Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• Human Axl belongs to the TAM subfamily of receptor tyrosine kinases that includes Mer. TAM kinases are characterized by an extracellular ligand binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in a number of tumor cell types and was initially cloned from patients with chronic myelogenous leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is believed to cause tumor growth through activation of proliferative and anti-apoptotic signaling pathways.
• Axl has been associated with cancers including, but not limiting to lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer.
• the over-expression of Axl results in a poor prognosis for patients with the indicated cancers.
• Activation of Mer like Axl, conveys downstream signaling pathways that cause tumor growth and activation.
• Mer binds ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer on its intracellular domain, resulting in downstream signal activation.
• c-Met is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with invasive cell growth.
• KDR is a tyrosine kinase receptor that binds vascular endothelial growth factor (VEGF).
• VEGF vascular endothelial growth factor
• the compounds are of formula (I'''): or a pharmaceutically acceptable salt, a stereoisomer, tautomer or a mixture of stereoisomers thereof.
• a compound, or a pharmaceutically acceptable salt, stereoisomer, or a mixture of stereoisomers thereof selected from Table 1, Table 2, or Table 3.
• pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.
• Some embodiments provide for methods of modulating in vivo activity of a protein kinase in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein.
• Some embodiments provide for methods of treating a disease, disorder, or syndrome in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein, wherein the disease, disorder, or syndrome is mediated at least in part by modulating in vivo activity of a protein kinase.
• Some embodiments provide for methods of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein, in combination with a therapeutic agent or therapy.
• the disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and method of using (or administering) and making the compounds.
• the disclosure further provides compounds or compositions for use in a method of treating a disease, disorder, or condition that is mediated, at least in part, by c-Met, Axl, Mer and/or KDR activity.
• the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is mediated, at least in part, by c- Met, Axl, Mer and/or KDR.
• DETAILED DESCRIPTION Definitions [0015] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0016] A dash (“-” ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH 2 is attached through the carbon atom.
• a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
• a wavy line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
• the prefix “C u-v ” indicates that the following group has from u to v carbon atoms. For example, “C 1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
• references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
• the term “about” includes the indicated amount ⁇ 10%.
• the term “about” includes the indicated amount ⁇ 5%.
• the term “about” includes the indicated amount ⁇ 1%.
• to the term “about X” includes description of “X”.
• the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
• reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
• alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
• alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
• butyl includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ); and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., - CH(CH 3 ) 2 ).
• a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
• a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
• combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
• Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
• alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
• Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
• alkynyl also includes those groups having one triple bond and one double bond.
• Alkoxy refers to the group “alkyl-O-”.
• alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2- dimethylbutoxy.
• Alkylthio refers to the group “alkyl-S-”.
• Alkylsulfinyl refers to the group “alkyl-S(O)-”.
• Alkylsulfonyl refers to the group “alkyl-S(O) 2 -”.
• Alkylsulfonylalkyl refers to -alkyl-S(O) 2 -alkyl.
• acyl refers to a group -C(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.
• “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N- amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocycloalkyl; each of which may be optionally substituted, as defined herein.
• Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Amino refers to -C(NR y )(NR z 2), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
• aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
• Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl.
• Aryl does not encompass or overlap in any way with heteroaryl defined below.
• aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocycloalkyl, the resulting ring system is heterocycloalkyl.
• Arylalkyl or “Aralkyl” refers to the group “aryl-alkyl-”.
• Carbamoyl refers to –C(O)NR y R z .
• O-carbamoyl refers to -O-C(O)NR y R z and “N- carbamoyl” refers to -NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Carboxyl ester or “ester” refer to both -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems.
• cycloalkyl includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
• cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
• Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like.
• one or more ring carbons of “cycloalkyl” can be optionally replaced by a carbonyl group. Examples of such cycloalkyl include cyclohexanone-4-yl, and the like.
• cycloalkyl is intended to encompass moieties that have one or more aromatic ring fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
• a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
• cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
• spirocycloalkyl refers to the group “cycloalkyl-alkyl-”.
• “Hydrazino” refers to -NHNH 2 .
• Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.
• Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
• a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
• Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
• haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.
• Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
• Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.
• “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom.
• the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
• Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , - CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 , - CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , - CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.) and amines (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 ,
• heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
• “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, boron, phosphorus and sulfur.
• heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
• ring carbon atoms i.e., C 1-20 heteroaryl
• 3 to 12 ring carbon atoms i.e., C 3-12 heteroaryl
• 3 to 8 carbon ring atoms i.e., C 3-8 heteroaryl
• 1 to 5 ring heteroatoms 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
• heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
• the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
• the heteroaryl has 5-14, or 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
• the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
• the heteroaryl is a five-membered or six-membered heteroaryl ring.
• the heteroaryl is an eight-membered, nine- membered or ten-membered fused bicyclic heteroaryl ring.
• heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxide
• any ring-forming N in a heteroaryl moiety can be an N-oxide.
• a fused heteroaryl refers to a heteroaryl ring fused to another heteroaryl ring.
• the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system.
• Heteroarylalkyl refers to the group “heteroaryl-alkyl-”.
• Heterocycloalkyl or “heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from boron, phosphorus, nitrogen, oxygen and sulfur.
• heterocycloalkyl includes heterocycloalkenyl groups (i.e., the heterocycloalkyl group having at least one double bond), bridged-heterocycloalkyl groups, fused- heterocycloalkyl groups and spiro-heterocycloalkyl groups.
• a heterocycloalkyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro.
• One or more ring carbon atoms and ring heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc.) or a nitrogen atom can be quaternized.
• the heterocycloalkyl group can be attached through a ring carbon atom or a ring heteroatom. Any non-aromatic ring containing at least one heteroatom is considered a heterocycloalkyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
• heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocycloalkyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocycloalkyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocycloalkyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
• heterocycloalkyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-
• heterocycloalkyl also includes “spiroheterocycloalkyl” when there are two positions for substitution on the same carbon atom.
• spiro-heterocycloalkyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2- oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl.
• heterocycloalkyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring is fused to one or more aryl or heteroaryl rings, regardless of the attachment to the remainder of the molecule (i.e., a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring atom including a ring atom of the fused aromatic ring).
• fused-heterocycloalkyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocycloalkyl can be bound via either ring of the fused system.
• Heterocycloalkylalkyl refers to the group “heterocycloalkyl-alkyl-.”
• “Sulfonyl” refers to the group -S(O) 2 R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.
• “Sulfinyl” refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.
• “Sulfonamido” refers to the groups -SO 2 NR y R z and -NR y SO 2 R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• the terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• the term “optionally substituted” refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
• substituted used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and/or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carb
• R q and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and/or heteroarylalkyl.
• substituted also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, N-heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R q and R h and R i are taken together with the atoms to which they are attached to form a heterocycloalkyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl,
• the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.
• the term “substituted” may describe other chemical groups defined herein.
• the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three.
• Any compound or structure given herein, is intended to represent unlabeled forms as well as isotopically labeled forms (isotopologues) of the compounds.
• Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
• isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
• Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• the term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom.
• Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [0061] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME).
• ADME drug metabolism and pharmacokinetics
• Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index (see e.g., A. Kerekes et.al. J. Med. Chem.2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm.2015, 58, 308-312).
• An 18 F, 3 H, 11 C labeled compound may be useful for PET or SPECT or other imaging studies.
• Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. [0062] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom.
• one or more hydrogen atoms in a compound presented herein can be replaced or substituted by deuterium (e.g., one or more hydrogen atoms of a C 1-6 alkyl group can be replaced by deuterium atoms, such as -CH 3 being replaced for –CD 3 ).
• the compound includes two or more deuterium atoms.
• the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms.
• all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F.
• Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays. [0063] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor.
• any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
• a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
• any atom specifically designated as a deuterium (D) is meant to represent deuterium.
• the corresponding deuterated analog is provided.
• the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• a pharmaceutically acceptable salt isotopically enriched analog, deuterated analog, isomer (such as a stereoisomer), mixture of isomers (such as a mixture of stereoisomers), and prodrug of the compounds described herein.
• “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
• pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
• “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
• Pharmaceutically acceptable acid addition salts may be prepared from non-toxic inorganic and organic acids.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
• non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
• tautomer means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom of the molecule.
• the tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
• the compounds described herein may have one or more tautomers and therefore include various isomers.
• Tautomers are in equilibrium with one another.
• amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
• the compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
• the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
• a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
• “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).
• “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
• Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
• Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively.
• prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like.
• esters e.g., acetate, formate and benzoate derivatives
• amides e.g., guanidines
• carbamates e.g., N,N-dimethylaminocarbonyl
• Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B.
• leaving group refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
• the non-limiting examples of a leaving group include, halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro- benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4- methoxy-benzene)sulfonyloxy, and the like.
• amide coupling conditions refers to the reaction conditions under which an amine and a carboxylic acid couple to form an amide using a coupling reagent in presence of a base.
• the non- limiting examples of coupling reagents include 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) with hydroxybenzotriazole monohydrate (HOBt), O-(7-Azabenzotriazole-1-yl)-N,N,N,N’- tetramethyluronium hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole, and the like.
• the non-limiting examples of the base include N-methylmorpholine, pyridine, morpholine, imidazole, and the like.
• the term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
• the chemical substructure of a protective group varies widely.
• One function of a protective group is to serve as an intermediate in the synthesis of the parental drug substance.
• Chemical protective groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991.
• Protective groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. [0078] The non-limiting examples of protective groups for a hydroxy (i.e.
• hydroxy protecting group examples include methoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether, t- butyldiphenylsilyl ether, acetate ester, pivalate ester, benzoate ester, benzylidene acetal, acetonide, silyl ether, and the like.
• List of Abbreviations and Acronyms Abbreviation Meaning ACN acetonitrile Amphos 2 PdCl 2 bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) anhyd.
• R a is H, methyl, benzyl, piperidin-4-yl, (piperidin-4-yl)methyl, (1-methylpiperidin-4-yl)methyl, or (1-t-butoxypiperidin-4- yl)methyl.
• a compound of Formula (I''') with the proviso that when X 1 is CH, X 2 is CF, X 3 is CH, X 4 is CR 2 , X 5 is CH, m is 0, R 9 is H, R 10 is H, n is 1, R 1 is OCH 3 or CN, R 2 is OCH 3 , R 7 is fluoro and is para to ring A, and Z 3 is CR 42 , then R 42 cannot be CN, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 OCH 3 , or OH.
• a compound of Formula (I''') with the proviso that when X 1 is CH, X 3 is CH, X 4 is CR 2 , R 1 is OCH 3 , R 2 is OCH 3 , R 9 is H, n is 1, R 7 is fluoro and is para to ring A, one of X 2 and X 5 is N, or X 2 and X 5 are each N, then R 43 is not cyclopropyl or isopropyl.
• a compound of Formula (I''') with the proviso that the compound is not: 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl- 4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclopropyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclobutyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-
• R a is H, methyl, benzyl, piperidin-4-yl, (piperidin-4-yl)methyl, (1-methylpiperidin-4-yl)methyl, or (1-t-butoxypiperidin-4- yl)methyl.
• a compound of Formula (I’) with the proviso that when X 1 is CH, X 2 is CF, X 3 is CH, X 4 is CR 2 , X 5 is CH, m is 0, R 9 is H, R 10 is H, n is 1, R 1 is OCH 3 or CN, R 2 is OCH 3 , R 7 is fluoro and is para to ring A, and Z 3 is CR 42 , then R 42 cannot be CN, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 OCH 3 , or OH.
• a compound of Formula (I’) with the proviso that when X 1 is CH, X 3 is CH, X 4 is CR 2 , R 1 is OCH 3 , R 2 is OCH 3 , R 9 is H, n is 1, R 7 is fluoro and is para to ring A, one of X 2 and X 5 is N, or X 2 and X 5 are each N, then R 43 is not cyclopropyl or isopropyl.
• a compound of Formula (I’) with the proviso that the compound is not: 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl- 4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclopropyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclobutyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclo
• a compound of Formula (I) with the proviso that when X 1 is CH, X 2 is CF, X 3 is CH, m is 0, R 9 is H, n is 1, R 1 is OCH 3 or CN, R 2 is OCH 3 , R 7 is fluoro and is para to ring A, and Z 3 is CR 42 , then R 42 cannot be CN, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 OCH 3 , or OH.
• a compound of Formula (I) with the proviso that when X 1 is CH, X 3 is CH, R 1 is OCH 3 , R 2 is OCH 3 , R 9 is H, n is 1, R 7 is fluoro and is para to ring A, and X 2 is N, then R 43 is not cyclopropyl or isopropyl.
• a compound of Formula (I) with the proviso that the compound is not: 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl- 4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclopropyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclobutyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; 6-cyano-1-cyclobut
• a compound of Formula (I’’ or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof.
• X 1 is N.
• R 4 , R 15 , R 16 and R 20 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene-, C3-14 cycloalkyl-C1-4 alkylene-, (5-14 membered heteroaryl
• R 4 , R 15 , R 16 and R 20 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene-, C 3-14 cycloalkyl-C 1-4 alkylene-, (5-14 membere
• Some embodiments provide for a compound of Formula (II): or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof, wherein: X 1 is N or CR 11 ; X 2 is CR 3 or CH, and R 3 is halo; X 3 is N or CH; X 4 is N or CR 2 ; m is 0, 1 ,or 2; n is 0, 1, 2, or 3; and the remaining variables are as defined herein. [0098] Some embodiments provide for a compound of formula (Ia): or pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. [0099] In some embodiments, R 10 is H.
• Some embodiments provide for a compound of formula (Ib): or pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. [0101] Some embodiments provide for a compound of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), or (It):
• Some embodiments provide for a compound of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), or (Ibb): , (Ij) (Ik)
• Some embodiments provide for a compound of formula (Ia-1): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
• Some embodiments provide for a compound of formula (Ia-2): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
• Some embodiments provide for a compound of formula (III-1): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
• Some embodiments provide for a compound of formula (III-2): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. [0107] Some embodiments provide for a compound of formula (IV-1): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. [0108] Some embodiments provide for a compound of formula (IV-1), or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 16 is H, C 1-6 alkyl, or C 1-6 haloalkyl; and R 17 is H or C 1-6 alkyl.
• Some embodiments provide for a compound of formula (IV-2): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
• a compound having formula (III-3) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: R 1 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH
• R 2 is C 1-6 alkoxy
• R 3 is H or halo
• R 12 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH
• R 13 is H or C 1-6 alkyl optionally substitute
• R 1 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH
• R 2 is C 1-6 alkoxy
• R 3 is H or halo
• R 4 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH
• R 5 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH
• R 6 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH
• R 7 is H or C 1-6
• R 1 is H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH;
• R 2 is C 1-6 alkoxy;
• R 3 is H or halo;
• R 4 is H, C 1-6 haloalkyl, or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH;
• R 5 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH;
• R 6 is H or C 1-6 alkyl optionally substituted with C 1-6 alk
• R 1 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 is optionally substituted with C 1-6 alkoxy or OH
• R 2 is C 1-6 alkoxy
• R 3 is H or halo
• R 22 is H or C 1-6 alkyl optionally substituted with C 1-6 alkoxy or OH
• R 23 is H, C 1-6 alkyl or C 1-6 alkyl-C(O)-, wherein the C 1-6 alkyl and C 1-6 alkyl-C(O)- of R 23 are each optionally substituted with C 1-6 alky
• Some embodiments provide for a compound of formula (V): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH; R 2 is C 1-6 alkoxy; R 16 is H, C 1-6 alkyl, or C 1-6 haloalkyl; and R 17 is H or C 1-6 alkyl.
• Some embodiments provide for a compound of formula (VI): or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH; R 2 is C 1-6 alkoxy; R 7 is H or C 1-6 alkyl.
• R 8 is H or C 1-6 alkyl; and R 17 is H or C 1-6 alkyl.
• R 1 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH;
• R 2 is C 1-6 alkoxy;
• R 42 and R 43 taken together with the atoms to which they are attached form 5- to 6-membered fused heterocycloalkyl having 0-1 additional ring heteroatoms selected from O and N; and
• R 45 is H or C 1-6 alkyl.
• Some embodiments provide for a compound of formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, NH 2 C(O)-, C 1-6 alkyl-NHC(O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-C(O)- and C 1-6 alkyl-NHC(O)- of R 1 are each optionally substituted with C 1-6 alkoxy or OH; R 2 is C 1-6 alkoxy; R 43 and R 45 taken together with the atoms to which they are attached form 5- to 6-membered fused heterocycloalkyl having 0-1 additional ring heteroatoms selected from O and N; and R 42 is H or C 1-6 alkyl.
• R 1 is H, C 1-6 alkyl, C 1-6 alkoxy, halo, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkylNHC(O)-, or C 1-6 alkylSO 2 NH-.
• R 2 is H, C 1-6 alkyl, C 1-6 alkoxy, halo, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkylNHC(O)-, CF 3 , C 1-6 alkylOC(O)-, pyridyl, C 1-6 alkylSO 2 NH- or 1H-pyrazol-4-yl optionally substituted with R g .
• R 3 is H or halo.
• R 7 is H, halo, C 1-6 alkyl or C 1-6 alkoxy.
• R 7 is H, CH 3 , F, Cl or OCH 3 .
• R 9 is H.
• R 45 , R 42 , R 44 , R 5 , R 17 and R 6 are each independently selected from H, OH, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl-C(O)- and C 1-6 alkylamino, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl-C(O)- and C 1-6 alkylamino of R 45 , R 42 , R 44 , R 5 , R 17 and R 6 are each optionally substituted with 1 or 2 independently selected R g substituents.
• R 45 , R 42 , R 44 , R 5 and R 6 are each independently selected from H, CH 3 , propen-2-yl, Br, Cl, CN, methoxy, 2-fluoroethyl, isopropyl, CH 3 C(O)-, OH, t-butyl, ethyl, hydroxymethyl, isopropylthio, and methoxymethyl.
• R 45 , R 42 , and R 44 are each independently selected from H and C 1-6 alkyl optionally substituted with 1 or 2 independently selected R g substituents.
• R 40 , R 41 and R 43 are each independently selected from H, halo, and C 1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents.
• R 46 , R 8 and R 32 are each independently H or C 1-6 alkyl.
• R 18 is H or halo.
• X 1 is N.
• X 2 is CH.
• X 2 is CR 3 .
• X 2 is CR 3
• R 3 is halo.
• X 3 is CH.
• X 1 is N and X 3 is CH.
• X 4 is CR 2 . In some embodiments, X 4 is N.
• X 1 is N
• X 3 is CH
• X 4 is CR 2 .
• X 1 is CH
• X 3 is CH
• X 4 is N.
• X 5 is CH. In some embodiments, X 5 is CR 3 .
• X 2 is CR 3
• X 5 is CH
• R 3 is halo.
• the subscript m is 0.
• n is 1 and R 3 is F or H. In other embodiments, m is 1 and R 3 is F. [0142] In some embodiments, the subscript n is 0. [0143] In some embodiments, the subscript n is 1 and R 7 is F. In other embodiments, the n is 2 and R 7 is independently selected from CH 3 , F, Cl and OCH 3 . [0144] In some embodiment, the subscript p is 1. [0145] In some embodiment, the subscript q is 1.
• Some embodiments provide for a compound selected from: N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-6-methyl-4-oxo-1- propan-2-ylpyridine-3-carboxamide; N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-5-(4-fluorophenyl)-6-methyl-4-oxo-1-propan-2- ylpyridine-3-carboxamide; 5-(3,4-dichlorophenyl)-N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-6-methyl-4-oxo-1-propan-2- ylpyridine-3-carboxamide; 5-(3-chloro-4-fluorophenyl)-N-[4-[(
• Some embodiments provide for a compound of Table 1 or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof.
• a compound, or a pharmaceutically acceptable salt thereof, of Table 3 Table 3 Treatment Methods and Uses
• “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results.
• Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
• prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
• Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
• Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
• the subject is a mammal.
• the subject is a human.
• terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
• a therapeutically effective amount may be an amount sufficient to decrease a symptom of a sickle cell disease.
• the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
• the methods described herein may be applied to cell populations in vivo or ex vivo.
• “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
• “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
• the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
• the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
• Some embodiments provide for a method of modulating in vivo activity of a protein kinase in a subject, the method comprising: administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as described herein.
• Some embodiments provide for methods of modulating in vivo activity of a protein kinase in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein.
• Some embodiments provide for a method of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as described herein, wherein the disease, disorder, or syndrome is mediated at least in part by modulating in vivo activity of a protein kinase.
• Some embodiments provide for methods of treating a disease, disorder, or syndrome in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein, wherein the disease, disorder, or syndrome is mediated at least in part by modulating in vivo activity of a protein kinase.
• the protein kinase is AXL, KDR, Mer, or Met.
• the disease is cancer.
• Some embodiments provide for methods of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as described herein, in combination with a therapeutic agent or therapy.
• Some embodiments provide for methods of treating a disease, disorder, or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described herein, in combination with a therapeutic agent or therapy.
• the therapeutic agent is an immunotherapeutic agent or a cancer vaccine.
• the immunotherapeutic agent is an anti-PD-1 antibody or anti-PD-L1 antibody.
• Provided herein are methods for treating cancer.
• Cancer includes tumor types such as tumor types including breast, colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas as well as other cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus
• the term “cancerous cell,” as provided herein, includes a cell afflicted by any one of the above- identified conditions.
• the cancer is selected from ovarian cancer, prostate cancer, lung cancer, medullary thyroid cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, bone cancer, hematologic cancer, skin cancer, kidney cancer, breast cancer, colon cancer, and fallopian tube cancer.
• the cancer is clear cell carcinoma, clear cell renal cell carcinoma, non- clear cell carcinoma, non-clear cell renal cell carcinoma, urothelial carcinoma, salivary gland cancer, penile squamous cell carcinoma, neuroendocrine tumors, adrenocortical carcinoma, or merkel cell carcinoma.
• the disease or disorder is ovarian cancer. [0169] In another embodiment, the disease or disorder is prostate cancer. [0170] In another embodiment, the disease or disorder is lung cancer. [0171] In another embodiment, the disease or disorder is medullary thyroid cancer. [0172] In another embodiment, the disease or disorder is liver cancer. [0173] In another embodiment, the disease or disorder is gastrointestinal cancer. [0174] In another embodiment, the disease or disorder is pancreatic cancer. [0175] In another embodiment, the disease or disorder is bone cancer. [0176] In another embodiment, the disease or disorder is hematologic cancer. [0177] In another embodiment, the disease or disorder is skin cancer. [0178] In another embodiment, the disease or disorder is kidney cancer.
• the disease or disorder is breast cancer. [0180] In another embodiment, the disease or disorder is colon cancer. In another embodiment, the disease or disorder is fallopian cancer. In another embodiment, the disease or disorder is liver cancer, wherein the liver cancer is hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemagioma.
• the disease or disorder is gastrointestinal cancer, wherein the gastrointestinal cancer is cancer of the esophagus which is squamous cell carcinoma, adenocarcinoma, or leiomyosarcoma; cancer of the stomach which is carcinoma, or lymphoma; cancer of the pancreas, which is ductal adenocarcinoma, insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma; cancer of the small bowel, which is adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemagioma, lipoma, or cancer of the large bowel, which is adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma.
• the gastrointestinal cancer is cancer of the esophagus which is squamous cell carcinoma
• the disease or disorder is cancer of the pancreas, wherein the cancer of the pancreas is ductal adenocarcinoma, insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma.
• the disease or disorder is bone cancer, wherein the bone cancer is osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteocartiliginous exostoses, chondroblastoma, chondromyxofibroma, or osteoid osteoma.
• the bone cancer is osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteocartiliginous exostoses, chondroblastoma, chondromyxofibroma, or osteoid osteoma.
• the disease or disorder is hematologic cancer, wherein the hematologic cancer is myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, or myelodysplastic syndrome.
• the disease or disorder is skin cancer, wherein the skin cancer is malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or Karposi's sarcoma.
• the disease or disorder is a renal tumor or renal cell carcinoma.
• the disease or disorder is breast cancer.
• the disease or disorder is a colon cancer tumor.
• the disease or disorder is fallopian tube carcinoma.
• Combination Therapies [0190] A compound as disclosed herein can be administered as a single therapy or in combination (“co-administered”) with one or more additional therapies for the treatment of a disease or disorder, for instance a disease or disorder associated with hyper-proliferation such as cancer.
• Therapies that may be used in combination with a compound disclosed herein include: (i) surgery; (ii) radiotherapy (for example, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T- cell therapy; and (v) other chemotherapeutic agents.
• co-administered refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment.
• any agent that has activity against a disease or condition being treated may be co- administered. Examples of such agents for cancer treatment can be found, for instance, at https://www.cancer.gov/about-cancer/treatment/drugs and in publicly available sources such as Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 1 I th edition (2016), Lippincott Williams & Wilkins Publishers.
• the treatment method includes the co-administration of a compound as disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, and at least one immunotherapy.
• Immunotherapy also called biological response modifier therapy, biologic therapy, biotherapy, immune therapy, or biological therapy
• Immunotherapy can help the immune system recognize cancer cells, or enhance a response against cancer cells.
• Immunotherapies include active and passive immunotherapies. Active immunotherapies stimulate the body's own immune system while passive immunotherapies generally use immune system components created outside of the body.
• Examples of active immunotherapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti- idiotype vaccines, DNA vaccines, viral vaccines, or Tumor- Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine- Activated Killer (LAK) Cell Therapy.
• TIL Tumor- Infiltrating Lymphocyte
• IL-2 Interleukin-2
• LAK Lymphokine- Activated Killer
• Naked monoclonal antibodies do not have a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or a toxin (immunotoxin).
• Examples of these naked monoclonal antibody drugs include, but are not limited to rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non- Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer.
• rituximab an antibody against the CD20 antigen
• conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell non-Hodgkin lymphoma; radiolabeled antibody tositumomab (Bexxar) which is used to treat, for example, certain types of non-Hodgkin lymphoma; and immunotoxin gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML).
• Zevalin Radiolabeled antibody ibritumomab tiuxetan
• Bexxar radiolabeled antibody tositumomab
• Mylotarg immunotoxin gemtuzumab ozogamicin
• BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScint for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.
• HERCEPTIN® (trastuzumab) (Genentech, Calif.) which is a humanized anti- HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer
• REOPRO® (abciximab) (Centocor) which is an anti-glycoprotein Ilb/IIIa receptor on the platelets for the prevention of clot formation
• ZENAPAXTM (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection
• PANOREXTM which is a murine anti-l7-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor)
• BEC2 which is a murine anti-idiotype (GD3epitope) IgG antibody (ImClone System)
• IMC-C225 which is a chimeric
• IDEC-l 51 is a primatized anti-CD4 IgGl antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti- CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha.
• IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha4 beta7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA (ruplizumab) is a humanized anti-CD40L IgG antibody (Biogen); ANTEGRENTM is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-beta 2 antibody (Cambridge Ab Tech).
• Immunotherapies that can be used in combination with a compound as disclosed herein include adjuvant immunotherapies.
• cytokines such as granulocyte- macrophage colony- stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-l -alpha, interleukins (including IL-l, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN- beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IF A); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of, interleukins, for example, IL-2 with other cytokines, such as IFN-
• an immunological therapy or an immunological therapeutic agent can include, one or more of the following: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy.
• CAR chimeric antigen receptor
• the function or at least one of the functions of the immunological therapy or immunological therapeutic agent collectively referred to herein as an “immunotherapeutic agent.”
• an exemplary immunotherapeutic agent is an immune cell (e.g.
• the immunotherapeutic agent can be an antibody that modulates a costimulatory molecule, bind to an antigen on the surface of an immune cell, or a cancer cell.
• the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific format antibody, a fusion protein, or a fragment thereof, for example, a Diabody, a Single-chain (sc)- diabody (scFv)2, a Miniantibody, a Minibody, a Bamase- barstar, a scFv-Fc, a sc(Fab)2, a Trimeric antibody construct, a Triabody antibody construct, a Trimerbody antibody construct, a Tribody antibody construct, a Collabody antibody construct, a (scFv- TNFa)3, or a F(ab)3/DNL antibody construct.
• a Diabody a Single-chain (sc)- diabody (scFv)2, a Miniantibody, a Minibody, a Bamase- barstar, a scFv-Fc, a sc(Fab)2, a Trimeric antibody
• the immunotherapeutic agent is an agent that modulates immune responses, for example, a checkpoint inhibitor or a checkpoint agonist.
• the immunotherapeutic agent is an agent that enhances anti-tumor immune responses.
• the immunotherapeutic agent is an agent that increases cell-mediated immunity.
• the immunotherapeutic agent is an agent that increases T-cell activity.
• the immunotherapeutic agent is an agent that increases cytolytic T-cell (CTL) activity.
• the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e g., CEACAM-l, -3 and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, 0X40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and/or BTNL2 among others known in the art.
• the immunotherapeutic agent is an agent that increases natural killer (NK) cell activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppression of an immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors. [0201] In some embodiments, the immunotherapeutic agent includes a T cell modulator chosen from an agonist or an activator of a costimulatory molecule.
• the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of GITR, 0X40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-l, LFA-l (CD1 la/CDl8), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligand.
• an agonist e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion
• GITR e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion
• SLAM e.g., SLAMF7
• HVEM e.g., SLA
• the effector cell combination includes a bispecific T cell engager (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2 among others).
• a bispecific T cell engager e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2 among others).
• the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L 1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of 0X40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDOl activity, a modulator of SIRP-alpha activity, a modulator of TIGIT activity, a modulator of VSIG8 activity, a modulator of BTLA activity, a modulator of SIGLEC7 activity,
• the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor e.g. an inhibitor of PD-1 activity, a modulator of PD-L 1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi) an 0X40 agonist (e.g., an anti- 0X40 antibody molecule), or (xii) a CD27 agonist (e.g., an anti-CD27 antibody molecule).
• an immune checkpoint modulator e.g., an immune checkpoint inhibitor e.g. an inhibitor of PD-1 activity, a modulator of PD-L 1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi) an 0X40 agonist (e.g., an anti-
• the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-l, -3 and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGF beta.
• the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-l, -3 and/or -5), CTLA-4, or any combination thereof.
• Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level.
• an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
• the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand (e.g., PD-l-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof,, for example, a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody/fusion protein/construct known in the art that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as "an antibody molecule") that binds to PD-1, PD-Ll, PD-L2, CEACAM (e.g., CEACAM-l, -3 and/or -5), CTLA-4, TIM-3, LAG-3
• a polypeptide e.g., a soluble ligand
• the treatment method includes the co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent.
• cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
• Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
• radioactive isotopes e.g., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu
• chemotherapeutic agents e.g., At 211 , 1 131 , 1 125
• cytotoxic agents can be selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
• “Chemotherapeutic agents” include chemical compounds useful in the treatment of cancer.
• chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, l7-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SETTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), fmasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FET (5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapati
• dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
• Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifme citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA
• Chemotherapeutic agents also include antibodies, as described above, including alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITETX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITETXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
• alemtuzumab Campath
• bevacizumab AVASTIN®, Genentech
• cetuximab ERBITETX®, Imclone
• panitumumab VECTIBIX®, Amgen
• Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nivolu
• Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitor such as mubritonib (TAK165, Takeda); CP- 724.714, (Axon Medchem BV, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase); dual- HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo- SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-l inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-l signaling;
• Tyrosine kinase inhibitors also include erlotinib (Tarceva®), gefitinib (Iressa®), dasatinib (Sprycel®), nilotinib (Tasigna®), crizotinib (Xalkori®), ruxolitinib (Jakafi®), vemurafenib (Zelboraf®), Vandetanib (Caprelsa®), pazopanib (Votrient®), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, le
• Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, opre
• Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-l7-butyrate, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-l 7-butyrate, clobetasol-l 7-propionate, fluocortolone caproate, fluocortolone pivalate and flupred
• celecoxib or etoricoxib proteosome inhibitor
• CCI-779 tipifamib (R11577); orafenib, ABT510
• Bcl-2 inhibitor such as oblimersen sodium (GENASENSE) pixantrone
• farnesyltransferase inhibitors such as lonafamib (SCH 6636, SARASARTM)
• pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
• FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
• Chemotherapeutic agents also include Poly ADP ribose polymerase (PARP) inhibitors: olaparib (Lynparza®), rucaprib (Rubraca®) niraparib (Zejula®), talzoparib (Talzenna®).
• PARP Poly ADP ribose polymerase
• Exemplary kinase inhibitors include imatinib, baricitinib gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib
• a compound as described herein can be used in combination with a HSP90 inhibitor (e.g., XL888), liver X receptor (LXR) modulators, retinoid-related orphan receptor gamma (RORy) modulators, a CK1 inhibitor, a CKl-a inhibitor, a Wnt pathway inhibitor (e.g., SST-215), or a mineralocorticoid receptor inhibitor, (e.g., esaxerenone or XL- 550) for the treatment of a disease disclosed herein such as cancer.
• HSP90 inhibitor e.g., XL888
• LXR liver X receptor
• RORy retinoid-related orphan receptor gamma
• CK1 inhibitor e.g., CKl-a inhibitor
• Wnt pathway inhibitor e.g., SST-215
• a mineralocorticoid receptor inhibitor e.g., esaxerenone or XL- 550
• compounds as disclosed herein may be used in combination with inhibitors of PD-1 or inhibitors of PD-L1, e.g., an anti-PD-1 monoclonal antibody, an anti-PD-1 bispecific antibody or an anti-PD-L 1 monoclonal antibody, an anti-PD-L1 bispecific antibody, for example, nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, avelumab, AB122, AMP-224, AMP- 514, PDR001, durvalumab, pidilizumab (Imfinzi®, CT-011), CK-301, BMS 936559, and MPDL3280A; CTLA-4 inhibitors, e.g., an anti-CTLA-4 antibody, for example, ipilimumab (Yervoy) and tremelimumab; and phosphatidylserine
• the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
• a compound as described herein can be used in combination with a vaccination protocol for the treatment of cancer.
• a compound as described herein can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective.
• compounds as disclosed herein may be used in combination with inhibitors of PARP, for example, olaparib (Lynparza®), rucaprib (Rubraca®), niraparib (Zejula®), talzoparib (Talzenna®) for the treatment of cancer.
• inhibitors of PARP for example, olaparib (Lynparza®), rucaprib (Rubraca®), niraparib (Zejula®), talzoparib (Talzenna®) for the treatment of cancer.
• compounds as disclosed herein may be used in combination with esaxerenone (XL-550) or XL-888 for the treatment of cancer.
• the compounds as disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-bR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, 1NS-R, IGF-1R, IR-R, PDGFaR, PDGFb/R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl
• compositions and Modes of Administration Compounds provided herein are usually administered in the form of pharmaceutical compositions.
• compositions that comprise one or more of the compounds described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
• Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
• Such compositions are prepared in a manner well known in the pharmaceutical art.
• the pharmaceutical compositions may be administered in either single or multiple doses.
• the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
• the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
• One mode for administration is parenteral, for example, by injection.
• the forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
• Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
• the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
• a carrier that can be in the form of a capsule, sachet, paper or other container.
• the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
• excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
• the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
• compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
• Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug- polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
• Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
• transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
• the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.5,023,252, 4,992,445 and 5,001,139.
• Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
• the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof.
• the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
• the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
• compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases.
• Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.
• Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
• Dosing [0227] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
• a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
• the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0229] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different.
• the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure. [0230] Preparation of compounds as disclosed herein can involve the protection and deprotection of various chemical groups.
• protecting groups can be readily determined by one skilled in the art.
• the chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
• a compound of formula (I’) can be synthesized from carboxylic acid A and aniline B-a by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.
• Scheme 1B a compound of formula (I''') can be synthesized from carboxylic acid A and aniline B-b by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.
• Scheme 1C shows that
• a compound of formula (I) can be synthesized from carboxylic acid A and aniline B by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.
• coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures.
• a process for preparing a compound of formula (I) comprising contacting a compound of formula A with a compound of formula B, under conditions suitable to provide a compound of formula (I).
• a compound of formula (I’) can be made from a two-step process starting from bromocarboxylic acid D, where Q is a leaving group (including Cl, Br, I, triflate and the like), and aniline B-a which are coupled together by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures to form a compound of formula E-a.
• coupling agents appropriate for this transformation that are well known in the art
• HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures
• compounds of formula E-a can be converted to compounds of formula (I’) by coupling with boron compounds of the formula F using coupling chemistry known to those skilled in the art.
• Typical procedures to accomplish this type of coupling involve the use palladium-containing complexes as a catalyst in the presence of an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• a compound of formula (I''') can be made from a two-step process starting from bromocarboxylic acid D, where Q is a leaving group (including Cl, Br, I, triflate and the like), and aniline B-b which are coupled together by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures to form a compound of formula E-b.
• coupling agents appropriate for this transformation that are well known in the art
• HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures
• compounds of formula E-b can be converted to compounds of formula (I''') by coupling with boron compounds of the formula F using coupling chemistry known to those skilled in the art.
• Typical procedures to accomplish this type of coupling involve the use palladium-containing complexes as a catalyst in the presence of an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• a compound of formula (I) can be made from a two-step process starting from bromocarboxylic acid D, where Q is a leaving group, including Cl, Br, I or triflate, and aniline B which are coupled together by standard methods to form amide bonds using coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures to form a compound of formula E.
• coupling agents appropriate for this transformation that are well known in the art such as HATU in the presence of a base such as DIEA in organic solvents such as DMF at room or elevated temperatures
• compounds of formula E can be converted to compounds of formula (I) by coupling with boron compounds of the formula F using coupling chemistry known to those skilled in the art.
• Typical procedures to accomplish this type of coupling involve the use palladium-containing complexes as a catalyst in the presence of an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• an inorganic base such as tripotassium phosphate in a mixture of water and a water-miscible solvent such as dioxane.
• a process for preparing a compound of formula (I'''), comprising: contacting a compound of formula D with a compound of formula B-b, under conditions suitable to provide a compound of formula E-b; and contacting a compound of formula E-b with a compound of formula F, under conditions suitable to provide a compound of Formula (I''').
• a process for preparing a compound of formula (I) comprising: contacting a compound of formula D with a compound of formula B, under conditions suitable to provide a compound of formula E; and contacting a compound of formula E with a compound of formula F, under conditions suitable to provide a compound of Formula (I).
• Scheme 4A a compound of formula J-a can be prepared by reacting a compound of formula G-a with a compound of formula H-a in the presence of a base such as cesium carbonate in an appropriate organic solvent, typically at room temperature.
• a compound of formula B-a can be made from a compound of formula J-a by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• Scheme 4B
• a compound of formula J-b can be prepared by reacting a compound of formula G-b with a compound of formula H-a in the presence of a base such as cesium carbonate in an appropriate organic solvent, typically at room temperature.
• a compound of formula B-b can be made from a compound of formula J-b by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• Scheme 4C [0248] As shown in Scheme 4C, a compound of formula J can be prepared by reacting a compound of formula G with a compound of formula H in the presence of a base such as cesium carbonate in an appropriate organic solvent, typically at room temperature.
• a compound of formula B can be made from a compound of formula J by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• a process for preparing a compound of formula B-a comprising: contacting a compound of formula G-a with a compound of formula H-a, under conditions suitable to provide a compound of formula J-a; and reducing a compound of formula J-a under conditions suitable to provide a compound of formula B-a.
• a process for preparing a compound of formula B-b comprising: contacting a compound of formula G-b with a compound of formula H-a, under conditions suitable to provide a compound of formula J-b; and reducing a compound of formula J-b under conditions suitable to provide a compound of formula B-b.
• a process for preparing a compound of formula B comprising: contacting a compound of formula G with a compound of formula H, under conditions suitable to provide a compound of formula J; and reducing a compound of formula J under conditions suitable to provide a compound of formula B.
• a compound of formula J-a can also be synthesized by reacting a compound of formula K-a with a compound of formula L-a in an appropriate solvent such as 2,6- dimethylpyridine in the presence of a catalytic amount of dimethylaminopyridine at elevated temperatures.
• a compound of formula B-a can be prepared from a compound of formula J-a by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• a compound of formula J-b can also be synthesized by reacting a compound of formula K-b with a compound of formula L-a in an appropriate solvent such as 2,6- dimethylpyridine in the presence of a catalytic amount of dimethylaminopyridine at elevated temperatures.
• a compound of formula B-b can be prepared from a compound of formula J-b by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• a compound of formula J can also be synthesized by reacting a compound of formula K with a compound of formula L in an appropriate solvent such as 2,6- dimethylpyridine in the presence of a catalytic amount of dimethylaminopyridine at elevated temperatures.
• a compound of formula B can be prepared from a compound of formula J by reducing the nitro group with a mixture of ammonium chloride and iron typically in a solvent mixture of water and an alcohol such as methanol or ethanol at elevated temperatures.
• a process for preparing a compound of formula B-a comprising: contacting a compound of formula K-a with a compound of formula L-a, under conditions suitable to provide a compound of formula J-a; and reducing a compound of formula J-a under conditions suitable to provide a compound of formula B-a.
• a process for preparing a compound of formula B-b comprising: contacting a compound of formula K-b with a compound of formula L-a, under conditions suitable to provide a compound of formula J-b; and reducing a compound of formula J-b under conditions suitable to provide a compound of formula B-b.
• a process for preparing a compound of formula B comprising: contacting a compound of formula K with a compound of formula L, under conditions suitable to provide a compound of formula J; and reducing a compound of formula J under conditions suitable to provide a compound of formula B.
• Step 2 N,N-Dimethylformamide dimethylacetal (DMF-DMA) (2 – 10 eq) was added to a solution of Compound 2 (1 eq) in toluene (2 – 3 mL/mmol of substrate (2)) at room temperature.
• DMF-DMA N,N-Dimethylformamide dimethylacetal
• Step 3 Compound 3 (1 eq) was mixed with NaOH (2M, 1 – 20 eq) in THF or MeOH (5 – 20 mL/mmol of 3) and stirred at room temperature until hydrolysis was complete as monitored by LC-MS and/or TLC. The mixture was diluted with water (5 – 20 mL/mmol of 3) and washed with an organic solvent such as EtOAc or DCM (2x). The aqueous phase was acidified to pH 2 with aq.6M HCl. If acidification gave a precipitate, the resulting suspension was filtered, and the material was washed with water and dried to give Compound PA1.
• Step 1 Ethyl 4-(4-fluorophenyl)-3-oxobutanoate (A2-3): To a stirred solution of Compound A1-3 (10 g, 65 mmol, 1 eq), Meldrum’s acid (9.4 g, 65 mmol, 1 eq) and DMAP (15.8 g, 130 mmol, 2 eq) in DCM (200 mL), was added DCC (13.4 g, 65 mmol, 1 eq) in portions.
• Step 2 Ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate (A3-3): DMF-DMA (1.0 mL, 13 mmol, 5.8 eq) was added to a solution of Compound A2-3 (500 mg, 2.23 mmol, 1 eq) in toluene (5 mL) at room temperature, and the mixture was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure to dryness and EtOH (8 mL) was added, followed by the addition of isopropylamine (0.5 mL, 6.1 mmol, 2.7 eq).
• Step 3 5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (PA1-3): A mixture of Compound A3-3 (480 mg, 1.58 mmol, 1 eq) and aq 2 N NaOH (5 mL) in MeOH (15 mL) was stirred at room temperature for 1 h and then concentrated to remove most of the MeOH. The resulting residue was diluted with water (15 mL) and washed with EtOAc. The aqueous phase was acidified to pH 2 with aq.6 N HCl and extracted with EtOAc (3x). The combined organic extracts were dried over anhyd.
• PA1-3 5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid
• Step 2 To a solution of crude Compound 5 (31.3 mmol) in DCE (100 mL) was added solid NBS (9.0 g, 50.6 mmol) in portions. The mixture was stirred at room temperature overnight, diluted with DCM, washed with water, aq. saturated NaCl, dried over anhyd. Na 2 SO 4 and concentrated to give the crude Compound PA2 which was generally used in subsequent reactions without further purification.
• Step 1 1-Isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (B5-2): To a suspension of Compound B4-2 (15 g, 119 mmol, 1 eq) in toluene (40 mL) was added DMF-DMA (15.2 g, 127 mmol, 1.1 eq). The resulting mixture was stirred at 15 °C for 2 h.
• Step 2 5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (PA2- 2).
• PA2- 2 5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid
• Step 1 Bromination of 4-Pyridone carboxylic acids or esters (PA2a) [0299]
• Step 1 Commercially available pyridone carboxylic acids or esters or any pyridone carboxylic acids or esters (5B) generated by the methods described within were brominated using NBS in appropriate organic solvents such as, but not limited to, DCE, NMP or ACN.
• NBS organic solvents
• Method 1 The reaction mixture was diluted with DCM, washed with water, washed with aq saturated NaCl, dried over anhyd. Na 2 SO 4 and concentrated to give crude brominated product PA2a.
• Method 2 To the reaction mixture was added water and the resulting mixture was stirred at room temperature for 15 min. The resulting precipitate was filtered, washed with water and allowed to air-dry to give crude brominated product PA2a. Regardless of the method of work up, the crude PA2a was generally used in subsequent reactions without further purification.
• Appropriate palladium sources include, but are not limited to, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd 2 (dba) 3 or Amphos 2 PdCl 2 .
• the resulting mixture was degassed with nitrogen and then stirred at 80-100 °C until the reaction was complete as monitored by LC-MS and/or TLC.
• the resulting reaction mixture was worked up by one of the following methods or a very similar variation. Method 1: The reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum to remove dioxane.
• the reaction mixture was cooled to room temperature, diluted with water (3.0 mL/mmol of PA-Br used) and washed with EtOAc (3x).
• the aqueous phase was acidified using aq.6 N HCl to pH 2.
• the resulting solid was filtered and dried to give PA-Ph. Regardless of the method of work up, the crude PA-Ph was generally used in subsequent reactions without further purification.
• Step 2 To a solution of Compound C2 (1 eq) in water (1.0-3.2 mL/mmol of C2) was added 30-40% ammonium hydroxide in water (0.9-1.0 mL/mmol of C2). The resulting mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and solvent was partially removed in vacuo. The resulting reaction mixture was cooled to 0 °C and acidified using aq.6 N HCl to pH 2. The resulting solid was filtered and dried in the open air to give Compound C3.
• Step 3 See General Procedure B1 above for the bromination of 4-pyridone carboxylic acids or esters.
• Step 4 See General Procedure C1 above for Suzuki reactions with 5-bromo-4-pyridone carboxylic acids or esters.
• Step 1 4-Hydroxy-3-(2-methoxyacetyl)-6-methyl-2H-pyran-2-one (C2-A): To a solution of Compound B4-2 (10 g, 79 mmol, 1 eq) in toluene (100 mL) was added 2-methoxyacetic acid (7.1 g, 79 mmol, 1 eq), DCC (16.3 g, 79 mmol, 1 eq) and DMAP (9.6 g, 79 mmol, 1 eq).
• Step 2 2-(Methoxymethyl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (C3-A): To a solution of Compound C2-A (12.5 g, 63 mmol, 1eq) in water (200 mL) was added ammonium hydroxide (40% in water, 60 mL). The resulting mixture was heated to reflux overnight.
• Step 3 5-Bromo-2-(methoxymethyl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (C4-A): Compound C4-A was synthesized from Compound C3-A using General Procedure B1. MS for C 9 H 10 BrNO 4 : m/z 276 (MH+).
• Step 4 5-(4-Fluorophenyl)-2-(methoxymethyl)-6-methyl-4-oxo-1,4-dihydropyridine-3- carboxylic acid (PA5-11): Compound PA5-11 was synthesized from Compound C4-A using General Procedure C1. MS for C 15 H 14 FNO 4 : m/z 292 (MH+).
• Step 2 5-Bromo-2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (C4-B): Compound C4-B was synthesized from Compound C3-B using General Procedure B1. MS for C 8 H 8 BrNO 3 : m/z 246 (MH+).
• Step 3 5-(4-Fluoro-2-methylphenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (PA7-2): Compound PA7-2 was synthesized from Compound C4-B using a procedure similar to General Procedure C1.
• Step 2 Following procedures similar to General Procedure C or General Procedure C1, Compound 9 recovered from Step 1 was dissolved in a mixture of dioxane and water (40/20 mL, 1:1 vv). Boronic acid 6 (1.5-2.5 eq) was added to the resulting solution of Compound 9 followed by the addition of K 2 CO 3 or KH 3 PO 4 (3 eq) and a palladium source such as tetrakis or Amphos 2 PdCl 2 (0.06 eq). The reaction mixture was purged with nitrogen 3 times and then heated to 90 o C for 1 h. Upon completion of the reaction as monitored by LC-MS, the reaction mixture was allowed to cool to room temperature followed by dilution with water (60 mL).
• Step 2 To Compound 11 (0.38 mmol) in DMF (2 mL) was added alkyl halide R 1a -X (1.2 eq) and Cs 2 CO 3 (3 eq). The resulting mixture was heated to 60 o C overnight. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure.
• the carboxylic acids of HP can be generated by any of the methods described within.
• the esters of HP can be generated en route to the carboxylic acids previously described such as intermediate C3 in General Procedure C or can be generated from the acids by standard esterification techniques.
• the acid can be dissolved in anhyd. MeOH to which is added 4 M HCl in dioxane. After stirring the resulting mixture at room temperature overnight, the corresponding crude methyl ester is recovered by concentration of the reaction mixture under vacuum.
• the resulting mixture was heated to 60 o C for 15 min.
• the reaction mixture was allowed to cool to room temperature, diluted with water (3 ml) and extracted with EtOAc (3x).
• the combined organic extracts were washed with water, washed with aq. saturated NaCl, dried over anhyd. Na 2 SO 4 and concentrated.
• the resulting residue was dissolved in MeOH (2 mL) and 1 N NaOH (2 mL) was added.
• the resulting solution was stirred at room temperature for 2 h.
• the solvent was partially removed, and the resulting aqueous mixture was washed with EtOAc (3x).
• the aqueous layer was acidified with aq.6 N HCl to pH neutral.
• Step 1 A mixture of Compound 12 (32 mmol, 1 eq) and Compound 13 (5.92 g, 32 mmol, 1 eq) in toluene (50 mL, 1.5-1.6 mL/mmol of 12) was stirred at 105 o C for 1.5 h and cooled to room temperature. Hexane (50 mL, 1.5-1.6 mL/mmol of 12 used) was added and the suspension filtered.
• Step 2 A mixture of Compound 14 (4.8 mmol, 1 eq), Compound 15 (6.8 mmol, 1.4 eq), and Cs 2 CO 3 (6.6 g, 20 mmol, 4.2 eq) in acetonitrile (20 mL, 4.2 mL/mmol of 14) was stirred at room temperature overnight. EtOAc (80 mL, 16-17 mL/mmol of 14 was used) was added and the resulting mixture filtered. The filtrate was evaporated, and residue purified by silica gel column chromatography to give Compound 16.
• Step 3 A mixture of Compound 16 (1.8 mmol, 1 eq), NH 4 Cl (500 mg, 9.3 mmol, 5.2 eq), and Fe (260 mg, 4.6 mmol, 2.6 eq) in MeOH / water (20 / 5 mL) (11 mL MeOH/mmol of 16 and 2.8 mL water/mmol of 16) was refluxed for 1 h and then cooled to room temperature. The resulting mixture was filtered through Celite and the filtrate concentrated to remove MeOH. To the residue was added aq. saturated NaHCO 3 (6 mL, 3.3 mL/mmol of 16 used) and the resulting aqueous mixture was extracted with EtOAc.
• Step 1 6,7-Dimethoxy-1,5-naphthyridin-4-ol (G3-1): A mixture of 2,2-dimethyl-1,3- dioxane-4,6-dione (2.7 g, 18.7 mmol, 1 eq) in trimethoxymethane (19.6 g, 185 mmol, 20.3 mL, 10 eq) was stirred at 110 °C for 1.5 h to form a yellow solution of Compound 13.
• Step 2 8-(2-Fluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthyridine (G5-1): To mixture of Compound G3-1 (2.1 g, 10.2 mmol, 1 eq) and 1,2-difluoro-4-nitro-benzene (1.6 g, 10.2 mmol, 1.13 mL, 1 eq) in ACN (50 mL) was added Cs 2 CO 3 (6.6 g, 20.4 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 15 h.
• Step 3 4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluoroaniline (NA1-1): To a mixture of Compound G5-1 (1.4 g, 3.9 mmol, 1 eq) in EtOH (20 mL) and water (5 mL) was added Fe (1.1 g, 19 mmol, 5 eq) and NH 4 Cl (2.1 g, 39 mmol, 10 eq) and the resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (2 x 30 mL) and the filtrate concentrated under reduced pressure.
• Step 1 To a mixture of Compound 17 (44.7 mmol, 1 eq) and Compound H2 (62.5 mmol, 1.4 eq) in 2,6-dimethylpyridine (50 mL) was added DMAP (1.10 g, 9.0 mmol, 0.2 eq). The mixture was stirred at 140 °C for 36 h. The reaction was cooled to room temperature, MeOH (32 g) was added, followed by aq. K 2 CO 3 (4 g in water (62 g)). The resulting mixture was stirred at 0 °C for 2 h.
• Step 1 can also be performed as follows: A mixture of Compound 17 (1 eq) and Compound H2 (1.2-1.4 eq) in an appropriate solvent such as, but not limited to, 2,6-dimethylpyridine or diphenyl ether (1.1-2.2 mL/mmol of 17) was stirred at 140 °C for typically 36-66 h. DMAP (0.2 eq) can also be optionally added as a catalyst. Upon completion of the reaction as monitored by LC-MS and/or TLC, the reaction mixture was allowed to cool to room temperature and typically worked up by one of the following methods or a similar variation.
• an appropriate solvent such as, but not limited to, 2,6-dimethylpyridine or diphenyl ether (1.1-2.2 mL/mmol of 17) was stirred at 140 °C for typically 36-66 h.
• DMAP 0.2 eq
• the reaction mixture was allowed to cool to room temperature and typically worked up by one of the following methods or a similar variation.
• Method 1 MeOH (0.9 mL/mmol of 17 used) was added, followed by aq.6.5% K 2 CO 3 (1.4 mL/mmol of 17 used). The resulting mixture was stirred at 0 °C for 2 h. The resulting mixture was filtered and washed with water (4.5 mL/mmol of 17 used) to give Compound 18.
• Method 2 The mixture was diluted with MTBE (2.2 mL/mmol of 17 used) and filtered. The resulting solid was washed with MTBE (0.4 mL/mmol of 17 used) and dried under vacuum to give Compound 18. Regardless of the method of work up, the crude Compound 18 was generally used in subsequent reactions without further purification.
• Step 2 To a mixture of Compound 18 (6.1 mmol, 1 eq) in EtOH (40 mL) and water (8 mL) was added Fe (1.71 g, 30.6 mmol, 5.0 eq) and NH 4 Cl (2.62 g, 49.0 mmol, 8.0 eq). The mixture was stirred at 85 °C for 3 h. The reaction was filtered, and the filtrate was dried over anhyd. Na 2 SO 4 and concentrated to give crude product. To this crude product was added EtOAc (150 mL) and DCM (150 mL). The resulting mixture was filtered, and the filtrate was concentrated to give Compound QA1.
• Step 2 can also be performed as follows: To a mixture of Compound 18 (1 eq) in EtOH (4.5-6.5 mL/mmol of 18) and water (1.1-1.3 mL/mmol of 18) was added Fe (5.0 eq) and NH 4 Cl (8-10 eq). The mixture was stirred at 85 °C for 3-4 h. Upon completion of the reaction as monitored by LC-MS and/or TLC, the reaction mixture was allowed to cool to room temperature and typically worked up by one of the following methods or a similar variation. Method 1: The reaction was filtered, and the filtrate was dried over anhyd. Na 2 SO 4 and concentrated to give crude product.
• Step 1 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (H3-1): A suspension of Compound H1-1 (10 g, 45 mmol, 1 eq) and 2-fluoro-4-nitro-phenol (8.4 g, 54 mmol, 1.2 eq) in Ph 2 O (100 mL) was heated and stirred at 140 °C for 66 h.
• Step 2 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (QA1-1): Fe (12.5 g, 223 mmol, 5 eq) was added to a mixture of Compound H3-1 (16.2 g, 45 mmol, 1 eq) and NH 4 Cl (23.9 g, 447 mmol, 10 eq) in EtOH (200 mL) and water (50 mL). The mixture was heated and stirred at 85 °C for 3.5 h. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum and the residue was dissolved in EtOAc (500 mL).
• Compound I1 can be any of the heterocyclic acids described herein (i.e. PA-Br, PA-Ph, PA1, PA2, PA3, PA4, PA5, PA6, PA7, HA1, HA2, HA3, HA4, and the like).
• the hydroxyl of Compound I2 can optionally be protected with a benzyl group, which is then removed after the coupling reaction by standard hydrogenation techniques.
• reaction mixture was diluted with water (167 mL/mmol of J1 used), sonicated, filtered and the resulting solid was washed with water. Regardless of which reaction or work up was used, the resulting residue/solid was purified by prep-HPLC to give Compound J2.
• Example 1 N-[4-[(6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-6- methyl-4-oxo-1-propan-2-ylpyridine-3-carboxamide (21) [0432] Step 1: 5-Bromo-N-(4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-1- isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (19).
• Step 2 N-(4-((6,7-Dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-5-(4- fluorophenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (21): A mixture of Compound 19 (57 mg, 0.10 mmol), Compound 20 (70 mg, 0.50 mmol), K 3 PO 4 , (64 mg, 0.30 mmol), XPhos Pd G2 (20 mg, 0.1 mmol), water (0.5 mL) and dioxane (3.0 mL) was degassed with nitrogen for 3 minutes and then stirred at 90 o C for 5h.
• Compound 33 can be made by replacing Compound PA2-2 with Compound PA4-1 and replacing Compound 20 with phenylboronic acid. Compound 33 was also made using the method exemplified in Example 2 where Compound PA1-2 was replaced with Compound PA3-8.
• Compound 34 can be made by replacing Compound PA2-2 with Compound PA4-1 and replacing Compound 20 with (3-fluorophenyl)boronic acid.
• Compound 34 was also made using the method exemplified in Example 2 where Compound PA1-2 was replaced with Compound PA3-9.
• Compound 35 can be made by replacing Compound PA2-2 with Compound PA4-1 and replacing Compound 20 with (4-methoxyphenyl)boronic acid. Compound 35 was also made using the method exemplified in Example 2 where Compound PA1-2 was replaced with Compound PA3-10.
• Compound NA1-1 was replaced with Compound NA1-3.
• Compound 40 can be made by replacing Compound PA2-2 with Compound PA4-1 and replacing Compound 20 with phenylboronic acid.
• Compound 40 was also made using the method exemplified in Example 2 where Compound PA1-2 was replaced with Compound PA3-8.
• Example 2 1-Cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-(4- fluorophenyl)-4-oxopyridine-3-carboxamide (41) [0457] 1-Cyclopropyl-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-5-(4- fluorophenyl)-4-oxopyridine-3-carboxamide (41).
• Compound NA1-1 was coupled to Compound PA1- 2 using standard HATU coupling procedures similar to that used in Step 1 of Example 1 for coupling Compound NA1-1 to Compound PA2-2. After the reaction was complete and the reaction mixture was poured into the aq. saturated NaHCO 3 and the resulting suspension was filtered, the recovered material was purified by silica gel column chromatography or prep-HPLC to give Compound 41.

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