of 215 to 230 mL.

To this solution was added Boc₂O (30 mL, 129 mmol, 1.2 eq.) over 15 min and the reaction mixture was stirred at r.t. for 1 h. A solution of taurine (1.5 q., 20.22 g, 162 mmol) in NaOH 2M (1.5 eq., 81 ml) was added slowly and the resultant mixture was stirred at r.t. for 16 h. Finally, 1N NaOH solution (100 mL) and 2-MeTHF (251 mL) were added and the mixture was stirred for 15 minutes. The layers were separated. The organic phase was collected, washed with 1N NaOH solution (100 mL), water (100 mL) and brine (100 mL) then dried over MgSO₄ and concentrated to a volume of 50-60 mL containing tert-butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate (10). The solution of 10 was used in the next step.

To a solution of 7-chlorothieno[3,2-b]pyridine (6, scheme 1) (27.4 g 162 mmol, 1.5 eq.) in THF (260 mL at −10 to −15° C.) was added n-BuLi (65.2 mL, 2.5 M in hexane, 1.5 eq., 162 mmol) over 10 min. The reaction mixture was stirred at −10 to −15° C. for 30 minutes then added via canula to a suspension of zinc chloride (1.5 eq., 22.03 g, 162 mmol) in THF (100 mL) at −10 to −15° C. over a period of 15 min. The combined reaction mixture was stirred for 15 min at −10 to −15° C., then at r.t. for another 45 min.

Pd(PPh₃)₄ (2.49 g, 2.15 mmol, 0.02 eq.) was dissolved in the solution of tert-butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate (10) (made during the step 2). This pooled solution was added to the reaction mixture which was heated at reflux for 1.5 h. After cooling down to r.t., 2-MeTHF (400 mL), water (400 mL) and NH₄OH (270 mL) were added. The mixture was stirred at r.t. for 30 min and the layers were separated. The aqueous phase was extracted with 2-MeTHF (2×200 mL). The organic phase and the extracts were combined, washed with water (250 mL) and brine (250 mL), and concentrated to dryness. The brown solid residue was triturated with MTBE (135 mL) for 1 h, collected by filtration and washed with MTBE (2×30 mL). The product was dried in a vacuum oven (45° C.) to afford title compound 11 as a beige solid (40.65 g, 94 mmol, 87% yield over three steps).

¹H NMR (400 MHz, DMSO-d6): 8.64 (d, J=5.2 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=2.0 and 8.0 Hz, 1H), 7.57 (d, J=5.2 Hz, 1H), 4.48 (s, 2H), 3.46-3.20 (m, 4H), 3.22 (s, 3H), 1.48-1.30 (m, 9H). M+H:434.2

Step 4: tert-butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (13)

To a solution of 4-amino-2-fluorophenol (4, scheme 1) (14.29 g, 112 mmol 1.2 eq.), in DMSO (117 mL) was added potassium tert-butoxide (13.66 g, 122 mmol, 1.3 eq.), over 5 min. The reaction mixture was stirred at r.t. for 30 minutes. tert-Butyl (6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl) methyl(2-methoxyethyl)carbamate (11) (40.65 g, 94 mmol, 1 eq) was added and the reaction mixture was heated at 100° C. for 1.5 h. Additional amounts of the phenol 4 (0.83 g, 6.53 mmol, 0.07 eq.) in DMSO (5 mL) and potassium tert-butoxide (1.05 g, 9.38 mmol, 0.1 eq.) were added to the reaction mixture which was heated at 100° C. for an additional 30 min. After cooling down to r.t., the reaction mixture was poured into water (900 mL) at 40° C. over 15 min. After stirring for 15 min at 40° C., the mixture was cooled to r.t. over 1 h. The solid was collected by filtration and the cake was washed with water (2×115 mL). The product was dried in vacuum for 16 h then triturated with MTBE (115 mL) for 1 h, collected by filtration and the cake was washed with MTBE (2×20 mL). The product was dried in a vacuum oven (45° C.) to afford title compound 13 as a beige solid (44.02 g, 84 mmol, 90% yield).

¹H NMR (400 MHz, DMSO-d6): 8.51 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.78 (dd, J=2.4 and 8.0 Hz, 1H), 7.12 (dd, J=9.2 Hz, 1H), 6.60 (dd, J=0.4 and 5.6 Hz, 1H), 6.54 (dd, J=2.4 and 13.0 Hz, 1H), 6.45 (ddd, J=0.4, 2.4 and 9.2 Hz, 1H), 5.55 (s, 2H), 4.47 (s, 2H), 3.48-3.32 (m, 4H), 3.22 (s, 3H), 1.48-1.30 (m, 9H). M+H, 525.3

Step 5: tert-butyl (6-(7-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (14)

To a solution of 4-fluorophenylacetic acid (1, scheme 1) (26.5 g, 172 mmol) in DCM (93 mL) was added oxalyl chloride (2 eq., 30.1 mL, 344 mmol) over 5 min and DMF (0.005 eq., 0.067 mL, 0.86 mmol) over 1 min. The reaction mixture was stirred at r.t for 2 h then concentrated. The residual DCM was removed as an azeotrope with toluene (2×20 mL) to afford intermediate 2-(4-fluorophenyl)acetyl chloride (1a) (30.85 g, 179 mmol, assumed quantitative yield) as yellow oil. Part of that material was used as is in the next step.

To a solution of crude 1a (27.4 g, 159 mmol) from the previous step in MeCN (159 mL) was added ammonium thiocyanate (12.69 g, 167 mmol, 1.05 eq.). The fine yellow slurry was heated at 50° C. for 1 h. After cooling down to 0° C., the reaction mixture was filtered through a Celite pad and the cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to a volume of 30-40 mL, cooled again to 0° C. and filtered through a Celite pad. The cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to the same volume of 30-40 mL. The resultant solution contained 2-(4-fluorophenyl)acetyl isothiocyanate (2, assumed quantitative yield, Method B). Half of this solution was used in the next step.

To a solution of 13 (39.02 g, 74.4 mmol, 1 eq.) in IPA (780 mL), at 70° C. was added a solution of crude 2 in MeCN (19.5 mL) from the previous step, over 15 min. The reaction mixture was heated at 70° C. for 20 min. After cooling down to r.t. over 2 h, the reaction mixture turned into a suspension and was stirred at r.t. for an additional 14 h. After cooling down to 0° C., the solid was collected by filtration and the product cake was washed with cold IPA (50 mL) then dried in vacuum to produce the title compound 14 as a beige solid (47.62 g, 66.2 mmol, 89% yield).

¹H NMR (400 MHz, DMSO-d6): 12.48 (s, 1H), 11.84 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.4 (dd, J=2.0 and 13.2 Hz, 1H), 7.79 (dd, J=2.0 and 8.0 Hz, 1H), 7.58-7.50 (m, 2H), 7.42-7.35 (m, 2H), 7.23-7.15 (m, 2H), 6.68 (d, J=5.6 Hz, 1H), 4.47 (s, 2H), 3.83 (s, 2H), 3.48-3.32 (m, 4H), 3.22 (s, 3H), 1.50-1.30 (m, 9H). M+H, 720.2

Step 6: N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridine-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide (15)

To a suspension of 14 (45.06 g, 62.6 mmol, 1 eq.), in AcOH (338 mL) was added 1N HCl (188 mL) over 1 min. The reaction mixture was heated at 40° C. for 2 h. After cooling down to r.t., water (676 mL) was added. The reaction mixture turned into a suspension and was stirred at r.t. for 15 min. The solid was collected by filtration and the product cake was washed with water (2×100 mL) then dried in vacuum for 30 min to afford a crude hydrochloride salt of 15 as a white solid.

To a suspension of crude hydrochloride salt of 15 in THF (300 mL) was added a saturated solution of NaHCO₃ (1 L). After 2 h, EtOAc was added (1.2 L) and the mixture was stirred at r.t. for 10 min. The layers were separated. The aqueous phase was collected, extracted with a mixture of EtOAc (400 mL) and THF (100 mL). The organic layer and the extract were combined and washed with brine (600 mL), dried over Na₂SO₄, filtered and concentrated to a volume of 120-140 mL. EtOAc (120 mL) was added to that solution which once again was concentrated to a volume of 120-140 mL. EtOAc (120 mL) was added for the third time and the solution was concentrated again to a volume of 120-140 mL to form a suspension. The solid was collected by filtration and washed with EtOAc (2×40 mL) then dried in vacuum over 17 h to afford the title compound 15 as a beige solid (29.14 g, 47 mmol, 75% yield).

¹H NMR (400 MHz, DMSO-d6): 8.58 (d, J=1.6 Hz, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 8.04 (dd, J=1.6 and 13.2 Hz, 1H), 7.92 (dd, J=2.0 and 8.4 Hz, 1H), 7.58-7.52 (m, 2H), 7.42-7.35 (m, 2H), 7.22-7.16 (m, 2H), 6.68 (dd, J=0.8 and 5.2 Hz, 1H), 3.83 (s, 4H), J=5.6 Hz, 2H), 3.24 (s, 3H), 2.70 (t, J=5.6 Hz, 2H). M+H, 620.2

Analytical Methods. Purity of both target compounds and synthetic intermediates were determined by a standard HPLC method using H₂O (0.1% formic acid)/MeOH (0.05% formic acid) gradient as a mobile phase on an Agilent Zorbax XDB-C8 50×4.6 mm (3.5 μm) column and/or Thermo Aquasil C18 100×4.6 mm (5 μm) column.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

1. A compound having the structure: