PYRIDONE COMPOUNDS AND METHODS FOR USE

Description

FIELD

[0001] Provided herein are compounds and pharmaceutical compositions suitable as modulators of protein kinases, and their use in methods of treating disorders mediated, at least in part by, protein kinases.BACKGROUND

[0002] Human Axl belongs to the TAM subfamily of receptor tyrosine kinases that includes Mer. TAM kinases are characterized by an extracellular ligand binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in a number of tumor cell types and was initially cloned from patients with chronic myelogenous leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is believed to cause tumor growth through activation of proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers including, but not limiting to lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. The over-expression of Axl results in a poor prognosis for patients with the indicated cancers.

[0003] Activation of Mer, like Axl, conveys downstream signaling pathways that cause tumor growth and activation. Mer binds ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer on its intracellular domain, resulting in downstream signal activation. Over-expression of Mer in cancer cells leads to increased metastasis, most likely by generation of soluble Mer extracellular domain protein as a decoy receptor. Tumor cells secrete a soluble form of the extracellular Mer receptor which reduces the ability of soluble Gas-6 ligand to activate Mer on endothelial cells, leading to cancer progression.

[0004] c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with invasive cell growth. Signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells.

[0005] KDR is a tyrosine kinase receptor that binds vascular endothelial growth factor (VEGF). The binding of VEGF to the KDR receptor leads to angiogenesis. High levels of VEGF are found in various cancers causing tumor angiogenesis and permitting the rapid growth of cancerous cells.

[0006] Therefore, a need exists for new compounds that modulate Axl, Mer, c-Met, and / or KDR kinases for the treatment of cancers.

[0007] Wei Zhang et al: EJMC, vol. 80, 1 June 2014, pages 254-266 discusses type II c-Met inhibitors based on BMS-777607. WO 2013 / 180949 discusses substituted quinoline compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity. CN 108530426 discusses quinoxalinone-containing 4-phenoxy substituted quinoline derivatives with c-Met inhibitory activity. CN 104072480 discusses quinoline derivatives with c-Met inhibitory activity. EP 3239147 discusses quinoline derivatives with Axl inhibitory activity. WO 2007 / 033196 discusses compounds that are useful for treating cancer. Li Sai et al: EJMC, vol. 64, 15 April 2013, pages 62-73 disucsses the design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety. Qidong Tang et al: EJMC vol. 158, 1 October 2018, pages 201 -213, discusses synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety. Wei Zhang et al: Molecules, vol. 19, no. 2, 24 February 2014, pages 2655-2673 discusses c-Met inhibitors bearing a 3-carboxyl piperidin-2-one scaffold. Liu Ju et al: Bioorganic, vol. 25, no. 16, 27 June 2017, pages 4475-4486 discusses th design, synthesis and biological evaluation of 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors. EP 3 026 045 discusses compounds with Axl inhibitory activity. Tang Qidong et al: , EJMC, vol. 69, 19 August 2013 (2013-08-19), pages 77-89 discusses design, synthesis, and structure-activity relationships of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents. WO 2013 / 074633 discusses uracil derivatives as Axl and c-Met inhibitors.SUMMARY

[0008] Provided herein are compounds that inhibit c-Met, Axl, Mer and / or KDR. In certain embodiments, the compounds are of Formula (Ia), Formula (Ib), or Formula (Ic) as described in the detailed description section: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0009] Some embodiments provide for a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, selected from Table 1.

[0010] Also provided herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0011] The invention also provides a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition of the invention, for use in a method of treating a disease, disorder, or syndrome which is mediated by modulating in vivo activity of a protein kinase, optionally wherein the protein kinase is AXL, KDR, Mer, or Met.

[0012] Also provided herein are compositions, including pharmaceutical compositions, kits that include the compounds, and method of using (or administering) and making the compounds. Also provided herein are compounds or compositions for use in a method of treating a disease, disorder, or condition that is mediated, at least in part, by c-Met, Axl, Mer and / or KDR activity.

[0013] The invention also provides a process for preparing a compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: the process comprises contacting a compound of Formula A-a, Formula A-b, or Formula A-c: with a compound of Formula B-c: under amide bond forming conditions to provide the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: X 1< , X 2< , R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 8< , R 9< , R 10< , G and m are as defined herein. DETAILED DESCRIPTION Definitions

[0014] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH 2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0016] The prefix "C u-v " indicates that the following group has from u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0017] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Also, to the term "about X" includes description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0019] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, an "arylene" group or an "arylenyl" group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0020] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0021] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0022] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0023] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O) 2 -". "Alkylsulfonylalkyl" refers to -alkyl-S(O) 2 -alkyl.

[0024] "Acyl" refers to a group -C(O)R y< , wherein R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0025] "Amido" refers to both a "C-amido" group which refers to the group -C(O)NR y< R z< and an "N-amido" group which refers to the group -NR y< C(O)R z< , wherein R y< and R z< are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or R y< and R z< are taken together to form a cycloalkyl or heterocycloalkyl; each of which may be optionally substituted, as defined herein.

[0026] "Amino" refers to the group -NR y< R z< wherein R y< and R z< are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0027] "Amidino" refers to -C(NR y< )(NR z< 2 ), wherein R y< and R z< are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocycloalkyl, the resulting ring system is heterocycloalkyl.

[0029] "Arylalkyl" or "Aralkyl" refers to the group "aryl-alkyl-".

[0030] "Carbamoyl" refers to -C(O)NR y< R z< . "O-carbamoyl" refers to -O-C(O)NR y< R z< and "N-carbamoyl" refers to -NR y< C(O)OR z< , wherein R y< and R z< are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0031] "Carboxyl ester" or "ester" refer to both -OC(O)R x< and -C(O)OR x< , wherein R x< is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3< carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. In some embodiments, one or more ring carbons of "cycloalkyl" can be optionally replaced by a carbonyl group. Examples of such cycloalkyl include cyclohexanone-4-yl, and the like. Further, the term cycloalkyl is intended to encompass moieties that have one or more aromatic ring fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Still further, cycloalkyl also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0033] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0034] "Guanidino" refers to -NR y< C(=NR z< )(NR y< R z< ), wherein each R y< and R z< are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0035] "Hydrazino" refers to -NHNH 2 .

[0036] "Imino" refers to a group -C(NR y< )R z< , wherein R y< and R z< are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0037] "Imido" refers to a group -C(O)NR y< C(O)R z< , wherein R y< and R z< are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0038] "Halogen" or "halo" refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[0039] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0040] "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0041] "Hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0042] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR y< -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.) and amines (e.g., -CH 2 NR y< CH 3 , -CH(CH 3 )NR y< CH 3 , -CH 2 CH 2 NR y< CH 3 , -CH 2 CH 2 NR y< CH 2 CH 2 NR y< CH 3 , etc., where R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0043] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, boron, phosphorus and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-14, or 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide.

[0044] In certain instances, a fused heteroaryl refers to a heteroaryl ring fused to another heteroaryl ring. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0045] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0046] "Heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from boron, phosphorus, nitrogen, oxygen and sulfur. The term "heterocycloalkyl" includes heterocycloalkenyl groups (i.e., the heterocycloalkyl group having at least one double bond), bridged-heterocycloalkyl groups, fused-heterocycloalkyl groups and spiro-heterocycloalkyl groups. A heterocycloalkyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro. One or more ring carbon atoms and ring heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc.) or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached through a ring carbon atom or a ring heteroatom. Any non-aromatic ring containing at least one ring heteroatom is considered a heterocycloalkyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). As used herein, heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocycloalkyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocycloalkyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocycloalkyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocycloalkyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. The term "heterocycloalkyl" also includes "spiroheterocycloalkyl" when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocycloalkyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl.

[0047] Further, the term heterocycloalkyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring is fused to one or more aryl or heteroaryl rings, regardless of the attachment to the remainder of the molecule (i.e., a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring atom including a ring atom of the fused aromatic ring). Examples of the fused-heterocycloalkyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocycloalkyl can be bound via either ring of the fused system. Further, heterocycloalkyl, as defined herein, does not overlap with heteroaryl, as defined herein.

[0048] "Heterocycloalkylalkyl" refers to the group "heterocycloalkyl-alkyl-."

[0049] "Oxime" refers to the group -CR y< (=NOH) wherein R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0050] "Sulfonyl" refers to the group -S(O) 2 R y< , where R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0051] "Sulfinyl" refers to the group -S(O)R y< , where R y< is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0052] "Sulfonamido" refers to the groups -SO 2 NR y< R z< and -NR y< SO 2 R z< , where R y< and R z< are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0053] The terms "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0054] The term "substituted" used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -NHNH 2 , =NNH 2 , imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O) 2 OH, sulfonamido, thiol, thioxo, N-oxide or -Si(R y< ) 3 , wherein each R y< is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl.

[0055] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR q< R h< , -NR q< C(=O)R h< , -NR q< C(=O)NR q< R h< , -NR q< C(=O)OR h< , -NR q< S(=O) 1-2 R h< , -C(=O)R q< , -C(=O)OR q< , -OC(=O)OR q< , -OC(=O)R q< , -C(=O)NR q< R h< , -OC(=O)NR q< R h< , -OR q< , -SR q< , -S(=O)R q< , -S(=O) 2 R q< , -OS(=O) 1-2 R q< , -S(=O) 1-2 OR q< , -NR q< S(=O) 1-2 NR q< R h< , =NSO 2 R q< , =NOR q< , -S(=O) 1-2 NR q< R h< , -SF 5 , -SCF 3 or -OCF 3 . In certain embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(=O)R q< , -C(=O)OR q< , -C(=O)NR q< R h< , -CH 2 SO 2 R q< , or -CH 2 SO 2 NR q< R h< . In the foregoing, R q< and R h< are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, N-heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and / or heteroarylalkyl, or two of R q< and R h< and R i< are taken together with the atoms to which they are attached to form a heterocycloalkyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0056] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein.

[0057] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0058] Any compound or structure given herein, is intended to represent unlabeled forms as well as isotopically labeled forms (isotopologues) of the compounds. These forms of compounds may also be referred to as and include "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2< H, 3< H, 11< C, 13< C, 14< C, 13< N, 15< N, 15< O, 17< O, 18< O, 31< P, 32< P, 35< S, 18< F, 36< Cl, 123< I, and 125< I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3< H and 14< C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0059] The term "isotopically enriched analogs" includes "deuterated analogs" of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0060] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index (see e.g., A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). An 18< F, 3< H, 11< C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0061] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound presented herein can be replaced or substituted by deuterium (e.g., one or more hydrogen atoms of a C 1-6 alkyl group can be replaced by deuterium atoms, such as -CH 3 being replaced for -CD 3 ). In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0062] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. Further, in some embodiments, the corresponding deuterated analog is provided.

[0063] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0064] Provided also are a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, stereoisomer, tautomer, and a mixture of stereoisomers, of the compounds described herein.

[0065] "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0066] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from non-toxic inorganic and organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences , 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0067] The term "tautomer" means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom of the molecule. The tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Non-limiting examples include enol-keto, imine-enamine, amide-imidic acid tautomers, the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles, and the tautomeric forms of hydroxy substituted 6-membered heteroaryl groups (e.g., hydroxy substituted pyridine, pyrimidine, pyrazine or pyridazine) such as 4-hydroxypyridine and puridin-4(1H)-one, and the like. The compounds described herein may have one or more tautomers and therefore include various isomers. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0068] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0069] The compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0070] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[0071] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0072] Relative centers of the compounds as depicted herein are indicated graphically using the "thick bond" style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0073] The term "leaving group" refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. The non-limiting examples of a leaving group include, halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitrobenzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, and the like.

[0074] The term "amide coupling conditions" refers to the reaction conditions under which an amine and a carboxylic acid couple to form an amide using a coupling reagent in presence of a base. The non-limiting examples of coupling reagents include 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) with hydroxybenzotriazole monohydrate (HOBt), O-(7-Azabenzotriazole-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole, and the like. The non-limiting examples of the base include N-methylmorpholine, pyridine, morpholine, imidazole, and the like.

[0075] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protective group varies widely. One function of a protective group is to serve as an intermediate in the synthesis of the parental drug substance. Chemical protective groups and strategies for protection / deprotection are well known in the art. See: "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protective groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0076] The non-limiting examples of protective groups for a hydroxy (i.e. a "hydroxy protecting group") include methoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether, t-butyldiphenylsilyl ether, acetate ester, pivalate ester, benzoate ester, benzylidene acetal, acetonide, silyl ether, and the like.List of Abbreviations and Acronyms

[0077] Abbreviation Meaning AcacetylACNacetonitrileAmphos 2 PdCl 2 bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)anhyd.anhydrousaq.aqueousBINAP2,2'-Bis(diphenylphosphino)-1,1'-binaphthalenecatcatalytical amountδchemical shift (ppm)dbadibenzylideneacetoneDCEdicholoroethaneDCMdichloromethaneDIADdiisopropyl azodicarboxylateDIEAdiisopropylethylamineDMAPdimethylaminopyridineDMFdimethylformamideDMSOdimethylsulfoxidedppf1,1'-ferrocenediyl-bis(diphenylphosphine)eq or equiv.equivalent(s)EIelectron ionizationEtethylEt 2 OdiethyletherEtOAcethyl acetateEtOHethanolhhourHATUN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxideHPLChigh performance liquid chromatographyLC-MSLiquid chromatography - mass spectrometryMeOHmethanolNaOMesodium methoxideMemethylMSMass Spectrumm / zMass to charge ratioNaOAcsodium acetateNBSN-bromosuccinimideNISN-iodosuccinimideNH 2 Boctert-butyl carbamateNMPN-methyl-2-pyrrolidoneNMRnuclear magnetic resonance spectroscopyPd(Amphos) 2 Cl 2 bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)PhphenylPMB-4-methoxybenzylPR 3 tertiary organophosphinePreppreparatoryrac-racemicSPhos2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl t< Bu or tButert-butylTEAtriethylamineTHFtetrahydrofuranTLCthin layer chromatographyXPhos Pd G2chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) Compounds

[0078] Provided herein is are compounds of Formula (Ia), Formula (Ib), or Formula (Ic): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: G is C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, halo, C(O)OR a< , or C(O)NR a< R a< , wherein the C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 1-6 alkyl, C 2-6 alkenyl and C 1-6 alkoxy of G are each optionally substituted with 1, 2, 3, or 4 independently selected R 7< substituents; X 1< is N; X 2< is CH or CF; R 1< and R 2< are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene-, C 3-14 cycloalkyl-C 1-4 alkylene-, (5-14 membered heteroaryl)-C 1-4 alkylene-, (4-14 membered heterocycloalkyl)-C 1-4 alkylene-, CN, NO 2 , OR a< , SR a< , NHOR a< , C(O)R a< , C(O)NR a< R a< , C(O)OR a< , C(O)NR a< S(O) 2 R a< , OC(O)R a< , OC(O)NR a< R a< , NHR a< , NR a< R a< , NR a< C(O)R a< , NR a< C(=NR a< )R a< , NR a< C(O)OR a< , NR a< C(O)NR a< R a< , C(=NR a< )R a< , C(=NOH)R a< , C(=NOH)NR a< , C(=NCN)NR a< R a< , NR a< C(=NCN)NR a< R a< , C(=NR a< )NR a< R a< , NR a< C(=NR a< )NR a< R a< , NR a< S(O)R a< , NR a< S(O) 2 R a< , NR a< S(O) 2 NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , S(O) 2 NR a< C(O)R a< , P(O)R a< R a< , P(O)(OR a< )(OR a< ), B(OH) 2 , B(OR a< ) 2 , and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene-, C 3-14 cycloalkyl-C 1-4 alkylene-, (5-14 membered heteroaryl)-C 1-4 alkylene-, and (4-14 membered heterocycloalkyl)-C 1-4 alkylene- of R 1< and R 2< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; each R 3< is independently selected from halo, OH, CN, -C(O)OH, -C(O)NH(C 1-6 alkyl), -SO 2 (C 1-6 alkyl), -SO 2 NH(C 1-6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and C 3 -C 6 cycloalkyl of R 3< are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; R 4< is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene-, C 3-14 cycloalkyl-C 1-4 alkylene-, (5-14 membered heteroaryl)-C 1-4 alkylene-, (4-14 membered heterocycloalkyl)-C 1-4 alkylene-, CN, NO 2 , OR a< , SR a< , NHOR a< , C(O)R a< , C(O)NR a< R a< , C(O)OR a< , C(O)NR a< S(O) 2 R a< , OC(O)R a< , OC(O)NR a< R a< , NHR a< , NR a< R a< , NR a< C(O)R a< *, N=C(NR a< R a< ) 2 , NR a< C(=NR a< )R a< , NR a< C(O)OR a< , NR a< C(O)NR a< R a< , C(=NR a< )R a< , C(=NOH)R a< , C(=NOH)NR a< , C(=NCN)NR a< R a< , NR a< C(=NCN)NR a< R a< , C(=NR a< )NR a< R a< , NR a< C(=NR a< )NR a< R a< , NR a< S(O)R a< , NR a< S(O) 2 R a< , NR a< S(O) 2 NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , S(O) 2 NR a< C(O)R a< , P(O)R a< R a< , P(O)(OR a< )(OR a< ), B(OH) 2 , B(OR a< ) 2 , and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene-, C 3-14 cycloalkyl-C 1-4 alkylene-, (5-14 membered heteroaryl)-C 1-4 alkylene- and (4-14 membered heterocycloalkyl)-C 1-4 alkylene- of R 4< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 5< , R 6< and R 10< are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylthio, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy, OH, C 1-4 alkyl-C(O)-, C 1-4 alkyl-OC(O)-, -C(O)NH(C 1-4 alkyl), NH 2 , -NHC 1-4 alkyl, or -N(C 1-4 alkyl) 2 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl-C(O)- and C 1-4 alkyl of -NH(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 of R 5< , R 6< and R 10< are each optionally substituted with 1 or 2 independently selected R g< substituents; each R 7< is independently selected from halo, OH, C(O)OR a< , C(O)R a< , C(O)NR a< R a< , CN, NH 2 , - NH(C 1- C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2- C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1- C 6 haloalkoxy, C(O)NR a< R a< , NR a< C(O)R a< , NR a< C(O)NR a< R a< , SO 2 R a< , NR a< S(O) 2 R a< , NR a< S(O) 2 NR a< R a< , C 3- C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, C 3- C 6 cycloalkyl-C 1- C 4 alkylene-, (4- to 6-membered heterocycloalkyl)-C 1 -C 4 alkylene-, phenyl-C 1- C 2 alkylene, and (5- or 6-membered heteroaryl)-C 1- C 4 alkylene-, wherein the C 1 -C 6 alkyl, C 1- C 6 alkoxy, C 3- C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, C 3- C 6 cycloalkyl-C 1- C 4 alkylene-, (4-to 6-membered heterocycloalkyl)-C 1- C 4 alkylene-, phenyl-C 1- C 2 alkylene, and (5- or 6-membered heteroaryl)-C 1- C 4 alkylene- of R 7< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; R 8< is H, C 1-6 alkyl optionally substituted with 1 or 2 R g< substituents or a hydroxy protecting group; R 9< is H or C 1-6 alkyl optionally substituted with 1, 2, or 3 independently selected R g< substituents; or R 4< and R 5< taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected R g< substituents; or R 10< and R 5< taken together with the atoms to which they are attached form fused C 3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, fused 5- or 6-membered heteroaryl or fused phenyl, wherein the fused C 3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- or 6-membered heteroaryl, or fused phenyl is each optionally substituted with 1 or 2 independently selected R g< substituents, and wherein one or two ring carbon atoms of the fused C 3-7 cycloalkyl or fused heterocycloalkyl are optionally replaced by a carbonyl group; or R 12< and R 10< taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected R g< substituents; or R 6< and R 4< taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected R g< substituents; or R 6< and R 10< taken together with the atoms to which they are attached form fused C 3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- to 6-membered fused heteroaryl, or fused heteroaryl, wherein the fused C 3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- to 6-membered fused heteroaryl, and fused heteroaryl are each optionally substituted with 1 or 2 independently selected R g< substituents and wherein one or two ring carbon atoms of the fused C 3-7 cycloalkyl or 4- to 6-membered fused heterocycloalkyl are optionally replaced by a carbonyl; each R a< is independently selected from H, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6 -C 10 aryl-C 1- C 4 alkylene-, C 3 -C 10 cycloalkyl-C 1- C 4 alkylene-, (5-14 membered heteroaryl)-C 1- C 4 alkylene-, and (4-14 membered heterocycloalkyl)-C 1- C 4 alkylene-; wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6 -C 10 aryl-C 1- C 4 alkylene-, C 3 -C 10 cycloalkyl-C 1- C 4 alkylene-, (5-14 membered heteroaryl)-C 1- C 4 alkylene-, and (4-14 membered heterocycloalkyl)-C 1- C 4 alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; or any two R a< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R b< is independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6- C 10 aryl-C 1- C 4 alkylene-, C 3- C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, (4-10 membered heterocycloalkyl)-C 1- C 4 alkylene-, CN, OH, NH 2 , NO 2 , NHOR c< , OR c< , SR c< , C(O)R a< , C(O)NR c< R c< , C(O)OR c< , C(O)NR c< S(O) 2 R c< , OC(O)R c< , OC(O)NR c< R c< , C(=NOH)R c< , C(=NOH)NR c< , C(=NCN)NR c< R c< , NR c< C(=NCN)NR c< R c< , C(=NR c< )NR c< R c< , NR c< C(=NR c< )NR c< R c< , NHR c< , NR c< R c< , NR c< C(O)R c< , NR c< C(=NR c< )R c< , NR c< C(O)OR c< , NR c< C(O)NR c< R c< , NR c< S(O)R c< , NR c< S(O) 2 R c< , NR c< S(O) 2 NR c< R c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< , S(O) 2 NR c< C(O)R c< , Si(R c< ) 3 , P(O)R c< R c< , P(O)(OR c< )(OR c< ), B(OH) 2 , B(OR c< ) 2 , and S(O) 2 NR c< R c< ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1- C 4 alkylene-, C 3- C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, and (4-10 membered heterocycloalkyl)-C 1 -C 4 alkylene- of R b< are each further optionally substituted with 1, 2, or 3 independently selected R d< substituents; each R c< is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1- C 4 alkylene-, C 3 -C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, and (4-10 membered heterocycloalkyl)-C 1- C 4 alkylene-; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1- C 4 alkylene-, C 3 -C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, and (4-10 membered heterocycloalkyl)-C 1- C 4 alkylene- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; or any two R c< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R d< is independently selected from C 1 -C 6 alkyl, C 1- C 6 haloalkyl, halo, C 6- C 10 aryl, 5-10 membered heteroaryl, C 3- C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6- C 10 aryl-C 1- C 4 alkylene-, C 3- C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, (4-10 membered heterocycloalkyl)-C 1- C 4 alkylene-, CN, NH 2 , NHOR e< , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , OC(O)R e< , OC(O)NR e< R e< , NHR e< , NR e< R e< , NR e< C(O)R e< , NR e< C(O)NR e< R e< , NR e< C(O)OR e< , C(=NR e< )NR e< R e< , NR e< C(=NR e< )NR e< R e< , NR e< C(=NOH)NR e< R e< , NR e< C(=NCN)NR e< R e< , S(O)R e< , S(O)NR e< R e< , S(O) 2 R e< , NR e< S(O) 2 R e< , NR e< S(O) 2 NR e< R e< , and S(O) 2 NR e< R e< ; wherein the C 1 -C 6 alkyl, C 6- C 10 aryl, 5-10 membered heteroaryl, C 3- C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6- C 10 aryl-C 1- C 4 alkylene-, C 3- C 10 cycloalkyl-C 1- C 4 alkylene-, (5-10 membered heteroaryl)-C 1- C 4 alkylene-, and (4-10 membered heterocycloalkyl)-C 1- C 4 alkylene- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from H, C 1 -C 6 alkyl, C 1- C 6 alkoxy, C 3- C 6 cycloalkyl, C 3- C 6 cycloalkyl-C 1- C 4 alkylene-, C 6- C 10 aryl, C 6- C 10 aryl-C 1- C 4 alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-C 1- C 4 alkylene-, 4-7-membered heterocycloalkyl, (4-7-membered heterocycloalkyl)-C 1- C 4 alkylene-, C 1 -C 6 haloalkyl, C 1- C 6 haloalkoxy, C 2- C 4 alkenyl, and C 2- C 4 alkynyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3- C 6 cycloalkyl, C 6- C 10 aryl, 5 or 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 6- C 10 aryl-C 1- C 4 alkylene-, (5- or 6-membered heteroaryl)-C 1- C 4 alkylene-, (4-7-membered heterocycloalkyl)-C 1- C 4 alkylene-, C 2- C 4 alkenyl, and C 2- C 4 alkynyl of R e< are each optionally substituted with 1, 2, or 3 R f< substituents; or any two R e< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R f< is independently selected from t halo, OH, CN, C(O)OH, NH 2 , -NH(C 1- C 6 alkyl), -N(C 1- C 6 alkyl) 2 , C 1- C 6 alkyl, vinyl, C 1- C 6 alkoxy, C 1- C 6 alkylthio, C 1- C 6 haloalkyl, C 1- C 6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and C 3- C 6 cycloalkyl, wherein the C 1- C 6 alkyl, C 1- C 6 alkoxy, C 1- C 6 alkylthio, phenyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R f< are each optionally substituted with 1, 2, or 3 substituents selected from halo, OH, CN, - C(O)OH, -NH 2 , C 1- C 4 alkyl, C 1- C 4 alkoxy, C 1- C 4 haloalkyl, C 1- C 4 haloalkoxy, phenyl, C 3- C 10 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; each R g< is independently selected from halo, OH, CN, C(O)OH, -C(O)O-C 1- C 4 alkyl, NH 2 , - NH(C 1- C 6 alkyl), -N(C 1- C 6 alkyl) 2 , C 1- C 6 alkyl, C 1- C 6 alkoxy, C 1- C 6 alkylthio, C 1- C 6 haloalkyl, C 1- C 6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and C 3- C 6 cycloalkyl; and the subscript m is 0.

[0079] In some embodiments, R 1< is H or alkoxy. In some embodiments, R 1< is H or C 1-6 alkoxy. In some embodiments, R 2< is H or alkoxy. In some embodiments, R 2< is H or C 1-6 alkoxy optionally substituted with C 1-6 alkoxy. In some embodiments, one of R 1< and R 2< is H and the other of R 1< and R 2< is alkoxy. In some embodiments, both R 1< and R 2< are alkoxy.

[0080] In some embodiments, R 1< is H, C 1-6 alkyl, C 1-6 alkoxy, halo, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkylNHC(O)-, or C 1-6 alkylSO 2 NH-. In some embodiments, R 2< is H, C 1-6 alkyl, C 1-6 alkoxy, halo, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkylNHC(O)-, CF 3 , C 1-6 alkylOC(O)-, pyridyl, C 1-6 alkylSO 2 NH- or 1H-pyrazol-4-yl optionally substituted with R g< .

[0081] In some embodiments, one of R 1< and R 2< is OR a< and R a< is C 1-6 alkyl substituted 1 R d< . In some embodiments, R 2< is OR a< and R a< is C 1-6 alkyl substituted 1 R d< . In some embodiments, R d< is OR e< or C 3-10 cycloalkyl. In some embodiments, R e< is C 1-6 alkyl.

[0082] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl.

[0083] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutene-1-yl, cyclopenten-1-yl, cyclohexten-1-yl, 3,6-dihydro-2H-pyran-4-yl, piperidin-1-yl, pyrrolidine-1-yl or morpholino.

[0084] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy or halo.

[0085] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is C 2-6 alkenyl substituted with C 1- C 6 alkyl or C 3- C 6 cycloalkyl.

[0086] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is cyano, C(O)OR a< , or C(O)NR a< R a< .

[0087] In some embodiments, in the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, G is C 1-6 alkyl, vinyl, methoxy or halo.

[0088] In some embodiments, G is ring B as described below.

[0089] In some embodiments, the compound is a compound of formula (Ia): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0090] In some embodiments, the compound is a compound of formula (Ia-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3 or 4.

[0091] In some embodiments, the compound is a compound of formula (Ib): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0092] In some embodiments, the compound is a compound of formula (Ib-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3 or 4.

[0093] In some embodiments, the compound is a compound of formula (Ic): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0094] In some embodiments, the compound is a compound of formula (Ic-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3 or 4.

[0095] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 1< is H, C 1-6 alkyl, C 1-6 alkoxy, halo, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkylNHC(O)-, or C 1-6 alkylSO 2 NH-.

[0096] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 1< is H or C 1-6 alkoxy.

[0097] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 2< is H, C 1-6 alkyl, C 1-6 alkoxy, halo, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkylNHC(O)-, CF 3 , C 1-6 alkylOC(O)-, pyridyl, C 1-6 alkylSO 2 NH- or 1H-pyrazol-4-yl optionally substituted with R g< .

[0098] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 2< is H or C 1-6 alkoxy optionally substituted with C 1-6 alkoxy.

[0099] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 3< is H or halo.

[0100] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 7< is H, halo, C 1-6 alkyl or C 1-6 alkoxy.

[0101] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 9< is H or methyl. In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 9< is H.

[0102] In compounds of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, X 1< is N.

[0103] In compounds of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, X 2< is CH or CF and m is 0.

[0104] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 4< is selected from H, C 1-6 alkyl, C 1-6 alkoxy, OH, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C 1-4 alkylene-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C 1-4 alkylene-, and N=C[N(C 1-6 alkyl)(C 1-6 alkyl)] 2 , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C 1-4 alkylene-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C 1-4 alkylene-, and N=C[N(C 1-6 alkyl)(C 1-6 alkyl)] 2 of R 4< are each optionally substituted with 1 or 2 independently selected R b< or R g< substituents.

[0105] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 4< is C 1-6 alkyl or C 1-6 haloalkyl.

[0106] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 4< and R 5< taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl.

[0107] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 5< and R 6< are each independently selected from H, CH 3 , propen-2-yl, Br, Cl, CN, methoxy, 2-fluoroethyl, isopropyl, CH 3 C(O)-, OH, t-butyl, ethyl, hydroxymethyl, isopropylthio, and methoxymethyl.

[0108] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R 10< is H, CH 3 , propen-2-yl, Br, Cl, CN, methoxy, 2-fluoroethyl, isopropyl, CH 3 C(O)-, OH, t-butyl, ethyl, hydroxymethyl, isopropylthio or methoxymethyl.

[0109] In some embodiments of a compound of Formula (Ia), Formula (Ib), or Formula (Ic)) or any sub-formula thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, each R 8< is independently H or C 1-6 alkyl.

[0110] The invention also provides a process for preparing a compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: the process comprises contacting a compound of Formula A-a, Formula A-b, or Formula A-c: with a compound of Formula B-c: under amide bond forming conditions to provide the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: X 1< , X 2< , R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 8< , R 9< , R 10< , G and m are as defined above. In some embodiments, the amide bond forming conditions comprise HATU in the presence of a base in an organic solvent.

[0111] In some embodiments, a compound of the invention is selected from: 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c][1,4]oxazine-9-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c][1,4]oxazine-9-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c] [1,4]oxazine-9-carboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c] [1,4]oxazine-9-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c][1,4]oxazine-9-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0112] In some embodiments a compound of the invention is selected from 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-4-hydroxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; 1-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; 1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide; 5-bromo-1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide; 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 4-hydroxy-5-methoxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 5-bromo-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-6-ethyl-1-methyl-4-oxopyridine-3-carboxamide; 5-bromo-6-ethyl-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-methyl-4-oxopyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c][1,4]oxazine-9-carboxamide; N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 4-hydroxy-5-methoxy-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo0-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; N-[4-[[7-(2-cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl]oxy]-3-fluorophenyl]-5-(cyclopenten-1-yl)-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2, 1-c][1,4]oxazine-9-carboxamide; 5-cyano-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 3-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-5-morpholin-4-yl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-pyrrolidin-1-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-piperidin-1-ylpyridine-3-carboxamide; 3-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 5-[[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]carbamoyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxylic acid; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,5-N,2,6-tetramethylpyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-N-propan-2-ylpyridine-3,5-dicarboxamide; 5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-3-N,3-N,1,2,6-pentamethyl-4-oxopyridine-3,5-dicarboxamide; 3-N-cyclopropyl-5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,2,6-trimethylpyridine-3,5-dicarboxamide; 5-N-cyclopropyl-3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; and 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0113] In some embodiments a compound of the invention is 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0114] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, selected from Table 1: Table 1 Cpd # Structure Name G1-1 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamideG1-2 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamideG1-3 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamideG1-4 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamideG1-5 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamideG1-6 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamideG1-7 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamideG1-8 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide1-2 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide1-3 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-4 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-5 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-6 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-7 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-8 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide1-9 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide2-3 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide1 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide2 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide3 N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide4 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide5 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide6 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide7 5-(3,6-dihydro-2H-pyran-4-yl)-4-hydroxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methylpyridine-3-carboxamide8 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide9 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide10 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide11 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide12 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide13 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide14 1-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide15 1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide16 5-(cyclopenten-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide17 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide18 5-(cyclopenten-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide19 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide20 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide21 N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide22 5-bromo-1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide23 5-(cyclohexen-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide24 5-(cyclohexen-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide25 5-[(E)-2-cyclopentylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide26 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide27 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide28 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide29 N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide30 N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide31 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide32 N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide33 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide34 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide35 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide36 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide37 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide38 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide39 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide40 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide41 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide42 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide43 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide44 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide45 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide46 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide47 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide48 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide49 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide50 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide51 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide52 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide53 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide54 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide55 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide56 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide57 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide58 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide59 4-hydroxy-5-methoxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide60 N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5 -methoxy-2,6-dimethylpyridine-3-carboxamide61 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide62 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide63 5-bromo-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-6-ethyl-1-methyl-4-oxopyridine-3-carboxamide64 5-bromo-6-ethyl-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-methyl-4-oxopyridine-3-carboxamide65 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide66 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide67 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide68 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide69 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide70 N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide71 4-hydroxy-5-methoxy-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide72 N-[3-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide73 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide74 N-[4-[[7-(2-cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl]oxy]-3-fluorophenyl]-5-(cyclopenten-1-yl)-1,2,6-trimethyl-4-oxopyridine-3-carboxamide75 N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide76 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide77 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide78 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide79 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide80 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide81 5-cyano-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide82 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide83 5-cyano-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide84 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide85 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide86 3-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide87 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide88 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-5-morpholin-4-yl-4-oxopyridine-3-carboxamide89 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-pyrrolidin-1-ylpyridine-3-carboxamide90 N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-piperidin-1-ylpyridine-3-carboxamide91 3-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide92 5-[[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]carbamoyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxylic acid93 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,5-N,2,6-tetramethylpyridine-3,5-dicarboxamide94 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-N-propan-2-ylpyridine-3,5-dicarboxamide95 5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-3-N,3-N,1,2,6-pentamethyl-4-oxopyridine-3,5-dicarboxamide96 3-N-cyclopropyl-5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3,5-dicarboxamide97 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,2,6-trimethylpyridine-3,5-dicarboxamide98 5-N-cyclopropyl-3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide99 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide100 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide101 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide Treatment Methods and Uses

[0115] "Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0116] "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0117] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. The subject may be a mammal. The subject may be a human.

[0118] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a sickle cell disease. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

[0119] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0120] The method may be a method of modulating in vivo activity of a protein kinase in a subject, the method comprising: administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein.

[0121] The methods may be methods of modulating in vivo activity of a protein kinase in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein.

[0122] The method may be a method of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, wherein the disease, disorder, or syndrome is mediated at least in part by modulating in vivo activity of a protein kinase.

[0123] The methods may be methods of treating a disease, disorder, or syndrome in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, wherein the disease, disorder, or syndrome is mediated at least in part by modulating in vivo activity of a protein kinase.

[0124] The protein kinase may be AXL, KDR, Mer, or Met. The disease may be cancer.

[0125] Also described herein are methods of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, in combination with a therapeutic agent or therapy.

[0126] Also described herein are methods of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, in combination with a therapeutic agent or therapy.

[0127] The therapeutic agent may be an immunotherapeutic agent or a cancer vaccine. The immunotherapeutic agent may be an anti-PD-1 antibody or anti-PD-L1 antibody.

[0128] Also described herein are methods for treating cancer.

[0129] "Cancer" includes tumor types such as tumor types including breast, colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas as well as other cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma, small cell carcinoma of the prostate), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis defornians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma; as well as cancers of the thyroid including medullary thyroid cancer. Thus, the term "cancerous cell," as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0130] The cancer may be selected from ovarian cancer, prostate cancer, lung cancer, medullary thyroid cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, bone cancer, hematologic cancer, skin cancer, kidney cancer, breast cancer, colon cancer, and fallopian tube cancer.

[0131] The cancer may clear cell carcinoma, clear cell renal cell carcinoma, non-clear cell carcinoma, non-clear cell renal cell carcinoma, urothelial carcinoma, salivary gland cancer, penile squamous cell carcinoma, neuroendocrine tumors, adrenocortical carcinoma, or merkel cell carcinoma.

[0132] The disease or disorder may be ovarian cancer.

[0133] The disease or disorder may be prostate cancer.

[0134] The disease or disorder may be lung cancer.

[0135] The disease or disorder may be medullary thyroid cancer.

[0136] The disease or disorder may be liver cancer.

[0137] The disease or disorder may be gastrointestinal cancer.

[0138] The disease or disorder may be pancreatic cancer.

[0139] The disease or disorder may be bone cancer.

[0140] The disease or disorder may be hematologic cancer.

[0141] The disease or disorder may be skin cancer.

[0142] The disease or disorder may be kidney cancer.

[0143] The disease or disorder may be breast cancer.

[0144] The disease or disorder may be colon cancer. The disease or disorder may be fallopian cancer. The disease or disorder may be liver cancer, wherein the liver cancer is hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemagioma.

[0145] The disease or disorder may be gastrointestinal cancer, wherein the gastrointestinal cancer is cancer of the esophagus which is squamous cell carcinoma, adenocarcinoma, or leiomyosarcoma; cancer of the stomach which is carcinoma, or lymphoma; cancer of the pancreas, which is ductal adenocarcinoma, insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma; cancer of the small bowel, which is adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemagioma, lipoma, or cancer of the large bowel, which is adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma.

[0146] The disease or disorder may be cancer of the pancreas, wherein the cancer of the pancreas is ductal adenocarcinoma, insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma.

[0147] The disease or disorder may be bone cancer, wherein the bone cancer is osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteocartiliginous exostoses, chondroblastoma, chondromyxofibroma, or osteoid osteoma.

[0148] The disease or disorder may be hematologic cancer, wherein the hematologic cancer is myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, or myelodysplastic syndrome.

[0149] The disease or disorder may be skin cancer, wherein the skin cancer is malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or Karposi's sarcoma.

[0150] The disease or disorder may be a renal tumor or renal cell carcinoma.

[0151] The disease or disorder may be breast cancer.

[0152] The disease or disorder may be a colon cancer tumor.

[0153] The disease or disorder may be fallopian tube carcinoma.Combination Therapies

[0154] A compound as disclosed herein can be administered as a single therapy or in combination ("co-administered") with one or more additional therapies for the treatment of a disease or disorder, for instance a disease or disorder associated with hyper-proliferation such as cancer. Therapies that may be used in combination with a compound disclosed herein include: (i) surgery; (ii) radiotherapy (for example, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T- cell therapy; and (v) other chemotherapeutic agents.

[0155] The term "co-administered" ("co-administering") refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

[0156] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents for cancer treatment can be found, for instance, at https: / / www.cancer.gov / about-cancer / treatment / drugs and in publicly available sources such as Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 1 Ith edition (2018), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0157] The treatment method may include the co-administration of a compound as disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and at least one immunotherapy. Immunotherapy (also called biological response modifier therapy, biologic therapy, biotherapy, immune therapy, or biological therapy) is treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells, or enhance a response against cancer cells. Immunotherapies include active and passive immunotherapies. Active immunotherapies stimulate the body's own immune system while passive immunotherapies generally use immune system components created outside of the body.

[0158] Examples of active immunotherapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or Tumor- Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine- Activated Killer (LAK) Cell Therapy.

[0159] Examples of passive immunotherapies include but are not limited to monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or a toxin (immunotoxin). Examples of these naked monoclonal antibody drugs include, but are not limited to rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of the conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell non-Hodgkin lymphoma; radiolabeled antibody tositumomab (Bexxar) which is used to treat, for example, certain types of non-Hodgkin lymphoma; and immunotoxin gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML). BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScint for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.

[0160] Further examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN ®< (trastuzumab) (Genentech, Calif.) which is a humanized anti- HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO ®< (abciximab) (Centocor) which is an anti-glycoprotein Ilb / IIIa receptor on the platelets for the prevention of clot formation; ZENAPAX ™< (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX ™< which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome / Centocor); BEC2 which is a murine anti-idiotype (GD3epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ™< which is a humanized anti-alpha V beta 3 integrin antibody (Applied Molecular Evolution / Medlmmune); Campath 1H / LDP-03 which is a humanized anti CD52 IgG1 antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab / Kanebo); RITETXAN ™< which is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm / Genentech, Roche / Zettyaku); LYMPHOCIDE ™< which is a humanized anti- CD22 IgG antibody (Immunomedics); LYMPHOCIDE ™< Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled; radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-1 14 is a primatized anti-CD80 antibody (IDEC Pharm / Mitsubishi); ZEVALIN ™< is a radiolabeled murine anti-CD20 antibody (IDEC / Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC / Seikagaku); SMART anti-CD3 is a humanized anti- CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-alpha antibody (CAT / BASF); CDP870 is a humanized anti-TNF-alpha. Fab fragment (Celltech); IDEC-1 51 is a primatized anti-CD4 IgG1 antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab); CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha. IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha4 beta7 antibody (LeukoSite / Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA (ruplizumab) is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN ™< is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-beta 2 antibody (Cambridge Ab Tech).

[0161] Immunotherapies that can be used in combination with a compound as disclosed herein include adjuvant immunotherapies. Examples include cytokines, such as granulocyte- macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-l -alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IF A); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of, interleukins, for example, IL-2 with other cytokines, such as IFN-alpha.

[0162] An immunological therapy or an immunological therapeutic agent can include, one or more of the following: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy. The function or at least one of the functions of the immunological therapy or immunological therapeutic agent, collectively referred to herein as an "immunotherapeutic agent."

[0163] An exemplary immunotherapeutic agent is an immune cell (e.g. T-cell, dendritic cell, a natural killer cell and the like) modulator chosen from an agonist or an activator of a costimulatory molecule, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art). The immunotherapeutic agent can be an antibody that modulates a costimulatory molecule, bind to an antigen on the surface of an immune cell, or a cancer cell. The antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific format antibody, a fusion protein, or a fragment thereof, for example, a Diabody, a Single-chain (sc)- diabody (scFv)2, a Miniantibody, a Minibody, a Bamase-barstar, a scFv-Fc, a sc(Fab)2, a Trimeric antibody construct, a Triabody antibody construct, a Trimerbody antibody construct, a Tribody antibody construct, a Collabody antibody construct, a (scFv-TNFa)3, or a F(ab)3 / DNL antibody construct.

[0164] The immunotherapeutic agent may be an agent that modulates immune responses, for example, a checkpoint inhibitor or a checkpoint agonist. The immunotherapeutic agent may be an agent that enhances anti-tumor immune responses. The immunotherapeutic agent may be an agent that increases cell-mediated immunity. The immunotherapeutic agent may be an agent that increases T-cell activity. The immunotherapeutic agent may be an agent that increases cytolytic T-cell (CTL) activity. The immunotherapeutic agent may be an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, 0X40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and / or BTNL2 among others known in the art. The immunotherapeutic agent may be an agent that increases natural killer (NK) cell activity. The immunotherapeutic agent may be an agent that inhibits suppression of an immune response. The immunotherapeutic agent may be an agent that inhibits suppressor cells or suppressor cell activity.The immunotherapeutic agent may be an agent or therapy that inhibits Treg activity. The immunotherapeutic agent may be an agent that inhibits the activity of inhibitory immune checkpoint receptors.

[0165] The immunotherapeutic agent may include a T cell modulator chosen from an agonist or an activator of a costimulatory molecule. The agonist of the costimulatory molecule may be chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of GITR, 0X40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la / CDl8), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligand. The effector cell combination may include a bispecific T cell engager (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2 among others).

[0166] The immunotherapeutic agent may be a modulator of PD-1 activity, a modulator of PD-L 1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of 0X40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a modulator of SIRP-alpha activity, a modulator of TIGIT activity, a modulator of VSIG8 activity, a modulator of BTLA activity, a modulator of SIGLEC7 activity, a modulator of SIGLEC9 activity, a modulator of ICOS activity, a modulator of B7H3 activity, a modulator of B7H4 activity, a modulator of FAS activity, a modulator of BTNL2 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. The immunotherapeutic agent may be an immune checkpoint modulator (e.g., an immune checkpoint inhibitor e.g. an inhibitor of PD-1 activity, a modulator of PD-L 1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi) an 0X40 agonist (e.g., an anti- 0X40 antibody molecule), or (xii) a CD27 agonist (e.g., an anti-CD27 antibody molecule). The immunomodulator may be an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and / or TGF beta. The inhibitor of an immune checkpoint molecule may inhibit PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, or any combination thereof.

[0167] Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level. An inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. The inhibitor of an inhibitory signal may be, a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof,, for example, a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as "an antibody molecule") that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4, TGF beta, or a combination thereof.

[0168] The treatment method may include the co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211< , 1 131< , 1 125< , Y 90< , Re 186< , Re 188< , Sm 153< , Bi 212< , P 32< , Pb 212< and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof.

[0169] Exemplary cytotoxic agents can be selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

[0170] "Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ®< , Genentech / OSI Pharm.), bortezomib (VELCADE ®< , Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ®< , AstraZeneca), sunitib (SETTENT ®< , Pfizer / Sugen), letrozole (FEMARA ®< , Novartis), imatinib mesylate (GLEEVEC ®< , Novartis), finasunate (VATALANIB ®< , Novartis), oxaliplatin (ELOXATIN ®< , Sanofi), 5-FET (5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE ®< , Wyeth), lapatinib (TYKERB ®< , GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR ®< , Bayer Labs), gefitinib (IRESSA ®< , AstraZeneca), AG1478; alkylating agents such as thiotepa and CYTOXAN ®< ); cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5 alpha-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin omega I (Angew Chem. Inti. Ed. Engl. 1994 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN ®< (doxorubicin), morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK ®< polysaccharide complex (JHS Natural Products, Eugene, Ore.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside "Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE ®< (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE ®< (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR ®< (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE ®< (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ®< ); ibandronate; CPT-1 1; topoisomerase inhibitor RFS 2000; difluorom ethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0171] Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ®< ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON ®< (toremifme citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE ®< (megestrol acetate), AROMASIN ®< (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ®< (vorozole), FEMARA ®< (letrozole; Novartis), and ARIMIDEX ®< (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME ®< ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN ®< , LEUVECTIN ®< , and VAXID ®< ; PROLEUKIN ®< , rIL-2; a topoisomerase 1 inhibitor such as LEIRTOTECAN ®< ; ABARELIX ®< ; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0172] Chemotherapeutic agents also include antibodies, as described above, including alemtuzumab (Campath), bevacizumab (AVASTIN ®< , Genentech); cetuximab (ERBITETX ®< , Imclone); panitumumab (VECTIBIX ®< , Amgen), rituximab (RITETXAN ®< , Genentech / Biogen Idee), pertuzumab (OMNITARG ®< , 2C4, Genentech), trastuzumab (HERCEPTIN ®< , Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG ®< , Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nivolumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-l2 (ABT-8744695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG 1 λ antibody genetically modified to recognize interleukin- 12 p40 protein.

[0173] Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitor such as mubritonib (TAK165, Takeda); CP-724.714, (Axon Medchem BV, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo- SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC ®< , available from Glaxo SmithKline); multi -targeted tyrosine kinase inhibitors such as sunitinib (SLTTENT ®< , available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase 1 inhibitor Cl- 1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); affmitac (ISIS 3521; Isis / Lilly); PKI166 (Novartis); Semaxinib (Pfizer); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE ®< ); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Cyanamid); WO 1997 / 38983 (Warner Lambert); WO 1999 / 06378 (Warner Lambert); WO 1999 / 06396 (Warner Lambert); WO 1996 / 30347 (Pfizer, Inc); WO 1996 / 33978 (Zeneca); WO 1996 / 3397 (Zeneca) and WO 1996 / 33980 (Zeneca). Tyrosine kinase inhibitors also include erlotinib (Tarceva ®< ), gefitinib (Iressa ®< ), dasatinib (Sprycel ®< ), nilotinib (Tasigna ®< ), crizotinib (Xalkori ®< ), ruxolitinib (Jakafi ®< ), vemurafenib (Zelboraf ®< ), Vandetanib (Caprelsa ®< ), pazopanib (Votrient ®< ), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, veliparib, vismodegib, volasertib, cobimetinib (Cotellic ®< ), and others.

[0174] Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0175] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-1 7-butyrate, clobetasol-1 7-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNF alpha) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA ®< ); Interleukin 13 (IL-1 3) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Ml prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal / l32 blockers such as Anti-lymphotoxin alpha (LTa); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET- I8-OCH3, or famesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL ®< ); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9- aminocamptothecin); podophyllotoxin; tegafur (UFTORAL ®< ); bexarotene (TARGRETIN ®< ); bisphosphonates such as clodronate (for example, BONEFOS ®< or OSTAC ®< ), etidronate (DIDROCAL ®< ), NE-58095, zoledronic acid / zoledronate (ZOMETA ®< ), alendronate (FOSAMAX ®< ), pamidronate (AREDIA ®< ), tiludronate (SKELID ®< ), or risedronate (ACTONEL ®< ); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE ®< vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifamib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE) pixantrone; farnesyltransferase inhibitors such as lonafamib (SCH 6636, SARASAR ™< ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN ™< ) combined with 5-FU and leucovorin. [000354] Chemotherapeutic agents also include Poly ADP ribose polymerase (PARP) inhibitors: olaparib (Lynparza ®< ), rucaprib (Rubraca ®< ) niraparib (Zejula ®< ), talzoparib (Talzenna ®< ).

[0176] Compounds as disclosed herein may be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, gilter, larotrectinib, lorlatinib, netarsudil, osimertinib, pexidartinib, ribociclib, temsirolimus, XL-092, XL-147, XL-765, XL-499, and XL-880. In some embodiments, a compound as described herein can be used in combination with a HSP90 inhibitor (e.g., XL888), liver X receptor (LXR) modulators, retinoid-related orphan receptor gamma (RORy) modulators, a CK1 inhibitor, a CKl-a inhibitor, a Wnt pathway inhibitor (e.g., SST-215), or a mineralocorticoid receptor inhibitor, (e.g., esaxerenone or XL- 550) for the treatment of a disease disclosed herein such as cancer.

[0177] For treatment of cancer, compounds as disclosed herein may be used in combination with inhibitors of PD-1 or inhibitors of PD-L1, e.g., an anti-PD-1 monoclonal antibody, an anti-PD-1 bispecific antibody or an anti-PD-L 1 monoclonal antibody, an anti-PD-L1 bispecific antibody, for example, nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, avelumab, AB122, AMP-224, AMP- 514, PDR001, durvalumab, pidilizumab (Imfinzi ®< , CT-011), CK-301, BMS 936559, and MPDL3280A; CTLA-4 inhibitors, e.g., an anti-CTLA-4 antibody, for example, ipilimumab (Yervoy) and tremelimumab; and phosphatidylserine inhibitors, for example, bavituximab (PGN401); antibodies to cytokines (IL-10, TGF-b, and the like.); other anti-cancer agents such as cemiplimab. The anti-PD-1 monoclonal antibody may be nivolumab or pembrolizumab.

[0178] A compound as described herein can be used in combination with a vaccination protocol for the treatment of cancer. A compound as described herein can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

[0179] Compounds as disclosed herein may be used in combination with inhibitors of PARP, for example, olaparib (Lynparza ®< ), rucaprib (Rubraca ®< ), niraparib (Zejula ®< ), talzoparib (Talzenna ®< ) for the treatment of cancer.

[0180] Compounds as disclosed herein may be used in combination with esaxerenone (XL-550) or XL-888 for the treatment of cancer.

[0181] The compounds as disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, 1NS-R, IGF-1R, IR-R, PDGFαR, PDGFβ / R, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYR, FRK, JAK, ABL, ALK, CDK7, CDK12, KRAS, and B-Raf.Pharmaceutical Compositions and Modes of Administration

[0182] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds described herein (e.g., compounds of Formula (Ia), Formula (Ib), or Formula (Ic) or subformulas thereof) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0183] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0184] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0185] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or tautomer thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0186] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0187] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or tautomer thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0188] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or tautomer thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0189] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0190] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.Dosing

[0191] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.Synthesis of the Compounds

[0192] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0193] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.

[0194] Preparation of compounds as disclosed herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0195] The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.

[0196] Compounds of the invention, or any subformulas as disclosed herein and certain intermediates can be prepared, for example, using a process as illustrated in Schemes 1A-5B. The variables employed in the Schemes below are as defined throughout the specification.

[0197] As shown in Scheme 1A, a compound of formula (I) can be synthesized from carboxylic acid A and aniline B-a by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.

[0198] As shown in Scheme 1B, a compound of formula (I) can be synthesized from carboxylic acid A and aniline B by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.

[0199] In some embodiments, provided is a process for preparing a compound of formula (I), comprising contacting a compound of formula A with a compound of formula B-b, under conditions suitable to provide a compound of formula (I).

[0200] In some embodiments, provided is a process for preparing a compound of formula (I), comprising contacting a compound of formula A with a compound of formula B, under conditions suitable to provide a compound of formula (I).

[0201] As shown in Scheme 2A, a compound of formula (I) can be made from a two-step process starting from bromocarboxylic acid D, where Q is a leaving group (including Cl, Br, I, triflate and the like), and aniline B-a which are coupled together by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures to form a compound of formula E-a. In a second step, compounds of formula E-a can be converted to compounds of formula (I) by coupling with boron compounds of the formula F using coupling chemistry known to those skilled in the art. Typical procedures to accomplish this type of coupling involve the use palladium-containing complexes as a catalyst in the presence of an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.

[0202] As shown in Scheme 2B, a compound of formula (I) can be made from a two-step process starting from bromocarboxylic acid D, where Q is a leaving group (including Cl, Br, I, triflate and the like), and aniline B which are coupled together by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures to form a compound of formula E. In a second step, compounds of formula E can be converted to compounds of formula (I) by coupling with boron compounds of the formula F using coupling chemistry known to those skilled in the art. Typical procedures to accomplish this type of coupling involve the use palladium-containing complexes as a catalyst in the presence of an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.

[0203] In some embodiments, provided is a process for preparing a compound of formula (I), comprising: contacting a compound of formula D with a compound of formula B-a, under conditions suitable to provide a compound of formula E-a; and contacting a compound of formula E-a with a compound of formula F, under conditions suitable to provide a compound of Formula (I).

[0204] In some embodiments, provided is a process for preparing a compound of formula (I), comprising: contacting a compound of formula D with a compound of formula B, under conditions suitable to provide a compound of formula E; and contacting a compound of formula E with a compound of formula F, under conditions suitable to provide a compound of Formula (I).

[0205] As shown in Scheme 3, a compound of formula D-3 (Q = Br) can be prepared from carboxylic acid F-3 through treatment with NBS in an appropriate solvent typically at room temperature.

[0206] As shown in Scheme 4A, a compound of formula J-a can be prepared by reacting a compound of formula G-a with a compound of formula H-a in the presence of a base such as cesium carbonate in an appropriate organic solvent, typically at room temperature. A compound of formula B-a can be made from a compound of formula J-a by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.

[0207] As shown in Scheme 4B, a compound of formula J can be prepared by reacting a compound of formula G with a compound of formula H in the presence of a base such as cesium carbonate in an appropriate organic solvent, typically at room temperature. A compound of formula B can be made from a compound of formula J by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.

[0208] In some embodiments, provided is a process for preparing a compound of formula B-a, comprising: contacting a compound of formula G-a with a compound of formula H-a, under conditions suitable to provide a compound of formula J-a; and reducing a compound of formula J-a under conditions suitable to provide a compound of formula B-a.

[0209] In some embodiments, provided is a process for preparing a compound of formula B, comprising: contacting a compound of formula G with a compound of formula H, under conditions suitable to provide a compound of formula J; and reducing a compound of formula J under conditions suitable to provide a compound of formula B.

[0210] As shown in Scheme 5A, a compound of formula J-a can also be synthesized by reacting a compound of formula K-a with a compound of formula L-a in an appropriate solvent such as 2,6-dimethylpyridine in the presence of a catalytic amount of dimethylaminopyridine at elevated temperatures. A compound of formula B-a can be prepared from a compound of formula J-a by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.

[0211] As shown in Scheme 5B, a compound of formula J can also be synthesized by reacting a compound of formula K with a compound of formula L in an appropriate solvent such as 2,6-dimethylpyridine in the presence of a catalytic amount of dimethylaminopyridine at elevated temperatures. A compound of formula B can be prepared from a compound of formula J by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.

[0212] In some embodiments, provided is a process for preparing a compound of formula B-a, comprising: contacting a compound of formula K-a with a compound of formula L-a, under conditions suitable to provide a compound of formula J-a; and reducing a compound of formula J-a under conditions suitable to provide a compound of formula B-a.

[0213] In some embodiments, provided is a process for preparing a compound of formula B, comprising: contacting a compound of formula K with a compound of formula L, under conditions suitable to provide a compound of formula J; and reducing a compound of formula J under conditions suitable to provide a compound of formula B. EXAMPLES

[0214] The following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention.

[0215] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.Synthetic Examples General Procedure A1: 4-((1,5-Naphthyridin-4-yl)oxy)anilines

[0216]

[0217] Step 1: A mixture of Compound A1-1 (32 mmol, 1 eq) and Compound A1-2 (5.92 g, 32 mmol, 1 eq) in toluene (50 mL, 1.5-1.6 mL / mmol of A1-1 used) was stirred at 105 °C for 1.5 h and then cooled to room temperature. Hexanes (50 mL, 1.5-1.6 mL / mmol of A1-1 used) was added and the suspension was filtered. This material was mixed with Ph 2 O (50 mL, 1.5-1.6 mL / mmol of A1-1 used) and the resulting mixture was stirred at 220-230 °C for 1 h, cooled to room temperature and poured into Et 2 O (100 mL, 3.0-3.2 mL / mmol of A1-1 used). The resulting suspension was filtered, washed with Et 2 O, and dried to give Compound A1-3. Compound A1-2 can easily be generated from heating 2,2-dimethyl-1,3-dioxane-4,6-dione (1 eq) in trimethyl orthoformate (10 eq) at 110°C for 1-2 h.

[0218] Step 2: A mixture of Compound A1-3 (4.8 mmol, 1 eq), Compound A1-4 (6.8 mmol, 1.4 eq), and Cs 2 CO 3 (6.6 g, 20 mmol, 4.2 eq) in acetonitrile (ACN) (20 mL, 4.2 mL / mmol of A1-3 used) was stirred at room temperature overnight. EtOAc (80 mL, 16-17 mL / mmol of A1-3 used) was added and the resulting mixture filtered. The filtrate was evaporated, and residue purified by silica gel column chromatography to give Compound A1-5.

[0219] Step 3: A mixture of Compound A1-5 (1.8 mmol, 1 eq), NH 4 Cl (500 mg, 9.3 mmol, 5.2 eq), and Fe powder (260 mg, 4.6 mmol, 2.6 eq) in 4:1 MeOH:water (13.8 mL / mmol of A1-5 used) was refluxed for 1 h and then cooled to room temperature. The resulting mixture was filtered through Celite and the filtrate concentrated to remove MeOH. To the residue was added aq saturated NaHCO 3 (6 mL, 3.3 mL / mmol of A1-5 used) and the resulting aqueous mixture was extracted with EtOAc. The organic extract was dried over anhyd. Na 2 SO 4 and evaporated give Compound A1-6. Example of General Procedure A1: 4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluoroaniline (A1-10)

[0220]

[0221] Step 1: 6,7-Dimethoxy-1,5-naphthyridin-4-ol (A1-8): A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (2.7 g, 18.7 mmol, 1 eq) in trimethyl orthoformate (19.6 g, 185 mmol, 20.3 mL, 10 eq) was stirred at 110 °C for 1.5 h to form a yellow solution of Compound A1-2. Compound A1-7 (2.8 g, 18.5 mmol, 1 eq) was added to the above solution and the mixture was stirred at 110 °C for 0.5 h. The resulting brown suspension was filtered and the solid washed with petroleum ether (2 x 30 mL) and dried under vacuum to give the intermediate 5-[(E)-(5,6-dimethoxy-3-pyridyl)iminomethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione. A portion of this compound (2.2 g, 7.1 mmol) in Ph 2 O (25 mL) was stirred at 230 °C for 0.5 h. Upon cooling to room temperature, to the reaction mixture was added methyl tert-butyl ether (MTBE) (100 mL) and the mixture stirred for 5 min and then filtered. The resulting solid was washed with MTBE (2 x 30 mL) and dried under vacuum to give Compound A1-8. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.62 (br s, 1H), 7.93-7.79 (m, 1H), 7.27 (s, 1H), 6.28-6.08 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H).

[0222] Step 2: 8-(2-Fluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthyridine (A1-9): To mixture of Compound A1-8 (2.1 g, 10.2 mmol, 1 eq) and 1,2-difluoro-4-nitrobenzene (1.6 g, 10.2 mmol, 1.13 mL, 1 eq) in ACN (50 mL) was added Cs 2 CO 3 (6.6 g, 20.4 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 15 h. The reaction mixture was filtered, and any solids washed with ACN (2 x 30 mL) and the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc) to give Compound A1-9. 1< H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, 1H), 8.12 (dd, 1H), 8.01-7.96 (m, 1H), 7.53 (s, 1H), 7.17 (d, 1H), 7.03 (dd, 1H), 4.02 (s, 3H), 3.75 (s, 3H).

[0223] Step 3: 4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluoroaniline (A1-10): To a mixture of Compound A1-9 (1.4 g, 3.9 mmol, 1 eq) in EtOH (20 mL) and water (5 mL) was added Fe powder (1.1 g, 19 mmol, 5 eq) and NH 4 Cl (2.1 g, 39 mmol, 10 eq) and the resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was filtered, and the filter cake was washed with hot MeOH (2 x 30 mL) and the filtrate concentrated under reduced pressure. The resulting solid was washed with water (2 x 50 mL) and dried under vacuum to give Compound A1-10, which was used in subsequent reactions without further purification. MS of C 16 H 14 FN 3 O 3 : m / z: 315.9 (MH+).

[0224] The following additional intermediates were made following General Procedure A1 for the synthesis of 4-((1,5-Naphthyridin-4-yl)oxy)anilines A1-6:

[0225] 4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)aniline (A1-11): For the synthesis of Compound A1-11, in General Procedure A1, Step 1, Compound A1-1 = 5,6-dimethoxypyridin-3-amine and, in Step 2, Compound A1-4 = 1-fluoro-4-nitrobenzene. MS for C 16 H 15 N 3 O 3 : m / z 298 (MH+).

[0226] 3-Fluoro-4-((7-methoxy-1,5-naphthyridin-4-yl)oxy)aniline (A1-12): For the synthesis of Compound A1-12, in General Procedure A1, Step 1, Compound A1-1 = 5-methoxypyridin-3-amine and, in Step 2, Compound A1-4 = 1,2-difluoro-4-nitrobenzene.. MS for C 15 H 12 FN 3 O 2 : m / z 286 (MH+).

[0227] 4-((7-Methoxy-1,5-naphthyridin-4-yl)oxy)aniline (A1-13): For the synthesis of Compound A1-13, in General Procedure A1, Step 1, Compound A1-1 = 5-methoxypyridin-3-amine and, in Step 2, Compound A1-4 = 1-fluoro-4-nitrobenzene. MS for C 15 H 13 N 3 O 2 : m / z 268 (MH+).

[0228] 3-Fluoro-4-((6-methoxy-1,5-naphthyridin-4-yl)oxy)aniline (A1-14): For the synthesis of Compound A1-14, in General Procedure A1, Step 1, Compound A1-1 = 6-methoxypyridin-3-amine and, in Step 2, Compound A1-4 = 1,2,4-trifluoro-5-nitrobenzene. MS for C 15 H 12 FN 3 O 2 : m / z 286.0 (MH+).

[0229] 4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-2,5-difluoroaniline (A1-15): For the synthesis of Compound A1-15, in General Procedure A1, Step 1, Compound A1-1 = 5,6-dimethoxypyridin-3-amine and, in Step 2, Compound A1-4 = 2,4,5-trifluoroaniline. MS for C 16 H 13 F 2 N 3 O 3 : m / z 334.0 (MH+).Procedure A2: Alternative Method for 4-((1,5-Naphthyridin-4-yl)oxy)anilines

[0230]

[0231] Step 1: 5-Bromo-2-methoxy-3-(2-methoxyethoxy)pyridine (A2-2): 2-Methoxyethanol (8.68 g, 114 mmol, 1.2 eq) was slowly added to a cooled mixture of 60% NaH (4.56 g, 114. mmol, 1.2 eq) in THF (200 mL) at 0 °C. A solution of Compound A2-1 (20 g, 95 mmol, 1 eq) in THF (20 mL) was then added and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with aq saturated NaCl (3 x 10 mL), dried over anhyd. Na 2 SO 4 and concentrated under vacuum to give 5-bromo-2-chloro-3-(2-methoxyethoxy)pyridine as a light yellow solid. The crude 5-bromo-2-chloro-3-(2-methoxyethoxy)pyridine was dissolved in MeOH (300 mL) to which was added NaOMe (25.3 g, 469 mmol, 5 eq). The reaction mixture was heated to 80 °C with stirring for 12 h. The reaction mixture was concentrated to remove the solvent and the resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with aq saturated NaCl (20 mL), dried over anhyd. Na 2 SO 4 and concentrated under vacuum to give crude Compound A2-2 as a light yellow solid (25 g, 99% yield) which was used for next step without purification. 1< H NMR (400 MHz, DMSO-d 6 ) δ = 7.80 (d, 1H), 7.51 (d, 1H), 4.14 (dd, 2H), 3.85 (s, 3H), 3.65 (dd, 2H), 3.29 (s, 3H); MS for C 9 H 12 BrNO 3 : m / z 261.9 (MH+).

[0232] Step 2: 6-Methoxy-5-(2-methoxyethoxy)pyridin-3-amine (A2-3): A mixture of diphenylmethanimine (41.6 g, 229 mmol, 2.4 eq), Compound A2-2 (25 g, 95 mmol, 1 eq), Pd(OAc) 2 (2.6 g, 11.4 mmol, 0.12 eq), rac-BINAP (10.7 g, 17.2 mmol, 0.18 eq) and KOtBu (19.8 g, 176 mmol, 1.85 eq) in toluene (300 mL) was stirred at 85 °C for 12 h under an atmosphere of nitrogen. The reaction was washed with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were concentrated to dryness. The resulting brown oil was dissolved in MeOH (300 mL) to which was added NH 2 OH-HCl (13.4 g, 193 mmol, 2 eq) and NaOAc (20.6 g, 251 mmol, 2.6 eq). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum and the residue was dissolved in DCM(100 mL). The resulting mixture was treated with aq 2 M HCl solution until pH = 3-4. The aqueous layer was separated. Aq saturated NaHCO 3 (200 mL) was added with the resulting pH > 7. The mixture was extracted with DCM (3 x 300 mL). The combined organic extracts were dried over anhyd. Na 2 SO 4 and concentrated under vacuum to give Compound A2-3 as a brown oil (10 g, 52% yield) which was used for next step without purification. MS for C 9 H 14 N 2 O 3 : m / z 198.9 (MH+).

[0233] Step 3: 6-Methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-ol (A2-4): Compound A2-4 was synthesized from Compound A2-3 using Step 1 of General Procedure A1. 1< H NMR (400 MHz, DMSO-d 6 ) 11.59 (br s, 1H), 7.77 (br d, 1H), 7.25 (br s, 1H), 6.09 (br d, 1H), 4.20 (br s, 2H), 4.02 (s, 3H), 3.77 - 3.70 (m, 2H), 3.34 (s, 3H).

[0234] Step 4: 8-Chloro-2-methoxy-3-(2-methoxyethoxy)-1,5-naphthyridine (A2-5): To a solution of Compound A2-4 (8.0 g, 32 mmol, 1 eq) in ACN (40 mL) was added POCl 3 (19.6 g, 128 mmol, 4 eq) and the reaction mixture was stirred at 90 °C for 2 h. After cooling to ambient temperature, the reaction mixture was concentrated and then quenched with water (100 mL). The pH was adjusted to 7 with aq NaHCO 3 (100 mL). The resulting suspension was filtered and the solid was dried to give Compound A2-5 as a brown solid (7.3 g, 85% yield) which was used in the next step without further purification.

[0235] Step 5: 8-(2-Fluoro-4-nitrophenoxy)-2-methoxy-3-(2-methoxyethoxy)-1,5-naphthyridine (A2-6): To a mixture of Compound A2-5 (3.3 g, 12.3 mmol, 1 eq) and 2-fluoro-4-nitrophenol (3.1 g, 19.6 mmol, 1.6 eq) in Ph 2 O (30 mL) was added DIEA (4.76 g, 36.8 mmol, 3 eq) and the resulting mixture was heated to 170 °C with stirring for 3 h. The reaction mixture was cooled and petroleum ether (100 mL) was added. The resulting suspension was filtered. The solid was dried and then purified by flash silica gel chromatography (0~80% EtOAc / petroleum ether) to give Compound A2-6 as a yellow solid (2.6 g, 54% yield). MS for C 18 H 16 FN 3 O 6 : m / z 390.0 (MH+).

[0236] Step 6: 3-Fluoro-4-((6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl)oxy)aniline (A2-7): Compound A2-7 was synthesized from Compound A2-6 using Step 3 of General Procedure A1. 1< H NMR (400 MHz, DMSO-d6) δ 8.47 (d, 1H), 7.64 (s, 1H), 7.05 (t, 1H), 6.61 - 6.50 (m, 2H), 6.46 (dd, 1H), 5.47 (s, 2H), 4.31 (t, 2H), 4.04 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H); MS for C 18 H 18 FN 3 O 4 : m / z 360.2 (MH+).

[0237] The following additional intermediates were made following Procedure A2 for the alternative synthesis of 4-((1,5-Naphthyridin-4-yl)oxy)anilines:

[0238] 4-((6-Methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl)oxy)aniline (A2-8): The 2-fluoro-4-nitrophenol in step 5 was replaced with 4-nitrophenol. 1< H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.39 (m, 1H), 7.75 - 7.52 (m, 1H), 7.03 - 6.47 (m, 5H), 5.12 (br s, 2H), 4.30 (br d, 2H), 4.03 (br s, 3H), 3.75 (br d, 2H), 3.36 (br s, 3H); MS for C 18 H 19 N 3 O 4 : m / z 342.2 (MH+).

[0239] 3-Fluoro-4-((7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl)oxy)aniline (A2-9): Step 1 was replaced with the following method: To a mixture of 5-bromopyridin-3-ol (2 g, 11.5 mmol, 1 eq) and 1-bromo-2-methoxy-ethane (2.4 g, 17 mmol, 11.5 eq) in DMF (20 mL) was added Cs 2 CO 3 (4.9 g, 14.9 mmol, 1.3 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 x 30 mL), washed with aq saturated NaCl (30 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure to give 3-bromo-5-(2-methoxyethoxy)pyridine as a yellow solid (4.2 g, crude) which was used to replace Compound A2-2 in Step 2. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (d, 1H), 8.63 (d, 1H), 7.77 (d, 1H), 6.93 (d, 2H), 6.68 (d, 2H), 6.58 (d, 1H), 5.21 (br s, 2H), 4.35 (dd, 2H), 3.80 - 3.74 (m, 2H), 3.35 (s, 3H); MS for C 17 H 17 N 3 O 3 : m / z 312.1 (MH+).

[0240] 2,5-Difluoro-4-((6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl)oxy)aniline (A2-10): The 2-fluoro-4-nitrophenol in step 5 was replaced with 2,5-difluoro-4-nitrophenol. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d, 1H), 7.65 (br s, 1H), 7.18-7.31 (m, 1H), 6.72-6.82 (m, 1H), 6.69 (br s, 1H), 5.49 (br s, 2H), 4.31 (br s, 2H), 4.02 (br s, 3H), 3.75 (br s, 2H), 3.33 (br s, 3H).; MS for C 18 H 17 F 2 N 3 O 4 : m / z 378.2 (MH+).General Procedure B1: 4-(Quinolin-4-yloxy)anilines

[0241]

[0242] Step 1: A mixture of Compound B1-1 (1 eq) and Compound A1-4a (1.2-1.4 eq) in an appropriate solvent such as, but not limited to, 2,6-dimethylpyridine or diphenyl ether (1.1-2.2 mL / mmol of B1-1 used) was stirred at 140 °C for typically 36-66 h. DMAP (0.2 eq) can also be optionally added as a catalyst. Upon completion of the reaction as monitored by LC-MS and / or TLC, the reaction mixture was allowed to cool to room temperature and typically worked up by one of the following methods or a similar variation. Method 1: MeOH (0.9 mL / mmol of B1-1 used) was added, followed by aq 6.5% K 2 CO 3 (1.4 mL / mmol of B1-1 used). The resulting mixture was stirred at 0 °C for 2 h. The resulting mixture was filtered and washed with water (4.5 mL / mmol of B1-1 used) to give Compound B1-2. Method 2: The mixture was diluted with MTBE (2.2 mL / mmol of B1-1 used) and filtered. The resulting solid was washed with MTBE (0.4 mL / mmol of B1-1 used) and dried under vacuum to give Compound B1-2. Regardless of the method of work up, the crude Compound B1-2 was generally used in subsequent reactions without further purification.

[0243] Step 2: To a mixture of Compound B1-2 (1 eq) in EtOH (4.5-6.5 mL / mmol of B1-2 ) and water (1.1-1.3 mL / mmol of B1-2) was added Fe powder (5.0 eq) and NH 4 Cl (8-10 eq). The mixture was stirred at 85 °C for 3-4 h. Upon completion of the reaction as monitored by LC-MS and / or TLC, the reaction mixture was allowed to cool to room temperature and typically worked up by one of the following methods or a similar variation. Method 1: The reaction was filtered, and the filtrate was dried over anhyd. Na 2 SO 4 and concentrated to give crude product. To this crude product was added EtOAc (25 mL / mmol of B1-2 used) and DCM (25 mL / mmol of B1-2 used). The resulting mixture was filtered, and the filtrate was concentrated to give Compound B1-3. Method 2: The mixture was filtered through Celite, the filtrate was concentrated under vacuum and the residue was dissolved in EtOAc (11.2 mL / mmol of B1-2 used). The organic layer was washed with aq saturated NaHCO 3 (6.7 mL / mmol of B1-2 used), washed with water (6.7 mL / mmol of B1-2 used), washed with aq saturated NaCl (6.7 mL / mmol of B1-2 used), dried over anhyd. Na 2 SO 4 and concentrated under vacuum to give Compound B1-3. Regardless of the method of work up, the crude Compound B1-3 was generally used in subsequent reactions without further purification.Example of General Procedure B1: 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (B1-6)

[0244]

[0245] Step 1: 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (B1-5): A suspension of Compound B1-4 (10 g, 45 mmol, 1 eq) and 2-fluoro-4-nitro-phenol (8.4 g, 54 mmol, 1.2 eq) in Ph 2 O (100 mL) was heated and stirred at 140 °C for 66 h. After cooling to room temperature, the mixture was diluted with MTBE (100 mL) and filtered. The filter cake was washed with MTBE (20 mL) and dried under vacuum to give Compound B1-5, which was used in subsequent steps without further purification. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (d, 1H), 8.56 (dd, 1H), 8.35-8.27 (m, 1H), 7.89 (t, 1H), 7.79-7.71 (m, 2H), 7.17 (d, 1H), 4.04 (d, 6H); MS for C 17 H 13 FN 2 O 5 : m / z 344.9 (MH+).

[0246] Step 2: 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (B1-6): Fe powder (12.5 g, 223 mmol, 5 eq) was added to a mixture of Compound B1-5 (16.2 g, 45 mmol, 1 eq) and NH 4 Cl (23.9 g, 447 mmol, 10 eq) in EtOH (200 mL) and water (50 mL). The mixture was heated and stirred at 85 °C for 3.5 h. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum and the residue was dissolved in EtOAc (500 mL). The organic layer was washed with aq NaHCO 3 (300 mL), washed with water (300 mL), washed with aq saturated NaCl (300 mL), dried over anhyd. Na 2 SO 4 and concentrated under vacuum to give Compound B1-6, which was used in subsequent reactions without further purification. MS for C 17 H 15 FN 2 O 3 : m / z 315.0 (MH+).

[0247] The following additional intermediate was made following General Procedure B1 for the synthesis of 4-(quinolin-4-yloxy)anilines B1-3:

[0248] 4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline (B1-7): For the synthesis of Compound B1-7, in General Procedure B1, Step 1, Compound B1-1 = 4-chloro-6,7-dimethoxyquinoline and Compound A1-4a = 4-nitrophenol. MS for C 17 H 16 N 2 O 3 : m / z 297.2 (MH+).Procedure C1: 4-(Pyrido[3,2-d]pyrimidin-4-yloxy)anilines

[0249]

[0250] Step 1: tert-Butyl (6-methoxy-5-(2-methoxyethoxy)pyridin-3-yl)carbamate (C1-1): Cs 2 CO 3 (12.1 g, 37 mmol, 2.1 eq) was added to a mixture of Compound A2-2 (6.13 g, 18 mmol, 1.0 eq), NH 2 Boc (3.33 g, 28 mmol, 1.6 eq), Pd(OAc) 2 (211 mg, 0.94 mmol, 0.05 eq) and XPhos (1.0 g, 2.1 mmol, 0.12 eq) in anhyd. 1,4-dioxane (80 mL) under an atmosphere of N 2 . The resulting mixture was heated to 120 °C under N 2 with stirring for 36 h. The reaction mixture was partitioned between EtOAc (180 mL) and water (60 mL). The organic phase was washed with aq saturated NaCl (2 x 65 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (21-31% EtOAc in petroleum ether) to give Compound C1-1 as a red gum (3.73 g, 70% yield). 1< H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.49 (d, 1H), 6.38 (s, 1H), 4.21-4.15 (m, 2H), 3.95 (s, 3H), 3.82-3.76 (m, 2H), 3.44 (s, 3H), 1.51 (s, 9H); MS for C 14 H 22 N 2 O 5 : m / z 299.1 (MH+).

[0251] Step 2: tert-Butyl (2-bromo-6-methoxy-5-(2-methoxyethoxy)pyridin-3-yl)carbamate (C1-2): To a solution of C1-1 (3.73 g, 12.4 mmol, 1.0 eq) in ACN (61 mL) was added NBS (2.34 g, 13.1 mmol, 1.06 eq) in portions at 25 °C. The resulting mixture stirred at 25 °C for 3 h. The reaction mixture was quenched with aq saturated Na 2 SO 3 solution (100 mL) and extracted with EtOAc (2 x 120 mL). The combined organic extracts were washed with water (100 mL), washed with aq saturated NaCl (150 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure to give Compound C1-2 as a red gum (4.58 g, 98% yield) which was used directly in the next step. 1< H NMR (400 MHz, CDCl 3 ) δ 8.04 (brs, 1H), 6.70 (s, 1H), 4.22-4.16 (m, 2H), 3.95 (s, 3H), 3.81-3.75 (m, 2H), 3.44 (s, 3H), 1.52 (s, 9H); MS for C 14 H 21 BrN 2 O 5 : m / z 379.1 (MH+).

[0252] Step 3: 2-Bromo-6-methoxy-5-(2-methoxyethoxy)pyridin-3-amine (C1-3): To a solution of Compound C1-2 (4.58 g, 12.1 mmol, 1.0 eq) in anhyd. DCM (12 mL) was added 4 M HCl in 1,4-dioxane (28 mL, 9.23 eq) at 20 °C. The resulting mixture was stirred at 20 °C for 2 h. The resulting reaction mixture was slowly added to a solution of aq 2 M K 2 CO 3 solution (80 mL) with vigorously stirring. After gas evolution ceased, the mixture was extracted with DCM, first with 150 mL and then with 90 mL. The combined organic layers were washed with aq saturated NaCl (100 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure to give Compound C1-3 as a purple gum (3.14 g, 89% yield) which was used directly in the next step. MS for C 9 H 13 BrN 2 O 3 : m / z 279.0 (MH+).

[0253] Step 4: 3-Amino-6-methoxy-5-(2-methoxyethoxy)picolinonitrile (C1-4): To a solution of Compound C1-3 (3.14 g, 10.8 mmol, 1.0 eq) in anhyd. DMF (27 mL) was added Pd 2 (dba) 3 (248 mg, 0.271 mmol, 0.025 eq), dppf (239 mg, 0.43 mmol, 0.040 eq) and zinc cyanide (860 mg, 7.32 mmol, 0.68 eq). The resulting mixture was degassed and purged with N 2 , then heated to 130 °C with stirring for 2.75 h. The reaction mixture was allowed to cool to ambient temperature and then concentrated under reduced pressure to remove most of the volatiles. The resulting residue was diluted with 14% aq ammonia (40 mL) and extracted with EtOAc, first with 60 mL, then with 30 mL. The combined organic layers were washed with aq saturated NaCl (50 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (21-41% EtOAc in petroleum ether) to give Compound C1-4 as a red solid (2.19 g, 90% yield). MS for C 10 H 13 N 3 O 3 : m / z 224.0 (MH+).

[0254] Step 5: 3-Amino-6-methoxy-5-(2-methoxyethoxy)picolinamide (C1-5): Compound C1-4 (2.19 g, 9.7 mmol, 1.0 eq) was suspended in a mixture of hydrogen peroxide (30% aqueous, 8.5 mL, 88 mmol, 9.1 eq) and aq NH 4 OH (14 M, 34.0 mL, 49 eq). The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was then filtered, and the collected solid was washed with water (2 x 5 mL) and dried under vacuum to give Compound C1-5 (2.20 g, 92% yield) which was used directly in the next step. MS for C 10 H 15 N 3 O 4 : m / z 242.0 (MH+).

[0255] Step 6: 6-Methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-ol (C1-6): To a suspension of Compound C1-5 (2.20 g, 8.9 mmol, 1.0 eq) in anhyd. toluene (37.5 mL) was added triethyl orthoformate (7.5 mL,45.1 mmol, 5 eq) and p-toluenesulfonic acid monohydrate (153 mg, 0.80 mmol, 0.09 eq). The resulting mixture was heated to 120 °C with stirring for 5 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with 4:1 petroleum ether:EtOAc (15 mL). The resulting solid was filtered and dried under high vacuum to give Compound C1-6 as a yellow solid (1.93 g, 83% yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (brs, 1H), 8.03 (d, 1H), 7.42 (s, 1H), 4.31-4.23 (m, 2H), 3.98 (s, 3H), 3.76-3.66 (m, 2H), 3.32 (s, 3H); MS for C 11 H 13 N 3 O 4 : m / z 252.0 (MH+).

[0256] Step 7: 4-Chloro-6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidine (C1-7): A suspension of Compound C1-6 (1.93 g, 7.37 mmol, 1.0 eq) in phosphorus oxychloride (32.0 mL, 344 mmol, 47 eq) was heated to 120 °C with stirring for 3 h. The reaction mixture was concentrated under reduced pressure to remove most of the volatiles. The resulting residue was suspended in DCM (100 mL) and neutralized with aq saturated NaHCO 3 solution (150 mL), then extracted with DCM 2 x (50 mL×2). The combined extracts were washed with aq saturated NaCl (150 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure to give Compound C1-7 as a light brown solid (1.73 g, 87% yield) which was used directly in the next step. 1< H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 7.42 (s, 1H), 4.39-4.30 (m, 2H), 4.22 (s, 3H), 3.94-3.84 (m, 2H), 3.48 (s, 3H); MS for C 11 H 12 ClN 3 O 3 : m / z 270.1 (MH+).

[0257] Step 8: 4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidine (C1-8): A mixture of Compound C1-7 (1.73 g, 6.41 mmol, 1.0 eq) and 2-fluoro-4-nitrophenol (1.11 g, 6.93 mmol, 1.1 eq) in o-xylene (43 mL) was heated to 137 °C with stirring for 37 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was triturated with 8:1 MTBE:MeOH (9 mL) for 30 min. The resulting solid was collected by filtration, washed with petroleum ether (2 x 1.5 mL) and dried under vacuum to give crude Compound C1-8 as a yellow solid (2.72 g) crude) which was used directly in the next step without further purification. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.41 (dd, 1H), 8.27-8.20 (m, 1H), 7.84 (dd, 1H), 7.72 (s, 1H), 4.42-4.35 (m, 2H), 4.09 (s, 3H), 3.79-3.73 (m, 2H), 3.34 (s, 3H); MS for C 17 H 15 FN 4 O 6 : m / z 391.0 (MH+).

[0258] Step 9: 3-Fluoro-4-((6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl)oxy)aniline (C1-9): To a stainless autoclave charged with a solution of crude Compound C1-8 (2.72 g) in THF (150 mL) was added 10% Pd / C (600 mg) under argon. The resulting mixture was degassed and purged with argon. The atmosphere was exchanged with H 2 (50 psi) 3 times. The resulting mixture was heated to 60 °C with stirring for 45 h under H 2 (50 psi). The reaction mixture was cooled down and filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (41 ~ 83% EtOAc in petroleum ether) to give Compound C1-9 as a light yellow solid (1.06 g, 46% yield over 2 steps). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 7.41 (s, 1H), 7.10 (t, 1H), 6.58-6.53 (m, 1H), 6.53-6.47 (m, 1H), 4.38-4.29 (m, 2H), 4.22 (s, 3H), 3.95-3.85 (m, 2H), 3.77 (brs, 2H), 3.48 (s, 3H); MS for C 17 H 17 FN 4 O 4 : m / z 361.2 (MH+).General Procedure D1: Halogenation

[0259]

[0260] Step 1: Compound D1-1 can be a carboxylic acid or an ester. Compound D1-1 was halogenated using NBS or NIS in an appropriate organic solvent such as, but not limited to, DCE, NMP, DMF or ACN. To a solution of Compound D1-1 (1 eq) in solvent (1.1-3.2 mL / mmol of D1-1) was added solid NBS (1-1.6 eq) in portions. The resulting mixture was stirred at room temperature to 80 °C (30 min to overnight). Upon completion of the reaction as monitored by LC-MS and / or TLC, in cases where heating was used, the reaction mixture was allowed to cool to room temperature. The reaction mixture was then typically worked up by one of the following methods or a very similar variation. Method 1: The reaction mixture was partitioned between an aqueous solvent such as, but not limited to, water or aq saturated NaHCO 3 and an organic solvent such as, but not limited to, EtOAc or DCM. The organic phase was further washed with aq saturated NaCl, dried over anhyd. Na 2 SO 4 and concentrated to give crude brominated product D1-2. Method 2: To the reaction mixture was added water and the resulting mixture was stirred at room temperature for 15 min. The resulting precipitate was filtered, washed with water, and allowed to air-dry to give crude brominated product D1-2. Method 3: If the desired product precipitated out of the reaction mixture without diluting with water, the reaction mixture was filtered, the collected solid washed with the same solvent the reaction was run in or a similar solvent and then the solid was airdried. Regardless of the method of work up, the crude D1-2 was generally used in subsequent reactions without further purification.Example of General Procedure D1: Methyl 7-bromo-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (D1-4)

[0261]

[0262] Methyl 7-bromo-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (D1-4): To a solution of Compound D1-3 (210 mg, 1.00 mmol, 1 eq) in DMF (2 mL) was added NBS (214 mg, 1.20 mmol, 1.2 eq) and the resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was diluted with aq saturated NaHCO 3 (50 mL) and extracted with DCM (3 x 50 mL). The combined DCM extracts were washed with aq saturated NaCl (20 mL), dried over anhyd. Na 2 SO 4 and concentrated to give Compound D1-4 as a yellow solid (260 mg, 90% yield). MS for C 10 H 10 BrNO 4 : m / z 289.7 (MH+). See Example 3 for the synthesis of Compound D1-3.

[0263] The following additional compounds were made in a similar fashion using General Procedure D1:

[0264] 5-Bromo-4-hydroxy-6-methylnicotinic acid (D1-5): Compound D1-3 was replaced with 4-hydroxy-6-methylnicotinic acid. MS for C 7 H 6 BrNO 3 : m / z 232 / 234 (MH+).

[0265] 4-Hydroxy-5-iodo-6-methylnicotinic acid (D1-6): Compound D1-3 was replaced with 4-hydroxy-6-methylnicotinic acid and the NBS was replaced with NIS. MS for C 7 H 6 INO 3 : m / z 279.7 (MH+).

[0266] 5-Bromo-4-hydroxy-2,6-dimethylnicotinic acid (D1-7): Compound D1-3 was replaced with 4-hydroxy-2,6-dimethylnicotinic acid (See Example 4 for the synthesis of 4-hydroxy-2,6-dimethylnicotinic acid (Compound 2-1)). MS for C 8 H 8 BrNO 3 : m / z 246 (MH+).

[0267] 5-Bromo-6-ethyl-4-hydroxynicotinic acid (D1-8): See the procedure used in Bannen, L., et. al. WO2021062245, which is incorporated by reference.

[0268] Methyl 5-bromo-4-hydroxy-2,6-dimethylnicotinate (D1-9): Compound D1-3 was replaced with methyl 4-hydroxy-2,6-dimethylnicotinate (can be prepared by the method of Bradbury, R.H.; et al J. Med. Chem 1993, 36, 1245-54, which is incorporated by reference herein). MS for C 9 H 10 BrNO 3 : m / z 260 / 262 (MH+).

[0269] Ethyl 5-bromo-4-hydroxy-2,6-dimethylnicotinate (D1-10): Compound D1-3 was replaced with ethyl 4-hydroxy-2,6-dimethylnicotinate (can be prepared by the method of Dean, A.; et al Inorganica Chimica Acta 2011,373, 179-186, which is incorporated by reference herein). MS for C 10 H 12 BrNO 3 : m / z 274 / 276 (MH+).

[0270] Methyl 7-bromo-6-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (D1-11): Compound D1-3 was replaced with Compound 26-2. MS for C 11 H 12 BrNO 4 : m / z 301.9 / 303.9 (MH+)General Procedure E1: Suzuki Reaction

[0271]

[0272] A mixture of the Compound D1-2 (1 eq), boronic acid / ester E1-1 (1-5 eq), catalytic Pd / PR 3 complex such as, but not limited to, Pd(PPh 3 ) 4 (5-10 mol%), Pd(dppf)Cl 2 (mol10-20%), Pd(Amphos) 2 Cl 2 (10-20 mol%) / SPhos (1 eq), and a base (2-5 eq) such as, but not limited to, Cs 2 CO 3 , K 2 CO 3 , NaOH, Na 2 CO 3 , K 3 PO 4 , KF, in dioxane / water (1 / 1 to 5 / 1) (1.5-5 mL / mmol of D1-2 used) was degassed and purged with nitrogen 3 times. The resulting mixture was stirred at 80 - 160 °C, with or without microwave irradiation, under an atmosphere of nitrogen until the starting material D1-2 was consumed (0.5-20 h) as monitored by LC-MS and / or TLC. The reaction mixture was then concentrated under reduced pressure. To the resulting residue was added water and resulting mixture was washed with EtOAc, followed by DCM. The aqueous phase was acidified with aq 2 N HCl to pH 2 - 5. If a suspension resulted, the mixture was filtered, the solid washed with water and dried under reduced pressure to give crude Compound E1-2. If a filterable solid did not result, the acidic aqueous phase was extracted with an organic solvent such as, but not limited to, EtOAc or DCM. The combined organic extracts were dried over anhyd. Na 2 SO 4 or MgSO 4 and concentrated to provide crude Compound E1-2. Crude Compound E1-2 was either purified by silica gel chromatography or used directly in subsequent steps without further purification (9 - 97% yield).Example of General Procedure E1: Methyl 7-(cyclopent-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-3)

[0273]

[0274] Methyl 7-(cyclopent-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-3): To a solution of Compound D1-4 (60 mg, 0.21 mmol, 1 eq) and 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (121 mg, 0.62 mmol, 3 eq) in 1,4-dioxane (3 mL) and water (0.3 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (17.0 mg, 0.021 mmol, 0.1 eq) and Na 2 CO 3 (66.2 mg, 0.62 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The resulting residue was purified by flash silica gel chromatography (0~10% DCM / MeOH) to give Compound E1-3 as a yellow solid (55 mg, 96% yield). MS for C 15 H 17 NO 4 : m / z 275.9 (MH+).

[0275] The following additional compounds were made using General Procedure E1:

[0276] Methyl 7-(cyclohex-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-4): The 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with cyclohexen-1-ylboronic acid. MS for C 16 H 19 NO 4 : m / z 289.9 (MH+).

[0277] Methyl 7-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-5): The 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS for C 15 H 17 NO 5 : m / z 291.9 (MH+).

[0278] 5-(Cyclopent-1-en-1-yl)-4-hydroxy-6-methylnicotinic acid (E1-6): Compound D1-4 was replaced with Compound D1-5. MS for C 12 H 13 NO 3 : m / z 220.2 (MH+).

[0279] 5-(Cyclohex-1-en-1-yl)-4-hydroxy-6-methylnicotinic acid (E1-7): Compound D1-4 was replaced with Compound D1-6 and the 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS for C 13 H 15 NO 3 : m / z 233.8 (MH+).

[0280] 4-Hydroxy-2,6-dimethyl-5-(prop-1-en-2-yl)nicotinic acid (E1-8): Compound D1-4 was replaced with Compound D1-9 and the 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with isopropenylboronic acid. Prior to work up of the reaction, the resulting methyl ester product was hydrolyzed by adding aq NaOH solution to the crude reaction mixture with stirring at 100 °C until hydrolysis was complete. MS for C 11 H 13 NO 3 : m / z 208 (MH+).

[0281] 1,2,6-Trimethyl-4-oxo-5-(prop-1-en-2-yl)-1,4-dihydropyridine-3-carboxylic acid (E1-9): Compound D1-4 was replaced with Compound 9-3 and the 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with 2 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane. MS for C 12 H 15 NO 3 : m / z 222 (MH+).

[0282] Methyl 7-(cyclopent-1-en-1-yl)-6-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-10): Compound D1-4 was replaced with Compound D-11. MS for C 16 H 19 NO 4 : m / z 290.1 (MH+).

[0283] Methyl 7-(cyclohex-1-en-1-yl)-6-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (E1-11): Compound D1-4 was replaced with Compound D-11 and the 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with cyclohexen-1-ylboronic acid. MS for C 17 H 21 NO 4 : m / z 304.1 (MH+).

[0284] 7-(3,6-Dihydro-2H-pyran-4-yl)-4-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (E1-12): Compound D1-4 was replaced with Compound D-11 and the 2-(cyclopenten-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The methyl ester was hydrolyzed during the course of the reaction. MS for C 15 H 17 NO 5 : m / z 292.1 (MH+).Procedure F1: Ester Hydrolysis: 7-(Cyclopent-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (F1-1)

[0285]

[0286] 7-(Cyclopent-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (F1-1): To a solution of Compound E1-3 (55 mg, 0.20 mmol, 1 eq) in THF (2 mL) and water (2 mL) was added LiOH.H 2 O (25.2 mg, 0.60 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous phase was acidified to pH = 3 with aq 2 N HCl. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with aq saturated NaCl (10 mL), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure to give Compound F1-1 as a yellow solid (40 mg, 77% yield). MS for C 14 H 15 NO 4 : m / z 261.9 (MH+).

[0287] The following additional compounds were made using General Procedure F1:

[0288] 7-(Cyclohex-1-en-1-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (F1-2): Compound E1-3 was replaced with Compound E1-4. MS for C 15 H 17 NO 4 : m / z 276.0 (MH+).

[0289] 7-(3,6-Dihydro-2H-pyran-4-yl)-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c] [1,4]oxazine-9-carboxylic acid (F1-3): Compound E1-3 was replaced with Compound E1-5. MS for C 14 H 15 NO 5 : m / z 277.9 (MH+).

[0290] 7-(Cyclopent-1-en-1-yl)-6-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (F1-4): Compound E1-3 was replaced with Compound E1-10. MS for C 15 H 17 NO 4 : m / z 276.1 (MH+).

[0291] 7-(Cyclohex-1-en-1-yl)-6-methyl-8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid (F1-5): Compound E1-3 was replaced with Compound E1-11. MS for C 166 H 19 NO 4 : m / z 290.1 (MH+).Procedure F2: Double Bond Reduction: 5-Isopropyl-2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (F2-1)

[0292]

[0293] 5-Isopropyl-2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (F2-1): Compound E1-8 (200 mg, 0.97 mmol) and Pd / C (10%, wet, 80 mg) in EtOH (10 ml) was stirred at room temperature under H 2 (1 atm) until hydrogenation was complete. The mixture was filtered through Celite and the filtrate was concentrated to give Compound F2-1 (162 mg, 80% yield). MS for C 11 H 15 NO 3 : m / z 210 (MH+).

[0294] The following compounds were made using standard hydrogenation conditions such as that used in General Procedure F2 as exemplified by the conversion of Compound E1-8 to Compound F2-1:

[0295] 1-Cyclopentyl-4,6-dimethyl-2-oxo-pyridine-3-carboxylic acid (F2-2): Compound E1-8 was replaced with Compound 12-3. MS for C 13 H 17 NO 3 : m / z 236.0 (MH+).

[0296] 5-Isopropyl-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (F2-3): Compound E1-8 was replaced with Compound E1-9. MS for C 12 H 17 NO 3 : m / z 224 (MH+).General Procedure G1: HATU Coupling

[0297]

[0298] To a solution of Compound G1a (1 eq) in DMF (2-5 mL / mmol of G1a used) was added the aniline G1b (0.7-1.1 eq), HATU (1.1-2 eq), and DIEA (3-5 eq). The mixture was stirred (room temperature to 40 °C) until Compound G1a was consumed based on LC-MS and / or TLC (4-15 h). The reaction was quenched with water and extracted with EtOAc twice. The combined organic extracts were washed with aq saturated NaCl (3 - 5 times), dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the Compound G1c (6 - 63% yield).Example of General Procedure G1: 7-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-1)

[0299]

[0300] 7-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-1): To a solution of Compound F1-1 (20 mg, 0.076 mmol, 1 eq) and Compound A1-10 (31 mg, 0.099 mmol, 1.3 eq) in DMF (2 mL) was added HATU (38 mg, 0.0995 mmol, 1.3 eq) and DIEA (30 mg, 0.23 mmol, 3 eq). The mixture was stirred at 16 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC to give Compound G1-1 as a white solid (13.2 mg, 31% yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 8.54 (d, 1H), 7.97 (m, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.38-7.43 (m, 1H), 7.29-7.36 (m, 1H), 7.18 (br s, 1H), 6.80 (d, 1H), 5.19 (s, 2H), 4.18-4.23 (m, 2H), 4.05 (br m, 2H), 3.96 (d, 6H), 2.62 (br d, 2H), 2.44 (br s, 2H), 1.88 (m, 2H); MS for C 30 H 27 FN 4 O 6 : m / z 559.2 (MH+).

[0301] The following additional compounds were made using General Procedure G1: 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide hydrochloride (G1-2): Compound F1-1 was replaced with Compound E1-6. Compound G1-2 was isolated as the hydrochloride salt from prep HPLC purification using a mobile phase that contained HCl. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.29 (s, 1H), 12.65 - 12.57 (m, 1H), 8.73 (d, 1H), 8.43 (d, 1H), 8.07 (dd, 1H), 7.75 (s, 1H), 7.54 - 7.40 (m, 2H), 7.06 (br d, 1H), 5.64 (s, 1H), 4.07 - 3.99 (m, 6H), 2.47 (br s, 4H), 2.30 (s, 3H), 2.01 - 1.89 (m, 2H); MS for C 28 H 25 FN 4 O 5 : m / z 517.2 (MH+).

[0302] 5-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (G1-3): Compound F1-1 was replaced with Compound E1-7. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.34 (s, 1H), 12.60 (br d, 1H), 8.79 (d, 1H), 8.43 (d, 1H), 8.10 (dd, 1H), 7.81 (s, 1H), 7.58 - 7.51 (m, 1H), 7.51 - 7.42 (m, 1H), 7.13 (d, 1H), 5.49 (br s, 1H), 4.05 (d, 6H), 2.29 (s, 3H), 2.17 - 2.07 (m, 4H), 1.76 - 1.57 (m, 4H); MS for C 29 H 27 FN 4 O 5 : m / z 531.0 (MH+).

[0303] 7-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-4): Compound F1-1 was replaced with Compound F1-2. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.37 (s, 1H), 8.54 (d, 1H), 7.89-8.04 (m, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.37-7.42 (m, 1H), 7.27-7.34 (m, 1H), 6.80 (d, 1H), 6.07 (br s, 1H), 5.21 (s, 2H), 4.12-4.19 (m, 2H), 4.03 (m, 2H), 3.96 (d, 6H), 2.33-2.39 (m, 2H), 2.14 (br s, 2H), 1.64 (br d, 4H); MS for C 31 H 29 FN 4 O 6 : m / z 573.1 (MH+).

[0304] 7-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-5): Compound F1-1 was replaced with Compound F1-2 and Compound A1-10 was replaced with Compound A1-11. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.18 (s, 1H), 8.53 (d, 1H), 7.70-7.78 (m, 3H), 7.64 (s, 1H), 7.17 (br d, 2H), 6.78 (d, 1H), 6.07 (br s, 1H), 5.22 (s, 2H), 4.15 (br d, 2H), 4.03 (br d, 2H), 3.96 (d, 6H), 2.34 (br d, 2H), 2.14 (br s, 2H), 1.64 (br d, 4H); MS for C 31 H 30 N 4 O 6 : m / z 555.2 (MH+).

[0305] 7-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-6): Compound A1-10 was replaced with Compound A1-11. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 8.53 (d, 1H), 7.73-7.80 (m, 3H), 7.64 (s, 1H), 7.15-7.21 (m, 3H), 6.78 (d, 1H), 5.20 (s, 2H), 4.17-4.22 (m, 2H), 4.02-4.06 (m, 2H), 3.96 (d, 6H), 2.62 (br d, 2H), 2.37-2.44 (m, 2H), 1.83-1.93 (m, 2H); MS for C 30 H 28 N 4 O 6 : m / z 541.2 (MH+).

[0306] 7-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-7): Compound F1-1 was replaced with Compound F1-3. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.15 (s, 1H), 8.54 (d, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.36-7.43 (m, 1H), 7.29-7.35 (m, 1H), 6.80 (d, 1H), 6.54 (br s, 1H), 5.19 (s, 2H), 4.13-4.25 (m, 4H), 4.01-4.08 (m, 2H), 3.96 (d, 6H), 3.79 (m, 2H), 2.44 (br s, 2H); MS for C 30 H 27 FN 4 O 7 : m / z 575.2 (MH+).

[0307] 7-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (G1-8): Compound F1-1 was replaced with Compound F1-3 and Compound A1-10 was replaced with Compound A1-11. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 8.53 (d, 1H), 7.71-7.83 (m, 3H), 7.64 (s, 1H), 7.17 (d, 2H), 6.77 (d, 1H), 6.54 (s, 1H), 5.20 (s, 2H), 4.15-4.23 (m, 4H), 4.04 (m, 2H), 3.96 (d, 6H), 3.79 (m, 2H), 2.41-2.44 (m, 2H); MS for C 30 H 28 N 4 O 7 : m / z 557.2 (MH+).Example 1: 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (1-2):

[0308]

[0309] Step 1: 5-Bromo-N-(4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-4-hydroxy-2,6-dimethylnicotinamide (1-1): Compound 1-1 was synthesized from Compound D1-7 and Compound A1-10 using General Procedure G1. MS for C 24 H 20 BrFN 4 O 5 : m / z 545.1 (MH+).

[0310] Step 2: 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide hydrochloride (1-2): Compound 1-2 was synthesized from Compound 1-1 using General Procedure E1. Compound 1-2 was isolated as the hydrochloride salt from prep HPLC purification using a mobile phase that contained HCl. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.45 (s, 1H), 12.10 (br s, 1H), 8.80 (d, 1H), 8.12 - 8.03 (m, 1H), 7.78 (s, 1H), 7.52 - 7.43 (m, 2H), 7.13 (d, 1H), 5.63 (d, 1H), 4.06 (d, 6H), 2.71 (s, 3H), 2.50 - 2.48 (m, 4H), 2.30 (s, 3H), 1.99 - 1.91 (m, 2H); MS for C 29 H 27 FN 4 O 5 : m / z 531.1 (MH+).

[0311] The following compounds were made using the same two step procedure, using General Procedure G1 followed by General Procedure E1, as exemplified by the synthesis of Compound 1-2 inExample 1.

[0312] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-3): In Step 1, Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.16 (s, 1H), 12.42 (s, 1H), 8.48 (d, 1H), 8.39 (s, 1H), 7.95 (dd, 1H), 7.59 (s, 1H), 7.42 - 7.31 (m, 1H), 7.26 (t, 1H), 6.75 (d, 1H), 5.53 (t, 1H), 4.10 (q, 2H), 3.88 (s, 6H), 3.73 (s, 2H), 2.23 (s, 3H), 2.16 (s, 2H). MS for C 28 H 25 FN 4 O 6 : 533.1 (MH+).

[0313] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-4): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-12. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.22 (s, 1H), 12.50 (d, 1H), 8.83 - 8.62 (m, 2H), 8.47 (d, 1H), 8.07 (dd, 1H), 7.81 (d, 1H), 7.56 - 7.28 (m, 2H), 6.76 (dd, 1H), 5.61 (s, 1H), 4.18 (d, 2H), 4.01 (s, 3H), 3.81 (t, 2H), 2.31 (s, 3H), 2.24 (s, 2H). MS for C 27 H 23 FN 4 O 5 : 503.1 (MH+).

[0314] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-5): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-14. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.12 (s, 1H), 12.41 (s, 1H), 8.55 (d, 1H), 8.39 (s, 1H), 8.22 (d, 1H), 7.97 (dd, 1H), 7.43 - 7.31 (m, 1H), 7.26 (dd, 2H), 6.90 (d, 1H), 5.54 (s, 1H), 4.11 (d, 2H), 3.87 (s, 3H), 3.74 (s, 2H), 2.24 (s, 3H), 2.16 (s, 2H). MS for C 27 H 23 FN 4 O 5 : 503.1 (MH+).

[0315] 5-(Cyclohexen-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-6): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-14. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.27 (s, 1H), 12.41 (d, 1H), 8.63 (d, 1H), 8.43 (d, 1H), 8.30 (d, 1H), 8.04 (dd, 1H), 7.57 - 7.07 (m, 3H), 6.97 (d, 1H), 5.56 - 5.30 (m, 1H), 3.94 (s, 3H), 2.28 (s, 3H), 2.12 (s, 4H), 1.80 - 1.56 (m, 4H). MS for C 28 H 25 FN 4 O 4 : 501 (MH+).

[0316] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-7): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-14. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 12.40 (d, 1H), 8.55 (d, 1H), 8.37 (d, 1H), 8.22 (d, 1H), 7.97 (dd, 1H), 7.45 - 7.20 (m, 3H), 6.90 (d, 1H), 5.57 (t, 1H), 3.87 (s, 3H), 2.49 (s, 2H), 2.41 (d, 2H), 2.22 (s, 3H), 1.89 (dd, 2H). MS for C 27 H 23 FN 4 O 4 : 487.1 (MH+).

[0317] 5-(Cyclohexen-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-8): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-12. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.23 (s, 1H), 12.35 (s, 1H), 8.82 - 8.55 (m, 2H), 8.37 (s, 1H), 8.00 (dd, 1H), 7.74 (d, 1H), 7.51 - 7.15 (m, 2H), 6.68 (dd, 1H), 5.53 - 5.33 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 2.05 (s, 4H), 1.60 (d, 4H). MS for C 28 H 25 FN 4 O 4 : 501.2 (MH+).

[0318] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (1-9): ): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 12.43 (s, 1H), 8.84 - 8.51 (m, 2H), 8.38 (s, 1H), 8.00 (dd, 1H), 7.74 (d, 1H), 7.52 - 7.26 (m, 2H), 6.68 (dd, 1H), 5.56 (s, 1H), 3.94 (s, 3H), 2.49 (s, 2H), 2.40 (s, 2H), 2.22 (s, 3H), 1.89 (q, 2H). MS for C 27 H 23 FN 4 O 4 : 487.2 (MH+).

[0319] 5-(3,6-Dihydro-2H-pyran-4-yl)-4-hydroxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methylpyridine-3-carboxamide (7): In Step 1, Compound D1-7 was replaced with Compound D1-5 and Compound A1-10 was replaced with Compound A1-13. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 12.37 (s, 1H), 8.66 (d, 1H), 8.63 (d, 1H), 8.38 (s, 1H), 7.76 (d, 2H), 7.72 (d, 1H), 7.17 (d, 2H), 6.67 (d, 1H), 5.54 (s, 1H), 4.11 (d, 2H), 3.93 (s, 3H), 3.74 (t, 2H), 2.24 (s, 3H), 2.17 (s, 2H). MS (EI) for C 27 H 24 N 4 O 5 , found 485.2 (MH+).

[0320] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide (12): In Step 1, Compound A1-10 was replaced with Compound A1-12 and Compound D1-7 was replaced with 5-bromo-1,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Bannen, L., et. al. WO2021173591, which is incorporated by reference). In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 8.69 (d, 1H), 8.64 (d, 2H), 7.99 (dd, 1H), 7.74 (d, 1H), 7.50 - 7.39 (m, 1H), 7.35 (t, 1H), 6.68 (d, 1H), 5.50 (s, 1H), 4.12 (d, 2H), 3.94 (s, 3H), 3.77 (d, 5H), 2.32 (s, 3H), 2.31 - 2.23 (m, 2H). MS (EI) for C 28 H 25 FN 4 O 5 , found 517.1 (MH+).

[0321] 5-(Cyclopenten-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (16): In Step 1, Compound A1-10 was replaced with Compound B1-7 and Compound D1-7 was replaced with Compound D1-5. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (s, 1H), 12.34 (d, 1H), 8.44 (d, 1H), 8.36 (d, 1H), 7.85 - 7.67 (m, 2H), 7.47 (s, 1H), 7.34 (s, 1H), 7.29 - 7.12 (m, 2H), 6.47 (d, 1H), 5.57 (s, 1H), 3.88 (d, 6H), 2.48 (d, 2H), 2.38 (bm, 2H), 2.23 (s, 3H), 1.89 (p, 2H). MS (EI) for C 29 H 27 N 3 O 5 , found 498.1 (MH+).

[0322] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (17): In Step 1, Compound A1-10 was replaced with Compound B1-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 12.36 (d, 1H), 8.42 (d, 1H), 8.38 (d, 1H), 7.78 (d, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 7.19 (d, 2H), 6.44 (d, 1H), 5.54 (s, 1H), 4.11 (s, 2H), 3.88 (d, 6H), 3.74 (t, 2H), 2.24 (s, 3H), 2.17 (s, 2H). MS (EI) for C 29 H 27 N 3 O 6 , found 514.1 (MH+).

[0323] 5-(Cyclopenten-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (18): In Step 1, Compound A1-10 was replaced with Compound B1-6 and Compound D1-7 was replaced with Compound D1-5. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.23 (s, 1H), 12.45 (s, 1H), 8.42 (d, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.47 (s, 1H), 7.41 (d, 1H), 7.38 (d, 1H), 7.34 (s, 1H), 6.42 (dd, 1H), 5.57 (t, 1H), 3.89 (s, 6H), 2.53 - 2.46 (m, 2H), 2.39 (s, 2H), 2.23 (s, 3H), 1.89 (p, 2H). MS (EI) for C 29 H 26 FN 3 O 5 , found 516.25 (MH+).

[0324] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (19): In Step 1, Compound A1-10 was replaced with Compound B1-6 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.16 (s, 1H), 12.42 (s, 1H), 8.51 - 8.26 (m, 2H), 7.99 (dd, 1H), 7.56 - 7.21 (m, 4H), 6.42 (dd, 1H), 5.54 (s, 1H), 4.11 (d, 2H), 3.89 (d, 6H), 3.74 (t, 2H), 2.24 (s, 3H), 2.17 (s, 2H). MS (EI) for C 29 H 26 FN 3 O 6 , found 532.5 (MH+).

[0325] 5-(Cyclohexen-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (23): In Step 1, Compound A1-10 was replaced with Compound B1-6 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.24 (s, 1H), 12.36 (s, 1H), 8.42 (d, 1H), 8.37 (s, 1H), 7.99 (dd, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.38 (d, 1H), 7.35 (s, 1H), 6.42 (dd, 1H), 5.42 (s, 1H), 3.89 (d, 6H), 2.21 (s, 3H), 2.05 (s, 4H), 1.60 (d, 4H). MS (EI) for C 30 H 28 FN 3 O 5 , found 530.2 (MH+).

[0326] 5-(Cyclohexen-1-yl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (24): In Step 1, Compound A1-10 was replaced with Compound B1-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 12.28 (s, 1H), 8.41 (d, 1H), 8.35 (s, 1H), 7.77 (d, 2H), 7.45 (s, 1H), 7.33 (s, 1H), 7.18 (d, 2H), 6.43 (d, 1H), 5.48 - 5.26 (m, 1H), 3.87 (d, 6H), 2.21 (s, 3H), 2.14 - 1.92 (m, 4H), 1.60 (d, 4H). MS (EI) for C 30 H 29 N 3 O 5 , found 512.2 (MH+).

[0327] 5-[(E)-2-Cyclopentylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3- fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (25): In Step 1, Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopentylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.25 (s, 1H), 12.43 (s, 1H), 8.48 (d, 1H), 8.32 (s, 1H), 7.96 (dd, 1H), 7.59 (s, 1H), 7.37 (ddd, 1H), 7.26 (t, 1H), 6.76 (d, 1H), 6.61 (dd, 1H), 6.24 (dd, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.51 (q, 1H), 2.35 (s, 3H), 1.84 - 1.70 (m, 2H), 1.70 - 1.46 (m, 4H), 1.31 (dt, 2H). MS (EI) for C 30 H 20 FN 4 O 5 , found 545.20 (MH+).

[0328] 5-[(E)-2-Cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (26): In Step 1, Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopropylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.22 (s, 1H), 12.38 (d, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 7.96 (dd, 1H), 7.59 (s, 1H), 7.39 - 7.31 (m, 1H), 7.28 (t, 1H), 6.79 (d, 1H), 6.42 - 6.24 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.35 (s, 3H), 1.51 (tt, 1H), 0.75 (dd, 2H), 0.43 (dd, 2H). MS (EI) for C 28 H 25 FN 4 O 5 , found 517.0 (MH+).

[0329] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide (27): In Step 1, Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(3,3-dimethylbut-1-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.23 (s, 1H), 12.41 (s, 1H), 8.48 (d, 1H), 8.33 (s, 1H), 7.97 (dd, 1H), 7.59 (s, 1H), 7.39 (ddd, 1H), 7.26 (t, 1H), 6.76 (dd, 1H), 6.51 (d, 1H), 6.17 (d, 1H), 3.89 (d, 6H), 2.35 (s, 3H), 1.04 (s, 9H). MS (EI) for C 29 H 29 FN 4 O 5 , found 533.2 (MH+).

[0330] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide (28): In Step 1, Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(4-methylpent-1-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 12.38 (s, 1H), 8.48 (d, 1H), 8.33 (s, 1H), 7.96 (dd, 1H), 7.59 (s, 1H), 7.37 (ddd, 1H), 7.26 (t, 1H), 6.76 (dd, 1H), 6.57 (dt, 1H), 6.23 (d, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.36 (s, 3H), 2.04 (td, 2H), 1.64 (dt, 1H), 0.88 (s, 3H), 0.86 (s, 3H). MS (EI) for C 29 H 29 FN 4 O 5 , found 533.2 (MH+).

[0331] N-[4-(6,7-Dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide (29): In Step 1, Compound A1-10 was replaced with Compound B1-6 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(4-methylpent-1-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 12.42 (s, 1H), 8.42 (d, 1H), 8.34 (s, 1H), 7.99 (dd, 1H), 7.52 - 7.25 (m, 4H), 6.58 (dd, 1H), 6.42 (dd, 1H), 6.23 (dt, 1H), 3.88 (s, 6H), 2.36 (s, 3H), 2.04 (td, 2H), 1.65 (dt, 1H), 0.88 (s, 3H), 0.86 (s, 3H). MS (EI) for C 30 H 30 FN 3 O 5 , found 532.0 (MH+).

[0332] N-[4-(6,7-Dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide (30): In Step 1, Compound A1-10 was replaced with Compound B1-6 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(3,3-dimethylbut-1-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.24 (s, 1H), 12.43 (s, 1H), 8.42 (d, 1H), 8.34 (s, 1H), 8.00 (dd, 1H), 7.54 - 7.41 (m, 2H), 7.41 - 7.27 (m, 2H), 6.52 (d, 1H), 6.43 (dd, 1H), 6.17 (d, 1H), 3.89 (s, 6H), 2.36 (s, 3H), 1.04 (s, 9H). MS (EI) for C 30 H 30 FN 3 O 5 , found 532.25 (MH+).

[0333] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (33): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.16 (s, 1H), 12.38 (s, 1H), 8.47 (d, 1H), 8.37 (s, 1H), 7.95 (dd, 1H), 7.61 (s, 1H), 7.36 (ddd, 1H), 7.26 (t, 1H), 6.75 (dd, 1H), 5.56 (t, 1H), 4.30 - 4.15 (m, 2H), 3.89 (s, 3H), 3.74 - 3.62 (m, 2H), 3.27 (s, 3H), 2.48 (d, 2H), 2.40 (s, 2H), 2.22 (s, 3H), 1.96 - 1.72 (m, 2H). MS (EI) for C 30 H 20 FN 4 O 6 , found 561 (MH+).

[0334] 5-(Cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (34): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.18 (s, 1H), 12.33 (s, 1H), 8.48 (d, 1H), 8.36 (s, 1H), 7.95 (dd, 1H), 7.61 (s, 1H), 7.38 (ddd, 1H), 7.25 (t, 1H), 6.75 (dd, 1H), 5.41 (s, 1H), 4.42 - 4.20 (m, 2H), 3.89 (s, 3H), 3.76 - 3.62 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H), 2.04 (s, 4H), 1.59 (d, 4H). MS (EI) for C 31 H 31 FN 4 O 6 , found 575 (MH+).

[0335] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (35): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 12.40 (s, 1H), 8.48 (d, 1H), 8.38 (s, 1H), 7.95 (dd, 1H), 7.61 (s, 1H), 7.37 (ddd, 1H), 7.26 (t, 1H), 6.75 (dd, 1H), 5.54 (p, 1H), 4.37 - 4.20 (m, 2H), 4.11 (d, 2H), 3.88 (s, 3H), 3.74 (t, 2H), 3.72 - 3.63 (m, 2H), 3.27 (s, 3H), 2.24 (s, 3H), 2.16 (s, 2H). MS (EI) for C 30 H 29 FN 4 O 7 , found 577 (MH+).

[0336] 5-[(E)-2-Cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (36): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopentylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 12.40 (s, 1H), 8.48 (d, 1H), 8.32 (s, 1H), 7.96 (dd, 1H), 7.61 (s, 1H), 7.37 (ddd, 1H), 7.27 (t, 1H), 6.76 (dd, 1H), 6.61 (dd, 1H), 6.24 (dd, 1H), 4.37 - 4.18 (m, 2H), 3.89 (s, 3H), 3.80 - 3.61 (m, 2H), 3.27 (s, 3H), 2.52 (q, 1H), 2.35 (s, 3H), 1.83 - 1.70 (m, 2H), 1.70 - 1.44 (m, 4H), 1.41 - 1.25 (m, 2H). MS (EI) for C 32 H 33 FN 4 O 6 , found 589 (MH+).

[0337] 5-[(E)-2-Cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (37): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopropylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.21 (s, 1H), 12.38 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 7.96 (dd, 1H), 7.61 (s, 1H), 7.35 (ddd, 1H), 7.26 (t, 1H), 6.76 (dd, 1H), 6.33 (d, 2H), 4.31 - 4.21 (m, 2H), 3.89 (s, 3H), 3.74 - 3.65 (m, 2H), 3.27 (s, 3H), 2.35 (s, 3H), 1.51 (tt, 1H), 0.74 (dd, 2H), 0.43 (dd, 2H). MS (EI) for C 30 H 29 FN 4 O 6 , found 561.0 (MH+).

[0338] 5-[(E)-3,3-Dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide (40): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound D1-5. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(3,3-dimethylbut-l-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 12.42 (s, 1H), 8.48 (d, 1H), 8.33 (s, 1H), 59927.97 (dd, 1H), 7.61 (s, 1H), 7.44 - 7.33 (m, 1H), 7.26 (t, 1H), 6.76 (dd, 1H), 6.51 (d, 1H), 6.16 (d, 1H), 4.35 - 4.18 (m, 2H), 3.89 (s, 3H), 3.78 - 3.62 (m, 2H), 3.27 (s, 3H), 2.35 (s, 3H), 1.04 (s, 9H). MS (EI) for C 51 H 33 FN 4 O 6 , found 577 (MH+).

[0339] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (41): In Step 1, Compound A1-10 was replaced with Compound A2-7. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.43 (s, 1H), 11.71 (s, 1H), 8.47 (d, 1H), 7.93 (dd, 1H), 7.61 (s, 1H), 7.34 - 7.29 (m, 1H), 7.23 (t, 1H), 6.72 (dd, 1H), 5.68 - 5.44 (m, 1H), 4.37 - 4.16 (m, 2H), 3.90 (s, 3H), 3.75 - 3.55 (m, 2H), 3.27 (s, 3H), 2.63 (s, 3H), 2.46 (s, 2H), 2.38 (s, 2H), 2.19 (s, 3H), 1.87 (p, 2H). MS (EI) for C 31 H 31 FN 4 O 6 , found 575 (MH+).

[0340] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (42): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.45 (d, 1H), 7.88 (dd, 1H), 7.61 (s, 1H), 7.47 - 7.33 (m, 1H), 7.26 (t, 1H), 6.70 (dd, 1H), 5.48 - 5.36 (m, 1H), 4.33 - 4.19 (m, 2H), 3.91 (s, 3H), 3.77 - 3.57 (m, 2H), 3.53 (s, 3H), 3.27 (s, 3H), 2.45 (s, 3H), 2.38 (s, 4H), 2.29 (s, 3H), 1.87 (q, 2H). MS (EI) for C 32 H 33 FN 4 O 6 , found 589 (MH+).

[0341] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (43): In Step 1, Compound A1-10 was replaced with Compound A2-7. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.38 (s, 1H), 11.73 (s, 1H), 8.47 (d, 1H), 7.93 (dd, 1H), 7.61 (s, 1H), 7.32 (ddd, 1H), 7.23 (t, 1H), 6.72 (dd, 1H), 5.49 (dd, 1H), 4.34 - 4.19 (m, 2H), 4.10 (q, 2H), 3.90 (s, 3H), 3.72 (t, 2H), 3.70 - 3.66 (m, 2H), 3.27 (s, 3H), 2.64 (s, 3H), 2.21 (s, 3H), 2.15 (s, 2H). MS (EI) for C 31 H 31 FN 4 O 7 , found 591 (MH+).

[0342] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (44): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 8.45 (d, 1H), 7.88 (dd, 1H), 7.61 (s, 1H), 7.49 - 7.35 (m, 1H), 7.27 (t, 1H), 6.70 (dd, 1H), 5.41 (d, 1H), 4.36 - 4.17 (m, 2H), 4.09 (d, 2H), 3.91 (s, 3H), 3.83 - 3.63 (m, 4H), 3.53 (s, 3H), 3.27 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.10 (s, 2H). MS (EI) for C 32 H 33 FN 4 O 7 , found 605 (MH+).

[0343] 5-[(E)-3,3-Dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (45): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(3,3-dimethylbut-1-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 8.45 (d, 1H), 7.89 (dd, 1H), 7.61 (s, 1H), 7.40 (ddd, 1H), 7.27 (t, 1H), 6.70 (dd, 1H), 6.12 (d, 2H), 4.30 - 4.19 (m, 2H), 3.92 (s, 3H), 3.76 - 3.64 (m, 2H), 3.54 (s, 3H), 3.27 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 1.02 (s, 9H). MS (EI) for C 33 H 37 FN 4 O 6 , found 605 (MH+).

[0344] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (49): In Step 1, Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(3,3-dimethylbut-l-en-1-yl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.27 (s, 1H), 8.54 (d, 1H), 7.96 (dd, 1H), 7.66 (s, 1H), 7.50 - 7.43 (m, 1H), 7.34 (t, 1H), 6.78 (dd, 1H), 6.20 (s, 2H), 3.98 (d, 6H), 3.61 (s, 3H), 2.52 (s, 3H), 2.48 (s, 3H), 1.09 (s, 9H). MS (EI) for C 31 H 33 FN 4 O 5 , found 561 (MH+).

[0345] 5-[(E)-2-Cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (50): In Step 1, Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced (E)-(2-cyclopropylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.46 (d, 1H), 7.88 (dd, 1H), 7.58 (s, 1H), 7.39 (ddd, 1H), 7.27 (t, 1H), 6.70 (dd, 1H), 6.29 (d, 1H), 5.91 (dd, 1H), 3.91 (d, 6H), 3.53 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 1.55 - 1.40 (m, 1H), 0.71 (dd, 2H), 0.36 (dd, 2H). MS (EI) for C 30 H 29 FN 4 O 5 , found 545 (MH+).

[0346] 5-[(E)-2-Cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (51): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopropylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.45 (d, 1H), 7.88 (dd, 1H), 7.61 (s, 1H), 7.39 (ddd, 1H), 7.27 (t, 1H), 6.69 (dd, 1H), 6.29 (d, 1H), 5.91 (dd, 1H), 4.31 - 4.18 (m, 2H), 3.92 (s, 3H), 3.71 - 3.61 (m, 2H), 3.53 (s, 3H), 3.27 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 1.49 (dt, 1H), 0.76 - 0.61 (m, 2H), 0.41 - 0.28 (m, 2H). MS (EI) for C 32 H 33 FN 4 O 6 , found 589 (MH+).

[0347] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (53): In Step 1, Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 8.46 (d, 1H), 7.88 (dd, 1H), 7.58 (s, 1H), 7.39 (ddd, 1H), 7.26 (t, 1H), 6.71 (dd, 1H), 5.41 (t, 1H), 4.19 - 3.99 (m, 2H), 3.90 (d, 6H), 3.71 (t, 2H), 3.53 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.10 (s, 2H). MS (EI) for C 30 H 29 FN 4 O 6 , found 561 (MH+).

[0348] 5-[(E)-2-Cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (54): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with (E)-(2-cyclopentylvinyl)boronic acid or the corresponding boronic acid pinacol ester. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (s, 1H), 8.45 (d, 1H), 7.88 (dd, 1H), 7.61 (s, 1H), 7.45 - 7.33 (m, 1H), 7.27 (t, 1H), 6.70 (dd, 1H), 6.19 (d, 2H), 4.31 - 4.22 (m, 2H), 3.92 (s, 3H), 3.69 (dd, 2H), 3.53 (s, 3H), 3.27 (s, 3H), 2.53 - 2.46 (m, 1H), 2.44 (s, 3H), 2.40 (d, 3H), 1.80 - 1.68 (m, 2H), 1.68 - 1.55 (m, 2H), 1.55 - 1.47 (m, 2H), 1.28 (t, 2H). MS (EI) for C 34 H 37 FN 4 O 6 , found 617.25 (MH+).

[0349] 5-(Cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (58): In Step 1, Compound A1-10 was replaced with Compound A2-7 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 8.46 (d, 1H), 7.88 (dd, 1H), 7.61 (s, 1H), 7.39 (ddd, 1H), 7.26 (t, 1H), 6.70 (dd, 1H), 5.32 (t, 1H), 4.24 (d, 2H), 3.91 (s, 3H), 3.84 - 3.63 (m, 2H), 3.52 (s, 3H), 3.27 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 2.03 (s, 2H), 1.65 (d, 6H).MS (EI) for C 33 H 35 FN 4 O 6 , found 603 (MH+).

[0350] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (65): In Step 1, Compound A1-10 was replaced with Compound A2-9 and Compound D1-7 was replaced with Compound 9-3. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.46 (s, 1H), 8.69 (d, 1H), 8.62 (d, 1H), 7.92 (dd, 1H), 7.76 (d, 1H), 7.48 - 7.39 (m, 1H), 7.34 (t, 1H), 6.67 (dd, 1H), 5.42 (t, 1H), 4.40 - 4.20 (m, 2H), 3.77 - 3.66 (m, 2H), 3.53 (s, 3H), 3.29 (s, 3H), 2.45 (s, 3H), 2.42 - 2.34 (m, 4H), 2.29 (s, 3H), 1.87 (p, 2H). MS (EI) for C 31 H 31 FN 4 O 5 , found 559 (MH+).

[0351] 5-(Cyclohexen-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (66): In Step 1, Compound A1-10 was replaced with Compound A2-9 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 8.70 (d, 1H), 8.63 (d, 1H), 7.92 (dd, 1H), 7.76 (d, 1H), 7.43 (ddd, 1H), 7.33 (t, 1H), 6.67 (dd, 1H), 5.32 (s, 1H), 4.38 - 4.23 (m, 2H), 3.78 - 3.64 (m, 2H), 3.52 (s, 3H), 3.29 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 2.04 (s, 2H), 1.66 (d, 6H). MS (EI) for C 32 H 33 FN 4 O 5 , found 573 (MH+).

[0352] 5-(3,6-Dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (67): In Step 1, Compound A1-10 was replaced with Compound A2-9 and Compound D1-7 was replaced with Compound 9-3. In Step 2, 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or the corresponding boronic acid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 8.77 (d, 1H), 8.70 (d, 1H), 7.99 (dd, 1H), 7.83 (d, 1H), 7.51 (ddd, 1H), 7.41 (t, 1H), 6.74 (dd, 1H), 5.49 (d, 1H), 4.47 - 4.29 (m, 2H), 4.17 (d, 2H), 3.85 - 3.71 (m, 4H), 3.60 (s, 3H), 3.36 (s, 3H), 2.52 (s, 3H), 2.39 (s, 3H), 2.20 (d, 2H). MS (EI) for C 51 H 31 FN 4 O 6 , found 575 (MH+).

[0353] 5-(Cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (101): In Step 1, Compound A1-10 was replaced with Compound A2-9. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.53 (s, 1H), 11.80 (s, 1H), 8.77 (d, 1H), 8.71 (d, 1H), 8.04 (dd, 1H), 7.83 (d, 1H), 7.46 - 7.26 (m, 2H), 6.74 (dd, 1H), 5.60 (s, 1H), 4.45 - 4.29 (m, 2H), 3.86 - 3.68 (m, 2H), 3.36 (s, 3H), 2.71 (s, 3H), 2.6 - 2.5 (bm, 2H), 2.47 - 2.42 (m, 2H), 2.27 (s, 3H), 2.05 - 1.85 (m, 2H); MS (EI) for C 30 H 29 FN 4 O 5 , found 545 (MH+).Example 2: 5-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (2-3):

[0354]

[0355] Step 1: N-(4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-4-hydroxy-2,6-dimethylnicotinamide (2-2): Compound 2-2 was synthesized from Compound 2-1 and Compound A1-10 using General Procedure G1. MS for C 24 H 21 FN 4 O 5 : m / z 465.1 (MH+). See Example 4 for the synthesis of Compound 2-1.

[0356] Step 2: 5-Bromo-N-(4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-4-hydroxy-2,6-dimethylnicotinamide (1-1): Compound 1-1 was synthesized from Compound 2-2 using General Procedure D1. MS for C 24 H 20 BrFN 4 O 5 : m / z 544.7 (MH+).

[0357] Step 3: 5-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (2-3): Compound 2-3 was synthesized from Compound 1-1 using General Procedure E1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.14 (br s, 1H), 12.80 (br s, 1H), 8.90 - 8.79 (m, 1H), 8.18 - 8.04 (m, 1H), 7.90 (s, 1H), 7.56 - 7.47 (m, 2H), 7.21 - 7.15 (m, 1H), 5.54 (br s, 1H), 4.13 - 4.05 (m, 6H), 2.70 (s, 3H), 2.35 (s, 3H), 2.12 (br s, 4H), 1.68 (br d, 4H); MS for C 30 H 20 FN 4 O 5 : m / z 545.1 (MH+).Example 3: Methyl 8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (D1-3)

[0358]

[0359] Step 1: 5-Ethoxy-3,6-dihydro-2H-1,4-oxazine (3-2): To a solution of Compound 3-1 (5 g, 49.4 mmol, 1 eq) in DCM (80 mL) was added Et 3 OBF 4 (10.3 g, 54.4 mmol, 1.1 eq) at 20 °C and the resulting reaction mixture was stirred at 20 °C for 12 h . The reaction mixture was quenched by the addition of aq saturated Na 2 CO 3 to pH=8. The organic layer was separated, dried over anhyd. Na 2 SO 4 and concentrated in vacuo to give crude Compound 3-2 as a yellow oil (6.3 g, 99% yield) which was used without further purification. 1< H NMR (400 MHz, CDCl 3 ) δ 4.09 (m, 2H), 4.03 (s, 2H), 3.62-3.68 (m, 2H), 3.49-3.55 (m, 2H), 1.26 (m, 3H).

[0360] Step 2: 2,2-Dimethyl-5-(morpholin-3-ylidene)-1,3-dioxane-4,6-dione (3-3): A solution of Compound 3-2 (5 g, 39 mmol, 1 eq), 2,2-dimethyl-1,3-dioxane-4,6-dione (5.6 g, 39 mmol, 1 eq) and Et 3 N (1.08 mL, 7.74 mmol, 0.2 eq) in toluene (50 mL) was stirred at 105 °C for 3 h. The mixture was cooled to room temperature and the solvent evaporated in vacuo. The resulting residue was purified by flash silica gel chromatography (0~50% EtOAc / petroleum ether) to give Compound 3-3 as a yellow solid (1.4 g, 16% yield). 1< H NMR (400 MHz, CDCl 3 ) δ 11.48 (br s, 1H), 5.05 (s, 2H), 3.94 (m, 2H), 3.55-3.63 (m, 2H), 1.68 (s, 6H).

[0361] Step 3: Methyl (E)-2-(morpholin-3-ylidene)acetate (3-4): A solution of Compound 3-3 (1.3 g, 5.7 mmol, 1 eq) and NaOMe (371 mg, 6.9 mmol, 1.2 eq) in MeOH (30 mL) was stirred at 80 °C for 12 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting residue was dissolved in aq saturated NH 4 Cl (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhyd. Na 2 SO 4 and concentrated in vacuo to give Compound 3-4 as a yellow solid (617 mg, 69% yield) which was used without further purification. 1< H NMR (400 MHz, CDCl 3 ) δ 8.56 (br s, 1H), 4.34 (s, 1H), 4.28 (s, 2H), 3.88-3.94 (m, 2H), 3.64 (s, 3H), 3.36 (m, 2H); MS for C 7 H 11 NO 3 : m / z 157.9 (MH+).

[0362] Step 4: 5 Methyl 8-oxo-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-9-carboxylate (D1-3): A mixture of Compound 3-4 (300 mg, 1.9 mmol, 1 eq) and Compound 3-5 (596 mg, 3.8 mmol, 2 eq) was stirred at 130 °C for 1.5 h with Dean-Stark trap removal of water. The reaction mixture was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (0~10% MeOH in DCM) to give Compound D1-3 as a yellow solid (220 mg, 55% yield). 1< H NMR (400 MHz, CDCl 3 ) δ 7.17 (d, 1H), 6.48 (d, 1H), 4.83 (s, 2H), 4.08 - 4.05 (t, 2H), 3.95 - 3.92 (t, 2H), 3.90 (s, 3H); MS for C 10 H 11 NO 4 : m / z 209.9 (MH+).Example 4: 4-Hydroxy-2,6-dimethylnicotinic acid (2-1)

[0363]

[0364] 4-Hydroxy-2,6-dimethylnicotinic acid (2-1): To a solution of commercially available Compound 4-1 (10 g, 59.88 mmol) in water (60 mL) was added ammonium hydroxide (60 mL, 30% in water). The resulting mixture was heated to reflux overnight. The mixture was partially concentrated and then acidified to pH 2 with aq 6 M HCl. The resulting precipitate was filtered and allowed to dry in the open air to afford Compound 2-1 as a white solid (2.5 g, 25% yield). MS for C 8 H 9 NO 3 : m / z 168 (MH+).Example 5: 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide (1)

[0365]

[0366] 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide (1): A mixture of Compound G1-2 (49 mg, 0.095 mmol), DMF (0.70 mL), K 2 CO 3 (50 mg, 0.36 mmol) and iodomethane (100 mg, 0.70 mmol) was stirred at ambient temperature. After 6 h, the reaction was diluted with water (5 mL). The resulting precipitate was collected and purified over silica (24 g, 0% to 10% MeOH in DCM) to give Compound 1 as a white solid (24 mg, 48% yield). 1< H NMR (400 MHz, CDCl 3 ) δ 12.84 (s, 1H), 8.47 - 8.39 (m, 2H), 7.89 (dd, 1H), 7.49 (s, 1H), 7.31 (ddd, 1H), 7.09 (t, 1H), 6.67 (dd, 1H), 5.61 - 5.55 (p, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.72 (s, 3H), 2.51 (t, 4H), 2.31 (s, 3H), 2.01 (m, 2H); MS for C 29 H 27 FN 4 O 5 : m / z 531.1 (MH+).

[0367] The following compounds were synthesized using similar alkylation methods to that exemplified in Example 5 in the conversion of Compound G1-2 to Compound 1:

[0368] 5-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide (8): Compound G1-2 was replaced with Compound G1-4, iodomethane was replaced by 1-fluoro-2-iodo-ethane. 1< H NMR (400 MHz, CD 3 OD) δ 8.67 (d, 1H), 8.49 (dd, 1H), 7.99 (ddd, 1H), 7.55 - 7.49 (m, 1H), 7.42 - 7.35 (m, 1H), 7.29 (td, 1H), 6.84 (dd, 1H), 5.60 (dq, 1H), 4.88 (t, 1H), 4.76 (t, 1H), 4.60 (t, 1H), 4.54 (t, 1H), 4.08 - 4.04 (m, 3H), 4.03 (d, 3H), 2.51 - 2.46 (m, 3H), 2.42 - 2.34 (m, 1H), 2.25 - 2.21 (m, 2H), 1.99 - 1.63 (m, 5H); MS for C 31 H 30 F 2 N 4 O 5 : m / z 577.1 (MH+).

[0369] 5-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide (11): Iodomethane was replaced by 1-fluoro-2-iodo-ethane. MS for C 30 H 28 F 2 N 4 O 5 : m / z 563.2 (MH+).Example 6: 5-Cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide (2)

[0370]

[0371] 5-Cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide (2). A mixture of Compound 1 (17 mg, 0.032 mmol), MeOH (0.5 mL) ammonium formate (100 mg, 1.59 mmol) and palladium hydroxide (10 mg, 0.071 mmol) was heated to reflux in a sealed 2-dram vial fit with a pressure release cap. After 4 h, the mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated to dryness to give Compound 2 as a colorless solid (11.3 mg, 66% yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.06 (s, 1H), 8.52 (d, 1H), 8.49 (s, 1H), 7.96 (dd, 1H), 7.51 (s, 1H), 7.42 (dt, 1H), 7.18 (t, 1H), 6.73 (d, 1H), 4.13 (s, 3H), 4.03 (s, 3H), 3.77 (s, 3H), 3.49 (t, 1H), 2.44 (s, 3H), 2.03 - 1.89 (m, 4H), 1.85 - 1.77 (m, 2H), 1.70 (s, 2H); MS for C 20 H 20 FN 4 O 5 : m / z 533.2 (MH+).Example 7: N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide (3)

[0372]

[0373] N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy] phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide (3): Compound 3 was made from Compound E1-8 and Compound A1-12 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.51 (s, 1H), 11.81 (s, 1H), 8.76 (d, 1H), 8.71 (d, 1H), 8.04 (dd, 1H), 7.81 (d, 1H), 7.43 (dd, 1H), 7.40 (d, 1H), 6.74 (dd, 1H), 5.27 - 5.21 (m, 1H), 4.79 (d, 1H), 4.01 (s, 3H), 2.71 (s, 3H), 2.28 (s, 3H), 1.94 (s, 3H). MS for C 26 H 23 FN 4 O 4 : m / z 475 (MH+).

[0374] The following compounds were made using General Procedure G1 in the same manner that Compound 3 was made from Compound A1-12 and Compound E1-8 in Example 7:

[0375] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide (4): Compound 4 was made from Compound E1-8 and Compound A1-11 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.25 (s, 1H), 11.74 (s, 1H), 8.53 (d, 1H), 7.80 - 7.72 (m, 2H), 7.64 (s, 1H), 7.21 - 7.12 (m, 2H), 6.77 (d, 1H), 5.26 - 5.20 (m, 1H), 4.78 (t, 1H), 3.96 (d, 6H), 2.70 (s, 3H), 2.27 (s, 3H), 1.94 (s, 3H). MS for C 27 H 26 N 4 O 5 : m / z 487 (MH+).

[0376] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide (5): Compound 5 was made from Compound E1-8 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.43 (s, 1H), 11.73 (s, 1H), 8.47 (d, 1H), 7.93 (dd, 1H), 7.58 (s, 1H), 7.31 (dd, 1H), 7.24 (t, 1H), 6.72 (d, 1H), 5.19 - 5.13 (m, 1H), 4.71 (d, 1H), 3.90 (d, 6H), 2.63 (s, 3H), 2.20 (s, 3H), 1.86 (s, 3H). MS for C 27 H 25 FN 4 O 5 : m / z 505 (MH+).

[0377] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide (6): Compound 6 was made from Compound E1-8 and Compound A1-15 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 14.18 (s, 1H), 11.91 (s, 1H), 8.60 - 8.51 (m, 2H), 7.67 (s, 1H), 7.52 (dd, 1H), 6.92 (d, 1H), 5.25 (s, 1H), 4.79 (s, 1H), 3.96 (d, 6H), 2.77 (s, 3H), 2.29 (s, 3H), 1.93 (s, 3H). MS for C 27 H 24 F 2 N 4 O 5 : m / z 523 (MH+).

[0378] 1-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide (14): Compound 14 was made from Compound 12-3 and Compound A1-10 using General Procedure G1. MS for C 29 H 27 FN 4 O 5 m / z 531.1 (MH+).

[0379] 1- 1-Cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide (15): Compound 15 was made from Compound F2-2 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 8.46 (d, 1H), 7.87 (dd, 1H), 7.58 (s, 1H), 7.39 (ddd, 1H), 7.27 (t, 1H), 6.71 (dd, 1H), 6.09 (s, 1H), 4.65 (p, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.38 (s, 3H), 2.18 (s, 2H), 2.13 (s, 3H), 1.92 - 1.82 (m, 2H), 1.79 - 1.72 (m, 2H), 1.54 - 1.45 (m, 2H). MS for C 29 H 29 FN 4 O 5 : m / z 533.2 (MH+).

[0380] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide (20): Compound 20 was made from Compound 12-4 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 8.53 (d, 1H), 7.95 (dd, 1H), 7.65 (s, 1H), 7.46 (ddd, 1H), 7.34 (dd, 1H), 6.79 (dd, 1H), 6.28 (s, 1H), 5.47 (d, 1H), 5.04 (s, 1H), 3.99 - 3.95 (m, 6H), 2.30 (s, 3H), 2.30 (s, 3H), 2.02 (s, 3H). MS for C 27 H 25 FN 4 O 5 : m / z 505.1 (MH+).

[0381] N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide (21): Compound 21 was made from Compound 12-4 and Compound A1-12 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.76 (d, 1H), 8.71 (d, 1H), 7.99 (dd, 1H), 7.81 (d, 1H), 7.51 (ddd, 1H), 7.41 (dd, 1H), 6.76 (dd, 1H), 6.29 (s, 1H), 5.48 (d, 1H), 5.05 (s, 1H), 4.01 (s, 3H), 2.31 (s, 3H), 2.31 (s, 3H), 2.04 (s, 3H). MS for C 26 H 23 FN 4 O 4 : m / z 475.1 (MH+).

[0382] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide (31): Compound 31 was made from Compound F2-1 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.58 (s, 1H), 11.47 - 11.43 (m, 1H), 8.47 (d, 1H), 7.93 (dd, 1H), 7.58 (s, 1H), 7.30 (dd, 1H), 7.23 (t, 1H), 6.73 (d, 1H), 3.90 (d, 6H), 3.12 - 3.04 (m, 1H), 2.59 (s, 3H), 2.27 (s, 3H), 1.21 (d, 6H). MS for C 27 H 27 FN 4 O 5 : m / z 507 (MH+).

[0383] N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide (32): Compound 32 was made from Compound F2-1 and Compound A1-12 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.60 (s, 1H), 11.45 (s, 1H), 8.68 (d, 1H), 8.64 (d, 1H), 7.96 (dd, 1H), 7.73 (d, 1H), 7.35 (dd, 1H), 7.32 (d, 1H), 6.67 (dd, 1H), 3.94 (s, 3H), 3.08 (p, 1H), 2.60 (s, 3H), 2.28 (s, 3H), 1.22 (d, 6H). MS for C 26 H 25 FN 4 O 4 : m / z 477 (MH+).

[0384] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide (38): Compound 38 was made from Compound 12-5 and Compound A1-10 using General Procedure G1, purified by preparative HPLC and recovered as the partial formic acid salt. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 8.62 (d, 1H), 8.04 (dd, 1H), 7.88 (d, 1H), 7.74 (s, 1H), 7.57 (ddd, 1H), 7.44 (t, 1H), 6.88 (dd, 1H), 6.40 (d, 1H), 5.18 (hept, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 2.33 (s, 3H), 1.41 (d, 6H). MS for C 26 H 25 FN 4 O 5 : m / z 493.1 (MH+).

[0385] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide (39): Compound 39 was made from Compound 12-5 and Compound A1-11 using General Procedure G1, purified by preparative HPLC and recovered as the partial formic acid salt. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 8.45 (d, 1H), 7.77 - 7.67 (m, 3H), 7.57 (s, 1H), 7.16 - 7.08 (m, 2H), 6.68 (d, 1H), 6.23 (d, 1H), 5.01 (h, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 2.17 (s, 3H), 1.25 (d, 6H); MS for C 26 H 26 N 4 O 5 : m / z 475.1 (MH+).

[0386] 5-Cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (46): Compound 46 was made from Compound 14-1 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 8.53 (d, 1H), 7.96 (dd, 1H), 7.66 (s, 1H), 7.49 - 7.42 (m, 1H), 7.34 (t, 1H), 6.78 (dd, 1H), 3.98 (d, 6H), 3.57 (s, 3H), 2.54 (s, 6H), 1.49 - 1.37 (m, 1H), 0.95 - 0.85 (m, 2H), 0.55 - 0.47 (m, 2H). MS for C 28 H 27 FN 4 O 5 : m / z 519 (MH+).

[0387] 5-Cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (47): Compound 47 was made from Compound 14-1 and Compound A1-15 using General Procedure G1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.80 (s, 1H), 8.57 (d, 1H), 8.48 (dd, 1H), 7.67 (s, 1H), 7.52 (dd, 1H), 6.93 (d, 1H), 3.96 (d, 6H), 3.64 (s, 3H), 2.81 (s, 3H), 2.58 (s, 3H), 1.55 - 1.45 (m, 1H), 1.01 - 0.91 (m, 2H), 0.51 - 0.42 (m, 2H). MS for C 28 H 26 F 2 N 4 O 5 : m / z 537 (MH+).

[0388] 5-Cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (48): Compound 48 was made from Compound 14-1 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.37 (s, 1H), 8.52 (d, 1H), 7.79 (d, 2H), 7.65 (s, 1H), 7.18 (d, 2H), 6.75 (d, 1H), 3.98 (d, 6H), 3.57 (s, 3H), 2.54 (s, 6H), 1.43 (s, 1H), 0.94 - 0.85 (m, 2H), 0.55 - 0.46 (m, 2H); MS for C 28 H 28 N 4 O 5 : m / z 501 (MH+).

[0389] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide (52): Compound 52 was made from Compound E1-9 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.46 (d, 1H), 7.89 (dd, 1H), 7.58 (s, 1H), 7.38 (d, 1H), 7.27 (t, 1H), 6.71 (d, 1H), 5.14 (t, 1H), 4.64 (d, 1H), 3.91 (d, 6H), 3.52 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 1.83 (s, 3H); MS for C 28 H 27 FN 4 O 5 : m / z 519 (MH+).

[0390] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide (55): Compound 55 was made from Compound E1-9 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.27 (s, 1H), 8.52 (d, 1H), 7.83 - 7.75 (m, 2H), 7.64 (s, 1H), 7.23 - 7.14 (m, 2H), 6.75 (d, 1H), 5.21 (dd, 1H), 4.71 (dd, 1H), 3.98 (d, 6H), 3.59 (s, 3H), 2.52 (s, 3H), 2.38 (s, 3H), 1.91 (s, 3H); MS for C 28 H 28 N 4 O 5 : m / z 501 (MH+).

[0391] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide (56): Compound 56 was made from Compound F2-3 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 8.53 (d, 1H), 7.97 (dd, 1H), 7.66 (s, 1H), 7.47 (ddd, 1H), 7.34 (t, 1H), 6.78 (dd, 1H), 3.98 (d, 6H), 3.57 (s, 3H), 3.40 (d, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 1.26 (d, 6H); MS for C 28 H 29 FN 4 O 5 : m / z 521 (MH+).

[0392] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide (57): Compound 57 was made from Compound F2-3 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 8.52 (d, 1H), 7.80 (d, 2H), 7.65 (s, 1H), 7.18 (d, 2H), 6.75 (d, 1H), 3.98 (d, 6H), 3.56 (s, 3H), 3.40 (m, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 1.26 (d, 6H); MS for C 28 H 30 N 4 O 5 : m / z 503 (MH+).

[0393] 4-Hydroxy-5-methoxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide (59): Compound 59 was made from Compound 16-1 and Compound A1-13 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.08 (s, 1H), 11.73 (s, 1H), 8.69 - 8.60 (m, 2H), 7.77 - 7.68 (m, 3H), 7.20 - 7.11 (m, 2H), 6.66 (d, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.60 (s, 3H), 2.21 (s, 3H); MS for C 24 H 22 N 4 O 5 : m / z 447 (MH+).

[0394] N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (60): Compound 60 was made from Compound 16-1 and Compound A1-12 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.31 (s, 1H), 11.79 (s, 1H), 8.68 (d, 1H), 8.64 (d, 1H), 7.96 (dd, 1H), 7.73 (d, 1H), 7.39 - 7.28 (m, 2H), 6.67 (dd, 1H), 3.94 (s, 3H), 3.70 (s, 3H), 2.60 (s, 3H), 2.21 (s, 3H); MS for C 24 H 21 FN 4 O 5 : m / z 465 (MH+).

[0395] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (61): Compound 61 was made from Compound 16-1 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.06 (s, 1H), 11.73 (s, 1H), 8.46 (d, 1H), 7.73 - 7.65 (m, 2H), 7.57 (s, 1H), 7.14 - 7.07 (m, 2H), 6.71 (d, 1H), 3.89 (d, 6H), 3.69 (s, 3H), 2.60 (s, 3H), 2.20 (s, 3H); MS for C 25 H 24 N 4 O 6 : m / z 477 (MH+).

[0396] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (62): Compound 62 was made from Compound 16-1 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.25 (s, 1H), 11.78 (s, 1H), 8.47 (d, 1H), 7.93 (dd, 1H), 7.58 (s, 1H), 7.35 - 7.29 (m, 1H), 7.25 (t, 1H), 6.73 (dd, 1H), 3.90 (d, 6H), 3.69 (s, 3H), 2.60 (s, 3H), 2.21 (s, 3H); MS for C 25 H 23 FN 4 O 6 : m / z 495 (MH+).

[0397] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (68): Compound 68 was made from Compound 16-1 and Compound A1-15 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.97 (s, 1H), 11.92 (s, 1H), 8.53 - 8.43 (m, 2H), 7.60 (s, 1H), 7.45 (dd, 1H), 6.85 (d, 1H), 3.89 (d, 6H), 3.69 (s, 3H), 2.67 (s, 3H), 2.23 (s, 3H); MS for C 25 H 22 F 2 N 4 O 6 : m / z 513 (MH+).

[0398] 7-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (69): Compound 69 was made from Compound F1-4 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, CDCl 3 ) δ 13.55 (s, 1H), 8.51 (d, 1H), 7.89 (dd, 1H), 7.52 (s, 1H), 7.36 (d, 1H), 7.15 (t, 1H), 6.72 (d, 1H), 5.67 (s, 1H), 5.52 (s, 2H), 4.17 - 4.06 (m, 5H), 4.03 (s, 5H), 2.60 (t, 4H), 2.43 (s, 3H), 2.11 - 2.01 (m, 2H); MS for C 31 H 20 FN 4 O 6 : m / z 573.3 (MH+).

[0399] N-[3-Fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (70): Compound 70 was made from Compound 16-1 and Compound A2-7 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.34 (s, 1H), 11.87 (s, 1H), 8.54 (d, 1H), 8.01 (dd, 1H), 7.68 (s, 1H), 7.42 - 7.29 (m, 2H), 6.80 (dd, 1H), 4.36 - 4.29 (m, 2H), 3.98 (s, 3H), 3.79 - 3.72 (m, 5H), 2.67 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H); MS for C 27 H 27 FN 4 O 7 : m / z 539 (MH+).

[0400] 4-Hydroxy-5-methoxy-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide (71): Compound 71 was made from Compound 16-1 and Compound A2-8 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 11.81 (s, 1H), 8.53 (d, 1H), 7.81 - 7.73 (m, 2H), 7.67 (s, 1H), 7.22 - 7.14 (m, 2H), 6.77 (d, 1H), 4.35 - 4.28 (m, 2H), 3.97 (s, 3H), 3.76 (s, 3H),3.80 - 3.60 (m, 2H), 2.67 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H); MS for C 27 H 28 N 4 O 7 : m / z 521 (MH+).

[0401] N-[3-Fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide (72): Compound 72 was made from Compound 16-1 and Compound C1-9 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.28 (s, 1H), 11.78 (s, 1H), 8.53 (s, 1H), 7.93 - 7.85 (m, 1H), 7.62 (s, 1H), 7.39 - 7.28 (m, 2H), 4.35 - 4.28 (m, 2H), 4.03 (s, 3H), 3.70 (s, 5H), 3.28 (s, 3H), 2.60 (s, 3H), 2.21 (s, 3H); MS for C 26 H 26 FN 5 O 7 : m / z 540 (MH+).

[0402] 7-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (73): Compound 73 was made from Compound E1-12 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, CDCl 3 ) δ 13.24 (s, 1H), 8.50 (d, 1H), 7.76 (d, 2H), 7.52 (s, 1H), 7.13 (d, 2H), 6.74 (d, 1H), 5.71 - 5.48 (m, 3H), 4.42 - 4.20 (m, 2H), 4.17 - 4.12 (m, 3H), 4.10 (d, 2H), 4.08 - 3.95 (m, 7H), 2.48 (s, 3H), 2.01 (s, 2H); MS for C 31 H 30 N 4 O 7 : m / z 571.3 (MH+).

[0403] N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (75): Compound 75 was made from Compound 17-1 and Compound A1-12 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.24 (s, 1H), 8.69 (d, 1H), 8.63 (d, 1H), 7.92 (dd, 1H), 7.74 (d, 1H), 7.43 (dd, 1H), 7.35 (t, 1H), 6.68 (dd, 1H), 3.94 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H); MS for C 25 H 23 FN 4 O 5 : m / z 479 (MH+).

[0404] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (76): Compound 76 was made from Compound 17-1 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 8.45 (d, 1H), 7.77 - 7.68 (m, 2H), 7.57 (s, 1H), 7.16 - 7.08 (m, 2H), 6.67 (d, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.66 (s, 3H), 3.51 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H); MS for C 26 H 26 N 4 O 6 : m / z 491 (MH+).

[0405] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (77): Compound 77 was made from Compound 17-1 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.22 (s, 1H), 8.46 (d, 1H), 7.89 (dd, 1H), 7.59 (s, 1H), 7.39 (dd, 1H), 7.28 (t, 1H), 6.71 (d, 1H), 3.91 (d, 6H), 3.66 (s, 3H), 3.51 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H); MS for C 26 H 25 FN 4 O 6 : m / z 509 (MH+).

[0406] 5-Cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (78): Compound 78 was made from Compound 18-1 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.46 (d, 1H), 7.86 (dd, 1H), 7.59 (s, 1H), 7.39 (dd, 1H), 7.30 (t, 1H), 6.72 (d, 1H), 3.91 (d, 6H), 3.56 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H); MS for C 26 H 22 FN 5 O 5 : m / < z 504 (MH+).

[0407] 7-(3,6-Dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (79): Compound 79 was made from Compound E1-12 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, CDCl 3 ) δ 13.46 (s, 1H), 8.51 (d, 1H), 7.90 (dd, 1H), 7.60 - 7.52 (m, 1H), 7.42 - 7.33 (m, 1H), 7.17 (t, 1H), 6.74 (d, 1H), 5.66 (s, 1H), 5.54 (s, 2H), 4.40 - 4.32 (m, 2H), 4.14 (s, 3H), 4.11 (d, 2H), 4.07 - 3.99 (m, 7H), 2.53 - 2.18 (m, 5H); MS for C 31 H 29 FN 4 O 7 : m / z 589.3 (MH+).

[0408] 7-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (80): Compound 80 was made from Compound F1-5 and Compound A1-10 using General Procedure G1. 1< H NMR (400 MHz, CDCl 3 ) δ 13.57 (s, 1H), 8.51 (d, 1H), 7.90 (dd, 1H), 7.54 (s, 1H), 7.41 - 7.36 (m, 1H), 7.16 (t, 1H), 6.73 (d, 1H), 5.60 (s, 1H), 5.53 (d, 2H), 4.15 - 4.02 (m, 10H), 2.45 (s, 3H), 2.34 - 2.13 (m, 2H), 1.90 - 1.78 (m, 3H), 1.64 - 1.54 (m, 3H); MS for C 32 H 31 FN 4 O 6 : m / z 587.3 (MH+).

[0409] 5-Cyano-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (81): Compound 81 was made from Compound 18-1 and Compound A1-12 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 8.70 (dd, 1H), 8.65 (dd, 1H), 7.89 (dd, 1H), 7.74 (d, 1H), 7.43 (dd, 1H), 7.37 (t, 1H), 6.76 - 6.70 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H); MS for C 25 H 20 FN 5 O 4 : m / z 474 (MH+).

[0410] 5-Cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (82): Compound 82 was made from Compound 18-1 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.45 (d, 1H), 7.75 - 7.67 (m, 2H), 7.58 (s, 1H), 7.18 - 7.10 (m, 2H), 6.69 (d, 1H), 3.90 (d, 6H), 3.55 (s, 3H), 2.58 (s, 3H), 2.35 (s, 3H); MS for C 26 H 23 N 5 O 5 : m / z 486 (MH+).

[0411] 5-Cyano-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (83): Compound 83 was made from Compound 18-1 and Compound A2-10 using General Procedure G1 . MS for C 28 H 25 F 2 N 5 O 6 : m / z 566 (MH+).

[0412] 3-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide (84): Compound 84 was made from Compound 19-2 and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 11.83 (s, 1H), 8.58 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.59 (s, 1H), 7.39 - 7.31 (m, 1H), 7.27 (t, 2H), 6.72 (dd, 1H), 3.90 (d, 6H), 2.48 (s, 3H), 2.42 (s, 3H); MS for C 25 H 22 FN 5 O 6 : m / z 508 (MH+).

[0413] 3-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide (85): Compound 85 was made from Compound 19-2 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 11.78 (s, 1H), 8.65 (s, 1H), 8.46 (d, 1H), 7.74 - 7.66 (m, 2H), 7.57 (s, 1H), 7.28 (s, 1H), 7.16 - 7.07 (m, 2H), 6.69 (d, 1H), 3.90 (d, 6H), 2.48 (s, 3H), 2.42 (s, 3H); MS for C 25 H 23 N 5 O 6 : m / z 490 (MH+).

[0414] 3-N-[2,5-Difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide (86): Compound 86 was made from Compound 19-2 and Compound A2-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.64 (s, 1H), 11.98 (s, 1H), 8.52 - 8.41 (m, 2H), 8.02 (s, 1H), 7.62 (s, 1H), 7.47 (dd, 1H), 7.38 (s, 1H), 6.85 (d, 1H), 4.25 (dd, 2H), 3.87 (s, 3H), 3.71 - 3.65 (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); MS for C 27 H 25 F 2 N 5 O 7 : m / z 570 (MH+).

[0415] 5-Cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide (87): Compound 87 was made from 5-cyano-4-hydroxy-2,6-dimethylnicotinic acid (made from the ester hydrolysis of Compound 19-1) and Compound A1-10 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.47 (s, 1H), 8.46 (d, 1H), 7.90 (dd, 1H), 7.59 (s, 1H), 7.30 (dt, 2H), 6.72 (dd, 1H), 6.48 (s, 1H), 3.90 (s, 6H), 2.47 (s, 3H), 2.39 (s, 3H); MS for C 25 H 20 FN 5 O 5 : m / z 490.1 (MH+).

[0416] 3-N-[3-Fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide (91): Compound 91 was made from Compound 19-2 and Compound A1-12 using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 11.84 (s, 1H), 8.78 - 8.68 (m, 2H), 8.56 (s, 1H), 7.96 (dd, 1H), 7.74 (d, 1H), 7.45 - 7.34 (m, 2H), 7.32 (s, 1H), 6.79 (q, 1H), 3.96 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H); MS for C 24 H 20 FN 5 O 5 : m / z 478 (MH+).

[0417] 7-(Cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (99): Compound 99 was made from Compound F1-4 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, CDCl 3 ) δ 13.37 (s, 1H), 8.49 (d, 1H), 7.77 (d, 2H), 7.57 (s, 1H), 7.13 (d, 2H), 6.75 (d, 1H), 5.67 (s, 1H), 5.54 (s, 2H), 4.18 - 4.00 (m, 10H), 2.60 (t, 4H), 2.43 (s, 3H), 2.10 (s, 2H); MS for C 31 H 30 N 4 O 6 : m / z 555.3 (MH+).

[0418] 7-(Cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide (100): Compound 100 was made from Compound F1-5 and Compound A1-11 using General Procedure G1 . 1< H NMR (400 MHz, CDCl 3 ) δ 13.36 (s, 1H), 8.50 (d, 1H), 7.76 (d, 2H), 7.51 (s, 1H), 7.13 (d, 2H), 6.74 (d, 1H), 5.60 (br s, 1H), 5.46-5.57 (m, 2H), 4.14 (s, 3H), 4.10 (br d, 2H), 4.03 (s, 5H), 2.44 (s, 3H), 2.07-2.36 (m, 2H), 1.72-1.89 (m, 4H), 1.61-1.71 (m, 2H); MS for C 32 H 32 N 4 O 6 : m / z 569.4 (MH+).Example 8: 8-(4-Amino-2-fluorophenoxy)-2-methoxy-1,5-naphthyridin-3-ol (8-7)

[0419]

[0420] 8-(4-Amino-2-fluorophenoxy)-2-methoxy-1,5-naphthyridin-3-ol (8-7): Compound 8-7 was made in 7 steps from 5-bromo-2-chloropyridin-3-ol following the procedure used in Bannen, L., et. al. WO2021062245. MS for C 15 H 12 FN 3 O 3 , found 302 (MH+).Example 9: 5-Bromo-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (9-3)

[0421]

[0422] 5-Bromo-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (9-3): Compound 9-3 was made in 3 steps from methyl 3-(methylamino)but-2-enoate and 2,2,6-trimethyl-4H-1,3-dioxin-4-one following the procedure used in Bannen, L., et. al. WO2021173591. MS for C 9 H 10 BrNO 3 : m / z 260 / 262 (MH+).Example 10: N-[4-[[7-(2-Cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl]oxy]-3-fluorophenyl]-5-(cyclopenten-1-yl)-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (74)

[0423]

[0424] Step 1: 5-Bromo-N-(3-fluoro-4-((7-hydroxy-6-methoxy-1,5-naphthyridin-4-yl)oxy)phenyl)-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (10-1): Compound 10-1 was synthesized from Compound 8-7 and Compound 9-3 using General Procedure G1. MS for C 24 H 20 BrFN 4 O 5 : m / z 543 (MH+).

[0425] Step 2: 5-Bromo-N-(4-((7-(2-cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxamide (10-2): A mixture of Compound 10-1 (54 mg, 0.1 mmol, 1 eq), triphenylphosphine (78 mg, 0.30 mmol, 3.0 eq) and 2-cyclobutylethanol (11 mg, 0.11 mmol, 1.1eq) in THF (0.5 mL, 0.2M) was cooled to 0 °C in an ice bath followed by the addition of DIAD (61 mg, 0.3 mmol, 3.0 eq). The resulting mixture was allowed to warm to room temperature overnight with stirring. The reaction mixture was then concentrated under reduced pressure. EtOAc was added to the resulting residue and the solution with washed with water, dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography over silica gel (DCM / MeOH) to give Compound 10-2 as an oil (40 mg, 64% yield). 1< H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.58 (d, 1H), 7.96 (dd, 1H), 7.55 - 7.43 (m, 2H), 7.40 (t, 1H), 6.86 (d, 1H), 4.14 (t, 2H), 4.01 (s, 3H), 3.67 (s, 3H), 2.70 (s, 3H), 2.46 (m, 1H), 2.42 (s, 3H), 2.08 (dt, 2H), 1.93 (q, 2H), 1.89 - 1.78 (m, 2H), 1.78 - 1.61 (m, 2H); MS for C 30 H 30 BrFN 4 O 5 : m / z 627 (MH+).

[0426] Step 3: N-[4-[[7-(2-Cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl]oxy]-3-fluorophenyl]-5-(cyclopenten-1-yl)-1,2,6-trimethyl-4-oxopyridine-3-carboxamide (74): Compound 74 was made from Compound 10-2 and cyclopent-1-en-1-ylboronic acid using General Procedure E1. 1< H NMR (400MHz, DMSO-d 6 ) δ 11.44 (s, 1H), 8.45 (d, 1H), 8.31 (s, 1H), 7.55 (s, 1H), 7.39 (ddd, 1H), 7.26 (t, 1H), 6.69 (dd, 1H), 5.44 - 5.36 (m, 1H), 4.04 (t, 2H), 3.90 (s, 3H), 3.52 (s, 3H), 2.44 (s, 3H), 2.41 - 2.36 (m, 4H), 2.29 (s, 3H), 2.00 (dddd, 2H), 1.91 - 1.80 (m, 5H), 1.80 - 1.70 (m, 2H), 1.70 - 1.52 (m, 2H); MS for C 35 H 37 FN 4 O 5 : m / z 613 (MH+).Example 11: N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide (9)

[0427]

[0428] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide (9): Compound 9 was prepared from Compound 4 using standard hydrogenation techniques (hydrogen gas, 1 atm, Pd / C, MeOH) followed by purification by flash chromatography on silica gel. 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.35 (s, 1H), 11.45 (s, 1H), 8.46 (d, 1H), 7.73 - 7.65 (m, 2H), 7.57 (s, 1H), 7.14 - 7.05 (m, 2H), 6.70 (d, 1H), 3.90 (d, 6H), 3.09 - 3.01 (m, 1H), 2.59 (s, 3H), 2.27 (s, 3H), 1.21 (d, 6H). MS for C 27 H 28 N 4 O 5 : m / z 489 (MH+).

[0429] The following compounds were made using the same method used to convert Compound 4 to Compound 9 in Example 11:

[0430] N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide (10): Compound 4 was replaced with Compound 6 and the resulting product was purified by preparative HPLC. 1< H NMR (400 MHz, DMSO-d 6 ) δ 14.36 (s, 1H), 11.6 (s, 1H), 8.54 - 8.41 (m, 2H), 7.60 (s, 1H), 7.43 (dd, 1H), 6.84 (d, 1H), 3.91 (s 3H), 3.87 (s, 3H), 3.13 - 3.05 (m, 1H), 2.65 (s, 3H), 2.28 (s, 3H), 1.21 (d, 6H). MS for C 27 H 26 F 2 N 4 O 5 : m / z 525 (MH+).

[0431] 5-Cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide (13): Compound 4 was replaced with Compound 11. MS for C 30 H 30 F 2 N 4 O 5 : m / z 565.2 (MH+).Example 12: 1-(Cyclopent-1-en-1-yl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (12-3)

[0432]

[0433] Step 1: Ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (12-1): (Z)-4-aminopent-3-en-2-one (5.0 g, 50 mmol, 1 eq) and ethyl 2-cyanoacetate (5.8 g, 51 mmol, 1.02 eq) were added to a stirring solution of THF (56 mL) and TEA (2.0 g, 20 mmol, 0.4 eq). After heating for 48 h, the reaction was cooled to ambient temperature and allowed to sit for 4 days. The resulting mixture was filtered, and the solids were washed with EtOAc to give Compound 12-1 (2.98 g, 30% yield). MS for C 10 H 13 NO 3 : m / z 196 (MH+).

[0434] Step 2: Ethyl 1-(cyclopent-1-en-1-yl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (12-2): Compound 12-1 (500 mg, 2.5612 mmol), cupric acetate (700 mg, 3.5061 mmol), cyclopentylboronic acid (600 mg, 5.2655 mmol), 1,2-dichloroethane (3.0 mL) and pyridine (1.0 mL) were heated to 45 °C under an atmosphere of oxygen (1 atm). After overnight reaction, the contents were cooled, diluted with EtOAc and filtered through a short plug of silica gel. The crude product was concentrated onto Celite and purified over silica (220 g, 0% to 2% MeOH in DCM) to give Compound 12-2 as a tan solid (227 mg, 0.87 mmol, 34% yield). 1< H NMR (400 MHz, CDCl 3 ) δ 5.94 (s, 1H), 5.71 (t, 1H), 4.37 (q, 2H), 2.55 (ddd, 2H), 2.20 (d, 3H), 2.20 (s, 3H), 2.10 (s, 2H), 2.06 - 1.92 (m, 2H), 1.36 (t, 3H); MS for C 15 H 19 NO 3 : m / z 262.1 (MH+).

[0435] Step 3: 1-(Cyclopent-1-en-1-yl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (12-3): Compound 12-3 was synthesized from Compound 12-2 using standard ester hydrolysis conditions such as that employed in General Procedure F1 to convert Compound E1-3 to Compound F1-1. MS for C 13 H 15 NO 3 : m / z 234 (MH+).

[0436] The following compounds were made using the same three step procedure to make Compound 12-3 in Example 12:

[0437] 1-Isopropenyl-4,6-dimethyl-2-oxo-pyridine-3-carboxylic acid (12-4): Cyclopentylboronic acid was replaced with isopropenylboronic acid. MS for C 11 H 13 NO 3 : m / z 208 (MH+).

[0438] 1-isopropyl-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (12-5): Cyclopentylboronic acid was replaced with isopropylboronic acid. MS, for the corresponding methyl ester, C 11 H 13 NO 3 : m / z 208 (MH+).Example 13: 5-Bromo-1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide (22)

[0439]

[0440] 5-Bromo-1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide (22): To a stirring solution of Compound 15 (105 mg, 0.20 mmol) and ACN (2 mL) was added 1-bromopyrrolidine-2,5-dione (90 mg, 0.50 mmol). The resulting solution was stirred for 1 h at ambient temperature then diluted with 10 mL DCM and an equal volume of dilute aq NaOH. The aqueous layer was washed with an additional amount of DCM, and the combined organic layers were washed with conc aq Na 2 S 2 O 3 , then water. The organic phase was concentrated and purified by prep HPLC (10% to 100% ACN in water (+0.1% FA) to give the formic acid salt of Compound 22 as a colorless solid (26.3 mg, 21% yield). 1< H NMR (400MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 8.45 (d, 1H), 7.83 (dd, 1H), 7.59 (s, 1H), 7.38 (dt, 1H), 7.30 (t, 1H), 6.71 (dd, 1H), 4.86 - 4.78 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.65 (s, 3H), 2.16 (s, 3H), 2.14 - 2.05 (m, 2H), 1.90 - 1.72 (m, 4H), 1.54 - 1.42 (m, 2H). MS for C 29 H 28 BrFN 4 O 5 : m / z 611.1 (MH+).Example 14: 5-Cyclopropyl-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (14-1)

[0441]

[0442] 5-Cyclopropyl-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (14-1): Compound 14-1 was synthesized using General Procedure E-1, followed by ester hydrolysis via standard hydrolysis conditions using NaOH. Specifically, in this case, Compound 9-2 (500 mg, 2.0 mmol), cyclopropylboronic acid (750 mg, 8.7 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline-dichloropalladium (144 mg, 0.2 mmol) and NaOH (300 mg, 7.5 mmol) were combined in dioxane (6 mL) and the resulting mixture was stirred under nitrogen at 100 °C overnight, after which was added more NaOH (400 mg), MeOH (6 mL), and water (5 mL). The resulting mixture was stirred at 90 °C overnight, concentrated to remove organic solvent, and washed with EtOAc (2x). The aqueous phase was filtered to remove solid, acidified with aq 6 M HCl to pH 3, and extracted with EtOAc (2x). The combined EtOAc extracts were concentrated to dryness and the resulting residue was purified by silica gel chromatography (0-5% MeOH in EtOAc), to give Compound 14-1 as a white solid (100 mg, 23% yield). MS for C 12 H 15 NO 3 : m / z 222 (MH+).Example 15: 5-Bromo-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-6-ethyl-1-methyl-4-oxopyridine-3-carboxamide (63)

[0443]

[0444] Step 1: 5-Bromo-6-ethyl-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (15-1): Compound 15-1 was made from Compound D1-8 in two steps. In the first step, Compound D1-8 was alkylated using the same type of procedure used in Example 5 to form methyl 5-bromo-6-ethyl-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (MS for C 10 H 12 BrNO 3 : m / z 275.9 (MH+). In the second step, the methyl ester of methyl 5-bromo-6-ethyl-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate was hydrolyzed using standard NaOH hydrolysis methods to form Compound 15-1. MS for C 9 H 10 BrNO 3 : m / z 260 (MH+).

[0445] Step 2: 5-Bromo-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-6-ethyl-1-methyl-4-oxopyridine-3-carboxamide (63): Compound 63 was synthesized from Compound 15-1 and Compound A1-15 using General Procedure G1 . 1< H NMR (400MHz, DMSO-d 6 ) δ 13.10 (d, 1H), 8.78 (s, 1H), 8.60 - 8.48 (m, 2H), 7.67 (s, 1H), 7.66 - 7.55 (m, 1H), 6.96 (d, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.94 (s, 3H), 3.02 (q, 2H), 1.26 - 1.16 (m, 3H); MS for C 25 H 21 BrF 2 N 4 O 5 : m / z 577 (MH+).

[0446] The following compound was made using the same two step procedure to make Compound 63 in Example 15: 5-Bromo-6-ethyl-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-methyl-4-oxopyridine-3-carboxamide (64): Compound A1-15 was replaced with Compound A2-8 in Step 2. 1< H NMR (400MHz, DMSO-d 6 ) δ 12.65 (s, 1H), 8.74 (s, 1H), 8.54 (d, 1H), 7.85 - 7.76 (m, 2H), 7.67 (s, 1H), 7.27 - 7.19 (m, 2H), 6.80 (d, 1H), 4.35 - 4.28 (m, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.79 - 3.72 (m, 2H), 3.35 (s, 3H), 3.02 (q, 2H), 1.24 - 1.16 (m, 3H); MS for C 27 H 27 BrN 4 O 6 : m / z 585.1 (MH+).Example 16: 4-Hydroxy-5-methoxy-2,6-dimethylnicotinic acid (16-1)

[0447]

[0448] 4-Hydroxy-5-methoxy-2,6-dimethylnicotinic acid (16-1): To a solution of Compound D1-9 (1.3 g, 5 mmol) and copper(I) iodide (0.5 g, 2.6 mmol) in DMF (15 mL), were added NaOMe (2.5 g) and MeOH (4 mL). The reaction mixture was stirred at 105 °C for 100 min. After cooling, ice water (10 mL) was added, and the resulting mixture stirred at 90 °C until ester hydrolysis was complete. The mixture was concentrated to remove MeOH and filtered to remove solids. The aqueous filtrate was acidified to pH 3-4, and the resulting suspension was filtered, washed with water and dried to give crude Compound 16-1 (610 mg, 62%). MS for C 9 H 11 NO 4 : m / z 198 (MH+).Example 17: 5-Methoxy-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (17-1)

[0449]

[0450] 5-Methoxy-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (17-1): A mixture of Compound 9-2 (0.866 g, 3 mmol), copper(I) iodide (0.45 g, 2.4 mmol), NaOMe (1.6 g) and MeOH (15 mL) was stirred at 140 °C under microwave irradiation for 1 h, cooled to room temperature, and filtered through Celite. The filtrate was treated with 3 N NaOH at 80 °C until ester hydrolysis was complete, and the resulting mixture was washed with EtOAc (2x). The aqueous phase was acidified to pH 2-3; the resulting suspension was filtered, washed with water and dried to provide crude Compound 17-1 (88 mg). MS for C 10 H 13 NO 4 : m / z 212 (MH+).Example 18: 5-Cyano-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (18-1)

[0451]

[0452] 5-Cyano-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (18-1): A suspension of ethyl 5-bromo-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.5 g, 5.2 mmol) and CuCN (0.6 g, 7 mmol) in DMF (12 mL) was stirred at 170 °C under microwave irradiation for 2h. The resulting mixture was concentrated to dryness, the residue suspended in DCM / MeOH (4 / 1), the resulting suspension stirred for 20 min and then filtered through Celite; the filtrate was concentrated to dryness to give ethyl 5-cyano-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylate as a light brown solid (780 mg). MS: m / z 235 (MH+). This solid was treated with 2 N NaOH (8 mL) in MeOH (10 mL) at 80 °C overnight. The resulting mixture was concentrated to remove MeOH. The resulting aqueous solution was acidified with HCl (1 M) to pH 2-3; the resulting suspension was filtered, washed with water and dried to provide crude Compound 18-1 (300 mg). MS for C 10 H 10 N 2 O 3 : m / z 207 (MH+).

[0453] Note: Ethyl 5-bromo-1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3-carboxylate can be made using the same method as that used to make Compound 9-2 in Example 9, substituting ethyl 3-(methylamino)but-2-enoate for the methyl 3-(methylamino)but-2-enoate in Step 1.Example 19: 5-Carbamoyl-4-hydroxy-2,6-dimethylnicotinic acid (19-2)

[0454]

[0455] Step 1: Ethyl 5-cyano-4-hydroxy-2,6-dimethylnicotinate (19-1): A suspension of Compound D1-10 (1.4 g, 5.1 mmol) and CuCN (0.6 g, 7 mmol) in DMF (12 mL) was stirred at 170 °C under microwave irradiation for 2 h. The mixture was concentrated to dryness and the residue suspended in DCM / MeOH (4 / 1) and the resulting suspension stirred for 20 min, then filtered through Celite. The filtrate was concentrated to give crude Compound 19-1 as a light brown solid (850 mg). MS for C 11 H 12 N 2 O 3 : m / z 221 (MH+).

[0456] Step 2: 5-Carbamoyl-4-hydroxy-2,6-dimethylnicotinic acid (19-2): Compound 19-1 (221 mg, 1 mmol) was treated with conc H 2 SO 4 (5 mL) at 70 °C overnight. The resulting mixture was basified with aq NaOH (10%) carefully to pH >14. The resulting mixture was filtered, and the filtrate was stirred at 100 °C until ester hydrolysis was complete. The mixture was then acidified to pH 2 and concentrated to almost dryness. The resulting residue was extracted with DCM / MeOH (8 / 2 mL, twice) and the combined extracts were concentrated to give the crude Compound 19-2. MS for C 9 H 10 N 2 O 4 : m / z 211 (MH+).Example 20: 4-Hydroxy-2,6-dimethylpyridine-3,5-dicarboxylic acid (20-4)

[0457]

[0458] Step 1: Bis(dimethyl-3-hydroxypent-2-enedioate) Mg Complex (20-1): To a mixture of dimethyl 3-oxopentanedioate (17.4 g, 100 mmol) and MgCl 2 (9.6 g, 100 mmol) in 150 mL water was added ammonia (30 mL) dropwise and the resulting mixture was stirred at room temperature for 5 h. The resulting suspension was filtered, washed with water (3x) and recrystallized from MeOH to give 14.8 g of the desired Mg complex. MS for C 14 H 18 MgO 10 : m / z 371 (MH+).

[0459] Step 2: Dimethyl 2,6-dimethyl-4-oxo-4H-pyran-3,5-dicarboxylate (20-2): Compound 20-1 (14.7 g, 39.7 mmol) in Ac 2 O (15 mL) was stirred at 100 °C 30 min. The mixture was concentrated to remove most of the Ac 2 O, neutralized to pH 9 and extracted with EtOAc (3x). The combined extracts were evaporated, and the resulting residue was purified over silica gel (0-60-% EtOAc in hexane), to give Compound 20-2 as a white solid (6.7 g). MS for C 11 H 12 O 6 : m / z 241 (MH+). Monatshefte fuer Chemie (2005), 136(7), 1197-1203; Chemistry of Heterocyclic Compounds (New York, NY, United States) (2009), 45(6), 666-671.

[0460] Step 3: Dimethyl 4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxylate (20-3): A mixture of Compound 20-2 (3 g.), NH 3 (5 mL, 7M in MeOH) and AcOH (15 mL) was refluxed for 1 h, diluted with 3 volumes of water, and neutralized with NH 4 OH to give a suspension, which was filtered. The resulting solid was washed with water and dried to give Compound 20-3 (1.5 g). MS for C 11 H 13 NO 5 : m / z 240 (MH+).

[0461] Step 4: 4-Hydroxy-2,6-dimethylpyridine-3,5-dicarboxylic acid (20-4): Compound 20-3 (1.0 g) was treated with NaOH (3 M in water, 10 eq) at 100 °C until ester hydrolysis was complete. The resulting solution was washed with EtOAc (2x) and the aqueous phase was acidified to pH 2 to give a suspension, which was filtered to give crude Compound 20-4 (0.5 g). MS for C 9 H 9 NO 5 : m / z 212 (MH+).Example 21: 4-Hydroxy-2,6-dimethylpyridine-3,5-dicarboxylic acid (21-2)

[0462]

[0463] Step 1: Dimethyl 1,2,6-trimethyl-4-oxo-1,4-dihydropyridine-3,5-dicarboxylate (21-1): Compound 21-1 was prepared from Compound 20-2 in the same way Compound 20-3 was prepared from Compound 20-2 in Step 3 of Example 20, using MeNH 2 in place of NH 3 . MS for C 12 H 15 NO 5 : m / z 254 (MH+).

[0464] Step 2: 4-Hydroxy-2,6-dimethylpyridine-3,5-dicarboxylic acid (21-2): Compound 21-2 was prepared from Compound 21-1 in the same way Compound 20-4 was prepared from Compound 20-3 in Step 4 of Example 20. MS for C 10 H 11 NO 5 : m / z 226 (MH+).Example 22: 5-[[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]carbamoyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxylic acid (92)

[0465]

[0466] 5-[[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]carbamoyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxylic acid (92): To a mixture of Compound 21-2 (300 mg, 1.33 mmol) in DCM (12 mL) was added (COCl) 2 (0.15 mL) and 2 drops of DMF. The mixture was stirred at room temperature for 1 h and then concentrated to dryness. To the residue was added Compound A1-10 (120 mg, 0.38 mmol), followed by the addition of DCM (10 mL) and DIEA (140 mg, 1.08 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and 0.1 M HCl (aq) was added to adjust the pH to ~5. The resulting suspension was filtrated, washed with water and dried to give crude Compound 92 (108 mg), a small sample of which was purified by prep HPLC to give a white solid. The remaining crude material was used in subsequent reactions without further purification. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.66 (s, 1H), 10.74 (s, 1H), 8.47 (d, 1H), 7.87 (dd, 1H), 7.59 (s, 1H), 7.41 (dd, 1H), 7.31 (t, 1H), 6.73 (d, 1H), 3.91 (d, 6H), 2.71 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H); MS for C 26 H 23 FN 4 O 7 : m / z 523 (MH+).Example 23: 5-((4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-hydroxy-2,6-dimethylnicotinic acid (23-1)

[0467]

[0468] 5-((4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-hydroxy-2,6-dimethylnicotinic acid (23-1): Compound 23-1 was made from Compound 20-4 and Compound A1-10 using the same procedure that was used to make Compound 92 in Example 22. MS for C 25 H 21 FN 4 O 7 : m / z 509 (MH+).Example 24: 3-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,5-N,2,6-tetramethylpyridine-3,5-dicarboxamide (93)

[0469]

[0470] 3-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,5-N,2,6-tetramethylpyridine-3,5-dicarboxamide (93): Compound 93 was made from Compound 23-1 and dimethylamine using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.05 (s, 1H), 11.97 (s, 1H), 8.50 (d, 1H), 7.93 (dd, 1H), 7.59 (s, 1H), 7.34 (dd, 1H), 7.26 (t, 1H), 6.76 (d, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.90 (s, 3H), 2.77 (s, 3H), 2.64 (s, 3H), 2.13 (s, 3H); MS for C 27 H 26 FN 5 O 6 : m / z 536 (MH+).

[0471] The following compounds were made using General Procedure G1 in the same manner that Compound 93 was made in Example 24:

[0472] 3-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-N-propan-2-ylpyridine-3,5-dicarboxamide (94): Compound 94 was made from Compound 23-1 and isopropylamine using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.00 (s, 1H), 11.83 (s, 1H), 9.19 (d, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.59 (s, 1H), 7.40 - 7.33 (m, 1H), 7.27 (t, 1H), 6.72 (dd, 1H), 3.98 - 3.91 (m, 1H), 3.90 (s, 6H), 2.47 (s, 3H), 2.41 (s, 3H), 1.06 (d, 6H); MS for C 28 H 28 FN 5 O 6 : m / z 550 (MH+).

[0473] 5-N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-3-N,3-N,1,2,6-pentamethyl-4-oxopyridine-3,5-dicarboxamide (95): Compound 95 was made from Compound 92 and dimethylamine using General Procedure G1 . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.25 (s, 1H), 8.47 (d, 1H), 7.88 (d...

Claims

1. A compound of Formula (Ia), Formula (Ib), or Formula (Ic): or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: G is C3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, cyano, halo, C(O)ORa, or C(O)NRaRa, wherein the C3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy of G are each optionally substituted with 1, 2, 3, or 4 independently selected R7 substituents; X1 is N; X2 is CH or CF; R1 and R2 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene-, C3-14 cycloalkyl-C1-4 alkylene-, (5-14 membered heteroaryl)-C1-4 alkylene-, (4-14 membered heterocycloalkyl)-C1-4 alkylene-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, C(O)NRaS(O)2Ra, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(=NRa)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NOH)Ra, C(=NOH)NRa, C(=NCN)NRaRa, NRaC(=NCN)NRaRa, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, S(O)2NRaC(O)Ra, P(O)RaRa, P(O)(ORa)(ORa), B(OH)2, B(ORa)2, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene-, C3-14 cycloalkyl-C1-4 alkylene-, (5-14 membered heteroaryl)-C1-4 alkylene-, and (4-14 membered heterocycloalkyl)-C1-4 alkylene- of R1 and R2 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents; each R3 is independently selected from halo, OH, CN, -C(O)OH, -C(O)NH(C1-6 alkyl), -SO2(C1-6 alkyl), -SO2NH(C1-6 alkyl), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6alkyl), -N(C1-C6 alkyl)2, and C3-C6 cycloalkyl of R3 are each optionally substituted with 1, 2, or 3 independently selected Rg substituents; R4 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene-, C3-14 cycloalkyl-C1-4 alkylene-, (5-14 membered heteroaryl)-C1-4 alkylene-, (4-14 membered heterocycloalkyl)-C1-4 alkylene-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, C(O)NRaS(O)2Ra, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, N=C(NRaRa)2, NRaC(=NRa)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NOH)Ra, C(=NOH)NRa, C(=NCN)NRaRa , NRaC(=NCN)NRaRa, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, S(O)2NRaC(O)Ra, P(O)RaRa, P(O)(ORa)(ORa), B(OH)2, B(ORa)2, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene-, C3-14 cycloalkyl-C1-4 alkylene-, (5-14 membered heteroaryl)-C1-4 alkylene-, and (4-14 membered heterocycloalkyl)-C1-4 alkylene- of R4 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rb substituents; R5, R6 and R10 are each independently H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, CN, C1-4 haloalkyl, C1-4 haloalkoxy, OH, C1-4alkyl-C(O)-, C1-4alkyl-OC(O)-, -C(O)NH(C1-4 alkyl), NH2, -NHC1-4alkyl, or -N(C1-4 alkyl)2, wherein the C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl-C(O)- and C1-4 alkyl of -NH(C1-4alkyl), or -N(C1-4 alkyl)2 of R5, R6, and R10 are each optionally substituted with 1 or 2 independently selected Rg substituents; each R7 is independently selected from halo, OH, C(O)ORa, C(O)Ra, C(O)NRaRa, CN, NH2, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C(O)NRaRa, NRaC(O)Ra, NRaC(O)NRaRa, SO2Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, C3-C6 cycloalkyl-C1-C4 alkylene-, (4- to 6-membered heterocycloalkyl)-C1-C4 alkylene-, phenyl-C1-C2 alkylene, and (5- or 6-membered heteroaryl)-C1-C4 alkylene-, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, C3-C6 cycloalkyl-C1-C4 alkylene-, (4-to 6-membered heterocycloalkyl)-C1-C4 alkylene-, phenyl-C1-C2 alkylene, and (5- or 6-membered heteroaryl)-C1-C4 alkylene- of R7 are each optionally substituted with 1, 2, or 3 independently selected Rf substituents; R8 is H, C1-6 alkyl optionally substituted with 1 or 2 Rg substituents or a hydroxy protecting group; R9 is H or C1-6 alkyl optionally substituted with 1, 2, or 3 independently selected Rg substituents; or R4 and R5 taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected Rg substituents; or R10 and R5 taken together with the atoms to which they are attached form fused C3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, fused 5- or 6-membered heteroaryl or fused phenyl, wherein the fused C3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- or 6-membered heteroaryl, or fused phenyl is each optionally substituted with 1 or 2 independently selected Rg substituents, and wherein one or two ring carbon atoms of the fused C3-7 cycloalkyl or fused heterocycloalkyl are optionally replaced by a carbonyl group; or R12 and R10 taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected Rg substituents; or R6 and R4 taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl or 5- to 6-membered fused heteroaryl, wherein the 4- to 7-membered fused heterocycloalkyl and 5- to 6-membered fused heteroaryl are each optionally substituted with 1 or 2 independently selected Rg substituents; or R6 and R10 taken together with the atoms to which they are attached form fused C3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- to 6-membered fused heteroaryl, or fused heteroaryl, wherein the fused C3-7 cycloalkyl, 4- to 6-membered fused heterocycloalkyl, 5- to 6-membered fused heteroaryl, and fused heteroaryl are each optionally substituted with 1 or 2 independently selected Rg substituents and wherein one or two ring carbon atoms of the fused C3-7 cycloalkyl or 4- to 6-membered fused heterocycloalkyl are optionally replaced by a carbonyl; each Ra is independently selected from H, CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-14 membered heteroaryl)-C1-C4 alkylene-, and (4-14 membered heterocycloalkyl)-C1-C4 alkylene-, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-14 membered heteroaryl)-C1-C4 alkylene-, and (4-14 membered heterocycloalkyl)-C1-C4 alkylene- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents; or any two Ra substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents; each Rb is independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, (4-10 membered heterocycloalkyl)-C1-C4 alkylene-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, C(O)NRcS(O)2Rc, OC(O)Rc, OC(O)NRcRc, C(=NOH)Rc, C(=NOH)NRc, C(=NCN)NRcRc, NRcC(=NCN)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(=NRc)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc, S(O)2NRcC(O)Rc, Si(Rc)3, P(O)RcRc, P(O)(ORc)(ORc), B(OH)2, B(ORc)2, and S(O)2NRcRc, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, and (4-10 membered heterocycloalkyl)-C1-C4 alkylene- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents; each Rc is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, and (4-10 membered heterocycloalkyl)-C1-C4 alkylene-, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, and (4-10 membered heterocycloalkyl)-C1-C4 alkylene- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; or any two Rc substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents; each Rd is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, (4-10 membered heterocycloalkyl)-C1-C4 alkylene-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, C3-C10 cycloalkyl-C1-C4 alkylene-, (5-10 membered heteroaryl)-C1-C4 alkylene-, and (4-10 membered heterocycloalkyl)-C1-C4 alkylene- of Rd are each optionally substituted with 1, 2, or 3 independently selected Rf substituents; each Re is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkylene-, C6-C10 aryl, C6-C10 aryl-C1-C4 alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-C1-C4 alkylene-, 4-7-membered heterocycloalkyl, (4-7-membered heterocycloalkyl)-C1-C4 alkylene-, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C4 alkenyl, and C2-C4 alkynyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5 or 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkylene-, (5- or 6-membered heteroaryl)-C1-C4 alkylene-, (4-7-membered heterocycloalkyl)-C1-C4 alkylene-, C2-C4 alkenyl, and C2-C4 alkynyl of Re are each optionally substituted with 1, 2, or 3 Rf substituents; or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents; each Rf is independently selected from halo, OH, CN, C(O)OH, NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, vinyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6haloalkyl, C1-C6haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, phenyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rf are each optionally substituted with 1, 2, or 3 substituents selected from halo, OH, CN, - C(O)OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, C3-C10 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; each Rg is independently selected from halo, OH, CN, C(O)OH, -C(O)O-C1-C4 alkyl, NH2, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and C3-C6 cycloalkyl; and the subscript m is 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein G is: C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutene-1-yl, cyclopenten-1-yl, cyclohexten-1-yl, 3,6-dihydro-2H-pyran-4-yl, piperidin-1-yl, pyrrolidine-1-yl, or morpholino; C1-6 alkyl, C2-6 alkenyl, C1-6alkoxy, or halo; or C1-6 alkyl, vinyl, methoxy, or halo.

3. The compound of claim 1 or claim 2, having formula (Ia-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl, or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3, or 4.

4. The compound of claim 1 or claim 2, having formula (Ib-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl, or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3, or 4.

5. The compound of claim 1 or claim 2, having formula (Ic-1): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is cyclopentene-1-yl, cyclohexen-1-yl, or 3,6-dihydro-2H-pyran-4-yl and the subscript n is 0, 1, 2, 3 or 4.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R' is H, C1-6 alkyl, C1-6 alkoxy, halo, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylNHC(O)-, or C1-6alkylSO2NH-; R1 is H or C1-6 alkoxy; R2 is H, C1-6 alkyl, C1-6 alkoxy, halo, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkylNHC(O)-, CF3, C1-6 alkylOC(O)-, pyridyl, C1-6alkylSO2NH-, or 1H-pyrazol-4-yl optionally substituted with Rg; and / or R2 is H or C1-6 alkoxy optionally substituted with C1-6 alkoxy.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: one of R1 and R2 is ORa and Ra is C1-6 alkyl substituted with one Rd; or R2 is ORa; Ra is C1-6 alkyl substituted with one Rd; and Rd is ORe or C3-10 cycloalkyl, and wherein Re is C1-6 alkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R7 is H, halo, C1-6 alkyl or C1-6 alkoxy; and / or R9 is H or methyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R4 is selected from H, C1-6 alkyl, C1-6 alkoxy, OH, C3-6 cycloalkyl, C1-6 haloalkyl, C3-6 cycloalkyl-C1-4 alkylene-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C1-4 alkylene-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C1-4 alkylene-, and N=C[N(C1-6 alkyl)(C1-6 alkyl)]2, wherein the C1-6 alkyl, C1-6 alkoxy,C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkylene-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-C1-4 alkylene-, 5-6 membered heteroaryl, (5-6 membered heteroaryl)-C1-4 alkylene-, and N=C[N(C1-6 alkyl)(C1-6 alkyl)]2 of R4 are each optionally substituted with 1 or 2 independently selected Rb or Rg substituents; R4 is C1-6 alkyl or C1-6 haloalkyl; or R4 and R5 taken together with the atoms to which they are attached form 4- to 7-membered fused heterocycloalkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein : R5 and R6 are each independently selected from H, CH3, propen-2-yl, Br, Cl, CN, methoxy, 2-fluoroethyl, isopropyl, CH3C(O)-, OH, t-butyl, ethyl, hydroxymethyl, isopropylthio, and methoxymethyl; R10 is H, CH3, propen-2-yl, Br, Cl, CN, methoxy, 2-fluoroethyl, isopropyl, CH3C(O)-, OH, t-butyl, ethyl, hydroxymethyl, isopropylthio, or methoxymethyl; and / or R8 is independently H or C1-6 alkyl.

11. The compound of claim 1, wherein the compound is selected from: A: 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(6-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; and 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; and pharmaceutically acceptable salts, stereoisomers or tautomers thereof, or B: 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-prop-1-en-2-ylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-4-hydroxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,6-dimethyl-4-oxopyridine-3-carboxamide; 5-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-(2-fluoroethyl)-6-methyl-4-oxopyridine-3-carboxamide; 1-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; 1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4,6-dimethyl-2-oxo-1-prop-1-en-2-ylpyridine-3-carboxamide; 5-bromo-1-cyclopentyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4,6-dimethyl-2-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-6-methyl-5-[(E)-4-methylpent-1-enyl]pyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethyl-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-methyl-2-oxo-1-propan-2-ylpyridine-3-carboxamide; 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-6-methylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-3,3-dimethylbut-1-enyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-[(E)-3,3-dimethylbut-1-enyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopropylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-[(E)-2-cyclopentylethenyl]-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-prop-1-en-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxo-5-propan-2-ylpyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 4-hydroxy-5-methoxy-N-[4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 5-bromo-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-6-ethyl-1-methyl-4-oxopyridine-3-carboxamide; 5-bromo-6-ethyl-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-methyl-4-oxopyridine-3-carboxamide; 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(cyclohexen-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; N-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-5-methoxy-2,6-dimethylpyridine-3-carboxamide; 4-hydroxy-5-methoxy-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-2,6-dimethylpyridine-3-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; N-[4-[[7-(2-cyclobutylethoxy)-6-methoxy-1,5-naphthyridin-4-yl]oxy]-3-fluorophenyl]-5-(cyclopenten-1-yl)-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-tfluorophenyl]-5-methoxy-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 7-(3,6-dihydro-2H-pyran-4-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 5-cyano-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 5-cyano-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 3-N-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 5-cyano-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-5-morpholin-4-yl-4-oxopyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-pyrrolidin-1-ylpyridine-3-carboxamide; N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxo-5-piperidin-1-ylpyridine-3-carboxamide; 3-N-[3-fluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 5-[[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]carbamoyl]-1,2,6-trimethyl-4-oxopyridine-3-carboxylic acid; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,5-N,2,6-tetramethylpyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethyl-5-N-propan-2-ylpyridine-3,5-dicarboxamide; 5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-3-N,3-N,1,2,6-pentamethyl-4-oxopyridine-3,5-dicarboxamide; 3-N-cyclopropyl-5-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1,2,6-trimethyl-4-oxopyridine-3,5-dicarboxamide; 3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-5-N,2,6-trimethylpyridine-3,5-dicarboxamide; 5-N-cyclopropyl-3-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-4-hydroxy-2,6-dimethylpyridine-3,5-dicarboxamide; 7-(cyclopenten-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; 7-(cyclohexen-1-yl)-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-6-methyl-8-oxo-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazine-9-carboxamide; and 5-(cyclopenten-1-yl)-N-[3-fluoro-4-[[7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-4-hydroxy-2,6-dimethylpyridine-3-carboxamide; and pharmaceutically acceptable salts, stereoisomers, or tautomers thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

13. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 12, for use in a method of treating a disease, disorder, or syndrome which is mediated by modulating in vivo activity of a protein kinase, optionally wherein the protein kinase is AXL, KDR, Mer, or Met.

14. A process for preparing a compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, as defined in any one of claims 1 to 11, wherein: the process comprises contacting a compound of Formula A-a, Formula A-b, or Formula A-c: with a compound of Formula B-c: under amide bond forming conditions to provide the compound of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: X1, X2, R1, R2, R3, R4, R5, R6, R8, R9, R10, G and m are as defined in claim 1.

15. The process of claim 14, wherein the amide bond forming conditions comprise HATU in the presence of a base in an organic solvent.