^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a)₂, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)R^a(where t is 1 or 2), —R^b—S(O)OR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the R^a, R^b, or R^csubstituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^c-aryl where R^cis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^d-aryl where R^dis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^e-aryl, where R^eis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-aryl where R^cis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a)₂, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)R^a(where t is 1 or 2), —R^b—S(O)OR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the R^a, R^b, or R^csubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^c-carbocyclyl where R^cis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula —R^c-carbocyclyl where R^cis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-carbocyclyl where R^cis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a)₂, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)R^a(where t is 1 or 2), —R^b—S(O)OR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the R^a, R^b, or R^csubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula —R^c-heterocyclyl where R^cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-heterocyclyl where R^cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, —R^b—OR^a, —R^b—OC(O)—R^a, —R^b—OC(O)—OR^a, —R^b—OC(O)—N(R^a)₂, —R^b—N(R^a)₂, —R^b—C(O)R^a, —R^b—C(O)OR^a, —R^b—C(O)N(R^a)₂, —R^b—O—R^c—C(O)N(R^a)₂, —R^b—N(R^a)C(O)OR^a, —R^b—N(R^a)C(O)R^a, —R^b—N(R^a)S(O)_tR^a(where t is 1 or 2), —R^b—S(O)_tR^a(where t is 1 or 2), —R^b—S(O)OR^a(where t is 1 or 2) and —R^b—S(O)_tN(R^a)₂(where t is 1 or 2), where each R^ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^bis independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^cis a straight or branched alkylene or alkenylene chain, and where each of the R^a, R^b, or R^csubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^c-heteroaryl, where R^cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^c-heteroaryl, where R^cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[Image Omitted]

and the like.

A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[Image Omitted]

The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. In some embodiments, isotopic substitution with ¹⁸F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

In certain embodiments, the compounds disclosed herein have some or all of the ¹H atoms replaced with ²H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)]2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d₃(CD₃I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD₃I is illustrated, by way of example only, in the reaction schemes below.

[Image Omitted]

Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD₄), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD₄is illustrated, by way of example only, in the reaction schemes below.

[Image Omitted]

Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[Image Omitted]

In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable ¹H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the MEK kinase inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

“Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

MEK Kinase

Phosphorylation of mitogen-activated protein kinase (MAPK) occurs through the action of MEK. MAPK is localized to the cytoplasm of the cell through its specific association of the N-terminal 1-32 residues of MEK in unstimulated cells. To date, there are 7 MEK enzymes that have been identified, and these enzymes selective phosphorylate serin/threonine and tyrosine residues within the activation loop of their specific mitogen-activated protein kinase (MAPK) substrates. MEK family of genes consists of seven genes with MEK1 and MEK2 being the more significant genes. MEK1 exists in human chromosome 15q22.31 and is encoded by the gene MAP2K. MEK2 exists in human chromosome 9q13.3 and is encoded by the geneMAP2K2.

MEK proteins have a molecular weight range between about 43 and 50 kDa. MEKs can have amino- and carboxy-terminal domains which are more diverse between the different MEK proteins but share extensive homology with the kinase domain. The MEK1 and MEK2 proteins are closely related and have three important domains: (1) a core protein kinase domain (that contains ATP binding site and catalytic apparatus); (2) an N-terminal domain (which contains the inhibitory/allosteric segment, nuclear export sequence, and docking site (D-domain) that aids in binding ERK substrates), and (3) a shorter C-terminal region (which contains the domain for versatile docking (DVD), serving as a determinant binding site for upstream components of the Ras/Raf/MEK/ERK signaling cascade).

MEK3 and MEK6 are similar functionally to MEK1 and MEK2, and encoded by MAP2K3 and MAP2K6 genes, respectively, located on chromosome 17q. MEK3 has a 347 amino acid residues and MEK6 has 334 amino acid residues. While MEK6 differs from MEK3 in terms of the C- and N-terminal regions, the serine/threonine and tyrosine catalytic sites and ATP binding sites are conserved. MEK3 and MEK6 signaling pathways can be activated by growth factor stimulation through RTK, G-protein coupled receptors, intracellular receptors, and toll-like receptors. The cascade can be activated in response to various stimuli include, but not limited to tumor necrosis factor, interleukine-1, cytokines, UV irradiation, physical and chemical stress, and hormones. MEK3 and MEK6 can be activated by MPAK kinase kinases (MAPKKK), which in turn allows MEK3 and MEK to activate p38 MAPK. There are four isoforms of p38 MAP kinase (a, 3, 7 and 6). MEK6 can active all four isoforms, whereas MEK3 can only active the p38a and p38p isoforms. The MEK3 and MEK6 with p38 MAPK cascade can promote p53-dependent growth arrest to arrest the cell cycle.

MEK4 and MEK7 are part of the stress-activated protein kinase (SAPK) signaling cascade. MEK4 is encoded by MAP2K4 located on chromosome 17p11.2, and MEK7 is encoded by MAP2K7 located on chromosome 19p13.3. MEK4 and MEK7 are homologous to the other MEK inhibitors through the kinase domains, but differ in their N- and C-terminal subunits. After activation by upstream kinases, such as MAPKKK, Tpl-2, DLK, TAO1, TAO2, TAK1, ASK1, and ASK2, the threonine residues in the activation segment of MEK4 and MEK7, or MEK4 only is phosphorylated. MEK4 and MEK7 can work synergistically to activate JNK protein kinases such as JK1, JNK2, and JNK3. Further, the MEK4 and MEK7 with JNK signaling pathway can act as a key tumor suppression pathway. MEK4 and MEK7 along with substrate JNK can promote apoptosis by phosphorylating and inactivating anti-apoptoic proteins such as, but not including to Bcl2, Bcl-XL, and Mcl-1. MEK4 activity has been shown for normal hepatogensis, B and T-cell lymphopoiesis, and erythropoiesis. MEK4 has also been shown to be down-regulated in 75% of cases of ovarian cancer. There is also hypothesized that loss of MEK4-p38MAPK signaling cascade may be relevant to tumorigenesis.

MEK5 shares about a 40% identify with the other MEK protein kinases, and has a 448 amino acid sequence. MEK5 can be activated by hyperosmotic conditions, oxidative stress, and growth factors. The downstream target of MEK5 is ERK5, which is also known as big MAP kinase 1 (BMK1) since it is twice the size of other MAPKs. The PB1 domain of MEK5 mediates the MEK5 interaction with MEKK2, MEKK3, or ERK5. MEK5-ERK5 signaling can enhance progression through the cell cycle. Overexpression of MEK5 has been associated with cancers of the colon, prostate, breast, lymphoma, and malignant mesothelioma.

MEK Activation and Intracellular Signaling Pathways

Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, which is a key cell signaling pathway in regulating proliferation, cellular growth, and survival. MEK transmits mitogenic signals from outside of the cell to the nucleus through the signaling pathway. MEK1 and MEK2 participate in the in Ras/Raf/MEK/ERK signal transduction cascade, and are activated by ligands binding to receptor tyrosine kinases (RTK), which can lead to dimerization of the receptors and autophosphorylation of specific tyrosine residues in its C-terminal region. The activated receptors can then recruit and phosphorylate adaptor proteins Grb2 and SOS, which interact with GTPase Ras to activate it. H-Ras, K-Ras, and N-Ras function as molecular switches when inactive Ras-GDP is converted to active Ras-GTP. In the activated GTP-bound form, Ras activate Ras kinases (A-Raf, B-Raf, and C-Raf/RaF-1) which in turn activates MEK1 and MEK2 leading to the activation of ERK1 and ERK2.

Activated ERKs can translocate into the nucleus to initiate cellular responses such as apoptosis, angiogenesis, motility, cell proliferation, survival, differentiation, and stress response. The Raf/MEK/ERP MAP kinase pathway promotes cell survival by blocking NF-kB, which will lead to increased transcription of anti-apoptotic and pro-survival genes such as Bcl-2 and Mcl-1. The Ras/Raf/MEK/ERK signaling pathway is activated by several different mechanisms in human cancers. For example, increased ERK1 and ERK2 signaling is often due to direct mutational activity or amplification of genes encoding key components of the Ras/Raf/MEK/ERK pathway. In particular, studies have found that B-Raf is mutated in about 20% of all cancers and more than 60% of melanomas. ERK 1 and ERK2 can also be activated by MEKs in solid tumors including, but not limited to, melanoma, colon, and lung carcinomas.

In tumor cells, specific growth factors combine with transmembrane receptors on the cell surface, leading to increase in RAS activation, and once RAS is activated, the plasma membrane of the cell secretes and activates the downstream molecule RAF kinase. Activation of RAF kinase stimulates a series of protein kinases which form the RAS/RAF/MEK ERK signaling pathway. Further, BRAF and KRAS are two key oncogenes in the MEK signaling pathway, as well as the RAS/RAF/MAPK signaling pathways. Mutations in both KRAS and BRAF genes lead to proliferation, differentiation, and apoptosis of tumor cells by activating the MEK/RAS/RAF/ERK signaling pathway. Both KRAS and BRAF gene mutations have also been identified in non-small cell lung cancer (NSCLC). MEK inhibitors combined with chemotherapy treatment, BRAF inhibitors, immune checkpoint inhibitors, or epidermal growth factor receptor-tyrosine kinase inhibitors have shown improving clinical efficacy and causing delay in the occurrence of drug resistance (Han, J. et al. J Hematol Oncol 14; 1, 2021).

The BRAF gene is an important gene in the MAPK pathway, and associated with multiple tumor types, including, but not limited to melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC). BRAF inhibitors have shown efficacy in several cancers. Combination therapy targeting BRAF and MEK have been studied and demonstrated synergistic benefits. The combination blockade of BRAF and MEK are able to delay, or prevent resistance, in patients who develop resistance when BRAF inhibitors are administered as a single agent. BRAF and MEK inhibitor combinations have been approved by the FDA for use in cancer types including, but not limited to, BRAF mutations in melanoma, NSCLC, and ATC (Subbiah, V. et al. Trends in Cancer, Vol. 6, No. 9 2020). Further, patents treated with a combination of BRAF and MEK inhibitors have shown overall survival for metastatic melanoma.

MEK Inhibitors

Several agents have been developed to target MEK, including small molecule inhibitors. Most small molecular inhibitors of MEK target the MEK1 and/or MEK2 enzyme. MEK inhibitors include, but are not limited to trametinib, GSK1120212, JTP 74057, pimasertib, selumetinib, PD-0325901, Refametinib, RDEA119, BAY 869766, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655, CH4987655, GDC-0973, AZD8330, ARRY-424704, ARRY-704, and E6201. Small molecule inhibitors currently FDA-approved or undergoing clinical evaluations include TAK-733, binimetinib, cobimetrinib, trametinib, and selumetinib. Other MEK inhibitors include mirdametinib and pimasertib, along with the compounds disclosed in WO2006/045514. Other compounds suitable as MEK inhibitors are also disclosed in U.S. Pat. No. 5,525,625; WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077855; WO03/077914; WO2004/005284; and WO2004/O56789.

MEK inhibitors can be divided into two major classes, ATP non-competitive and ATP competitive inhibitors. Most MEK inhibitors are ATP non-competitive, and bind to an allosteric site adjacent to the ATP site. This allows for high specificity of non-competitive MEK inhibitors.

Trametinib is an allosteric ATP non-competitive inhibitor with potent activity against MEK1 and MEK2 kinases. Trametinib can include cell-cycle arrest by inhibition of p-ERK1 and p-ERK2. Pimasertib is a selective allosteric ATP non-competitive inhibitor of MEK1 and MEK2. Pimasertib can inhibit tumor growth and regression. Selumetinib is also an ATP non-competitive inhibitor which is highly selective for MEK1 and MEK2. Studies have shown that its antitumor activity correlated with decreasing phosphorylation of ERK1 and ERK2. Refametinib is a cyclopropane-1-sulfonamide derivative which exhibits selective allosteric inhibition of MEK1 and MEK2. Rafametinib shows potent activity against xenographs of human melanoma, colon carcinoma, pancreatic cancer, and skin carcinoma in tumor models.

PD-0325901 is a specific and potent synthetic analog of CI-1040, another MEK inhibitor. PD-0325901 also inhibits phosphorylation of ERK1 and ERK2 in melanoma and papillary thyroid cancer cell lines with B-RAF mutation. MEK162 is an inhibitor which targets MEK1 and MEK2. Studies have examined MEK162 in patients with N-Ras and B-Raf mutated advanced melanoma. RO5126766 is a very potent dual MEK/RAF inhibitor, and selectively binds to MEK1 and MEK2 to form a stable complex. The primary mechanism was shown to be through cell cycle arrest. RO4987655 is a highly selective small molecule MEK inhibitor. The compound is a 3-oxo-oxazinane ring structure which confers metabolic stability, and has antitumor efficacy. GDC-0973 is a derivative of methanone, and is a potent small molecule inhibitor of MEK1. GDC-0973 has antineoplastic activity in BRAF and KRAS mutant cancer cell lines. AZD8330 is a newer inhibitor of MEK1 and MEK2 which has been studied in patients with advanced solid tumors.

E6201 is an ATP competitive MEK inhibitor, and exhibits potent activity against melanoma cells. Since melanoma has a high probability to metastasize to the CNS, E6201 may be useful for permeating an intact blood-brain barrier (BBB) (Gampa, G. et al. Drug Metab Dispos., 46(5): 658-666, 2018). E6201 may be beneficial for treating melanoma as a single agent or in combination with a BRAF inhibitor. Further, E6201 may be able to penetrate the BBB to achieve therapeutically active levels.

Despite the increased knowledge of cellular signaling pathways and limited success in translating this knowledge to medicines, there is a large unmet medical need for therapies operating via selective MEK inhibition.

MEK Kinase Inhibitory Compounds

In one aspect, provided herein is a MEK kinase inhibitory compound.

One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

[Image Omitted]

wherein,

- R¹is optionally substituted alkyl;
- R²is optionally substituted alkyl; optionally, R¹and R²join with a carbon-carbon bond to form a phosphorous-containing ring;
- R³is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy;
- R⁴is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy;
- R⁵is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; and
- R¹¹, R¹², R¹³, R¹⁴, and R¹⁵are independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹is optionally substituted C1-C3 alkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R²is optionally substituted C1-C3 alkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹is CH₃. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R²is CH₃.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹is optionally substituted C1-C3 alkyl, R²is optionally substituted C1-C3 alkyl, and R¹and R²join with a carbon-carbon bond to form a phosphorous-containing ring. In one embodiment is the compound, or pharmaceutically acceptable salt or solvate thereof, wherein phosphorous-containing ring is a 5-membered ring.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R³is hydrogen. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R³is halo. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R³is optionally substituted C1-C3 alkyl.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁴is hydrogen. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁴is halo. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁴is optionally substituted C1-C3 alkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁴is optionally substituted C1-C3 alkoxy.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁵is hydrogen. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁵is halo. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁵is optionally substituted C1-C3 alkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R⁵is optionally substituted C1-C3 alkoxy.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹¹is fluoro. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹¹is hydrogen.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹²is hydrogen or fluoro. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹²is fluoro. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹²is hydrogen.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is selected from iodo, bromo, optionally substituted C2-C3 alkynyl, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is iodo. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is optionally substituted C1 alkyl. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is —CF₃. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is bromo. Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹³is optionally substituted cyclopropyl.

Provided herein is the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R¹⁴and R¹⁵are hydrogen.

One embodiment provides an MEK kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.

TABLE 1

Synthetic

Chemistry

Example
Compound Structure
Compound Name

1

[Image Omitted]

4-(Dimethylphosphoryl)-N-(2-fluoro-4- iodophenyl)pyridin-3-amine

2

[Image Omitted]

2-(Dimethylphosphoryl)-5-fluoro-N-(2- fluoro-4-iodophenyl)aniline

3

[Image Omitted]

N-(2,3-Difluoro-4-iodophenyl)-4- (dimethylphosphoryl)pyridin-3-amine

4

[Image Omitted]

6-(Dimethylphosphoryl)-2,3-difluoro-N-(2- fluoro-4-iodophenyl)aniline

5

[Image Omitted]

1-(3-((2-Fluoro-4- iodophenyl)amino)pyridin-4- yl)phospholane 1-oxide

6

[Image Omitted]

4-(Diethylphosphoryl)-N-(2-fluoro-4- iodophenyl)pyridin-3-amine

7

[Image Omitted]

4-[Ethyl(methyl)phosphoryl]-N-(2-fluoro- 4-iodophenyl)pyridin-3-amine

8

[Image Omitted]

(R)-4-[Ethyl(methyl)phosphoryl]-N-(2- fluoro-4-iodophenyl)pyridin-3-amine

9

[Image Omitted]

(S)-4-[ethyl(methyl)phosphoryl]-N-(2- fluoro-4-iodophenyl)pyridin-3-amine

10

[Image Omitted]

N-(4-Bromo-2-fluoropheny1)-4- (dimethylphosphoryl)pyridin-3-amine

11

[Image Omitted]

N-(4-bromo-2-fluoropheny1)-4- (diethylphosphoryl)pyridin-3-amine

12

[Image Omitted]

1-(3-((4-Bromo-2- fluorophenyl)amino)pyridin-4- yl)phospholane 1-oxide

13

[Image Omitted]

5-Chloro-4-(dimethylphosphoryl)-N-(2- fluoro-4-iodophenyl)pyridin-3-amine

14

[Image Omitted]

(3-((4-Ethynyl-2- fluorophenyl)amino)pyridin-4- yl)dimethylphosphine oxide

15

[Image Omitted]

1-(3-((4-Ethynyl-2- fluorophenyl)amino)pyridin-4- yl)phospholane 1-oxide

16 and 17

[Image Omitted]

N-(4-Bromo-2-fluorophenyl)-4-[(R)- ethyl(methyl)phosphoryl]pyridin-3-amine and N-(4-Bromo-2-fluorophenyl)-4-[(S)- ethyl(methyl)phosphoryl]pyridin-3-amine

[Image Omitted]

4-(Diethylphosphoryl)-N-(4-ethynyl-2- fluorophenyl)pyridin-3-amine

19 and 20

[Image Omitted]

4-[(R)-Ethyl(methyl)phosphoryl]-N-(4- ethynyl-2-fluorophenyl)pyridin-3-amine and 4-[(S)-Ethyl(methyl)phosphoryl]-N-(4- ethynyl-2-fluorophenyl)pyridin-3-amine

[Image Omitted]

(2-Fluoro-5-((2-fluoro-4- iodophenyl)amino)pyridin-4- yl)dimethylphosphine oxide

22

[Image Omitted]

4-(Dimethylphosphoryl)-N-(4- iodophenyl)pyridin-3-amine

23

[Image Omitted]

N-(4-Cyclopropyl-2-fluorophenyl)-4- (dimethylphosphoryl)pyridin-3-amine

24

[Image Omitted]

4-(Dimethylphosphoryl)-5-fluoro-N-(2- fluoro-4-iodophenyl)pyridin-3-amine

25

[Image Omitted]

(2-Fluoro-3-((2-fluoro-4- iodophenyl)amino)pyridin-4- yl)dimethylphosphine oxide

26

[Image Omitted]

N-(4-bromo-2-chlorophenyl)-4- (dimethylphosphoryl)-5-fluoropyridin-3- amine

27

[Image Omitted]

N-(4-bromo-2-chloropheny1)-4- (dimethylphosphoryl)pyridin-3-amine

28

[Image Omitted]

N-(4-Bromo-2-chlorophenyl)-5-chloro-4- (dimethylphosphoryl)pyridin-3-amine

29

[Image Omitted]

(3-((4-Bromo-2-fluorophenyl)amino)-5- chloropyridin-4-yl)dimethylphosphine oxide

30

[Image Omitted]

4-(Dimethylphosphoryl)-N-(2-fluoro-4- iodophenyl)-5-methylpyridin-3-amine

31

[Image Omitted]

4-(Dimethylphosphoryl)-N-(4-ethynyl-2- fluorophenyl)-5-fluoropyridin-3-amine

32

[Image Omitted]

(3-Chloro-5-((4-cyclopropyl-2- fluorophenyl)amino)pyridin-4- yl)dimethylphosphine oxide

Preparation of Compounds

The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the MEK kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the MEK kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^stEd. Mack Pub. Co., Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one MEK kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the MEK kinase inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the MEK kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21^stEd. Mack Pub. Co., Easton, PA (2005)).

In some embodiments, the MEK kinase inhibitory compound as described by Formula (I) or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

The dose of the composition comprising at least one MEK kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

Methods of Treatment

One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Another embodiment provides the use wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease. One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Another embodiment provides the method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

One embodiment provides a method of inhibiting a MEK kinase enzyme comprising contacting the MEK kinase enzyme with a compound of Formula (I) or Table 1. Another embodiment provides the method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vitro setting.

Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES
I. Chemical Synthesis

In some embodiments, the MEK kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

- ° C. degrees Celsius
- δ_Hchemical shift in parts per million downfield from tetramethylsilane
- DCM dichloromethane (CH₂Cl₂)
- DMF dimethylformamide
- DMSO dimethylsulfoxide
- EA ethyl acetate
- ESI electrospray ionization
- Et ethyl
- g gram(s)
- h hour(s)
- HPLC high performance liquid chromatography
- Hz hertz
- J coupling constant (in NMR spectrometry)
- LCMS liquid chromatography mass spectrometry
- μ micro
- m multiplet (spectral); meter(s); milli
- M molar
- M⁺ parent molecular ion
- Me methyl
- MHz megahertz
- min minute(s)
- mol mole(s); molecular (as in mol wt)
- mL milliliter
- MS mass spectrometry
- nm nanometer(s)
- NMR nuclear magnetic resonance
- pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution
- PE petroleum ether
- RT room temperature
- s singlet (spectral)
- t triplet (spectral)
- T temperature
- TFA trifluoroacetic acid
- THE tetrahydrofuran

Intermediate 1: Phospholane 1-oxide

[Image Omitted]

To a stirred mixture of magnesium (3.61 g, 148.440 mmol) in tetrahydrofuran (45 mL) was added 1,3-dibromopropane (14.62 g, 72.41 mmol) in tetrahydrofuran (15 mL) at 15° C. under nitrogen atmosphere. The reaction mixture was stirred for 1.5 h at room temperature. Diethyl phosphonate (5.0 g, 36.20 mmol) in tetrahydrofuran (15 mL) was added the mixture at 15° C. and the reaction mixture was stirred for another 1 h at room temperature. Gradual addition of an ice-cooled solution potassium carbonate (21 g) in water (35 mL) generated a heavy off-white precipitate of magnesium carbonate, which was rapidly filtered off in air and washed with degassed ethanol (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford phospholane 1-oxide (1.3 g, 34%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 2.15-1.94 (m, 4H), 1.94-1.69 (m, 4H).

Intermediate 2: Ethyl(methyl)phosphine oxide

[Image Omitted]

To a stirred solution of 1 M ethylmagnesium bromide in tetrahydrofuran (27.76 mL, 27.76 mmol) was added ethyl methylphosphinate (2.0 g, 18.51 mmol) in tetrahydrofuran (6.0 mL) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Gradual addition of a solution potassium carbonate (12 g) in water (20 mL) generated a heavy off-white precipitate of magnesium carbonate, which was rapidly filtered off in air and washed with degassed ethanol (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product was combined and concentrated to afford ethyl(methyl)phosphine oxide (1.0 g, 59%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 1.94-1.77 (m, 2H), 1.60-1.56 (m, 3H), 1.26-1.17 (m, 3H).

Intermediate 3: (3-Aminopyridin-4-yl)dimethylphosphine oxide

[Image Omitted]

To a stirred mixture of 4-iodopyridin-3-amine (3.0 g, 13.64 mmol), (methylphosphonoyl)methane (1.28 g, 16.36 mmol) and palladium (II) acetate (0.15 g, 0.68 mmol) in N,N-dimethylformamide (30 mL) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.39 g, 0.68 mmol) and potassium phosphate tribasic (3.18 g, 15.00 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 120° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)pyridin-3-amine (2.18 g, 94%) as a light yellow solid. MS ESI calculated for C₇H₁₁N₂OP [M+H]⁺, 171.06, found 171.05; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=5.5 Hz, 1H), 7.96 (dd, J=5.0, 3.6 Hz, 1H), 6.87 (dd, J=13.3, 5.0 Hz, 1H), 5.44 (s, 2H), 1.80 (s, 3H), 1.77 (s, 3H); ³¹P NMR (162 MHz, CDCl₃) δ 40.73.

The following compounds in Table 2 were prepared using procedures similar to those described in Intermediate 3 using appropriate starting materials.

TABLE 2

Exact Mass

No.
Structure
Name
[M + H]⁺

4

[Image Omitted]

2-(Dimethylphos- phoryl)-5- fluoroaniline
Calc'd 188.06, found 188.00

5

[Image Omitted]

1-(3-Aminopyridin-4- yl)phospholane 1-oxide
Calc'd 197.08, found 197.05.

6

[Image Omitted]

4-(Diethylphos- phoryl)pyridin-3- amine
Calc'd 199.09, found 199.00

7

[Image Omitted]

(3-Aminopyridin-4- yl)(ethyl)(methyl)- phosphine oxide
Calc'd 185.08, found 185.00

Intermediate 8: 6-(Dimethylphosphoryl)-2,3-difluoroaniline

[Image Omitted]

To a stirred mixture of 6-bromo-2,3-difluoroaniline (0.70 g, 3.36 mmol) and (methylphosphonoyl)methane (0.31 g, 4.03 mmol) in N, N-dimethylformamide (1.00 mL) were added palladium acetate (37.78 mg, 0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (97.36 mg, 0.16 mmol) and potassium phosphate (0.79 g, 3.70 mmol) at room temperature. The reaction mixture was stirred at 150° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford 6-(dimethylphosphoryl)-2,3-difluoroaniline (200 mg, 29%) as a grey solid. MS ESI calculated for C₈H₁₀F₂NOP [M+H]⁺, 206.05, found 206.05; ¹H NMR (400 MHz, CDCl₃) δ 6.54-6.50 (m, 1H), 5.26 (s, 2H), 1.80 (d, J=12.1 Hz, 6H); ¹⁹F NMR (377 MHz, CDCl₃) δ-132.99 (1F), −160.67 (1F).

The following compounds in Table 3 were prepared using procedures similar to those described in Intermediate 8 using appropriate starting materials.

TABLE 3

Exact Mass

No.
Structure
Name
[M + H]⁺

9

[Image Omitted]

5-Chloro-4- (dimethylphosphoryl) pyridin-3-amine
Calc'd 205.02, 207.02, found 204.95, 206.95

10

[Image Omitted]

(5-Amino-2- fluoropyridin-4- yl)dimethylphosphine oxide
Calc'd 189.05, found 189.15.

Example 1: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[Image Omitted]

Step 1. 4-(Dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine

To a stirred mixture of 4-(dimethylphosphoryl)pyridin-3-amine (2.18 g, 12.81 mmol), 1-bromo-2-fluorobenzene (3.36 g, 19.22 mmol), methanesulfonato2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-bipheny)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (1.16 g, 1.28 mmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (BrettPhos) (1.38 g, 2.56 mmol) in 1,4-dioxane (25 mL) was added sodium tert-butoxide (3.69 g, 38.44 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 100° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine (2.6 g, 77%) as a yellow oil. MS ESI calculated for C₁₃H₁₄FN₂OP [M+H]⁺, 265.08, found 265.00; ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.41 (d, J=5.3 Hz, 1H), 8.12 (t, J=4.3 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.16-7.04 (m, 4H), 1.89 (s, 3H), 1.86 (s, 3H); ¹⁹F NMR (377 MHz, CDCl3) δ-123.53.

Step 2. 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

To a stirred mixture of 4-(dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine (2.6 g, 9.84 mmol) in tetrahydrofuran (25 mL) and methanol (25 mL) were added p-toluenesulfonic acid monohydrate (5.24 g, 27.55 mmol) and N-iodosuccinimide (6.64 g, 29.52 mmol) at room temperature. The reaction mixture was stirred for 1 h at 60° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/ethanol (10/1) to afford crude product (3.3 g) which was further purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase: acetonitrile in water (Plus 10 mmol/L NH₄HCO₃), 15% to 50% gradient in 30 min; detector: UV 254/220 nm. The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (1.08 g, >98% purity, 28%) as an off-white solid and −1 g 95% purity product. MS ESI calculated for C₁₃H₁₃FIN₂OP [M+H]⁺, 390.98, found 391.05; ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.50-7.45 (m, 2H), 7.26 (t, J=8.6 Hz, 1H), 1.83 (s, 3H), 1.80 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-124.70.

The following compounds in Table 4 were prepared using procedures similar to those described in Example 1 using appropriate starting materials.

TABLE 4

Exact

Mass

No.
Structure
Name
[M + H]⁺

2

[Image Omitted]

2-(Dimethyl- phosphoryl)- 5-fluoro-N- (2-fluoro-4- iodophenyl)- aniline
Calc'd 407.97, found 407.90

3

[Image Omitted]

N-(2,3- Difluoro-4- iodophenyl)-4- (dimethyl- phosphoryl)- pyridin-3- amine
Calc'd 408.97, found 409.90

4

[Image Omitted]

6-(Dimethyl- phosphoryl)- 2,3-difluoro- N-(2-fluoro-4- iodophenyl)- aniline
Calc'd 425.97, found 425.80

5

[Image Omitted]

1-(3-((2- Fluoro-4- iodophenyl)- amino)- pyridin-4- yl)phos- pholane 1-oxide
Calc'd 417.00, found 417.00

6

[Image Omitted]

4-(Di- ethylphos- phoryl)-N- (2-fluoro-4- iodophenyl)- pyridin-3- amine
Calc'd 419.01, found 419.40

7

[Image Omitted]

4-[Ethyl- (methyl)- phosphoryl]- N-(2- fluoro-4- iodophenyl)- pyridin-3- amine
Calc'd 405.00, found 405.00

13

[Image Omitted]

5-Chloro-4- (dimethyl- phosphoryl)-N- (2-fluoro-4- iodophenyl)- pyridin-3- amine
Calc'd 424.94, found 424.95

21

[Image Omitted]

(2-Fluoro-5- ((2-fluoro-4- iodophenyl)- amino)py- ridin-4- yl)dimethyl- phos- phine oxide
Calc'd 408.97, found 409.00

22

[Image Omitted]

4-(Dimethyl- phosphoryl)- N-(4- iodophenyl)- pyridin-3- amine
Calc'd 372.99, found 372.95

Example 8 & 9: (R)-4-[Ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine and (S)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[Image Omitted]

The 4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (54 mg) was purified by Prep-chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2×25 cm; Mobile Phase A: hexanes (0.5% 2 M NH₃-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 14 min; Wave Length: 220/254 nm; RT1 (min): 10.92; RT2 (min): 12.85; Sample Solvent: MeOH:DCM=1: 1-HPLC; Injection Volume: 0.3 mL. The faster peak (RT1: 10.92 min) contained desired product were combined and concentrated to afford one enantiomer (absolute chiral configuration was not determined) (19.9 mg, 36%) as a light yellow semi-solid. MS ESI calculated for C₁₄H₁₅FIN₂OP [M+H]⁺, 405.00, found 405.00; ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.18 (t, J=5.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.49-7.42 (m, 2H), 7.27 (t, J=8.6 Hz, 1H), 2.08-2.00 (m, 2H), 1.82 (d, J=13.6 Hz, 3H) 1.06-0.98 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-124.71. The slower peak (RT2: 12.85 min) contained desired product were combined and concentrated to afford second enantiomer (absolute chiral configuration was not determined) (19.8 mg, 36%) as a light yellow semi-solid. MS ESI calculated for C₁₄H₁₅FIN₂OP [M+H]⁺, 405.00, found 405.00; ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.18 (t, J=5.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.49-7.42 (m, 2H), 7.27 (t, J=8.6 Hz, 1H), 2.08-2.00 (m, 2H), 1.82 (d, J=13.6 Hz, 3H) 1.06-0.98 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ-124.68.

Example 10: N-(4-Bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[Image Omitted]

To a stirred mixture of 4-(dimethylphosphoryl)pyridin-3-amine (0.25 g, 1.46 mmol) and 4-bromo-2-fluoro-1-iodobenzene (0.66 g, 2.20 mmol) in 1,4-dioxane (2.50 mL) were added 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (BrettPhos) (0.15 g, 0.29 mmol), methanesulfonato2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-bipheny)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G₃) (0.13 g, 0.14 mmol) and sodium tert-butoxide (0.42 g, 4.40 mmol) in portions at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred at 100° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Xselect CSH C18 OBD Column 30×150 mm 5 m; Mobile Phase A: Water (10 mmol/L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: 27% B to 37% B in 11 min; Wavelength: 254 nm. The fractions contained desired product were combined and concentrated to afford N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (10 mg, 2%) as a light yellow oil. MS ESI calculated for C13H₁₃BrFN₂OP [M+H]⁺, 342.99, 344.99, found 342.95, 344.95; ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.19 (dd, J=4.9, 3.2 Hz, 1H), 7.61 (dd, J=10.8, 2.2 Hz, 1H), 7.53-7.38 (m, 2H), 7.35 (dd, J=8.8, 2.2 Hz, 1H), 1.82 (d, J=13.7 Hz, 6H); ¹⁹F NMR (377 MHz, DMSO-d₆) δ-123.94 (1F).

The following compounds in Table 5 were prepared using procedures similar to those described in Example 10 using appropriate starting materials.

TABLE 5

No.
Structure
Name
Exact Mass [M + H]⁺

11

[Image Omitted]

N-(4-bromo-2- fluorophenyl)-4- (diethylphosphoryl)pyridin- 3-amine
Calc'd 371.02, 373.02, found 370.95, 372.95

12

[Image Omitted]

1-(3-((4-Bromo-2- fluorophenyl)amino)pyridin- 4-yl)phospholane 1- oxide
Calc'd 369.01, 371.01, found 369.00, 371.00

26

[Image Omitted]

N-(4-bromo-2- chlorophenyl)-4- (dimethylphosphoryl)-5- fluoropyridin-3-amine
Calc'd 376.95, 378.95, found 376.95, 378.95

27

[Image Omitted]

N-(4-bromo-2- chlorophenyl)-4- (dimethylphosphoryl) pyridin-3-amine
Calc'd 358.96, 360.96, found 359.00, 361.00

28

[Image Omitted]

N-(4-Bromo-2- chlorophenyl)-5-chloro-4- (dimethylphosphoryl) pyridin-3-amine
Calc'd 392.92, 394.92, found 392.90, 394.90

29

[Image Omitted]

(3-((4-Bromo-2- fluorophenyl)amino)-5- chloropyridin-4- yl)dimethylphosphine oxide
Calc'd 376.95, 378.95, found 376.90, 378.90

Example 14: (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[Image Omitted]

Step 1. (3-((2-Fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide

To a stirred mixture of 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (0.30 g, 0.77 mmol), trimethylsilylacetylene (0.23 g, 2.31 mmol), trans-dichlorobis(triphenylphosphine)palladium (53.97 mg, 0.08 mmol) and cuprous iodide (29.29 mg, 0.15 mmol) in N,N-dimethylformamide (3.00 mL) was added triethylamine (0.23 g, 2.31 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford (3-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide (0.25 g, 90%) as a brown solid. MS ESI calculated for C₁₈H₂₂FN₂OPSi [M+H]⁺, 361.12, found 361.10.

Step 2: (3-((4-Ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

To a stirred solution of (3-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide (0.27 g, 0.75 mmol) in tetrahydrofuran (3.00 mL) was added TBAF in tetrahydrofuran (1.12 mL, 1 M) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1) to afford the crude product. The crude product (0.20 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile phase A: Water (10 mmol/L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 31% B in 8 min, 31% B; Wave length: 254 nm; RT: 7 min. The fractions contained desired product were combined and concentrated to afford (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (60.90 mg, 28%) as a light yellow semi-solid. MS ESI calculated for C₁₅H₁₄FN₂OP [M+H]⁺, 289.08, found 289.05; ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (d, J=1.7 Hz, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.23 (dd, J=4.9, 3.2 Hz, 1H), 7.51 (dd, J=13.2, 4.9 Hz, 1H), 7.46-7.36 (in, 2H), 7.26 (dd, J=8.3, 1.9 Hz, 1H), 4.18 (s, 1H), 1.82 (d, J=13.8 Hz, 6H).

The following compounds in Table 6 were prepared using procedures similar to those described in Example 14 using appropriate starting materials.

TABLE 6

Exact

Mass

No.
Structure
Name
[M + H]⁺

15

[Image Omitted]

1-(3-((4- Ethynyl-2- fluoro- phenyl)- amino)- pyridin-4- yl)phos- pholane 1-oxide
Calc'd 315.10, found 315.10

18

[Image Omitted]

4-(Diethyl- phosphoryl)- N-(4- ethynyl- 2-fluoro- phenyl)- pyridin-3- amine
Calc'd 317.11, found 317.00

31

[Image Omitted]

4-(Dimeth- ylphos- phoryl)- N-(4- ethynyl-2- fluoro- phenyl)-5- fluoro- pyridin- 3-amine
Calc'd 307.07, found 307.00

Example 16 & 17: N-(4-Bromo-2-fluorophenyl)-4-[(R)-ethyl(methyl)phosphoryl]pyridin-3-amine & N-(4-Bromo-2-fluorophenyl)-4-[(S)-ethyl(methyl)phosphoryl]pyridin-3-amine

[Image Omitted]

Step 1. N-(4-Bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine

To a stirred mixture of 4-[ethyl(methyl)phosphoryl]pyridin-3-amine (180 mg, 0.98 mmol), methanesulfonato2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-bipheny)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (CAS:1470372-59-8) (88.59 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (BrettPhos) (CAS:1070663-78-3) (104.92 mg, 0.20 mmol) and sodium tert-butoxide (281.77 mg, 2.93 mmol) in 1,4-dioxane (1.8 mL) was added 4-bromo-2-fluoro-1-iodobenzene (441.10 mg, 1.47 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 100° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: A: Water (Plus 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 37% B in 8 min, 37% B; Wave Length: 254 nm; RT1 (min): 7. The fractions contained desired product were combined and concentrated to afford N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine (79 mg, 22%) as a colorless oil. MS ESI calculated for C₁₄H₁₅BrFN₂OP [M+H]⁺, 357.01, 359.01, found 357.00, 359.00.

Step 2: N-(4-Bromo-2-fluorophenyl)-4-[(R)-ethyl(methyl)phosphoryl]pyridin-3-amine & N-(4-Bromo-2-fluorophenyl)-4-[(S)-ethyl(methyl)phosphoryl]pyridin-3-amine

The (N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine) (79 mg) was purified by Prep-HPLC with the following conditions: Column: CHIRALPAK IE, 2×25 cm, 5 m; Mobile Phase A: methyl tert-butyl ether (0.5% 2 M NH₃-methyl alcohol)-HPLC, Mobile Phase B: ethyl alcohol: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12 min; Wave Length: 220/254 nm; RT1 (min): 9.29; RT2 (min): 11.34. The faster peak (RT1: 9.29 min) contained desired product were combined and concentrated to afford one enantiomer (19.5 mg, 25%) as a colorless oil. MS ESI calculated for C₁₄H₁₅BrFN₂OP [M+H]⁺, 357.01, 359.01, found 357.15, 359.15; ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.18 (dd, J=4.9, 3.2 Hz, 1H), 7.60 (dd, J=10.7, 2.2 Hz, 1H), 7.49-7.38 (m, 2H), 7.35-7.29 (m, 1H), 2.04-1.96 (m, 2H), 1.82 (d, J=13.3 Hz, 3H), 1.03-0.98 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-123.83 (1F).

The slower peak contained desired product were combined and concentrated to afford second enantiomer (18 mg, 23%) as a colorless oil. MS ESI calculated for C₁₄H₁₅BrFN₂OP [M+H]⁺, 357.01, 359.01, found 357.15, 359.15; ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.18 (dd, J=4.9, 3.2 Hz, 1H), 7.60 (dd, J=10.7, 2.2 Hz, 1H), 7.49-7.38 (m, 2H), 7.35-7.28 (m, 1H), 2.04-1.95 (m, 2H), 1.82 (d, J=13.3 Hz, 3H), 1.04-0.95 (3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-123.83 (1F).

Example 19 & 20: 4—[(R)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine & 4-[(S)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine

[Image Omitted]

Step 1. 4-[Ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine

To a stirred mixture of 4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (400 mg, 0.99 mmol) and CuI (37.70 mg, 0.20 mmol) in DMF (4 mL) were added trimethylsilylacetylene (0.42 mL, 2.97 mmol) and triethylamine (0.41 mL, 2.97 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford 4-[ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine (270 mg, 73%) as a brown solid. MS ESI calculated for C₁₉H₂₄FN₂OPSi [M+H]⁺, 375.15, found 375.00.

Step 2. 4-[Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine

To a stirred solution of 4-[ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2 (trimethylsilyl)ethynyl]phenyl}pyridin-3-amine (230 mg, 0.61 mmol) in tetrahydrofuran (2.3 mL) was added TBAF (0.92 mL, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature under. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 m, 120 g; Eluent A: Water (Plus 10 mmol/L NH₄HCO₃); Eluent B: ACN; Gradient: 25%-45% B in 25 min; Flow rate: 60 mL/min; Detector: 220/254 nm. The fractions contained desired product were combined and concentrated to afford 4-[ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine (90 mg, 48%) as a yellow solid. MS ESI calculated for C₁₆H₁₆FN₂OP [M+H]⁺, 303.10, found 303.00.

Step 3. 4-[(R)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine & 4-[(S)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine

The 4-[ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine (90 mg, 0.30 mmol) was purified by Prep-HPLC with the following conditions: Column: CHIRALPAK IE, 2×25 cm, 5 m; Mobile Phase A: Hex (0.5% 2 M NH₃-MeOH)-HPLC, Mobile Phase B: methyl alcohol: dichloromethane=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 13 min; Wave Length: 220/254 nm; RT1 (min): 10.21; RT2 (min): 11.86. The faster peak contained desired product were combined and concentrated to afford one enantiomer (12.2 mg, 13%) as a yellow solid. MS ESI calculated for C₁₆H₁₆FN₂OP [M+H]⁺, 303.10, found 303.05; ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.23 (dd, J=4.9, 3.1 Hz, 1H), 7.52-7.37 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 4.19 (s, 1H), 2.04-1.98 (m, 2H), 1.83 (d, J=13.4 Hz, 3H), 1.02-0.95 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-127.61 (1F); ³¹P NMR (162 MHz, DMSO-d₆) δ 49.17 (1P).

The slower peak contained desired product were combined and concentrated to afford second enantiomer (23 mg, 25%) as a yellow solid. MS ESI calculated for C₁₆H₁₆FN₂OP [M+H]⁺, 303.10, found 303.05; ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.23 (dd, J=4.9, 3.1 Hz, 1H), 7.52-7.37 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 4.19 (s, 1H), 2.06-2.00 (m, 2H), 1.83 (d, J=13.4 Hz, 3H), 1.04-0.99 (m, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-127.61 (1F); ³¹P NMR (162 MHz, DMSO-d₆) δ 48.956 (1P).

Example 23: N-(4-Cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[Image Omitted]

To a stirred solution of 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (200 mg, 0.51 mmol) and cyclopropylboronic acid (132.11 mg, 1.54 mmol) and Dichlorobis(triphenylphosphine)palladium(II) (83.52 mg, 0.10 mmol) and Potassium phosphate tribasic (326.45 mg, 1.54 mmol) in dioxane (2 mL) and water (0.2 mL) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (12/1). The crude product was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 m; Mobile Phase A: Water (Plus 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 33% B in 8 min, 33% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (50.3 mg) as an off-white solid. MS ESI calculated for C₁₆H₁₈FN₂OP [M+H]⁺, 305.11, found 305.10; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.22 (m, 1H), 8.08 (dd, J=4.9, 3.3 Hz, 1H), 7.40-7.36 (m, 1H), 7.30 (t, J=8.5 Hz, 1H), 7.00 (dd, J=12.5, 2.1 Hz, 1H), 6.93 (dd, J=8.2, 2.1 Hz, 1H), 1.99-1.87 (m, 1H), 1.81 (d, J=13.7 Hz, 6H), 1.01-0.89 (m, 2H), 0.73-0.64 (m, 2H).

The following compounds in Table 7 were prepared using procedures similar to those described in Example 23 using appropriate starting materials.

TABLE 7

Exact

Mass

No.
Structure
Name
[M + H]⁺

32

[Image Omitted]

(3-Chloro-5- ((4-cyclo- propyl-2- fluorophenyl)- amino)- pyridin-4- yl)dimethyl- phosphine oxide
Calc'd 339.08, 341.08, found 338.95, 340.95

Example 24: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[Image Omitted]

Step 1: N-(5-Fluoropyridin-3-yl)-2,2-dimethylpropanamide

To a stirred mixture of trifluoroacetic acid (27.08 g, 267.60 mmol) and 5-fluoropyridin-3-amine (10 g, 89.20 mmol) in dichlormethane (100 mL) was added 2,2-dimethylpropanoyl chloride (13.98 g, 115.96 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (100 mL). The aqueous layer was extracted with dichlormethane (3×100 mL). The combined organic layers was washed with brine (3×100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide (9.35 g, crude) as a yellow solid. MS ESI calculated for C₁₀H₁₃FN₂O [M+H]⁺, 197.10 found 197.25; ¹H NMR (400 MHz, CDCl₃) δ 8.33-8.28 (m, 1H), 8.22-8.20 (m, 2H), 7.56 (s, 1H), 1.35 (s, 9H).

Step 2: N-(5-Fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide

To a stirred solution of N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide (5.00 g, 25.48 mmol) and N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (8.88 g, 76.44 mmol) in tetrahydrofuran (15 mL) was added n-Butyllithium (30.58 mL, 76.44 mmol, 2.5 M in hexanes) dropwise over 1 h at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h at −78° C. under nitrogen atmosphere. To the above mixture was added iodine (19.40 g, 76.44 mmol) in THE (5 mL) dropwise over 30 min at −78° C. The resulting mixture was stirred for additional 1 h at −78° C. The reaction was quenched by the addition of Water (50 mL) at −78° C. The resulting mixture was decolorized by the addition of Sodium thiosulfate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with brine (2×100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (1/1). The fractions contained desired product were combined and concentrated to afford N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (4.7 g, 57%) as a white crystal. MS ESI calculated for C₁₀H₁₂FN₂O [M+H]⁺, 323.00, found 322.95; ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1H), 8.13 (d, J=0.8 Hz, 1H), 7.75 (s, 1H), 1.42 (d, J=0.8 Hz, 9H).

Step 3: 5-Fluoro-4-iodopyridin-3-amine

A mixture of N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (4.7 g, 14.591 mmol, 1 equiv) in aqueous HCl (50 mL, 3 M) was stirred for 3 h at 100° C. The resulting mixture was basified with aqueous sodium hydroxide (50 mL, 3 M) at room temperature. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layers was washed with brine (1×50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5-fluoro-4-iodopyridin-3-amine (3.5 g, crude) as a white solid. MS ESI calculated for C₅H₄FIN [M+H]⁺, 238.94, found 238.90; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.74 (s, 1H), 4.35 (s, 2H).

Step 4: 4-(Dimethylphosphoryl)-5-fluoropyridin-3-amine

To a stirred mixture of 5-fluoro-4-iodopyridin-3-amine (200 mg, 0.84 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.08 mmol), Potassium phosphate tribasic (356 mg, 1.68 mmol,) and Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium (74 mg, 0.08 mmol) in 1,4-dioxane (5 mL) was added (methylphosphonoyl)methane (98 mg, 1.26 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 100° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 m, 120 g; Eluent A: Water (Plus 10 mmol/L formic acid); Eluent B: Acetonitrile; Gradient: 2%-15% B in 25 min; Flow rate: 60 mL/min; Detector: 220/254 nm. The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 mg, 82%) as a yellow oil. MS ESI calculated for C₇H₁₀FN₂OP [M+H]⁺, 189.05, found 189.05; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.77 (s, 1H), 5.94 (s, 2H), 1.90-1.86 (m, 6H).

Step 5: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine

To a stirred mixture of 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 mg, 0.69 mmol), methanesulfonato2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-bipheny)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (62 mg, 0.06 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (BrettPhos) (37 mg, 0.06 mmol) and sodium tert-butoxide (199 mg, 2.07 mmol) in 1,4-dioxane (2 mL) was added benzene, 1-fluoro-2-iodo-(153.40 mg, 0.69 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 60° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 m, 40 g; Eluent A: Water (Plus 10 mmol/L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30%-60% B in 25 min; Flow rate: 30 mL/min; Detector: 220/254 nm; desired fractions were collected at 50% B and concentrated under reduced pressure to afford 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine (100 mg, 51%) as a yellow solid. MS ESI calculated for C₁₃H₁₃F₂N₂OP [M+H]⁺, 283.07 found 282.95; ¹H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H), 8.20-8.14 (m, 1H), 7.89 (d, J=4.4 Hz, 1H), 7.40-7.38 (m, 1H), 7.22-7.10 (m, 3H), 1.96 (dd, J=13.6, 1.8 Hz, 6H).

Step 6: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

To a stirred mixture of 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine (100 mg, 0.35 mmol) and N-iodosuccinimide (79 mg, 0.35 mmol) in tetrahydrofuran (0.5 mL) and methyl alcohol (0.5 mL) was added p-toluenesulfonic acid monohydrate (188 mg, 0.99 mmol). The reaction mixture was stirred for 1 h at 60° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 m, 40 g; Eluent A: Water (Plus 10 mmol/L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30%-60% B in 25 min; Flow rate: 30 mL/min; Detector: 220/254 nm. The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (50 mg, 34%) as a white solid. MS ESI calculated for C₁₃H₁₂F₂₁N₂OP [M+H]⁺, 408.97, found 408.95; ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.25 (d, J=3.6 Hz, 1H), 8.08 (d, J=4.4 Hz, 1H), 7.71 (dd, J=10.4, 2.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.33 (t, J=8.4 Hz, 1H), 1.90 (dd, J=14.0, 1.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) −119.12 (1F), 123.01 (1F); ¹⁹P-NMR (162 MHz, DMSO-d₆) 43.20 (1P).

Example 25: (2-Fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[Image Omitted]

Step 1: Tert-butyl (2-fluoro-4-iodopyridin-3-yl)carbamate

To a stirred mixture of 2-fluoro-4-iodopyridine-3-carboxylic acid (3 g, 11.24 mmol) and DPPA (3.09 g, 11.24 mmol) in t-BuOH (30.00 mL) was added TEA (1.14 g, 11.24 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 80° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2-fluoro-4-iodopyridin-3-yl)carbamate (2.1 g, 55%) as a brown oil. MS ESI calculated for C₁₀H₁₂FIN₂O₂[M+H]⁺, 338.99, found 338.95.

Step 2: 2-Fluoro-4-iodopyridin-3-amine hydrochloride

To a stirred solution of tert-butyl (2-fluoro-4-iodopyridin-3-yl)carbamate (2.1 g, 6.21 mmol) in DCM (10 mL) was added 4 M HCl (g) (20.99 mL, 83.97 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with DCM (3×30 mL). The crude product 2-fluoro-4-iodopyridin-3-amine hydrochloride (1.7 g, crude) was used in the next step directly without further purification. MS ESI calculated for C₅H₅ClFIN₂[M+H−HCl]⁺, 238.94, found 239.05.

Step 3: (3-Amino-2-fluoropyridin-4-yl)dimethylphosphine oxide

To a stirred mixture of 2-fluoro-4-iodopyridin-3-amine hydrochloride (0.7 g, 2.94 mmol), (methylphosphonoyl)methane (0.28 g, 3.53 mmol), Pd(OAc)₂(33.02 mg, 0.15 mmol) and XantPhos (85.09 mg, 0.15 mmol) in DMF (7.00 mL) was added K₃PO₄(1.25 g, 5.88 mmol) in portions at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 120° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (10/1). The fractions contained desired product were combined and concentrated to afford 4-(dimethylphosphoryl)-2-fluoropyridin-3-amine (170 mg, 31%) as a brown solid. MS ESI calculated for C