TYK2 inhibitors and uses thereof

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 11, 2018, is named 394482-30TYUS(156543)_SL.txt and is 1,073 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine-protein kinase 2 (“TYK2”), also known as Tyrosine kinase 2. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is the protein kinase family.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of TYK2 kinase.

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating TYK2 kinases. Such diseases, disorders, or conditions include those described herein.

Compounds provided by this invention are also useful for the study of TYK2 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are useful as inhibitors of TYK2 protein kinase.

The pseudokinase binding pocket of TYK2 contains a plurality of hydration sites, each of which is occupied by a single molecule of water. Each of these water molecules has a stability rating associated with it. As used herein, the term “stability rating” refers to a numerical calculation which incorporates the enthalpy, entropy, and free energy values associated with each water molecule. This stability rating allows for a measurable determination of the relative stability of water molecules that occupy hydration sites in the binding pocket of TYK2.

Water molecules occupying hydration sites in the binding pocket of TYK2 having a stability rating of >2.5 kcal/mol are referred to as “unstable waters.”

Without wishing to be bound by any particular theory, it is believed that displacement or disruption of an unstable water molecule (i.e., a water molecule having a stability rating of >2.5 kcal/mol), or replacement of a stable water (i.e., a water molecule having a stability rating of <1 kcal/mol), by an inhibitor results in tighter binding of that inhibitor. Accordingly, inhibitors designed to displace one or more unstable water molecules (i.e., those unstable water molecules not displaced by any known inhibitor) will be a tighter binder and, therefore, more potent inhibitor as compared to an inhibitor that does not displace unstable water molecules.

It was surprisingly found that provided compounds displace or disrupt one or more unstable water molecules. In some embodiments, a provided compound displaces or disrupts at least two unstable water molecules.

In certain embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein each of X, L1, R1, R2, and Cy1is as defined below and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition comprising administering to a patient in need thereof, a compound of formula I or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof, wherein each of X, L1, R1, R2, and Cy1is as defined below and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula VIII, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition comprising administering to a patient in need thereof, a a compound of formula VIII or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a compound of formula XVI′:

or a pharmaceutically acceptable salt thereof, wherein each of Q, X, Y1, Y2, Z1, Z2, L1, R1, R2, and Cy1is as defined below and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula XVI′, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition comprising administering to a patient in need thereof, a a compound of formula XVI′ or a pharmaceutically acceptable salt thereof.

2. Compounds and Definitions

As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

As used herein, the term “inhibitor” is defined as a compound that binds to and/or inhibits TYK2 with measurable affinity. In certain embodiments, an inhibitor has an IC50and/or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeably with the term “label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium,32P,33P,35S, or14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a TYK2 protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a TYK2 protein kinase, and an equivalent sample comprising an TYK2 protein kinase, in the absence of said compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R3);R1is R, RD, or —OR;R2is H, RC, —N(R)C(O)Cy2, —N(R)S(O)2Cy2, —N(R)Cy2, —OCy2, —SCy2, or Cy2;R3is H, halogen, or C1-6aliphatic; orR2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4;each of Cy1and Cy2is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5; and; wherein Cy2is substituted with p instances of R6;L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—;each instance of R4, R5, R6, and R7is independently RAor RB, and is substituted by q instances of RC;each instance of RAis independently oxo, halogen, —CN, —NO2, —OR, —ORD, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R;each instance of RBis independently C1-6aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of RCis independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RDis a C1-4aliphatic group wherein one or more hydrogens are replaced by deuterium;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of m, n, p, and q is independently 0, 1, 2, 3, or 4.

As defined generally above, X is N or C(R3). In some embodiments, X is N. In some embodiments, X is C(R3). In some embodiments, X is C(H). In some embodiments, X is C(R3), where R3is halogen. In some embodiments, X is C(R3), where R3is fluoro.

In some embodiments, R2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4. In some embodiments, R2and R3are taken together with their intervening atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4.

As defined generally above, Cy1is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5.

In some embodiments, Cy1(R5)ntaken together is selected from the following:

wherein each of R, RC, and q is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, Cy1(R5)ntaken together is selected from the groups in the preceding paragraph or the following:

In some embodiments, Cy1(R5)ntaken together is selected from the groups in the preceding two paragraph or the following:

As defined generally above, Cy2is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with p instances of R6.

In some embodiments, Cy2is selected from the following, each of which is substituted by p instances of R6:

In some embodiments, Cy2is selected from the groups in the preceding paragraph, or the following, each of which is substituted by p instances of R6:

In some embodiments, p is 1 or 2 and at least one instance of R6is —CN, —CH3, —CHF2, or —CF3.

As defined generally above, L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—. In some embodiments, L1is a covalent bond. In some embodiments, L1is a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—. In some embodiments, L1is —N(R)—. In some embodiments, L1is —N(H)—.

As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the present invention provides a compound of formula I, wherein L1is —N(H)—, thereby forming a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula I, wherein X is N or C(R3), thereby forming a compound of formulas I-b or I-c respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy1, L1, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula I-a, wherein L1is N or C(R3), thereby forming a compound of formulas II-a or II-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy1, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula II-a or II-b wherein Cy1is phenyl, thereby forming a compound of formulas III-a or III-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, and n is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula III-a or III-b, wherein n is 1, 2 or 3, and at least one instance of R5is ortho to the NH point of attachment, thereby forming a compound of formulas IV-a or IV-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula IV-a or IV-b, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas V-a, V-b, V-c, V-d, V-e, V-f, V-g, or V-h respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula V-a or V-b, wherein a second R5group (R5b) is meta to the NH point of attachment, thereby forming a compound of formulas VI-a, or VI-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein R5is RB. In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein R5is —C(O)NR2or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by q instances of RC.

In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein —OR is methoxy, fluoromethoxy, or difluoromethoxy.

In some embodiments, the present invention provides a compound of formula II-a or II-b wherein Cy1is pyridyl, n is 2, and one instance of R5is oxo, thereby forming a pyridone compound of formulas VII-a or VII-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R5, is as defined above and described in embodiments herein, both singly and in combination.

As described above, in certain embodiments, the present invention provides a compound of formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R3);Y is N or C(R1);R1is H, D, or halogen;R, RD, or —OR;R2is H, RC, —N(R)C(O)Cy2, —N(R)S(O)2Cy2, —N(R)Cy2, —OCy2, —SCy2, or Cy2;R3is H, halogen, or C1-6aliphatic; orR2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4;each of Cy1and Cy2is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy1is substituted with n instances of R5; and; wherein Cy2is substituted with p instances of R6;Cy3is a 5-6 membered monocyclic partially unsaturated or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy3is substituted with r instances of R8;L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —OC(O)N(R)—, —N(R)C(O)O—, —S—, —S(O)— or —S(O)2—;each instance of R4, R5, R6, R7and R8is independently RAor RB, and is substituted by q instances of RC;each instance of RAis independently oxo, halogen, —CN, —NO2, —OR, —ORD, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R;each instance of RBis independently C1-6aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of RCis independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RDis a C1-4aliphatic group wherein one or more hydrogens are replaced by deuterium;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.

As defined generally above, X is N or C(R3). In some embodiments, X is N. In some embodiments, X is C(R3). In some embodiments, X is C(H). In some embodiments, X is C(R3), where R3is halogen. In some embodiments, X is C(R3), where R3is fluoro.

As defined generally above, Y is N or C(R1). In some embodiments, Y is N. In some embodiments, Y is C(R1). In some embodiments, Y is C(H). In some embodiments, Y is C(D). In some embodiments, Y is C(R1), where R1is halogen. In some embodiments, X is C(R1), where R3is fluoro.

In some embodiments, R2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4. In some embodiments, R2and R3are taken together with their intervening atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4.

As defined generally above, Cy1is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5.

In some embodiments, Cy1(R5)ntaken together is selected from the following:

wherein each of R, RC, and q is as defined above and described in embodiments herein, both singly and in combination.

As defined generally above, Cy2is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with p instances of R6.

In some embodiments, Cy2is selected from the following, each of which is substituted by p instances of R6:

In some embodiments, Cy2is selected from the groups in the preceding paragraph, or the following, which is substituted by p instances of R6:

As defined generally above, Cy3is a 5-6 membered monocyclic partially unsaturated or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy3is substituted with r instances of R8. In some embodiments, Cy3is a 5-membered monocyclic partially unsaturated or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy3is a 5-membered monocyclic partially unsaturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy3is a 5-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Cy3is selected from the following, each of which is substituted by r instances of R8:

As defined generally above, L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—. In some embodiments, L1is a covalent bond. In some embodiments, L1is a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—. In some embodiments, L1is —N(R)—. In some embodiments, L1is —N(H)—.

As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

In some embodiments, the present invention provides a compound of formula VIII, wherein L1is —N(H)—, thereby forming a compound of formula VIII-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula VIII, wherein X is C(R3) and Y is C(R1), or X is C(R3) and Y is N, or X is N and Y is C(R1), or both X and Y are N; thereby forming a compound of formulas IX-a, IX-b, IX-c, or IX-d respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy1, Cy3, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formulas IX-a, IX-b, IX-c, or IX-d, wherein L1is —N(H)—, thereby forming a compound of formulas X-a or X-b, X-c, or X-d respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy1, Cy3, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula VIII-a, wherein Cy1is phenyl, thereby forming a compound of formula XI-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, R2, R5, and n is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula X-a, X-b, X-c, or X-d wherein Cy1is phenyl, thereby forming a compound of formulas XI-b, XI-c, XI-d, or XI-e respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, and n is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XI-a, wherein n is 1, 2 or 3, and at least one instance of R5is ortho to the NH point of attachment, thereby forming a compound of formula XII-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, Cy3, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XI-b, XI-c, XI-d, or XI-e wherein n is 1, 2 or 3, and at least one instance of R5is ortho to the NH point of attachment, thereby forming a compound of formula XII-b, XII-c, XII-d, or XII-e respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R1, R2, R3and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-a, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas XII-a-i, XII-a-ii, XII-a-iii, or XII-a-iv respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, Cy3, R, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-b, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas XII-b-i, XII-b-ii, XII-b-iii, or XII-b-iv respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-c, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas XII-c-i, XII-c-ii, XII-c-iii, or XII-c-iv respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-d, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas XII-d-i, XII-d-ii, XII-d-iii, or XII-d-iv respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R, R1, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-e, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formulas XII-e-i, XII-e-ii, XII-e-iii, or XII-e-iv respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-a-i, wherein a second R5group is meta to the NH point of attachment, thereby forming a compound of formula XIII-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, Cy3, R, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XII-b-i, XII-c-i, XII-d-i, or XII-e-i, wherein a second R5group is meta to the NH point of attachment, thereby forming a compound of formula XIII-b, XIII-c, XIII-d, or XIII-e, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e wherein R5is RB. In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e wherein R5is —C(O)NR2or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by q instances of RC.

In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e wherein —OR is methoxy, fluoromethoxy, or difluoromethoxy.

In some embodiments, the present invention provides a compound of formula I-a, wherein Cy1is pyridyl, n is 2, and one instance of R5is oxo, thereby forming a pyridone compound of formula XIV-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, Cy3, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula X-a or X-b, X-c, or X-d, wherein Cy1is pyridyl, n is 2, and one instance of R5is oxo, thereby forming a pyridone compound of formula XV-a, XV-b, XV-c, or XV-d:

or a pharmaceutically acceptable salt thereof, wherein each of Cy3, R1, R2, R3, and R5is as defined above and described in embodiments herein, both singly and in combination.

As described above, in certain embodiments, the present invention provides a compound of formula XVI′:

or a pharmaceutically acceptable salt thereof, wherein:Q is CH or N;X is N or C(RX);one of Y1, Y2, Z1, and Z2is N, and the other three are C;R1is D, R, RD, —NR2, —NRRD, —N(RD)2, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)C(O)NRRD, —N(R)C(NR)NRRD, —OR, or —ORD;R2is H, RC, —N(R)C(O)Cy2, —N(R)S(O)2Cy2, —N(R)Cy2, —OCy2, —SCy2, or Cy2; R3is H, halogen, or C1-6aliphatic; orR2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4;each of Cy1and Cy2is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5; and; wherein Cy2is substituted with p instances of R6;L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—;each instance of R4, R5, R6, and R7is independently RAor RB, and is substituted by q instances of RC.each instance of RAis independently oxo, halogen, —CN, —NO2, —OR, —ORD, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R;each instance of RBis independently C1-6aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of RCis independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RDis a C1-4aliphatic group wherein one or more hydrogens are replaced by deuterium;RXis H, halogen, or C1-6aliphaticeach R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of m, n, p, and q is independently 0, 1, 2, 3, or 4.

As defined generally above, Q is CH or N. In some embodiments, Q is CH. In some embodiments, Q is N.

As defined generally above, X is N or C(RX). In some embodiments, X is N. In some embodiments, X is C(RX). In some embodiments, X is C(H). In some embodiments, X is C(RX), where RXis halogen. In some embodiments, X is C(RX), where RXis fluoro.

In some embodiments, R2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4. In some embodiments, R2and R3are taken together with their intervening atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4.

As defined generally above, Cy1is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5.

In some embodiments, Cy1(R5)ntaken together is selected from the following:

wherein each of R, RC, and q is as defined above and described in embodiments herein, both singly and in combination.

As defined generally above, Cy2is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with p instances of R6.

In some embodiments, Cy2is selected from the following, each of which is substituted by p instances of R6:

As defined generally above, L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—. In some embodiments, L1is a covalent bond. In some embodiments, L1is a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—.

As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the present invention provides a compound of formula XVI′ wherein Q is N, thereby forming a compound of formula XVI:

or a pharmaceutically acceptable salt thereof, wherein:X is N or C(RX);one of Y1, Y2, Z1, and Z2is N, and the other three are C;R1is D, R, RD, —NR2, —NRRD, —N(RD)2, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)C(O)NRRD, —N(R)C(NR)NRRD, —OR, or —ORD;R2is H, RC, —N(R)C(O)Cy2, —N(R)S(O)2Cy2, —N(R)Cy2, —OCy2, —SCy2, or Cy2;R3is H, halogen, or C1-6aliphatic; orR2and R3are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R4;each of Cy1and Cy2is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with n instances of R5; and; wherein Cy2is substituted with p instances of R6;L1is a covalent bond or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R7)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—;each instance of R4, R5, R6, and R7is independently RAor RB, and is substituted by q instances of RC;each instance of RAis independently oxo, halogen, —CN, —NO2, —OR, —ORD, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R;each instance of RBis independently C1-6aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of RCis independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RDis a C1-4aliphatic group wherein one or more hydrogens are replaced by deuterium;RXis H, halogen, or C1-6aliphaticeach R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of m, n, p, and q is independently 0, 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound of formula XVI, wherein L1is a covalent bond, thereby forming a compound of formula XVI-a:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y1, Y2, Z1, Z2, Cy1, R1, R2and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI, wherein X is N or C(RX), thereby forming a compound of formula XVI-b or XVI-c respectively:

or a pharmaceutically acceptable salt thereof, wherein each of L1, Y1, Y2, Z1, Z2, Cy1, RX, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI-b or XVI-c, wherein RXand R3are both H, thereby forming a compound of formula XVII-a or XVII-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVII-a or XVII-b, wherein L1is a covalent bond, thereby forming a compound of formula XVIII-a or XVIII-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVIII-a or XVIII-b wherein Cy1is phenyl, thereby forming a compound of formula XIX-a or XIX-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, R2, and n is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XIX-a or XIX-b, wherein n is 1, 2 or 3, and at least one instance of R5is ortho to the NH point of attachment, thereby forming a compound of formula XX-a or XX-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XX-a or XX-b, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formula XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, or XXI-h respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXI-a or XXI-b, wherein a second R5group is meta to the NH point of attachment, thereby forming a compound of formula XXII-a, or XXII-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R, R1, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R5is RB. In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R5is —CN, —C(O)NR2or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by q instances of RC.

In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein —OR is methoxy, fluoromethoxy, or difluoromethoxy.

In some embodiments, the present invention provides a compound of formula XVIII-a or XVIII-b wherein Cy1is pyridyl, n is 2, and one instance of R5is oxo, thereby forming a pyridone compound of formula XXIII-a or XXIII-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, R2, and R5, is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula I wherein Z2is N, and Y1, Y2, and Z1are C; or wherein Y2is N, and Y1, Z1, and Z2are C, thereby forming a compound of formula XXIV-a or XXIV-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, L1, Cy1, R1, and R2, is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXIV-a or XXIV-b wherein L1is a covalent bond, thereby forming a compound of formula XXV-a or XXV-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXV-a or XXV-b wherein X is C, and RXis H, thereby forming a compound of formula XXVI-a or XXVI-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI′ wherein Q is CH, thereby forming a compound of formula XVI′:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y1, Y2, Z1, Z2, Cy1, R1, R2and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI″, wherein L1is a covalent bond, thereby forming a compound of formula XVI-a′:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y1, Y2, Z1, Z2, Cy1, R1, R2and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI″, wherein X is N or C(RX), thereby forming a compound of formula XVI-b′ or XVI-c′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of L1, Y1, Y2, Z1, Z2, Cy1, RX, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVI-b′ or XVI-c′, wherein RXand R3are both H, thereby forming a compound of formula XVII-a′ or XVII-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, R2, and R3is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVII-a′ or XVII-b′, wherein L1is a covalent bond, thereby forming a compound of formula XVIII-a′ or XVIII-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XVIII-a′ or XVIII-b′ wherein Cy1is phenyl, thereby forming a compound of formula XIX-a′ or XIX-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, R2and n is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XIX-a′ or XIX-b′, wherein n is 1, 2 or 3, and at least one instance of R5is ortho to the NH point of attachment, thereby forming a compound of formula XX-a′ or XX-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XX-a′ or XX-b′, wherein the ortho R5group is —OR, —S(O)2R, —C(O)NR2, or —N(R)S(O)2R, thereby forming a compound of formula XXI-a′, XXI-b′, XXI-c′, XXI-d′, XXI-e′, XXI-g′, or XXI-h′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R, R1, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXI-a′ or XXI-b′, wherein a second R5group is meta to the NH point of attachment, thereby forming a compound of formula XXII-a′, or XXII-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R, R1, R2, and R5is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXII-a′ or XXII-b′, wherein R5is RB. In some embodiments, the present invention provides a compound of formula XXII-a′ or XXII-b′, wherein R5is —CN, —C(O)NR2or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by q instances of RC.

In some embodiments, the present invention provides a compound of formula XXII-a′ or XXII-b′, wherein —OR is methoxy, fluoromethoxy, or difluoromethoxy.

In some embodiments, the present invention provides a compound of formula XVIII-a′ or XVIII-b′ wherein Cy1is pyridyl, n is 2, and one instance of R5is oxo, thereby forming a pyridone compound of formula XXIII-a′ or XXIII-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R1, R2, and R5, is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula I′ wherein Z2is N, and Y1, Y2, and Z1are C; or wherein Y2is N, and Y1, Z1, and Z2are C, thereby forming a compound of formula XXIV-a′ or XXIV-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Q, X, L1, Cy1, R1, and R2, is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXIV-a′ or XXIV-b′ wherein L1is a covalent bond, thereby forming a compound of formula XXV-a′ or XXV-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Q, X, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of formula XXV-a′ or XXV-b′ wherein X is C, and RXis H, thereby forming a compound of formula XXVI-a′ or XXVI-b′ respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Q, Cy1, R1, and R2is as defined above and described in embodiments herein, both singly and in combination.

Exemplary compounds of the invention are set forth in Table 1, below.

Exemplary compounds of the invention are set forth in Table 2, below.

Exemplary compounds of the invention are set forth in Table 3, below.

In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the method employs a compound set forth in Table 2, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 2, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the method employs a compound set forth in Table 3, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 3, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 3 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

Without wishing to be bound by any particular theory, it is believed that proximity of an inhibitor compound, or pendant moiety of an inhibitor compound, to the water of interest facilitates displacement or disruption of that water by the inhibitor compound, or pendant moiety of an inhibitor compound. In some embodiments, a water molecule displaced or disrupted by an inhibitor compound, or pendant moiety of an inhibitor compound, is an unstable water molecule.

In certain embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water of TYK2 is displaced or disrupted by the inhibitor. In some embodiments, at least two unstable waters selected are displaced or disrupted by the inhibitor.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

In some embodiments, compounds of formula I are prepared according to the following general procedure, depicted in Scheme 1.

In some embodiments, where L1is NH, intermediates of formula Cy1-NH2are prepared according to the methods described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, the entirety of each of which is incorporated herein by reference.

In some embodiments, compounds of formula VIIII are prepared according to the following general procedure, depicted in Scheme 2.

In some embodiments, where L1is NH, intermediates of formula Cy1-NH2are prepared according to the methods described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, the entirety of each of which is incorporated herein by reference.

In some embodiments, compounds of formula XXIV-b are prepared according to the following general procedure, depicted in Scheme 3.

wherein each of X, L1, and Cy1is as defined above and in embodiments herein, singly and in combination.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit a TYK2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit a TYK2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a TYK2 protein kinase, or a mutant thereof.

Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods of the invention is TYK2

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Velasquez et al., “A protein kinase in the interferon α/β signaling pathway,” Cell (1992) 70:313; Stahl et al., “Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,” Science (1994) 263:92; Finbloom et al., “IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,” J. Immunol. (1995) 155:1079; Bacon et al., “Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12,” J. Exp. Med. (1995) 181:399; Welham et al., “Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin,” J. Biol. Chem. (1995) 270:12286; Parham et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R,” J. Immunol. (2002) 168:5699. The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., “A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene,” Science (2006) 314:1461-1463. As the downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behçet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nat. Genet. (2013) 45(7):730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease,” Nat. Genet. (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis. Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi: 10.1093/intimm/dxt062.

TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway,” FASEB J. (2012) 26:1-11.

Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Th1/Th17-related cytokines and matrix metalloproteases, and other key markers of inflammation. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582. TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183:7539-7546. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17:1309-1313. Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

TYK2 is the sole signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics (2011) 7(10):e1002341.

TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects. Simma et al. “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance,” Cancer Res. (2009) 69:203-211.

However, paradoxically to the decreased tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STAT1-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in failure to transform. Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013) 3(5):564-577.

Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. Fontan et al. “Discovering What Makes STAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3:494-496.

TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. Wan et al. “Tyk/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease,” J. Neurosci. (2010) 30(20):6873-6881.

Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20: 1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth,” Sci. Adv. (2015) 1(9):e1500973.

Accordingly, compounds that inhibit the activity of TYK2 are beneficial, especially those with selectivity over JAK2. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK2.

Even though TYK2 inhibitors are known in the art, there is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased activity, selectivity over other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties. Thus, in some embodiments, the present invention provides inhibitors of TYK2 which show selectivity over JAK2.

The activity of a compound utilized in this invention as an inhibitor of TYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated TYK2, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TYK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/TYK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with TYK2 bound to known radioligands. Representative in vitro and in vivo assays useful in assaying a TYK2 inhibitor include those described and disclosed in, e.g., each of which is herein incorporated by reference in its entirety. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of TYK2, or a mutant thereof, are set forth in the Examples below.

Provided compounds are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with activity of TYK2 or mutants thereof. Thus, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

As used herein, the term “TYK2-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.

In some embodiments, the present invention provides a method for treating one or more disorders, wherein the disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder is an autoimmune disorder. In some embodiments the disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

In some embodiments the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

In some embodiments, the disorder is associated with transplantation. In some embodiments the disorder associated with transplantation is transplant rejection, or graft versus host disease.

In some embodiments the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disorder is associated with type I interferon signaling. In some embodiments the disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disorder is associated with IL-23 signaling.

Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a Th1 or Th17 mediated disease. In some embodiments the Th17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

Furthermore, the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and)Rebif®, Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.

As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treating systemic lupus erythematosus comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.

In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII, or XVI′ and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small-cell lung cancer, non-small-cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.

In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments the JH2 binding compound is a compound of formula I, VIII, or XVI′. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, the entirety of each of which is incorporated herein by reference. Suitable JH1 domain binding compounds include those described in WO2015131080A1, the entirety of which is incorporated herein by reference.

The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

According to one embodiment, the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method of inhibiting TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

In another embodiment, the invention provides a method of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, a compound of the present invention is more than 2-fold selective over JAK1/2/3. In some embodiments, a compound of the present invention is more than 5-fold selective over JAK1/2/3. In some embodiments, a compound of the present invention is more than 10-fold selective over JAK1/2/3. In some embodiments, a compound of the present invention is more than 50-fold selective over JAK1/2/3. In some embodiments, a compound of the present invention is more than 100-fold selective over JAK1/2/3.

Inhibition of TYK2 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method of inhibiting activity of TYK2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of TYK2, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™ Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an anti estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term “gonadorelin agonist” as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™) daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed. under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

The term “microtubule active agent” relates to microtubule stabilizing, microtubule destabilizing compounds and microtubulin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; colchicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

The term “alkylating agent” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No. 8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.

Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.

Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term “biological response modifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (Zarnestra™). The term “telomerase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “compounds used in the treatment of hematologic malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

The term “antiproliferative antibodies” as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan™), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. In some embodiments, the present invention provides a method of treating AML associated with an ITD and/or D835Y mutation, comprising administering a compound of the present invention together with a one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e.g. midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat. No. 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl) 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term “ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4thEdition, Vol. 1, pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.

The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications).

A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of an inventive compound can be administered.

In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01-1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.

The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

Synthesis of Compound 1.2

Synthesis of Compound 1.3

To 1.2 (50 g, 236.7 mmol, 1.0 eq) was added aq. NH4OH (300 mL) followed by methanolic NH3(1600 mL). Reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure and residue was washed with ice cold water. Precipitate was dried to furnish 1.3 (45.0 g, 96.0%). MS(ES): m/z 197.2 [M+H]+.

Synthesis of Compound 1.4

To a suspension of NaN3(21.8 g, 336 mmol, 3.0 eq) in acetonitrile (220 mL) was added SiCl4(28.6 g, 168 mmol, 1.5 eq). To the stirred suspension was added compound 1.3 (22.0 g, 112 mmol, 1.0 eq) and the reaction mixture was stirred at 75° C. for 16 h. Reaction mixture was cooled to room temperature and water was added. Solid precipitated out was filtered to provide 1.4 (18.0 g, 72.5%). MS(ES): m/z 222.2 [M+H]+.

Synthesis of Compound 1.5

To a stirred solution of 1.4 (15.0 g, 67.8 mmol, 1.0 eq) in DMF (150 mL) was added K2CO3(23.4 g, 169.7 mmol, 2.5 eq) at 0° C. To this added MeI (19.1 g, 135.7 mmol, 2.0 eq) dropwise. Reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, mixture was transferred into water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to pressure to obtain crude material. The crude was purified by column chromatography to provide desired regioisomer 1.5 (10.0 g, 62.7%). MS(ES): m/z 236.2 [M+H]−.

Synthesis of Compound 1.6

To a solution of 1.5 (10.0 g, 42.5 mmol, 1.0 eq) in MeOH (100 mL), 10% Pd/C (2.0 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of the reaction, mixture was filtered through Celite-bed and washed with MeOH. Filtrate was concentrated under reduced pressure to obtain 1.6. (5.3 g, 60.7%). MS(ES): m/z 206.3 [M+H]+.

Synthesis of Compound 1.8

To 1.7 (1.0 g, 4.42 mmol, 1.0 eq) was added SOCl2(5.0 mL) followed by DMF (catalytic) and refluxed for 16 h. Reaction mixture was concentrated under reduced pressure to obtain acyl chloride. Methyl hydrazine (0.20 g, 42.5 mmol, 1.0 eq) was dissolved in CH2Cl2(20.0 mL) followed by addition of solution of NaOH (0.72 g, 177 mmol, 4.0 eq) in water (5.0 mL). To the solution was added previously made acyl chloride solution in CH2Cl2(20.0 mL) dropwise. Reaction mixture was refluxed for 15 min. After completion of reaction, reaction mixture was transferred into water and extracted with CH2Cl2. Organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to pressure to obtain crude which was purified by column chromatography to provide 1.8. (1.1 g, 97.0%). MS(ES): m/z 255.5 [M+H]+.

Synthesis of Compound 1.9

To a suspension of 1.8 (1.0 g, 3.93 mmol, 1.0 eq) in 1-pentanol (15.0 mL) was added Na2CO3(0.49 g, 3.93 mmol, 1.0 eq) and reaction mixture was stirred at 120° C. for 16 h. After completion of the reaction, reaction mixture was cooled to room temperature and pH=6.0 was adjusted using 1 N HCl. Reaction mixture was concentrated under reduced pressure to obtain crude which was purified by preparative HPLC to furnish 1.9. (0.15 g, 17.5%). MS(ES): m/z 219.2 [M+H]+.

Synthesis of Compound 1.91

To a solution of 1.9 (0.1 g, 0.45 mmol, 1.0 eq) and 1.6 (0.188 g, 0.917 mmol, 2.0 eq) in THF (2.0 mL) was added 1.0 M solution of LHMDS (1.6 mL, 1.57 mmol, 3.5 eq) in tetrahydrofuran at −78° C. Reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, reaction mixture was transferred into water and extracted with EtOAc. Aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to pressure to get pure 1.91. (0.1 g, 56.37%). MS(ES): m/z 387.9 [M+H]+.

Synthesis of Compound I-1

Synthesis of Compound 28.1

Following the procedure used to prepare 1.91, 28.1 was obtained (Yield: 24%). MS (ES): m/z 340.2 [M+H]+.

Synthesis of Compound 29.1

Following the procedure used to prepare 1.91, 29.1 was obtained (Yield: 57.32%). MS (ES): m/z 335.8 [M+H]+.

Synthesis of Compound 30.1

Following the procedure used to prepare 1.91, 30.1 was obtained (Yield: 57.51%). MS (ES): m/z 349.8 [M+H]+.

Synthesis of Compound 31.1

Following the procedure used to prepare 1.91, 31.1 was obtained (Yield: 49.08%). MS (ES): m/z 400.7 [M+H]+.

Synthesis of Compound 32.1

Following the procedure used to prepare 1.91, 32.1 was obtained (Yield: 21.10%). MS (ES): m/z 402.7 [M+H]+.

Synthesis of Compound 33.1

Following the procedure used to prepare 1.91, 33.1 was obtained (Yield: 54.05%). MS (ES): m/z 323.7 [M+H]+.

Following the procedure used to prepare 1.91, 34.1 was obtained (Yield: 47.14%). MS (ES): m/z 340.2 [M+H]+.

Following the procedure used to prepare 1.91, 35.1 was obtained (Yield: 54.80%). MS (ES): m/z 345.7 [M+H]+.

Following the procedure used to prepare 1.91, 36.1 was obtained (Yield: 50.64%). MS (ES): m/z 359.8 [M+H]+.

Following the procedure used to prepare 1.91, 37.1 was obtained (Yield: 68.77%). MS (ES): m/z 387.7 [M+H]+.

Following the procedure used to prepare 1.91, 38.1 was obtained (Yield: 68.16%). MS (ES): m/z 400.8 [M+H]+.

Following the procedure used to prepare 1.91, 39.1 was obtained (Yield: 62.17%). MS (ES): m/z 386.6 [M+H]+.

Following the procedure used to prepare 1.91, 40.1 was obtained (Yield: 48.16%). MS (ES): m/z 385.7 [M+H]+.

Following the procedure used to prepare 1.91, 41.1 was obtained (Yield: 58.80%). MS (ES): m/z 371.8 [M+H]+.

Following the procedure used to prepare 1.91, 42.1 was obtained (Yield: 37.77%). MS (ES): m/z 385.5 [M+H]+.

Following the procedure used to prepare 1.91, 46.1 was obtained (Yield: 75.13%). MS (ES): m/z 305.7 [M+H]+.

Following the procedure used to prepare 1.91, 51.1 was obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H]+.

Following the procedure used to prepare 1.91, 52.1 was obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H]+.

Following the procedure used to prepare 1.91, 53.1 was obtained (Yield: 56.84%). MS (ES): m/z 384.6 [M+H]+.

Following the procedure used to prepare 1.91, 54.1 was obtained (Yield: 65.13%). MS (ES): m/z 335.8 [M+H]+.

Following the procedure used to prepare 1.91, 55.1 was obtained (Yield: 81.07%). MS (ES): m/z 323.7 [M+H]+.

Following the procedure used to prepare 1.91, 60.1 was obtained (Yield: 24.74%). MS (ES): m/z 388.8 [M+H]+.

Following the procedure used to prepare 1.91, 66.1 was obtained (Yield: 56.22%). MS (ES): m/z 388.7 [M+H]+.

Following the procedure used to prepare 1.91, 70.1 was obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H]+.

Following the procedure used to prepare 1.91, 73.1 was obtained (Yield: 70.71%). MS (ES): m/z 340.2 [M+H]+.

Following the procedure used to prepare 1.91, 81.1 was obtained (Yield: 63.99%). MS (ES): m/z 341.7 [M+H]+.

Synthesis of Compound 82.1

To 2,4,6-trichloronicotinic acid (0.25 g, 1.10 mmol, 1.0 eq) was added thionyl chloride (1.2 mL) followed by N,N-dimethylformamide(catalytic) and refluxed for 16 h. Reaction mixture was concentrated under reduced pressure to obtain acid chloride. Methyl hydrazine d3 sulfate (0.16 g, 1.10 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) followed by addition of solution of sodium hydroxide (0.18 g, 4.40 mmol, 4.0 eq) in water (1.2 mL). To this added solution of previously made acid chloride in dichloromethane (5 mL) dropwise and reaction mixture was refluxed for 15 min. After completion of reaction, reaction mixture was transferred into water and extracted with dichloromethane. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 30% ethyl acetate in hexane to get pure 1.1. (0.2 g, 70.35%). MS(ES): m/z 258.5 [M+H]+.

Synthesis of Compound 82.2

To a suspension of 83.1 (0.2 g, 0.776 mmol, 1.0 eq) in 1-pentanol (5 mL) was added sodium carbonate (0.083 g, 0.776 mmol, 1.0 eq) and reaction mixture was stirred at 120° C. for 18 h. After completion of reaction, reaction mixture was cooled to room temperature and pH=6 was adjusted using 1N hydrochloric acid. Reaction mixture was concentrated under reduced pressure to obtain crude material. This was further purified by Preparative HPLC using 0.1% Formic acid in water/Acetonitrile in gradient method to obtain pure 1.2. (0.085 g, 49.51%). MS(ES): m/z 222.06 [M+H]+.

Synthesis of Compound 82.3

Following the procedure used to prepare 1.91, 82.3 was obtained (Yield: 30.78%). MS (ES): m/z 390.82 [M+H]+.

Synthesis of Compound 83.1

Synthesis of Compound 83.2

To 83.1 (5 g, 23.67 mmol, 1.0 eq) was added aqueous ammonia (30 mL) followed by methanolic ammonia (160 mL). Reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and residue was washed with ice cold water. Solid was dried well to obtain 83.2 (4.5 g, 96%). MS(ES): m/z 197.2 [M+H]+.

Synthesis of Compound 83.3

To a solution of 83.2 (4.5 g, 22.94 mmol, 1.0 eq) in methanol (45 mL), 10% palladium on charcoal (1.0 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 83.3. (3.0 g, 78.69%). MS(ES): m/z 167.18 [M+H]+.

Synthesis of Compound 83.4

Following the procedure used to prepare 1.91, 84.4 was obtained (Yield: 62.70%). MS (ES): m/z 348.76 [M+H]+.

Compound 84.1 was prepared from compound 84 and 2,6-dimethylpyrimidin-4-amine using procedure described in Example 2 (Yield: 19.00%). MS (ES): m/z 417.45 [M+H]+.

Synthesis of Compound I-103

Compound 85.1 was prepared from compound 85 and 5-fluoro-4-methylpyridin-2-amine using procedure described in Example 2 (Yield: 19.65%). MS (ES): m/z 420.42 [M+H]+.

Synthesis of Compound I-106

Following the procedure used to prepare 1.91, 86.1 was obtained (Yield: 76.89%). MS (ES): m/z 321.80 [M+H]+.

Synthesis of Compound 86.2

Synthesis of Compound 92.1

To 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.45 mmol, 1.0 eq) in dimethylformamide (1 ml) was added zinc cyanide (1.456 g, 12.45 mmol, 1.0 eq). The reaction mixture was then heated in microwave at 150° C. for 15 min. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain 92.1. (Yield: 68.69%). MS (ES): m/z 188.13 [M+H]+.

Synthesis of Compound 92.2

To compound 92.1 (1.6 g, 8.55 mmol, 1.0 eq) and sodium hydroxide (1.0 g, 25.65 mmol, 3.0 eq) was added in water (30 mL) The reaction mixture was stirred at 100° C. for 16 h. After completion of reaction, reaction mixture was extracted with ethyl acetate. Aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 5% methanol in dichloromethane to obtain 93.2. (Yield: 62.41%). MS (ES): m/z 207.12 [M+H]+.

Synthesis of Compound 92.3

To a cooled solution of 92.2 (0.5 g, 2.43 mmol, 1.0 eq) and pyrrolidine (0.19 g, 2.67 mmol, 1.1 eq) in N,N-dimethylformamide (5 mL) at 0° C. was added ((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro-phosphate)) (1.846 g, 4.86 mmol, 2.0 eq) followed by N,N-Diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 3% methanol in dichloromethane to obtain pure 92.3 (0.39 g, 62.34%). MS(ES): m/z 260.23 [M+H]+.

Synthesis of Compound 93.1

To a cooled solution of 6-amino-2-(trifluoromethyl)nicotinic acid (0.5 g, 2.43 mmol, 1.0 eq) and morpholine (0.23 g, 2.67 mmol, 1.1 eq) in N,N-dimethylformamide (5 mL) at 0° C. was added ((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro-phosphate)) (1.846 g, 4.86 mmol, 2.0 eq) followed by N,N-Diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 3% methanol in dichloromethane to obtain pure 93.1 (0.4 g, 59.91%). MS(ES): m/z 276.23 [M+H]+.

Synthesis of Compound 94.1

To 6-bromopyridin-2-amine (2.0 g, 11.56 mmol, 1.0 eq) in dimethylformamide (1 ml) was added zinc cyanide (1.35 g, 11.56 mmol, 1.0 eq). The reaction mixture was then heated in microwave at 150° C. for 15 min. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain 94.1. (1.0 g, Yield: 72.62%). MS (ES): m/z 120.13 [M+H]+.

Synthesis of Compound 94.2

To compound 94.1 (1.0 g, 8.39 mmol, 1.0 eq) in acetonitrile was added N-Bromosuccinimide (2.24 g, 12.58 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 25% ethyl acetate in hexane to obtain 94.2. (0.42 g, Yield: 25.27%). MS (ES): m/z 199.02 [M+H]+.

Synthesis of Compound 94.3

To a solution of 94.2 (0.42 g, 2.12 mmol, 1.0 eq) in mixture of water (5 mL) and 1,4-dioxane (15 mL) was added trimethylboroxine (0.4 g, 3.18 mmol, 1.5 eq), tetrakis (0.073 g, 0.064 mmol, 0.03 eq) and potassium carbonate (0.878 g, 6.36 mmol, 3.0 eq). The reaction mixture was degassed by argon for 30 min. Further reaction mixture was stirred at 110° C. for 4 h. After completion of reaction, reaction mixture was cooled to room temperature transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified in 20% ethyl acetate in hexane to get pure 95.3 (0.1 g, 35.41%). MS(ES): m/z 134.15 [M+H]+.

Synthesis of Compound 98.1

To a solution of 2-chloro-6-nitropyridine (2.0 g, 22.96 mmol, 1.5 eq) and 3-methoxyazetidine (2.43 g, 15.30 mmol, 1.0 eq) in dimethyl sulfoxide (20 mL) was added sodium bicarbonate (2.57 g, 30.60 mmol, 2.0 eq). Reaction mixture was stirred at 80° C. for 4 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluant to obtain pure 98.1 (2.0 g, 62.47%). MS(ES): m/z 210.21 [M+H]+.

Synthesis of Compound 98.2

To a solution of 1.2 (2.0 g, 9.56 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.4 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 98.2. (1.5 g, 87.55%). MS(ES): m/z 180.22 [M+H]+.

Synthesis of Compound 100.1

To a solution of 5-bromopyridin-2-amine (1 g, 5.78 mmol, 1.0 eq) in mixture of toluene (12 mL) and water (1 mL) were added cyclopropyl boronic acid (0.65 g, 7.51 mmol, 1.3 eq) and potassium phosphate (2.45 g, 11.56 mmol, 2.0 eq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.13 g, 0.578 mmol, 0.1 eq) and Tricyclohexylphosphine (0.324 g, 1.15 mmol, 0.2 eq) were added. Reaction mixture was again degassed for 10 min and stirred at 110° C. for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain 101.1. (0.5 g, 64.47%). MS(ES): m/z 135.18 [M+H]+.

Synthesis of Compound 101.1

To 6-bromopyridin-2-amine (2.0 g, 11.56 mmol, 1.0 eq) in dimethylformamide (1 ml) was added zinc cyanide (1.35 g, 11.56 mmol, 1.0 eq). The reaction mixture was then heated in microwave at 150° C. for 15 min. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain 101.1. (1.0 g, Yield: 72.62%). MS (ES): m/z 120.13 [M+H]+.

Synthesis of Compound 101.2

To compound 101.1 (1.0 g, 8.39 mmol, 1.0 eq) in acetonitrile was added N-Bromosuccinimide (2.24 g, 12.58 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 25% ethyl acetate in hexane to obtain 101.2. (0.42 g, Yield: 25.27%). MS (ES): m/z 199.02 [M+H]+.

Synthesis of Compound 101.3

To a solution of 101.2 (2.0 g, 10.10 mmol, 1.0 eq) 1,4-dioxane (20 mL) was added azetidine hydrochloride (1.9 g, 20.20 mmol, 2.0 eq) followed by Tris(dibenzylideneacetone)dipalladium(0) (0.277 g, 0.303 mmol, 0.03 eq), 9,9-Dimethyl-4,5-bis(dI-tert-butylphosphino)xanthene (0.351 g, 0.606 mmol, 0.06 eq) and cesium carbonate (16.4 g, 50.50 mmol, 5.0 eq). The reaction mixture was degassed by argon for 30 min. Further reaction mixture was stirred at 120° C. for 5 h. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 102.3 (0.52 g, 29.95%). MS(ES): m/z 175.21 [M+H]+.

Synthesis of Compound 102.1

To a solution of 6-amino-3-bromopicolinonitrile (0.5 g, 7.57 mmol, 1.0 eq) in 1,4-dioxane (20 mL) was added (S)-3-methoxypyrrolidine hydrochloride (2.1 g, 15.14 mmol, 2.0 eq), Tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.227 mmol, 0.03 eq), 9,9-Dimethyl-4,5-bis(dI-tert-butylphosphino)xanthene (0.26 g, 0.454 mmol, 0.06 eq) and potassium carbonate (3.13 g, 22.71 mmol, 3.0 eq). The reaction mixture was degassed by argon for 30 min. Further reaction mixture was stirred at 120° C. for 5 h. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 102.1 (0.055 g, 9.07%). MS(ES): m/z 219.26 [M+H]+.

Synthesis of Compound 103.1

To a solution of 6-amino-3-bromopyrazine-2-carbonitrile (1 g, 5.02 mmol, 1.0 eq) in mixture of toluene (12 mL) and water (1 mL) was added Potassium cyclopropyltrifluoroborate (0.965 g, 6.526 mmol, 1.3 eq), potassium phosphate (2.13 g, 10.04 mmol, 2.0 eq). The reaction mixture was degassed for 10 min under argon atmosphere, and then [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.205 g, 0.251 mmol, 0.05 eq) was added, again degassed for 10 min. The reaction was then stirred at 110° C. for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain 103.1. (0.49 g, 60.88%). MS(ES): m/z 161.18 [M+H]+.

Synthesis of Compound 104.1

To a solution of 6-amino-3-bromopyrazine-2-carbonitrile (0.2 g, 1.0 mmol, 1.0 eq) in mixture of toluene (2.5 mL) and water (0.5 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.201 g, 1.31 mmol, 1.3 eq) and potassium phosphate (0.424 g, 2.0 mmol, 2.0 eq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.022 g, 0.1 mmol, 0.1 eq) and Tricyclohexylphosphine (0.056 g, 0.2 mmol, 0.2 eq) were added. Reaction mixture was again degassed for 10 min and stirred at 100° C. for 24 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 104.1. (0.12 g, 81.70%). MS(ES): m/z 147.15 [M+H]+.

Synthesis of Compound 104.2

To a solution of 104.1 (0.12 g, 0.821 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal (0.030 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filter through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 104.2 (0.09 g, 73.98%). MS(ES): m/z 149.17 [M+H]+.

Synthesis of Compound 109.1

To a solution of 2-fluoro-4-bromonitrobenzene (1.0 g, 4.55 mmol, 1.0 eq) in mixture of toluene (12 mL) and water (5 mL) were added cyclopropyl boronic acid (0.51 g, 5.91 mmol, 1.3 eq) and potassium carbonate (1.25 g, 9.1 mmol, 2.0 eq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.102 g, 0.455 mmol, 0.1 eq) and Tricyclohexylphosphine (0.255 g, 0.91 mmol, 0.2 eq) were added. Reaction mixture was again degassed for 10 min and stirred at 80° C. for 5 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 10% ethyl acetate in hexane as eluent to obtain 109.1. (0.81 g, 98.36%). MS(ES): m/z 182.17 [M+H]+.

Synthesis of Compound 109.2

To a solution of 109.1 (0.81 g, 4.47 mmol, 1.0 eq) and sodium thiomethoxide (0.313 g, 4.47 mmol, 1.0 eq) in N,N-Dimethylformamide (10 mL) was added. Reaction mixture was stirred at 150° C. for 5 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 110.2. (0.78 g, 83.37%). MS(ES): m/z 210.26 [M+H]+.

Synthesis of Compound 109.3

To a solution of 109.2 (0.78 g, 3.73 mmol, 1.0 eq) in ethanol (10 mL), 10% palladium on charcoal (0.060 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 109.3 (0.63 g, 94.28%). MS(ES): m/z 180.28 [M+H]+.

Synthesis of Compound 109.4

Compound was synthesized from 109.3 and 1.9 using general procedure A to obtain 109.4 (Yield: 58.41%). MS (ES): m/z 361.86 [M+H]+.

Synthesis of Compound 109.5

Synthesis of Compound 114.1

Compound was synthesized from 3-amino-2-methoxybenzonitrile and 1.9 using general procedure A to obtain 114.1 (Yield: 66.12%). MS(ES): m/z 330.74 [M+H]+.

Synthesis of Compound 115.1

To a solution of N-Methyl methane sulfonamide (0.85 g, 7.79 mmol, 1.1 eq) in acetonitrile (10 mL) was added cesium carbonate (0.608 g, 14.18 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min. 1-Fluoro-2-nitrobenzene (1.0 g, 7.09 mmol, 1.0 eq) was added dropwise into reaction mixture and stirred at room temperature for 3 h. After completion of reaction, reaction mixture was filtered. Filtered solid was transferred into water, stirred for 30 min and dried under reduced pressure to obtain pure 115.1. (0.48 g, 29.42%). MS(ES): m/z 231.24 [M+H]+.

Synthesis of Compound 115.2

To a solution of 115.1 (0.48 g, 2.08 mmol, 1.0 eq) in methanol (1 mL), 10% palladium on charcoal (0.08 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 115.2 (0.322 g, 77.13%). MS(ES): m/z 201.26 [M+H]+.

Synthesis of Compound 115.3

Compound 115.3 was synthesized from 1.9 and 115.2 using general procedure A (Yield: 34.26%).

Example 116: Synthesis of I-133

Synthesis of Compound 116.1

To a solution of 5-bromo-1H-imidazole (3.0 g, 20.41 mmol, 1.0 eq) in dichloromethane (30 mL) were added triethyl amine (5.833 g, 57.76 mmol, 2.83 eq). Trityl chloride (6.15 g, 22.04 mmol, 1.08 eq) was added dropwise into reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 3 h. After completion of reaction, reaction mixture was transferred into water and product was extracted with dichloromethane. Combined organic layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further triturated with diethyl ether to obtain pure 116.1. (6.0 g, 75.51%). MS(ES): m/z 390.30 [M+H]+.

Synthesis of Compound 116.2

A mixture of 116.1 (3.0 g, 12.93 mmol, 1.0 eq), 1-bromo-2-methoxy-3-nitrobenzene (16.42 g, 64.65 mmol, 5.0 eq), Tetrakis(triphenylphosphine)palladium(0) (0.746 g, 0.646 mmol, 0.05 eq) and potassium acetate (3.80 g, 38.79 mmol, 3.0 eq) in dimethoxyethane (15 mL) was degassed with argon for 30 min. Further reaction mixture was refluxed for 16 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 116.2 (3.0 g, 83.14%). MS(ES): m/z 280.10 [M+H]+.

Synthesis of Compound 116.3

A mixture of 116.2 (3.0 g, 10.75 mmol, 1.0 eq), 116.1 (6.28 g, 16.12 mmol, 1.5 eq), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.393 g, 0.537 mmol, 0.05 eq) and potassium carbonate (4.45 g, 32.25 mmol, 3.0 eq) in mixture of toluene (25 mL) and water (09 mL) was degassed with argon for 30 min. Further reaction mixture was stirred at 110° C. for 48 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane to obtain pure 116.3 (2.5 g, 50.39%). MS(ES): m/z 462.52 [M+H]+.

Synthesis of Compound 116.4

To a solution of 116.3 (2.5 g, 5.42 mmol, 1.0 eq) in ethanol (25 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filter through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 117.4 (1.79 g, 76.57%). MS(ES): m/z 432.54 [M+H]+.

Synthesis of Compound 116.5

Compound 116.5 was synthesized from 1.9 and 116.4 using general procedure A (Yield: 49.79%).

Synthesis of Compound 116.6

Compound was synthesized from 116.5 and 5-fluoro-4-methylpyridin-2-amine using general procedure B (Yield: 28.66%).

Synthesis of Compound I-133

Synthesis of Compound 117.1

To a solution of 4-bromo-3-fluoro-2-methoxyaniline (2.0 g, 9.09 mmol, 1.0 eq) in methanol (40 mL) was added triethyl amine (7.344 g, 72.72 mmol, 8.0 eq) and degassed with argon for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.742 g, 0.909 mmol, 0.1 eq) was added and again degassed for 15 min. The reaction mixture was stirred at 110° C. under carbon monoxide atmosphere for 10 h. After completion of reaction, reaction mixture was filtered through pad of celite. Filtrate was concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 117.1 (0.8 g, 44.19%). MS(ES): m/z 200.18 [M+H]+.

Synthesis of Compound 117.2

To a solution of 1.1 (0.8 g, 4.02 mmol, 1.0 eq) in methanol (40 mL) was added aqueous sodium hydroxide (0.322 g, 8.04 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 4 h. After completion of reaction, reaction mixture was transferred into water and acidified with citric acid. Obtained solid precipitate was washed with water followed by hexane. The solid was dried under reduced pressure to obtain pure 117.2 (0.8 g, 80.68%). MS(ES): m/z 186.15 [M+H]+.

Synthesis of Compound 113.3

To a solution of 117.2 (0.6 g, 3.24 mmol, 1.0 eq) and pyrrolidine (0.230 g, 3.24 mmol, 1.0 eq) in dichloromethane (10 mL) was added triethylamine (0.981 g, 9.72 mmol, 3.0 eq). The reaction mixture was cooled to 0° C. and hydroxybenzotriazole (0.991 g, 6.48 mmol, 2.0 eq) was added and stirred for 10 min followed by addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.0 g, 6.48 mmol, 2.0 eq). Reaction mixture was stirred at room temperature for 4 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 2% methanol in dichloromethane to obtain pure 117.3 (0.485 g, 58.28%). MS(ES): m/z 238.26 [M+H]+.

Synthesis of Compound 117.4

Compound 117.4 was synthesized from 1.9 and 118.3 using general procedure A (Yield: 51.93%).

Synthesis of Compound I-141

Synthesis of Compound 118.1

To a solution of 4-chloroaniline (3.0 g, 23.52 mmol, 1.0 eq) in acetic acid (90 mL) were added Potassium thiocyanate (2.28 g, 23.52 mmol, 1.0 eq). The reaction mixture was cooled at 10° C. and bromine solution (3.76 g, 23.52 mmol, 1.0 eq) was added dropwise. Reaction mixture was further stirred at room temperature for 3 h. After completion of reaction, reaction mixture was filtered and washed with acetic acid. Filtered solid was heated in water and then neutralized with aqueous ammonia to obtain solid which was filtered and dried well to obtain pure 118.1. (2.5 g, 57.58%). MS(ES): m/z 185.64 [M+H]+.

Synthesis of Compound 118.2

To 118.1 (2.5 g, 13.54 mmol, 1.0 eq) a solution of potassium hydroxide (9.1 g, 162.48 mmol, 12.0 eq) in water (50 mL) was added. Reaction mixture was refluxed for 17 h. Reaction mixture was cooled to room temperature and methyl iodide was added (2.11 g, 14.89 mmol, 1.1 eq) and stirred for 1 h. After completion of reaction, reaction mixture was extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain 118.2. (1.3 g, 55.29%). MS(ES): m/z 174.66 [M+H]+.

Synthesis of Compound 118.3

Synthesis of Compound 118.4

Synthesis of Compound I-157

Synthesis of Compound 119.1

To a solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (0.25 g, 2.40 mmol, 1.0 eq) in acetone (4 mL) were added triethyl amine (0.364 g, 3.6 mmol, 1.5 eq) and ethyl chloroformate (0.286 g, 2.64 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 1 h. Reaction mixture was filtered and added aqueous ammonia (4 mL) to filtrate dropwise. Further, reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was filtered. Filtered solid was dried under reduced pressure to obtain pure 119.1. (0.2 g, 80.76%). MS(ES): m/z 104.10 [M+H]+.

Synthesis of Compound I-210

Synthesis of Compound I-216

Synthesis of Compound I-228

Synthesis of Compound 122.1

A mixture of N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (1.5 g, 4.85 mmol, 1.0 eq), trimethyl boroxine (1.83 g, 14.55 mmol, 3.0 eq), Tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.242 mmol, 0.05 eq) and potassium carbonate (2.0 g, 14.55 mmol, 3.0 eq) in 1,4-dioxane (15 mL) were degassed with argon for 30 min. Further reaction mixture was stirred at 110° C. for 4 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 122.1 (0.9 g, 75.93%). MS(ES): m/z 245.27 [M+H]+.

Synthesis of Compound 122.2

To a solution of 123.1 (0.9 g, 3.68 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filter through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 122.2 (0.7 g, 88.66%). MS(ES): m/z 215.28 [M+H]+.

Synthesis of Compound 122.3

Compound 122.3 was synthesized from 122.2 and 1.9 using general procedure A (Yield: 41.31%).

Synthesis of Compound I-229

Synthesis of Compound I-209

Synthesis of Compound I-215

Synthesis of Compound I-232

Synthesis of Compound I-198

Synthesis of Compound 127.1

To a solution of N-Methyl methane sulfonamide (5.733 g, 52.60 mmol, 1.1 eq) in acetonitrile (100 mL) were added cesium carbonate (31.18 g, 95.64 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min. Compound 1 (10.0 g, 47.82 mmol, 1.0 eq) was added dropwise into reaction mixture and stirred at room temperature for 3 h. After completion of reaction, reaction mixture was filtered. Filtered solid was transferred into water, stirred for 30 min and dried under reduced pressure to obtain pure 127.1. (10 g, 70.11%). MS(ES): m/z 299.24 [M+H]+.

Synthesis of Compound 127.2

To a solution of 128.1 (10.0 g, 33.53 mmol, 1.0 eq) in acetic acid (100 mL) was added zinc powder (10.9 g, 167.65 mmol, 5.0 eq) portion wise. The reaction mixture was stirred at room temperature for 20 h. After completion of reaction, reaction mixture was transferred into saturated solution of sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further triturated with diethyl ether to obtain pure 127.2. (8.0 g, 88.94%). MS(ES): m/z 269.25 [M+H]+.

Synthesis of Compound 127.3

Compound 127.3 was synthesized from 127.2 using general procedure A (Yield: 56.59%).

Synthesis of Compound 127.4

Compound 127.4 was synthesized from 128.3 and cyclopropanecarboxamide using procedure B (Yield: 54.99%).

Synthesis of Compound I-235

Synthesis of Compound 128.1

To a solution of diethyl phosphonate (5.0 g, 36.20 mmol, 1 eq) in tetrahydrofuran was added methyl magnesium chloride (5.43 g, 72.4 mmol, 2 eq) and potassium carbonate (14.98 g, 108.6 mmol, 3 eq). The reaction mixture was stirred at 0° C. for 4 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain 128.1. (2.3 g, 81.39%). MS(ES): m/z 79.05 [M+H]+.

Synthesis of Compound 128.2

To a solution of 2-iodoaniline (1.0 g, 4.57 mmol, 1.0 eq) in dimethylformamide (10 mL) were added compound 128.1 (0.463 g, 5.94 mmol, 1.3 eq) and potassium phosphate (1.937 g, 9.14 mmol, 2.0 eq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.103 g, 0.457 mmol, 0.1 eq) and 4,5-Bis(Diphenylphosphino)-9,9-dimethylxanthene (0.529 g, 0.914 mmol, 0.2 eq) were added. Reaction mixture was again degassed for 10 min and stirred at 120° C. for 6 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 3% methanol in dichloromethane as eluent to obtain 128.2. (0.48 g, 62.15%). MS(ES): m/z 170.16 [M+H]+.

Synthesis of Compound 128.3

Compound was synthesized from 1.9 and 128.2 using general procedure A to obtain 128.3 (Yield: 5.02%). MS(ES): m/z 351.74 [M+H]+.

Synthesis of Compound I-125

Synthesis of Compound 129.1

To a solution of 1.4 (0.300 g, 1.28 mmol, 1.0 eq) in tetrahydrofuran (25 mL), was added dihydropyran (0.430 g, 5.12 mmol, 4.0 eq) and Pyridinium p-toluenesulfonate (0.032 g, 0.128 mmol, 0.1 eq) under nitrogen atmosphere and stirred at 90° C. for overnight. After completion of reaction, reaction mixture was concentrated under reduced pressure and to obtain crude material. This was further purified by column chromatography and compound was eluted in 30% ethyl acetate-hexane to get pure to get 1291.1 (0.325 g, 79.71%). MS(ES): m/z 319.33 [M+H]+.

Synthesis of Compound 129.2

To a solution of 129.1 (0.325 g, 1.02 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal (0.065 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filter through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 129.2 (0.215 g, 73.03%). MS(ES): m/z 289.35 [M+H]+.

Synthesis of Compound 129.3

To a solution of 1.9 (0.1 g, 0.458 mmol, 1.0 eq) and 129.2 (1.0 g, 1.603 mmol, 3.5 eq) in Tetrahydrofuran (1 mL) at 0° C. was added Lithium bis(trimethylsilyl)amide (1M in THF) (2.0 mL, 1.603 mmol, 3.5 eq). The resulting mixture was stirred at room temperature for 1 h. After completion of reaction, reaction mixture was transferred in water and washed with ethyl acetate. Aqueous layer was acidified with 1N Hydrochloric acid, solid precipitated was filtered and washed with water, dried well to obtain 129.3 (0.162 g, 75.16%). MS (ES): m/z 470.93 [M+H]+.

Synthesis of Compound 129.4

To 129.3 (0.162 g, 0.344 mmol, 1.0 eq) in dimethylacetamide (2.5 mL) was added cyclopropanecarboxamide (0.117 g, 1.376 mmol, 4.0 eq), cesium carbonate (0.336 g, 1.032 mmol, 3.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0)(0.031 g, 0.034 mmol, 0.1 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.0399 g, 0.069 mmol, 0.2 eq) were added, again degassed for 5 min. The reaction was then heated at 140° C. under microwave irradiation. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by Preparative HPLC using 0.1% Formic acid in water/Acetonitrile in gradient method. The pure fractions were concentrated under reduced pressure to obtain pure 129.4 (0.120 g, 67.13%). MS(ES): m/z 519.58 [M+H]+

Synthesis of Compound I-62

Synthesis of Compound 130.1

phosphate (5.78 g, 15.21 mmol, 2.0 eq) followed by N,N-Diisopropylethylamine (2.95 g, 22.82 mmol, 3.0 eq). Reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 50% ethyl acetate in hexane as eluant to obtain pure 130.1 (1.0 g, 52.52%). MS(ES): m/z 251.25 [M+H]+.

Synthesis of Compound 130.2

To a solution of 130.1 (1.0 g, 3.99 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 130.2. (0.8 g, 90.89%). MS(ES): m/z 221.27 [M+H]+.

Synthesis of Compound 130.3

Synthesis of Compound I-70

Synthesis of Compound 131.1

To a cooled solution of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol, 1.0 eq) and morpholine (0.485 g, 5.57 mmol, 1.1 eq) in N,N-dimethylformamide (10 mL) at 0° C. was added (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) (3.85 g, 10.14 mmol, 2.0 eq) followed by N,N-Diisopropylethylamine (1.96 g, 15.21 mmol, 3.0 eq). Reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 50% ethyl acetate hexane to obtain pure 131.1 (1.2 g, 88.85%). MS(ES): m/z 267.25 [M+H]+.

Synthesis of Compound 131.2

To a solution of 131.1 (1.2 g, 4.51 mmol, 1.0 eq) in methanol (12 mL), 10% palladium on charcoal (0.25 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 131.2. (0.9 g, 84.52%). MS(ES): m/z 237.27 [M+H]+.

Synthesis of Compound 131.3

Compound was synthesized from 1.9 and 131.2 using general procedure A to obtain 131.3 (Yield: 33.92%). MS (ES): m/z 418.85 [M+H]+.

Synthesis of Compound I-71

Synthesis of Compound 55.1

Synthesis of Compound I-73

Synthesis of Compound I-74

Synthesis of Compound I-75

Synthesis of Compound I-76

Synthesis of Compound 136.1

To a cooled solution of (2-aminopyridin-4-yl)methanol (0.5 g, 4.03 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL) at 0° C., imidazole (0.274 g, 4.03 mmol, 1.0 eq) was added and reaction mixture was stirred for 5 min. To this added tert-Butyldimethylsilyl chloride (0.616 g, 4.03 mmol, 1.0 eq) and stirred at 0° C. for 12 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 2-3% ethyl acetate hexane to obtain pure 55.1 (0.6 g, 62.49%). MS(ES): m/z 239.41 [M+H]+.

Synthesis of Compound 136.2

Synthesis of Compound I-101

Synthesis of I-113

Synthesis of Compound 138.1

To a cooled solution of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol, 1.0 eq) and ethyl amine (0.296 g, 6.59 mmol, 1.3 eq) in N,N-dimethylformamide (10 mL) at 0° C. was added (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro-phosphate)) (2.9 g, 7.60 mmol, 1.5 eq) followed by N,N-Diisopropylethylamine (1.96 g, 15.21 mmol, 3.0 eq). Reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 50% ethyl acetate in hexane as eluant to obtain pure 138.1 (1.0 g, 87.93%). MS(ES): m/z 225.22 [M+H]+.

Synthesis of Compound 138.2

To a solution of 138.1 (1.0 g, 4.46 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 139.2 (0.85 g, 98.12%). MS(ES): m/z 195.23 [M+H]+.

Synthesis of Compound 138.3

Synthesis of Compound I-114

Synthesis of Compound I-115

Synthesis of Compound 140.1

To a solution of 3-methoxyazetidine (2.0 g, 22.96 mmol, 1.5 eq) and 2-chloro-6-nitropyridine (2.43 g, 15.30 mmol, 1.0 eq) in dimethyl sulfoxide (20 mL) was added sodium bicarbonate (2.57 g, 30.60 mmol, 2.0 eq). Reaction mixture was stirred at 80° C. for 4 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluant to obtain pure 141.1 (2.0 g, 62.47%). MS(ES): m/z 210.21 [M+H]+.

Synthesis of Compound 140.2

To a solution of 140.1 (2.0 g, 9.56 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.4 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 141.2. (1.5 g, 87.55%). MS(ES): m/z 180.22 [M+H]+.

Synthesis of Compound I-116

Synthesis of Compound 141.1

To a solution of 5-bromo-2-nitropyridine (2.0 g, 9.85 mmol, 1.0 eq), piperidine (1.674 g, 19.7 mmol, 2.0 eq) and triethyl amine (1.09 g, 10.83 mmol, 1.1 eq) in dimethyl sulfoxide (20 mL) was added. Reaction mixture was stirred at 120° C. for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluant to obtain pure 141.1 (1.1 g, 53.88%). MS(ES): m/z 208.23 [M+H]+.

Synthesis of Compound 141.2

To a solution of 141.1 (1.1 g, 5.31 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 141.2. (0.7 g, 74.40%). MS(ES): m/z 178.25 [M+H]+.

Synthesis of Compound I-118

Synthesis of Compound I-119

Synthesis of Compound I-120

Synthesis of Compound I-121

Synthesis of Compound I-122

Synthesis of Compound I-123

Synthesis of Compound I-124

Synthesis of Compound I-191

Synthesis of Compound 149.1

To a solution 5-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.66 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise borane tetrahydrofuran complex (194 mL, 190.98 mmol, 3.0 eq) at −0.5° C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was cooled to −0.5° C., water (30 mL) was added followed by 4N hydrochloric acid (30 mL). The reaction mixture was stirred at 110° C. for 2 h. After completion of reaction, reaction mixture was filtered, washed with ethyl acetate. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain 149.1 (5.8 g, 63.67%). MS(ES): m/z 144.10 [M+H]+.

Synthesis of Compound 149.2

To a solution of 149.1 (5.8 g, 40.53 mmol, 1.0 eq) in N,N-dimethylformamide (70 mL) was added cesium carbonate (16.12 g, 49.45 mmol, 1.22 eq). 1,2-dibromoethane (60.91 g, 324.24 mmol, 1.22 eq) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2.5 h. After completion of reaction, reaction mixture was transferred in to 10% solution of sodium phosphate (90 mL) and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 35% ethyl acetate in hexane as eluent to obtain 149.2. (4.0 g, 39.47%). MS(ES): m/z 251.05 [M+H]+.

Synthesis of Compound 149.3

To a solution of 149.2 (3.0 g, 12.00 mmol, 1.0 eq) in N-methyl pyrrolidine (12 mL) was added. The reaction mixture was stirred at 135° C. for 18 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 1% methanol in dichloromethane as eluent to obtain 149.3. (0.30 g, 14.78%). MS(ES): m/z 170.14 [M+H]+.

Synthesis of Compound 149.4

To a solution of 149.3 (0.3 g, 1.77 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.05 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 149.4 (0.22 g, 89.13%). MS(ES): m/z 140.16 [M+H]+.

Synthesis of Compound I-221

Synthesis of Compound 150.1

Synthesis of Compound I-134

Synthesis of Compound 151.1

To a solution of 6-aminopyrazine-2-carbonitrile (1.0 g, 8.33 mmol, 1.0 eq) in acetonitrile (0.5 mL) was added N-Bromosuccinimide (2.22 g, 12.50 mmol, 1.5 eq). The reaction was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 20% ethyl acetate in hexane to obtain pure 151.1 (0.75 g, 45.27%). MS(ES): m/z 200.01 [M+H]+

Synthesis of Compound 151.2

To 151.1 (0.75 g, 3.77 mmol, 1.0 eq) in mixture of 1,4-dioxane (0.5 mL) and water (mL) was added Trimethylboroxine (0.40 g, 7.54 mmol, 2.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. Potassium carbonate (1.56 g, 11.31 mmol, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (0.435 g, 0.377 mmol, 0.1 eq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 110° C. for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 151.2 (0.15 g, 29.67%). MS(ES): m/z 135.14 [M+H]+

Synthesis of Compound I-135

Synthesis of Compound 152.1

To a solution of 4-ethylaniline (3.0 g, 24.76 mmol, 1.0 eq) in acetic acid (30 mL) were added Ammonium thiocyanate (1.88 g, 24.76 mmol, 1.0 eq). The reaction mixture was cooled to 0° C. and added dropwise bromine solution (3.96 g, 24.76 mmol, 1.0 eq). Reaction mixture was stirred at 10° C. for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed by saturated solution of sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 152.1. (1.10 g, 24.93%). MS(ES): m/z 179.25 [M+H]+.

Synthesis of Compound 152.2

To a solution of 152.1 (1.1 g, 6.17 mmol, 1.0 eq) in water (10 mL) was added aqueous solution of potassium hydroxide (4.14 g, 74.04 mmol, 12.0 eq). Reaction mixture was refluxed for 48 h. The reaction mixture was maintained at room temperature, methyl iodide (0.963 g, 6.78 mmol, 1.1 eq) was added, and the reaction stirred for 1 h. After completion of reaction, reaction mixture was extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain 152.2. (0.5 g, 48.44%). MS(ES): m/z 168.27 [M+H]+.

Synthesis of Compound 152.3

Synthesis of Compound 152.4

Synthesis of Compound I-152

Synthesis of Compound 153.1

To a cooled suspension of zinc dust (6.08 g, 93.03 mmol, 7.0 eq) in water (7 mL) at 0° C. was added difluoromethanesulfinic hypochlorous anhydride (2.0 g, 13.29 mmol, 1.0 eq) dropwise. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was filtered, washed with ethyl acetate. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain 153.1. (2.10 g, 53.48%). MS(ES): m/z 296.53 [M+H]+.

Synthesis of Compound 153.2

To a solution of 6-chloropyridin-2-amine (0.5 g, 3.89 mmol, 1.0 eq) and 153.1 (3.45 g, 11.67 mmol, 3.0 eq) in mixture of dichloromethane (1 mL) and water (0.4 mL) was added dropwise tert-Butyl hydroperoxide (1.75 g, 19.45 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 8 h in closed vessel. After completion of reaction, reaction mixture was transferred in to saturated solution of sodium bicarbonate and extracted with dichloromethane. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 153.2. (0.095 g, 13.68%). MS(ES): m/z 179.57 [M+H]+.

Synthesis of Compound 153.3

To a solution of 153.2 (0.095 g, 0.532 mmol, 1.0 eq) and zinc cyanide (0.037 g, 0.319 mmol, 0.6 eq) in N,N-dimethylformamide (2.0 mL). The reaction mixture was degassed for 10 min. under argon atmosphere. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.008 g, 0.011 mmol, 0.02 eq) was added and again degassed for 10 min. under argon atmosphere. The reaction mixture was stirred at 160° C. for 4 h. After completion of reaction, reaction mixture was transferred in to saturated solution of sodium bicarbonate and extracted with dichloromethane. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 153.3. (0.06 g, 66.68%). MS(ES): m/z 170.13 [M+H]+.

Synthesis of Compound I-156

Synthesis of Compound I-21

Synthesis of Compound I-19

Synthesis of Compound I-24

Synthesis of Compound I-20

Synthesis of Compound I-31

Synthesis of Compound I-159

Synthesis of Compound I-12

Synthesis of Compound I-13

Synthesis of Compound I-28

Synthesis of Compound I-29

Synthesis of Compound I-18

Synthesis of Compound I-15

Synthesis of Compound I-30

Synthesis of Compound I-22

Synthesis of Compound I-23

Synthesis of Compound I-17

Synthesis of Compound 1.2

Synthesis of Compound I-126

Synthesis of Compound 171.1

Synthesis of Compound I-223

Synthesis of Compound 172.1

To a cooled solution 2-methoxy-3-nitrobenzamide of (2.0 g, 10.20 mmol, 1.0 eq) in 1,4-dioxane (80 mL) were added dropwise pyridine (2.417 g, 30.6 mmol, 3.0 eq) and Trifluoromethanesulfonic anhydride (5.75 g, 20.40 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with dichloromethane. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further triturated in dichloromethane to obtain pure 172.1 (1.0 g, 55.06%). MS(ES): m/z 179.15 [M+H]+.

Synthesis of Compound 172.2

To a solution of 172.1 (2.5 g, 14.03 mmol, 1.0 eq) in ethanol (40 mL) were added 50% solution of hydroxyl amine (25 mL). The reaction mixture was stirred at 90° C. for 1 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 1% methanol in dichloromethane to obtain pure 172.2 (1.3 g, 43.87%). MS(ES): m/z 212.18 [M+H]+.

Synthesis of Compound 172.3

To a solution of 172.2 (0.7 g, 3.31 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) were added potassium phosphate (2.10 g, 9.93 mmol, 3.0 eq). The reaction mixture was cooled at 0° C. and added acetyl chloride (0.516 g, 6.62 mmol, 2.0 eq). The reaction mixture was stirred at 120° C. for 2 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 1% methanol in dichloromethane to obtain pure 172.3 (0.3 g, 38.48%). MS(ES): m/z 236.20 [M+H]+.

Synthesis of Compound 172.4

To a solution of 172.3 (0.1 g, 0.425 mmol, 1.0 eq) in methanol (1 mL), 10% palladium on charcoal (0.08 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 172.4 (0.04 g, 45.84%). MS(ES): m/z 206.22 [M+H]+.

Synthesis of Compound 172.5

Compound 172.5 was synthesized from 1.9 and 172.4 using general procedure A to obtain 1.5 (Yield: 26.31%).

Synthesis of Compound I-131

Compound I-131 was synthesized from 172.5 and cyclopropanecarboxamide using general procedure B. (Yield: 4.44%).

Synthesis of Compound I-136

Synthesis of Compound 174.1

To compound 6-aminopyrazine-2-carbonitrile (5.0 g, 41.63 mmol, 1.0 eq) in acetonitrile was added N-Bromosuccinimide (11.115 g, 62.44 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 6 h. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 2% methanol in dichloromethane to obtain 174.1. (5.3 g, Yield: 63.98%). MS (ES): m/z 200.01 [M+H]+.

Synthesis of Compound 174.2

To a solution of 174.1 (0.5 g, 2.51 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.10 g, 6.53 mmol, 2.6 eq) in mixture of toluene (13 mL) and water (2 mL). The reaction mixture was degassed by argon for 30 min. Palladium acetate (0.056 g, 0.251 mmol, 0.1 eq), triphenyl phosphine (0.131 g, 0.502 mmol, 0.2 eq) and potassium phosphate (1.59 g, 7.53 mmol, 3.0 eq) was added into reaction mixture and again reaction mixture was degassed by argon for 30 min. Further reaction mixture was stirred at 100° C. for 24 h. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 2% methanol in dichloromethane to obtain pure 174.2 (0.3 g, 74.55%). MS(ES): m/z 161.18 [M+H]+.

Synthesis of Compound 174.3

To a solution of 174.2 (0.4 g, 2.50 mmol, 1.0 eq) in methanol (4 mL), 10% palladium on charcoal (0.016 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 1.3 (0.38 g, 93.82%). MS(ES): m/z 163.20 [M+H]+.

Synthesis of Compound I-158

Synthesis of Compound 175.1

Synthesis of Compound I-149

Synthesis of Compound 176.1

Synthesis of Compound 176.2

To a solution of compound 176.1 (1.5 g, 6.07 mmol, 1.0 eq) in a mixture of methanol (104 mL) and water (26 mL), sodium hydroxide (1.94 g, 48.56 mmol, 8.0 eq) was added. The reaction mixture was stirred at 60° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to 0° C. The pH of the solution was adjusted to 6-7 by using 2N HCl to get solid precipitation which was filtered and dried to obtain 176.2 (1.0 g, 70.68%). MS(ES): m/z 234.76 [M+H]+.

Synthesis of Compound 176.3

To a solution of 176.2 (0.1 g, 0.42 mmol, 1.0 eq) in dimethylformamide (3 mL), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (0.195 g, 0.51 mmol, 1.2 eq) and diisopropylethylamine (0.083 g, 0.64 mmol, 1.5 eq) were added at 0° C. Reaction mixture was stirred at 0° C. for 30 min. Then pyrrolidine (0.045 g, 0.64 mmol, 1.5 eq) was added and reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, reaction mixture was transferred to water and extracted with ethyl acetate. Organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude material. This was further purified by column chromatography using 1% methanol in dichloromethane to obtain 176.3 (0.120 g, 56.12%). MS(ES): m/z 229.48 [M+H]+.

Synthesis of Compound 176.4

To a solution of 176.3 (0.48 g, 1.68 mmol, 1.0 eq) in acetic acid (6 mL), iron powder (0.275 g, 5 mmolmmol, 3.0 eq) was added. Reaction mixture was stirred at 70° C. for 2 h. After completion of the reaction, reaction mixture was transferred to water and extracted with ethyl acetate. Organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 176.4 (0.350 g, 81.11%). MS(ES): m/z 257.29 [M+H]+.

Synthesis of Compound 176.5

To a solution of 176.4 (0.48 g, 1.68 mmol, 1.0 eq) in tetrahydrofuran (6 mL), lithium bis(trimethylsilyl)amide (0.275 g, 5 mmol, 3.0 eq) was added dropwise at 0° C. Reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, reaction mixture was transferred to water and extracted with ethyl acetate. Organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 176.5 (0.055 g, 10.73%). MS(ES): m/z 438.52 [M+H]+.

Synthesis of Compound I-151

Synthesis of Compound 177.1

To a suspension of Cesium carbonate (2.8 g, 0.008 mmol, 1.9 eq) in acetonitrile (28 mL), N-methyl methane sulfonamide (0.5 g, 0.004 mmol, 1.1 eq) was added and cooled to 0° C. Then 4-bromo-2-fluoro-1-nitrobenzene (1 g, 0.004 mmol, 1 eq) was added dropwise in the reaction mixture within 15 min. Reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 177.1. (0.8 g, 56.93%). MS(ES): m/z 310.12 [M+H]+.

Synthesis of Compound 177.2

To a solution of compound 177.1 (0.2 g, 0.64 mmol, 1.0 eq) and vinyl boronic acid (0.24 g, 1.61 mmol, 2.5 eq) in a mixture of toluene (5 mL) and water (0.2 mL), potassium phosphate (0.48 g, 2.26 mmol, 3.5 eq) and tetrakis (0.03 g, 0.12 mmol, 0.2 eq) were added and the reaction mixture was degassed for 10 min. Then palladium acetate (0.014 g, 0.064 mmol, 0.1 eq) was added and the reaction mixture was again degassed for 5 min. Reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. Organic layer combined, dried over sodium sulphate and concentrated under pressure to obtain 177.2. (0.8 g, 80.14%). MS(ES): m/z 257.86 [M+H]+.

Synthesis of Compound 177.3

To a solution of 177.2 (0.2 g, 1.77 mmol, 1.0 eq) in methanol (2 mL), 10% palladium on charcoal (0.06 g) was added. Hydrogen was purged through reaction mixture for 12 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 177.3 (0.1 g, 56.12%). MS(ES): m/z 229.48 [M+H]+.

Synthesis of Compound 177.4

Synthesis of Compound I-217

Synthesis of Compound 178.1

To a solution of diisopropyl amine (30.11 g, 298.1 mmol, 2.4 eq) in tetrahydrofuran (150 mL) was cooled to −78° C. followed by addition of n-butyl lithium (19.08 g, 298.1 mmol, 2.4 eq) and stirred reaction mixture for 30 min at the same temperature. Tributyltin hydride (86.75 g, 298.1 mmol, 2.4 eq) was added to reaction mixture at same temperature and then maintained 0° C. and stirred for 30 min. The reaction mixture was cooled to −78° C., added compound chloro(methoxy)methane (10 g, 124.21 mmol, 1.0 eq) and reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 5 h. After completion of reaction, reaction mixture was transferred in to brine solution and extracted with diethyl ether. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted hexane as eluant to obtain 178.1. (7.0 g, 16.82%). MS(ES): m/z 336.12 [M+H]+.

Synthesis of Compound 178.2

To a solution of 177.1 (3.0 g, 9.70 mmol, 1.0 eq) in N-methyl pyrrolidine (35 mL) was added 178.1 (7.0 g, 20.89 mmol, 2.15 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. Tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol, 0.1 eq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 60° C. for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 178.2 (1.2 g, 45.03%). MS(ES): m/z 275.29 [M+H]+

Synthesis of Compound 178.3

To a solution of 178.2 (1.2 g, 4.37 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.5 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 178.3. (0.750 g, 70.17%). MS(ES): m/z 245.31 [M+H]+.

Synthesis of Compound 178.4

Synthesis of Compound I-218

Synthesis of Compound 179.1

2-chlorocyclopentan-1-one (1.0 g, 4.58 mmol, 1.0 eq) in water (20 mL) was heated to 100° C., to which a preheated solution of ferric chloride (1.48 g, 9.17 mmol, 2 eq) was added. Reaction mixture was stirred at 100° C. for 20 min. After completion of the reaction, the reaction mixture was cooled to room temperature. The pH of the solution was adjusted to 7 by using ammonium sulfate solution and then extracted by ethyl acetate. Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 179.1. (0.55 g, 66.47%). MS(ES): m/z 99.25 [M+H]+.

Synthesis of Compound 179.2

To a solution of compound 179.1 (0.100 g, 0.10 mmol, 1.0 eq) in ethanol (5 mL) at 0° C., aminoacetamide dihyrobromide (0.23 g, 0.10 mmol, 1.0 eq) was added. Reaction mixture was stirred for 10 min. Then, pH of the reaction mixture was adjusted to 8-9 by using ammonium hydroxide solution. Reaction mixture was stirred at room temperature overnight. After completion of the reaction, pH of the reaction mixture was adjusted to 7 by using 1N HCl and extracted with dichloromethane. Organic layer was combined, dried over sodium sulfate, filtered and concentrated to obtain pure 179.2 (0.021 g, 15.83%). MS(ES): m/z 136.48 [M]+.

Synthesis of Compound I-225

Synthesis of Compound 180.1

To a solution of N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (2.0 g, 8.06 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.35 g, 9.83 mmol, 1.22 eq) followed by addition of 3-methoxyazetidine hydrochloride (1.21 g, 9.83 mmol, 1.22 eq) dropwise. The reaction mixture was stirred at 60° C. for 48 h. After completion of reaction, reaction mixture was transferred into 10% solution of sodium phosphate (90 mL) and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 35% ethyl acetate in hexane as eluent to obtain 180.1. (1.6 g, 62.97%). MS(ES): m/z 316.34 [M+H]+.

Synthesis of Compound 180.2

To a solution of 180.1 (1.6 g, 5.07 mmol, 1.0 eq) in ethanol (20 mL), 10% palladium on charcoal (0.6 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 180.2. (1.2 g, 82.88%). MS(ES): m/z 286.36 [M+H]+.

Synthesis of Compound 180.3

Synthesis of Compound I-220

Synthesis of Compound 181.1

To a solution of N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (5.0 g, 20.14 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added cesium carbonate (7.98 g, 24.57 mmol, 1.22 eq) followed by addition of azetidine hydrochloride (1.88 g, 24.57 mmol, 1.22 eq). The reaction mixture was stirred at 60° C. for 48 h. After completion of reaction, reaction mixture was transferred in to 10% solution of sodium phosphate (90 mL) and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 35% ethyl acetate in hexane as eluent to obtain 181.1. (3.4 g, 59.16%). MS(ES): m/z 286.32 [M+H]+.

Synthesis of Compound 181.2

To a solution of 181.1 (2.0 g, 7.01 mmol, 1.0 eq) in ethanol (20 mL), 10% palladium on charcoal (0.8 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 181.2. (1.5 g, 83.84%). MS(ES): m/z 256.34 [M+H]+.

Synthesis of Compound 181.3

Synthesis of Compound I-219

Synthesis of Compound I-214

Synthesis of Compound 183.1

To a cooled solution of 4,5-difluoro-2-nitroaniline (5.0 g, 0.287 mmol, 1.0 eq) in dichloromethane (100 mL) was added dropwise triethylamine (9.6 mL, 0.0686 mmol, 2.39 eq) followed by methane sulfonyl chloride (4.8 mL, 0.0619 mmol, 2.16 eq). Reaction mixture was stirred at room temperature for 18 h. After completion of reaction, reaction mixture was transferred into water and extracted with dichloromethane. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain intermediate 5.2 g. To this intermediate was added 1M sodium hydroxide (50 mL) in mixture of water and tetrahydrofuran. Reaction mixture was stirred at room temperature for 18 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 30% ethyl acetate in hexane as eluent to obtain intermediate 183.1. (2.1 g, 29.00%). MS(ES): m/z 253.19 [M+H]+.

Synthesis of Compound 183.2

To a solution of 183.1 (2.1 g, 8.33 mmol, 1.0 eq) in dimethyl sulfoxide (10 mL) was added potassium carbonate (4.6 g, 33.32 mmol, 4.0 eq) and methyl iodide (3.55 g, 24.99 mmol, 3.0 eq). The reaction mixture was stirred at 80° C. for 24 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 30% ethyl acetate in hexane as eluent to obtain 183.2. (1.5 g, 67.67%). MS(ES): m/z 267.22 [M+H]+.

Synthesis of Compound 183.3

To a solution of 183.2 (1.5 g, 5.63 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.2 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 183.3 (0.3 g, 22.54%). MS(ES): m/z 237.24 [M+H]+.

Synthesis of Compound 183.4

Synthesis of Compound I-230

Synthesis of Compound 184.1

Synthesis of Compound I-231

Synthesis of Compound 185.1

To a solution of 3-nitro-1H-pyrazole (5.0 g, 44.22 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was added sodium hydride (1.6 g, 66.33 mmol, 1.5 eq) at 0° C. and reaction mixture was stirred for 30 min followed by 2-(Trimethylsilyl)ethoxymethyl chloride (8.86 g, 53.06 mmol, 1.2 eq) was added at the same temperature. The reaction mixture was allowed to come at room temperature and stirred for 24 h. After completion of reaction, reaction mixture was transferred in to ice cold water and extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted on 15% ethyl acetate in hexane as eluent to obtain 185.1. (7.9 g, 73.42%). MS(ES): m/z 244.34 [M+H]+.

Synthesis of Compound 185.2

To a cooled solution of diisopropyl amine (0.622 g, 6.165 mmol, 1.5 eq) in tetrahydrofuran (10 mL) at −78° C. n-butyl lithium (0.394 g, 6.165 mmol, 1.5 eq) was added and stirred reaction mixture for 30 min. at the same temperature. Compound 185.1 (1.0 g, 4.11 mmol, 1.0 eq) was added to reaction mixture and stirred at −78° C. for 1 h. Iodine solution (0.635 g, 2.50 mmol, 0.5 eq) in tetrahydrofuran was added at same temperature. After 1 h reaction mixture was brought to room temperature and stirred for 20 h. After completion of reaction, reaction mixture was transferred in to aqueous sodium thiosulphate solution and extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 15% ethyl acetate in hexane as eluent to obtain 185.2. (1.0 g, 65.90%). MS(ES): m/z 370.23 [M+H]+.

Synthesis of Compound 185.3

To a solution of 185.2 (0.15 g, 0.406 mmol, 1.0 eq) and potassium vinyl trifluoroborate (0.098 g, 0.731 mmol, 1.8 eq) in mixture of tetrahydrofuran (1 mL) and water (0.2 mL) was added potassium carbonate (0.168 g, 1.22 mmol, 3.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. The [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (0.017 g, 0.020 mmol, 0.05 eq) was added, again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 100° C. for 24 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 5% ethyl acetate in hexane to obtain pure 185.3 (0.080 g, 73.10%). MS(ES): m/z 270.38 [M+H]+.

Synthesis of Compound 185.4

To a solution of 185.3 (0.07 g, 0.259 mmol, 1.0 eq) in mixture of dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0° C. The reaction was stirred at room temperature for 6 h. After completion of reaction, reaction mixture was concentrated under vacuum and basified with sodium bicarbonate solution then extracted with ethyl acetate to obtain pure 185.4 (0.025 g, 69.16%). MS(ES): m/z 140.11 [M+H]+.

Synthesis of Compound 185.5

To a solution of 185.4 (0.5 g, 3.59 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.486 g, 10.77 mmol, 3.0 eq) at 0° C. and 4-bromobut-1-ene (0.534 g, 3.95 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted on 10% ethyl acetate in hexane as eluent to obtain 185.5. (0.34 g, 48.96%). MS(ES): m/z 194.21 [M+H]+.

Synthesis of Compound 185.6

To a solution of 185.5 (0.34 g, 1.76 mmol, 1.0 eq) in dichloromethane (7 mL) was added Grubb's second generation catalyst (0.110 g, 0.176 mmol, 0.1 eq). The reaction mixture was stirred at 50° C. for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted on 15% ethyl acetate in hexane as eluent to obtain 185.6. (0.19 g, 65.37%). MS(ES): m/z 166.15 [M+H]+.

Synthesis of Compound 185.7

To a solution of 185.6 (0.19 g, 1.15 mmol, 1.0 eq) in methanol (2 mL), 10% palladium on charcoal (0.05 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 185.7 (0.13 g, 82.37%). MS(ES): m/z 138.19 [M+H]+.

Synthesis of Compound I-222

Synthesis of Compound 181.1

Synthesis of Compound 186.2

A solution of diisopropyl amine (16.27 g, 161.16 mmol, 2.4 eq) in tetrahydrofuran (70 mL) was cooled to −78° C. followed by n-butyl lithium (10.31 g, 161.16 mmol, 2.4 eq) was added and stirred reaction mixture for 30 min. at the same temperature. Tributyltin hydride (46.90 g, 161.16 mmol, 2.4 eq) was added to reaction mixture at same temperature and then maintained 0° C. and stirred for 30 min. The reaction mixture was cooled to −78° C., added compound 1 (20 g, 67.15 mmol, 1.0 eq) and reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 5 h. After completion of reaction, reaction mixture was transferred into brine solution and extracted with diethyl ether. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted hexane as eluent to obtain 186.2. (0.85 g, 2.03%). MS(ES): m/z 625.17 [M+H]+.

Synthesis of Compound 186.3

Synthesis of Compound 186.4

Synthesis of Compound 186.5

Synthesis of Compound I-227

Synthesis of Compound I-241

Synthesis of Compound 188.1

To a cooled solution of 3-fluoro-4-nitrophenol (5.0 g, 31.83 mmol, 1.0 eq) in dichloromethane (50 mL) at 0° C. was added Trifluoromethanesulfonic anhydride (0.520 g, 4.14 mmol, 2.0 eq), stirred for 15 min followed by dropwise addition of triethylamine (0.520 g, 4.14 mmol, 2.0 eq) at the same temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was transferred in to water and extracted with dichloromethane. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography in neutral alumina and compound was eluted on 15% ethyl acetate in hexane as eluent to obtain 188.1. (3.0 g, 32.60%). MS(ES): m/z 290.16 [M+H]+.

Synthesis of Compound 188.2

To a solution of 1.1 (3.0 g, 10.38 mmol, 1.0 eq) and cyclobutyl boronic acid (1.3 g, 12.97 mmol, 1.25 eq) in toluene (30 mL) was added cesium carbonate (6.74 g, 20.76 mmol, 2.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. The [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.607 g, 0.83 mmol, 0.08 eq) was added, again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 90° C. for 4 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 5% ethyl acetate in hexane to obtain pure 188.2 (0.32 g, 15.80%). MS(ES): m/z 196.19 [M+H]+.

Synthesis of Compound 188.3

To a solution of 188.2 (0.34 g, 1.64 mmol, 1.0 eq) in mixture of N-N-dimethylformamide (6 mL) and water (4 mL) was added dropwise sodium thiomethoxide water solution (0.252 g, 3.61 mmol, 2.2 eq) at 0° C. The reaction was stirred at 15-20° C. for 1 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 5% ethyl acetate in hexane to obtain pure 188.3 (0.24 g, 65.56%). MS(ES): m/z 224.29 [M+H]+.

Synthesis of Compound 188.4

To a solution of 188.3 (0.14 g, 0.623 mmol, 1.0 eq) in methanol (5 mL), 10% palladium on charcoal (0.05 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 188.4 (0.08 g, 66.01%). MS(ES): m/z 194.31 [M+H]+.

Synthesis of Compound 188.5

Synthesis of Compound 188.6

Synthesis of Compound I-182

Synthesis of Compound 189.1

To a solution of 5-bromo-6-(trifluoromethyl)pyridin-2-amine (0.500, 2.07 mmol, 1.0 eq) in 1,4-dioxane (0.5 mL) was added Tri methyl boroxine (0.520 g, 4.14 mmol, 2.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. Potassium carbonate (0.858 g, 6.22 mmol, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (0.239 g, 0.207 mmol, 0.1 eq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 110° C. for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 189.1 (0.230 g, 62.94%). MS(ES): m/z 177.14 [M+H]+.

Synthesis of Compound I-208

Synthesis of Compound 190.1

Synthesis of Compound 190.2

To a solution of compound 190.1 (0.18 g, 0.4 mmol, 1.0 eq) in tetrahydrofuran (5 mL), methyl magnesium bromide (0.36 g, 1.09 mmol, 2.2 eq) was added at 0° C. Reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, reaction mixture transferred into water and extracted with ethyl acetate. Combined organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 190.2. (0.15 g, 83.32%). MS(ES): m/z 368.43 [M+H]+.

Synthesis of Compound 190.3

To a solution of 190.2 (0.15 g, 0.413 mmol, 1.0 eq) in dimethylformamide (1 mL), sodium hydride (0.025 g, 0.490 mmol, 1.2 eq) was added at 0° C. within 5 min. Then methyl iodide (0.07 g, 0.490 mmol, 1.2 eq) was added and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, reaction mixture transferred into water and extracted with ethyl acetate. Combined organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 190.3. (0.1 g, 64.22%). MS(ES): m/z 382.51 [M+H]+.

Synthesis of Compound 190.4

To a solution of 190.3 (0.08 g, 0.29 mmol, 1.0 eq) in dimethylacetamide (1 mL), zinc dust (0.003 g, 0.041 mmol, 0.2 eq) and zinc cyanide (0.012 g, 0.10 mmol, 0.5 eq) was added. Reaction mixture was degassed for 15 min and then palladium tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.020 mmol, 0.1 eq) was added and the reaction mixture was kept microwave irradiation for 30 min at 120° C. After completion of the reaction, reaction mixture transferred into water and extracted with ethyl acetate. Combined organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 190.4. (0.05 g, 64.08%). MS(ES): m/z 373.28 [M+H]+.

Synthesis of Compound 190.5

Synthesis of Compound I-155

Synthesis of Compound I-190

Synthesis of Compound 192.1

To a solution of N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (0.6 g, 1.94 mmol, 1.0 eq) in mixture of 1,4-dioxane (4 mL) and water (2 mL) was added 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.611 g, 2.91 mmol, 1.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. Potassium carbonate (0.803 g, 5.82 mmol, 3.0 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.224 g, 0.194 mmol, 0.1 eq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 100° C. for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 192.1 (0.5 g, 82.48%). MS(ES): m/z 313.34 [M+H]+

Synthesis of Compound 192.2

To a solution of 192.1 (0.5 g, 1.6 mmol, 1.0 eq) in ethanol (25 mL), 10% palladium on charcoal (0.3 g) was added. Hydrogen was purged through reaction mixture for 4 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with methanol. Filtrate was concentrated under reduced pressure to obtain 192.2. (0.4 g, 87.87%). MS(ES): m/z 285.37 [M+H]+.

Synthesis of Compound 192.3

Synthesis of Compound I-240

Synthesis of Compound 193.1

To a solution of N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (1.0 g, 3.58 mmol, 1.0 eq) in mixture of tetrahydrofuran (10 mL) and water (5 mL) was added 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.51 g, 7.16 mmol, 2.0 eq) and potassium carbonate (1.48 g, 10.74 mmol, 3.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.262 g, 0.358 mmol, 0.1 eq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 60° C. for 20 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 193.1 (1.0 g, 98.86%). MS(ES): m/z 283.36 [M+H]+.

Synthesis of Compound 193.2

To a solution of 193.1 (1 g, 3.54 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal (0.15 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 193.2 (0.42 g, 41.70%). MS(ES): m/z 285.37 [M+H]+.

Synthesis of Compound 193.3

Synthesis of Compound I-234

Synthesis of Compound 194.1

Synthesis of Compound 194.2

To a solution of compound 194.1 (0.150 g, 0.33 mmol, 1.0 eq) in 1,4-dioxane (5 mL), 2,2-difluorocyclopropane-1-carboxamide (0.123 g, 1.013 mmol, 3.0 eq) and cesium carbonate (0.44 g, 1.35 mmol, 4.0 eq) was added. The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.031 g, 0.033 mmol, 0.1 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.040 g, 0.65 mmol, 0.2 eq) were added, again degassed for 5 min. The reaction mixture was then heated in microwave at 130° C. for 60 min. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 13% ethyl acetate in hexane as eluant to obtain pure 194.2 (0.140 g, 78.42%). MS(ES): m/z 530.46 [M]+.

Synthesis of Compound 194.3

To a solution of 194.2 (0.2 g, 0.04 mmol, 1.0 eq) in ethyl acetate (3 mL), meta-chloroperoxybenzoic acid (0.28 g, 0.12 mmol, 3.0 eq) was added at 0° C. Reaction mixture was stirred at 0° C. for 3 h. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 194.3. (0.15 g, 70.73%). MS(ES): m/z 562.47 [M+H]+.

Synthesis of Compound I-239

Synthesis of Compound 195.1

To a cooled solution of 3-fluoro-4-nitrophenol (5.0 g, 31.83 mmol, 1.0 eq) in dichloromethane (50 mL) at 0° C. was added Trifluoromethanesulfonic anhydride (0.520 g, 4.14 mmol, 2.0 eq), stirred for 15 min followed by dropwise addition of triethylamine (0.520 g, 4.14 mmol, 2.0 eq) at the same temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was transferred in to water and extracted with dichloromethane. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography in neutral alumina and compound was eluted on 15% ethyl acetate in hexane as eluent to obtain 195.1. (3.0 g, 32.60%). MS(ES): m/z 290.16 [M+H]+.

Synthesis of Compound 195.2

To a solution of 1.1 (3.0 g, 10.38 mmol, 1.0 eq) and cyclobutyl boronic acid (1.3 g, 12.97 mmol, 1.25 eq) in toluene (30 mL) was added cesium carbonate (6.74 g, 20.76 mmol, 2.0 eq). The reaction mixture was degassed for 10 min. under argon atmosphere. The [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.607 g, 0.83 mmol, 0.08 eq) was added, again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 90° C. for 4 h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 5% ethyl acetate in hexane to obtain pure 195.2 (0.32 g, 15.80%). MS(ES): m/z 196.19 [M+H]+.

Synthesis of Compound 195.3

To a solution of N-Methyl methane sulfonamide (0.615 g, 5.64 mmol, 1.1 eq) in acetonitrile (6 mL) were added cesium carbonate (3.33 g, 10.24 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min. Compound 195.2 (1.0 g, 5.12 mmol, 1.0 eq) was added dropwise into reaction mixture and stirred at room temperature for 3 h. After completion of reaction, reaction mixture was filtered. Filtered solid was transferred into water, stirred for 30 min and dried under reduced pressure to obtain pure 195.3. (1.0 g, 68.65%). MS(ES): m/z 285.33 [M+H]+.

Synthesis of Compound 195.4

To a solution of 195.3 (0.14 g, 0.492 mmol, 1.0 eq) in methanol (5 mL), 10% palladium on charcoal (0.05 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 195.4 (0.08 g, 63.88%). MS(ES): m/z 255.35 [M+H]+.

Synthesis of Compound 195.5

Synthesis of Compound 195.6

Synthesis of Compound 195.7

To a solution of 195.6 (0.1 g, 0.206 mmol, 1 eq), in methanol (4 mL), and 5M sodium hydroxide (1.5 mL) was added. Reaction mixture stirred at room temperature for 36 h. After completion of reaction, reaction mixture transferred in water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 5% methanol in Dichloromethane to obtain pure 195.7. (0.070 g, 81.44%). MS(ES): m/z 417.50 [M+H]+.

Synthesis of Compound I-236

Synthesis of Compound 198.1

To a solution of 4-bromopyridin-3-ol (5.0 g, 28.74 mmol, 1.0 eq) in dichloromethane (75 mL) was added dropwise triethylamine (11.61 g, 114.96 mmol, 4.0 eq) followed by acetyl chloride (4.512 g, 57.48 mmol, 2.0 eq) at 0° C. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was filtered by bed of celite. The filtrate was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted on 5% ethyl acetate in hexane as eluent to obtain 198.1. (4.9 g, 78.93%). MS(ES): m/z 217.03 [M+H]+.

Synthesis of Compound 198.2

To a solution of 198.1 (16.0 g, 74.06 mmol, 1.0 eq), Trimethylsilylacetylene (9.43 g, 96.78 mmol, 1.3 eq) and triethylamine (112.2 g, 1110.9 mmol, 15 eq) in tetrahydrofuran (1.6 L). The reaction mixture was degassed for 10 min. under argon atmosphere. The [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.6 g, 2.22 mmol, 0.03 eq) and copper iodide (0.843 g, 4.44 mmol, 0.06 eq) was added, again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at room temperature for 24 h. After completion of reaction, reaction mixture was filtered and residue was concentrated under vacuum. The residue was diluted with methanol (2.2 L) and potassium fluoride was added into reaction mixture. The reaction mixture was stirred at room temperature for 48 h. After completion of reaction, reaction mixture was filtered through bed of celite and washed with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 10% ethyl acetate in hexane to obtain pure 1.2 (3.82 g, 43.30%). MS(ES): m/z 120.12 [M+H]+.

Synthesis of Compound 198.3

To a solution of 198.2 (3.82 g, 32.07 mmol, 1.0 eq) in methanol (300 mL), 10% palladium on charcoal (7.0 g) was added. Hydrogen was purged through reaction mixture for 2-3 h. After completion of reaction, reaction mixture was filtered through celite-bed and washed with ethanol. Filtrate was concentrated under reduced pressure to obtain 198.3 (3.5 g, 90.11%). MS(ES): m/z 122.14 [M+H]+.

Synthesis of Compound 198.4

To a solution of 198.3 (3.5 g, 28.89 mmol, 1.0 eq) in dichloromethane (140 mL) was added meta-chloroperbenzoic acid (5.96 g, 34.66 mmol, 1.2 eq). The reaction was stirred at room temperature for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography in basic alumina using 0.1% methanol in dichloromethane to obtain pure 198.4 (3.4 g, 85.81%). MS(ES): m/z 138.14 [M+H]+.

Synthesis of Compound 198.5

To a solution of 198.4 (1.1 g, 8.02 mmol, 1.0 eq) in chloroform (33 mL) was added phosphoryl chloride (4.91 g, 32.08 mmol, 4.0 eq). The reaction was stirred at 70° C. for 7 h. After completion of reaction, reaction mixture was transferred in ice and basified with sodium bicarbonate solution then extracted with ethyl acetate. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted on 15% ethyl acetate in hexane as eluent to obtain 198.5. (0.3 g, 24.04%). MS(ES): m/z 156.58 [M+H]+.

Synthesis of Compound 198.6

Synthesis of Compound 198.7

Synthesis of Compound 198.8

To a solution of 198.7 (0.16 g, 0.311 mmol, 1 eq), in methanol (6 mL) and 5N sodium hydroxide (1 mL) was added. Reaction mixture stirred at 50° C. for 24 h. After completion of reaction, reaction mixture transferred in water and extracted with ethyl acetate. Combined organic layer dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further triturated in 30% diethyl ether in hexane to obtain pure 198.8. (0.12 g, 86.43%). MS(ES): m/z 447.53 [M+H]+.

Synthesis of Compound 198.9

Synthesis of Compound I-226

Synthesis of Compound 199.2

Synthesis of Compound 199.3

To a solution of 199.2 (1.0 g, 3.63 mmol, 1.0 eq) in THF (20 mL) was added n-BuLi (7.5 mL, 18.18 mmol, 5.0 eq) at −78° C. and stirred for 30 min. To the solution was added triisopropyl-borate (3.4 mL, 14.53 mmol, 4.0 eq) and reaction was stirred at −78° C. for 1 h. After completion reaction was quenched slowly and solvents were removed under reduced pressure. Residue was acidified with 1.0 N HCl. Obtained precipitate was filtered off, washed with ice cold water to provide 199.3 (0.35 g, 40.1%). MS(ES): m/z 241.5 [M+H]+.

Synthesis of Compound 199.4

To a solution of 2-bromo-5-chlorothiazole (0.068 g, 0.34 mmol, 1.0 eq) in 1,4-dioxane (2.0 mL) was added compound 199.3 (0.10 g, 0.41 mmol, 1.2 eq) followed by addition of 1M aq. Na2CO3(0.68 mL, 0.68 mmol, 2.0 eq). Reaction mixture was degassed with argon for 10 min and Pd(PPh3)4(0.037 g, 0.034 mmol, 0.1 eq) was added. Reaction mixture was stirred at 100° C. for 16 h. After completion of reaction was quenched with water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to obtain crude material. The crude was purified by column chromatography to furnish 1.4. (0.025 g, 23.0%). MS(ES): m/z 314.4 [M]−.

Synthesis of Compound VIII-1

Synthesis of Compound 2.1

Compound 200.1 was prepared from compound 199.3 and 2-bromo-5-fluorothiazole using procedure described in Example 7.

Synthesis of Compound VIII-2

Synthesis of Compound 201.2

To compound 202.4 (0.3 g, 0.802 mmol, 1.0 eq) in toluene (3.0 mL) was added TFAA (1.5 mL) and reaction mixture was refluxed for 1 h. After completion of the reaction, mixture was concentrated under reduced pressure to obtain crude which was purified by column chromatography to provide 201.2. (0.070 g, 19.31%). MS(ES): m/z 452.7 [M]+.

Synthesis of Compound VIII-3

Synthesis of Compound 202.3

To solution of compound 202.1 (2.0 g, 9.09 mmol, 1.0 eq) in EtOH (20.0 mL) was added compound 202.2 (1.86 g, 9.09 mmol, 1.0 eq) followed by the addition of conc. HCl (catalytic). Reaction mixture was refluxed for 4 h. After completion of the reaction, mixture was concentrated under reduced pressure. Residue was dissolved in CH2Cl2washed with satd. NaHCO3, brine, then dried over Na2SO4and concentrated under reduced pressure to pressure to obtain crude material. The crude was purified by column chromatography to provide 202.3. (1.4 g, 39.7%). MS(ES): m/z 388.7 [M]+.

Synthesis of Compound 202.4

Synthesis of Compound 202.5

To solution of 202.4 (0.7 g, 1.87 mmol, 1.0 eq) in CH2Cl2(7.0 mL) was added Et3N (0.56 g, 5.63 mmol, 3.0 eq). Solution was cooled to 0° C., then methyl oxalyl chloride (0.275 g, 2.25 mmol, 1.2 eq) was added. Mixture was stirred for 4 h at room temperature. To this was added p-TsCl (0.73 g, 3.75 mmol, 2.0 eq). Reaction was stirred at room temperature for 16 h. After completion, of the reaction was quenched with water and extracted with CH2Cl2. Organic layer were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to obtain crude which was purified by column chromatography to provide 202.5. (0.3 g, 36.3%). MS(ES): m/z 442.6 [M]+.

Synthesis of Compound VIII-4

Synthesis of Compound 6.1

Compound 6.1 was prepared from 1.3 and (2-bromothiazol-5-yl)methanol using procedure described in Example 7.

Synthesis of Compound VIII-6

Synthesis of Compound 205.1

To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (0.62 g, 3.47 mmol, 1.0 eq) in DME (10 mL) was added compound 1.3 (1.0 g, 4016 mmol, 1.2 eq) followed by addition of Na2CO3(0.735 g, 6.94 mmol, 2.0 eq). Reaction mixture was degassed with argon for 10 min and (dppf)PdCl2(0.253 g, 0.347 mmol, 0.1 eq) was added. Reaction mixture was stirred at 90° C. for 16 hours. After completion of the reaction, mixture was transferred into water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to obtain crude which was purified by preparative HPLC to furnish 7.1. (0.08 g, 7.83%). MS(ES): m/z 295.7 [M]+.

Synthesis of Compound VIII-7

Synthesis of Compound 206.1

To a solution of 202.1 (10 g, 0.045 mmol, 1.0 eq) in dichloromethane (100 mL) at −78° C., diisobutyl aluminium hydride (54 mL, 0.054 mmol, 1.2 eq) was added. Reaction mixture was stirred at −78° C. for 1 h. After completion of reaction, methanol was slowly added to the reaction mixture at −78° C. followed by addition of 1N HCl and extracted with dichloromethane. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 206.1. (7.0 g, 87.52%). MS(ES): m/z 175.48 [M]+.

Synthesis of Compound 206.2

To a solution of 206.1 (8.0 g, 0.045 mmol, 1.0 eq) in methanol (150 mL) was added hydroxylamine (70 mL, 0.045 mmol, 1.0 eq) at 0° C. Reaction mixture was stirred at 40° C. for 24 h. After completion of reaction, reaction mixture was transferred into water slowly and extracted with dichloromethane. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 206.2. (2.0 g, 23.03%). MS(ES): m/z 192.38 [M]+.

Synthesis of Compound 206.3

To a solution of compound 206.2 (2.0 g, 10.4 mmol, 1.0 eq) in dichloromethane (20 mL) at 0° C., pyridine (4.2 mL, 41.88 mmol, 5.0 eq), N-chloro succinimide (7.0 g, 52.35 mmol, 5.0 eq) was added. Reaction mixture was stirred at room temperature for 3 h. Then, trimethylsilane acetylene (4.11 g, 41.8 mmol, 4.0 eq) and triethylamine (5.9 mL, 41.8 mmol, 4.0 eq) was added. Reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 3% ethyl acetate in hexane to obtain 206.3. (1.0 g, 33.25%). MS(ES): m/z 288.41 [M]+.

Synthesis of Compound 206.4

To a solution of compound 206.3 (0.4 g, 1.3 mmol, 1.0 eq) in isopropyl alcohol (4 mL), potassium carbonate (0.192 mL, 1.3 mmol, 1.0 eq) was added. Reaction mixture was stirred at room temperature for 24 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 5% ethyl acetate in hexane to obtain 206.4. (0.150 g, 50.09%). MS(ES): m/z 216.53 [M]+.

Synthesis of Compound 206.5

To a solution of compound 206.4 (0.150 g, 0.69 mmol, 1.0 eq) in dimethylformamide (1 mL), sodium azide (0.045 g, 0.69 mmol, 1.0 eq) was added. Reaction mixture was stirred at 90° C. for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 10% ethyl acetate in hexane to obtain 206.5. (0.060 g, 38.81%). MS(ES): m/z 222.53 [M]+.

Synthesis of Compound 206.6

To a solution of compound 206.5 (0.060 g, 0.26 mmol, 1.0 eq) in a mixture of tetrahydrofuran (2.4 mL) and water (0.4 mL), triphenylphosphine (0.14 g, 0.54 mmol, 2.0 eq) was added. Reaction mixture was stirred at 75° C. for 3 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 10% ethyl acetate in hexane to get 1.6. (0.050 g, 68.41%). MS(ES): m/z 196.35 [M]+.

Synthesis of Compound 206.7

To a solution of compound 206.6 (0.050 g, 0.2 mmol, 1.0 eq) in pyridine (0.5 mL), 4-dimethylaminopyridine (0.071 mL, 0.27 mmol, 2.0 eq) and cyclopropyl carbonyl chloride (0.1 mL, 1.22 mmol, 5 eq) was added. Reaction mixture was heated in microwave at 90° C. for 1 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 10% ethyl acetate in hexane to obtain 206.7. (0.050 g, 74.15%). MS(ES): m/z 264.53 [M]+.

Synthesis of VIII-8

Synthesis of Compound 207.2

To a solution of compound 4.2 (2 g, 9.8 mmol, 1.0 eq) in 1,4-dioxane (20 mL) was added 207.1 (1.7 g, 9.8 mmol, 1.0 eq), potassium carbonate (3.38 g, 24.5 mmol, 2.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.89 g, 0.098 mmol, 0.1 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (1.13 g, 1.9 mmol, 0.2 eq) were added, again degassed for 5 min. The reaction was stirred at 110° C. for 2 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 1% methanol in dichloromethane as eluant to obtain pure 207.2 (0.9 g, 22.84%). MS(ES): m/z 341.45 [M+H]+.

Synthesis of Compound 207.3

To a solution of 207.2 (0.270 g, 0.79 mmol, 1.0 eq) in 1,4-dioxane (3 mL) was added cyclopropane carboxamide (0.101 g, 1.19 mmol, 1.5 eq), potassium carbonate (0.27 g, 1.98 mmol, 2.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.072 g, 0.079 mmol, 0.1 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.091 g, 0.158 mmol, 0.2 eq) were added, again degassed for 5 min. The reaction was stirred at 130° C. for 2 h under microwave irradiation. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 2% methanol in dichloromethane as eluant to obtain pure 207.3 (0.250 g, 81.03%). MS(ES): m/z 390.25 [M+H]+.

Synthesis of Compound 207.4

To a solution of 207.3 (0.250 g, 0.64 mmol, 1.0 eq) in ethanol (2 mL) was added hydroxylamine (2 mL). Reaction mixture was stirred at 80° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and solvent was evaporated to get the crude material. This was further transferred into ice water to get the solid precipitate which was filtered, dried well to obtain pure 207.4 (0.220 g, 81.81%). MS(ES): m/z 423.58 [M+H]+.

Synthesis of VIII-9

Synthesis of Compound 208.2

Synthesis of Compound 208.3

To a solution of compound 208.2 (4.5 g, 16.36 mmol, 1.0 eq) in tetrahydrofuran (60 mL) at 0° C., compound 4.2 (4.0 g, 19.63 mmol, 1.2 eq) was added. Then, lithium-bis(trimethylsilyl)amide (49 mL, 49.09 mmol, 3 eq) was added dropwise at 0° C. Reaction mixture was stirred at 50° C. for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude material. This was further purified by column chromatography using 30% ethyl acetate in hexane to obtain pure 208.3. (3.5 g, 48.34%). MS(ES): m/z 444.25 [M]+.

Synthesis of Compound 208.4

To a solution of compound 208.3 (0.5 g, 1.12 mmol, 1.0 eq) in dimethylformamide (5 mL), pyrazole ethyl ester (0.48 g, 3.35 mmol, 3 eq) was added. Reaction mixture was degassed with argon for 15 min. Then, copper iodide (0.010 g, 0.05 mmol, 0.05 eq) and potassium carbonate (0.4 g, 2.84 mmol, 2.5 eq) was added. Reaction mixture was stirred in microwave at 180° C. for 40 min. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 0.5% methanol in dichloromethane to obtain 208.4. (0.045 g, 7.94%). MS(ES): m/z 502.64 [M]+.

Synthesis of VIII-10

Synthesis of Compound 209.1

To a solution of compound 208.3 (2.0 g, 4.50 mmol, 1.0 eq) in 1,4-dioxane (40 mL) was added bis-pinacolato-diboron (4.59 g, 18.02 mmol, 4.0 eq). Reaction mixture was degassed with argon for 15 min. Then, potassium acetate (0.88 g, 9.05 mmol, 2.0 eq) was added and again degassed with argon for 10 min. Then, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride complex with dichloromethane (0.36 g, 0.45 mmol, 0.1 eq) was added and the reaction mixture was heated at 120° C. for 2 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by trituration using diethyl ether and hexane to obtain 209.1 (1.7 g, 76.84%). MS(ES): m/z 491.26 [M]+.

Synthesis of VIII-11

Synthesis of Compound 210.1

To a solution of compound 202.5 (0.15 g, 1.13 mmol, 1.0 eq) in a mixture of water (5 mL) and tetrahydrofuran (5 mL) at 0° C., lithium borohydride (2.93 mL, 20.9 mmol, 3 eq) was added. Reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated, transferred to water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude material. This was further purified by column chromatography using 10% ethyl acetate in hexane to obtain pure 210.1. (0.1 g, 71.18%). MS(ES): m/z 414.57 [M]+.

Synthesis of VIII-12

Synthesis of VIII-13

Synthesis of VIII-14

Synthesis of Compound 213.1

To a solution of compound VIII-1 (0.3 g, 0.62 mmol, 1.0 eq) in ethanol (5 mL) was added 4M sodium hydroxide solution (4.1 mLg, 3.11 mmol, 5.0 eq). Reaction mixture was stirred at 60° C. for 3 h. After completion of reaction, reaction mixture concentrated under reduced pressure to obtain residue which was transferred into water and extracted with dichloromethane. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 213.1 (0.25 g, 83.15%). MS(ES): m/z 416.57 [M]+.

Synthesis of VIII-15

Synthesis of VIII-16

Synthesis of Compound 215.2

To a solution of 215.1 (2 g, 9.9 mmol, 1.0 eq) in tetrahydrofuran (30 mL) at 0° C., boron trifluoride etherate (4.18 g, 29.7 mmol, 3.0 eq) was added dropwise. Reaction mixture was stirred at room temperature for 3 h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 1.1 (1.4 g, 75.21%). MS(ES): m/z 189.65 [M]+.

Synthesis of Compound 215.3

Synthesis of VIII-17

Synthesis of Compound 216.2

Synthesis of Compound 216.3

To a suspension of 216.2 (1.5 g, 3.91 mmol, 1.0 eq) in water (3 mL) was added 4M hydrogen chloride in dioxane (15 mL) and stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This was further purified by trituration with dichloromethane and diethyl ether to obtain 216.3 (0.7 g, 69.98%). MS(ES): m/z 256.46 [M+H]+.

Synthesis of Compound 216.4

To a solution of compound 216.3 (0.4 g, 1.8 mmol, 1.0 eq) in ethanol (5 mL), dichloropyridine carbonitrile (0.35 g, 1.8 mmol, 1.0 eq) was added. Reaction mixture was heated in microwave at 140° C. for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using 5% methanol in dichloromethane to obtain pure 216.4. (0.09 g, 16.17%). MS(ES): m/z 356.48 [M]+.

Synthesis of Compound 216.5

To a solution of compound 216.4 (0.050 g, 0.14 mmol, 1.0 eq) in methanol (5 mL), paraformaldehyde (0.025 g, 0.84 mmol, 6.0 eq) and sodium methoxide (0.023 g, 0.43 mmol, 3.0 eq) were added. Reaction mixture was stirred at 60-65° C. for 3 h. Reaction mixture was cooled to room temperature and sodium borohydride (0.005 g, 0.35 mmol, 2.5 eq) was added in portions. Reaction mixture was again stirred at 60-65° C. for 24 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with dichloromethane. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get 216.5. (0.04 g, 76.97%). MS(ES): m/z 370.28 [M]+.

Synthesis of XVI-1

Synthesis of Compound 217.2

To a solution of compound 217.1 (0.1 g, 0.37 mmol, 1.0 eq) in diethyl ether (1 mL), n-butyl lithium (0.7 mL, 0.74 mmol, 2.0 eq) was added dropwise under argon atmosphere at −78° C. Reaction mixture was stirred at −78° C. for 40 min and carbon dioxide was bubbled through the reaction mixture for 45 min. After completion of the reaction, the reaction mixture was transferred in 1N hydrochloric acid, neutralized using 1N sodium hydroxide solution and extracted with dichloromethane. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 217.2 (0.070 g, 80.43%). MS(ES): m/z 235.48 [M+H]+.

Synthesis of Compound 217.3

To a solution of 217.2 (0.083 g, 0.35 mmol, 1.0 eq) in N,N-dimethylformamide (1.5 mL) was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.1 g, 24.6 mmol, 1.0 eq) at 0° C. Reaction mixture was stirred at 0° C. for 40 min. Then, compound 1.2 and di-isopropylethylamine was added at 0° C. Reaction mixture was stirred at room temperature for 4 h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 10% ethyl acetate in hexane to obtain 217.3 (0.080 g, 38.46%). MS(ES): m/z 360.54 [M+H]+.

Synthesis of Compound 217.4

To a solution of compound 217.3 (0.1 g, 0.27 mmol, 1.0 eq) in N,N-dimethylformamide (0.7 mL), phosphorous oxychloride (0.7 mL) was added. Reaction mixture was stirred at 55° C. for 3 h. After completion of the reaction, the reaction mixture was quenched using aqueous ammonia solution and extracted with dichloromethane. Organic layer combined, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. This was further purified by column chromatography using 1% methanol in dichloromethane to obtain pure 217.4. (0.070 g, 73.69%). MS(ES): m/z 342.52 [M]+.

Synthesis of Compound 217.5

To a solution of compound 217.4 (0.050 g, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (1 mL), N-iodo succinimide (0.035 mL, 0.15 mmol, 1.05 eq) was added. Reaction mixture was stirred at 60° C. for 3 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 0.2% methanol in dichloromethane to obtain pure 217.5. (0.045 g, 65.77%). MS(ES): m/z 468.51 [M]+.

Synthesis of Compound 217.6

To a solution of compound 217.5 (0.16 g, 0.34 mmol, 1.0 eq) in 1,4-dioxane (10 mL), tert-butyl carbamate (0.4 g, 3.42 mmol, 10.0 eq) was added. Reaction mixture was degassed with argon for 15 min followed by addition of N,N-dimethylcyclohexylamine (0.097 g, 0.68 mmol, 2.0 eq) and again degassed with argon for 5 min. Then, copper iodide (0.067 g, 0.34 mmol, 2.0 eq) was added. Reaction mixture was stirred 75° C. for 6 h. After completion of the reaction, the reaction mixture was concentrated, transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography using 40% ethyl acetate in hexane to obtain pure 217.6. (0.055 g, 35.18%). MS(ES): m/z 457.82 [M]+.

Synthesis of Compound 217.7

To a solution of compound 217.6 (0.055 g, 0.12 mmol, 1.0 eq) in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added. Reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 min. After completion of the reaction, reaction mixture was transferred into water, neutralized using sodium bicarbonate solution and then extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 217.7. (0.037 g, 86.15%). MS(ES): m/z 357.28 [M]+.

Synthesis of Compound 217.8

Synthesis of XVI-2

Synthesis of Compound 218.2

Synthesis of Compound 218.3

To a suspension of 218.2 (1.7 g, 4.4 mmol, 1.0 eq) in water (2 mL) was added 4M hydrogen chloride in dioxane (17 mL) dropwise. Reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude material. This was further purified by trituration with dichloromethane and ether to obtain 218.3 (0.8 g, 70.48%). MS(ES): m/z 256.46 [M+H]+.

Synthesis of Compound 218.4

To a solution of dichloropyridinecarbonitrile (0.3 g, 1.3 mmol, 1.0 eq) in butanol (2 mL), compound 218.3 (0.23 g, 1.3 mmol, 1.0 eq) was added. Reaction mixture was heated in microwave at 120° C. for 5 h. After completion of the reaction, the reaction mixture was concentrated to get the crude product. This was further purified by column chromatography using 5% methanol in dichloromethane to obtain pure 218.4. (0.17 g, 40.77%). MS(ES): m/z 357.48 [M]+.

Synthesis of Compound 218.5

Synthesis of XVI-3

Synthesis of Compound 219.2

To a solution of compound 219.1 (0.5 g, 2.61 mmol, 1.0 eq) in tetrahydrofuran (10 mL), 1,1′-carbonyldiimidazole (0.63 g, 3.91 mmol, 1.5 eq) was added. Reaction mixture was stirred for 30 min at room temperature. Then, di-isopropylethylamine (0.67 g, 5.22 mmol, 2.0 eq) and N,O-dimethylhydroxyamine hydrochloride (0.30 g, 3.13 mmol, 1.2 eq) was added and the reaction mixture was stirred for 18 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography using 20% ethyl acetate in hexane to obtain pure 219.2 (0.3 g, 49.01%). MS(ES): m/z 236.06 [M+H]+.

Synthesis of Compound 219.3

To a solution of 219.2 (0.1 g, 0.42 mmol, 1.0 eq) in tetrahydrofuran (0.5 mL) was added ethyl magnesium bromide (1M in THF) (0.84 mL, 0.84 mmol, 2.0 eq) at 0° C. Reaction mixture was stirred at room temperature for 18 h. After completion of reaction, the reaction mixture was transferred to ammonium chloride and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 10% ethyl acetate in hexane to get 219.3 (0.8 g, 92.16%). MS(ES): m/z 205.48 [M+H]+.

Synthesis of Compound 219.4

Synthesis of Compound 219.6

Synthesis of XVI-4

Synthesis of Compound 220.2

To a solution of compound 220.1 (0.5 g, 1.85 mmol, 1.0 eq) in 1,4-dioxane (1 mL), compound bispinacolato diboron (0.70 g, 2.2 mmol, 1.2 eq), (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.04 g, 0.05 mmol, 0.03 eq) and potassium acetate (0.54 g, 5.52 mmol, 3 eq) was added. Reaction mixture was degassed with argon for 15 min and then stirred at 120° C. for 5 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain pure 220.2 (0.4 g, 68.09%). MS(ES): m/z 317.58 [M+H]+.

Synthesis of Compound 220.4

To a solution of 220.3 (1.0 g, 0.50 mmol, 1.0 eq) in dimethylformamide (10 mL) was added potassium hydroxide (0.54 g, 0.75 mmol, 1.5 eq) and iodine (2.2 g, 0.75 mmol, 1.5 eq) at room temperature. Reaction mixture was stirred at room temperature for 2 h. After completion of reaction, to the reaction mixture was added solution of sodium carbonate slowly and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 220.4 (1.3 g, 71.44%). MS(ES): m/z 280.53 [M+H]+.

Synthesis of Compound 220.5

To a solution of compound 220.5 (1.5 g, 5.30 mmol, 1.0 eq) in dimethylformamide (15 mL) at 0° C., ethyl iodide (0.32 g, 6.3 mmol, 1.2 eq) was added. Then, sodium hydride (1.0 g, 7.9 mmol, 1.5 eq) was added in portions at 0° C. Reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was transferred to water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 10% ethyl acetate in hexane to obtain pure 220.5. (1.0 g, 60.58%). MS(ES): m/z 308.56 [M]+.

Synthesis of Compound 220.6

To a solution of compound 220.5 (0.1 g, 0.32 mmol, 1.0 eq) in a mixture of toluene (1.0 mL), ethanol (0.5 mL) and water (0.5 mL), compound 220.2 (0.12 g, 0.39 mmol, 1.2 eq) was added. Then, sodium bicarbonate (0.08 g, 0.9 mmol, 3.0 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.032 mmol, 0.1 eq) was added. Reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with dichloromethane. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 60% ethyl acetate in hexane to obtain pure 220.6 (0.033 g, 27.44%). MS(ES): m/z 370.43 [M]+.

Synthesis of XVI-5

Synthesis of Compound 221.2

To a solution of compound 221.1 (2 g, 11.62 mmol, 1.0 eq) in dimethylformamide (10 mL), dimethylformamide dimethyl acetal (2 mL) was added. Reaction mixture was stirred at 90° C. for 2 h. After completion of the reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 221.2 (1.2 g, 45.48%). MS(ES): m/z 228.15 [M+H]+.

Synthesis of Compound 221.3

To a solution of 221.2 (1.0 g, 4.4 mmol, 1.0 eq) in acetic acid (10 mL) was added iron powder (1.2 g, 22.0 mmol, 5.0 eq) at room temperature. Reaction mixture was stirred at 90° C. for 2 h. After completion of reaction, to the reaction mixture was added solution of sodium carbonate slowly and extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and the product was eluted in 30% ethyl acetate in hexane to obtain 221.3 (0.65 g, 96.98%). MS(ES): m/z 153.47 [M+H]+.

Synthesis of Compound 221.4

To a solution of compound 221.3 (1.2 g, 7.7 mmol, 1.0 eq) in dimethylformamide (5 mL), bromine solution (1.2 g, 7.7 mmol, 1.0 eq) was added. Reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was transferred into water to obtain the precipitate which was filtered, washed with water and dried well under vacuum to obtain 221.4. (1.1 g, 60.42%). MS(ES): m/z 232.53 [M]+.

Synthesis of Compound 221.5

To a solution of compound 221.4 (1.1 g, 7.2 mmol, 1.0 eq) in dimethylformamide (20 mL) at 0° C., sodium hydride (0.5 mL, 10.8 mmol, 1.5 eq) was added. Reaction mixture was stirred at 0° C. for 20 min. Then, ethyl iodide (1.6 mL, 10.8 mmol, 1.5 eq) was added. Reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was transferred into water to obtain the precipitate which was filtered, washed with water and dried well under vacuum to obtain 221.5. (0.9 g, 72.97%). MS(ES): m/z 260.37 [M]+.

Synthesis of Compound 221.6

To a solution of compound 221.5 (0.4 g, 1.5 mmol, 1.0 eq) in a mixture of water (2 mL), ethanol (4 mL) and toluene (4 mL), compound 220.2 (0.63 mL, 2.0 mmol, 1.3 eq) and sodium bicarbonate (0.3 g, 3.6 mmol, 3.0 eq) was added. Reaction mixture was degassed with argon for 15 min. Then, tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol, 0.1 eq) was added and again degassed for 5 min. Reaction mixture was stirred at 110° C. for 24 h. After completion of the reaction, the reaction mixture was concentrated, transferred to water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 55% ethyl acetate in hexane to obtain pure 221.6. (0.15 g, 26.39%). MS(ES): m/z 369.43 [M]+.

Synthesis of XVI-6

Binding constants for compounds of the present invention against the JH2 domain were determined by the following protocol for a KINOMEscan® assay (DiscoveRx). A fusion protein of a partial length construct of human TYK2 (JH2domain-pseudokinase) (amino acids G556 to D888 based on reference sequence NP_003322.3) and the DNA binding domain of NFkB was expressed in transiently transfected HEK293 cells. From these HEK 293 cells, extracts were prepared in M-PER extraction buffer (Pierce) in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) per manufacturers' instructions. The TYK2 (JH2domain-pseudokinase) fusion protein was labeled with a chimeric double-stranded DNA tag containing the NFkB binding site (5′-GGGAATTCCC-3′ (SEQ ID NO: 1)) fused to an amplicon for qPCR readout, which was added directly to the expression extract (the final concentration of DNA-tag in the binding reaction is 0.1 nM).

Streptavidin-coated magnetic beads (Dynal M280) were treated with a biotinylated small molecule ligand for 30 minutes at room temperature to generate affinity resins the binding assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.

The binding reaction was assembled by combining 16 μl of DNA-tagged kinase extract, 3.8 μl liganded affinity beads, and 0.18 μl test compound (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 μg/ml sonicated salmon sperm DNA)]. Extracts were used directly in binding assays without any enzyme purification steps at a ≥10,000-fold overall stock dilution (final DNA-tagged enzyme concentration <0.1 nM). Extracts were loaded with DNA-tag and diluted into the binding reaction in a two step process. First extracts were diluted 1:100 in 1× binding buffer (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 μg/ml sonicated salmon sperm DNA) containing 10 nM DNA-tag. This dilution was allowed to equilibrate at room temperature for 15 minutes and then subsequently diluted 1:100 in 1× binding buffer. Test compounds were prepared as 111× stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kdmeasurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 mL. Assays were incubated with shaking for 1 hour at room temperature. Then the beads were pelleted and washed with wash buffer (1×PBS, 0.05% Tween 20) to remove displaced kinase and test compound. The washed based were re-suspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. qPCR reactions were assembled by adding 2.5 μL of kinase eluate to 7.5 μL of qPCR master mix containing 0.15 μM amplicon primers and 0.15 μM amplicon probe. The qPCR protocol consisted of a 10 minute hot start at 95° C., followed by 35 cycles of 95° C. for 15 seconds, 60° C. for 1 minute.

Test compounds were prepared as 111× stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kdmeasurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. The Kds were determined using a compound top concentration of 30,000 nM. Kdmeasurements were performed in duplicate.

Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation:

The Hill Slope was set to −1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm (Levenberg, K., A method for the solution of certain non-linear problems in least squares,Q. Appl. Math.2, 164-168 (1944)). In some cases

Results of the JH2 binding assay are reported in Table 4. Compounds described as “A” have a Kdless than 100 pM. Compounds described as “B” have a Kdequal to or greater than 100 pM and less than 500 pM. Compounds described as “C” have a Kdequal to or greater than 500 pM and less than 1 nM. Compounds described as “D” have a Kdequal to or greater than 1 nM and less than 10 nM. Compounds described as “E” have a Kdequal to or greater than 10 nM.

Results of the JH2 binding assay are listed in Table 5, below. Compounds designated as “A” had a Kdbetween 100 pM and 1 nM. Compounds designated as “B” had a Kdbetween 1 nM and 10 nM. Compounds designated as “C” had a Kdbetween 10 nM and 100 nM. Compounds designated as “D” had a Kdgreater than 100 nM.

Results of the Tyk2 JH2 Domain Binding Assay indicate that compounds XVI-1 and XVI-3 have a Kdbetween 7-10 uM, and compounds XVI-2 and XVI-4 through XVI-6 have a Kd between 10-185 nM.

Peptide substrate, [KKSRGDYMTMQIG (SEQ ID NO: 2)], (20 μM) is prepared in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na3PO4, 2 mM DTT, 1% DMSO. TYK2 (Invitrogen) kinase is added, followed by compounds in DMSO. 33PATP is added to initiate the reaction in ATP at 10 μM. Kinase reaction is incubated for 120 min at room temp and reactions are spotted onto P81 ion exchange paper (Whatman #3698-915), and then washed extensively in 0.75% phosphoric acid, prior to reading the radioactivity counts. For JAK2 (Invitrogen) kinase assay the peptide substrate poly[Glu:Tyr] (4:1), 0.2 mg/ml is used, in the reaction carried out the same as for TYK2.

Results of the active kinase assay indicate that compounds I-1 and I-2 have no detectable inhibitory activity against TYK2 JH1 kinase function.

Results of the active kinase assay indicate that compounds VIII-1, VIII-2, VIII-3, and VIII-4 have no detectable inhibitory activity against TYK2 or JAK2 JH1 kinase function.

The caliper machine employs an off chip mobility shift assay to detect phosphorylated peptide substrates from kinase assays, using microfluidics technology. The assays are carried out at ATP concentration equivalent to the ATP Km, and at 1 mM ATP. Compounds are serially diluted in DMSO then further diluted in assay buffer (25 mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5 mM EGTA). 5 ul of diluted compound was added into wells first, then 10 ul of enzyme mix was added into wells, followed by 10 uL of substrate mix (peptide and ATP in 10 mM MgCl2) to start reaction. Reaction was incubated at 28° C. for 25 min and then added 25 ul stop buffer (100 mM HEPES, 0.015% Brij-35, 50 mM EDTA), followed by reading with Caliper. JAK2 at 1 nM final concentration and TYK2 at 9.75 nM are from Carna, and substrates used are ATP at 20 and 16 uM, respectively. JAK2 assay uses peptide 22 and TYK2 uses peptide 30 (Caliper), each at 3 uM.

Example 225. IL-12 Induced pSTAT4 in Human PBMC

Human PBMC are isolated from buffy coat and are stored frozen for assays as needed. Cells for assay are thawed and resuspended in complete media containing serum, then cells are diluted to 1.67 E6 cells/ml so that 120 μl per well is 200,000 cells. 15 μl of compound or DMSO is added to the well at the desired concentrations and incubated at 1 hr at 37 C. 15 μl of stimulus (final concentration of 1.7 ng/mL IL-12) is added for 30 minutes prior to pSTAT4 and total STAT4 analysis using cell lysates prepared and analyzed by MSD reagents as per manufacturer protocol. The final DMSO concentration of compound in the assay is 0.1%.

Results of the IL-12 induced pSTAT4 assay in human PBMC indicate that each of compounds VIII-1 through VIII-17 inhibited pSTAT4 production with an IC50of between 100 nM and 10 uM.

Example 226. GM-CSF Induced pSTAT5 in Human PBMC

Cells are prepared for analysis as in the above procedure and 15 μl of GM-CSF (final concentration 5 ng/mL) is added for 20 minutes prior to pSTAT5 and total STAT5 analysis using cell lysates prepared and analyzed by MSD reagents as per manufacturer protocol. The final DMSO concentration of compound in the assay is 0.1%.

Results of the GM-CSF Induced pSTAT5 assay in human PBMC indicate that compound VIII-1 inhibits pSTAT5 production with an IC50of greater than 50 uM.

Example 227. Ex Vivo Mouse IL-12 Induced IFNγ Studies

C57/BL6 mice are given a single oral dose of either vehicle or different doses of compound at a volume of 10 mL/kg. 30 minutes to 1 hour after dosing, animals are euthanized and blood was collected via vena cava into sodium heparin blood collection tubes and inverted several times. Blood is then plated on anti-CD3 coated plates and stimulated with 2 ng/ml of mouse IL-12 in RPMI media for 24 hours at 37° C. in humidified incubator with 5% CO2. At the end of the incubation, blood is centrifuged at 260 g for 5 minutes to collect supernatant. IFNγ concentration in the supernatant is determined with mouse IFNγ MSD kit per manufacture's instruction (Meso Scale Discovery). At the time of the blood collection, plasma is collected for drug level analysis by LC-MS/MS.

Example 228. T-ALL Cell Proliferation Assay

T-ALL cell lines KOPT-K1, HPB-ALL, DND-41, PEER, and CCRF-CEM are cultured in RPMI-1640 medium with 10% fetal bovine serum and penicillin/streptomycin. Cells are plated in triplicate at 1×104cells per well in 96-well plates. T-ALL cell lines DU.528, LOUCY, and SUP-T13 are cultured in the same medium and plated at a density of 1.5×104cells per well. The cells are treated with DMSO or different concentrations of each compound of the invention. Cell viability at 72 hour exposure to the drug is assessed by CellTiter-Glo Luminescent Cell Viability Assay (Promega). CellTiter-Glo Reagent is added into the well and incubated for 10 minutes. Luminescence is measured subsequently using a 96-well plate luminescence reader. Cell viability is calculated by using the DMSO treated samples as 100%. IC50value is calculated by nonlinear regression using GraphPad Prism software.