Classifications

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  • C07D401/14—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 three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • 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
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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Definitions

• EGFR INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS
• BACKGROUND EGFR is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors.
• EGFR epidermal growth factor
• EGFR can form a homodimer on the cell membrane or form a heterodimer with other receptors in the family, such as erbB2, erbB3, or erbB4.
• EGFR signal transduction pathways including increased expression of ligands and receptors, EGFR gene amplification and alterations such as mutations, deletions and the like, can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis.
• alterations such as mutations and deletions in the EGFR gene are found in non-small lung cancer (NSCLC) tumors.
• NSCLC non-small lung cancer
• EGFR alternations found in NSCLC tumors are short in- frame deletions in exon 19 (del19) and L858R, a single missense mutation in exon 21 (Cancer Discovery 20166(6) 601). These two alterations, referred to as sensitizing mutations, cause ligand- independent EGFR activation and are referred to as primary or activating mutations in EGFR mutant NSCLC (EGFR M+).
• Clinical experience shows an objective response rate (ORR) of approximately 60-85% in EGFR M+ NSCLC patients treated first line (1L) with EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib and osimertinib (Lancet Oncol.2010 Vol.11, 121; Lancet Oncol. 2016 Vol.17, 577; N. Engl. J.
• ORR objective response rate
• Osimertinib is a covalent third (3 rd ) generation EGFR TKI that is now the approved standard of care (SOC) in first line (1L) for the treatment of NSCLC harboring del19 and L858R mutations.
• the most prominent on-target resistance mechanism is due to the secondary mutation in EGFR of C797X (where “X” can be an “S” or a “G” or an “N” or a “Y” or a “T” or a “D”), which occurs in 7 % to 22 % of patients progressing on 3rd generation EGFR inhibitors used in front line (Blakely, 2012; Kobayashi, 2005).
• This secondary C797S mutation reduces the affinity of the drug with the target, thereby producing drug resistance, and resulting in tumor recurrence or disease progression.
• the resulting “double mutant” tumors that harbors the sensitizing mutations del19 or L858R and the resistance mutation C797X (e.g., C797S), are no longer sensitive to 2 nd and 3 rd generation TKIs. There is no approved drug to treat the double mutant patients.1 st generation TKIs (gefitinib and erlotinib) are active against C797X (e.g., C797S) but they are poorly tolerated due to activity associated with wild-type EGFR inhibition, and do not control brain disease due to their low abiltiy to cross the blood brain barrier (BBB).
• BBB blood brain barrier
• EGFR with LRCS mutations e.g., C797S
• double mutant EGFR EGFR with LRCS mutations
• the disclosed compounds are selective EGFR inhibitors, i.e., the disclosed compounds have no or low activity against wild-type EGFR and the kinome. Advantages associated with such selectivity may include facilitating efficacious dosing and reducing EGFR-mediated on-target toxicities.
• the compounds of the disclosure exhibit good penetration of the brain and blood brain barrier (e.g., a PGP efflux ratio of less than 5).
• the compounds of the disclosure or pharmaceutically acceptable salts thereof are expected to be effective for the treatment of metastatic cancer, including brain metastesis, including leptomeningeal disease and other systemic metastesis.
• Some of the disclosed compounds also have the advantage of having high microsomal stability.
• Compounds of the disclosure also may have favorable toxicity profiles related to other non-kinase targets.
• the present disclosure provides a compound represented by the following structural Formula (A) or (I): (A) or (I), or a pharmaceutically acceptable salt thereof, the definition of each variable is provided below.
• the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof (a “pharmaceutical composition of the disclosure”).
• the present disclosure provides a method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure.
• the cancer is non-small cell lung cancer.
• the subject cancer has metastasized to the brain.
• the subject has brain metastasis from non-small cell lung cancer.
• the cancer to be treated has epidermal growth factor receptor (EGFR) L858R mutation or exon 19 deletion mutation.
• the cancer to be treated may further has epidermal growth factor receptor (EGFR) L858R mutation or exon 19 deletion mutation and the C797X (e.g., C797S) mutation.
• the cancer to be treated in either of the foregoing embodiments is lung cancer, e.g., non-small cell lung cancer.
• the cancer is non-small cell lung cancer with brain metastasis or leptomeningeal disease.
• the treatment method disclosed herein further comprises administering to the subject an effective amount of an EGFR inhibitor (e.g., afatinib and/or osimertinib), and a MET inhibitor in combination with an effective amount of a compound of the disclosure.
• an EGFR inhibitor e.g., afatinib and/or osimertinib
• a MET inhibitor in combination with an effective amount of a compound of the disclosure.
• the present disclosure also provides a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (A) or (I)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure.
• the present disclosure also provides the use of an effective amount of a compound of the disclosure (e.g., a compound of Formula (A) or (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for the preparation of a medicament for the treatment of cancers.
• a compound of Formula (A) or (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in treating cancers.
• halo as used herein means halogen and includes chloro, fluoro, bromo and iodo.
• alkyl used alone or as part of a larger moiety, such as “alkoxy” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. (C 1 -C 6 )alkyl. As used herein, a “(C 1 -C 6 )alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.
• haloalkyl or "C 1-4 haloalkyl” refers to an alkyl group wherein at least one of the hydrogen atoms is replaced by a halo atom.
• the C 1-4 haloalkyl group can be monohalo-C 1-4 alkyl, dihalo-C 1-4 alkyl or polyhalo-C 1-4 alkyl including perhalo-C 1-4 alkyl.
• a monohalo-C 1-4 alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
• Dihalo-C 1-4 alkyl and polyhalo-C 1-4 alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
• the polyhalo-C 1-4 alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups.
• Non-limiting examples of C 1-4 haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
• a perhalo-C 1-4 alkyl group refers to a C 1-4 alkyl group having all hydrogen atoms replaced with halo atoms.
• alkoxy means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl.
• (C1-C4)alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
• cycloalkyl refers to a monocyclic or bicyclic or polycyclic saturated hydrocarbon ring system. Cycloalkyl may include fused and/or bridged rings and/or spirocyclic rings.
• Non-limiting examples of fused/bridged cycloalkyl include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like.
• Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings share one ring atom).
• spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
• cycloalkyl has from 3-12 carbon atoms.
• a C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• a “cycloalkyl” has from three to six carbon atoms.
• heterocyclyl refers to a radical of a 4- to 12-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (“4-12 membered heterocyclyl”).
• a heterocyclyl group is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 (typically 1 to 2) ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-8 membered heterocyclyl”).
• heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or a tricyclic system (“tricyclic heterocyclyl”)).
• a polycyclic ring system includes fused, bridged, or spiro ring systems. When a heterocyclyl group is a polycyclic ring system, said ring system includes at least one non-aromatic ring.
• Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.
• Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system—including polycyclic ring systems having a non-aromatic ring fused to a phenyl or heteroaryl ring.
• Exemplary polycyclic heterocyclic groups include 2H-benzo[b][1,4]oxazin-3(4H)-onyl, isoindolin-1-onyl, isoquinolin- 1(2H)-onyl, 3-oxabicyclo[3.1.0] hexanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, tetrahydropyrazolo[1,5-a]pyridinyl, and the like. Substituents may be present on one or more rings in the polycyclic ring system.
• Heteroaryl refers to a radical of a 4- to 12-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
• a heteroaryl group is a 5 or 6 membered heteroaryl having ring carbon atoms and 1 to 4 ring heteroatoms (typically 1 to 2).
• heteroaryl groups include ring systems where each ring comprises a heteroatom and is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• aromatic e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• a bridged bicyclic system has two non-aromatic rings containing from 5-12 ring atoms (heterocyclyl or cycloalkyl) and which share three or more ring atoms, with the two bridgehead ring atoms separated by a bridge containing at least one atom.
• “Bridged heterocyclyl” includes bicyclic or polycyclic hydrocarbon or aza-bridged hydrocarbon groups; examples include bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, and 8-oxa-3-azabicyclo[3.2.1]octanyl.
• a fused bicyclic system has two rings containing from 6-12 ring atoms and which share two adjacent ring atoms. When the fused bicyclic system is heterocyclyl, at least one of the rings is non- aromatic. Examples of fused bicyclic systems include hexahydro-1H-furo[3,4-b]pyrrolyl, and hexahydro-1H-furo[3,4-c]pyrrolyl.
• a spiro bicyclic system has two non-aromatic rings containing (heterocyclyl or cycloalkyl) from 7-12 ring atoms and which share one ring atom.
• spiro bicyclic systems include 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.
• Compounds of the Present Disclosure Disclosed herein are embodiments of compounds having a general structure of Formula (A) or (I). These compounds are selective inhibitors of L858R, Ex19del, L858RC797S and Ex19DelC797S EGFR.
• the compounds of the disclosure are non-covalent inhibitors.
• the present disclosure provides a compound represented by the following structural formula (A): or a pharmaceutically acceptable salt thereof, wherein X is CR x or N; R x is H or F; L 1 is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; wherein -* represents the point which attaches to R 1 ; L 2 is a bond or O; R 1 is H; or C1-C4alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b , C3-C6cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroary
• the compound according to strutural formula (A) is represented by a structural formula selected from (B) and (C): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first embodiment.
• the present disclosure provides a compound according to structural formulas (A), (B) or (C), or a pharmaceutically acceptable salt thereof, wherein when L 1 and L 2 are each a bond, R 1 is H, R 2 is not H, and wherein the remainder of the variables are as defined in the first embodiment.
• the present disclosure provides a compound according to structural formulas (A), (B) or (C), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C4alkyl, C3- C8cycloalkyl, C2-C4alkenyl or C2-C4alkynyl, each of which is optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b and 4 to 12 membered heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C1-C4alkyl; or 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, C1-C4alkyl, C(O)R a and 4 to 12 membered heterocyclyl which is optionally substituted with 1 to 4 groups selected from halo,
• the present disclosure provides a compound according to structural formula (A), (B) or (C), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F or methyl, and wherein the remainder of the variables are as defined in the first, third or fourth embodiment.
• the present disclosure provides a compound represented by the following structural formula (I): , or a pharmaceutically acceptable salt thereof, wherein X is CR x or N; R x is H or F; L 1 is a bond, NH, -NHC(O)-*, -NHC(O)O-*, O, or -OC(O)-*; wherein -* represents the point which attaches to R 1 ; L 2 is a bond or O; R 1 is H; or C1-C4alkyl optionally substituted with 1 to 4 groups independently selected from halo, deuterium, OR a , NR a R b , C3-C6cycloalkyl, 4 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with 1 to 4 groups independently selected from halo, deuterium and C1-C4alkyl; or C3-C8cycloalky
• the variables in Structural Formula (I) are as defined in the first, third or fourth embodiment.
• the compound according to strutural formula (I) is represented by one of the structural formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II- 11) or (II-12): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, or sixth embodiment.
• the compound of formula (I) is represented by one of structural formulas (II-1a), (II-3a), (II-3b), (II-4a), (II-5a), (II-7a), (II-7b), (II-8a), (II-9a), (II-9b), (II-11a), (II-11b) or (II-12a): , (II-7b) , (II-8a) , or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, or sixth embodiment.
• the present disclosure provides a compound according to structural formulas (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R x is H, and wherein the remainder of the variables are as defined in the first, third, fourth, fifth, or sixth embodiment.
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II- 6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II- 12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 1 is H; or C 1 -C 3 alkyl optionally substituted with 1 to 2 groups independently selected from halo, OR a , NR a R b , C 3- C 5 cycloalkyl, 4 to 6 membered heterocyclyl and 5 to 6 membere
• the present disclosure provides a compound according to structural formulas (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 1 is H; or R 1 is selected from -CH3, -CH2CH3, -CH2CH3CH3 and -CH(CH3)2, each of which is optionally substituted with 1-3 groups selected from F, –OH, -OCH3, -N(CH3)2, cyclopropy
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II- 6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II- 12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, -CH 3 , - CH 2 (R 11 ), -CH(R 11 ) 2 , -CH 2 CH 3 , -CH(R 11 )-CH 3 , -CH(CH 3 ) 2 , -C(CH
• the present disclosure provides a compound according to structural formula (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from halo, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from halo, OR a , C(O)R a , C(O)NR a R b , NR a C(O)OR a , NR a R b , C1-C3alkyl, morpholinyl,
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II- 6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II- 12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from Cl, F, -OH, -OCH3, -C(O)CH2CH3, -N(CH3)2, -NHC(O)OC(CH3)3, -CH3, -CD3, - CHF2, -CF3, -CH2OH,
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein L 2 is a O, and wherein the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 4 alkyl, C 3 - C 8 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, each of which is optionally substituted with 1 to 3 groups independently selected from halo, OR a ,
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C3alkyl, C3- C5cycloalkyl or C3-C4alkynyl, each of which is optionally substituted with 1 to 2 groups independently selected from halo, OR a , NR a R b and 4 to 6 membered
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is –CH3, – CH2CH3, -CH(CH3)2, cyclopropyl or , each of which is optionally substituted with F, - OCH3, -N(CH3)2, morpholinyl or oxetanyl; or R 2 is diazaspiro
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II-11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 2 is –CH3, -CHF2, –CH2CH3, -CH2CH2-OCH3, -CH2CH2-N(CH3)2, -CH(CH3)2, cyclopropyl, or ; or R 2 is , , , , or , each of which is optionally
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4 to 6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl represented by R 3 are each optionally substituted with 1 to 3 groups independently
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, cyclopropyl, oxetanyl, tetrahydropyanyl or C1-C3alkyl optionally substituted with 1 to 3 groups independently selected from halo, deuterium, OH, N(CH3)2 and cyclopropy
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, –CH3, -CHF2, -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 -OH, -CH 2 CH 2 -N(CH 3 ) 2
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein each R 4 is halo or OR a ; each R a is independently selected from H and C 1 -C 4 alkyl; and n is 0, 1, 2 or 3, and wherein the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, nineth, tenth,
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein n is 0, and wherein the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first,
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-4), (II-4a), (II-5), (II-5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12) or (II-12a), or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, and each R 4 is independently selected from F and OH, and wherein the remainder of the variables are as defined in the first, third, fourth, fifth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeen
• the compound of formula (I) is represented by one of structural formula (II-3c) or (II-3b): , or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty- fifth or twenty-sixth embodiment.
• the compound of formula (I) is represented by one of structural formula (II-7a) or (II-7b): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty- fifth or twenty-sixth embodiment.
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is: C1-C4alkyl optionally substituted with 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted with C1-C2alkyl, or C3-C8cycloalkyl, 4 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 3 groups independently selected from R 11 ; each R 11 is independently selected from halo, NR a R b , C3-C6cycloalkyl, and C1-C4alkyl optionally substituted with 1 to 3 halo, and each R a is independently selected from H and C1-C4alkyl
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is: C1-C2alkyl optionally substituted with 5 membered heteroaryl wherein the 5 membered heteroaryl is optionally substituted with C1-C2alkyl, or C3-C5cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl represented by R 1 are each optionally substituted with 1 to 2 groups independently selected from R 11 ; each R 11 is independently selected from halo, N(CH3)2, C3-C5cycloalkyl, and C1-C2alkyl optionally substituted with 1 to 3 halo; R 2 and R 3 are each independently C 1 -C 2 alkyl; R 4 is halo; and n is 0, 1,
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 2 CH 3 substituted with oxadiazolyl optionally substituted with –CH 3 ; or R 1 is selected from azabicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cyclopropyl, 3-oxabicyclo[3.1.0] hexanyl, piperidinyl, pyrazolyl and pyridinyl, each of which is optionally substituted with 1 to 2 groups independently selected from R 11 , each R 11 is independently selected from F, -N(CH 3 ) 2 , -CH 3 , -CF 3 , , and and wherein the remainder of the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteen
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from , , , , and , and each R 11 is independently selected from F, -N(CH 3 ) 2 , -CH 3 , -CF 3 , and , and wherein the remainder of the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenth-nineth, thirtieth or thirty-first embodiment.
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C4alkyl; R 3 is C1-C4alkyl; each R 4 is independently halo; and n is 0, 1 or 2, and wherein the remainder of the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenth- nineth, thirtieth, thirty-first or thirty-second embodiment.
• the present disclosure provides a compound according to structural formula (II-3c), (II-3b), (II-7a) or (II-7b), or a pharmaceutically acceptable salt thereof, wherein R 2 is –CH3 or –CH2CH3; R 3 is –CH3; R 4 is F; and n is 0 or 1, and wherein the remainder of the variables are as defined in the first, third, fourth, sixth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenth-nineth, thirtieth, thirty-first, thirty-second or thirty-third embodiment.
• the compound of formula (I) is represented by the following structural formula (III): , or a pharmaceutically acceptable salt thereof, and wherein the variables are as defined in the first, third, fourth, sixth, nineth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, thirty-third and thirty-fourth embodiment.
• the compound of formula (I) is represented by one of the following structural formula (III-1) or (III-2): (III-1) , (III-2) , or a pharmaceutically acceptable salt thereof, and wherein the variables are as defined in the first, third, fourth, sixth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth twenty-sixth, thirty-third and thirty-fourth embodiment.
• the present disclosure provides a compound according to structural formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond, and wherein the remainder of the variables are as defined in the first, third, fourth, sixth, nineth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, thirty-third and thirty-fourth embodiment.
• a compound of the present disclosure is any one of the compounds disclosed in the examples (including neutral form, pharmaceutically acceptable salts, and intermediates) and Table 1, or a pharmaceutically acceptable salt thereof. Table 1
• the compounds of Examples 455-457 and 458A in Table 3, and pharmaceutically acceptable salts thereof, are excluded from the disclosure.
• the present disclosure provides a compound according to structural formula (A), (B), (C), (I), (II-1), (II-1a), (II-2), (II-3), (II-3a), (II-3b), (II-3c), (II-4), (II-4a), (II-5), (II- 5a), (II-6), (II-7), (II-7a), (II-7b), (II-8), (II-8a), (II-9), (II-9a), (II-9b), (II-10), (II-11), (II-11a), (II- 11b), (II-12), (II-12a), (III), (III-1) or (III-2), or any one of the compounds of disclosed in the examples (including intermediates) and Table 1, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen is replaced
• pharmaceutically-acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19. Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s).
• Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids).
• Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
• Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
• Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.
• the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight.
• the stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
• a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center.
• a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
• a racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer.
• the present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically-enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein.
• Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well- known asymmetric synthetic methods.
• First eluting compound or “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction.
• the second intended product compound is referred to as “Second eluting compound” or “Peak 2”.
• any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at 50, 80, 90, 95, 98 or 99%.
• “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds.
• H When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance.
• One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”.
• many moieties e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl
• a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure.
• the optional substituents can be any substituents that are suitable to attach to the moiety.
• Compounds of the disclosure are selective EGFR inhibitors.
• selective EGFR inhibitor means a compound which selectively inhibits certain mutant EGFR kinases over wild-type EGFR and the kinome.
• a selective EGFR inhibitor has no or low activity against wild-type EGFR and the kinome.
• a selective EGFR inhibitor ’s inhibitory activity against certain mutant EGFR kinases is more potent in terms of IC 50 value (i.e., the IC 50 value is subnanomolar) when compared with its inhibitory activity against wild-type EGFR and many other kinases. Potency can be measured using known biochemical assays.
• Some compounds of the disclosure have the advantage of good penetration of the brain. The ability of a particular compound to cross the BBB and penetrate the brain can be assessed using a variety of known methods or combinations of such methods.
• P-gp efflux ratio One in vitro method that is frequently used to predict a compound’s in vivo brain penetration is P-gp efflux ratio.
• P-gp P-glycoprotein
• BBB blood-brain barrier
• CNS central nervous system
• a compound of the disclosure has a P-gp efflux ratio of less than 2, less than 3, less than 4, less than 5.
• Hepatic metabolism is a predominant route of elimination for small molecule drugs.
• the clearance of compounds by hepatic metabolism can be assessed in vitro using human liver microsomes (HLMs) or human hepatocytes.
• HLMs human liver microsomes
• Compounds are incubated with HLMs plus appropriate co-factors or human hepatocytes and compound depletion is measured to determine an in vitro intrinsic clearance (Clint).
• the Clint is scaled to total body clearance (CL), and a hepatic extraction ratio (ER) is determined by dividing CL to standard human hepatic blood flow. Compounds that have a low hepatic extraction ratio are considered to have good metabolic stability.
• compositions of the disclosure (also referred to herein as the “disclosed pharmaceutical compositions”) comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and a compound of the disclosure (e.g., a compound of Formula (A) or (I)), or a pharmaceutically acceptable salt thereof.
• “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.
• Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like.
• Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
• auxiliary agents such
• excipients such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
• the carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
• Methods of Treatment The present disclosure provides a method of inhibiting certain mutant forms of epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.
• Mutant forms of EGFR include for example, EGFR with LRCS mutation (the exon 19 deletion (del19) or exon 21 (L858R) substitution mutation, and C797X (e.g., C797S) mutation).
• Subjects “in need of inhibiting EGFR” are those having a disease for which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, e.g., a slowing in disease progression, alleviation of one or more symptoms associated with the disease or increasing the longevity of the subject in view of the disease.
• the disclosure provides a method of treating a disease/condition/or cancer associated with or modulated by mutant EGFR, wherein the inhibition of the mutant EGFR is of therapeutic benefit, including but not limited to the treatment of cancer in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein.
• the disclosure provides a method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.
• Cancers to be treated according to the disclosed methods include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancers, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastasis (in particular brain metastasis) of all cancers listed.
• the cancer is characterized by at one or more EGFR mutations described herein.
• the cancer has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
• the disease has progressed on or after first line 3 rd generation TKI, e.g. osimertinib.
• the cancer was not previously treated.
• the cancer to be treated is lung cancer.
• the cancer is non-small cell lung cancer (NSCLC).
• the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology and NSCLC with non-squamous histology.
• the lung cancer is NSCLC adenocarcinoma.
• the lung cancer (or non-small cell lung cancer) has metastasized to the brain.
• the disease/condition/or cancer being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19.
• the disease/condition/or cancer being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 C797S.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 C797X (C797G or C797N or C797Y or C797T or C797D).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt, or or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792X (L792F, L792H or L792Y).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 G796R (G796S).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).
• the disease/condition/or cancer being treated with a disclosed compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del19 L718Q (L718V).
• the disease/condition/or cancer e.g., NSCLC
• being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R C797S.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R C797X (797G or C797N or C797Y or C797T or C797D).
• the disease/condition/or cancer being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L792X (L792F, L792H or L792Y).
• the disease/condition/or cancer being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R G796R (G796S).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L792R (L792V or L792P).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR L858R L718Q (L718V).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR del18.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR E709X (E709K, E709H, or E709A).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR S768I.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins L718Q.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR comprising EGFR ex20ins C797S.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by an EGFR genotype selected from genotypes 1-36.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to osimertinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to afatinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to dacomitinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to lazertinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to osimertinib and afatinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to osimertinib and dacomitinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to amivantamab.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to amivantamab and lazertinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to aumolertinib (formerly almonertinib).
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to olmutinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to clawinib.
• the disease/condition/or cancer (e.g., NSCLC) being treated with a disclosed compound, a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein is characterized by EGFR mutations that confer resistance to avitinib.
• Another embodiment is the treatment a subject with metastatic NSCLC with tumors harboring activating Exon 19 Deletion or L858R EGFR mutations, G719X (A, S, C, D, R, V), S768I and L861Q, as well as a resistance mutation disclosed herein as detected by an approved molecular testing methodology.
• Another embodiment is a disclosed compound used in combination with a 2 nd or 3 rd generation TKI indicated for the treatment of subject with metastatic NSCLC with tumors harboring C797X mutations as detected by an approved test, and whose disease has progressed on or after 1 or 2 prior EGFR TKI therapies.
• Another embodiment is a disclosed compound for the treatment of subjects with metastatic NSCLC whose disease with on-target EGFR resistance has progressed on or after any EGFR TKI.
• the disclosed compound is used in combination with a 2 nd or 3 rd generation TKI indicated for the treatment of subject with metastatic NSCLC.
• Another embodiment is a disclosed compound for the treatment of subjects with metastatic EGFR C797X mutation–positive NSCLC as detected by an approved molecular test, whose disease has progressed on or after first-line or second-line osimertinib.
• the disclosed compound is used in combination with a 2 nd or 3 rd generation TKI indicated for the treatment of subject with metastatic NSCLC.
• the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.
• a person of ordinary skill in the art can readily determine the certain EGFR alterations a subject possesses in a cell, cancer, gene, or gene product, e.g., whether a subject has one or more of the mutations or deletions described herein using a detection method selected from those known in the art such as hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.
• a detection method selected from those known in the art such as hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next-generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.
• a primary tumor sample circulating tumor DNA (ctDNA), circulating tumor cells (CTC), and/or circulating exosomes may be collected from a subject.
• the samples are processed, the nucleic acids are isolated using techniques known in the art, then the nucleic acids are sequenced using methods known in the art. Sequences are then mapped to individual exons, and measures of transcriptional expression (such as RPKM, or reads per kilobase per million reads mapped), are quantified.
• Raw sequences and exon array data are available from sources such as TCGA, ICGC, and the NCBI Gene Expression Omnibus (GEO).
• exon coordinates are annotated with gene identifier information, and exons belonging to kinase domains are flagged. The exon levels are then z-score normalized across all tumors samples.
• the compounds of the disclosure, pharmaceuctically acceptable salts thereof or pharmaceutical compositions disclosed herein may be used for treating to a subject who has become refractory to treatment with one or more other EGFR inhibitors. “Refractory” means that the subject’s cancer previously responded to drugs but later responds poorly or not at all. In some some embodiments, the subject has become refractory to one or more first generation EGFR inhibitors such as erlotinib, gefitinib, icotinib or lapatinib.
• the subject has been become refractory to treatment with one or more second generation EGFR inhibitors such as afatinib, dacomitinib, poziotinib, or neratinib.
• the subject has become refractory to treatment with one or more first generation inhibitors and one or more second generation inhibitors.
• the subject has become refractory to treatment with one or more third generation inhibitors such as osimertinib, clawartinib, or avitinib.
• the subject has become refractory to treatment with one or more first generation EGFR inhibitors and one or more third generation EGFR inhibitors.
• the subject has become refractory to treatment with one or more second generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more first generation inhibitors, and one or more third generation EGFR inhibitors.
• Combinations The compounds of the disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein can be used in combination with one or more additional pharmacologically active substances.
• the disclosure includes methods of treating a condition/disease/ or cancer comprising administering to a subject in need thereof a compound of the disclosure or a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein thereof in combination with an EGFR (or EGFR mutant) inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, clawinib (EGF 816), avitinib, PCC- 0208027, rezivert
• a compound of the disclosure or pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein in combination with a first line therapy for example a first, second, or third generation EGFR inhibitor (i.e., as an initial treatment before the cancer has become refractory) may forestall or delay the cancer from becoming refractory.
• the cancer is characterized by one of the EGFR genotypes described herein.
• a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein can be administered in combination with a compound disclosed in International Application Publication No. WO 2021/133809, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
• a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein can be administered in combination with a compound provided below, (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1- yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol, (3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1- yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-
• a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein can be administered in combination with other anti- cancer agents that are not EGFR inhibitors e.g., in combination with MEK, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib, glumetinib, tepotinib) and MET antibodies (emibetuzumab, telisotuzumab vedotin (ABBV 339)); mitotic kinase inhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib, abemacicilb, GIT38); anti-angiogenic agents e.g., bevacizumab, nintedanib
• a “subject” is a human in need of treatment.
• Methods of Administration and Dosage Forms The precise amount of compound administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the cancer, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
• an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used.
• Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of Formula (A) or (I) being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th Ed., 2003). “Treating” or “treatment” refers to obtaining a desired pharmacological and/or physiological effect.
• the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or substantially reducing the extent of the disease, condition or cancer; ameliorating or improving a clinical symptom or indicator associated with the disease, condition or cancer; delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or cancer; or decreasing the likelihood of recurrence of the disease, condition or cancer.
• effective amount means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
• a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day; and in another alternatively from 10 mg to 1 gram per day).
• the terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
• Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
• a compound of the disclosure, a pharmacuetically acceptable salt thereof or a pharmaceutical composition of the disclosure can be co-administered with other therapeutic agents.
• the terms “co-administration”, “administered in combination with”, and their grammatical equivalents are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
• the one or more compounds of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure will be co-administered with other agents.
• These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
• the compounds described herein and the other agent(s) are administered in a single composition.
• the compounds described herein and the other agent(s) are admixed in the composition.
• the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g.
• Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.
• daily such as weekly or monthly etc.
• a person of ordinary skill in the art would immediately recognize appropriate and/or equivalent doses looking at dosages of approved compositions for treating a disease using the disclosed EGFR inhibitors for guidance.
• the compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
• the compounds of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
• Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
• the pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
• the pharmaceutical composition is formulated for intravenous administration.
• a compound of the disclosure or a pharmaceutically acceptable salt thereof may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• solutions of a compound of the disclosure can generally or a pharmaceutically acceptable salt thereof be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils.
• LG is a suitable leaving group, typically halo or triflate and preferably, Cl or Br or triflate
• the compound of Formula (I)(A) may be prepared from the compound of Formula (II) and R 1 MgBr, by process step (a) an Fe catalysed cross-coupling reaction with a Grignard reagent in the presence of NMP as described by Mu ⁇ oz et. al. Angew. Chem. Int. Ed.2018, 57, 6496.
• Preferred conditions comprise, reaction of the compound of Formula (II) with R 1 MgBr, Fe(III)acetylacetone, NMP in THF at between 0°C and rt.
• the compound of Formula (I)(A) may be prepared from the compound of Formula (II) and R 1 Sn(alkyl)3, by process step (b) a palladium catalysed cross-coupling reaction with a suitable alkyl or aryl stannane, a Stille Reaction.
• Typical cross-coupling reaction conditions comprise a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in a suitable aqueous solvent at between rt and the reflux temperature of the reaction.
• Preferred conditions comprise reaction of the compound of Formula (II) with R 1 SnBu3, in the presence of a suitable catalyst such as Pd(PPh3)2Cl2, Pd(PPh3)4, optionally in the presence of an additive, typically LiCl, in a suitable solvent such as dioxane, at elevated temperature, such as 90-100°C.
• a suitable catalyst such as Pd(PPh3)2Cl2, Pd(PPh3)4, optionally in the presence of an additive, typically LiCl, in a suitable solvent such as dioxane, at elevated temperature, such as 90-100°C.
• the compound of Formula (I)(A) may be prepared from the compound of Formula (II) and R 1 BPin or R 1 B(OH)2 according to process step (c) a palladium catalysed, cross-coupling reaction, such as a Suzuki reaction.
• Typical cross-coupling reaction conditions comprise reaction of the compound of Formula (II) with R 1 BPin or R 1 B(OH)2, and a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in a suitable aqueous solvent at between rt and the reflux temperature of the reaction.
• Preferred conditions comprise, reaction of the compound of Formula (II) and R 1 BPin or R 1 B(OH)2, in the presence of Xphos Pd G3, Pd(dppf)Cl2, Pd2(dppf)3 Pd(PPh 3 ) 4, cataCXium A Pd G3 or PdCl 2 (Amphos) 2 and a suitable base such as K 3 PO 4 , KHCO 3 , K 2 CO 3 or Cs 2 CO 3 in a suitable solvent such as aqueous dioxane, DME or DMSO at between 70 ⁇ C and 100 ⁇ C.
• compounds of Formula (I)(A), wherein R 1 is C1-C4 alkyl or C3-C6cycloalkyl substituted by OH may be prepared from the compound of Formula (II) and R 1 C(O)R a or R 1 C(O), by process step (d).
• Preferred conditions comprise reaction of the compound of Formula (II) and R 1 C(O)R a or R 1 C(O) in the presence of a strong base such as n-BuLi, in a suitable solvent such as THF at low temperature, such as -78 °C.
• Compounds of Formula (III), wherein R 1 is an alkyl, cycloalkyl, or heterocyclyl and R 1’ is its unsaturated pre-cursor, may be prepared from the compounds of Formula (II) and R 1’ H by process step (e), a palladium catalysed, cross-coupling reaction, such as a Heck reaction.
• Preferred conditions comprise reaction of the compound of Formula (II) with R 1’ H in the presence of a suitable palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, in the presence of a suitable base such as K2CO3 or K3PO4, in a suitable solvent such as aqueous dioxane, or THF at elevated temperature such as 80°C.
• the compound of Formula (I)(A may be prepared from the compound of Formula (III) by process step (f) a reduction reaction.
• Preferred conditions comprise reaction of the compound of Formula (III) with a suitable reducing agent such as NaCNBH 3 in the presence of AcOH in a suitable alcoholic solvent such as MeOH at rt.
• a suitable reducing agent such as NaCNBH 3
• the compound of Formula (I)(A) may be prepared from the compound of Formula (II) and R 1 H by process step (e) as previously described.
• Compounds of Formula (IV)) may be prepared from the compound of Formula (II) and R 1 (BPin)2 by process step (c) as previously described above.
• the compound of Formula (I)(A), wherein R 1 is a cycloalkyl group substituted by OH may be prepared from the compound of Formula (IV) by process step (g) an oxidation reaction. Typical conditions comprise reaction of the compound of Formula (IV) with a suitable oxidising agent such as NaBO3 in a suitable solvent such as aqueous THF at about rt.
• a suitable oxidising agent such as NaBO3
• a suitable solvent such as aqueous THF at about rt.
• compounds of Formula (I)(A), wherein L 1 is a bond may be prepared from the compounds of Formulae (II), (V), (VI) and (VII), as illustrated by Scheme 1B.
• the compound of Formula (V) may be prepared from the compound of Formula (II) and (C1- C4alkyl)OC(CH)Sn(alkyl)3, by process step (b) a palladium catalysed cross-coupling reaction with a suitable alkyl stannane, a Stille Reaction as previously described in Scheme 1A.
• the compound of Formula (VI) may be prepared from the compound of Formula (V) by process step (h) an oxidation reaction. Typical conditions comprise reaction of the compound of Formula (V) with KMnO4, NaIO4, in a suitable solvent such as aqueous DCM at rt.
• the compound of Formula (I)(A) may be prepared from the compound of Formula (VI), according to process step (i) a reduction reaction of an ester. Typical conditions comprise reaction of the compound of Formula (VI) with DIBAL-H in a suitable solvent such as THF at low temperature, such as -30°C.
• the compound of Formula (VII) may be prepared from the compound of Formula (V) by process step (j). Typical conditions comprise reaction of the compound of Formula (V) with TFA in DCM at rt.
• the compound of Formula (I)(A) may be prepared from the compound of Formula (VII) by process step (k) a reduction reaction of a ketone.
• Typical conditions comprise reaction of the compound of Formula (VII) with a suitable reducing agent such as NaBH4 in a suitable solvent such as MeOH.
• a suitable reducing agent such as NaBH4
• a suitable solvent such as MeOH.
• compounds of Formula (I)(B), wherein L 1 is O may be prepared from the compound of Formula (VIII), as illustrated by Scheme 1C.
• Scheme 1C The compound of Formula (I)(B) may be prepared from the compound of Formula (VIII) according to process step (l) a Mitsunobu reaction.
• Typical conditions comprise reaction of the alcohol of Formula (VIII) with R 1 OH in the presence of PPh3 and a suitable azo dicarboxylate such as DEAD, DIAD or DBAD in a suitable solvent such as THF at between -10°C and rt.
• the compound of Formula (I)(B) may be prepared from the compound of Formula (VIII) and R 1 OH by process step (m) an alkylation reaction.
• Typical conditions comprise reaction of the compound of Formula (VIII) with R 1 OH in the presence of an inorganic base such as NaH, KOtBu, KOH or K2CO3 in a suitable solvent such as DMF or THF at between rt and elevated temperature such as 80°C.
• compounds of Formula (I)(B), wherein L 1 is O may be prepared from the compound of Formula (II) as illustrated by Scheme 1D Scheme 1D
• the compound of Formula (I)(B) may be prepared from the compound of Formula (II) and R 1 OH by an alkylation reaction as previously described in Scheme 1C above.
• the compound of Formula (I)(C), wherein L 1 is OC(O) may be prepared from the compounds of Formulae (VIII) and (IX), as illustrated by Scheme 1E Scheme 1E
• the compound of Formula (IX) may be prepared from the compound of Formula (VIII) by process step (o) a phosgenation reaction.
• Typical conditions comprise reaction of the compound of Formula (VIII) with phosgene or triphosgene in the presence of a suitable organic base, such as DIPEA in a suitable solvent, such as THF at low temperatures to rt.
• a suitable organic base such as DIPEA in a suitable solvent, such as THF at low temperatures to rt.
• the compound of Formula (I)(C) may be prepared from the compound of Formula (IX) and R 1 H according to process step (p).
• Typical conditions comprise reaction of the compound of Formula (IX) with R 1 H in the presence of suitable organic base, such as TEA in a suitable organic solvent such as DCM at about rt.
• the compound of Formula (I)(C) may be prepared from the compound of Formula (VIII) and R 1 COCl, by process step (n).
• Typical conditions comprise reaction of the compound of Formula (VIII) with R 1 COCl in the presence of a suitable inorganic or organic base such as K2CO3 or TEA or pyridine in a suitable solvent such as DMF, THF, MeCN or DCM at between rt and elevated temperature such as 80°C.
• a suitable inorganic or organic base such as K2CO3 or TEA or pyridine
• a suitable solvent such as DMF, THF, MeCN or DCM at between rt and elevated temperature such as 80°C.
• compounds of Formula (I)(D), wherein L 1 is NH, or wherein L 1 is a bond and R 1 is an N-linked heterocycle may be prepared from the compounds of Formulae (II), as illustrated by Scheme 1F Scheme 1F
• the compound of Formula (I)(D) may be prepared from the compound of Formula (II) and R 1 NH 2 according to process step (q) a Buchwald-Hartwig cross-coupling.
• Typical conditions comprise, reaction of the compound of Formula (II) with R 1 NH 2 in the presence of a suitable inorganic base, a suitable catalyst in a suitable solvent at elevated temperature.
• Preferred conditions comprise, reaction of the compounds of Formula (II) and R 1 NH 2 in the presence of, BrettPhos Pd G3, Rockphos Pd, Xantphos Pd G3, RuPhos Pd, E-Phos Pd G4, PEPPSI Pd-Ipent-O-Picoline or BINAP Pd G2 or Xphos or Xphos Pd G3 in combination with Pd 2 (dba) 3 in the presence of a suitable base such as Cs 2 CO 3, K 2 CO 3 , K 3 PO 4 , KOAc or NaOtBu in a suitable solvent such as toluene, dioxane or MeCN, at between 80 ⁇ C and 120 ⁇ C.
• a suitable base such as Cs 2 CO 3, K 2 CO 3 , K 3 PO 4 , KOAc or NaOtBu
• a suitable solvent such as toluene, dioxane or MeCN, at between 80 ⁇ C and 120 ⁇ C.
• the compound of Formula (I)(D) may be prepared from the compound of Formula (II) and R 1 NH 2 according to process step (z), an amination reaction.
• Preferred conditions comprise reaction of the compound of Formula (II) and R 1 NH 2, optionally in the presence of an organic or inorganic base, optionally in a suitable solvent such as DMSO at elevated temperature, such as 100°C.
• compounds of Formula (I)(E), wherein L 1 is NHC(O) may be prepared from the compound of Formula (X), as illustrated by Scheme 1G.
• the compound of Formula (I)(E) may be prepared from the compound of Formula (X) and R 1 H according to process step (r).
• Typical conditions comprise reaction of the compound of Formula (XX) with a suitable “carbonylating agent”, such as 4-nitrophenyl chloroformate, 2,4,6- trichlorobenzoyl chloride or CDI, in the presence of a suitable organic base such as pyridine or TEA, optionally in a suitable solvent such as DCM at between -78°C and 60°C, followed by reaction with R 1 H optionally in the presence of an organic base such as TEA in a suitable solvent such as DCM at between rt and about 80°C.
• a suitable “carbonylating agent” such as 4-nitrophenyl chloroformate, 2,4,6- trichlorobenzoyl chloride or CDI
• a suitable organic base such as pyridine or TEA
• R 1 H optionally in the presence of an organic base such as TEA in a suitable
• the compound of Formula (I)(E) may be prepared from the compound of Formula (X) and R 1 C(O)Cl according to process step (n) as previously described in Scheme 1E above.
• the compound of Formula (I)(E) may be prepared from the compound of Formula (X) and R 1 CO2H according to process step (s), an amide bond forming reaction, in the presence of a suitable coupling agent and organic base, optionally in a suitable polar aprotic solvent.
• Preferred conditions comprise the reaction of the amine of Formula (X), with R 1 CO2H in the presence of coupling agent preferably, T3P®, CDI or HATU in combination with DMAP, in the presence of a suitable organic base such as TEA, DIPEA or pyridine, optionally in a suitable solvent, such as DMF, dioxane or THF at between rt and the reflux temperature of the reaction.
• a suitable organic base such as TEA, DIPEA or pyridine
• a suitable solvent such as DMF, dioxane or THF at between rt and the reflux temperature of the reaction.
• the compound of Formula (I)(E) may be prepared from the compound of Formula (X) and R 1 C(O)imidazole according to process step (t).
• Preferred conditions comprise, reaction of the compound of Formula (X) with R 1 C(O)imidazole, in the presence of a strong base such as NaH in a suitable solvent such as THF at low temperature, typically 0°C.
• compounds of Formula (I)(E) may be prepared from the compound of Formula (II), as illustrated by Scheme 1H.
• Scheme 1H The compound of Formula (I)(E) may be prepared from the compound of Formula (II) and R 1 CONH2 according to process step (q) as previously described in Scheme 1F.
• the compound of Formula (I)(E) may be prepared from the compound of Formula (II) and R 1 CONH2 according to process step (u), an Ullmann-type, copper mediated coupling reaction.
• Preferred conditions comprise, reaction of the compound of Formula (II) with R 1 CONH2 in the presence of CuI, a suitable ligand such as N1,N2-dimethylethane-1,2-diamine or L-proline, a suitable inorganic base such as K2CO3 or K3PO4, in dioxane or DMSO at between 90 and 120°C.
• a suitable ligand such as N1,N2-dimethylethane-1,2-diamine or L-proline
• a suitable inorganic base such as K2CO3 or K3PO4, in dioxane or DMSO at between 90 and 120°C.
• compounds of Formula (I)(F) wherein L 1 is NHC(O)O
• Scheme 1I The compound of Formula (I)(F) may be prepared from the compound of Formula (X) and R 1 OC(O)Cl according to process step (n) as previously described in Scheme 1E above.
• compounds of Formula (I)(G), wherein L 2 is O may be prepared from the compound of Formula (XI), as illustrated by Scheme 2A.
• Scheme 2A LG is as previously defined.
• the compound of Formula (I)(G) may be prepared from the compound of Formula (XI) and R 2 OH according to process step (v) a Buchwald-Hartwig cross-coupling reaction.
• Typical conditions comprise, reaction of the compound of Formula (XI) with R 2 OH in the presence of a suitable inorganic base, a suitable catalyst in a suitable solvent at elevated temperature.
• Preferred conditions comprise, reaction of the compounds of Formula (XI) and R 2 OH in the presence of, BrettPhos Pd G3, Rockphos Pd, Xantphos Pd G3, or t-BuXphos and Pd2(dba)3 with a suitable base such as Cs2CO3 in a suitable solvent such as toluene, DMSO or aqueous dioxane at about 95°C.
• a suitable base such as Cs2CO3
• a suitable solvent such as toluene, DMSO or aqueous dioxane at about 95°C.
• the compound of Formula (I)(G) may be prepared from the compound of Formula (XII) and R 2 OH according to process step (l) a Mitsunobu reaction, as previously described in Scheme 1C.
• the compound of Formula (I)(G) may be prepared from the compound of Formula (XII) and R 2 OH by process step (m) an alkylation reaction, as previously described in Scheme 1C above.
• compounds of Formula (I)(H), wherein L 2 is a bond may be prepared from the compound of Formula (XI), as illustrated by Scheme 2C.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 MgBr by process step (a) as previously described in Scheme 1A above.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 SnBu3 by process step (b) as previously described in Scheme 1A above.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 BPin by process step (c) as previously described in Scheme 1A above.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 C(O)R a by process step (d) as previously described in Scheme 1A above.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 ’H by process step (e) and (f) as previously described in Scheme 1A above.
• R 2 is a C2-C4alkynl group
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 H according to process step (w) a palladium catalysed cross coupling reaction, Sonagashira type reaction.
• Typical conditions comprise reaction of the compound of Formula (XI) with R 2 H in the presence of a suitable Cu(I) salt such as CuI, a suitable palladium catalyst such as Pd(PPh3)4, in the presence of an organic base such as TEA in DMF at elevated temperature, such as 100°C.
• a suitable Cu(I) salt such as CuI
• a suitable palladium catalyst such as Pd(PPh3)4
• an organic base such as TEA in DMF at elevated temperature, such as 100°C.
• the compound of Formula (I)(H) may be prepared from the compound of Formula (XI) and R 2 H, according to process step (q) a Buchwald reaction as previously described in Scheme 1F above.
• compounds of Formula (I) may be prepared from the compounds of Formulae (XIII) and (XIV), as illustrated by Scheme 3.
• Scheme 3 Hal is a halogen, preferably Cl or Br.
• the compound of Formula (I) may be prepared from the compounds of Formulae (XIII) and (XIV) according to process step (c) a Suzuki type cross-coupling reaction, as previously described in Scheme 1A above. According to a fourteenth process, compounds of Formula (II), may be prepared from the compounds of Formulae (XV), (XVI) and (XIV), as illustrated by Scheme 4.
• the compound of Formula (XVI) may be prepared from the compound of Formula (XV) by process step (x) a halogenation reaction reaction, with a suitable halogenating agent.
• Typical conditions comprise reaction of the compound of Formula (XV) with a suitable halogenating agent such as POCl 3 or CCl 4 or POBr 3 in the presence of PPh 3 , optionally in the presence of an organic base such as DIPEA or N,N-diethylaniline, optionally in a suitable solvent such as DCE or MeCN at elevated temperature such as 70 to 100°C.
• the compound of Formula (II) may be prepared from the compounds of Formulae (XVI) and (XIV) by process step (c) a Suzuki type cross-coupling reaction, as previously described in Scheme 1A above.
• compounds of Formula (VIII) may be prepared from the compounds of Formulae (II), (XIV) and (XVII), as illustrated by Scheme 5.
• Scheme 5 The compound of Formula (VIII) may be prepared from the compound of Formula (II) by process step (v) a Buchwald type cross coupling reaction as previously described in Scheme 2A above.
• the compound of Formula (VIII) may be prepared from the compounds of Formulae (XVII) and (XIV) by process step (c) a Suzuki type cross-coupling reaction, as previously described in Scheme 1A above.
• compounds of Formula (XI) may be prepared from the compounds of Formulae (XVIII) and (XIX) as illustrated by Scheme 6.
• the compound of Formula (XIX) may be prepared from the compound of Formula (XVIII) by process step (x) a halogenation reaction as described previously in Scheme 4.
• the compound of Formula (XI) may be prepared from the compounds of Formulae (XIX) and (XIV) according to process step (c) as previously described in Scheme 1A.
• compounds of Formula (XII) may be prepared from the compounds of Formulae (XX) and (XIV), as illustrated by Scheme 7.
• the compound of Formula (XII) may be prepared from the compounds of Formulae (XX) and (XIV) according to process step (c) as previously described in Scheme 1A.
• compounds of Formula (X) may be prepared from the compounds of Formulae (XIV), (XXI) and (XXII), as illustrated by Scheme 8.
• Scheme 8 The compound of Formula (XXII) may be prepared from the compounds of Formulae (XXI) and (XIV) by process step (c) a Suzuki cross coupling reaction as previously described in Scheme 1A.
• the compound of Formula (X) may be prepared from the compound of Formula (XXII) by process step (y) a reduction of a nitro group.
• Typical conditions comprise reaction of the compound of Formula (XXII) with iron in the presence of a mild acid, in a suitable alcoholic solvent such as aqueous EtOH at elevated temperature e.g., 80°C.
• compounds of Formula (XIII) may be prepared from the compounds of Formulae (XVII) and (XXIII), as illustrated by Scheme 9.
• Scheme 9 The compound of Formula (XIII) may be prepared from the compound of Formula (XVII) and R 1 OH according to process step (l), a Mitsunobu reaction as previously described in Scheme 1C.
• the compound of Formula (XIII) may be prepared from the compound of Formula (XXIII) according to process step (x), a halogenation reaction as previously described in Scheme 4.
• Compounds of Formula (I), (II), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) and (XXII) may be converted to alternative compounds of Formula (I), (II), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) and (XXII) by standard chemical transformations, known to those skilled in the art.
• transformations include, but are not limited to: reductive amination of an N atom, alkylation or acetylation of a heteroatom, such as N or O, a Chan-Lam coupling reaction of an N-H containing compound or reduction of an ester to an alcohol. It will be appreciated by those skilled in the art that it may be necessary to utilize a suitable protecting group strategy for the preparation of compounds of Formula (I).
• Typical protecting groups may comprise, carbamate and preferably Boc for the protection of amines, a TBS or benzyl group for the protection of a primary alcohol, a benzyl group, methyl or TBDMS for the protection of a phenolic OH, a THP or group for the protection of a pyrazole N atom. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
• the following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.
• Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
• a given reaction can be carried out in one solvent or a mixture of more than one solvent.
• suitable solvents for a particular reaction step can be selected by the skilled artisan.
• Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
• spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
• NMR nuclear magnetic resonance
• IR infrared
• MS mass spectrometry
• HPLC high performance liquid chromatography
• TLC thin layer chromatography
• LC-MS liquid chromatography-mass spectrometry (LC-MS) data (sample analyzed for purity and identity) were obtained with: an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES- API ionization fitted with an Agilent Poroshel 120 (EC-C18, 2.7 um particle size, 3.0 x 50mm dimensions) reverse-phase column at 22.4 degrees Celsius.
• the mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized.
• the flow rate was constant at 1mL/min; or Shimadzu LCMS system using a Shimadzu LCMS mass spectrometer utilizing ESI ionization fitted with an Agilent (Poroshel HPH-C182.7 um particle size, 3.0 x 50mm dimensions) reverse-phase column at 22.4 degrees Celsius.
• the mobile phase consisted of a mixture of solvent 5mM NH 4 HCO 3 (or 0.05%TFA) in water and acetonitrile. A constant gradient from 90% aqueous/10% organic to 5% aqueous/95% organic mobile phase over the course of 2 minutes was utilized.
• the flow rate was constant at 1.5 mL/min.
• Prep LC-MS Preparative HPLC was performed on a Shimadzu Discovery VP® Preparative system fitted with a Luna 5u C18(2) 100A, AXIA packed, 250 x 21.2 mm reverse-phase column at 22.4 degrees Celsius.
• the mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile.
• Silica gel chromatography Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit or a Biotage® Isolera Prime unit.
• Prep LC-MS Preparative HPLC was performed on a Waters Preparative system fitted with Column: XBridge Shield RP18 OBD Column, 30*150mm, 5um; The mobile phase consisted of a solvent mixture of aqueous: (Water(10 mmol/L NH4HCO3+0.05%NH3.H2O)) and organic (acetonitrile). A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase was utilized. The flow rate was constant and typically 60 mL/min. Reactions carried out in a microwave were done so in a Biotage Initiator microwave unit.
• the reaction mixture was diluted with water and EtOAc, the organic layer was separated, washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo.
• the crude product was purified by ISCO Combiflash (0-60% EtOAc in Hexanes) to give the title compound as an orange oil, 637 mg, 50% yield.
• Preparation 13 4-bromo-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole
• a mixture of 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole (Preparation 3, 2 g, 10.5 mmol), NBS (1.86 g, 10.5 mmol) in MeCN (5.00 mL) was stirred for 2 h at rt.
• the mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography with DCM/MeOH (20/1) to give the title compound, 1.5 g, 53% as a light yellow solid.
• LCMS m/z 269 [M+H] + .
• Preparation 17 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole To a solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole (Preparation 6, 637 mg, 3.62 mmol) in DMF (9 mL) was added NBS (643 mg, 3.62 mmol) portion wise over 10 mins and the reaction was stirred at rt for 3h. The reaction was quenched with water, extracted with EtOAc, the combined organic extracts were washed with brine, then dried over anhydrous Na2SO4, filtered and solvent removed under reduced pressure.
• Preparation 28 4-bromo-3-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
• the title compound was obtained as an off-white solid, 900 mg, 68% yield, from 4-bromo-3- (3-chlorophenyl)-1H-pyrazole (Preparation 25) and dihydropyran following a similar procedure to that described in Preparation 26.
• LCMS m/z 341, 343 [M+H] + .
• Preparation 29 4-bromo-3-(2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
• the title compound was obtained as a colourless liquid, 570 mg, 67% yield, from 4-bromo-3- (2,5-difluorophenyl)-1H-pyrazole (Preparation 21), using a similar procedure to that described in Preparation 26.
• LCMS m/z 343, 345 [M+H] + .
• Preparation 33 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole
• Preparation 34 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole
• the title compound was obtained as a whte solid, 364 mg, 49% from 4-bromo-3-(2,6- difluorophenyl)-1-methyl-1H-pyrazole (Preparation 19) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following a similar procedure to that described in Preparation 33.
• Preparation 68 1-(trifluoromethyl)cyclopropane-1-carboxamide To a mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.9 mmol) in DCM (150 mL) was added HOBt (10.5 g, 77.9 mmol) and EDCI (15.0 g, 77.9 mmol) in batches. The solution was stirred at rt for 2 h then 35% aq NH3 (5 mL) was added. The reaction was stirred at rt for 1 h then concentrated to dryness.
• Preparation 81 Methyl 1-(trifluoromethyl)-1H-pyrazole-5-carboxylate To a mixture of methyl 1-(bromodifluoromethyl)-1H-pyrazole-5-carboxylate (Preparation 80, 400 mg, 1.56 mmol) in DCM (20 mL) was added AgBF4 (912 mg, 4.68 mmol) at -78 °C under N2 atmosphere and the reaction was stirred overnight at rt. The resulting solution was diluted with water (40 mL) and extracted with DCM (2x 50 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4) and evaporated to dryness in vacuo.
• Preparation 84 Methyl 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate and methyl 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate AgBF4 (2.88 g, 14.8 mmol) was added to mixture of methyl 1-(bromodifluoromethyl)-3- methyl-1H-pyrazole-4-carboxylate and methyl 1-(bromodifluoromethyl)-5-methyl-1H-pyrazole-4- carboxylate (Preparation 83, 2 g, 7.43 mmol) in DCM (30 mL) at -78oC under N2 and the resulting mixture stirred at rt for 16h.
• Preparation 85 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 5-methyl- 1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid LiOH (343 mg, 14.3 mmol) was added to mixture of 3-methyl-1-(trifluoromethyl)-1H- pyrazole-4-carboxylate and methyl 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Preparation 84, 500 mg, 2.40 mmol) in THF/H2O (15 mL/5 mL) at rt and the resulting mixture was stirred at rt for 16h.
• Preparation 92 6-bromo-4-(3-(2,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy quinazoline
• the title compound was prepared as an off-white solid (160 mg, 88%) from 6-bromo-4- chloro-7-methoxyquinazoline and 3-(2,6-difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (Preparation 34) using an analogous method to that described for Preparation 90.
• LCMS: m/z 397 [M+H] + .
• Preparation 103 7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol
• 6-bromo-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 102, 37 mg, 0.087 mmol) in dioxane (1 mL) and H 2 O (0.25 mL) was added Pd 2 (dba) 3 (8.0 mg, 0.009 mmol), t-BuXphos (7.42 mg, 0.0175 mmol) and KOH (9.81 mg, 0.175 mmol) and the reaction was stirred at 80°C for 2 h under N 2 .
• Preparation 109 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol
• Preparation 110 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)quinazolin-6-ol
• 4-chloro-7-methoxyquinazolin-6-ol (315 mg, 1.5 mmol)
• 3-phenyl-1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Preparation 42, 634 mg, 1.79 mmol
• Pd(dppf)2Cl2 109 mg, 0.150 mmol
• K3PO4 (1.27 g, 6.0 mmol) in dioxane (9 mL) and H 2 O (3 mL) was heated to 80 °C for 3 h.
• Preparation 114 7-methoxy-4-(1-(oxetan-3-yl)-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol
• the title compound was obtained as a light yellow solid, 89.6 mg, 36% yield, from 1-(oxetan- 3-yl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 38) and 4- chloro-7-methoxyquinazolin-6-ol, following the procedure described in Preparation 112.
• Preparation 115 7-methoxy-4-(3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)quinazolin-6-ol
• Preparation 129 4-chloro-7-ethoxy-6-methoxyquinazoline DIAD (1.15 g, 5.68 mmol) was added dropwise to PPh3 (1.86 g, 7.10 mmol), 4-chloro-6- methoxyquinazolin-7-ol (300 mg, 1.42 mmol) and EtOH (327 mg, 7.10 mmol) in THF (15 mL) at 0°C and the reaction stirred at rt for 2 h. The resulting solution was extracted with EtOAc (3x50 mL), the combined organic layer was dried over Na2SO4 and concentrated under vacuum.
• Preparation 132 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6,7-diol
• BBr 3 (1.06 g, 4.21 mmol) dropwise at 0°C.
• the mixture was stirred at 25°C for 1 h, then quenched with H 2 O (10 mL) and extracted with DCM (10 mL x 2).
• Preparation 135 6-(benzyloxy)-4-chloro-7-methoxypyrido[3,2-d]pyrimidine
• CCl 4 1.0 mL
• DCE 2.0 mL
• PPh 3 277.8 mg, 1.06 mmol
• Preparation 139 7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4-dimethyl piperazine-1-carboxylate
• S 7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinazolin-6- yl
• 2S)-2,4-dimethylpiperazine-1-carboxylate (Preparation 138, 100 mg, 0.184 mmol) in DCM (5 mL), was added TFA (2 mL) at 0°C and the reaction stirred at rt for 3 h.
• Preparation 140 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl) (2S,5S)-2,5-dimethylpiperazine-1,4-dicarboxylate
• Preparation 86 100 mg, 0.301 mmol
• Preparation 58, 166.54 mg, 0.602 mmol in DMF (2 mL) was added K 2 CO 3 (83.17 mg, 0.602 mmol) and the reaction was stirred at 80°C for 1 h.
• Preparation 142 1-(tert-butyl) 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl) (2R,3S)-2,3-dimethylpiperazine-1,4-dicarboxylate
• Part 1 To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 500 mg, 1.50 mmol) and DIPEA (291.65 mg, 2.26 mmol) in THF (20 mL) was added triphosgene (1.050 g, 3.54 mmol) dropwise at 0°C and the reaction was strried at 25°C for 1 h.
• reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water (10mM NH4HCO3)-MeCN];B%: 30%-60%,10min) to give the title compound (80 mg, 27.6% yield) as a white solid.
• Preparation 143 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,5S)-2,5-dimethylpiperazine-1-carboxylate
• Preparation 144 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,3R)-2,3-dimethylpiperazine-1-carboxylate
• the title compound was obtained as a yellow solid, 36.2 mg, 58% yield, from 1-(tert-butyl) 4- (7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl) (2R,3S)-2,3-dimethylpiperazine- 1,4-dicarboxylate (Preparation 142), following a similar procedure to that described in Preparation 143.
• Preparation 145 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2- methylpiperazine-1-carboxylate trifluoroacetate
• S 4-(tert-butyl) 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl) (S)-2-methylpiperazine-1,4-dicarboxylate (Preparation 141, 100 mg, 0.179 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the reaction stirred at 20°C for 0.5 h.
• Preparation 152 7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol
• a solution of 6-(benzyloxy)-7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 151, 282 mg, 0.6 mmol) in TFA (20 mL) was heated to 80°C for 3h. After cooling down to rt, the mixture was evaporated under reduced pressure to afford the title compound (190 mg, 83%) as a yellow syrup.
• Preparation 153 7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4- dimethyl piperazine-1-carboxylate
• S 7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol
• Preparation 152 190 mg, 0.5 mmol
• (2S)-2,4-dimethylpiperazine-1-carbonyl chloride 176 mg, 1 mmol
• K2CO3 207 mg, 1.5 mmol
• Preparation 162 6-bromo-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7- ethoxyquinazoline
• a mixture of Cu(OAc) 2 (92 mg, 0.760 mmol) and bipyridine (118 mg, 0.760 mmol) in DCE (15 mL) was stirred at 80°C for 30 min, then allowed to cool.6-Bromo-7-ethoxy-4-(3-phenyl-1H- pyrazol-4-yl)quinazoline (Preparation 160, 150 mg, 0.380 mmol), cyclopropylboronic acid (65 mg, 0.760 mmol) and Na2CO3 (80 mg, 0.760 mmol) were added and the reaction stirred at 80°C under an atmosphere of O2 for 4 h.
• Preparation 163 6-(1-ethoxyvinyl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazoline
• To a solution of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethanesulfonate (Preparation 116, 1 g, 2.15 mmol) in dioxane/H2O (20 mL/5 mL) was added tributyl(1-ethoxyethenyl)stannane (776 mg, 2.15 mmol), K2CO3 (593 mg, 4.30 mmol) and Pd(PPh3)2Cl2 (171 mg, 0.21 mmol) under N2 and the reaction was stirred at 100 °C for 4 h.
• Preparation 164 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7- methoxy quinazoline
• the title compound was obtained as a white solid, 211 mg, 48%, from 4-(1-(2,2- difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Preparation 117) following the procedure described in Preparation 163.
• LCMS m/z 437 [M+H] + .
• Preparation 165 7-ethoxy-6-(1-ethoxyvinyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazoline
• Preparation 173 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)ethan-1-one
• 1-(4-(1-(2,2-Difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one was obtained from 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7- methoxyquinazoline (Preparation 164), following the procedure described in Preparation 172.
• Preparation 178 1-(7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1- one
• the title compound was obtained as an off-white solid, 100 mg 82% yield from 7-ethoxy-6- (1-ethoxyvinyl)-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 166), following the procedure described in Preparation 177.
• LCMS: m/z 387 [M+H] + .
• Preparation 180 1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)ethan-1-one
• Preparation 182 ethyl 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazoline-6-carboxylate
• Ethyl 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6- carboxylate was obtained as a white solid, 100 mg, 66.6% yield, from 4-(1-(2,2-difluoroethyl)-3- phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7-methoxyquinazoline (Preparation 164), following a similar procedure to that described in Preparation 181.
• Preparation 189 4-bromo-7-methoxy-6-nitroquinazoline Phosphoroyl tribromide (2.59 g, 9.04 mmol) was added to 7-methoxy-6-nitro-3,4- dihydroquinazolin-4-one (1 g, 4.52 mmol) in MeCN (10 mL) at rt and the resulting mixture heated to 90 °C for 1h. The reaction mixture was poured into 100 g of crushed ice and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na 2 SO 4 ) and evaporated to dryness in vacuo.
• Preparation 190 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine
• Part 1 A mixture of 4-bromo-7-methoxy-6-nitroquinazoline (Preparation 189, 350 mg, 1.23 mmol), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (417 mg, 1.47 mmol), K 2 CO 3 (344 mg, 2.46 mmol) and Pd(dppf)Cl 2 (100 mg, 0.123 mmol) in dioxane/water (10 mL/2.5mL) was heated at 80 °C for 16 h under N2.
• Preparation 191 tert-butyl (2S,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate
• pyridine 33.42 mg, 0.422 mmol
• 4-nitrophenyl chloroformate 63.87 mg, 0.317 mmol
• Preparation 192 tert-butyl (S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)carbamoyl)-3-methylpiperazine-1-carboxylate
• the title compound was obtained as a yellow solid, 50 mg, 30% yield, from 7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate and tert-butyl (3S)-3-methylpiperazine-1-carboxylate following a similar procedure to that described in Preparation 191.
• Preparation 193 tert-butyl (2R,5S)-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)carbamoyl)-2,5-dimethylpiperazine-1-carboxylate
• the title compound was obtained as a yellow solid, 190 mg, 55% yield, from 7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate, following a similar procedure to that described in Preparation 191.
• Preparation 202 N-(4-chloro-7-methoxyquinazolin-6-yl)propionamide POCl3 (167 mg, 1.09 mmol) was added to N-(7-methoxy-4-oxo-3,4-dihydroquinazolin-6- yl)propionamide (Preparation 200, 180 mg, 0.727 mmol) in MeCN (5 mL) was heated to 100°C for 1 h. The reaction was quenched with H2O (2mL) at 0°C and extracted with EtOAc (3x 15mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo.
• Preparation 206 N-(7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)quinazolin-6-yl)propionamide
• N-(4-chloro-7-methoxyquinazolin-6-yl)propionamide Preparation 202, 60 mg, 0.225 mmol
• 3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole Preparation 42, 87.5 mg, 0.247 mmol
• K 2 CO 3 63 mg, 0.450 mmol
• Pd(dppf)Cl2 18.3 mg, 0.0225 mmol) in dioxane/water (3 mL/0.8 mL) was heated at 80°C for 2 h under N2.
• Preparation 207 N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4- yl)-7-methoxyquinazolin-6-yl)-2-fluorobenzamide
• Preparation 208 N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4- yl)-7-methoxyquinazolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide
• the title compound was prepared as a yellow solid (159 mg, 86%) from 6-bromo-4-(1-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 106) and bicyclo[1.1.1]pentane-1-carboxamide (Preparation 70) using an analogous method to that described for Preparation 207.
• Preparation 210 7-methoxy-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)- one 1-(4-Methoxyphenyl)methanamine (45.2 g, 330 mmol) was added to 6-chloro-7- methoxypyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 209, 10 g, 47.2 mmol) in DMSO (50 mL) at rt and the resulting mixture stirred at 100°C for 2h. The mixture was diluted with EtOAc (100 mL) and washed with brine (2x 50 mL).
• Preparation 211 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6- amine POCl3 (15.7 g, 102 mmol) and N,N-diethylaniline (25.7 g, 153 mmol) were added to 7- methoxy-6-((4-methoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 210, 8 g, 25.6 mmol) in MeCN (15 mL) at rt and the reaction stirred at 80°C for 2h. The resulting mixture was added to ice-water and the pH adjusted to pH 8 using aq.
• Preparation 212 7-methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-amine
• Pd(dppf)Cl2 (1.76 g, 2.11 mmol
• K2CO3 (4.36 g, 31.6 mmol)
• 4-chloro-7- methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine Preparation 211, 7 g, 21.1 mmol) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.97 g, 31.6 mmol) in H2O (30 mL) and dioxane (120 mL) was stirred at 80°C for 2 h under N2.
• Preparation 213 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4- methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine
• the title compound was prepared as an off-white solid (550 mg, 80%) from 4-chloro-7- methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211) and 3-(2,4- difluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 45) using an analogous method to that described for Preparation 212.
• Preparation 216 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidin-6-amine TFA (5 mL) was added to 7-methoxy-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 212, 3 g, 5.49 mmol) at rt and the mixture stirred at 60oC for 3 h.
• Preparation 217 4-(3-(2,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7- methoxypyrido[3,2-d]pyrimidin-6-amine
• Preparation 218 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxypyrido[3,2- d]pyrimidin-6-amine
• the title compound was prepared as a yellow solid (400 mg, 90%) from 4-(3-(4- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6- amine (Preparation 214) using an analogous method to that described for Preparation 217.
• LCMS: m/z 351 [M+H] + .
• Preparation 220 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxy-N-(4- methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine
• a mixture of 4-chloro-7-methoxy-N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 211, 800 mg, 2.4 mmol), K 2 CO 3 (672 mg, 4.8 mmol), Pd(dppf)Cl 2 (174 mg, 0.24 mmol) and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 37, 724 mg, 2.4 mmol) in dioxane/H 2 O (10 mL/2 mL) was stirred at 80 o C for 1 h.
• Preparation 226 methyl 3-amino-5-ethoxypicolinate
• 2-bromo-5-ethoxypyridin-3-amine Preparation 225, 5.5 g, 25.3 mmol
• TEA 7.65 g, 75.8 mmol
• Pd(dppf)Cl2 1.84 g, 2.53 mmol
• MeOH 100 mL
• the reaction mixture was diluted with EtOAc (200 mL), washed with water (3x 200 mL) and saturated brine (200 mL).
• the organic layer was dried (Na2SO4) and evaporated to dryness in vacuo.
• Preparation 228 3-amino-6-chloro-5-ethoxypicolinic acid LiOH (996 mg, 41.5 mmol) was added to methyl 3-amino-6-chloro-5-ethoxypicolinate (Preparation 227, 1.6 g, 6.93 mmol) in THF/H2O (15mL/5mL) at rt and the resulting mixture stirred at rt for 16 h. The pH was adjusted to pH 3 with HCl (1 mmol). The reaction mixture was diluted with DCM (200 mL) and washed with water (3x 200 mL) and saturated brine (200 mL).
• Preparation 231 6-chloro-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine Pd(PPh3)4 (235 mg, 0.204 mmol) and K3PO4 (864 mg, 4.08 mmol) were added to 4,6- dichloro-7-ethoxypyrido[3,2-d]pyrimidine (Preparation 230, 500 mg, 2.04 mmol) and 1-methyl-3- phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (579 mg, 2.04 mmol) in dioxane/H 2 O (16mL/ 4mL) at rt and the resulting mixture was heated to 80 o C for 2 h under N 2 .
• Preparation 232 6-chloro-7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidine
• the title compound was obtained as a yellow solid, 1 g, 32%, from 4,6-dichloro-7- ethoxypyrido[3,2-d]pyrimidine (Preparation 230) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) following a similar procedure to that described in Preparation 97.
• Preparation 240 6-chloro-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxypyrido[3,2-d]pyrimidine
• the title compound was obtained as a yellow solid, 852 mg, 24% yield, from 4,6-dichloro-7- methoxypyrido[3,2-d]pyrimidine (Preparation 224) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41), following the procedure described in Preparation 239.
• Preparation 242 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine K 3 PO 4 (250 g, 1.18 mol) was added to Pd(dppf)Cl 2 .DCM (70.5 g, 86.4 mmol), 4,6-dichloro-7- methoxypyrido[3,2-d]pyrimidine (Preparation 224, 250 g, 1.08 mol) and 1-methyl-3-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (276 g, 972 mmol) in dioxane/H2O at rt and the resulting mixture stirred at 60 °C for 16 h.
• Preparation 245 6-chloro-4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7- methoxypyrido[3,2-d]pyrimidine
• a mixture of Cu(OAc) 2 (192 mg, 0.592 mmol), 2,2’-bipyridine (92.4 mg, 0.592 mmol) and DCE (15 mL) was stirred at 80oC for 0.5 h.6-Chloro-7-methoxy-4-(3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidine (Preparation 235, 100 mg, 0.296 mmol), cyclopropylboronic acid (50.8 mg, 0.592 mmol) and Na 2 CO 3 (62.7 mg, 0.592 mmol) were added and the resulting mixture stirred at 80oC for 4 h under N 2 .
• Preparation 247 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-6- chloro-7-methoxypyrido[3,2-d]pyrimidine
• the title compound was prepared as a yellow solid (120 mg, 41%) from 6-chloro-7-methoxy- 4-(3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 235) and (2-bromoethoxy)(tert- butyl)dimethylsilane using an analogous methos to that described for Preparation 246.
• Preparation 251 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin- 6-amine
• the title compound was prepared as a yellow solid (300 mg, 56%) from 4-bromo-7-methoxy- 6-nitroquinazoline (Preparation 189) and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41) using an analogous 2-part process as described for Preparation 190.
• LCMS: m/z 382 [M+H] + .
• Preparation 252 4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine
• the title compound was prepared as a white solid (120 mg) from 4-bromo-7-methoxy-6- nitroquinazoline (Preparation 189) and 1-ethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (Preparation 33) using an analogous 2-part process as described for Preparation 190.
• LCMS: m/z 346 [M+H] + .
• Preparation 253 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6- amine
• the title compound was prepared as a white solid (80 mg, 77%) from 7-methoxy-6-nitro-3,4- dihydroquinazolin-4-one and 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (Preparation 37) using an analogous 2-part method as described for Preparation 190.
• LCMS: m/z 350 [M+H] + .
• Preparation 254 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin- 6-amine
• the title compound was prepared as a yellow solid (100 mg, 54%) from 7-methoxy-6-nitro- 3,4-dihydroquinazolin-4-one and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (Preparation 43) using an analogous 2-part method as described for Preparation 190.
• LCMS: m/z 380 [M+H] + .
• Preparation 257 tert-butyl 1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
• Preparation 259 tert-butyl 1-((7-ethoxy-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
• the title compound was prepared as a yellow solid (320 mg, 71%) from 6-chloro-7-ethoxy-4- (3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 232) and tert- butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Preparation 65) using an analogous method to that described for Preparation 258.
• Preparation 261 N-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4- yl)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide
• the title compound was prepared as a yellow solid (80 mg, 58%) from 4-(1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-phenyl-1H-pyrazol-4-yl)-6-chloro-7-methoxypyrido[3,2-d]pyrimidine (Preparation 247) and bicyclo[1.1.1]pentane-1-carboxamide (Preparation 70) using an analogous method to that described for Preparation 260.
• Preparation 266 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline 7-(1-Methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (Preparation 265, 1.70 mg, 7.51 mmol), POCl3 (10.0 mL) and DIPEA (2.91 g, 22.5 mmol) were placed into a 40-mL pressure tank reactor under N2 and the resulting solution was stirred at 100 °C for 2 h. The mixture was concentrated under vacuum and the residue diluted with water (10 mL).
• Preparation 268 4-(3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7- (1-methyl-1H-pyrazol-4-yl)quinazoline
• the title compound was obtained as a light yellow solid, 80 mg, 54% yield from 3-(2- fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (Preparation 46) and 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline (Preparation 266), following the procedure described in Preparation 267.
• Preparation 273 4-chloro-5-fluoro-7-(1-methyl-1H-pyrazol-4-yl)quinazoline The title compound was obtained as a white solid, 200 mg, 47% yield, from 5-fluoro-7-(1- methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (Preparation 272), following a similar procedure to that described in Preparation 266.
• LCMS m/z 263 [M+H] + .
• Preparation 274 6-(benzyloxy)-7-bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4- yl)quinazoline
• 6-(benzyloxy)-7-bromo-4-chloroquinazoline Preparation 150, 1 g, 2.86 mmol
• 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole Preparation 41, 955 mg, 2.86 mmol) in dioxane (20 mL) and H2O (5 mL) was added Pd(dppf)Cl2 (209 mg, 0.286 mmol) and K2CO3 (789 mg, 5.72 mmol) under N2 and the reaction was stirred at 80 °C for 4 h.
• Preparation 275 6-(benzyloxy)-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1- methyl-1H-pyrazol-4-yl)quinazoline
• the title compound was obtained as a white solid, 550 mg, 79% yield, from 6-(benzyloxy)-7- bromo-4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 274) and 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, following a similar procedure to that described in Preparation 274.
• Preparation 278 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(1-ethoxyvinyl)-7- (1-methyl-1H-pyrazol-4-yl)quinazoline
• 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol- 4-yl)quinazolin-6-yl trifluoromethanesulfonate (Preparation 277, 500 mg, 0.886 mmol) in dioxane/H 2 O was added tributyl(1-ethoxyvinyl)stannane (319 mg, 0.885 mmol) K 2 CO 3 (244 mg, 1.77 mmol) and Pd(PPh 3 ) 2 Cl 2 (57.5 mg, 0.089 mmol) under N 2 .
• Preparation 279 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(1-methyl-1H- pyrazol-4-yl)quinazolin-6-yl)ethan-1-one
• Preparation 281 7-bromo-6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline
• the title compound was obtained as a yellow solid, 40 mg, 46%, from 7-bromo-4-chloro-6- methoxy quinazoline (Preparation 280) and 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole, following the procedure described in Preparation 231.
• LCMS m/z 395 [M+H] + .
• Preparation 282 7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazolin-4(3H)-one
• 7-bromo-6-nitro-3,4-dihydroquinazolin-4-one 500 mg, 1.85 mmol
• 1-methyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole 389 mg, 1.85 mmol
• K2CO3 511 mg, 3.70 mmol
• Pd(dppf)Cl2 270 mg, 0.370 mmol
• Preparation 283 4-bromo-7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazoline
• a solution of 7-(1-methyl-1H-pyrazol-3-yl)-6-nitroquinazolin-4(3H)-one (Preparation 282, 400 mg, 1.47 mmol), DIPEA (400 mg, 1.47 mmol) and POBr 3 (400 mg, 2.20 mmol) in MeCN (5 mL) was stirred at 80 o C for 2 h. The mixture was poured into ice-NaHCO 3 , extracted with EtOAc (3x20 mL) and washed with brine (10 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
• Preparation 290 7-chloro-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-amine
• Pd(dppf)Cl2 76.0 mg, 0.104 mmol
• K3PO4 330 mg, 1.56 mmol
• 4,7-dichloro- N-(4-methoxybenzyl)pyrido[3,2-d]pyrimidin-6-amine Preparation 289, 350 mg, 1.04 mmol) and 1- methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (295 mg, 1.04 mmol) in dioxane/H2O (8 mL/2 mL) was heated at 80°C for 16 h under N2.
• Preparation 291 7-chloro-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- amine
• a solution of 7-chloro-N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 290, 340 mg, 0.744 mmol) in TFA (3 mL) was heated to 60°C for 2h. The mixture was concentrated under vacuum.
• Preparation 296 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7-(3-morpholinoprop-1-yn-1- yl)pyrido[3,2-d]pyrimidin-6-amine TFA (5 mL) was added to N-(4-methoxybenzyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-7- (3-morpholinoprop-1-yn-1-yl)pyrido[3,2-d]pyrimidin-6-amine (Preparation 295, 80 mg, 0.146 mmol) at rt.
• Step 2 ethyl (1S,2S)-1,2-bis(hydroxymethyl)cyclopropane-1-carboxylate
• the reaction was performed for two batches in parallel: To a solution of ethyl (1R,5S)-2-oxo- 3-oxabicyclo[3.1.0]hexane-1-carboxylate (84.0 g, 493 mmol) in ethanol (850 mL) was added sodium borohydride (14.9 g, 395 mmol) in portions at 0 ⁇ 5 °C.
• Step 3 ethyl (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxylate
• the reaction was performed for two batches in parallel: To a solution of ethyl (1S,2S)-1,2- bis(hydroxymethyl)cyclopropane-1-carboxylate (63.0 g, 361 mmol), triethylamine (110 g, 1.09 mol) and N, N-dimethylpyridin-4-amine (8.84 g, 72.3 mmol) in dichloromethane (1.2 L) was added p- toluenesulfonylchloride (138 g, 723 mmol) slowly at 0-5 °C.
• Step 4 (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxylic acid
• ethyl (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxylate 130 g, crude
• methanol 200 mL
• lithium hydroxide hydrate 70.0 g, 1.67 mol
• water 400 mL
• the mixture was stirred at 20 °C for 3 hours.
• the mixture was diluted with water (2.5 L), extracted with tert-butylmethylether (1.0 L ⁇ 3).
• the aqueous phase was acidified with potassium hydrogen sulfate solid (700 g, 5.14 mol), the mixture was stirred for 0.5 hour. To the mixture was added ethyl acetate (1.5 L), the mixture was filtered and partitioned. The aqueous phase was extracted with ethyl acetate (1.5 L ⁇ 2). The combined organic layer was washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil.
• Step 5 (1S,5S)-3-oxabicyclo[3.1.0]hexane-1-carboxamide
• EDCI 225 mg, 1.17 mmol
• HOBt 158 mg, 1.17 mmol
• NH3 5% aq, 2 mL
• Preparation 301 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazoline
• 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Preparation 91, 100 mg, 253 ⁇ mol
• 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (271 mg, 506 ⁇ mol) in THF (10 mL) was added BuLi (0.2 mL, 2.5 M in hexane, 506 ⁇ mol) at -78 o C.
• Step 2 Synthesis of 7-methoxy-6-nitro-4-(3-phenyl-1H-pyrazol-4-yl)quinazoline: 7-methoxy-6-nitro-4-[1-(oxan-2-yl)-3-phenyl-1H-pyrazol-4-yl]quinazoline (500 mg, 1.15 mmol) was added to HCl in Dioxane (5 mL) and stirred for 2 hrs, then the title compound was collected by filter (400 mg, yield: 90%).
• Example 2 6-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)oxy)-7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazoline
• the title compound was obtained as a white solid, 35.7 mg, 17%, from tert-butyl (3S,4S)-3- fluoro-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)oxy)piperidine-1- carboxylate (Preparation 120) and formaldehyde, following the procedure described in Example 1.
• Example 3 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-(((3R,4R)-3-fluoro-1- methylpiperidin-4-yl)oxy)-7-methoxyquinazoline
• the title compound was obtained as a white solid, 81.7 mg, 66% yield, from tert-butyl (3R,4R)-4-((4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)oxy)-3- fluoropiperidine-1-carboxylate (Preparation 123) and formaldehyde, following a similar procedure to that described in Example 1, except the crude product was purified by Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmoL/L NH 4 HCO 3 +0.1%
• Example 4 and 5 6-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline and 6-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Cis-rac-6-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazoline was obtained as a white solid, 170 mg, 65% yield from cis-rac-tert-butyl (3S,4R)-3-fluoro-4-((7-methoxy-4-(1-methyl-3-phenyl-1H
• Example 5 (6- (((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazoline or 6-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazoline.
• Example 6 and 7 6-(((3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline and 6-(((3R,4R)-4-fluoro-1-methylpyrrolidin-3- yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Trans-rac-6-(((3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazoline was obtained as an off-white solid, 157 mg, 47%, from trans-rac- tert-butyl (3S,4S)-3-fluoro-4-((7-methoxy-4-(1-methyl-3-phenyl-1H-
• Example 7 6-(((3R,4R)-4-fluoro-1-methylpyrrolidin- 3-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline or 6-(((3S,4S)-4-fluoro-1- methylpyrrolidin-3-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline.
• Example 8 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-(piperidin-4- yloxy)quinazoline
• TFA 3 mL
• the mixture was concentrated under vacuum to afford crude product as a yellow oil.
• Example 9 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-((1-methylpiperidin-4- yl)oxy)quinazoline Na(OAc) 3 BH (49.1 mg, 0.232 mmol) was added batchwise to 7-ethoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)-6-((1-methylpiperidin-4-yl)oxy)quinazoline (Example 8, 50 mg, 0.116 mmol) and formaldehyde (25.5 mg, 0.580 mmol) in DCM (10 mL) and the reaction was stirred at rt for 2 h.
• Example 10 1-(4-((7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)oxy)piperidin-1-yl)propan-1-one TEA (21.1 mg, 0.209 mmol) was added to an ice-cooled mixture of 7-ethoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)-6-(piperidin-4-yloxy)quinazoline (Example 8, 30 mg, 0.07 mmol) and prop- 2-enoyl chloride (12.8 mg, 0.139 mmol) in DCM (3 mL) and the reaction mixture was stirred at 25°C for 1 h.
• Example 11 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-((tetrahydrofuran-3- yl)oxy)quinazoline
• the reaction mixture was concentrated to dryness.
• the crude product was purified by prep-HPLC, Column: YMC-Actus Triart C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, to afford the title compound, 38.9 mg as a white solid.
• Example 12 and 13 (R)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6- ((tetrahydrofuran-3-yl)oxy)quinazoline and (S)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6- ((tetrahydrofuran-3-yl)oxy)quinazoline 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-((tetrahydrofuran-3-yl)oxy)quinazoline (Example 11, 30 mg) was further purified by Column: CHIRALPAK AD-H, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH 3 -MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL/min; Gradient: 30% B isocratic to afford Peak 1, 9.3 mg as a white solid, Example 12,
• Example 14 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-((tetrahydro-2H-pyran-4- yl)oxy)quinazoline
• the title compound was obtained as a white solid, 54 mg, 51% yield, from 4-chloro-7- methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (Preparation 126) and 1-methyl-3-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, following a similar procedure to that described in Example 11, except the compound was purified by prep-HPLC, Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 + 0.1% NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient
• Example 15 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline
• the title compound was obtained as a white solid, 59.8 mg, 33% yield, from 4-chloro-6,7- dimethoxyquinazoline and 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (Preparation 41), following a similar procedure to that described in Example 11.
• Example 16 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6-methoxy-7-(2- methoxyethoxy)quinazoline
• Pd(PPh3)4 120 mg, 0.104 mmol
• K3PO4 332 mg, 1.56 mmol
• 4-chloro-6- methoxy-7-(2-methoxyethoxy)quinazoline Preparation 130, 280 mg, 1.04 mmol
• 1-(2,2- difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Preparation 41, 521 mg, 1.56 mmol
• dioxane Preparation 41, 521 mg, 1.56 mmol
• Example 17 and 18 6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline and 6-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Pd(dppf)Cl2 (26.9 mg, 35.1 umol) and K2CO3 (72.5 mg, 0.526 mmol) were added to trans-rac- 4-chloro-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-7-methoxyquinazoline (Preparation 127, 110 mg, 0.351 mmol) and 1-methyl-3-phenyl-4-(4,4,5,5-tetra
• Example 18 6-(((3R,4R)-3-fluorotetrahydro-2H- pyran-4-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline or 6-(((3S,4S)-3- fluorotetrahydro-2H-pyran-4-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline.
• Example 19 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-ethoxy-6- methoxyquinazoline Pd(dppf)Cl 2 (32.1 mg, 0.042 mmol) and K 2 CO 3 (86.5 mg, 0.627 mmol) were added to 4- chloro-7-ethoxy-6-methoxyquinazoline (Preparation 129, 100 mg, 0.418 mmol) and 1-(2,2- difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 41, 209 mg, 0.627 mmol) in H 2 O (0.5 mL) and dioxane (2 mL) and the reaction was heated to 80°C for 2h under N 2 .
• Example 20 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-6,7-dimethoxypyrido[3,2- d]pyrimidine
• 4-chloro-6,7-dimethoxypyrido[3,2-d]pyrimidine (Example 7, WO2019148036, 60 mg, 0.266 mmol)
• 1-(2,2-difluoroethyl)-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Preparation 41, 106.6 mg, 0.319 mmol
• K2CO3 74.04 mg, 0.532 mmol
• water 1.0 mL
• dioxane 5.0 mL
• Example 21 6-((1,4-dioxepan-6-yl)oxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazoline
• 1,4-dioxepan-6-ol Preparation 49, 106 mg, 0.902 mmol
• 7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol Preparation 86, 150 mg, 0.451 mmol
• THF (10 mL) was added PPh 3 (353 mg, 1.35 mmol) and the solution stirred for 10 mins.
• Example 22 (S)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-(1-(oxetan-3- yl)ethoxy)quinazoline
• the title compound was obtained as a white solid, 120.3 mg, 56% yield, from 7-methoxy-4- (1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86) and (1R)-1-(oxetan-3-yl) ethan-1-ol, following a similar procedure to that described in Example 21.
• Example 23 4-(3-((4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)oxy)propyl)morpholine
• the title compound was obtained as a white solid, 95.3 mg, 48% yield, from 4-(1-(2,2- difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-ol (Preparation 111) and 3- (morpholin-4-yl)propan-1-ol, following a similar procedure to that described in Example 21, except the crude product was purified by prep-HPLC (XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B
• Example 24 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-((tetrahydro-2H-pyran-4- yl)oxy)quinazoline
• PPh 3 158 mg, 0.606 mmol
• tetrahydro-2H-pyran-4-ol 53.0 mg, 0.519 mmol
• DBAD 119 mg, 0.519 mmol
• Example 25 7-ethoxy-6-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline
• iodoethane 378 mg, 2.43 mmol
• K2CO3 335 mg, 2.43 mmol
• Example 26 6,7-diisopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline
• 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6,7-diol (Preparation 132, 50 mg, 0.157 mmol) and KOH (26.44 mg, 0.471 mmol) in DMF (2 mL) was added 2- iodopropane (53.40 mg, 0.314 mmol) and the reaction was stirred at 60°C for 2 h. The reaction mixture was filtered and the filtrate concentrated in vacuo.
• Example 27 2-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidin-6-yl)oxy)ethyl)-5-methyl-1,3,4-oxadiazole
• 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine Preparation 242, 50 mg, 0.142 mmol
• 1-(5-methyl-1,3,4-oxadiazol-2-yl)ethanol 27.32 mg, 0.213 mmol
• KOtBu 31.90 mg, 0.284 mmol
• Example 34 7-methoxy-6-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine
• 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine Preparation 242, 75 mg, 0.213 mmol
• Example 35 and 36 (R)-6-(1-(1-ethyl-1H-1,2,3-triazol-4-yl)ethoxy)-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and (S)-6-(1-(1-ethyl-1H-1,2,3-triazol-4- yl)ethoxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine 6-(1-(1-Ethyl-1H-1,2,3-triazol-4-yl)ethoxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidine was obtained, 70 mg, 74% yield, from 6-chloro-7-methoxy-4-(1-methyl-3-phenyl
• Example 36 (S)-6-(1-(1-ethyl-1H-1,2,3-triazol-4- yl)ethoxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine or (R)-6-(1-(1- ethyl-1H-1,2,3-triazol-4-yl)ethoxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine.
• Example 37 and 38 (S)-2-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methyl-1,3,4-oxadiazole and (R)-2-(1-((7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methyl-1,3,4-oxadiazole 2-(1-((7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- yl)oxy)ethyl)-5-methyl-1,3,4-oxadiazole (Example 27) was further purified by Column: CHIRALPAK IH, 2*25 cm, 5
• Example 39 and 40 (S)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)oxazole and (R)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)oxazole 4-(1-((7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- yl)oxy)ethyl) oxazole (Example 28), was further purified by prep chiral-HPLC Column: Column: CHIRALPAK IG, 2*25 cm, 5 ⁇ m; Mobile Phase A: EtOH, Mobile Phase B: Hex (0
• Example 40 (R)-4-(1- ((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)oxazole or (S)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy) ethyl)oxazole.
• Example 41 and 42 (R)-7-methoxy-6-(1-(1-methyl-1H-1,2,3-triazol-5-yl)ethoxy)-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and (S)-7-methoxy-6-(1-(1-methyl-1H- 1,2,3-triazol-5-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine 7-Methoxy-6-(1-(1-methyl-1H-1,2,3-triazol-5-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol- 4-yl)pyrido[3,2-d]pyrimidine was obtained, 84 mg, from 6-chloro-7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)pyr
• Example 43 and 44 (R)-7-methoxy-6-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and (S)-7-methoxy-6-(1-(1-methyl-1H- 1,2,3-triazol-4-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine 7-Methoxy-6-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol- 4-yl)pyrido[3,2-d]pyrimidine (Example 34, 70 mg) was further purifed by Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 ⁇ m; Mobile
• Example 46 (R)-7-methoxy-6-(1-(1- methyl-1H-tetrazol-5-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine or (S)-7-methoxy-6-(1-(1-methyl-1H-tetrazol-5-yl)ethoxy)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidine.
• Example 47 and 48 (S)-6-(1-(2-fluoropyridin-3-yl)ethoxy)-7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine and (R)-6-(1-(2-fluoropyridin-3-yl)ethoxy)-7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine 6-(1-(2-Fluoropyridin-3-yl)ethoxy)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidine (Example 30) was further purified by HPLC (Column CHIRALPAK AD- H, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase
• Example 49 and 50 (R)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)thiazole and (S)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)thiazole 4-(1-((7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- yl)oxy)ethyl)thiazole (Example 31, 40 mg) was further purified by Prep-Chiral-HPLC Column: CHIRALPAK IG, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH3-M
• Example 50 ((S)-4-(1-((7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)thiazole or (R)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- yl)oxy)ethyl)thiazole).
• Example 51 and 52 (S)-2-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methyl-1,3,4-thiadiazole and (R)-2-(1-((7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methyl-1,3,4-thiadiazole KOtBu (126 mg, 1.13 mmol) was added to 1-(5-methyl-1,3,4-thiadiazol-2-yl)ethan-1-ol (Preparation 51, 162 mg, 1.13 mmol) and 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrim
• Example 53 and 54 (R)-4-(1-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methylthiazole and (S)-4-(1-((7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)-5-methylthiazole NaH (69.9 mg, 1.74 mmol) was added to 1-(5-methylthiazol-4-yl)ethan-1-ol (Preparation 50, 250 mg, 1.74 mmol) in THF (8 mL) at 0°C.
• Example 55 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl (S)-2,4-dimethylpiperazine-1-carboxylate
• S 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- ol
• K 2 CO 3 82.92 mg, 0.60 mmol
• S 2-,4-dimethylpiperazine-1-carbonyl chloride
• Example 56 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6-yl (R)-3-methylmorpholine-4-carboxylate
• 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- ol Preparation 137, 30 mg, 0.09 mmol
• (R)-3-methylmorpholine-4-carbonyl chloride 29.45 mg, 0.18 mmol
• K2CO3 37.32 mg, 0.27 mmol
• Example 57 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl 2,4- dimethylpiperazine-1-carboxylate
• Example 58 and 59 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (R)- 2,4-dimethylpiperazine-1-carboxylate and 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl (S)-2,4-dimethylpiperazine-1-carboxylate 7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl 2,4-dimethylpiperazine-1- carboxylate (Example 57) was further purified by Prep-HPLC Column: CHIRALPAK AD-H, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH, Flow rate: 23 mL/min; Gradient: 23% B isocratic,
• Example 60 7-methoxy-4-(3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-6- yl (S)-2,4-dimethylpiperazine-1-carboxylate K2CO3 (145 mg, 1.049 mmol) and (S)-2,4-dimethylpiperazine-1-carbonyl chloride (Preparation 53, 61.8 mg, 0.350 mmol) were added to a solution of 7-methoxy-4-(3-phenyl-1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 115, 70 mg, 0.175 mmol) in DMF (2.5 mL) and the reaction was stirred at rt overnight under N2.
• Example 71 7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (R)-3- methylmorpholine-4-carboxylate
• (R)-3-methylmorpholine-4-carbonyl chloride 14.53 mg, 0.089 mmol
• 6- bromo-7-isopropoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Preparation 102, 16 mg, 0.044 mmol
• DMF 0.50 mL
• K2CO3 18.41 mg, 0.133 mmol
• reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-MeCN]; B%: 25%-60%, 8 min) to give the title compound, 13 mg, 60.1% as yellow solid.
• Example 72 to 75 The compounds in the following table were prepared from the appropriate quinazolin-6-ol and carbonyl chloride following a similar procedure to that described in Example 71.
• (Quinazolin-6-ol) 6: 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 109) A MeCN was used instead of DMF
• Example 76 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl (S)-3-methylmorpholine-4-carboxylate To a solution of 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6- ol (Preparation 111, 45 mg, 0.118 mmol) in DMF (0.588 mL
• Example 77 to 85 The title compounds were prepared from 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-ol (Preparation 86) and the appropriate amine (RNH2) using a library protocol as outlined below. DIPEA (0.184 mL, 1.05 mmol) was added to a mixture of 7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 69.7 mg, 0.21 mmol) and triphosgene (62.4 mg, 0.21 mmol) in DCM (4 mL) with dry-ice cooling and shaking for 1 h.
• DIPEA 0.184 mL, 1.05 mmol
• DIPEA (0.184 mL, 1.05 mmol) was added to a mixture of 7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 69.7 mg, 0.21 mmol) and triphosgene (62.4 mg, 0.21 mmol) in DCM (4 mL) with dry-ice cooling and shaking for 1 h.
• the appropriate amine (0.32 mmol) was added and the reaction mixture was shaken at 30 o C for 2 h. The reaction was filtered and evaporated to dryness by Speedvac.
• Example 89 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2R,6R)- 2,4,6-trimethylpiperazine-1-carboxylate
• TEA 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2R,6R)- 2,6-dimethylpiperazine-1-carboxylate
• TEA 152.2 ⁇ L, 1.05 mmol
• AcOH 0.3 mL
• MeOH 3 mL
• formaldehyde 37%, 25.95 mg, 0.32 mmol
• 2-Picoline Borane Complex 66.34 mg, 0.62 mmol
• Example 90 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2R,6R)- 2,4,6-trimethylpiperazine-1-carboxylate
• the title compound was obtained from 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (Example 87) and formaldehyde, following the proecedure described in the Example 89.
• Example 92 62.0 mg, as a white solid, cis-rac-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2R,5S)-2,5-dimethylmorpholine-4-carboxylate or trans-rac-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,5S)-2,5- dimethylmorpholine-4-carboxylate.
• Example 94 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2R,3S)- 2,3-dimethylmorpholine-4-carboxylate
• 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-ol (Preparation 86, 100 mg, 0.301 mmol) and bis(trichloromethyl) carbonate (446.43 mg, 1.50 mmol) in THF (20 mL) was added DIPEA (50.55 mg, 0.391 mmol) dropwise at 0°C and the reaction was stirred at 25°C for 12 h.
• Example 95 4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl (S)-2,4- dimethylpiperazine-1-carboxylate
• a solution of 7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4- dimethylpiperazine-1-carboxylate (Preparation 139, 100 mg, 0.218 mmol) in DMF (5 mL) was added NaH (10 mg, 0.436 mmol) at 0°C and the solution stirred at rt for 1 h.
• Example 96 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4- dimethylpiperazine-1-carboxylate
• a mixture of 7-bromo-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (S)-2,4- dimethylpiperazine-1-carboxylate (Preparation 153, 104 mg, 0.20 mmol), EtOH (184 mg, 4 mmol), RockphosPd (20 mg, cat) and Cs2CO3 (195 mg, 0.60 mmol) in toluene (5 mL) was stirred for 3h at 95°C.
• Example 97 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,5S)- 2,4,5-trimethylpiperazine-1-carboxylate
• To a mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,5S)- 2,5-dimethylpiperazine-1-carboxylate (Preparation 143, 40 mg, 0.085 mmol) in MeOH (2 mL) was added HCHO (13.74 mg, 0.169 mmol, 37.0% purity) in H2O and the solution stirred at 20°C for 0.5 h.
• Example 98 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl (2S,3R)- 2,3,4-trimethylpiperazine-1-carboxylate
• Example 99 (7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol
• Example 100 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan- 1-ol
• 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan- 1-one (Preparation 172, 130 mg, 0.363 mmol) in MeOH in an ice-bath, was added NaBH4 (27.5 mg, 0.72 mmol) and the mixture was stirred at rt for 3 h. The solution was quenched with water and concentrated under vacuum.
• Example 101 and 102 (S)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)ethan-1-ol and (R)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)ethan-1-ol
• 1-(4-(1-(2,2-Difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-ol was obtained as a white solid, 30 mg, 50% yield, from 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H- pyrazol-4-yl)-7-methoxyquinazolin-6-yl)
• Example 103 and 104 (S)-1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)ethan-1-ol and (R)-1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol
• (S)-1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol and (R)-1-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol
• Example 104 (R)-1-(7-ethoxy-4- (1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol or (S)-1-(7-ethoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol.
• Example 105 and 106 (S)-1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6- yl)ethan-1-ol and (R)-1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-ol
• 1-(4-(1-Ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-ol was obtained from 1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)ethan-1-one (Preparation 179), following the procedure described in Examples 103 and 104.
• the racemic product was further purified by prep-CHIRAL-HPLC, Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH3/MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20% B isocratic, to give Peak 1, 6.9 mg, as a white solid, Example 105, (S)-1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)- 7-methoxyquinazolin-6-yl)ethan-1-ol or (R)-1-(4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)ethan-1-ol.
• Example 107 and 108 (S)-1-(7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)ethan-1-ol and (R)-1-(7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol
• Example 109 and 110 (R)-1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)ethan-1-ol and (S)-1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)ethan-1-ol
• 1-(7-Ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol was obtained from 1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-one (Preparation 180), following the procedure described in Examples 107 and 108.
• the racemic compound was further purified by prep-HPLC Column: Lux 5um Cellulose-2, 2.12*25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2M NH 3 -MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 10% B isocratic to give Peak 1, 6.7 mg as a white solid,
• Example 109 (R)-1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol or (S)-1-(7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)ethan-1-ol.
• Example 110 (S)-1-(7-ethoxy-4- (1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol or (R)-1-(7-ethoxy-4-(1-isopropyl- 3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol.
• Example 111 and 112 (R)-1-(4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7- ethoxyquinazolin-6-yl)ethan-1-ol and (S)-1-(4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7- ethoxyquinazolin-6-yl)ethan-1-ol
• 1-(4-(1-Cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethan-1-ol was obtained from 1-(4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethan-1-one (Preparation 176), following the procedure described in Examples 107 and 108.
• Example 112 (S)-1-(4-(1- cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethan-1-ol or (R)-1-(4-(1- cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6-yl)ethan-1-ol.
• Example 115 and 116 (R)-1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)ethan-1-ol and (S)-1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)ethan-1-ol
• Example 116 (S)-1-(7-methoxy- 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol or (R)-1-(7-methoxy-4-(1-methyl- 3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)ethan-1-ol.
• Example 117 and 118 (S)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(((S)- tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)ethan-1-ol and (R)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H- pyrazol-4-yl)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)ethan-1-ol and
• Example 118 (R)-1-(4-(1-(2,2- difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)ethan-1-ol or (S)-1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-(((S)-tetrahydrofuran-3- yl)oxy)quinazolin-6-yl)ethan-1-ol.
• Example 119 (7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol
• a solution of ethyl 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6- carboxylate (Preparation 181, 50 mg, 0.129 mmol) in anhydrous THF (3 mL) was cooled to -30 °C and DIBAL-H in toluene (1.0 M, 0.46 mL) was added dropwise over 5 min under an atmosphere of N2.
• Example 120 7-methoxy-6-(methoxymethyl)-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazoline
• a mixture of (7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol (Example 119, 50 mg, 0.144 mmol) in DMF (4 mL) was added NaH (10.3 mg, 3.33 mmol) at 0°C, the mixture stirred at 0°C for 15 min, then iodomethane (61.4 mg, 0.433 mmol) was added and the reaction mixture stirred at 25°C for 3 h.
• Example 121 2-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propan- 2-ol
• a solution of ethyl 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline-6- carboxylate (Preparation 181, 100 mg, 0.257 mmol) in anhydrous THF (5 mL) was cooled to -10 °C and MeMgBr (3.0 M in THF, 0.25 mL) was added over 5 min under an atmosphere of Ar. The reaction was stirred at -10 °C for 1 h, then quenched with sat.
• Example 122 2-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin- 6-yl)propan-2-ol
• the title compound was obtained as a white solid, 9.9 mg, 20%, from ethyl 4-(1-(2,2- difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline-6-carboxylate (Preparation 182), following a similar procedure to that described in Example 121, except the crude was purified by HPLC: Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to 42% B in 10 min.
• Example 123 (4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6- yl)methanol Pd(PPh3)2Cl2 (50.3 mg, 0.072 mmol) was added to 6-bromo-4-(1-(2,2-difluoroethyl)-3- phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazoline (Preparation 159, 330 mg, 0.72 mmol) and (tributylstannyl) methanol (343 mg, 1.07 mmol) in dioxane (10 mL) and the reaction was heated at 80 °C for 16 h under N2.
• the reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (100 mLx 3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure.
• Example 124 (7-ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol The title compound was obtained as a white solid, 19.9 mg, 22.5% yield from 6-bromo-7- ethoxy-4-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 93), following a similar procedure to that described in Example 123.
• Example 125 (7-ethoxy-4-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)methanol
• the title compound was obtained as a white solid, 5.8 mg, from 6-bromo-7-ethoxy-4-(1- isopropyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 161) and (tributylstannyl)methanol following a similar procedure to that described in Example 123, except the compound was purified by prep-HPLC, Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 55% B to 73% B in 7 min.
• Example 126 1-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin- 6-yl)cyclopropan-1-ol NaBO3 (2.07 g, 13.5 mmol) was added to 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)- 7-methoxy-6-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)quinazoline (Preparation 183, 2.4 g, 4.50 mmol) in THF/H2O (20 mL/20 mL) and the reaction was stirred at rt for 2h.
• Example 127 4-(4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazolin- 6-yl)tetrahydro-2H-pyran-4-ol n-Butyllithium (0.1 mL, 2.5 M, 0.25 mmol) was added dropwise to 6-bromo-4-(1-(2,2- difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (Preparation 157, 44.5 mg, 0.1 mmol) and tetrahydro-4H-pyran-4-one (40 mg, 0.4 mmol) in THF (10 mL) at -78°C under N2, and the reaction was warmed to rt slowly and stirred until the starting material had been consumed.
• THF 10 mL
• Example 128 cyclopropyl(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)methanol n-Butyllithium (2.5 M, 111 ⁇ l, 0.278 mmol) was added dropwise to a solution of 6-bromo-7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91, 100 mg, 0.253 mmol) in DCM (3 mL) and the solution stirred for 20 mins.
• Example 129 and 130 (S)-2-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin- 6-yl)-4-methylmorpholine and (R)-2-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin- 6-yl)-4-methylmorpholine 6-(7-Methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3,4-dihydro-2H-1,4- oxazine (Preparation 185, 40 mg, 0.10 mmol) and bis(formaldehyde) (0.5 mL) were added to MeOH (3 mL) and AcOH (0.3 mL) and the solution stirred at rt for 30 min.
• Example 131 7-methoxy-6-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazoline
• Paraformaldehyde (0.053 g, 0.710 mmol) and MeOH (3 mL) were added to 6-(2,5-dihydro- 1H-pyrrol-3-yl)-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline trifluoroacetate (Preparation 186, 54 mg, 0.142 mmol) and the solution stirred at rt. The solution was concentrated in vacuo and the process repeated.
• Example 132 and 133 (S)-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)-6-(tetrahydro-2H- pyran-2-yl)quinazoline and (R)-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)-6-(tetrahydro-2H-pyran-2- yl)quinazoline
• (S)-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)-6-(tetrahydro-2H-pyran-2-yl)quinazoline and (R)-7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)-6-(tetrahydro-2H-pyran-2- yl)quinazoline A solution of 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91,
• n-Butyllithium (253 ⁇ L, 0.632 mmol) was added dropwise and the solution stirred for 30 min.
• a solution of 5- chloropentanal (36.6 mg, 0.304 mmol) was added and the reaction warmed slowly to rt and stirred for 2 h.
• the mixture was partitioned between water and DCM and the organic layer concentrated in vacuo.
• the crude product was dissolved in DMF (1 mL), sodium hydride (25.3 mg, 0.632 mmol) was added and the solution stirred at rt for 1 h.
• the reaction was quenched with sat. NH4Cl and extracted with DCM.
• Example 133 4.6 mg, as an off-white solid, (R)-7-methoxy-4-(3-phenyl-1H- pyrazol-4-yl)-6-(tetrahydro-2H-pyran-2-yl)quinazoline or (S)-7-methoxy-4-(3-phenyl-1H-pyrazol-4- yl)-6-(tetrahydro-2H-pyran-2-yl)quinazoline.
• Example 134 7-ethoxy-6-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazoline
• Example 135 (4-(1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)-7-ethoxyquinazolin-6- yl)methanol
• the product was further purified on prep- HPLC, Column: YMC-Actus Triart C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in 8 min, to afford the title compound, (7.5 mg) as a white solid.
• Example 136 6-ethyl-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine
• Example 150 6-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazoline
• Example 151 7-methoxy-6-(7-methoxy-2H-indazol-4-yl)-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazoline
• K 2 CO 3 67.8 mg, 0.492 mmol
• Pd(dppf)Cl 2 26.7 mg, 0.033 mmol
• 7-methoxy- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 90 mg, 0.328 mmol
• 6-bromo-7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Preparation 91, 194 mg, 0.492 mmol
• H2O 2 mL
• dioxane 8 mL
• Example 152 5-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin- 6-yl)isoindolin-1-one
• 6-chloro-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2- d]pyrimidine Preparation 242, 200 mg, 0.568 mmol
• dioxane 4.00 mL
• H2O 1.0 mL
• 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one 176 mg, 0.681 mmol
• K2CO3 (234 mg, 1.70 mmol
• Pd(dppf)Cl2.DCM 46.3 mg, 0.057 mmol
• Example 158 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-N-(tetrahydro-2H-pyran-4- yl)pyrido[3,2-d]pyrimidin-6-amine Cs2CO3 (44.3 mg, 0.136 mmol) was added to tetrahydro-2H-pyran-4-amine (27.6 mg, 0.273 mmol), Ruphos Pd (5.70 mg, 0.007 mmol) and 6-chloro-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol- 4-yl)pyrido[3,2-d]pyrimidine (Preparation 231, 25 mg, 0.068 mmol) in dioxane (4 mL) and the reaction mixture was stirred at 100 °C for 3 h under N2.
• Example 159 4-(4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6- yl)morpholine
• 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Preparation 118, 240 mg, 0.5 mmol) in dioxane (10 mL) was added morpholine (108 mg, 1.24 mmol), Cs2CO3 (645 mg, 1.98 mmol) and BINAP Pd G3 (46.2 mg, 0.05 mmol) under N2 and the reaction was stirred at 100 °C for 3 h.
• the cooled reaction mixture was diluted with water (20 mL), extracted with EtOAc (2x20 mL) and the organic layers combined. The organic solution was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum.
• the crude product was purified by Prep-HPLC Column: YMC-Altus Traits C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 m mol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 19% B to 49% B in 7 min, to give the title compound, 42.1 mg, 20.2 % as an off-white solid.
• Example 160 4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)morpholine
• Example 161 6-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2-oxa- 6-azaspiro[3.3]heptane
• a mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl trifluoromethane sulfonate (Preparation 116, 40 mg, 0.086 mmol), Cs2CO3 (56.1 mg, 0.172 mmol) and Xantphos Pd G3 (8.17 mg, 0.0086 mmol) in dioxane (0.86 mL) was purged with N2 and stirred at 100 °C.
• Example 162 7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1- yl)quinazoline
• 6-bromo-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 90, 50 mg, 0.122 mmol) and 1-methylpiperazine (10.6 mg, 0.122 mmol) in dioxane (3 mL) was added Ruphos Pd (10.2 mg, 0.012 mmol) and Cs 2 CO 3 (79.5 mg, 0.244 mmol) and the reaction mixture was stirred at 100°C for 4 h under N 2 .
• Example 163 4-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)morpholine
• the title compound was obtained, 15.5 mg, 30.6% yield, from 6-bromo-7-ethoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 90) and morpholine, following the procedure described in Example 162.
• Example 164 (S)-1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)piperidin-3-ol
• 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline (Preparation 91, 100 mg, 0.253 mmol) in dioxane (8 mL) was added (3S)-piperidin-3-ol (76.6 mg, 0.758 mmol), Cs2CO3 (492 mg, 1.51 mmol) and PEPPSI Pd-Ipent-O-Picoline (21.2 mg, 25.2 ⁇ mol) and the reaction was stirred for 16 h at 120 °C.
• Example 172 and 173 (3S,4S)-4-fluoro-1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)piperidin-3-ol and (3R,4R)-4-fluoro-1-(7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)piperidin-3-ol
• a mixture of trans-rac-4-fluoropiperidin-3-ol 60 mg, 0.5 mmol
• 6-bromo-7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Preparation 91, 200 mg, 0.5 mmol
• BrettPhos Pd G3 39.3 mg, 0.05 mmol
• Cs2CO3 329 mg, 1 mmol
• Example 174 (S)-6-(2,4-dimethylpiperazin-1-yl)-7-ethoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazoline Part 1: TFA (2 mL) was added to tert-butyl (S)-4-(7-ethoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)-3-methylpiperazine-1-carboxylate (Preparation 188, 60 mg, 0.113 mmol) in DCM (6 mL) at rt and the reaction was stirred for 2 h.
• Example 175 6-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-6- yl)-2-oxa-6-azaspiro[3.3]heptane
• PEPPSI Pd-Ipent-O-Picoline (18.3 mg, 0.218 mmol) and Cs2CO3 (106 mg, 0.327 mmol) were added to 6-chloro-7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Preparation 231, 80 mg, 0.218 mmol) and 2-oxa-6-azaspiro[3.3]heptane (25.8 mg, 0.261 mmol) in dioxane (5 mL) at rt.
• reaction mixture was heated to 100 o C for 16 h under N2, then diluted with EtOAc (100 mL), washed with water (3x100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness.
• Example 176 1-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3- methylimidazolidin-2-one
• Example 177 (2S,3S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,3-dimethylmorpholine-4-carboxamide
• 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine Preparation 190, 50.0 mg, 0.151 mmol
• pyridine (23.9 mg, 0.302 mmol)
• 4-nitrophenyl chloroformate (45.6 mg, 0.226 mmol).
• reaction mixture was stirred at 25 °C for 1 h and then added to the HCl salt of (2S,3S)-2,3-dimethylmorpholine (91.5 mg, 0.604 mmol) and TEA (30.5 mg, 0.302 mmol) in DCM (1 mL).
• the reaction mixture was stirred at 45 °C for 12 h, then concentrated under reduced pressure.
• the residue was purified by prep-HPLC column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)-MeCN]; B%: 15%-45%, 8 min to give the title compound as a yellow solid (15.0 mg, 19%).
• Example 178 (2S,5S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,4,5-trimethylpiperazine-1-carboxamide
• (2S,5S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,5-dimethylpiperazine-1-carboxamide (Preparation 195, 30.0 mg, 0.064 mmol) in MeOH (2 mL) was added HCHO (5.16 mg, 0.064 mmol) and the solution was stirred at 25 °C for 1 h.
• Example 179 (2R,3S)-4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,3-dimethylmorpholine
• the title compound was obtained as a yellow solid, 27.3 mg, 57% yield, from 7-methoxy-4- (1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 4-nitrophenyl chloroformate and (2R,3S)-2,3-dimethylmorpholine (commercial) following a similar procedure to that described in Example 177.
• LCMS m/z 473 [M+H] + .
• Example 180 (2R,3S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,3,4-trimethylpiperazine-1-carboxamide or (2S,3R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)-2,3,4-trimethylpiperazine-1-carboxamide
• the title compound was obtained as a white solid, 7.1 mg, 35% yield, from (2R,3S)-N-(7- methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,3-dimethylpiperazine-1- carboxamide or (2S,3R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quina
• Example 181 (S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2- methyl-4-(methyl-d3)piperazine-1-carboxamide
• (S)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2- methylpiperazine-1-carboxamide trifluoroacetate (Preparation 197, 40 mg, 0.070 mmol) and K2CO3 (9.67 mg, 0.070 mmol) in DMF (1 mL) was added trideuterio(iodo)methane (20.3 mg, 0.140 mmol) at 0 °C.
• Example 182 (2S,5R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-2,4,5-trimethylpiperazine-1-carboxamide
• the title compound was obtained as a pale yellow solid, 11.9 mg, 9% yield, 92% purity, from (2S,5R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2,5-dimethyl piperazine-1-carboxamide (Preparation 198) following a similar procedure to that described in Example 178.
• LCMS m/z 486 [M+H] + .
• Example 183 to 186 The title compounds were prepared from 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl) quinazolin-6-amine (Preparation 190) and the appropriate amine (RNH 2 ) using a library protocol as outlined below.
• Example 187 N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-1- (trifluoromethyl)-1H-pyrazole-4-carboxamide
• a mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 200 mg, 0.604 mmol), 1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (108 mg, 603 ⁇ mol),T3P® (1.53 g, 2.41 mmol) and pyridine (0.5 mL) in THF was stirred at 50°C for 2 h.
• Example 188 1-((dimethylamino)methyl)-N-(4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4- yl)-7-methoxyquinazolin-6-yl)cyclopropane-1-carboxamide
• the title compound was prepared as a white solid (28.5 mg, 21%) from 4-(3-(2- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine (Preparation 253) and 1- ((dimethylamino) methyl)cyclopropane-1-carboxylic acid using an analogous method to that described for Example 187, except the compound was purified by Prep-HPLC (XBridge Shield RP18 OBD, 30 x 150 mm, 5 ⁇ m; 26-65% MeCN/H2O (10 mM NH4HCO3 + 0.1% NH4OH)).
• Example 189-213 The title compounds were prepared from the appropriate amine and appropriate carboxylic acid (RCO 2 H) using an analogous method to that described for Example 187.
• Amine-1 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190);
• Amine-2 4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine (Preparation 254);
• Amine-3 4-(1-(2,2-difluoroethyl)-3-phenyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-amine (Preparation 251)
• Example 214-228 The title compounds were prepared using a 1-step library protocol as outlined below. Pyridine (1 mL) and T3P® (1 mL) were added to a mixture of 7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 66.3 mg, 0.20 mmol) and the appropriate carboxylic acid (RCO 2 H, 0.20 mmol) in THF (1 mL) and the mixture shaken at 50 °C for 5 h. The reaction mixture was evaporated to dryness by Speedvac.
• Example 229 6-cyclopropyl-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)nicotinamide
• Part 1 DMF (44.6 mg, 0.304 mmol) was added to a mixture of 6-cyclopropylnicotinic acid (500 mg, 3.04 mmol) and oxalic dichloride (771 mg, 6.08 mmol) in DCM at 0°C. The reaction was warmed to rt and stirred at 25°C for 1 h. The mixture was evaporated to dryness in vacuo and used without further purification in the Part 2.
• reaction was purified by prep-HPLC (XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; 35-50% MeCN/H2O (10 mM NH4HCO3 + 0.1%NH4OH) to afford the title compound as a white solid (144 mg, 50 %).
• Example 230 6-cyclopropyl-N-(4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)nicotinamide he title compound was prepared as a white solid (72.9 mg, 30%) from 4-(3-(2-fluorophenyl)- 1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-amine (Preparation 253) and 6- cyclopropylnicotinic acid using an analogous 2-part process as described for Example 229, but using TEA as the base.
• Example 231 2,6-dichloro-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)benzamide
• the title compound was prepared as an off-white solid (27.4 mg, 22%) from 7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190) and 2,6-dichlorobenzoic acid using an analogous 2-part process as described for Example 229.
• Example 232 N-(7-ethoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-1- (trifluoromethyl)-1H-pyrazole-4-carboxamide
• Example 233 2-(4-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-1H- pyrazol-1-yl)-N,N-dimethylethan-1-amine
• 6-bromo-7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazoline Preparation 91, 100 mg, 0.252 mmol
• N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazol-1-yl)ethan-1-amine 133 mg, 0.504 mmol
• Pd(PPh3)4 15 mg, 12.9 ⁇ mol
• K2CO3 69.6 mg, 0.504 mmol
• reaction mixture was evaporated to dryness and the residue purified by prep-TLC (15:1 DCM/MeOH) and prep-HPLC (YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; 21-51% MeCN/H 2 O (10 mM NH 4 HCO 3 + 0.1%NH 4 OH)) to afford the title compound as a white solid (60.7 mg, 53%).
• Example 234 and 235 N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)-5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide and N-(7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide
• a mixture of 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine Preparation 190, 150 mg, 452 ⁇ mol
• 3-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 5-methyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid Preparation 85, 262 mg, 1.35 mmol
• Example 236 and 237 (S)-2-(dimethylamino)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)propenamide and (R)-2-(dimethylamino)-N-(7-methoxy-4-(1-methyl-3- phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propanamide Part 1.
• T3P® (2 mL) and pyridine (2 mL) were added to 7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190, 200 mg, 0.603 mmol) and 2-bromopropanoic acid (275 mg, 1.80 mmol) in THF (2 mL) at rt and the resulting mixture heated to 50oC for 16h.
• the reaction mixture was diluted with EtOAc (100 mL) and washed with water (3x 100 mL) and brine (100 mL).
• Example 238 and 239 (S)-3-(dimethylamino)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)-2-methylpropanamide and (R)-3-(dimethylamino)-N-(7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-2-methylpropanamide Part 1.
• Example 240 and 241 (1R,5R)-N-(4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-yl)-3-oxabicyclo[3.1.0]hexane-1-carboxamide and (1S,5S)-N-(4-(3-(2- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-6-yl)-3-oxabicyclo[3.1.0]hexane-1- carboxamide
• the title compounds were prepared from 4-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-7- methoxyquinazolin-6-amine (Preparation 253) and 3-oxabicyclo[3.1.0]hexane-1-carboxylic acid using an analogous 2-part procedure as described for Examples 238 and 239.
• the racemic product was purified by Chiral-HPLC (CHIRAL ART Amylose-C NEO, 20 x 250 mm, 5 ⁇ m; 30% IPA/Hex (0.5% 2M NH3-MeOH)) to afford: Peak 1, Example 240 (off-white solid, 136.2 mg, 45%).
• Example 242 and 243 (R)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)-1-methylpyrrolidine-2-carboxamide and (S)-N-(7-methoxy-4-(1-methyl-3-phenyl- 1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyrrolidine-2-carboxamide
• the title compounds were prepared from 7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-amine (Preparation 190) and 1-methylpyrrolidine-2-carboxylic acid using an analogous 2-part procedure as described for Examples 240 and 241.
• the racemic product was purified by Chiral-HPLC (Chiralpak IG, 20 x 250 mm, 5 ⁇ m; 50% EtOH/Hex(0.5% 2M NH 3 -MeOH)) to afford: Peak 1, Example 242 (white solid, 27.7 mg, 35%).
• Example 244 and 245 (S)-2-fluoro-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)propenamide and (R)-2-fluoro-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)propanamide
• the title compounds were obtained from 2-fluoro-N-(7-methoxy-4-(1-methyl-3-phenyl-1H- pyrazol-4-yl)quinazolin-6-yl)propenamide (Example 221) by prep-HPLC (CHIRALPAK IG, 20 x 250 mm, 5 ⁇ m; 7% EtOH/3:1 Hex/DCM (0.5% 2M NH3-MeOH).
• Example 246 2-(dimethylamino)-N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)-2-methylpropanamide
• the title compound was prepared as a white solid (14.2 mg, 8%) from 7-methoxy-4-(1- methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190), 2-bromo-2- methylpropanoic acid and dimethylamine using an analogous 2-part method to that described for Example 236 (Part 1 and Part 2).
• Example 247 N-(7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide
• N-(7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)quinazolin-6-yl)propionamide (Preparation 206, 20 mg, 43.7 ⁇ mol) in HCl (4M in dioxane, 1mL) was stirred at rt for 1 h.
• reaction mixture was concentrated in vacuo and the residue purified by prep-HPLC (XSelect CSH Prep C18 OBD, 19 x 250 mm, 5 ⁇ m; 25-60% MeCN/H2O (0.1% HCO2H)) afforded the title compound as a yellow solid (3.7mg, 22%).
• Example 248 N-(7-methoxy-4-(3-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)quinazolin-6-yl)propionamide
• a mixture of N-(7-methoxy-4-(3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)propionamide (Example 247, 120mg, 0.321 mmol), 4-iodotetrahydro-2H-pyran (68mg, 0.321 mmol), Cs 2 CO 3 (209mg, 0.642 mmol) in DMF (4 mL) was stirred at 80oC for 2h.
• Example 249-250 The title compounds were prepared from N-(7-methoxy-4-(3-phenyl-1H-pyrazol-4- yl)quinazolin-6-yl)propionamide (Example 247) and the appropriate halide using an analogous method to that described for Example 248.
• Example 251 N-(7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-yl)-1- methylazetidine-2-carboxamide Part 1.
• tert-Butyl 2-((7-methoxy-4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6- yl)carbamoyl)azetidine-1-carboxylate was prepared as a yellow solid (130 mg, 84%) from 7-methoxy- 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)quinazolin-6-amine (Preparation 190) and 1-(tert- butoxycarbonyl)azetidine-2-carboxylic acid using an analogous method to that described for Example 236 and 237, Part 1.

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