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WO2024086809A1 - Methods for treating cancer - Google Patents

Methods for treating cancer Download PDF

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Publication number
WO2024086809A1
WO2024086809A1 PCT/US2023/077441 US2023077441W WO2024086809A1 WO 2024086809 A1 WO2024086809 A1 WO 2024086809A1 US 2023077441 W US2023077441 W US 2023077441W WO 2024086809 A1 WO2024086809 A1 WO 2024086809A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
amino
prop
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/077441
Other languages
French (fr)
Inventor
Benjamin C. MILGRAM
Jack Anthony HENDERSON
Angel Guzman-Perez
JR. David St. Jean
Robert Hicklin
Heidi KOLDSOE
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Scorpion Therapeutics Inc
Original Assignee
Scorpion Therapeutics Inc
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Filing date
Publication date
Application filed by Scorpion Therapeutics Inc filed Critical Scorpion Therapeutics Inc
Priority to CN202380088588.8A priority Critical patent/CN120418247A/en
Priority to EP23809862.8A priority patent/EP4605392A1/en
Priority to AU2023364551A priority patent/AU2023364551A1/en
Priority to JP2025523024A priority patent/JP2025538097A/en
Priority to IL320332A priority patent/IL320332A/en
Priority to KR1020257016596A priority patent/KR20250110370A/en
Publication of WO2024086809A1 publication Critical patent/WO2024086809A1/en
Priority to MX2025004532A priority patent/MX2025004532A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
  • the tumor suppressor p53 encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370).
  • TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242).
  • TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2016) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53).
  • mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254).
  • the p53 Y220C mutation occurs in ⁇ 1% of human cancers; ⁇ 100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2016) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74).
  • X 1 is CR 1 or N;
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a p53-associated cancer in a subject the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a subject the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.
  • pharmaceutically acceptable excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents.
  • substituent(s) when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted.
  • Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl,
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • sulfhydryl refers to a –SH radical.
  • cyano refers to a -CN radical.
  • zido refers to a –N3 radical.
  • nitro refers to a –NO2 radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • Acyl groups can be substituted with cyano or with 1-3 independently selected halogens.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]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 are connected through just one 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.
  • heteroaryl as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxid
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • halocycloalkyl refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
  • haloalkenyl refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • haloalkynyl refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • alkoxyalkyl refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxyethyl).
  • hydroxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy.
  • alkoxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy.
  • alkoxyamino refers to an –O-amino radical (e.g., -OCH2CH2N(CH3)2).
  • haloalkoxy refers to an -O-haloalkyl radical (e.g., -OCF3).
  • alkenoxy refers to an -O-alkenyl radical (e.g., -O-allyl).
  • haloalkenoxy refers to an -O-haloalkenyl radical.
  • alkynoxy refers to an -O-alkynyl radical (e.g., -O-propargyl).
  • haloalkynoxy refers to an -O-haloalkynyl radical.
  • cycloalkoxy refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).
  • aryloxy refers to an -O-aryl radical (e.g., phenoxy).
  • heteroaryloxy refers to an -O-heteroaryl radical (e.g., pyridinoxy).
  • heterocyclyloxy refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or –O-oxetanyl).
  • aralkyl refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).
  • cycloalkylalkyl refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).
  • heteroarylkyl refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).
  • heterocyclylalkyl refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl).
  • alkyl group e.g., methyloxetanyl.
  • aralkoxy refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyloxy).
  • cycloalkylalkoxy refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).
  • aminoalkyl refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).
  • a “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • a “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CF3) or –S(CHF2)).
  • a “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl.
  • R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • a “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • S-sulfonamido refers to a -SO2N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • N-sulfonamido refers to a RSO2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • amino refers to a –NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • an amino group is –NH2
  • R is hydrogen and R’ is alkyl
  • a dialkylamine R and R’ are independently selected alkyl.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., ,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, one of X 2 , X 3 , X 4 , and X 5 is N. In some embodiments, two of X 2 , X 3 , X 4 , and X 5 are N. In some embodiments, X 1 is CR 1 . In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen.
  • R 4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are the same.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are different. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are each hydrogen. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are each an independently selected C1-C6 alkyl.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl.
  • R 1 is C2-C6 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 1 is C2-C3 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 1 is C2-C3 alkynyl. In some embodiments, R 1 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 1 is C3-C6 cycloalkyl.
  • R 1 is an optionally substituted phenyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 1 is 4-6 membered heterocyclyl. In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is 5-6 membered heteroaryl. In some embodiments, X 1 is N. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA1), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA2), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , , pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is pharmaceutically acceptable salt thereof, is .
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA7), or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , , , , pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • R A is hydrogen.
  • R A is –OR 6 .
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are the same.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are different. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each hydrogen. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each an independently selected C1-C6 alkyl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is an optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is substituted phenyl or optionally 5-10 membered heteroaryl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R A is an optionally substituted C1-C6 alkyl.
  • R A is C1-C6 alkyl. In some embodiments, R A is methyl, ethyl, or n-propyl. In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is C1-C3 haloalkyl. In some embodiments, R A is trifluoromethyl. In some embodiments, R A is an optionally substituted C2-C6 alkenyl. In some embodiments, R A is C2-C6 alkenyl. In some embodiments, R A is an optionally substituted C2-C3 alkenyl. In some embodiments, R A is C2-C3 alkenyl.
  • R A is an optionally substituted C2-C6 alkynyl. In some embodiments, R A is C2-C6 alkynyl. In some embodiments, R A is an optionally substituted C2-C3 alkynyl. In some embodiments, R A is C2-C3 alkynyl. In some embodiments, R A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R A is C3- C10 cycloalkyl. In some embodiments, R A is C3-C6 cycloalkyl. In some embodiments, R A is an optionally substituted phenyl.
  • R A is phenyl. In some embodiments, R A is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R A is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R A is 3-12 membered heterocyclyl. In some embodiments, R A is 4-8 membered heterocyclyl. In some embodiments, R A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R A is 5-10 membered heteroaryl. In some embodiments, R A is 5-6 membered heteroaryl.
  • R A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R A is a 9-10 membered heteroaryl. In some embodiments, R A is phenyl optionally substituted with 1-3 independently selected R A1 . In some embodiments, R A is pyridinyl, pyrimidinyl, pyridizinyl, or pyrazinyl, each optionally substituted with 1-3 independently selected R A2 . In some embodiments, R A is a 9 membered heteroaryl optionally substituted with 1-3 independently selected R A3 .
  • each R A1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.
  • each R A2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
  • each R A3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
  • R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • the optionally substituted C1-C3 alkyl of R 8 is a C1-C3 haloalkyl.
  • R 8 is substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen.
  • R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2, or 3 halogen (e.g., fluoro or chloro). In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogen.
  • halogen e.g., fluoro or chloro
  • R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
  • R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are the same.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are different. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each hydrogen. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each an independently selected C1-C6 alkyl.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R B is an optionally substituted C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl, ethyl, or n-propyl. In some embodiments, R B is C1-C6 haloalkyl.
  • R B is C1-C3 haloalkyl. In some embodiments, R B is a C1-C3 fluoroalkyl. In some embodiments, R B is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, R B is 2,2,2-trifluoroethyl. In some embodiments, R B is an optionally substituted C2-C6 alkenyl. In some embodiments, R B is C2-C6 alkenyl. In some embodiments, R B is an optionally substituted C2-C3 alkenyl. In some embodiments, R B is C2-C3 alkenyl. In some embodiments, R B is an optionally substituted C2-C6 alkynyl.
  • R B is C2-C6 alkynyl. In some embodiments, R B is an optionally substituted C2-C3 alkynyl. In some embodiments, R B is C2-C3 alkynyl. In some embodiments, R B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R B is C3- C10 cycloalkyl. In some embodiments, R B is C3-C6 cycloalkyl. In some embodiments, R B is an optionally substituted phenyl. In some embodiments, R B is phenyl.
  • R B is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R B is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R B is 3-12 membered heterocyclyl. In some embodiments, R B is 4-8 membered heterocyclyl. In some embodiments, R B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R B is 5-10 membered heteroaryl. In some embodiments, R B is 5-6 membered heteroaryl. In some embodiments, R B is methyl, ethyl, or n-propyl.
  • R is hydroxyl, , or . In some embodiments, R B is or . In some embodiments, R B is , , , In some embodiments, R B is –SR 8 , where R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R B is –SR 8 , where R 8 is a C1-C6 haloalkyl. In some embodiments, R B is –SCF3. In some embodiments, each . In some embodiments, one of X 2 , X 3 , X 4 , and X 5 is CR 2 and the remaining X 2 , X 3 , X 4 , and X 5 are CH, N, or CR 3 .
  • Z 1 is C2- C6 alkenylene. In some embodiments, Z 1 is C2-C3 alkenylene. In some embodiments, Z 1 is an optionally substituted C2-C6 alkynylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkynylene. In some embodiments, Z 1 is C2- C6 alkynylene. In some embodiments, Z 1 is C2-C3 alkynylene. In some embodiments, Z 1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z 1 is C3-C4 cycloalkylene. In some embodiments, Z 2 is N. In some embodiments, Z 2 is O and R 2B is absent.
  • Z 2 is a bond. In some embodiments, Z 2 is CR 2C . In some embodiments, R 2C is hydrogen. In some embodiments, R 2C is halogen. In some embodiments, R 2C is fluoro or chloro. In some embodiments, R 2C is C1-C6 alkyl. In some embodiments, R 2C is C1-C3 alkyl. In some embodiments, R 2C is methyl. In some embodiments, when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to Formula (I) via Z 1 . In some embodiments, when Z 2 is a bond, R 2B is absent and R 2A is directly connected to Z 1 .
  • Z 2 is O and R 2B is absent.
  • R 2 is –NR 2A R 2B , i.e., Z 1 is a bond and Z 2 is N.
  • R 2 is R 2B , i.e., Z 1 and Z 2 are both a bond, R 2A is absent and R 2B is directly connected to Formula (I) via Z 1 .
  • R 2A is hydrogen.
  • R 10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.
  • R 11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are the same.
  • R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are different. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each hydrogen. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each an independently selected C1-C6 alkyl.
  • one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 2A is an optionally substituted C1-C6 alkyl. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl or ethyl. In some embodiments, R 2A is C1-C6 haloalkyl.
  • R 2A is C1-C3 haloalkyl. In some embodiments, R 2A is trifluoromethyl. In some embodiments, R 2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is C2-C6 alkenyl. In some embodiments, R 2A is an optionally substituted C2- C3 alkenyl. In some embodiments, R 2A is C2-C3 alkenyl. In some embodiments, R 2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2A is C2-C6 alkynyl. In some embodiments, R 2A is an optionally substituted C2- C3 alkynyl.
  • R 2A is C2-C3 alkynyl. In some embodiments, R 2A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2A is C3-C10 cycloalkyl. In some embodiments, R 2A is C3-C6 cycloalkyl. In some embodiments, R 2A is an optionally substituted phenyl. In some embodiments, R 2A is phenyl. In some embodiments, R 2A is an optionally substituted 3-12 membered heterocyclyl.
  • R 2B is trifluoromethyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is C2-C6 alkenyl. In some embodiments, R 2B is an optionally substituted C2- C3 alkenyl. In some embodiments, R 2B is C2-C3 alkenyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is C2-C6 alkynyl. In some embodiments, R 2B is an optionally substituted C2- C3 alkynyl. In some embodiments, R 2B is C2-C3 alkynyl.
  • R 2B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2B is C3-C10 cycloalkyl. In some embodiments, R 2B is C3-C6 cycloalkyl. In some embodiments, R 2B is an optionally substituted phenyl. In some embodiments, R 2B is phenyl. In some embodiments, R 2B is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R 2B is an optionally substituted 4-8 membered heterocyclyl.
  • R 2B is 3-12 membered heterocyclyl. In some embodiments, R 2B is 4-8 membered heterocyclyl. In some embodiments, R 2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2B is 5-10 membered heteroaryl. In some embodiments, R 2B is 5-6 membered heteroaryl.
  • one of R 2A and R 2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl
  • one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is a substituted 4-12 membered heterocyclyl.
  • R 2A and R 2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.
  • optionally substituted alkylene and Z 2 is N.
  • R 2 is , , or .
  • R 2 is , , or , i.e., Z 1 is an optionally substituted alkylene, Z 2 is a bond, and R 2A is absent.
  • R 2A is hydrogen.
  • R 2B is . In some e , ,
  • R 2 as defined herein comprises an ⁇ , ⁇ -unsaturated system or an electrophilic group.
  • R 2 is selected from the group consisting of: , , ,
  • X 3 is CR 2 and R 2 as defined herein comprises an ⁇ , ⁇ -unsaturated system or an electrophilic group, as described herein.
  • one of X 2 , X 3 , X 4 , and X 5 is CR 2 , one of X 2 , X 3 , X 4 , and X 5 is CR 3 , and the remaining X 2 , X 3 , X 4 , and X 5 are CH or N.
  • one of X 2 , X 3 , X 4 , and X 5 is CR 2 , one of X 2 , X 3 , X 4 , and X 5 is CR 3 , and the remaining X 2 , X 3 , X 4 , and X 5 are CH.
  • R 3 is halogen.
  • R 12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 13 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are the same.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are different. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each hydrogen. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each an independently selected C1-C6 alkyl.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are the same. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are different. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each hydrogen.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each an independently selected C1-C6 alkyl. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkenyl.
  • R 3 is C2-C6 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 3 is C2-C3 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 3 is C2-C3 alkynyl. In some embodiments, R 3 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is C3-C6 cycloalkyl.
  • R 3 is an optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 3 is 4-6 membered heterocyclyl. In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is 5-6 membered heteroaryl. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene.
  • L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene.
  • Non-Limiting Exemplary Compounds the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in List 2, or a pharmaceutically acceptable salt thereof.
  • List 2 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4- methoxybenzamide; azetidin-1-yl(3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro
  • the compound is selected from the group consisting of the compounds delineated in List 1 and/or List 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A
  • compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Methods of Treatment Provided herein are methods for restoring p53 function, encoded by TP53 gene.
  • compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53-associated disease), such as cancer (e.g., p53-associated cancer).
  • the terms “restore” or “restoration of” means to increase the activity and/or function of the specified target by a measurable amount.
  • restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.
  • the ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and/or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value.
  • a compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value.
  • Compounds of Formula (I), or pharmaceutically acceptable salts thereof are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
  • the p53-associated disease or disorder is Li-Fraumeni syndrome.
  • Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the cancer is a p53-associated cancer.
  • Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the p53-associated cancer harbors a Y220C mutation.
  • Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1-510, or a pharmaceutically acceptable salt thereof.
  • the p53-associated cancer harbors a Y220C mutation.
  • Some embodiments provide a method of treating cancer in a subject that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53-associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.
  • a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject with Li-Fraumeni syndrome.
  • p53-associated disease refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein).
  • Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).
  • p53-associated cancer refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein.
  • wild type or wild-type describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.
  • a method of treating cancer e.g., a p53-associated cancer
  • the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • methods for treating p53- associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions.
  • p53 protein substitutions/insertions/deletions are described in Table 1.
  • the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y.
  • the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof.
  • the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.
  • the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein.
  • the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation.
  • the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.
  • Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPN
  • methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • methods for treating a subject identified or diagnosed as having a p53-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non- limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is an p53-associated cancer.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • a regulatory agency- approved e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same
  • the test or assay is provided as a kit.
  • the cancer is an p53-associated cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer.
  • an assay e.g., an in vitro assay
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53-associated cancer.
  • a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
  • a regulatory agency-approved e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
  • a p53-associated cancer includes those described herein and known in the art.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject is suspected of having a p53-associated cancer.
  • methods for treating a p53-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein.
  • the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the tumor with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • a method for restoring p53 function in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function.
  • the cell is a cancer cell.
  • the cancer cell is any cancer as described herein.
  • the cancer cell is a p53-associated cancer cell.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increase cell death in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increasing tumor cell death in a subject comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • the cancer e.g., p53- associated cancer
  • the cancer is selected from a hematological cancer and a solid tumor.
  • the cancer is a hematological cancer.
  • the hematological cancer is a leukemia.
  • the hematological cancer is a lymphoma.
  • the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL).
  • the hematological cancer is acute myeloid leukemia (AML).
  • the cancer e.g., p53- associated cancer
  • the cancer is a solid tumor.
  • the cancer e.g., p53- associated cancer
  • the cancer is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.
  • the cancer e.g., p53- associated cancer
  • the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.
  • the bladder cancer is bladder urothelial carcinoma.
  • the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.
  • the skin cancer is cutaneous melanoma.
  • the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.
  • the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.
  • the breast cancer is breast invasive ductal carcinoma.
  • the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.
  • the ovarian cancer is serous ovarian cancer.
  • the kidney cancer is chromophobe renal cell carcinoma.
  • the colorectal cancer is colon adenocarcinoma.
  • the liver cancer is hepatocellular carcinoma.
  • the pancreatic cancer is pancreatic adenocarcinoma.
  • the cancer is prostate cancer.
  • the p53-associated cancer is breast cancer.
  • the p53-associated cancer is colorectal cancer.
  • the p53-associated cancer is endometrial cancer.
  • the p53-associated cancer is lung cancer.
  • the p53-associated cancer is selected from the cancers described in Table 1. Table 1. p53 Protein Amino Acid Substitutions/Insertions/Deletions A
  • compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing.
  • chemotherapeutic agents such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing.
  • a surgery may be open surgery or minimally invasive surgery.
  • Compounds of Formula (I), or pharmaceutically acceptable salts thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy.
  • the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a cancer e.g., a locally advanced or metastatic tumor
  • standard therapy e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy.
  • a subject has undergone prior therapy.
  • a subject is na ⁇ ve to p53 restoration therapy. In some embodiments, a subject is not na ⁇ ve to p53 restoration therapy.
  • a subject is kinase inhibitor na ⁇ ve. In some embodiments, a subject is not kinase inhibitor na ⁇ ve.
  • the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein.
  • the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.
  • Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), anti- androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
  • EGFR inhibitors e.g., HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein)
  • PARP inhibitors e.g., CDK4/6 inhibitors,
  • the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELATM, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.
  • the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284)
  • the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440.
  • the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005)
  • the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride
  • the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).
  • the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), creartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 29
  • the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
  • HER2 inhibitors include trastuzumab (e.g., TRAZIMERATM, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSATM), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF2
  • a “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR.
  • a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator).
  • a RAS modulator is a covalent inhibitor.
  • a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.”
  • a KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR.
  • a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator).
  • a KRAS modulator is a covalent inhibitor.
  • Non-limiting examples of a KRAS-targeted therapeutic agents include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849).
  • RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.
  • the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.
  • the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof.
  • the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC
  • the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-aceta), ipat
  • the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.
  • a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVEN TM ), or combinations thereof.
  • the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.
  • the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.
  • the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing.
  • the antimetabolite is methotrexate, pemetrexed, or 5-FU.
  • Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.
  • the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.
  • the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.
  • Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289.
  • LYNPARZA® olaparib
  • rucaparib rucaparib
  • niraparib niraparib
  • veliparib BGB-290 (pamiparib)
  • Non-limiting examples of selective estrogen receptor modulators or degraders include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.
  • Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).
  • Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof.
  • CTLA-4 inhibitor is ipilimumab (YERVOY®).
  • the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof.
  • pembrolizumab KYTRUDA®
  • OPDIVO® nivolumab
  • LIBTAYO® cemiplimab
  • JEMPERLI® dostarlimab
  • JTX-4014 vopratelimab
  • PDR001 camrelizumab
  • SIBI308 sintilimab
  • the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • the LAG-3 inhibitor is IMP701 (LAG525).
  • the A2AR inhibitor is CPI-444.
  • the TIM-3 inhibitor is MBG453.
  • the B7-H3 inhibitor is enoblituzumab.
  • the VISTA inhibitor is JNJ-61610588.
  • the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol.11: 39 (2016).
  • the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.
  • additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and/or as palliative therapy, for example, opioids and corticosteroids.
  • EXAMPLES Compound Preparation
  • the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.
  • the synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field.
  • the compounds described herein can also be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.
  • Step 1 Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of ethoxy(iodo)ethyne: To a stirred solution of ethoxy-ethyne (2.0 g, 28.53 mmol, 1 equiv) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 11.4 mL, 28.53 mmol, 1 equiv) dropwise at -78°C under nitrogen atmosphere.
  • Step 2 Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine
  • 3-bromopyridin-2-amine 926.9 mg, 5.36 mmol, 1.40 equiv
  • ACN 20 mL
  • ethoxy(iodo)ethyne 2.50g, 12.76 mmol, 1 equiv
  • Cu(OAc)2 463.4 mg, 2.55 mmol, 0.20 equiv
  • Step 2 Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
  • 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde 390 mg, 1.27 mmol, 1 equiv
  • MeOH 3 mL
  • dimethyl (1-diazo-2- oxopropyl)phosphonate 488 mg, 2.54 mmol, 2 equiv
  • K2CO3 526.6 mg, 3.81 mmol, 3 equiv
  • Step 3 Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide
  • DMF dimethyl sulfoxide
  • Step 3 Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline
  • a mixture of 4-(ethanesulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 equiv) and Fe (3.53 g, 63.20 mmol, 5 equiv) in EtOH (20 mL)/sat.NH4Cl (5 mL) was stirred for 1 h at 70°C.
  • the resulting mixture was filtered, the filter cake was washed with EtOH.
  • the filtrate was concentrated under reduced pressure.
  • the result mixture was extracted with EtOAc (3*100mL).
  • Step 2 Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene
  • 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene To a stirred solution of 4-(isopropylsulfanyl)-2-methoxy-1-nitrobenzene (21 g) in Acetone (100 mL)/H2O (100 mL)/MeOH (10 mL) was added Oxone (103.58 g) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature, then filtered. The filter cake was washed with MeOH.
  • reaction mixture was stirred at room temperature for 2 h under nitrogen atmosphere, followed by the addition of 8-bromo-2-ethynyl-3- [(trifluoromethyl)sulfanyl]indolizine (3.16 g, 9.87 mmol, 1.00 equiv) in toluene (1.00 mL) dropwise at room temperature.
  • the mixture was stirred at 60°C for 1 h under nitrogen atmosphere.
  • POM (1.96 g, 21.72 mmol, 2.20 equiv) at room temperature.
  • the resulting mixture was stirred at 60°C for additional 16 h under nitrogen atmosphere.
  • the resulting mixture was concentrated under reduced pressure.
  • the resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere.
  • 8-bromo-3-[(difluoromethyl)sulfanyl]-2- ethynylindolizine (1.20 g, 3.97 mmol, 1.00 equiv) at room temperature.
  • the resulting mixture was stirred at 60°C for additional 1 h.
  • POM (1.07 g, 11.91 mmol, 3.00 equiv) in one portion at room temperature.
  • the resulting mixture was stirred at 60°C for additional 1 h.
  • the resulting mixture was concentrated under reduced pressure.
  • Desired product could be detected by LCMS.
  • the reaction was quenched with Water, the organic phase was separated, washed with aqueous10% sodium thiosulfate (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 60% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 1-bromo-5- chloroindolizine-2-carboxylate (1 g, 34.51%) as a white solid.
  • Desired product could be detected by LCMS.
  • the mixture was allowed to cool down to room temperature.
  • the reaction was quenched by the addition of sat. NH4Cl (aq.) (10mL) at 0°C.
  • the resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL).
  • the filtrate was concentrated under reduced pressure.
  • the resulting mixture was extracted with CH2Cl2 (3 x 10 mL).
  • the combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 35 min; detector, UV 254 nm(80%). This resulted in 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine (130 mg, 35.94%) as a black oil.
  • the crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford (3S,4R)-3-fluoro-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1- methylpiperidin-4-amine (5.9 mg, 5.24%) as a white solid.
  • Example 114 Synthesis of N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]heptan-6- amine
  • N- ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl ⁇ -4-methanesulfonyl-2-methoxyaniline 120 mg, 0.23 mmol, 1 equiv
  • 2-methyl-2- azaspiro[3.3]heptan-6-amine dihydrochloride 50.9 mg, 0.25 mmol, 1.1 equiv
  • t-BuONa 89.3 mg, 0.93 mmol, 4 equiv
  • Example 116 Synthesis of methyl 4-[(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate
  • methyl 4- aminopiperidine-1-carboxylate 31 mg, 0.20 mmol, 2 equiv
  • tBuXPhos Pd G3 8 mg, 0.01 mmol, 0.1 equiv
  • t-BuONa 28 mg,
  • Example 7 Synthesis of 1-cyclopropyl-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
  • 1- cyclopropylpiperidin-4-amine 55 mg, 0.38 mmol, 2 equiv
  • t-BuXPhos Pd G3 (16 mg, 0.02 mmol, 0.1 equiv) and t-BuONa (56 mg, 0.
  • Example 9 Synthesis of 1-isopropyl-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
  • the reaction mixture was heated at 100°C for 5 h under nitrogen atmosphere.
  • the resulted solution was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm).
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 20% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.25) to afford 4- ⁇ [3-(3-ethoxy-8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide (15.1 mg, 9.05%) as a yellow solid.
  • Example 19 Synthesis of 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
  • 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 4; 45 mg, 0.14 mmol, 1 equiv) in dioxane (3 mL) were added 1- methylpiperidin-4-amine (24.3 mg, 0.21 mmol, 1.5 equiv), RuPhos (13.2 mg, 0.02 mmol, 0.2 equiv), Cs2CO3 (228.2 mg, 0.70 mmol, 5 equiv) and RuPhos Palladacycle Gen.4 (11.9 mg, 0.01 mmol, 0.1 equiv).
  • Example 22 Synthesis of (3S,4R)-N-[3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2- a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
  • a solution of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Intermediate 6; 100 mg, 0.38 mmol, 1 equiv), t-BuONa (73.6 mg, 0.77 mmol, 2 equiv) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.1) to afford (3S,4R)-N- [3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (3.1 mg, 2.59%) as a off-white solid.
  • Example 23 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide Step 1.
  • Example 25 Synthesis of tert-butyl N-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino ⁇ -2-(3- ⁇ [2-methoxy-4-(methylcarbamoyl) phenyl] amino ⁇ prop-1-yn-1-yl) imidazo[1,2- a] pyridin-3-yl)-N-methylcarbamate Step 1.
  • Example 27 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl ⁇ -8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- ol, TFA salt trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl ⁇ -4-methanesulfonyl-2-methoxyaniline
  • 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 8; 760 mg, 1.63 mmol, 1 equiv), 4-methanesulfonyl-2-methoxy-N- (prop-2-yn-1-yl)
  • Example 28 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ - 3-methoxy-N-methylbenzamide, formic acid salt Step 1.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 30% B in 8 min; Wave Length: 254nm/220nm; RT(min): 7.68) to afford 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ -3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide (22.3 mg, 13.52%) as a light yellow solid.
  • Example 29 Synthesis of 4- ⁇ [3-(3-cyclopropyl-8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy- N-methylbenzamide Step 1.
  • Step 1 Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine
  • 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (Intermediate 11; 230.0 mg, 0.52 mmol, 1 equiv) in DMSO (5 mL) was treated with 3-methoxy- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 227.7 mg, 1.04 mmol, 2 equiv), i-Pr2NH (527.8 mg, 5.22 mmol, 10 equiv), Pd(PPh3)4 (120.6 mg, 0.10 mmol, 0.20 equiv) and CuI (49.7 mg, 0.26 mmol, 0.50 equiv).
  • Example 31 Synthesis of tert-butyl N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl ⁇ -8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate Step 1.
  • Example 32 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl ⁇ -N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8- diamine
  • the reaction mixture was concentrated in vacuo.
  • the resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 62 mL/min mL/min; Gradient: 71% B to 76% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl ⁇ - N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine (5.9 mg, 6.95%) as yellow solid.
  • Example 33 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl ⁇ -N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine Step 1.
  • reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with EA (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 20% to 40% gradient in 10 min; detector, UV 220 nm) to afford tert-butyl N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1- yl ⁇ -8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl)-N- methylcarbamate (130 mg, 67.01%) as black oil.
  • Example 34 Synthesis of N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -6-phenyl-3-(2,2,2-trifluoroethyl)imidazo [1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine, formic acid salt
  • a mixture of N-(6-bromo-2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine 100 mg, 0.15 mmol, 1 equiv), phenyl boronic acid (29 mg, 0.23 mmol, 1.50 equiv), Pd(dppf)Cl2 .
  • Example 35 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Example 36 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ 3-methoxy-N- methylbenzamide Step 1.
  • Example 37 and 38 Synthesis of 4- ⁇ [3-(8- ⁇ [(4R)-3,3-difluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N-methylbenzamide (37) and 4- ⁇ [3-(8- ⁇ [(4S)-3,3-difluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N-methylbenzamide (38) Step 1.
  • Example 39 Synthesis of tert-butyl N-[2-(3- ⁇ [2-methoxy-4-(methylcarbamoyl) phenyl] amino ⁇ prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate Step 1.
  • Example 40 Synthesis of 4-[(3- ⁇ 6-amino-8-[(1-methylpiperidin-4-yl) amino]-3- (2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide
  • Example 43 Synthesis of 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1- methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-ylamino)-3-methoxy-N-methylbenzamide, formic acid salt
  • Example 44 Synthesis of 3-methoxy-N-methyl-4-[(3- ⁇ 6-[(methylcarbamoyl)amino]-8- [(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop- 2-yn-1-yl) amino] benzamide
  • a mixture of 4-[(3- ⁇ 6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide 200 mg, 0.33 mmol, 1 equiv), methylurea (48.8 mg, 0.66 mmol, 2 equiv), XantPhos (38.1 mg, 0.07 mmol, 0.2 equiv), Cs2CO3 (32
  • Example 46 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N,N-dimethylbenzamide Step 1.
  • Example 47 Synthesis of N-ethyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxybenzamide Step 1.
  • Example 48 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N-isopropyl-3- methoxybenzamide Step 1.
  • the reaction mixture was stirred at 65°C for 30 min under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 30% gradient in 20 min; detector, UV 254 nm.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 .
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-N-cyclopropyl-3-methoxybenzamide
  • 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (10 mL) were added N-cyclopropyl- 3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 18; 241.3 mg, 0.99 mmol, 2 equiv), iPr2NH (499.8 mg, 4.94 mmol, 10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv) and Cu
  • Example 50 Synthesis of (3S,4R)-3-fluoro-N-[2-(3- ⁇ [2-methoxy-4-(pyrrolidine-1- carbonyl)phenyl]amino ⁇ prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]- 1-methylpiperidin-4-amine Step 1.
  • Step 1 Synthesis of 4-(azetidine-1-carbonyl)-N- ⁇ 3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl ⁇ -2-methoxyaniline
  • 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.50 mmol, 1 equiv) in DMSO (5 mL) was treated with 4-(azetidine- 1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 20; 132.7 mg, 0.54 mmol, 1.10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv), CuI (38.1 mg, 0.20 mmol, 0.40 equiv) and i- Pr
  • the crude product was purified using prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 54% B to 68% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.42; Number Of Runs: 6.
  • Example 52 Synthesis of 5- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylpyridine-2-carboxamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-yl ⁇ amino)-N-methyl-3-(trifluoromethoxy)benzamide
  • a mixture of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide (Intermediate 22; 300 mg, 1.10 mmol, 1.30 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (Intermediate 1; 344 mg, 0.85 mmol, 1 equiv), i-Pr2NH (858 mg, 8.47 mmol, 10 equiv), CuI (162 mg, 0.84 mmol, 1 equiv) and Pd(PPh3)4 (392 mg, 0.33 mmol, 0.40
  • Example 54 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N-methyl-3- (trifluoromethyl)benzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-3-chloro-N-methylbenzamide
  • Example 56 Synthesis of 3-cyano-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Example 57 Synthesis of 3-cyclopropyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino ⁇ -N-methylbenzamide Step 1.
  • Example 58 Synthesis of 3-ethyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl ⁇ amino)-3-ethoxy-N-methylbenzamide
  • Example 60 Synthesis of 3-(difluoromethoxy)-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino ⁇ -N-methylbenzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-N-methyl-3-(2,2,2-trifluoroethoxy) benzamide
  • a solution of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (Intermediate 30; 200 mg, 0.70 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 424 mg, 1.05 mmol, 1.5 equiv), DIEA (90 mg, 0.70 mmol, 1 equiv), CuI (133 mg, 0.70 mmol, 1 equiv) and Pd(PPh3)4 (161 mg, 0.14 m
  • Example 62 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-(2- methoxyethoxy)-N-methylbenzamide Step 1.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 44% B to 69% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.9; Number Of Runs: 3) to afford 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ -3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-(2-methoxyethoxy)-N- methylbenzamide (6.3 mg, 6.78%) as a white solid
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-3-methoxy-N,N-bis( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) benzenesulfonamide
  • a mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 50 mg, 0.12 mmol, 1 equiv), 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )benzenesulfonamide (Intermediate 32; 74.2 mg, 0.15 mmol, 1.2 equiv), CuI (23.5 mg, 0.12 mmol, 1 equiv),
  • the resulting mixture was stirred at 65 o C for 1h, then cooled down to room temperature, diluted with ethyl acetate (30 mL) and washed with 3*30 mL of brine. The resulting mixture was dried with anhydrous sodium sulfate and concentrated under vacuum.

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Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).

Description

METHODS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial Nos. 63/418,089, filed on October 21, 2022, 63/443,877, filed on February 7, 2023 and 63/469,252, filed on May 26, 2023; which are incorporated herein by reference in their entirety. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0107WO1_ST26_SL.XML.” The XML file, created on October 19, 2023, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human). BACKGROUND The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242). The great majority of TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187). Reactivation of the mutant p53 protein emerges as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). Theoretically, mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53Y220C mutation occurs in ~1% of human cancers; ~100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74). In some instances, such as the Y200C mutation, there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504). SUMMARY Some embodiments provide a compound of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein: X1 is CR1 or N; R1 is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5 are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N; RA is hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each R2 is ; Z1 is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent, and when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent; R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein. The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "hydroxyl" refers to an -OH radical. The term “sulfhydryl” refers to a –SH radical. The term "cyano" refers to a -CN radical. The term “azido” refers to a –N3 radical. The term “nitro” refers to a –NO2 radical. The term “nitroso” refers to a –N=O radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term “acyl” refers to a –C(=O)alkyl radical (e.g., acetyl), or a –C(=O)alkenyl radical (e.g., -C(=O)-CH=CH2), or –C(=O)alkynyl radical (e.g.,
Figure imgf000010_0001
). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens. As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]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 are connected through just one atom). Non-limiting examples of 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. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more ,
Figure imgf000011_0001
Figure imgf000011_0002
carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S- dioxide),valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1- 2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3- oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3- oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7- oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl. The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxyethyl). The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy. The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy. The term “alkoxyamino” refers to an –O-amino radical (e.g., -OCH2CH2N(CH3)2). The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3). The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl). The term “haloalkenoxy” refers to an -O-haloalkenyl radical. The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl). The term “haloalkynoxy” refers to an -O-haloalkynyl radical. The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl). The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy). The term “heteroaryloxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy). The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or –O-oxetanyl). The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl). The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl). The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl). The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl). The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyloxy). The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl). The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)). A “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CF3) or –S(CHF2)). A “sulfinyl” group refers to an -S(=O)R group in which R can be the same as defined with respect to sulfenyl. A “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl. A “sulfoximine” group refers to an –S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “sulfonimidamido” group refers to an –S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-carboxy” group refers to a RC(=O)O- group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The terms “ester” and “C-carboxy” refer to a -C(=O)OR group in which R can be the same as defined with respect to O-carboxy. A “thiocarbonyl” group refers to a -C(=S)R group in which R can be the same as defined with respect to O-carboxy. A “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen. A “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “S-sulfonamido” group refers to a -SO2N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-sulfonamido” group refers to a RSO2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-carbamyl” group refers to a -OC(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-carbamyl” group refers to an ROC(=O)N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-thiocarbamyl” group refers to a -OC(=S)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-thiocarbamyl” group refers to an ROC(=S)N(R’)— group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “C-amido” group refers to a -C(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-amido” group refers to a RC(=O)N(R’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The terms “ureido” or “urea” refer to an –NR(C=O)NR’R’’ group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The term “carboxaldehyde” refers to a –C(=O)H radical. The term “imine” or “imino” refers to a –N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The term “amino” refers to a –NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is –NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl). The term “phosphine oxide” refers to a –P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g.,
Figure imgf000017_0001
(ii) a single ring atom (spiro-fused ring systems) (
Figure imgf000017_0002
a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
Figure imgf000017_0003
,
Figure imgf000017_0004
In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:
Figure imgf000018_0002
encompasses the tautomeric form containing the moiety:
Figure imgf000018_0001
. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound. The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human). Formulae (I) Compounds Some embodiments provide a compound of Formula (I):
Figure imgf000018_0003
or a pharmaceutically acceptable salt thereof, wherein: X1 is CR1 or N; R1 is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5 are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N; RA is hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each
Figure imgf000019_0001
Z1 is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent, and when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent; R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000020_0001
a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000021_0001
a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, one of X2, X3, X4, and X5 is N. In some embodiments, two of X2, X3, X4, and X5 are N. In some embodiments, X1 is CR1. In some embodiments, R1 is hydrogen. In some embodiments, R1 is halogen. In some embodiments, R1 is cyano. In some embodiments, R1 is –OR4. In some embodiments, R1 is -NR4R5. In some embodiments, R1 is -C(=O)R4. In some embodiments, R1 is -OC(=O)R4. In some embodiments, R1 is –C(=O)OR4. In some embodiments, R1 is –C(=O)NR4R5. In some embodiments, R1 is –SR4. In some embodiments, R1 is –S(=O)R4. In some embodiments, R1 is –S(O2)R4. In some embodiments, R1 is -NR4C(=O)R5. In some embodiments, R1 is –R4C(=O)R5. In some embodiments, R4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are the same. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are different. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are each hydrogen. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are each an independently selected C1-C6 alkyl. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R5 is hydrogen and the other of R4 and R5 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R5 is hydrogen and the other of R4 and R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R1 is an optionally substituted C1-C6 alkyl. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is methyl or ethyl. In some embodiments, R1 is an optionally substituted C2-C6 alkenyl. In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, R1 is an optionally substituted C2-C3 alkenyl. In some embodiments, R1 is C2-C3 alkenyl. In some embodiments, R1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R1 is an optionally substituted C2-C3 alkynyl. In some embodiments, R1 is C2-C3 alkynyl. In some embodiments, R1 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is an optionally substituted phenyl. In some embodiments, R1 is phenyl. In some embodiments, R1 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R1 is 4-6 membered heterocyclyl. In some embodiments, R1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R1 is 5-6 membered heteroaryl. In some embodiments, X1 is N. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000024_0001
U), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000024_0002
a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000025_0001
Figure imgf000025_0002
pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000025_0003
AA1), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000026_0001
AA2), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , ,
Figure imgf000026_0002
Figure imgf000027_0001
pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000027_0002
acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0001
some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000028_0002
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0003
some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000028_0004
some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0005
some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000028_0006
pharmaceutically acceptable salt thereof, is
Figure imgf000029_0001
. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000029_0002
some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000029_0003
(I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
Figure imgf000029_0004
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000030_0001
Figure imgf000031_0001
a
Figure imgf000031_0002
pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000031_0003
AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B’ is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000032_0001
or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B’ is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000032_0002
AA7), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , , , ,
Figure imgf000033_0001
Figure imgf000034_0001
pharmaceutically acceptable salt of any of the foregoing, wherein R2B’ is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, RA is hydrogen. In some embodiments, RA is –OR6. In some embodiments, RA is -NR6R7. In some embodiments, RA is -C(=O)R6. In some embodiments, RA is -R6C(=O)R7. In some embodiments, RA is -OC(=O)R6. In some embodiments, RA is -OC(=O)NR6. In some embodiments, RA is –C(=O)OR6. In some embodiments, RA is –NR6C(=O)OR7. In some embodiments, RA is –C(=O)NR6R7. In some embodiments, RA is –SR6. In some embodiments, RA is –S(=O)R6. In some embodiments, RA is –S(O2)R6. In some embodiments, RA is –S(O2)NR6. In some embodiments, RA is –NR6S(O2)R7. In some embodiments, RA is -NR6C(=O)R7. In some embodiments, RA is -NR6C(=O)NR7. In some embodiments, RA is -SiR6R7R8. In some embodiments, R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are the same. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are different. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are each hydrogen. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are each an independently selected C1-C6 alkyl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is an optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is substituted phenyl or optionally 5-10 membered heteroaryl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, RA is an optionally substituted C1-C6 alkyl. In some embodiments, RA is C1-C6 alkyl. In some embodiments, RA is methyl, ethyl, or n-propyl. In some embodiments, RA is C1-C6 haloalkyl. In some embodiments, RA is C1-C3 haloalkyl. In some embodiments, RA is trifluoromethyl. In some embodiments, RA is an optionally substituted C2-C6 alkenyl. In some embodiments, RA is C2-C6 alkenyl. In some embodiments, RA is an optionally substituted C2-C3 alkenyl. In some embodiments, RA is C2-C3 alkenyl. In some embodiments, RA is an optionally substituted C2-C6 alkynyl. In some embodiments, RA is C2-C6 alkynyl. In some embodiments, RA is an optionally substituted C2-C3 alkynyl. In some embodiments, RA is C2-C3 alkynyl. In some embodiments, RA is an optionally substituted C3-C10 cycloalkyl. In some embodiments, RA is an optionally substituted C3-C6 cycloalkyl. In some embodiments, RA is C3- C10 cycloalkyl. In some embodiments, RA is C3-C6 cycloalkyl. In some embodiments, RA is an optionally substituted phenyl. In some embodiments, RA is phenyl. In some embodiments, RA is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, RA is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, RA is 3-12 membered heterocyclyl. In some embodiments, RA is 4-8 membered heterocyclyl. In some embodiments, RA is an optionally substituted 5-10 membered heteroaryl. In some embodiments, RA is an optionally substituted 5-6 membered heteroaryl. In some embodiments, RA is 5-10 membered heteroaryl. In some embodiments, RA is 5-6 membered heteroaryl. In some embodiments, RA is an optionally substituted 9-10 membered heteroaryl. In some embodiments, RA is a 9-10 membered heteroaryl. In some embodiments, RA is phenyl optionally substituted with 1-3 independently selected RA1. In some embodiments, RA is pyridinyl, pyrimidinyl, pyridizinyl, or pyrazinyl, each optionally substituted with 1-3 independently selected RA2. In some embodiments, RA is a 9 membered heteroaryl optionally substituted with 1-3 independently selected RA3. In some embodiments, each RA1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy. In some embodiments, each RA2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy. In some embodiments, each RA3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy. In some embodiments, each RA1, RA2 and RA3 is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, -C(=O)NRR’, -CO2H, -SO2(C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR’, - S(=O)(=NR)NRR’, or -P(=O)(C1-C3 alkyl)2, wherein each R and R’ are independently hydrogen or C1-C3 alkyl. In some embodiments, each RA1 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclyloxy, -SO2(C1-C3 alkyl), -SO2NRR’, or -P(=O)(C1-C3 alkyl)2, wherein R and R’ are independently hydrogen or C1-C3 alkyl.
Figure imgf000038_0001
, , , , , , ,
Figure imgf000039_0001
Figure imgf000040_0001
, , , , , , , , ,
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
, , ,
Figure imgf000043_0002
Figure imgf000044_0001
n some embodiments, RB is halogen. In some embodiments, RB is fluoro or chloro. In some embodiments, RB is cyano. In some embodiments, RB is hydroxyl. In some embodiments, RB is –NR8R9. In some embodiments, RB is -OR8. In some embodiments, RB is –C(=O)NR8R9. In some embodiments, RB is –C(=O)R8. In some embodiments, RB is -C(=O)OR8. In some embodiments, RB is -NR8C(=O)OR9 In some embodiments, RB is –OC(=O)R8. In some embodiments, RB is –OC(=O)NR8. In some embodiments, RB is –C(=O)NR8R9. In some embodiments, RB is –NR8C(=O)R9. In some embodiments, RB is –NR8C(=O)NR9. In some embodiments, RB is –SR8. In some embodiments, RB is –S(=O)R8. In some embodiments, RB is –S(O2)R8. In some embodiments, RB is –S(O2)NR8. In some embodiments, RB is –NR8S(O2)R9. In some embodiments, RB is -R8C(=O)R9. In some embodiments, RB is -NR8C(=O)R9. In some embodiments, RB is -NR8C(=O)NR9. In some embodiments, R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the optionally substituted C1-C6 alkyl of R8 is a C1-C6 haloalkyl. In some embodiments, R8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, the optionally substituted C1-C3 alkyl of R8 is a C1-C3 haloalkyl. In some embodiments, R8 is substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen. In some embodiments, R8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with halogen. In some embodiments, R8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2, or 3 halogen (e.g., fluoro or chloro). In some embodiments, R8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogen. In some embodiments, R8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogen. In some embodiments, R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are the same. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are different. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are each hydrogen. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are each an independently selected C1-C6 alkyl. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, one of R8 and R9 is hydrogen and the other of R8 and R9 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, one of R8 and R9 is hydrogen and the other of R8 and R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, RB is an optionally substituted C1-C6 alkyl. In some embodiments, RB is C1-C6 alkyl. In some embodiments, RB is methyl, ethyl, or n-propyl. In some embodiments, RB is C1-C6 haloalkyl. In some embodiments, RB is C1-C3 haloalkyl. In some embodiments, RB is a C1-C3 fluoroalkyl. In some embodiments, RB is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, RB is 2,2,2-trifluoroethyl. In some embodiments, RB is an optionally substituted C2-C6 alkenyl. In some embodiments, RB is C2-C6 alkenyl. In some embodiments, RB is an optionally substituted C2-C3 alkenyl. In some embodiments, RB is C2-C3 alkenyl. In some embodiments, RB is an optionally substituted C2-C6 alkynyl. In some embodiments, RB is C2-C6 alkynyl. In some embodiments, RB is an optionally substituted C2-C3 alkynyl. In some embodiments, RB is C2-C3 alkynyl. In some embodiments, RB is an optionally substituted C3-C10 cycloalkyl. In some embodiments, RB is an optionally substituted C3-C6 cycloalkyl. In some embodiments, RB is C3- C10 cycloalkyl. In some embodiments, RB is C3-C6 cycloalkyl. In some embodiments, RB is an optionally substituted phenyl. In some embodiments, RB is phenyl. In some embodiments, RB is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, RB is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, RB is 3-12 membered heterocyclyl. In some embodiments, RB is 4-8 membered heterocyclyl. In some embodiments, RB is an optionally substituted 5-10 membered heteroaryl. In some embodiments, RB is an optionally substituted 5-6 membered heteroaryl. In some embodiments, RB is 5-10 membered heteroaryl. In some embodiments, RB is 5-6 membered heteroaryl. In some embodiments, RB is methyl, ethyl, or n-propyl. B
Figure imgf000047_0001
In some embodiments, R is hydroxyl, , or . In some embodiments, RB is or . In some embodiments, RB is ,
Figure imgf000047_0002
,
Figure imgf000047_0003
,
Figure imgf000048_0001
In some embodiments, RB is –SR8, where R8 is an optionally substituted C1-C6 alkyl. In some embodiments, RB is –SR8, where R8 is a C1-C6 haloalkyl. In some embodiments, RB is –SCF3. In some embodiments, each
Figure imgf000048_0002
. In some embodiments, one of X2, X3, X4, and X5 is CR2 and the remaining X2, X3, X4, and X5 are CH, N, or CR3. In some embodiments, Z1 is a bond. In some embodiments, Z1 is -C=O-. In some embodiments, Z1 is -S(O2)-. In some embodiments, Z1 is an optionally substituted C1-C6 alkylene. In some embodiments, Z1 is an optionally substituted C1-C3 alkylene. In some embodiments, Z1 is C1-C6 alkylene. In some embodiments, Z1 is C1-C3 alkylene. In some embodiments, Z1 is methylene or ethylene. In some embodiments, Z1 is an optionally substituted C2-C6 alkenylene. In some embodiments, Z1 is an optionally substituted C2-C3 alkenylene. In some embodiments, Z1 is C2- C6 alkenylene. In some embodiments, Z1 is C2-C3 alkenylene. In some embodiments, Z1 is an optionally substituted C2-C6 alkynylene. In some embodiments, Z1 is an optionally substituted C2-C3 alkynylene. In some embodiments, Z1 is C2- C6 alkynylene. In some embodiments, Z1 is C2-C3 alkynylene. In some embodiments, Z1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z1 is C3-C4 cycloalkylene. In some embodiments, Z2 is N. In some embodiments, Z2 is O and R2B is absent. In some embodiments, Z2 is a bond. In some embodiments, Z2 is CR2C. In some embodiments, R2C is hydrogen. In some embodiments, R2C is halogen. In some embodiments, R2C is fluoro or chloro. In some embodiments, R2C is C1-C6 alkyl. In some embodiments, R2C is C1-C3 alkyl. In some embodiments, R2C is methyl. In some embodiments, when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1. In some embodiments, when Z2 is a bond, R2B is absent and R2A is directly connected to Z1. In some embodiments, Z2 is O and R2B is absent. In some embodiments, R2 is –NR2AR2B, i.e., Z1 is a bond and Z2 is N. In some embodiments, R2 is R2B, i.e., Z1 and Z2 are both a bond, R2A is absent and R2B is directly connected to Formula (I) via Z1. In some embodiments, when Z1 is a not a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Z1. In some embodiments, R2A is hydrogen. In some embodiments, R2A is -C(=O)R10. In some embodiments, R2A is –C(=O)OR10. In some embodiments, R2A is –C(=O)NR10R11. In some embodiments, R2A is –S(=O)R10. In some embodiments, R2A is –S(O2)R10. In some embodiments, R10 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl. In some embodiments, R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are the same. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are different. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are each hydrogen. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are each an independently selected C1-C6 alkyl. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, one of R10 and R11 is hydrogen and the other of R10 and R11 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, one of R10 and R11 is hydrogen and the other of R10 and R11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R2A is an optionally substituted C1-C6 alkyl. In some embodiments, R2A is C1-C6 alkyl. In some embodiments, R2A is methyl or ethyl. In some embodiments, R2A is C1-C6 haloalkyl. In some embodiments, R2A is C1-C3 haloalkyl. In some embodiments, R2A is trifluoromethyl. In some embodiments, R2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R2A is C2-C6 alkenyl. In some embodiments, R2A is an optionally substituted C2- C3 alkenyl. In some embodiments, R2A is C2-C3 alkenyl. In some embodiments, R2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R2A is C2-C6 alkynyl. In some embodiments, R2A is an optionally substituted C2- C3 alkynyl. In some embodiments, R2A is C2-C3 alkynyl. In some embodiments, R2A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2A is C3-C10 cycloalkyl. In some embodiments, R2A is C3-C6 cycloalkyl. In some embodiments, R2A is an optionally substituted phenyl. In some embodiments, R2A is phenyl. In some embodiments, R2A is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2A is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2A is 3-12 membered heterocyclyl. In some embodiments, R2A is 4-8 membered heterocyclyl. In some embodiments, R2A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2A is 5-10 membered heteroaryl. In some embodiments, R2A is 5-6 membered heteroaryl. In some embodiments, R2B is hydrogen. In some embodiments, R2B is -C(=O)R10. In some embodiments, R2B is –C(=O)OR10. In some embodiments, R2B is –C(=O)NR10R11. In some embodiments, R2B is –S(=O)R10. In some embodiments, R2B is –S(O2)R10. In some embodiments, R2B is an optionally substituted C1-C6 alkyl. In some embodiments, R2B is C1-C6 alkyl. In some embodiments, R2B is methyl or ethyl. In some embodiments, R2B is C1-C6 haloalkyl. In some embodiments, R2B is C1-C3 haloalkyl. In some embodiments, R2B is trifluoromethyl. In some embodiments, R2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R2B is C2-C6 alkenyl. In some embodiments, R2B is an optionally substituted C2- C3 alkenyl. In some embodiments, R2B is C2-C3 alkenyl. In some embodiments, R2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R2B is C2-C6 alkynyl. In some embodiments, R2B is an optionally substituted C2- C3 alkynyl. In some embodiments, R2B is C2-C3 alkynyl. In some embodiments, R2B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2B is C3-C10 cycloalkyl. In some embodiments, R2B is C3-C6 cycloalkyl. In some embodiments, R2B is an optionally substituted phenyl. In some embodiments, R2B is phenyl. In some embodiments, R2B is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2B is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2B is 3-12 membered heterocyclyl. In some embodiments, R2B is 4-8 membered heterocyclyl. In some embodiments, R2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2B is 5-10 membered heteroaryl. In some embodiments, R2B is 5-6 membered heteroaryl. In some embodiments, R2B is –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; and R2B is hydrogen. In some embodiments, one of R2A and R2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2A and R2B is hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl. In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B is a substituted 4-12 membered heterocyclyl. In some embodiments, R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl. In some embodiments,
Figure imgf000053_0001
optionally substituted alkylene and Z2 is N. In some embodiments,
Figure imgf000053_0002
Figure imgf000053_0003
, , , or . In some embodiments, R2 is , , or
Figure imgf000053_0004
, i.e., Z1 is an optionally substituted alkylene, Z2 is a bond, and R2A is absent. In some embodiments,
Figure imgf000053_0005
. In some embodiments, R2A is hydrogen. In some embodiments, R2B is
Figure imgf000054_0001
. In some e ,
Figure imgf000054_0002
Figure imgf000055_0001
,
Figure imgf000056_0001
Figure imgf000057_0001
,
Figure imgf000057_0002
,
o
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
, , , , , , , ,
Figure imgf000061_0001
Figure imgf000062_0001
, , ,
Figure imgf000063_0001
In some embodiments, R2 as defined herein, comprises an α, β-unsaturated system or an electrophilic group. In some embodiments, R2 is selected from the group consisting of:
Figure imgf000063_0002
, , ,
Figure imgf000063_0003
In some embodiments, X3 is CR2 and R2 as defined herein comprises an α, β-unsaturated system or an electrophilic group, as described herein. In some embodiments, one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH or N. In some embodiments, one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is cyano. In some embodiments, R3 is –NR12R13. In some embodiments, R3 is -OR12. In some embodiments, R3 is –C(=O)NR12R13. In some embodiments, R3 is –C(=O)R12. In some embodiments, R3 is -C(=O)OR12. In some embodiments, R3 is –OC(=O)R12. In some embodiments, R3 is –NR12(C=O)NR12R13. In some embodiments, R3 is –SR12. In some embodiments, R3 is –S(=O)R12. In some embodiments, R3 is –S(O2)R12. In some embodiments, R3 is –S(O2)NR12R13. In some embodiments, R3 is –NR12S(O2)NR13R14. In some embodiments, R3 is -R12C(=O)R13. In some embodiments, R3 is -NR12C(=O)R13. In some embodiments, R12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R13 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are the same. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are different. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are each hydrogen. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are each an independently selected C1-C6 alkyl. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, one of R12 and R13 is hydrogen and the other of R12 and R13 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, one of R12 and R13 is hydrogen and the other of R12 and R13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are the same. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are different. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are each hydrogen. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are each an independently selected C1-C6 alkyl. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, one of R13 and R14 is hydrogen and the other of R13 and R14 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, one of R13 and R14 is hydrogen and the other of R13 and R14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R3 is an optionally substituted C1-C6 alkyl. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is methyl or ethyl. In some embodiments, R3 is an optionally substituted C2-C6 alkenyl. In some embodiments, R3 is C2-C6 alkenyl. In some embodiments, R3 is an optionally substituted C2-C3 alkenyl. In some embodiments, R3 is C2-C3 alkenyl. In some embodiments, R3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R3 is C2-C6 alkynyl. In some embodiments, R3 is an optionally substituted C2-C3 alkynyl. In some embodiments, R3 is C2-C3 alkynyl. In some embodiments, R3 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R3 is C3-C6 cycloalkyl. In some embodiments, R3 is an optionally substituted phenyl. In some embodiments, R3 is phenyl. In some embodiments, R3 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R3 is 4-6 membered heterocyclyl. In some embodiments, R3 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R3 is 5-6 membered heteroaryl. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene. In some embodiments, L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof. List 1 N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- (prop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1- fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)-2H-indazol-7-amine; 3- ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- (prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N7- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazole-5,7-diamine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-vinylpyrazolo[1,5-c]pyrimidin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyrazin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-pyrazolo[3,4-c]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyrazin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-c]pyrimidin-8-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-pyrazolo[4,3-c]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2- yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)pyrazolo[1,5- a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)-2H-indazol-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)-2H-indazol-7-amine; 3- ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-ethynyl-N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)pyrazolo[1,5- a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1- yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)- 2H-indazol-7-amine; 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; 3-(2,2- difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; 4-((3-(7-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(7- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N,N-dimethylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)- 3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; N-ethyl-4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-ethyl-4-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-ethyl-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2- methoxyethyl)-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3- (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide; 4-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- 3-methoxy-N-methylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzenesulfonamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzenesulfonamide; N- ((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-1- ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 2-((3S,4R)-3- fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-ol; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N- ((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 1-((3S,4R)-3- fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 1-((3S,4R)-3-fluoro-4-((2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-yl)amino)piperidin-1-yl)ethan-1-one; 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-one; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1- yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylimidazo[1,2-a]pyridin-8-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4- ((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7- yl)amino)-N-methylpiperidine-1-carboxamide; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidine-1-carboxylate; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidine-1-carboxylate; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidine-1- carboxylate; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidin-1-yl)ethan-1-one; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-one; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7- yl)amino)piperidin-1-yl)ethan-1-one; 4-((3-(7-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)- 3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(8-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-1-ethyl-3-fluoropiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N7-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1- yn-1-yl)-3-vinyl-2H-indazole-5,7-diamine; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(1-fluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1- fluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2- yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- (1,2,2-trifluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2- trifluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2- trifluorovinyl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-((E)-prop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(3-ethynyl-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(3-ethynyl-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-ethynyl-7-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1- yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((Z)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en- 1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en-1-yl)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 5-fluoro-N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-amine; 6-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-amine; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-((R)-oxiran-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2-yl)-2H-indazol-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)pyrazolo[1,5-a]pyridin-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)-2H-indazol-7-amine; N-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)acrylamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)methacrylamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-6-yl)but-2-enamide; (E)-4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-enamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)but-2-ynamide; 4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-ynamide; 1-(3-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azetidin-1-yl)prop-2-en-1-one; 1- ((S)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; 1-((R)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; 1-(4-((8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)piperidin-1-yl)prop-2-en-1-one; 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-N-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)acrylamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)propiolamide; (E)-4-(3,3-difluoroazetidin-1-yl)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)-4-morpholinobut-2-enamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-ynamide; 1-(3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azetidin-1-yl)prop-2-en-1-one; 2- fluoro-1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)azetidin-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azetidin-1-yl)but-2-en-1-one; 1-((2S)-4- ((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one; 1-((2R)-4-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)-2-methylpiperidin-1-yl)prop-2-en- 1-one; 2-fluoro-1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)azetidin-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azetidin-1-yl)but-2-en-1-one; 1-(3- ((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)thio)azetidin-1-yl)prop-2-en-1-one; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol- 5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol- 5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)- 1H-pyrazole-4-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)- 1H-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1-(tert-butyl)- 1H-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)- 1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- (perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; (S)-2-methoxy-4-methyl-N-(3-(8-(4-methylpiperazin-2- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; 2-methoxy-N-(3- (8-(4-methylpiperazin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 4-(methylsulfonyl)aniline; (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-4-methylpiperazin-2-one; 6-(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)-4-methylpiperazin-2-one; (R)-2-methoxy-N-(3-(8-(6-methyl-1,6- diazaspiro[3.3]heptan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]heptan-2-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (R)- 2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]heptan-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-2- methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]heptan-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(2-oxa-6- azaspiro[3.3]heptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(2-oxa-6-azaspiro[3.3]heptan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8- ((2R,3aS,6aS)-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,3aR,6aR)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2S,3aS,6aS)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2S,3aR,6aR)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5S)-7-methyl-1,7- diazaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5R)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2- methoxy-N-(3-(8-((2S,5S)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy- N-(3-(8-((5R)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-7-oxa-1- azaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((2S,5S)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aR,6aR)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aS,6aS)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aR,6aR)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aS,6aS)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S,5R)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S,5S)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3R,5S)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-2-methoxy-N-(3-(8-(1- methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(1-methyl-1,4-diazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3- (8-(6,6-difluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(6,6-difluoro-1-methyl- 1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6R)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((5R,6R)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6S)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro- 1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6S)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline; N-(3-(8-((5S,6R)-6-fluoro-1,4-oxazepan-5-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((5R,6R)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(6,6-difluoro-1,4- oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7S)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7S)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; N-(3-(8-((2R,4S)-4-((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,4R)-4-((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4S)-4- ((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4R)-4- ((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (3R)-3-((dimethylamino)methyl)-5-(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)pyrrolidin-2-one; (3S)-3-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyrrolidin-2-one; (2R)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)morpholin-3-one; (2S)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)morpholin-3-one; 3-((dimethylamino)methyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyrazin-2(1H)-one; 2-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; (S)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; (R)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; N-(3-(8-(3-((dimethylamino)methyl)-1H-pyrazol-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(3-((dimethylamino)methyl)-1H-1,2,4-triazol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(4- ((dimethylamino)methyl)-1H-imidazol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(6-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-4,5,6,7-tetrahydro- 2H-pyrazolo[4,3-b]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(7-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(7-methyl-2,5,6,7-tetrahydropyrazolo[4,3- b][1,4]oxazin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-2,4,5,6-tetrahydropyrazolo[3,4- b][1,4]oxazin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; N-(3-(8-(7,7-difluoro-5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-(4,4-difluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; (R)-3-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-6-amine; (S)-3-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)-N,N-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-amine; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-N-(1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (R)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-1-methyl-N-(2,2,2-trifluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1H-pyrazol-5-amine; (R)-1-methyl-N-(2,2,2-trifluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1H-pyrazol-5-amine; N-(3-(8-((S)-amino((3R,4S)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3S,4S)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3S,4S)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((R)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; (R)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 2-methoxy-4-(methylsulfonyl)aniline; and (S)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro- 2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-2-methoxy-4-(methylsulfonyl)aniline. In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 2, or a pharmaceutically acceptable salt thereof. List 2 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4- methoxybenzamide; azetidin-1-yl(3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N,N- dimethylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylnicotinamide; 3-((3-(4-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylnicotinamide; 2-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-N-methyl-1H-imidazole-5-carboxamide; 2-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N,1-dimethyl-1H-imidazole-5-carboxamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-5-methoxy-N-methylpyrimidine-2-carboxamide; 4-((3-(8-(((3S,4S)-4-fluoro-1- methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)pyrimidin-2(1H)-one; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylpicolinamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6- methoxypicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 2- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpicolinamide; 6-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide; 6-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-5-methoxypicolinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxyisoindolin-1-one; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxypyridin- 2(1H)-one; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(8-(((3R,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-c]pyrimidin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3- methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 2-fluoro-5- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(8-(((3R,4S)-4- fluoro-1-methylpyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-5-methoxy-N-methylpicolinamide; 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxy-N-methylpicolinamide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-6-oxopiperidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-6-oxopiperidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 4-((3-(8- (((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(8-(((1S,5S,6S)-1-fluoro-3- methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1S,5S,6S)-1-fluoro-3- methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8- ((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8- tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8- tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1- methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4- ((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3- fluoroazetidin-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4- fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4- ((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(3-((difluoromethyl)thio)-7- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H- imidazole-5-carboxamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H- pyrazole-4-carboxamide; 3-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 3-((3-(3-((difluoromethyl)thio)-7-(((3S,4R)-3-fluoropiperidin-4- yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3- ((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8- (((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxy-N-methylpicolinamide; 3-((3-(8-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((2- oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3- methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((6- oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; 4-((3-(8-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 3-((3-(8-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 3-((3-(8-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 3-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 4-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin- 1(2H)-one; 6-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4- dihydroisoquinolin-1(2H)-one; and 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4- dihydroisoquinolin-1(2H)-one. In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1 and/or List 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A
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Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Methods of Treatment Provided herein are methods for restoring p53 function, encoded by TP53 gene. For example, provided herein are compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53-associated disease), such as cancer (e.g., p53-associated cancer). The terms “restore” or “restoration of” means to increase the activity and/or function of the specified target by a measurable amount. For example, restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound. The ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and/or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value. Indications Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53-associated disease or disorder is Li-Fraumeni syndrome. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53-associated cancer. Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation. Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1-510, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation. Some embodiments provide a method of treating cancer in a subject that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53-associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. The term “p53-associated disease” as used herein refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein). Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer). The term “p53-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein. The term “wild type” or “wild-type” describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein. Provided herein is a method of treating cancer (e.g., a p53-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53- associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions. Non-limiting examples of p53 protein substitutions/insertions/deletions are described in Table 1. In some embodiments, the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation. In some embodiments, the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation. Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD In some embodiments, compounds of Formula (I), or pharmaceutically acceptable thereof, are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided herein are methods for treating a subject identified or diagnosed as having a p53-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non- limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer. Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a p53-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53-associated cancer. In some embodiments, a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a p53-associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a p53-associated cancer. In some embodiments, provided herein are methods for treating a p53-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein. In some embodiments, the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a hematological cancer. In some embodiments, the hematological cancer is a leukemia. In some embodiments, the hematological cancer is a lymphoma. In some embodiments, the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the hematological cancer is acute myeloid leukemia (AML). In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer. In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme. In some embodiments, the bladder cancer is bladder urothelial carcinoma. In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma. In some embodiments, the skin cancer is cutaneous melanoma. In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma. In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma. In some embodiments, the breast cancer is breast invasive ductal carcinoma. In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma. In some embodiments, the ovarian cancer is serous ovarian cancer. In some embodiments, the kidney cancer is chromophobe renal cell carcinoma. In some embodiments, the colorectal cancer is colon adenocarcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers described in Table 1. Table 1. p53 Protein Amino Acid Substitutions/Insertions/DeletionsA
Figure imgf000184_0001
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Figure imgf000221_0001
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Figure imgf000227_0001
A Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 20122; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal.6, pl1 (2013). Combinations In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy. In some embodiments, a subject is naïve to p53 restoration therapy. In some embodiments, a subject is not naïve to p53 restoration therapy. In some embodiments, a subject is kinase inhibitor naïve. In some embodiments, a subject is not kinase inhibitor naïve. In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein. For example, in some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein. Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), anti- androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350. In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SM1-71, TG 100801, FGFR1 inhibitor-6, or TG 100572. In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440. In some embodiments, the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005), In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride). In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667). In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849). Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof. In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof. In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof. In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof. In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof. In some embodiments, a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVENTM), or combinations thereof. In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide. In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide. In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing. In some embodiments, the antimetabolite is methotrexate, pemetrexed, or 5-FU. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof. Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289. Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549. Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®). Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol.11: 39 (2018). In some embodiments, the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing. In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and/or as palliative therapy, for example, opioids and corticosteroids. EXAMPLES Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. The compounds described herein can be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.
Figure imgf000236_0001
Figure imgf000236_0002
The compounds described herein can also be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.
Figure imgf000237_0001
Intermediates Intermediate 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine
Figure imgf000237_0002
Step 1. Synthesis of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2- carboxylate: A mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10 g, 37.16 mmol, 1 equiv), sodium acetate (16.0 g, 195.09 mmol, 5.2 equiv) and formaldehyde (28 mL, 282.93 mmol, 7.6 equiv, 37% solution) in AcOH (60 mL) was stirred for 8 h at 110°C under nitrogen atmosphere. The mixture was diluted with water (200 mL), basified to pH 8 with saturated NaOH and NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The solids were collected by filtration and washed with EtOAc (3*10 mL) to afford ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 51.28%) as a yellow solid. LC-MS: (M+H)+ found 299.0. Step 2. Synthesis of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate: A mixture of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 19.06 mmol, 1 equiv) and MnO2 (11.60 g, 133.39 mmol, 7 equiv) in DCM (50 mL) was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3*3 mL). The filtrate was concentrated under reduced pressure to afford ethyl 8- bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g) as a light yellow solid. LC-MS: (M+H)+ found 296.9. Step 3. Synthesis of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate: A solution of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g, 19.52 mmol, 1 equiv) and difluoro(triphenylphosphaniumyl)acetate (13.91 g, 39.044 mmol, 2 equiv) in DMF (58 mL) was stirred for 1 h at 60°C under nitrogen atmosphere. Then the reaction was cooled down to room temperature and added 1 M TBAF in THF (58.56 mL, 58.57 mmol, 3 equiv). The resulting solution was stirred for 1 h at 60°C under nitrogen atmosphere, then diluted with water (300 mL). The aqueous layer was extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.9 g, 42.31%) as a light yellow solid. LC-MS: (M+H)+ found 352.9. Intermediate 2. Synthesis of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine
Figure imgf000239_0001
A mixture of but-1-yn-1-yltrimethylsilane (569.3 mg, 4.50 mmol, 1.30 equiv) and AgF (879.9 mg, 4.62 mmol, 2 equiv) in 1,2-dichlorobenzene (10 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered. To the filtrate was added 3-bromopyridin-2-amine (600.0 mg, 2.30 mmol, 1 equiv), I2 (586.8 mg, 2.30 mmol, 1 equiv) and Cu(OAc)2.H2O (419.9 mg, 2.30 mmol, 1 equiv). The reaction mixture was stirred at 120°C for 6 h. The resulted solution was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (200.0 mg, 16.4%) as a yellow solid. LC-MS: (M+H)+ found 350.9. Intermediate 3. Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine
Figure imgf000239_0002
Step 1: Synthesis of ethoxy(iodo)ethyne: To a stirred solution of ethoxy-ethyne (2.0 g, 28.53 mmol, 1 equiv) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 11.4 mL, 28.53 mmol, 1 equiv) dropwise at -78°C under nitrogen atmosphere. After stirred for 1 h, a solution of I2 (8.33 g, 32.81 mmol, 1.15 equiv) in THF (20 mL) was added and the reaction was warmed to r.t.. After stirring for 15 min, the reaction was diluted with EA (100 mL). The organic layer was washed with saturated sodiumthiosulfate solution (2*70 mL), brine (2*70 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethoxy(iodo)ethyne (2.50 g, 44.70%) as a black oil. LC-MS: (M+H)+ found 196.0. Step 2: Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromopyridin-2-amine (926.9 mg, 5.36 mmol, 1.40 equiv) in ACN (20 mL) was added ethoxy(iodo)ethyne (2.50g, 12.76 mmol, 1 equiv) and Cu(OAc)2 (463.4 mg, 2.55 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 60°C for 8 h. The solvent was removed. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine (1.50g, 32.04%) as a black oil. LC-MS: (M+H)+ found 367.0. Intermediate 4. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine
Figure imgf000240_0001
Step 1: Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde To a stirred solution of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate (1 g, 2.84 mmol, 1 equiv) in DCM (5 mL) was added DIBAL-H (1M in hexane, 3.42 mL, 3.42 mmol, 1.2 equiv) at -40°C under nitrogen atmosphere. The resulting mixture was stirred at -40°C for 4 h. The reaction was quenched by the addition of sat. NH4Cl (aq.) at -40°C. The resulted mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (400 mg, 45.7%) as a white solid. LC-MS: (M+H)+ found 307.2. Step 2: Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde (390 mg, 1.27 mmol, 1 equiv) in MeOH (3 mL) were added dimethyl (1-diazo-2- oxopropyl)phosphonate (488 mg, 2.54 mmol, 2 equiv) and K2CO3 (526.6 mg, 3.81 mmol, 3 equiv) at 0oC. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-ethynyl-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (340 mg, 88.33%) as a white solid. LC-MS: (M+H)+ found 302.8. Step 3. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine To a stirred solution of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (240 mg, 0.79 mmol, 1 equiv) in diethyl ether (4 mL) were added 1,3-bis(adamantan-1-yl)- 1lambda5-imidazol-1-ylium tetrafluoroborate (33.6 mg, 0.07 mmol, 0.1 equiv), CuI (30.2 mg, 0.15 mmol, 0.2 equiv), Cs2CO3 (335.4 mg, 1.03 mmol, 1.3 equiv), [PdCl(allyl)]2 (29 mg, 0.07 mmol, 0.1 equiv), MeI (134.9 mg, 0.95 mmol, 1.2 equiv) and DMF (2 mL). The resulting mixture was stirred for 3 h at 40°C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (120 mg, 47.79%) as a yellow solid. LC-MS: (M+H)+ found 317.3. Intermediate 5. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) pyrazolo[1,5-a]pyridine
Figure imgf000241_0001
Step 1. Synthesis of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2- yl]methanol To a stirred solution of methyl 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carboxylate (1.3 g, 3.85 mmol, 1 equiv) in DCM (3 mL) were added DIBAL-H (1 M in hexanes, 7.71 mL) at -45°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at -30°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) at - 20°C. The resulted mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in [7- bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (730 mg, 61.24%) as a yellow solid. LC-MS: (M+H)+ found 308.9. Step 2. Synthesis of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde To a stirred solution of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2- yl]methanol (700 mg, 2.26 mmol, 1 equiv) in DCM (3 mL) was added manganese dioxide (1.38 g, 15.85 mmol, 7 equiv). The resulting mixture was stirred overnight at 50°C. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This resulted in 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde (560 mg, 80.53%) as a white solid. LC-MS: (M+H)+ found 306.9. Step 3. Synthesis of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine To a stirred solution of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde (540 mg, 1.75 mmol, 1 equiv) in MeOH (3 mL) was added seyferth-gilbert homologation (675.7 mg, 3.51 mmol, 2 equiv) and K2CO3 (729.1 mg, 5.27 mmol, 3 equiv) at 0oC. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 7-bromo-2-ethynyl-3-(2,2,2- trifluoroethyl)pyrazolo[1,5-a]pyridine (320 mg, 60.04%) as a white solid. LC-MS: (M+H)+ found 302.9. Step 4. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5- a]pyridine To a stirred solution of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (310 mg, 1.02 mmol, 1 equiv) in Et2O (3 mL) was added methyl iodide (174.2 mg, 1.22 mmol, 1.2 equiv), CuI (39.0 mg, 0.20 mmol, 0.2 equiv), Cs2CO3 (433.2 mg, 1.33 mmol, 1.3 equiv), rac-1,3- bis[(3R,5S,7s)-adamantan-1-yl]-3H-1lambda5-imidazol-1-ylium; tetrafluoroboranuide (43.4 mg, 0.10 mmol, 0.1 equiv), [PdCl(allyl)]2 (37.4 mg, 0.10 mmol, 0.1 equiv) and DMF (3 mL). The resulting mixture was stirred for 3 h at 40 °C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)pyrazolo[1,5-a]pyridine (170 mg, 52.41%) as a white solid. LC-MS: (M+H)+ found 316.8. Intermediate 6. Synthesis of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2- a]pyridine
Figure imgf000243_0001
Step 1. Synthesis of ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4 g, 10.12 mmol, 1 equiv), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 10.13 mmol, 1 equiv), Na2CO3 (3.22 g, 30.38 mmol, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (824.9 mg, 1.01 mmol, 0.1 equiv) in dioxane (20 mL)/H2O (20 mL) was stirred for 1 h at 95°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (200 mL). The resulting mixture was extracted with CH2Cl2 (3* 200mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate (2.34 g, 78.29%) as a light pink solid. LC-MS: (M+H)+ found 295.0. Step 2. Synthesis of (8-bromo-3-vinylimidazo[1,2-a]pyridin-2-yl)methanol To a stirred solution of ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate (2.34 g, 7.93 mmol, 1 equiv) in DCM (20 mL) was added 1M DIBAl-H in DCM (15.86 mL, 15.86 mmol, 2 equiv) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at -40°C, then quenched by addition of sat.NH4Cl at 0°C. The resulting mixture was extracted with CH2Cl2 (4*100mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (8-bromo-3- vinylimidazo[1,2-a]pyridin-2-yl)methanol (1.5 g, 75.35%) as a light yellow solid. LC-MS: (M+H)+ found 253.1. Step 3. Synthesis of 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carbaldehyde A mixture of (8-bromo-3-vinylimidazo[1,2-a]pyridin-2-yl)methanol (1.5 g, 5.08 mmol, 1 equiv) and MnO2 (3.09 g, 35.54 mmol, 6.99 equiv) in DCM (10 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure to afford 8-bromo-3- ethenylimidazo[1,2-a]pyridine-2-carbaldehyde (970 mg, 76.01%) as a light yellow solid. LC-MS: (M+H)+ found 253.0. Step 4. Synthesis of 8-bromo-3-ethenyl-2-ethynylimidazo[1,2-a]pyridine To a stirred mixture of 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carbaldehyde (940 mg, 3.74 mmol, 1 equiv) and K2CO3 (1.55 g, 11.23 mmol, 3 equiv) in MeOH (10 mL) was added seyferth-gilbert homologation (1.44 g, 7.49 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3 *100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 8-bromo-3-ethenyl-2-ethynylimidazo[1,2- a]pyridine (740 mg, 79.99%) as a off-white solid. LC-MS: (M+H)+ found 246.9. Step 5. Synthesis of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine A mixture of 8-bromo-3-ethenyl-2-ethynylimidazo[1,2-a]pyridine (720 mg, 2.91 mmol, 1 equiv), methyl iodide (537.7 mg, 3.79 mmol, 1.3 equiv), CuI (111.0 mg, 0.58 mmol, 0.2 equiv), Cs2CO3 (1.42 g, 4.37 mmol, 1.5 equiv), 1,3-bis(1-asamantyl)imidazolium tetrafluoroborate (123.6 mg, 0.29 mmol, 0.1 equiv) and bis(chloro(prop-2-en-1-yl)palladium) (106.6 mg, 0.29 mmol, 0.1 equiv) in Et2O (5 mL)/DMF (5 mL) was stirred for 3 h at 40°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 8-bromo-3-ethenyl-2-(prop-1-yn-1- yl)imidazo[1,2-a]pyridine (480 mg, 63.09%) as a brown oil. LC-MS: (M+H)+ found 262.9. Intermediate 7. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3- yl}carbamate
Figure imgf000245_0001
Step 1. Synthesis of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid To a stirred mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (3 g, 8.55 mmol, 1 equiv), 2-methyl-2-butene (9 g, 128.22 mmol, 15 equiv), t-BuOH (14.6 mL) and KH2PO4 (6.96 g, 51.11 mmol, 5.98 equiv) in THF (146 mL) was added a solution of NaClO2 (7.74 g, 85.56 mmol, 10 equiv) in H2O (36 mL) dropwise at 0°C. The resulting mixture was stirred for 3 h at room temperature. The mixture turned to a transparent solution. The solution was acidified to pH 3~4 with 1M HCl and extracted with CH2Cl2 (3 * 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed with DCM/n-hexane (10:1) 3 times. The precipitated solids were collected by filtration to afford 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g) as a off-white solid. LC-MS: (M+H)+ found 368.7. Step 2. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate A mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g, 10.35 mmol, 1 equiv), TEA (3.14 g, 31.068 mmol, 3 equiv) and DPPA (7.12 g, 25.89 mmol, 2.5 equiv) in t- BuOH (50 mL) was stirred for 2 h at 80°C. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water (10 mmol/L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3- yl}carbamate (1.6 g, 35.27%) as a brown yellow solid. LC-MS: (M+H)+ found 439.8. Intermediate 8. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine
Figure imgf000246_0001
Step 1. Synthesis of 3-bromo-5-methoxypyridin-2-amine To a stirred solution of 5-methoxypyridin-2-amine (10 g, 80.55 mmol, 1 equiv) in AcOH (70 mL, 488.6 mmol) was added Br2 (12.87 g, 80.55 mmol, 1 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The resulting mixture was extracted with CH2Cl2 (5*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 3-bromo-5-methoxypyridin-2-amine (6.0 g, 36.69%) as a dark red solid. LC-MS: (M+H)+ found: 202.9. Step 2. Synthesis of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine To a stirred solution of 3-bromo-5-methoxypyridin-2-amine (6.50 g, 32.01 mmol, 1 equiv) and tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (9.96 g, 33.61 mmol, 1.05 equiv) in 1,2- dichlorobenzene (100 mL) was added Cu(OAc)2 (6.98 g, 38.41 mmol, 1.20 equiv) in portions at room temperature .The reaction was stirred at 120 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 60% to 90% gradient in 30 min; detector, UV 254 nm) to afford 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine (5.96 g, 37.44%) as a white solid. LC-MS: (M+H)+ found: 496.8. Step 3. Synthesis of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol To a stirred solution of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine (1.6 g, 3.22 mmol, 1 equiv) in THF (15 mL) was added Et3N.3HF (3.63 g, 22.52 mmol, 7 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with sat.NaHCO3 at 0 °C. The resulting mixture was extracted with CH2Cl2/MeOH (10/1) (10*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3- yl}methanol (700 mg, 56.80%) as a dark red solid. LC-MS: (M+H)+ found: 384.7. Step 4. Synthesis of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde To a stirred solution of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (500 mg, 1.30 mmol, 1 equiv) in DCM (30 mL) was added MnO2 (2.27 g, 26.12 mmol, 20 equiv) at room temperature. The resulting mixture was refluxed overnight. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6- methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (200 mg, 40.21%) as a brown solid. LC-MS: (M+H)+ found: 382.9. Step 5. Synthesis of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine To a stirred solution of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3- carbaldehyde (3.0 g, 7.87 mmol, 1 equiv) in DMF (30 mL) was added 2,2-difluoro-2- (triphenylphosphaniumyl)acetate (7.01 g, 19.68 mmol, 2.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. To the above mixture was added TBAF (23.60 mL, 23.60 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for additional 20 min at 60 °C. The reaction was quenched with water at room temperature and extracted with EtOAc (3* 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6- methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (2.5 g, crude) as a brown solid. The crude was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 8- bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.5 g, 43.79%) as a light yellow solid. LC-MS: (M+H)+ found: 434.9. Step 6. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol To a solution of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.1 g, 2.53 mmol, 1 equiv) in DCM (10 mL) was added BBr3 (12.64 mL, 12.64 mmol, 5 equiv) dropwise at 0°C. The mixture was stirred for 4 h at 0 oC. The mixture was basified to pH 8 with saturated NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin- 6-ol (1.0 g, 93.94%) as a yellow solid. LC-MS: (M+H)+ found: 420.9. Step 7. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1 g, 2.37 mmol, 1 equiv) and Cs2CO3 (1.93 g, 5.94 mmol, 2.5 equiv) in DMF (15 mL) was added methane, bromomethoxy- (445 mg, 3.56 mmol, 1.5 equiv) dropwise at 0 oC. The reaction mixture was stirred for 2 h at 0 oC before quenching with water (20 mL). The resulting mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 50% to 50% gradient in 5 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (760 mg, 68.80%) as a yellow solid. LC-MS: (M+H)+ found: 465.0. Intermediate 9. Synthesis of 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine
Figure imgf000249_0001
Step 1. Synthesis of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate To a stirred solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 3.80 mmol, 1 equiv) in DMF (15 mL) was added [(trifluoromethyl)sulfanyl]copper (937.7 mg, 5.70 mmol, 1.50 equiv) and 1,10-phenanthroline (68.4 mg, 0.38 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 60°C for 16 h under nitrogen atmosphere, then purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (5mmol/L NH4HCO3), 0% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylate (1.0 g, 71.33%) as a white solid. LC-MS: (M+H)+ found 369.2. Step 2. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate (1.0 g, 2.71 mmol, 1 equiv) and LiOH.H2O (170.5 mg, 4.06 mmol, 1.50 equiv) in THF (8 mL)/H2O (8 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (0.1% FA), 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylic acid (800 mg, 86.58%) as a light grey solid. LC-MS: (M+H)+ found 341.1. Step 3. Synthesis of tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}carbamate To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid (750.0 mg, 2.20 mmol, 1 equiv) in t-BuOH (6 mL) were added DPPA (1.21 g, 4.40 mmol, 2 equiv) and Et3N (445.0 mg, 4.40 mmol, 2 equiv) dropwise at room temperature. The resulting mixture was stirred at 80°C for 1 h under nitrogen atmosphere, then purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (0.1% FA), 0% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 66.20%) as a light brown solid. LC-MS: (M+H)+ found 412.2. Step 4. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-amine A solution of tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}carbamate (600.0 mg, 1.46 mmol, 1 equiv) in DCM (6 mL) and TFA (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (10mmol/L NH4HCO3), 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- amine (300.0 mg, 66.04%) as a light yellow solid. LC-MS: (M+H)+ found 312.1. Step 5. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- amine (230.0 mg, 0.74 mmol, 1 equiv) in ACN (3 mL) was added CuI (280.7 mg, 1.47 mmol, 2 equiv), 3-methylbutyl nitrite (129.5 mg, 1.11 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at 50°C for 4 h under nitrogen atmosphere, then purified by C18 reversed- phase flash chromatography with the following conditions: mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (180.0 mg, 57.75%) as a brown solid. LC-MS: (M+H)+ found 423.0. Intermediate 10. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine
Figure imgf000251_0001
Step 1: Synthesis of (2-iodoethynyl)cyclopropane To a stirred solution of ethynylcyclopropane (2.0 g, 30.26 mmol, 1 equiv) in THF (30 mL) was added n-BuLi (2.5 M in hexane, 12.10 mL, 30.26 mmol, 1 equiv) dropwise at - 78oC under nitrogen atmosphere. After stirred for 1 h, a THF solution of I2 (8.83 g, 34.79 mmol, 1.15 equiv) was added and the reaction was warmed to r.t.. After stirring for 1 h, the reaction was diluted with EA (50 mL) and washed with saturated sodiumthiosulfate solution (2*50 mL) and brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2-iodoethynyl)cyclopropane (4.18 g, 71.96%) as a yellow oil. Step 2. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromopyridin-2-amine (2.70 g, 15.63 mmol, 1.50 equiv) in ACN (20 mL) were added (2-iodoethynyl)cyclopropane (2.0 g, 10.42 mmol, 1 equiv) and Cu(OAc)2 (470.0 mg, 2.60 mmol, 0.25 equiv) at room temperature. The resulting mixture was stirred at 70°C for 16 h under air atmosphere, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 90% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2- a]pyridine (1.30 g, 34.38%) as a light brown solid. LC-MS: (M+H)+ found 363.0. Intermediate 11. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]pyridine
Figure imgf000251_0002
Step 1. Synthesis of ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl) imidazo[1,2-a]pyridine- 2-carboxylate To a solution of ethyl 8-bromoimidazo[1,2-a] pyridine-2-carboxylate (1.50 g, 5.57 mmol, 1 equiv) in ACN (30 mL) were added CsF (3.39 g, 22.29 mmol, 4 equiv), (acetyloxy)(phenyl)- lambda3-iodanyl acetate (3.59 g, 11.15 mmol, 2 equiv) and trimethyl (1,1,2,2,2- pentafluoroethyl)silane (4.29 g, 22.30 mmol, 4 equiv). The reaction mixture was stirred at 30oC for 4 h under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in ethyl 8-bromo-3-(1,1,2,2,2- pentafluoroethyl) imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 31.40%) as a yellow solid. LC-MS: (M+H)+ found 387.1. Step 2. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2- carboxylic acid To a solution of ethyl 8-bromo-3-(1,1,2,2,2 pentafluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate (630.0 mg, 1.63 mmol, 1 equiv) in MeOH (5 mL) was added NaOH (260.4 mg, 6.51 mmol, 4 equiv, in 3 mL water). The resulting mixture was stirred for 1h at room temperature, then adjusted pH to 3 with HCl (aq.). The resulted solution was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (420.0 mg, 68.60%) as a yellow solid. LC-MS: (M+H)+ found 360.9. Step 3. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine A solution of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (350.0 mg, 0.98 mmol, 1 equiv) in 1,2-dichlorobenzene (5 mL) was treated with I2 (742.2 mg, 2.93mmol, 3 equiv) and K3PO4 (206.9 mg, 0.98 mmol, 1 equiv). The resulting mixture was stirred for 2 h at 120°C, then cooled down to r.t. and purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 8-bromo-2- iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (230.0 mg, 48.2%) as a white solid. LC-MS: (M+H)+ found 449.8. Intermediate 12. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine
Figure imgf000253_0001
Step 1. Synthesis of 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a] pyridine To a stirred solution of 5-bromo-3-fluoropyridin-2-amine (1 g, 5.24 mmol, 1 equiv) and tert- butyl[(3-iodoprop-2-yn-1-yl) oxy] dimethylsilane (2.33 g, 7.85 mmol, 1.5 equiv) in toluene (5 mL) was added Cu(OAc)2 (190 mg, 1.05 mmol, 0.2 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred overnight at 120°C under air atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a] pyridine (1.2 g, 47.24%) as an off-white solid. Step 2. Synthesis of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol To the mixture of 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a]pyridine (5 g, 10.30 mmol, 1 equiv) in THF (50 mL) was added Et3N.3HF (4.98 g, 30.92 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature, then filtered. The filter cake was washed with DCM (3*50 mL). This resulted in {6- bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol (3.32 g, 87%) as an off-white solid. LC-MS: (M+H)+ found:371.0. Step 3. Synthesis of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde To a solution of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl}methanol (1 g, 2.70 mmol, 1 equiv), TEMPO (8.42 mg, 0.05 mmol, 0.02 equiv), KBr (32 mg, 0.27 mmol, 0.1 equiv) and NaHCO3 (29 mg, 0.35 mmol, 0.13 equiv) in DCM (7 mL)/H2O (1 mL) was added NaOCl (4.26 mL, 4.04 mmol, 1.5 equiv) dropwise at 0 oC. The mixture was stirred for 1 h at 0 oC. The precipitated solids were collected by filtration and washed with water. This resulted in 6-bromo- 8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (900 mg, 90.49%) as an off-white solid. LC-MS: (M+H+) found:369.0. Step 4. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine A mixture of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (9 g, 24.40 mmol, 1 equiv) and 2,2-difluoro-2-(triphenylphosphaniumyl) acetate (17.38 g, 48.79 mmol, 2 equiv) in DMF (90 mL) was stirred for additional 1 h at 60 oC under nitrogen atmosphere. To the above mixture was added TBAF (73.18 mL, 73.19 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 15 min at room temperature. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/ EtOAc (10:1) to afford 6-bromo-8-fluoro- 2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (12 g, 116.31%) as light yellow solid. LC- MS: (M+H)+ found:422.7. Intermediate 13. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)benzamide
Figure imgf000254_0001
A mixture of 4-amino-N-methylbenzamide (1 g, 6.66 mmol, 1 equiv), propargyl bromide (1.2 mL, 13.32 mmol, 2 equiv) and DIEA (5.8 mL, 33.30 mmol, 5 equiv) in CHCl3 (10 mL) was stirred for 3 h at 70°C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford N- methyl-4-(prop-2-yn-1-ylamino)benzamide (963 mg, 76.83%) as a brown yellow oil. LC-MS: (M+H)+ found 189.1. Intermediate 14. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000255_0001
Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (50 g, 253.62 mmol, 1 equiv) in DCM (500 mL) was added HATU (144.65 g, 380.43 mmol, 1.50 equiv) at 0oC. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added methanamine hydrochloride (18.83 g, 278.98 mmol, 1.10 equiv) and Et3N (76.99 g, 760.86 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water and extracted with DCM (500 mL*2). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (1:1) to afford 3- methoxy-N-methyl-4-nitrobenzamide (50 g, 93.79%) as a white solid. LC-MS: (M+H)+ found 211.1. Step 2. Synthesis of 4-amino-3-methoxy-N-methylbenzamide To a stirred mixture of 3-methoxy-N-methyl-4-nitrobenzamide (45 g, 214.09 mmol, 1 equiv) in THF (250 mL) were added Pd/C (5 g) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3*100 mL). The filtrate was concentrated under reduced pressure. This resulted in 4-amino-3-methoxy-N-methylbenzamide (36 g, 93.31%) as a white solid. LC-MS: (M+H)+ found 181.1. Step 3. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred mixture of 4-amino-3-methoxy-N-methylbenzamide (15 g, 83.24 mmol, 1 equiv) and DIPEA (32.27 g, 249.71 mmol, 3 equiv) in DMF (30 mL) were added propargyl bromide (9.90 g, 83.24 mmol, 1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 70 °C under nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford 3-methoxy-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (9 g, 49.54%) as a red solid. LC-MS: (M+H)+ found 219.1. Intermediate 15. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000256_0001
Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzamide To a stirred mixture of 3-methoxy-4-nitrobenzoic acid (2 g, 10.14 mmol, 1 equiv) in DCM (20 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the above mixture were added dimethylamine hydrochloride (1.24 g, 15.22 mmol, 1.50 equiv) and TEA (3.08 g, 30.44 mmol, 3 equiv) at room temperature. After stirring for 2 h at room temperature, the resulting solution was washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 96.72%) as a light yellow oil. LC-MS: (M+H)+ found 225.1. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzamide To a stirred solution of 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 9.81 mmol, 1 equiv) in THF (15 mL) was added Pd/C (250.0 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under hydrogen atmosphere. After filtration, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 78.71%) as a colorless oil. LC-MS: (M+H)+ found 195.1. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred mixture of 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 7.72 mmol, 1 equiv) in DMF (10 mL) was added propargyl bromide (1.38 g, 11.59 mmol, 1.50 equiv) and DIPEA (2.99 g, 23.17 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 12 h at 70°C. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 3-methoxy-N,N-dimethyl-4- (prop-2-yn-1-ylamino)benzamide (1.20 g, 66.70%) as a light yellow oil. LC-MS: (M+H)+ found 233.1. Intermediate 16. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide
Figure imgf000257_0001
Step 1. Synthesis of N-ethyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoyloxidanium (2 g, 10.14 mmol, 1 equiv) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) at room temperature. The mixture was stirred for 1h at room temperature. To the above mixture were added ethylamine (2.00 M in THF, 7 mL, 14 mmol, 1.40 equiv) and Et3N (3.08 g, 30.44 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature, then diluted with CH2Cl2 and washed with brine. The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 98.9%) as a reddish brown oil. LC-MS: (M+H)+ found 225.1 Step 2. Synthesis of 4-amino-N-ethyl-3-methoxybenzamide To a solution of N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 10.04 mmol, 1 equiv) in THF (15 mL) were added Pd/C (230.0 mg) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 97.5%) as a brown oil. LC-MS: (M+H)+ found 195.1 Step 3. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide A solution of 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 9.78 mmol, 1 equiv), propargyl bromide (1.75 g, 14.67 mmol, 1.50 equiv) and DIPEA (3.79 g, 29.35 mmol, 3 equiv) in DMF (10 mL) was stirred overnight at 70°C. The resulting mixture was diluted with water and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide (1.37 g, 60.3%) as a brown oil. LC-MS: (M+H)+ found 233.1. Intermediate 17. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000258_0001
Step 1. Synthesis of N-isopropyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3 g, 15.22 mmol, 1 equiv) in DMF (20 mL) was added Et3N (4.62 g, 45.65 mmol, 3 equiv), isopropylamine (1.35 g, 22.83 mmol, 1.50 equiv) and HATU (8.68 g, 22.83 mmol, 1.50 equiv) at 0oC. The resulting mixture was stirred at room temperature for 2 h, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 95.44%) as a yellow solid. LC-MS: (M+H)+ found 238.2. Step 2. Synthesis of 4-amino-N-isopropyl-3-methoxybenzamide To a stirred solution of N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 14.52 mmol, 1 equiv) in isopropanol (30 mL) was added Pd/C (350.0 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-isopropyl-3- methoxybenzamide (2.78 g, 91.91%) as a yellow solid. LC-MS: (M+H)+ found 208.3. Step 3. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 4-amino-N-isopropyl-3-methoxybenzamide (1 g, 4.80 mmol, 1 equiv) and DIPEA (1.86 g, 14.41 mmol, 3 equiv) in DMF (15 mL) was added propargyl bromide (628.3 mg, 5.28 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred at 70°C for 6 h, then cooled down to room temperature and purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in N-isopropyl-3-methoxy-4-(prop- 2-yn-1-ylamino)benzamide (800.0 mg, 67.64%) as a yellow solid. LC-MS: (M+H)+ found 246.3. Intermediate 18. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000259_0001
Step 1. Synthesis of N-cyclopropyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (2 g, 10.15 mmol, 1 equiv) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) at room temperature. The mixture was stirred for 1h at room temperature. To the above mixture were added aminocyclopropane (0.87 g, 15.22 mmol, 1.50 equiv) and Et3N (3.08 g, 30.44 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 12 h at room temperature, then diluted with CH2Cl2 (30 mL). The combined organic layer was washed with water (3*20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 60% B in 15 min; 254/220 nm). This resulted in N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.10 g, 87.6%) as a white solid..LC- MS: (M+H)+ found 237.1. Step 2. Synthesis of 4-amino-N-cyclopropyl-3-methoxybenzamide To a solution of N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.0 g, 8.47mmol, 1 equiv) in THF (15 mL) was added Pd/C (200.0 mg) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-cyclopropyl-3-methoxybenzamide (1.40 g, 80.1%) as a white solid. LC-MS: (M+H)+ found 207.1. Step 3. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide To a stirred solution of 4-amino-N-cyclopropyl-3-methoxybenzamide (1.30 g, 6.30 mmol, 1 equiv) in DMF (10 mL) was added propargyl bromide (1.12 g, 9.45 mmol, 1.50 equiv) and DIPEA (2.44 g, 18.91mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 12 h at 70°C. The resulting solution was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% TFA), 10% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.0 g, 64.9%) as a black oil. LC-MS: (M+H)+ found 245.1. Intermediate 19. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1- carbonyl)aniline
Figure imgf000260_0001
Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3.0 g, 15.22 mmol, 1 equiv) in DMF (30 mL) were added pyrrolidine (1.08 g, 15.22 mmol, 1 equiv), DIEA (4.92 g, 38.04 mmol, 2.5 equiv) and HATU (9.26 g, 24.35 mmol, 1.6 equiv). The reaction solution was stirred at room temperature for 3 h, then purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine (3.57 g, 93.7%) as a brown oil. LC-MS: (M+H)+ found 251.1. Step 2. Synthesis of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline To a solution of 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine (3.57 g, 14.27 mmol, 1 equiv) in MeOH (30 mL) was added Pd/C (360.0 mg) under nitrogen atmosphere. The resulted mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The resulted mixture was filtered through a celite pad and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 65 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) to afford 2-methoxy-4-(pyrrolidine- 1-carbonyl)aniline (3.03 g, 96.4%) as a light green solid. LC-MS: (M+H)+ found 221.1. Step 3. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline To a stirred solution of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (1.0 g, 4.54 mmol, 1 equiv) in DMF (8 mL) were added propargyl bromide (810.0 mg, 6.81 mmol, 1.5 equiv) and DIEA (1.76 g, 13.62 mmol, 3 equiv). The reaction mixture was stirred at 70°C for 12 h, then cooled down to room temperature and purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1- carbonyl)aniline (800 mg, 68.22%) as a yellow oil. LC-MS: (M+H)+ found 259.1. Intermediate 20. Synthesis of 4-(azetidine-1-carbonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline
Figure imgf000261_0001
Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl) azetidine A solution of 3-methoxy-4-nitrobenzoic acid (2.70 g, 13.69 mmol, 1 equiv) in DCM (30 mL) was treated with (COCl)2 (2.61 g, 20.54 mmol, 1.50 equiv) and DMF (0.10 mL) at 0°C. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added azetidine hydrochloride (1.67 g, 17.80 mmol, 1.30 equiv) and TEA (6.91 g, 68.45 mmol, 5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 1h at room temperature. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in 1-(3-methoxy-4-nitrobenzoyl) azetidine (3.20 g, 96.0%) as a yellow oil. LC-MS: (M+H)+ found 237.1. Step 2. Synthesis of 4-(azetidine-1-carbonyl)-2-methoxyaniline A solution of 1-(3-methoxy-4-nitrobenzoyl) azetidine (3.20 g, 14.82 mmol, 1 equiv) in IPA (100 mL) was treated with Pd/C (350.0 mg) under nitrogen atmosphere. The resulting mixture was stirred for 6 h at room temperature under hydrogen atmosphere. After filtration, the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure. This resulted in 4- (azetidine-1-carbonyl)-2-methoxyaniline (2.1 mg, 78.0%) as a yellow solid. LC-MS: (M+H)+ found 207.0. Step 3. Synthesis of azetidin-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone To a stirred mixture of 4-(azetidine-1-carbonyl)-2-methoxyaniline (1.0 g, 4.85 mmol, 1 equiv) in DMF (15 mL) was added propargyl bromide (576.8 mg, 4.85 mmol, 1 equiv) and DIPEA (1.88 g, 14.55 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 4h at 70°C, then cooled down to room temperature and purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in azetidin-1- yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (424.0 mg, 30.0%) as a yellow solid. LC-MS: (M+H)+ found 245.1. Intermediate 21. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2- carboxamide
Figure imgf000263_0001
Step 1. Synthesis of N-methyl-5-nitropyridine-2-carboxamide To a stirred solution of 5-nitropyridine-2-carboxylic acid (5 g, 29.74 mmol, 1 equiv), methanamine, hydrochloride (2.21 g, 32.72 mmol, 1.1 equiv) and DIPEA (15.38 g, 118.97 mmol, 4 equiv) in DMF (50 mL) was added HATU (12.44 g, 32.72 mmol, 1.1 equiv) at 0°C. The resulting solution was stirred overnight at room temperature, then diluted with EA (500 mL) and washed with brine (3*500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-methyl-5-nitropyridine-2- carboxamide (6.73 g) as a yellow solid. LC-MS: (M+H)+ found 182.0. Step 2. Synthesis of 5-amino-N-methylpyridine-2-carboxamide A mixture of N-methyl-5-nitropyridine-2-carboxamide (6.5 g, 35.88 mmol, 1 equiv) and Fe (10.02 g, 179.41 mmol, 5 equiv) in EtOH (52 mL)/sat.NH4Cl (13 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with DCM (5*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-amino-N-methylpyridine-2- carboxamide (4.5 g, 82.96%) as a brown solid. LC-MS: (M+H)+ found 152.0. Step 3. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide A mixture of 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 29.77 mmol, 1 equiv), K2CO3 (8.23 g, 59.54 mmol, 2 equiv) and propargyl bromide (17.71 g, 148.84 mmol, 5 equiv) in DMF (50 mL) was stirred for 3 h at 70°C. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (1.98 g, 35.21%) as a brown solid. LC-MS: (M+H)+ found 190.0. Intermediate 22. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy) benzamide
Figure imgf000264_0001
Step 1. Synthesis of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate A mixture of methyl 4-amino-3-(trifluoromethoxy) benzoate (2.0 g, 8.50 mmol, 1 equiv), propargyl bromide (1.52 g, 12.75 mmol, 1.50 equiv) and K2CO3 (3.53 g, 25.51 mmol, 3 equiv) in DMF (20 mL) was stirred overnight at 90°C. The reaction was quenched with water at room temperature and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 55% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy)benzoate (600 mg, 25.54%) as a white solid. LC-MS: (M+H)+ found 274.0. Step 2. Synthesis of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid To a stirred mixture of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy) benzoate (630 mg, 2.30 mmol, 1 equiv) in MeOH (5 mL) and THF (5 mL) was added a solution of NaOH (277 mg, 6.91 mmol, 3 equiv) in H2O (5 mL) dropwise at room temperature. The mixture was stirred for 1 h at 60°C. The mixture was allowed to cool down to room temperature, then acidified to pH 6 with 2N HCl. The precipitated solids were collected by filtration and washed with water. This resulted in 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (850 mg, crude) as a white solid. LC-MS: (M+H)+ found 260.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide To a stirred mixture of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy) benzoic acid (845 mg, 3.26 mmol, 1 equiv), methanamine, hydrochloride (441 mg, 6.52 mmol, 2 equiv) and NaHCO3 (1.37 g, 16.30 mmol, 5 equiv) in DMF (10 mL) was added HATU (1.49 g, 3.91 mmol, 1.20 equiv) in portions at 0°C. The mixture was stirred for 1h at room temperature, then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in N-methyl-4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy)benzamide (540 mg, 57.31%) as a yellow solid. LC-MS: (M+H)+ found 273.0. Intermediate 23. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl) benzamide
Figure imgf000265_0001
Step 1. Synthesis of N-methyl-4-nitro-3-(trifluoromethyl)benzamide To a stirred solution of 4-nitro-3-(trifluoromethyl)benzoic acid (5 g, 21.26 mmol, 1 equiv), methanamine, hydrochloride (1.58 g, 23.39 mmol, 1.1 equiv) and DIPEA (10.99 g, 85.06 mmol, 4 equiv) in DMF (50 mL) was added HATU (8.89 g, 23.39 mmol, 1.1 equiv) in portions at 0°C. The resulting solution was stirred overnight at room temperature, then diluted with water (200mL). The resulting mixture was extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 88.11%) as a yellow solid. LC-MS: (M-H)-found 246.9. Step 2. Synthesis of 4-amino-N-methyl-3-(trifluoromethyl)benzamide A solution of N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 18.74 mmol, 1 equiv) and Fe (5.23 g, 93.69 mmol, 5 equiv) in EtOH (40 mL) / sat.NH4Cl (10 mL) was stirred for 1 h at 70°C. The mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:7) to afford 4-amino- N-methyl-3-(trifluoromethyl)benzamide (4.1 g) as a off-white oil. LC-MS: (M+H)+ found 219.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide A solution of 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4 g, 18.33 mmol, 1 equiv), K2CO3 (12.67 g, 91.67 mmol, 5 equiv) and propargyl bromide (10.90 g, 91.67 mmol, 5 equiv) in DMF (40 mL) was stirred for 5 h at 70°C. The mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide (930 mg, 79.19%) as a brown yellow solid. LC-MS: (M+H)+ found 257.1. Intermediate 24. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
Figure imgf000266_0001
Step 1. Synthesis of 3-chloro-N-methyl-4-nitrobenzamide To a stirred solution of 3-chloro-4-nitrobenzoic acid (10 g, 49.61 mmol, 1 equiv), methanamine hydrochloride (3.68 g, 54.57 mmol, 1.1 equiv) and DIPEA (25.65 g, 198.45 mmol, 4 equiv) in DMF (100 mL) was added HATU (20.75 g, 54.57 mmol, 1.1 equiv) at 0oC. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (2*150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3- chloro-N-methyl-4-nitrobenzamide (9.9 g, 92.98%) as a yellow oil. LC-MS: (M+H)+ found 215.4. Step 2. Synthesis of 4-amino-3-chloro-N-methylbenzamide A mixture of 3-chloro-N-methyl-4-nitrobenzamide (5 g, 23.30 mmol, 1 equiv) and Fe (7.81 g, 139.79 mmol, 6 equiv) in sat.NH4Cl (25 mL)/EtOH (25 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was washed with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 4-amino-3-chloro-N-methylbenzamide (4 g, 93.0%) as a yellow solid. LC-MS: (M+H)+ found 185.1. Step 3. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-chloro-N-methylbenzamide (700 mg, 3.79 mmol, 1 equiv), propargyl bromide (902.1 mg, 7.58 mmol, 2 equiv) and K2CO3 (1.57 g, 11.38 mmol, 3 equiv) in DMF (2 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-chloro-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (520 mg, 61.59%) as a yellow oil. LC-MS: (M+H)+ found 223.1. Intermediate 25. Synthesis of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N- (prop-2-yn-1-yl)carbamate
Figure imgf000267_0001
Step 1. Synthesis of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate A solution of methyl 4-amino-3-cyanobenzoate (2 g, 11.35 mmol, 1 equiv), DMAP (1.39 g, 11.35 mmol, 1 equiv) and Boc2O (2.9 g, 13.29 mmol, 1.17 equiv) in dioxane (3 mL) was stirred overnight at 100 °C. The resulting solution was diluted with EtOAc (100 mL) and washed with water (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 4-[(tert-butoxycarbonyl)amino]-3- cyanobenzoate (2.7 g, 96.66%) as a yellow solid. LC-MS: (M+H)+ found 377.2. Step 2. Synthesis of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate A mixture of methyl 4-[bis(tert-butoxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 7.17 mmol, 1 equiv) and K2CO3 (2.97 g, 21.52 mmol, 3 equiv) in MeOH (27 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with DCM (2*150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 4-[(tert-butoxycarbonyl)amino]-3- cyanobenzoate (1.1 g, 55.50%) as a yellow solid. LC-MS: (M+H)+ found 277.1. Step 3. Synthesis of methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3- cyanobenzoate A mixture of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate (200 mg, 0.72 mmol, 1 equiv), Cs2CO3 (707.6mg, 2.17 mmol, 3 equiv) and 3-bromoprop-1-yne (238 mg, 2.08mmol, 2 eq) in DMF (2 mL) was stirred for 4 h at 70°C, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=5:1) to afford methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]- 3-cyanobenzoate (186 mg, 81.74%) as a yellow oil. LC-MS: (M+H)+ found 315.1. Step 4. Synthesis of 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid A mixture of methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (200 mg, 0.64 mmol, 1 equiv) and NaOH (76.3 mg, 1.91 mmol, 3 equiv) in H2O (1 mL)/MeOH (3 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with HCl (aq.) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (196 mg, 102.58%) as a yellow oil. LC-MS: (M+H)+ found 301.1. Step 5. Synthesis of afford tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2- yn-1-yl)carbamate To a stirred solution of 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (200 mg, 0.67 mmol, 1 equiv), DIPEA (344.3 mg, 2.66 mmol, 4 equiv) and methanamine hydrochloride (67.5 mg, 1.00 mmol, 1.5 equiv)in DMF (2 mL) was added HATU (379.8 mg, 1.00 mmol, 1.5 equiv) at 0 oC. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert- butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2-yn-1-yl)carbamate (192 mg, 92.0%) as a yellow oil. LC-MS: (M+H)+ found 314.1. Intermediate 26. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000269_0001
Step 1. Synthesis of methyl 4-amino-3-cyclopropylbenzoate A mixture of methyl 4-amino-3-bromobenzoate (10 g, 43.47 mmol, 1 equiv), cyclopropylboronic acid (5.60 g, 65.20 mmol, 1.5 equiv), K2CO3 (18.02 g, 130.40 mmol, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (1.77 g, 2.17 mmol, 0.05 equiv) in 1,4-dioxane (80 mL) / H2O (20 mL) was stirred for 1 h at 95°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-amino-3-cyclopropylbenzoate (8 g, 96.24%) as a yellow solid. LC-MS: (M+H)+ found 192.1. Step 2. Synthesis of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate A mixture of methyl 4-amino-3-cyclopropylbenzoate (8 g, 41.83 mmol, 1 equiv), propargyl bromide (9.95 g, 83.67 mmol, 2 equiv) and K2CO3 (17.35 g, 125.502 mmol, 3 equiv) in DMF (30 mL) was stirred for 4 h at 70°C. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was diluted with water (700 mL) and extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-cyclopropyl-4-(prop-2-yn-1- ylamino)benzoate (4 g, 41.70%) as a brown solid. LC-MS: (M+H)+ found 230.1. Step 3. Synthesis of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid A mixture of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4.3 g, 18.75 mmol, 1 equiv) and NaOH (3.75 g, 93.77 mmol, 5 equiv) in MeOH (20 mL) / H2O (20 mL) was stirred for 3 h at 60°C. The mixture residue was acidified to pH 5 with 1 M HCl, then extracted with DCM (3*300 mL). The combined layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (4 g, 99.09%) as an off-white solid. LC-MS: (M+H)+ found 216.1. Step 4. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (2 g, 9.29 mmol, 1 equiv), methanamine hydrochloride (0.94 g, 13.94 mmol, 1.5 equiv) and DIEA (4.80 g, 37.16 mmol, 4 equiv) in DMF (20 mL) was added HATU (5.30 g, 13.94 mmol, 1.5 equiv) at 0 oC. The resulting solution was stirred for 1 h at room temperature, then diluted with water (100 mL) and extracted withDCM (3*100 mL). The combined layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-cyclopropyl-N- methyl-4-(prop-2-yn-1-ylamino)benzamide (2 g, 94.29%) as a yellow solid. LC-MS: (M+H)+ found 229.1. Intermediate 27. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
Figure imgf000270_0001
Step 1. Synthesis of 4-amino-3-bromo-N-methylbenzamide To a stirred solution of methanamine hydrochloride (3.61 g, 53.46 mmol, 3 equiv), 4- amino-3-bromobenzoic acid (3.85 g, 17.82 mmol, 1 equiv) in DMF (30 mL) were added DIPEA (13.82 g, 106.93 mmol, 6 equiv) and HATU (20.33 g, 53.46 mmol, 3 equiv) in portions at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified directly by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 4-amino-3-bromo-N-methylbenzamide (3 g, 73.49%) as a white solid. LC-MS: (M+H)+ found 229.0. Step 2. Synthesis of 4-amino-3-ethenyl-N-methylbenzamide A mixture of 4-amino-3-bromo-N-methylbenzamide (3 g, 13.2 mmol, 1 equiv), 2-ethenyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 23.70 mmol, 1.8 equiv), Na2CO3 (4.14 g, 39.6 mmol, 3 equiv) and Pd(dppf)Cl2 (956.7 mg, 1.32 mmol, 0.1 equiv) in dioxane (45 mL) / H2O (4.5 mL) was stirred for 3 h at 95°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1) to afford 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) as a white solid. LC-MS: (M+H)+ found 176.2 Step 3. Synthesis of 4-amino-3-ethyl-N-methylbenzamide A mixture of 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) and 10% wet Pd/C (1 g) in MeOH (30 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-amino-3-ethyl-N-methylbenzamide (1.5 g) as a brown oil. LC-MS: (M+H)+ found 178.2. Step 4. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-ethyl-N-methylbenzamide (1.5 g, 8.42 mmol, 1 equiv), propargyl bromide (3.0 g, 25.25 mmol, 3 equiv) and K2CO3 (2.33 g, 16.83 mmol, 2 equiv) in DMF (20 mL) was stirred overnight at 70°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-ethyl-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (1.3 g, 71.42%) as a brown oil. LC-MS: (M+H)+ found 216.1. Intermediate 28. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide
Figure imgf000271_0001
Step 1. Synthesis of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 1.9 g, 8.70 mmol, 1 equiv) in DCM (50 mL) was added BBr3 (7.63 g, 30.47 mmol, 3.5 equiv, 1.0 M in DCM) dropwise at 0°C under nitrogen atmosphere. After stirring for 2 h at 0°C, the mixture was basified to pH 11 with NaOH (aq). The resulting mixture was washed with DCM (3*50 mL). Con. HCl was added into the water aqueous phase until the pH was 8, then extracted with EtOAc (3*50 mL). The combined organic layers (EtOAc) were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.2 g) was used directly without further purification. LC-MS: (M+H)+ found:371.0. Step 2. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (1.2 g, 5.87 mmol, 1 equiv), iodoethane (1.37 g, 8.81 mmol, 1.5 equiv) and K2CO3 (2.44 g, 17.63 mmol, 3 equiv) in DMF (15 mL) was stirred for 1 h at 50°C. The reaction mixture was quenched with water (50 mL) and the aqueous phase was extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in 0.1%NH4HCO3, 30% to 60% gradient in 10 min; detector, UV 220 nm) to afford 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1 g, 73.27%) as a yellow solid. LC-MS: (M+H)+ found:233.1. Intermediate 29. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000272_0001
Step 1. Synthesis of 3-hydroxy-4-nitrobenzamide To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (5 g, 27.3 mmol, 1 equiv) and HATU (12.5 g, 32.8 mmol, 1.2 equiv) in DMF (50 mL) were added NH2Me.HCl (2.76 g, 40.9 mmol, 1.5 equiv) and DIEA (10.6 g, 81.9 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for additional overnight at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3- hydroxy-4-nitrobenzamide (5.3 g, 99.05%) as a yellow solid. LC-MS: (M+H)+ found 197.1. Step 2. Synthesis of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide To a stirred solution of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1 equiv) and K2CO3 (1.06 g, 7.60 mmol, 1.5 equiv) in DMF (20 mL) was added difluoroiodomethane (1.09 g, 6.10 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 3- (difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 62.95%) as a yellow solid. LC-MS: (M+H)+ found 247.1. Step 3. Synthesis of 4-amino-3-(difluoromethoxy)-N-methylbenzamide A mixture of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 3.21 mmol, 1 equiv), Fe (1.79 g, 32.1 mmol, 10 equiv) and NH4Cl (1.72 g, 32.1 mmol, 10 equiv) in EtOH (15 mL) and H2O (3 mL) was stirred for 1.5 h at 70°C. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford 4-amino-3-(difluoromethoxy)-N-methylbenzamide (670 mg, 96.57%) as a yellow solid. LC-MS: (M+H)+ found 217.1. Step 4. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-(difluoromethoxy)-N-methylbenzamide (620 mg, 2.9 mmol, 1 equiv), K2CO3 (1.2 g, 8.6 mmol, 3 equiv) and propargyl bromide (682 mg, 5.7 mmol, 2 equiv) in DMF (6 mL) was stirred overnight at 70 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 3-(difluoromethoxy)- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (340 mg, 46.63%) as a light yellow solid. LC-MS: (M+H)+ found 255.05. Intermediate 30. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2- trifluoroethoxy)benzamide
Figure imgf000274_0001
A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (200 mg, 0.98 mmol, 1 equiv), 2-bromoacetonitrile (118 mg, 0.98 mmol, 2 equiv) and K2CO3 (271 mg, 1.96 mmol, 2 equiv) in DMF (2 mL) was stirred for 1 h at 50 °C. The resulting mixture was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N- methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (214 mg, 67.79%) as a white solid. LC-MS: (M+H)+ found 287.0. Intermediate 31. Synthesis of 3-(2-methoxyethoxy)-N-methyl-4- (prop-2-yn-1- ylamino)benzamide
Figure imgf000274_0002
A mixture of 4-amino-3-(2-methoxyethoxy)-N-methylbenzamide (654 mg, 2.92 mmol, 1 equiv), propargyl bromide (694 mg, 5.83 mmol, 2 equiv) and DIEA (2.54 mL, 14.58 mmol, 5 equiv) in CHCl3 (10 mL) was stirred overnight at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford 3-(2-methoxyethoxy)-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (435 mg, 54.42%) as a yellow solid. LC-MS: (M+H)+ found 263.1. Intermediate 32. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2- (trimethylsilyl)ethoxy]methyl})benzenesulfonamide
Figure imgf000275_0001
Step 1. Synthesis of 3-methoxy-4-nitrobenzenesulfonamide To a stirred mixture of NH3.H2O (80 mL, 25%) and THF (80 mL) was added a solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (900 mg, 3.58 mmol, 1 equiv) in THF (5 mL) dropwise at 0°C. The resulting mixture was stirred for 5 min at 0°C, then 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-methoxy-4- nitrobenzenesulfonamide (800 mg, 96.33%) as a yellow solid. LC-MS: (M+H)+ found 233.0. Step 2. Synthesis of 3-methoxy-4-nitro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)- benzenesulfonamide A solution of 3-methoxy-4-nitrobenzenesulfonamide (600 mg, 2.58 mmol, 1 equiv) in THF (6 mL) was treated with NaH (516.7 mg, 12.92 mmol, 5 equiv, 60%) for 30min at 0°C under nitrogen atmosphere, followed by the addition of [2-(chloromethoxy)ethyl]trimethylsilane (1.29 g, 7.75 mmol, 3 equiv) dropwise at room temperature. The mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with water/ice. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found 493.2. Step 3. Synthesis of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})- benzenesulfonamide A solution of 3-methoxy-4-nitro-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})- benzenesulfonamide (60 mg, 0.12 mmol, 1 equiv) and Fe (34.0 mg, 0.61 mmol, 5 equiv) in ethyl alcohol (0.8 mL) and sat.NH4Cl (0.2 mL) was stirred for 1h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL), then washed with 3*10 mL of brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (40 mg, 70.99%) as a white solid. LC-MS: (M+H)+ found 463.2. Step 4. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)- ethoxy]methyl})benzenesulfonamide A mixture of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzene- sulfonamide (1.5 g, 3.24 mmol, 1 equiv), propargyl bromide (1.93 g, 16.21 mmol, 5 equiv), DIPEA (2.09 g, 16.21 mmol, 5 equiv) and CHCl3 (15 mL) was stirred overnight at 70 oC. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N- bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (700 mg, 43.12%) as a yellow oil. LC-MS: (M+H)+ found 501.2. Intermediate 33. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide
Figure imgf000276_0001
Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide To a stirred solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 equiv) in DCM (10 mL) were added Methylamine (2.98 mL, 5.96 mmol, 1.5 equiv, 2M in THF) and TEA (1.21 g, 11.92 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature, then diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3*100 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (1.03 g) as a reddish oil, directly used in next step. LC-MS: (M+H)+ found 247.0. 2. Synthesis of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene- sulfonamide A solution of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (100 mg, 0.41 mmol, 1 equiv) in THF (1 mL) was treated with NaH (32.5 mg, 0.81 mmol, 2 equiv, 60%) for 30 min at 0°C under nitrogen atmosphere followed by the addition of [2- (chloromethoxy)ethyl]trimethylsilane (101.6 mg, 0.61 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with water/ice. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-methoxy-N-methyl-4-nitro-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (137 mg, 89.60%) as a brown oil. LC-MS: (M+H)+ found 377.1. Step 3. Synthesis of 4-amino-3-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-sulfonamide A mixture of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (710 mg, 1.89 mmol, 1 equiv) and Fe (44.5 mg, 0.80 mmol, 5 equiv) in EtOH (8 mL) and sat.NH4Cl (2 mL) was stirred for 1h at 70°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was diluted with water (30 mL) and extracted with CH2Cl2 (2*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-amino-3-methoxy-N- methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (650 mg, 99.47%) as a light yellow oil. LC-MS: (M+H)+ found 347.1. Step 4. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2- (trimethylsilyl)ethoxy] methyl}benzenesulfonamide A mixture of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (600 mg, 1.73 mmol, 1 equiv), DIPEA (1.12 g, 8.66 mmol, 5 equiv) and propargyl bromide (1.03 g, 8.66 mmol, 5 equiv) in CHCl3 (8 mL) was stirred for overnight at 70°C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (400 mg, 60.07%) as a yellow oil. LC-MS: (M+H)+ found 385.2. Intermediate 34. Synthesis of 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzene sulfonamide
Figure imgf000278_0001
Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide To a stirred solution of dimethylamine (2 M in THF) (2.98 mL, 5.96 mmol, 1.5 equiv) and Et3N (2.01 g, 19.86 mmol, 5 equiv) in DCM (20 mL) was added 3-methoxy-4- nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 equiv) dropwise at 0oC. The resulting solution was stirred for 2 h at room temperature. The resulting solution was concentrated under reduced pressure to afford 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g) as a yellow solid. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide A mixture of 3-methoxy-N, N-dimethyl-4-nitrobenzenesulfonamide (1.7 g, crude) and Fe (1.82 g, 32.66 mmol) in EtOH (20 mL)/sat.NH4Cl (5 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (730 mg) as a yellow solid. LC- MS: (M+H)+ found 231.05. Step 3. Synthesis of 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzenesulfonamide A mixture of 4-amino-3-methoxy-N, N-dimethylbenzenesulfonamide (630 mg, 2.73 mmol, 1 equiv), propargyl bromide (1.63 g, 13.68 mmol, 5 equiv) and DIEA (1.77 g, 13.68 mmol, 5 equiv) in CHCl3 (15 mL) was stirred overnight at 70°C. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (40:1) to afford 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzenesulfonamide (230 mg, 31.33%) as a white solid. LC-MS: (M+H)+ found 269.05. Intermediate 35. Synthesis of 1-(2-methanesulfonylethyl) piperidin-4-amine
Figure imgf000279_0001
Step 1. Synthesis of tert-butyl N-[1-(2-methanesulfonylethyl)piperidin-4-yl]carbamate To a stirred solution of tert-butyl N-(piperidin-4-yl)carbamate (4.3 g, 21.47 mmol, 1 equiv) and TEA (10.3 g, 101.79 mmol, 4.74 equiv) in EtOH (50 mL) was added methyl vinyl sulfone (5.4 g, 50.88 mmol, 2.37 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:20) to afford tert-butyl N-[1- (2-methanesulfonylethyl)piperidin-4-yl]carbamate (5 g, 76.0%) as a white solid. LC-MS: (M+H)+ found 306.4. Step 2. Synthesis of 1-(2-methanesulfonylethyl) piperidin-4-amine hydrochloride To a stirred solution of tert-butyl N-[1-(2-methanesulfonylethyl)piperidin-4-yl]carbamate (1 g, 21.21 mmol, 1 equiv) in DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was dissolved with DCM and basified with TEA. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:20) to afford 1-(2-methanesulfonylethyl) piperidin-4-amine (800 mg, 53.87%) as a white solid. LC-MS: (M+H)+ found 206.4. Intermediate 36. Synthesis of 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline
Figure imgf000280_0001
Step 1. Synthesis of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (3 g, 17.53 mmol, 1 equiv) in DMF (30 mL) was added (ethylsulfanyl)sodium (1.92 g, 22.79 mmol, 1.3 equiv) in portions at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat. NH4Cl at 0°C. The aqueous layer was extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 77.57%) as a yellow solid. LC-MS: (M+H)+ found 213.9. Step 2. Synthesis of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene A mixture of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 13.60 mmol, 1 equiv) and Oxone (14.13 g, 40.797 mmol, 3 equiv) in acetone (10 mL)/MeOH (1 mL)/H2O (10 mL) was stirred for 3 h at room temperature. The reaction was quenched with saturated sodium hyposulfite at 0°C. The aqueous layer was extracted with EtOAc (3*100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Step 3. Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline A mixture of 4-(ethanesulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 equiv) and Fe (3.53 g, 63.20 mmol, 5 equiv) in EtOH (20 mL)/sat.NH4Cl (5 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The result mixture was extracted with EtOAc (3*100mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.6 g) was used in the next step directly without further purification. LC-MS: (M+H)+ found 216.0. Step 4. Synthesis of 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl) aniline A mixture of 4-(ethanesulfonyl)-2-methoxyaniline (1 g, 4.65 mmol, 1 equiv), K2CO3 (1.93 g, 13.93 mmol, 3 equiv) and propargyl bromide (552.6 mg, 4.64 mmol, 1 equiv) in DMF (10 mL) was stirred overnight at 70°C. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (10mmol/L NH4HCO3), 0% to 80% gradient in 30 min; detector, UV 254 nm ) to afford 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (400 mg, 34%) as a white solid. LC-MS: (M+H)+ found 254.2. Intermediate 37. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline
Figure imgf000281_0001
Step 1. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxyaniline A solution of 4-bromo-2-methoxyaniline (2 g, 9.90 mmol, 1 equiv), sodium cyclopropanesulfinate (2.54 g, 19.80 mmol, 2 equiv), CuI (1.89 g, 9.90 mmol, 1 equiv), NaOH (395.9 mg, 9.90 mmol, 1 equiv) and pyrrolidine-2-carboxylic acid (569.8 mg, 4.95 mmol, 0.50 equiv) in DMSO (20 mL) was stirred overnight at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.63 g, 72.45%) as a yellow solid. LC-MS: (M-H)-found 228.1. Step 2. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline A mixture of 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.5 g, 6.60 mmol, 1 equiv), K2CO3 (2.74 g, 19.80 mmol, 3 equiv) and propargyl bromide (3.93 g, 33.00 mmol, 5 equiv) in DMF (15 mL) was stirred overnight at 70°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-(cyclopropanesulfonyl)- 2-methoxy-N-(prop-2-yn-1-yl)aniline (955 mg, 54.54%) as a yellow solid. LC-MS: (M+H)+ found 266.0. Intermediate 38. Synthesis of 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline
Figure imgf000282_0001
A mixture of 2-fluoro-4-methanesulfonylaniline (1 g, 5.29 mmol, 1 equiv), K2CO3 (2.21 g, 15.86 mmol, 3 equiv) and propargyl bromide (3.14 g, 26.43 mmol, 5 equiv) in DMF (10 mL) was stirred overnight at 70 oC. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (10mmol/L NH4HCO3), 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline (360 mg, 29.97%) as a white solid. LC-MS: (M-H)- found 226.1. Intermediate 39. Synthesis of 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1- yl)aniline
Figure imgf000282_0002
To a stirred mixture of 4-methanesulfonyl-2-methoxyaniline (5.0 g, 24.87 mmol, 1 equiv) and propargyl bromide (2.94 g, 24.87 mmol, 1 equiv) in DMF (50 mL) was added K2CO3 (6.86 g, 49.74 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 70°C under nitrogen atmosphere. Desired product could be detected by LCMS. Solid was filtered out and the filtrate was diluted with water and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase, eluted with MeOH/H2O to afford 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (2.4 g, 40.38%) as a light yellow solid. LC-MS: (M+H)+ found 240.0. Intermediate 40. Synthesis of 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline
Figure imgf000283_0001
A mixture of 4-methylsulfonylaniline (1 g, 5.84 mmol, 1 equiv), propargyl bromide (4.86 g, 40.89 mmol, 7 equiv) and K2CO3 (4.04 g, 29.20 mmol, 5 equiv) in DMF (10 mL) was stirred for 3 h at 70°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-methanesulfonyl-N-(prop-2-yn- 1-yl)aniline (790 mg, 64.64%) as a yellow solid. LC-MS: (M-H)- found 208.0. Intermediate 41. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2- sulfonyl)aniline
Figure imgf000283_0002
Step 1. Synthesis of isopropyl(3-methoxy-4-nitrophenyl)sulfane To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.44 mmol, 1 equiv) in DMF (100 mL) was added (isopropylsulfanyl)sodium (7.46 g, 75.97 mmol, 1.3 equiv) in portions at 0°C. The resulting mixture was stirred for 3 h at room temperature, then quenched with water. The resulting solution was extracted with DCM (3*700 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford isopropyl(3-methoxy-4-nitrophenyl)sulfane (21 g) as a grey oil. Step 2. Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene To a stirred solution of 4-(isopropylsulfanyl)-2-methoxy-1-nitrobenzene (21 g) in Acetone (100 mL)/H2O (100 mL)/MeOH (10 mL) was added Oxone (103.58 g) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature, then filtered. The filter cake was washed with MeOH. The filtrate was quenched with sat. NaS2O3. The resulting solution was extracted with EtOAc (3*700 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxy- 1-nitro-4-(propane-2-sulfonyl)benzene (7 g, 21.91%) as a white solid. Step 3. Synthesis of 2-methoxy-4-(propane-2-sulfonyl)aniline A mixture of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (4 g, 15.43 mmol, 1 equiv) and Pd/C (1 g, 0.94 mmol, 0.06 equiv, 10 wt%) in MeOH (40 mL) was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 2-methoxy-4- (propane-2-sulfonyl)aniline (3.1 g, 87.64%) as a yellow solid. LC-MS: (M+H)+ found 230.1. Step 4. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline A mixture of 2-methoxy-4-(propane-2-sulfonyl)aniline (1.5 g, 6.54 mmol, 1 equiv), propargyl bromide (2.34 g, 19.69 mmol, 3.01 equiv) and K2CO3 (2.70 g, 19.56 mmol, 2.99 equiv) in DMF (15 mL) was stirred overnight at 70°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 2-methoxy-N-(prop-2- yn-1-yl)-4-(propane-2-sulfonyl)aniline (800 mg, 45.74%) as a yellow solid. LC-MS: (M-H)- found 266.1. Intermediate 42. Synthesis of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline
Figure imgf000284_0001
A mixture of 5-methanesulfonyl-2-methoxyaniline (1 g, 4.97 mmol, 1 equiv), propargyl bromide (591.1 mg, 4.97 mmol, 1 equiv) and K2CO3 (2.06 g, 14.91 mmol, 3 equiv) in DMF (10 mL) was stirred 16 h at 70°C. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2*200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1%NH4HCO3), 25% to 30% gradient in 10 min; detector, UV 220 nm) to afford 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline (600 mg, 50.46%) as an off-white solid. LC-MS: (M+H)+ found:240.0. Intermediate 43. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1- ylamino)pyridine-2-carboxamide
Figure imgf000285_0001
Step 1. Synthesis of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide To a stirred solution of 6-methoxy-5-nitropyridine-2-carboxylic acid (3 g, 15.14 mmol, 1 equiv), methanamine hydrochloride (1.53 g, 22.71 mmol, 1.5 equiv) and DIPEA (9.78 g, 75.70 mmol, 5 equiv) in DMF (20 mL) was added HATU (8.64 g, 22.71 mmol, 1.5 equiv) at 0 oC. The resulting solution was stirred for 2 h at room temperature, then purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), 0 to 100% gradient in 30 min; detector, UV 254 nm) to afford 6-methoxy-N-methyl-5-nitropyridine-2- carboxamide (3 g, 93.82%) as a yellow solid. LC-MS: (M+H)+ found 212.1. Step 2. Synthesis of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide A mixture of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 14.21 mmol, 1 equiv) and Pd/C (3.02 g, 28.41 mmol, 2 equiv) in MeOH (25 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 5-amino-6- methoxy-N-methylpyridine-2-carboxamide (2.5 g, 97.12%) as a white solid. LC-MS: (M+H)+ found 182.2. Step 3. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide A mixture of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (1 g, 5.52 mmol, 1 equiv), propargyl bromide (1.31 g, 11.04 mmol, 2 equiv) and K2CO3 (2.29 g, 16.56 mmol, 3 equiv) in DMF (20 mL) was stirred overnight at 65°C. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (500 mg, 41.32%) as a yellow solid.LC-MS: (M+H)+ found 220.1. Intermediate 44. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3- dihydroisoindol-1-one
Figure imgf000286_0001
Step 1. Synthesis of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one To a stirred solution of 6-methoxy-2,3-dihydroisoindol-1-one (10 g, 61.28 mmol, 1 equiv) in TFAA (50 mL)/ACN (50 mL) was added HNO3 (3.90 g, 61.90 mmol, 1.01 equiv) dropwise at 0°C. The resulting mixture was stirred for 1 h at 0°C, then diluted with water. The solution was basified to pH 8 with sat.NaHCO3 (aq.). The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 62.71%) as a off- white solid. LC-MS: (M+H)+ found 209.0. Step 2. Synthesis of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one A mixture of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 38.43 mmol, 1 equiv) and Pd/C (2.0 g, 1.88 mmol, 0.05 equiv, 10wt%) in MeOH (80 mL) was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 5-amino-6- methoxy-2,3-dihydroisoindol-1-one (1.35 g, 19.71%) as a off-white solid. LC-MS: (M+H)+ found 179.0. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 4.7 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 2H), 3.81 (s, 3H). Step 3. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one A mixture of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one (1.35 g, 7.58 mmol, 1 equiv), propargyl bromide (919.3 mg, 7.73 mmol, 1.02 equiv) and K2CO3 (3.13 g, 22.65 mmol, 2.99 equiv) in DMF (13 mL) was stirred overnight at 70°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford 6-methoxy-5-(prop-2- yn-1-ylamino)-2,3-dihydroisoindol-1-one (400 mg, 24.42%) as a off-white solid. LC-MS: (M+H)+ found 217.1. Intermediate 45. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine
Figure imgf000287_0001
Step 1. Synthesis of 8-bromo-3-iodoimidazo[1,2-a] pyridine-2-carboxylate A solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10.0 g, 37.16 mmol, 1 equiv) and NIS (12.79 g, 56.86 mmol, 1.53 equiv) in ACN (100 mL) was stirred at 50oC for 2 h . The resulting mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (200 mL) and washed with brine (3 *100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford ethyl 8-bromo-3-iodoimidazo[1,2-a] pyridine-2-carboxylate (7.90 g, 53.82%) as a yellow solid. LC-MS: (M+H)+ found 395.0. Step 2. Synthesis of ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2- carboxylate A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4.0 g, 10.13 mmol, 1 equiv) and (trifluoromethyl)copper-1,10-phenanthroline (4.75 g, 15.19 mmol, 1.50 equiv) in DMF (40 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient in 20 min; detector, UV 254 nm) to afford ethyl 8-bromo-3- (trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 59.47%) as a dark green solid. LC-MS: (M+H)+ found 337.1. Step 3. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid To a solution of ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 6.02 mmol, 1 equiv) in THF (10 mL) / water (10 mL) was added LiOH (379.0 mg, 9.03 mmol, 1.50 equiv, 10 mL of water). The resulting solution was stirred at room temperature for 1 h. After removal of THF, the resulted mixture was acidified to pH 3 with HCl (aq.), then filtered and the filter cake was washed with water. The crude was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 20 min; detector, UV 254 nm) to afford 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2- carboxylic acid (1.48 g, 79.52%) as a white solid. LC-MS: (M+H)+ found 309.0. Step 4. Synthesis of tert-butyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]carbamate A mixture of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.40 g, 4.53 mmol, 1 equiv), DPPA (2.49 g, 9.06 mmol, 2 equiv) and Et3N (916.8 mg, 9.06 mmol, 2 equiv) in t-BuOH (15 mL) was stirred at 80 oC for 1 h under nitrogen atmosphere. The resulted mixture was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 70% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate (1.60 g, 92.90%) as a yellow solid. LC-MS: (M+H)+ found 380.2. Step 5. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine A solution of tert-butyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]carbamate (1.60 g, 4.21 mmol, 1 equiv) in DCM(13.50 mL) / TFA (4.50 mL) was stirred at room temperature for 1 h. The solvent was removed. The residue was basified to pH 8 with saturated NH4HCO3 and extracted with CH2Cl2 (3*10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford 8-bromo-3- (trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (1.2 g, crude) as a light yellow solid. LC-MS: (M+H)+ found 280.0. Step 6. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (500 mg, 1.79 mmol, 1 equiv) in ACN (5 mL) were added isoamyl nitrite (313.7 mg, 2.68 mmol, 1.50 equiv) and CuI (680.1 mg, 3.57 mmol, 2 equiv). The resulting mixture was stirred at 50°C for 4 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; detector, UV 254 nm) to afford 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (495.0 mg, 70.92%) as a light yellow solid. LC-MS: (M+H)+ found 390.9. Intermediate 46. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine
Figure imgf000289_0001
Step 1. Synthesis of 8-bromo-3-{[(tert-butyldimethylsilyl) oxy]methyl}-7-fluoro-2- iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromo-4-fluoropyridin-2-amine (4.50 g, 23.56 mmol, 1 equiv) and Cu(OAc)2 (855 mg, 4.71 mmol, 0.20 equiv) in toluene (35 mL) was added tert-butyl[(3- iodoprop-2-yn-1-yl) oxy]dimethylsilane (10.46 g, 35.34 mmol, 1.50 equiv) dropwise at 120 °C. The resulting mixture was stirred for 3 h at 120 °C, then cooled down to room temperature and diluted with ethyl acetate (200 mL). The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was washed with water, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 8-bromo-3-{[(tert-butyldimethylsilyl) oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine (4.0 g, 34.99%) as a light yellow solid. LC-MS: (M+H)+ found: 486.9. Step 2. Synthesis of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol To a stirred solution of 8-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-7-fluoro-2- iodoimidazo [1,2-a] pyridine (4.15 g, 8.55 mmol, 1 equiv) in THF (40 mL) was added Et3N.3HF (4.14 g, 25.65 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature, then concentrated to 1/3 volume under reduced pressure. The precipitated solids were collected by filtration and washed with DCM to afford {8-bromo-7-fluoro-2- iodoimidazo[1,2-a] pyridin-3-yl} methanol (2.70 g, 85.10%) as a white solid. LC-MS: (M+H)+ found: 372.6. Step 3. Synthesis of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde A mixture of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol (2.40 g, 6.47 mmol, 1 equiv) and MnO2 (11.24 g, 129.40 mmol, 20 equiv) in DCM (100 mL) was stirred overnight at 45 °C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 8-bromo-7-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (1.90 g, 79.60%) as a white solid. LC-MS: (M+H)+ found: 370.7. Step 4. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine A solution of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (2.0 g, 5.42 mmol, 1 equiv) and 2,2-difluoro-2-(triphenylphosphaniumyl) acetate (4.83 g, 13.55 mmol, 2.50 equiv) in DMF (20 mL) was stirred at 80 °C under nitrogen atmosphere, then tetrabutylazanium fluoride (16.2 mL, 16.26 mmol, 3 equiv) was added at 25 °C under nitrogen. The resulting mixture was stirred for 1h at 60°C under nitrogen atmosphere. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3*80 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 8- bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.3 g, 56.70%) as a yellow solid. LC-MS: (M+H)+ found: 423.0. Intermediate 47. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine
Figure imgf000291_0001
Step 1. Synthesis of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-fluoro-2- iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.0 g, 26.18 mmol, 1 equiv) in toluene (25 mL) were added tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (11.63 g, 39.27 mmol, 1.50 equiv) and Cu(OAc)2 (0.95 g, 5.24 mmol, 0.20 equiv). The resulting mixture was stirred overnight at 120°C under air atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (25:1) to afford 8-bromo-3-{[(tert- butyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine (7.0 g, 55.11%) as a yellow solid.LC-MS: (M+H)+ found:485.2. Step 2. Synthesis of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol To a stirred solution of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-fluoro-2- iodoimidazo[1,2-a]pyridine (7.0 g, 14.43 mmol, 1 equiv) in THF (35 mL) was added Et3N.3HF (6.98 g, 43.28 mmol, 3 equiv). The resulting mixture was stirred at 0°C for 3 h. The resulting mixture was filtered, the filter cake was washed with DCM to afford {8-bromo-6-fluoro-2- iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 89.69%) as a white solid. LC-MS: (M+H)+ found:370.9. Step 3. Synthesis of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde To a stirred solution of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 12.94 mmol, 1 equiv), tempo (40.44 mg, 0.26 mmol, 0.02 equiv), KBr (154 mg, 1.29 mmol, 0.10 equiv) and NaHCO3 (163 mg, 1.94 mmol, 0.15 equiv) in DCM (40 mL) was added NaClO (20 mL) dropwise at 0°C. The resulting mixture was stirred at 0°C for 3 h. The precipitated solids were collected by filtration and washed with water to afford 8-bromo-6-fluoro-2- iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 58.65%) as a yellow solid. LC-MS: (M+H+) found:368.9. Step 4. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine To a stirred solution of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 7.59 mmol, 1 equiv) in DMF (15 mL) was added 2,2-difluoro-2- (triphenylphosphaniumyl)acetate (3.24 g, 9.11 mmol, 1.20 equiv) under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 1 h. The mixture was allowed to cool down to room temperature, and a solution of TBAF (9.11 mL, 9.11 mmol, 1.20 equiv) was added. The resulting solution was stirred at 60°C for 1 h, then cooled down to room temperature and quenched with water (50 mL), extracted with EtOAc (3*150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/ EtOAc (10:1) to afford 8-bromo-6-fluoro-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (650.0 mg, 20.25%) as a white solid. LC-MS: (M+H)+ found:422.9. Intermediate 48. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2- iodoimidazo[1,2-a]pyridine
Figure imgf000292_0001
Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate To a stirred mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.72 mmol, 1 equiv) and 2-[(difluoromethyl)sulfanyl]isoindole-1,3-dione (1.02 g, 4.46 mmol, 1.2 equiv) in DCE (22 mL) was added TMSCl (0.71 mL, 5.57 mmol, 1.5 equiv). The resulting mixture was stirred overnight at 90°C under nitrogen atmosphere, then cooled down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2Cl2 = 1:19 to afford ethyl 8-bromo-3- [(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylate (855 mg, 65.52%) as a white solid. LC-MS: (M+H)+ found 351.0. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid A solution of ethyl 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate (855 mg, 2.43 mmol, 1 equiv) in H2O (8 mL)/THF (2 mL) was treated with LiOH (87 mg, 3.65 mmol, 1.5 equiv) at 0°C. The resulting mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 6~7 with 1M HCl. The precipitated solids were collected by filtration and washed with cold water, then dried under vacuum to afford 8-bromo-3- [(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H)+ found 323.0. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid (479 mg, 1.48 mmol, 1 equiv) in DMSO (5 mL) were added I2 (1.51 g, 5.92 mmol, 4 equiv) and K3PO4 (377 mg, 1.78 mmol, 1.2 equiv) in portions at room temperatur. The resulting mixture was stirred overnight at 120°C under nitrogen atmosphere, then allowed to cool down to room temperature. The reaction was quenched by the addition of 50% Na2S2O8 (30 mL) at 0°C. To the above mixture was added Na2CO3 (10 mL) in portions at 0°C, then extracted with CH2Cl2 (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE = 1:4 to afford 8-bromo-3-[(difluoromethyl)sulfanyl]-2- iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H)+ found 405.1. Intermediate 49. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1- ylamino)benzamide
Figure imgf000294_0001
Step 1. Synthesis of methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate A mixture of methyl 3-amino-4-methoxybenzoate (5.0 g, 27.59 mmol, 1 equiv), propargyl bromide (4.92 g, 41.39 mmol, 1.50 equiv) and K2CO3 (11.44 g, 82.78 mmol, 3 equiv) in DMF (50 mL) was stirred overnight at 70°C. The mixture was quenched with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, 52% to 54% gradient in 10 min; detector, UV 254 nm) to afford methyl 4-methoxy-3-(prop-2-yn-1-ylamino) benzoate (3.3 g, 54.55%) as a yellow solid. LC-MS: (M+H) + found:220.0. Step 2. Synthesis of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid A mixture of methyl 4-methoxy-3-(prop-2-yn-1-ylamino) benzoate (3.30 g, 15.05 mmol, 1 equiv) in MeOH (10 mL), H2O (10 mL) and THF (10 mL) was treated with LiOH (3.79 g, 90.31 mmol, 6 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60°C. The mixture was neutralized to pH 6 with HCl (aq.). The precipitated solids were collected by filtration and washed with EtOAc. The resulting solid was dried under vacuum to afford 4-methoxy-3-(prop-2- yn-1-ylamino) benzoic acid (3.30 g) as a brown solid. The product was used in the next step directly without further purification. LC-MS: (M+H) + found:205.9. Step 3. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino) benzoic acid (500 mg, 2.43 mmol, 1 equiv), methanamine hydrochloride (197 mg, 2.92 mmol, 1.20 equiv) and DIEA (1.57 g, 12.18 mmol, 5 equiv) in DMF (5 mL) was added HATU (1.11 g, 2.92 mmol, 1.20 equiv) in portions at 0°C. The resulting mixture was stirred for additional 1 h at room temperature. The mixture was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 40% to 50% gradient in 10 min; detector, UV 254 nm) to afford 4- methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (480 mg, 90.26%) as yellow oil. LC-MS: (M+H)+ found:218.9. Intermediate 50. Synthesis of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide
Figure imgf000295_0001
To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino) benzoic acid (300 mg, 1.46 mmol, 1 equiv), ethylamine, hydrochloride (119 mg, 1.46 mmol, 1 equiv) and DIEA (756 mg, 5.85 mmol, 4 equiv) in DMF (1 mL) was added HATU (1.11 g, 2.92 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3*50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 40% to 60% gradient in 10 min; detector, UV 254 nm) to afford N-ethyl-4-methoxy-3-(prop-2- yn-1-ylamino)benzamide (200 mg, 58.90%) as an off-white solid. LC-MS: (M+H+) found: 233.2. Intermediate 51. Synthesis of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino) benzamide
Figure imgf000295_0002
To a stirred solution of 4-methoxy-3-(prop-2-yn-1-ylamino) benzoic acid (300 mg, 1.46 mmol, 1 equiv), aminocyclopropane (125.2 mg, 2.19 mmol, 1.50 equiv) and DIEA (566.8 mg, 4.39 mmol, 3 equiv) in DMF (3 mL) was added HATU (667.0 mg, 1.75 mmol, 1.20 equiv) at 0 oC. The resulting mixture was stirred for 1h at room temperature. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 30% to 70% gradient in 10 min; detector, UV 254 nm) to afford N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (294 mg, 82.32%) as a white solid. LC-MS: (M+H)+ found 245.0. Intermediate 52. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H- isoquinolin-1-one
Figure imgf000296_0001
Step 1. Synthesis of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one To a stirred solution of 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (2 g, 11.28 mmol, 1 equiv) in ACN (8 mL) and TFAA (8 mL) was added HNO3 (0.69 mL, 10.157 mmol, 0.9 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The mixture was basified to pH 8 with saturated NaHCO3 and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford 7-methoxy-6-nitro-3,4-dihydro-2H- isoquinolin-1-one (2.2 g, 87.72%) as a light yellow solid. LC-MS: (M+H)+ found 223.1. Step 2. Synthesis of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one A mixture of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.2 g, 9.90 mmol, 1 equiv), NH4Cl (2.65 g, 49.51 mmol, 5 equiv) and Fe (2.76 g, 49.51 mmol, 5 equiv) in EtOH (20 mL)/H2O (4 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 6- amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 30.47%) as a light yellow solid. LC-MS: (M+H)+ found 193.0. Step 3. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1- one A mixture of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 3.02 mmol, 1 equiv), propargyl bromide (718 mg, 6.03 mmol, 2 equiv) and DIEA (1.17 g, 9.05 mmol, 3 equiv) in CHCl3 (6 mL) was stirred overnight at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin- 1-one (520 mg, 74.84%) as a yellow solid. LC-MS: (M+H)+ found 231.2. Intermediate 53. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide
Figure imgf000297_0001
Step 1. Synthesis of 4-amino-2-chloro-5-methoxybenzoic acid A mixture of methyl 4-amino-2-chloro-5-methoxybenzoate (500 mg, 2.32 mmol, 1 equiv) and LiOH (67 mg, 2.78 mmol, 1.2 equiv) in THF (6.5 mL)/H2O (2 mL) was stirred for 3 days at 35°C. The mixture was neutralized to pH 7 with 1 M HCl and extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 96.26%) as a yellow solid. LC-MS: (M+H)+ found 202.0. Step 2. Synthesis of 4-amino-2-chloro-5-methoxy-N-methylbenzamide A solution of 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 2.23 mmol, 1 equiv), HATU (1.27 g, 3.35 mmol, 1.5 equiv), DIEA (1.17 mL, 6.72 mmol, 3 equiv) and Methylamine hydrochloride (181 mg, 2.68 mmol, 1.2 equiv) in DMF (5 mL) was stirred for 2 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 25 min; detector, UV 254 nm) to afford 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 83.49%) as a light yellow solid. LC-MS: (M+H)+ found 215.1. Step 3. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 1.86 mmol, 1 equiv), propargyl bromide (665 mg, 5.59 mmol, 3 equiv) and K2CO3 (515 mg, 3.73 mmol, 2 equiv) in DMF (5 mL) was stirred overnight at 40°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 30 min; detector, UV 254 nm) to afford 2-chloro-5- methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (240 mg, 50.97%) as a brown solid. LC- MS: (M+H)+ found 352.9. Intermediate 54. Synthesis of N-(prop-2-yn-1-yl)aniline
Figure imgf000298_0001
A mixture of aniline (1 g, 10.74 mmol, 1 equiv), K2CO3 (4.45 g, 32.21 mmol, 3 equiv) and propargyl bromide (2.55 g, 21.48 mmol, 2 equiv) in DMF (10 mL) was stirred for 2 h at 30°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, ACN in water (10mmol/L NH4HCO3), 50% to 100% gradient in 20 min; detector, UV 254 nm) to afford N-(prop-2-yn-1-yl)aniline (380 mg, 21.37%) as a yellow oil. LC-MS: (M+H)+ found 132.2. Intermediate 55. Synthesis of ethyl 8-bromoindolizine-2-carboxylate
Figure imgf000298_0002
Step 1. Synthesis of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate To a solution of 3-bromopicolinaldehyde (15.00 g, 123.82 mmol, 1.00 equiv) and 2- ethoxybuta-1,3-diene (15.83 g, 161.28 mmol, 2.00 equiv) in 1,4-dioxane / H2O (1:1, 400.00 mL) was added DABCO (9.05 g, 80.64 mmol, 1.00 equiv) in portions. The reaction mixture was stirred at 25°C for 1 h. The resulting mixture was extracted with DCM (3x100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford ethyl 2-[(3- bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (22.00 g, 95.35%) as a yellow oil. LC-MS: (M+H)+ found 286.10. Step 2. Synthesis of ethyl 8-bromoindolizine-2-carboxylate A solution of ethyl 2-[(3-bromopyridin-2-yl) (hydroxy)methyl]prop-2-enoate (20.00 g, 69.90 mmol, 1.00 equiv) in acetic anhydride (300.00 mL) was stirred at 140°C for 16 h. The resulting mixture was extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30:1) to afford ethyl 8-bromoindolizine-2- carboxylate (14.00 g, 74.70%) as a white solid. LC-MS: (M+H)+ found 268.05. Intermediate 56. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carbaldehyde
Figure imgf000299_0001
Step 1. Synthesis of {8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol To a stirred solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl] indolizine-2- carboxylate (5.10 g, 13.85 mmol, 1.00 equiv) in DCM (80.00 mL) was added DIBAL-H (1M in toluene, 27.70 mL, 27.70 mmol, 2.00 equiv) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred at -20°C for 1 h under nitrogen atmosphere. The reaction was quenched with Na2SO4.10H2O at room temperature. The mixture was filtered. The filter cake was washed with DCM (3x100 mL). The filtrate was concentrated under reduced pressure. This resulted in {8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol (5.00 g, 110.71%) as a white solid. LC-MS: (M+H)+ found 326.10. Step 2. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde A solution of {8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol (5.00 g, 15.64 mmol, 1.00 equiv) and IBX (10.95 g, 39.09 mmol, 2.50 equiv) in EA (60.00 mL) was stirred at 80°C for 2 h. The mixture was filtered. The filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / PE (1:5) to afford 8-bromo-3- [(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde (4.00 g, 78.93%) as a light yellow solid. LC- MS: (M+H)+ found 325.90. Intermediate 57. Synthesis of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine
Figure imgf000300_0001
Step 1. Synthesis of 8-bromo-2-ethynyl-3-[(trifluoromethyl)sulfanyl]indolizine A solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde (4.00 g, 12.34 mmol, 1.00 equiv), dimethyl (1-diazo-2-oxopropyl)phosphonate (4.74 g, 24.68 mmol, 2.00 equiv) and K2CO3 (5.12 g, 37.02 mmol, 3.00 equiv) in MeOH (15.00mL) was stirred at 0°C for 2 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 90% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-2-ethynyl-3- [(trifluoromethyl)sulfanyl]indolizine (3.16 g, 79.98%) as a light yellow solid. LC-MS: (M+H)+ found 320.10. Step 2. Synthesis of 3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol To a solution of zinc(2+) ditrifluoromethanesulfonate (7.89 g, 21.72 mmol, 2.20 equiv) and TMEDA (2.52 g, 21.72 mmol, 2.20 equiv) in toluene (30.00 mL) was added Et3N (2.20 g, 21.72 mmol, 2.20 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 h under nitrogen atmosphere, followed by the addition of 8-bromo-2-ethynyl-3- [(trifluoromethyl)sulfanyl]indolizine (3.16 g, 9.87 mmol, 1.00 equiv) in toluene (1.00 mL) dropwise at room temperature. The mixture was stirred at 60°C for 1 h under nitrogen atmosphere. To the above mixture was added POM (1.96 g, 21.72 mmol, 2.20 equiv) at room temperature. The resulting mixture was stirred at 60°C for additional 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 72.33%) as a white solid. LC- MS: (M+H)+ found 350.20. Step 3. Synthesis of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine A solution of 3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 7.14 mmol, 1.00 equiv) and PPh3Br2 (3.92 g, 9.28 mmol, 1.30 equiv) in DCM (25.00 mL) was stirred for 1.5 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-2-(3-bromoprop-1-yn- 1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (2.25 g, 76.29%) as a light yellow oil. LC-MS: (M+H)+ found 413.80. Intermediate 58. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
Figure imgf000301_0001
A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (Intermediate 57, 300.00 mg, 0.73 mmol, 1.00 equiv), 4-amino-3-methoxy-N-methylbenzamide (143.97 mg, 0.80 mmol, 1.10 equiv) and K2CO3 (301.14 mg, 2.18 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 16 h. The resulted solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (160.00 mg, 43.00%) as a white solid. LC-MS: (M+H)+ found 512.0. Intermediate 59. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl}prop-2-yn-1-yl)amino]-6-methoxypyridine-3-carboxylate
Figure imgf000302_0001
A solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (Intermediate 57, 300.00 mg, 0.72 mmol, 1.00 equiv), methyl 5-amino-6-methoxypyridine-3- carboxylate (138.93 mg, 0.76 mmol, 1.05 equiv) and K2CO3 (301.14 mg, 2.17 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70°C for 2 h. The solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-6- methoxypyridine-3-carboxylate (170.00 mg, 45.51%) as a light yellow solid. LC-MS: (M+H)+ found 514.3. Intermediate 60. Synthesis of N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate
Figure imgf000302_0002
Step 1. Synthesis of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide To a stirred mixture of 4-methoxy-3-nitrobenzenesulfonyl chloride (800.00 mg, 3.18 mmol, 1.00 equiv) and CH3NH2.HCl (429.31 mg, 6.36 mmol, 2.00 equiv) in DCM (10.00 mL) was added Et3N (965.12 mg, 9.54 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was diluted with DCM (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm). This resulted in 4-methoxy-N-methyl-3- nitrobenzenesulfonamide (750.00 mg, 95.6%) as a yellow oil. LC-MS: (M+H)+ found 247.03. Step 2. Synthesis of 4-methoxy-N-methyl-3-nitro-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide To a stirred mixture of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide (600.00 mg, 2.44 mmol, 1.00 equiv) in THF (10.00 mL) was added NaH (60%, 195.20 mg, 4.88 mmol, 2.00 equiv) in portions at 0°C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added SEM-Cl (812.48 mg, 4.87 mmol, 2.00 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm). This resulted in 4-methoxy-N-methyl-3-nitro-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 76.3%) as a yellow oil. LC-MS: (M+H)+ found 377.11. Step 3. Synthesis of 3-amino-4-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide To a stirred mixture of 4-methoxy-N-methyl-3-nitro-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 1.86 mmol, 1.00 equiv) in i- PrOH (10.00 mL) was added Pd/C (100.00 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3 x 20.00 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-4- methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (500 mg, 77.6%) as a yellow oil. LC-MS: (M+H)+ found 347.14. Step 4. Synthesis of tert-butyl N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate To a stirred mixture of 3-amino-4-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl} benzenesulfonamide (450.00 mg, 1.30 mmol, 1.00 equiv) and (Boc)2O (283.42 mg, 1.30 mmol, 1.00 equiv) in dioxane (5.00 mL) was added DMAP (158.65 mg, 1.30 mmol, 1.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm). This resulted in tert-butyl N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (350.00 mg, 60.3%) as a yellow oil. LC-MS: (M+H)+ found 447.19.Intermediate 61. Synthesis of 6-amino-5-methoxy-N- methylpyridine-2-carboxamide
Figure imgf000304_0001
Step 1. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide To a stirred mixture of 5-methoxy-6-nitropyridine-2-carboxylic acid (400.00 mg, 2.02 mmol, 1.00 equiv) and HATU (1.15 g, 3.03 mmol, 1.50 equiv) in DMF (5.00 mL) were added DIEA (782.79 mg, 6.06 mmol, 3.00 equiv) and CH3NH2HCl (204.47 mg, 3.03 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulted solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310 mg, 72.71%) as a white solid. LC-MS: (M+H)+ found: 212.15. Step 2. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide To a stirred solution of 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310.00 mg, 1.47 mmol, 1.00 equiv) in IPA (6.00 mL) was added Pd/C (31.00 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (5x10 mL). The filtrate was concentrated under reduced pressure to afford 6- amino-5-methoxy-N-methylpyridine-2-carboxamide (240 mg, 90.23%) as a white solid. LC-MS: (M+H)+ found: 182.15. Intermediate 62. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide
Figure imgf000305_0001
Step 1. Synthesis of methyl 8-bromo-3-[(difluoromethyl)sulfanyl]indolizine-2-carboxylate To a stirred solution of methyl 8-bromoindolizine-2-carboxylate (2.00 g, 4.72 mmol, 1.00 equiv, 60%) in DCE (30.00 mL) were added 2-[(difluoromethyl)sulfanyl]isoindole-1,3-dione (1.30 g, 5.67 mmol, 1.20 equiv) and TMSCl (769.64 mg, 7.09 mmol, 1.50 equiv). The resulting mixture was stirred for 5 h at 90°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 8-bromo-3- [(difluoromethyl)sulfanyl]indolizine-2-carboxylate (1.50 g, 94.48%) as a light yellow solid. LC- MS: (M+H)+ found 336.05. Step 2. Synthesis of {8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}methanol To a stirred solution of methyl 8-bromo-3-[(difluoromethyl)sulfanyl]indolizine-2- carboxylate (1.50 g, 4.46 mmol, 1.00 equiv) in DCM (20.00 mL) was added DIBAL-H (1M in toluene, 8.92 mL, 8.92 mmol, 2.00 equiv) dropwise at -30°C under nitrogen atmosphere. The resulting mixture was stirred at -20°C for 1 h under nitrogen atmosphere. The reaction was quenched with Na2SO4.10H2O at 0°C. The resulting mixture was filtered. The filter cake was washed with EA. The filtrate was concentrated under reduced pressure. This resulted in {8-bromo- 3-[(difluoromethyl)sulfanyl]indolizin-2-yl}methanol (1.4 g, crude) as a dark grey solid. LC-MS: (M+H)+ found 308.00. Intermediate 63. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2- ethynylindolizine
Figure imgf000306_0001
Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]indolizine-2-carbaldehyde To a stirred solution of {8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}methanol (1.40 g, 4.54 mmol, 1.00 equiv) in EtOAc (20.00 mL) was added IBX (3.18 g, 11.36 mmol, 2.50 equiv). The resulting mixture was stirred at 80°C for 2 h. The resulting mixture was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 8-bromo-3-[(difluoromethyl)sulfanyl]indolizine-2-carbaldehyde (1.38 g, 99.22%) as a yellow solid. LC-MS: (M+H)+ found 305.95. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2-ethynylindolizine To a stirred solution of 8-bromo-3-[(difluoromethyl)sulfanyl]indolizine-2-carbaldehyde (1.30 g, 4.25 mmol, 1.00 equiv) in MeOH (20.00 mL) were added dimethyl (1-diazo-2- oxopropyl)phosphonate (1.63g, 8.50 mmol, 2 equiv) and K2CO3 (1.76 g, 12.74 mmol, 3.00 equiv) at 0oC. The resulting mixture was stirred at 0oC for 2 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-[(difluoromethyl)sulfanyl]-2-ethynylindolizine (1.23 g, 95.86%) as a light yellow solid. LC-MS: (M+H)+ found 302.00. Intermediate 64. Synthesis of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(difluoromethyl)sulfanyl]indolizine
Figure imgf000307_0001
Step 1. Synthesis of 3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol To a stirred solution of zinc(2+) ditrifluoromethanesulfonate (3.18g, 8.73 mmol, 2.20 equiv) in toluene (30.00 mL) were added TMEDA (1.02 g, 8.73 mmol, 2.20 equiv) and Et3N (884.20 mg, 8.73 mmol, 2.20 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. To the above mixture was added 8-bromo-3-[(difluoromethyl)sulfanyl]-2- ethynylindolizine (1.20 g, 3.97 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 60°C for additional 1 h. To the above mixture was added POM (1.07 g, 11.91 mmol, 3.00 equiv) in one portion at room temperature. The resulting mixture was stirred at 60°C for additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 65% gradient in 20 min; detector, UV 254 nm. This resulted in 3-{8- bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (1.16 g, 87.93%) as a light grey solid. LC-MS: (M+H)+ found 331.95. Step 2. Synthesis of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(difluoromethyl)sulfanyl]indolizine To a stirred solution of 3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn- 1-ol (1.17 g, 3.52 mmol, 1.00 equiv) in DCM (15.00 mL) was added PPh3Br2 (1.93 g, 4.58 mmol, 1.30 equiv). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-2-(3-bromoprop-1-yn- 1-yl)-3-[(difluoromethyl)sulfanyl]indolizine (880.00 mg, 63.24%) as a light yellow solid. LC-MS: (M+H)+ found 393.95. Intermediate 65. Synthesis of methyl 5-chloroindolizine-2-carboxylate
Figure imgf000308_0001
Step 1. Synthesis of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate A mixture of 6-chloropyridine-2-carbaldehyde (6 g, 42.388 mmol, 1 equiv) and methyl acrylate (4.38 g, 50.866 mmol, 1.2 equiv), 1,4-diazabicyclo[2.2.2]octane (290 mg, 2.543 mmol, 0.06 equiv) in dioxane (45 mL), H2O (15 mL) was stirred for 3h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 2- [(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (6.5 g, 63.05%) as a yellow solid. LC-MS: (M+H)+ found 228. Step 2. Synthesis of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(difluoromethyl)sulfanyl]indolizine
Figure imgf000308_0002
A mixture of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (3 g, 13.179 mmol, 1 equiv) in AC2O (58.80 mL) was stirred for 6h at 100°C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found 270. Step 3. Synthesis of methyl 5-chloroindolizine-2-carboxylate The resulting mixture Step 2 was stirred for 10h at 160°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. When poured into the mixture of ice and saturated aqueous sodium bicarbonate solution, and stirred for 1h, The aqueous layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 5-chloroindolizine-2-carboxylate (3 g) as a white solid. LC-MS: (M+H)+ found 210. Intermediate 66. Synthesis of methyl 5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylate
Figure imgf000309_0001
Step 1. Synthesis of methyl 1-bromo-5-chloroindolizine-2-carboxylate To a stirred mixture of methyl 5-chloroindolizine-2-carboxylate (2 g, 9.541 mmol, 1 equiv) in DCM (20 mL) was added Br2 (0.4 mL, 8.587 mmol, 0.90 equiv) in DCM (0.5 mL) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 0.5h at -78°C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with Water, the organic phase was separated, washed with aqueous10% sodium thiosulfate (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 60% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 1-bromo-5- chloroindolizine-2-carboxylate (1 g, 34.51%) as a white solid. LC-MS: (M+H)+ found 288. Step 2. Synthesis of methyl 5-chloro-1-iodoindolizine-2-carboxylate A mixture of methyl 1-bromo-5-chloroindolizine-2-carboxylate (1 g, 3.466 mmol, 1 equiv) and KI (1.73 g, 10.398 mmol, 3 equiv), CuI (1.98 g, 10.398 mmol, 3 equiv) in DMF (10 mL) was stirred for overnight at 130°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm.to afford methyl 5-chloro-1-iodoindolizine-2-carboxylate (1.07 g, 91.55%) as a brown solid. LC-MS: (M+H)+ found 336. Step 3. Synthesis of methyl 5-chloro-1-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate A mixture of methyl 5-chloro-1-iodoindolizine-2-carboxylate (2.3 g, 6.855 mmol, 1 equiv), CuI (2.61 g, 13.710 mmol, 2 equiv), silver(1+) (trifluoromethyl)sulfanide (4.30 g, 20.565 mmol, 3 equiv) and 2,2'-bipyridine (2.14 g, 13.710 mmol, 2 equiv) in ACN (23 mL) was stirred for overnight at 90°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NH4Cl (aq.) (10mL) at 0°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 100% gradient in 35 min; detector, UV 254 nm(85%). This resulted in methyl 5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.05 g, 49.46%) as a brown solid. LC-MS: (M+H)+ found 310. Intermediate 67. Synthesis of 5-chloro-2-ethynyl-1- [(trifluoromethyl)sulfanyl]indolizine
Figure imgf000310_0001
Step 1. Synthesis of {5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol A solution of methyl 5-chloro-1-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.2 g, 3.875 mmol, 1 equiv) in DCM (12 mL)at room temperature under nitrogen atmosphere followed by the addition of DIBAl-H/1M DCM (1.65 g, 12 mL, 11.625 mmol, 3 equiv) dropwise at -20°C. The resulting mixture was stirred for 1h at -20°C under nitrogen atmosphere. The reaction was quenched by the addition of Na2SO4.10H2O at -20°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in {5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol (975 mg, 89.33%) as a brown solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found 282. Step 2. Synthesis of 5-chloro-1-[(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde A solution of {5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}methanol (975 mg, 3.461 mmol, 1 equiv) in EA (10 mL)at room temperature under nitrogen atmosphere followed by the addition of IBX (2.91 g, 10.383 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for 4h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde (824 mg, 85.12%) as a black solid. LC-MS: (M+H)+ found 280. Step 3. Synthesis of 5-chloro-2-ethynyl-1-[(trifluoromethyl)sulfanyl]indolizine To a stirred mixture of 5-chloro-1-[(trifluoromethyl)sulfanyl]indolizine-2-carbaldehyde (709 mg, 2.535 mmol, 1 equiv)in MeOH (7 mL) were added seyferth-gilbert homologation (0.8 mL, 5.070 mmol, 2 equiv) and K2CO3 (1.05 g, 7.605 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of Potassium sodium tartrate (10 mL) at 0°C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 5-chloro-2-ethynyl-1- [(trifluoromethyl)sulfanyl]indolizine (420 mg, 60.10%) as a yellow solid. LC-MS: (M+H)+ found 276. Intermediate 68. Synthesis of 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine
Figure imgf000312_0001
Step 1. Synthesis of 3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol To a stirred mixture of Zn(OTf)2 (1.22 g, 3.353 mmol, 2.2 equiv) and TMEDA (0.5 mL, 3.353 mmol, 2.2 equiv) in Toluene (2 mL) was added TEA (0.5 mL, 3.353 mmol, 2.2 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. To the above mixture was added 5-chloro-2- ethynyl-1-[(trifluoromethyl)sulfanyl]indolizine (420 mg, 1.524 mmol, 1 equiv) in Toluene (1 mL) dropwise. The resulting mixture was stirred for additional 1h at 60°C. To the above mixture was added POM (301 mg, 3.353 mmol, 2.2 equiv) in Toluene (1 mL) dropwise. The resulting mixture was stirred for additional 1h at 60°C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 3-{5-chloro-1- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (330 mg, 70.85%) as a brown solid. LC- MS: (M+H)+ found 306. Step 2. Synthesis of 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine A solution of 3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (300 mg, 0.981 mmol, 1 equiv) in DCM (3 mL)at room temperature under nitrogen atmosphere followed by the addition of PPh3Br2 (538 mg, 1.275 mmol, 1.3 equiv) in portions at room temperature. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 35 min; detector, UV 254 nm(80%). This resulted in 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine (130 mg, 35.94%) as a black oil. LC-MS: (M+H)+ found 368. Intermediate 69. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2- iodoimidazo[1,2-a]pyridine
Figure imgf000313_0001
Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate To a stirred mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.716 mmol, 1 equiv) and 2-[(difluoromethyl)sulfanyl]isoindole-1,3-dione (1.02 g, 4.459 mmol, 1.2 equiv) in DCE (22 mL) was added TMSCl (0.71 mL, 5.574 mmol, 1.5 equiv). The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2Cl2 (5%) to afford ethyl 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2- a]pyridine-2-carboxylate (855 mg, 65.52%) as a white solid. LC-MS: (M+H)+ found 351; 353. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid A solution of ethyl 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate (855 mg, 2.43 mmol, 1 equiv) in H2O (2 mL) and THF (8 mL) was treated with LiOH (87 mg, 3.65 mmol, 1.5 equiv) in portions at 0°C. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6~7 with HCl (1N). Then the product was precipitated. The precipitated solids were collected by filtration and washed with cold water (3x5 mL). The resulting mixture was concentrated under vacuum. This resulted in 8- bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H)+ found 323; 325. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)sulfanyl]-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid (479 mg, 1.48 mmol, 1 equiv) in DMSO (5 mL) were added I2 (1.51 g, 5.92 mmol, 4 equiv) and K3PO4 (377 mg, 1.78 mmol, 1.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of 50% Na2S2O8 (30 mL) at 0°C. To the above mixture was added Na2CO3 (10 mL) in portions at 0°C. The resulting mixture was extracted with CH2Cl2 (3 x 20mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (20%) to afford 8- bromo-3-[(difluoromethyl)sulfanyl]-2-iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H)+ found 405; 407. Compounds Example 1. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)- 1-methylpiperidin-4-amine
Figure imgf000314_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline Into a 5 mL sealed tube were added 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 1; 110 mg, 0.27 mmol, 1 equiv), DMSO (4 mL), 4-methanesulfonyl-2- methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 39; 130 mg, 0.54 mmol, 2 equiv), Pd(PPh3)4 (63 mg, 0.05 mmol, 0.2 equiv), CuI (52 mg, 0.27 mmol, 1 equiv) and i-Pr2NH (275 mg, 2.72 mmol, 10 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere, then diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=1:2) to afford N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4- methanesulfonyl-2-methoxyaniline (140 mg, 83.85%) as a yellow solid. LC-MS: (M+H)+ found 516.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1- methylpiperidin-4-amine Into a 10 mL sealed tube were added N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 equiv), dioxane (4 mL), RuPhos (90 mg, 0.19 mmol, 1 equiv), Cs2CO3 (315 mg, 0.970 mmol, 5 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119 mg, 0.58 mmol, 3 equiv) and BrettPhos Pd G4 (149 mg, 0.097 mmol, 0.5 equiv) at room temperature. The resulting mixture was stirred for 1 h at 100°C under nitrogen atmosphere then diluted with water (30 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford 70 mg crude product. The crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1- methylpiperidin-4-amine (5.9 mg, 5.24%) as a white solid. LC-MS: (M+H)+ found 568.05. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (q, J = 10.7 Hz, 2H), 3.90 (s, 3H), 3.79 – 3.59 (m, 1H), 3.09 (s, 3H), 3.03 (t, J = 13.5 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.33 – 2.27 (m, 1H), 2.19 (s, 3H), 2.15 – 2.02 (m, 1H), 1.82 – 1.75 (m, 2H). Example 2. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop- 1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
Figure imgf000316_0001
Into a 10 mL sealed tube were added N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (70 mg, 0.14 mmol, 1 equiv), dioxane (2 mL), RuPhos (13 mg, 0.03 mmol, 0.2 equiv), Cs2CO3 (133 mg, 0.41 mmol, 3 equiv), 1-methylpiperidin-4-amine (46 mg, 0.41 mmol, 3 equiv) and BrettPhos Pd G4 (21 mg, 0.014 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 3 h at 100°C under nitrogen atmosphere, then diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH 10:1, +0.1% NH3·H2O) to afford N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (8.7 mg, 11.68%) as a yellow solid. LC-MS: (M+H)+ found 550.40.1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.3 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 – 4.01 (m, 2H), 3.90 (s, 3H), 3.37 (s, 1H), 3.10 (s, 3H), 2.77 (s, 2H), 2.21 (s, 3H), 2.09 (s, 2H), 1.88 (d, J = 11.7 Hz, 2H), 1.57 (d, J = 11.4 Hz, 2H). Example 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl}-N-(oxan-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine
Figure imgf000316_0002
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 equiv), oxan-4-amine (58.8 mg, 0.58 mmol, 1.5 equiv), t-BuONa (74.5 mg, 0.77 mmol, 2 equiv) and tBuXPhos Pd G3 (153.9 mg, 0.19 mmol, 0.50 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1). And Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 51% B to 77% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.75; Number Of Runs: 4) to afford 2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-N-(oxan-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-amine (32.5 mg, 15.61%) as a off-white solid. LC-MS: (M+H)+ found 537.15. 1H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.65 (d, J = 6.8 Hz, 1H), 7.44 – 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.30 – 7.21 (d, J = 2.0 Hz, 1H), 6.94 – 6.85 (d, J = 8.4 Hz, 1H), 6.83 – 6.73 (t, J = 7.1 Hz, 1H), 6.51 – 6.42 (t, J = 6.3 Hz, 1H), 6.32 – 6.22 (d, J = 7.5 Hz, 1H), 5.87 – 5.77 (d, J = 8.5 Hz, 1H), 4.37 – 4.26 (d, J = 6.3 Hz, 2H), 4.10 – 3.94 (m, 2H), 3.92 – 3.81 (m, 5H), 3.67 – 3.54 (s, 1H), 3.47 – 3.36 (td, J = 2.1, 11.6 Hz, 2H), 3.13 – 3.04 (s, 3H), 1.94 – 1.76 (m, 2H), 1.70 – 1.43 (m, 2H). Example 113. Synthesis of N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)- 1-(2-methoxyethyl)piperidin-4-amine
Figure imgf000317_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 equiv), 1-(2- methoxyethyl)piperidin-4-amine (23 mg, 0.15 mmol, 1.5 equiv), tBuXphos Pd G3 (41.0 mg, 0.05 mmol, 0.5 equiv), t-BuONa (18.6 mg, 0.19 mmol, 2 equiv) and THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere, then concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 55% B to 75% B in 11 min; Wave Length: 254nm/220nm nm; RT1(min): 9.33) to afford N-(2-{3-[(4-methanesulfonyl- 2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1- (2-methoxyethyl)piperidin-4-amine (6.1 mg, 10.14%) as a white solid. LC-MS: (M+H)+ found 594.30.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.90 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 3.09 (s, 3H), 2.84 (d, J = 11.3 Hz, 2H), 2.46 (t, J = 5.9 Hz, 2H), 2.18 – 2.00 (m, 3H), 1.87 (d, J = 12.5 Hz, 2H), 1.53 (m, 2H). Example 4. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop- 1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1lambda6-thiane-1,1- dione
Figure imgf000318_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 equiv), 4-amino-1lambda6- thiane-1,1-dione (21.7 mg, 0.15 mmol, 1.5 equiv), t-BuONa (18.6 mg, 0.19 mmol, 2 equiv) and tBuXPhos Pd G3 (38.5 mg, 0.05 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 45% B to 64% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 9.55) to afford 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1lambda6-thiane-1,1-dione (4.1 mg, 7.23%) as a off-white solid. LC-MS: (M+H)+ found 585.20. 1H NMR (400 MHz, DMSO-d6) δ 7.80 – 7.71 (d, J = 6.8 Hz, 1H), 7.44 – 7.35 (dd, J = 2.0, 8.4 Hz, 1H), 7.31 – 7.21 (d, J = 2.0 Hz, 1H), 6.92 – 6.78 (dd, J = 7.6, 13.9 Hz, 2H), 6.52 – 6.42 (t, J = 6.2 Hz, 1H), 6.35 – 6.25 (d, J = 7.6 Hz, 1H), 6.24 – 6.15 (d, J = 8.6 Hz, 1H), 4.38 – 4.25 (d, J = 6.3 Hz, 2H), 4.11 – 3.97 (m, 2H), 3.96 – 3.85 (s, 3H), 3.85 – 3.72 (d, J = 10.2 Hz, 1H), 3.31 – 3.27 (s, 2H), 3.16 – 3.06 (d, J = 15.4 Hz, 5H), 2.22 – 2.13 (d, J = 13.3 Hz, 2H), 2.13 – 2.00 (m, 2H). Example 5. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)-1-(2-methanesulfonylethyl) piperidin-4-amine
Figure imgf000319_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (150 mg, 0.29 mmol, 1 equiv), 1-(2- methanesulfonylethyl) piperidin-4-amine hydrochloride (Intermediate 35; 105.8 mg, 0.44 mmol, 1.50 equiv), t-BuONa (83.8 mg, 0.87 mmol, 3 equiv) and tBuXphos Pd G3 (69.2 mg, 0.09 mmol, 0.3 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 34% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.08; Number Of Runs: 2) to afford N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)-1-(2-methanesulfonylethyl)piperidin-4- amine (8.2 mg, 4.35%) as a white solid. LC-MS: (M+H)+ found 642.35. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 6.44 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.45 – 3.35 (m, 1H), 3.26 (s, 2H), 3.09 (s, 3H), 3.03 (s, 3H), 2.87 (d, J = 11.4 Hz, 2H), 2.70 (m, 2H), 2.16 – 2.09 (m, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.55 (m, 2H). Example 114. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]heptan-6- amine
Figure imgf000320_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 equiv), 2-methyl-2- azaspiro[3.3]heptan-6-amine dihydrochloride (50.9 mg, 0.25 mmol, 1.1 equiv), t-BuONa (89.3 mg, 0.93 mmol, 4 equiv) and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.5 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 49% B in 7 min; Wave Length: 254nm nm; RT1(min): 7.03; Number Of Runs: 2) to afford N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2- methyl-2-azaspiro[3.3]heptan-6-amine (9.0 mg, 6.90%) as a off-white solid. LC-MS: (M+H)+ found 562.20.1H NMR (400 MHz, DMSO-d6) δ 7.76 – 7.68 (d, J = 6.8 Hz, 1H), 7.42 – 7.35 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 – 7.18 (d, J = 2.0 Hz, 1H), 6.91 – 6.82 (d, J = 8.4 Hz, 1H), 6.82 – 6.72 (t, J = 7.1 Hz, 1H), 6.51 – 6.43 (t, J = 6.3 Hz, 1H), 6.26 – 6.19 (d, J = 6.6 Hz, 1H), 6.09 – 6.00 (d, J = 7.5 Hz, 1H), 4.36 – 4.25 (d, J = 6.3 Hz, 2H), 4.09 – 3.95 (m, 2H), 3.95 – 3.86 (s, 3H), 3.86 – 3.75 (m, 1H), 3.21 – 3.13 (s, 2H), 3.13 – 3.06 (s, 3H), 3.06 – 2.97 (s, 2H), 2.52 – 2.50 (d, J = 2.1 Hz, 2H), 2.16 – 2.12 (s, 3H), 2.12 – 2.05 (m, 2H). Example 115. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-N-{2-oxaspiro[3.3]heptan-6-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine
Figure imgf000321_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 equiv), 2- oxaspiro[3.3]heptan-6-amine hydrochloride (21.7 mg, 0.15 mmol, 1.5 equiv), tBuXPhos Pd G3 (38.5 mg, 0.05 mmol, 0.5 equiv) and t-BuONa (37.2 mg, 0.39 mmol, 4 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 57% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.68) to afford 2-{3-[(4- methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-{2-oxaspiro[3.3]heptan-6-yl}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine (9 mg, 16.45%) as a white solid. LC-MS: (M+H)+ found 549.10.1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (d, J = 6.7 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 4.62 (s, 2H), 4.48 (s, 2H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (d, J = 10.7 Hz, 2H), 3.89 (s, 3H), 3.79 (d, J = 7.2 Hz, 1H), 3.10 (s, 3H), 2.72 – 2.60 (m, 2H), 2.24 – 2.15 (m, 2H). Example 6. Synthesis of (3R,4S)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)- 1-methylpiperidin-4-amine
Figure imgf000322_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 equiv), (3R,4S)-3-fluoro- 1-methylpiperidin-4-amine (52.4 mg, 0.26 mmol, 1.1 equiv), t-BuONa (89.3 mg, 0.93 mmol, 4 equiv) and tBuXphos Pd G3 (92.3 mg, 0.12 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) to afford (3R,4S)-3-fluoro-N-(2-{3-[(4- methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine (40 mg, 30.32%) as a white solid. LC-MS: (M+H)+ found 568.20.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.74 (m, 2H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.80 – 3.60 (m, 1H), 3.09 (s, 4H), 2.76 (d, J = 11.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 116. Synthesis of methyl 4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate
Figure imgf000322_0002
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 equiv), methyl 4- aminopiperidine-1-carboxylate (31 mg, 0.20 mmol, 2 equiv), tBuXPhos Pd G3 (8 mg, 0.01 mmol, 0.1 equiv) and t-BuONa (28 mg, 0.29 mmol, 3 equiv) in THF (2 mL) was stirred for 0.5 h at 65°C under argon atmosphere. The resulting mixture was quenched with water and extracted with CH2Cl2 (2*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford crude product. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford methyl 4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate (3.8 mg, 6.33%) as a light yellow solid. LC-MS: (M+H)+ found 594.20.1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 – 6.70 (m, 2H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (dd, J = 7.7, 4.2 Hz, 1H), 5.86 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.19 – 3.72 (m, 7H), 3.59 (s, 4H), 3.09 (s, 3H), 2.94 (s, 2H), 1.91 – 1.88 (m, 2H), 1.47 – 1.40 (m, 2H). Example 7. Synthesis of 1-cyclopropyl-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
Figure imgf000323_0001
A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 equiv), 1- cyclopropylpiperidin-4-amine (55 mg, 0.38 mmol, 2 equiv), t-BuXPhos Pd G3 (16 mg, 0.02 mmol, 0.1 equiv) and t-BuONa (56 mg, 0.57 mmol, 3 equiv) in THF (2.5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with CH2Cl2 (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford crude product, then further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min; Gradient: 60% B to 80% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 8.78; Number Of Runs: 3) to afford 1- cyclopropyl-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (5.7 mg, 5.09%) as a white solid. LC- MS: (M+H)+ found 576.20.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.37 – 3.35 (m, 1H), 3.09 (s, 3H), 2.98 – 2.81 (m, 2H), 2.37 – 2.20 (m, 2H), 1.87 – 1.85 (m, 2H), 1.60 – 1.57 (m, 1H), 1.49 – 1.43 (m, 2H), 0.47 – 0.35 (m, 2H), 0.28 (m, 2H). Example 8. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
Figure imgf000324_0001
Step 1. Synthesis of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 equiv), tert-butyl (3S,4R)- 4-amino-3-fluoropiperidine-1-carboxylate (126.8 mg, 0.58 mmol, 1.5 equiv), t-BuONa (148.9 mg, 1.55 mmol, 4 equiv), and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.3 equiv) in THF (2 mL) was stirred at 65 oC for 1h. The mixture was allowed to cool down to room temperature, then diluted with ethyl acetate (20mL), washed with 3*20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford (3S,4R)-3-fluoro-4-[(2-{3-[(4- methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)amino]piperidine-1-carboxylate (220 mg, crude) as a black solid. LC-MS: (M+H)+ found 654.2. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate (150 mg, crude) in CH2Cl2 (2 mL) was added CF3COOH (1 mL). The reaction solution was stirred for 1h at room temperature, then basified to pH 8 with saturated NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 22% B to 48% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.8) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (17.1 mg, 13.45%) as a white solid. LC-MS: (M+H)+ found 554.20.1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.75 (m, 2H), 6.50 – 6.36 (m, 2H), 5.36 (d, J = 9.2 Hz, 1H), 4.71 (d, J = 50.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.86 – 3.68 (m, 1H), 3.09 (s, 4H), 3.00 – 2.89 (m, 1H), 2.81 (m, 1H), 2.64 – 2.54 (m, 1H), 2.41 – 2.04 (m, 1H), 1.73 (dd, J = 12.9, 4.2 Hz, 1H), 1.61 (m, 1H). Example 117. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1- carboxamide
Figure imgf000326_0001
Step 1. Synthesis of tert-butyl 4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (550 mg, 1.06 mmol, 1 equiv), tert-butyl 4- aminopiperidine-1-carboxylate (427 mg, 2.13 mmol, 2 equiv), t-BuONa (205 mg, 2.13 mmol, 2 equiv) and tBuXphos Pd G3 (254 mg, 0.32 mmol, 0.3 equiv) in THF (10 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2*30mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford tert-butyl 4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate (330 mg, 48.73%) as a yellow solid. LC-MS: (M+H)+ found 636.2. Step 3. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine A solution of tert-butyl 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (50 mg, 0.08 mmol, 1 equiv) in TFA (0.3 mL) and DCM (0.6 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 99.70%) as a red oil. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found 536.2. Step 4. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1- carboxamide A solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 equiv) in DCM (1 mL) was treated with TEA (119 mg, 1.17 mmol, 15 equiv) for 5 min at 0°C under nitrogen atmosphere followed by the addition of N-methylcarbamoyl chloride (8 mg, 0.09 mmol, 1.1 equiv) at 0°C. The resulting solution was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Xcelect CSH F- pheny OBD Column 30*150 mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 45% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.5) to afford 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1- carboxamide (22.9 mg, 48.98%) as a white solid. LC-MS: (M+H)+ found 593.35.1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.47 (d, J = 6.6 Hz, 1H), 6.40 (d, J = 4.6 Hz, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.31 (d, J = 5.3 Hz, 2H), 4.02 (m, 2H), 3.96 – 3.83 (m, 5H), 3.53 (s, 1H), 3.09 (s, 3H), 2.81 – 2.76 (m, 2H), 2.55 (d, J = 3.7 Hz, 3H), 1.91 – 1.82 (m, 2H), 1.45 – 1.31 (m, 2H). Example 9. Synthesis of 1-isopropyl-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
Figure imgf000327_0001
A solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.078 mmol, 1 equiv) in acetone (1 mL) was stirred for 30 min at room temperature. To the above solution was added NaBH(OAc)3 (83 mg, 0.39 mmol, 5 equiv) in three batches at room temperature. The resulting mixture was stirred for overnight at room temperature. The mixture was neutralized to pH 8 with saturated NaHCO3 and extracted with CH2Cl2 (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1)+0.1% NH3·H2O to afford crude product, then further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 1- isopropyl-N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (8.1 mg, 17.45%) as a white solid. LC-MS: (M+H)+ found 578.45.1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.76 (m, 2H), 6.49 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.77 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.38 (s, 1H), 3.10 (s, 3H), 2.83 (s, 3H), 2.28 (s, 1H), 1.93 (t, J = 8.0 Hz, 2H), 1.54 (s, 2H), 1.11 – 0.88 (m, 7H). Example 10. Synthesis of 1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidin-1-yl}ethanone
Figure imgf000328_0001
To a stirred solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 equiv) and TEA (119 mg, 1.17 mmol, 15 equiv) in DCM (1 mL) was added acetyl chloride (6 mg, 0.07 mmol, 0.9 equiv) at 0°C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.6) to afford 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}ethanone (22.3 mg, 48.94%) as a white solid. LC-MS: (M+H)+ found 578.30.
Figure imgf000329_0001
NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.48 (t, J = 6.3 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.87 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 3H), 4.06 – 3.98 (m, 2H), 3.89 (s, 3H), 3.82 (d, J = 13.9 Hz, 1H), 3.69 – 3.55 (m, 1H), 3.21 – 3.09 (m, 1H), 3.09 (s, 3H), 2.70 (td, J = 12.7, 2.9 Hz, 1H), 2.00 (s, 3H), 1.98 – 1.85 (m, 2H), 1.54 – 1.28 (m, 2H). Example 11. Synthesis of 1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-8- yl)amino]piperidin-1-yl}-2-methylpropan-2-ol
Figure imgf000329_0002
A mixture of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (60 mg, 0.12 mmol, 1 equiv), EtOH (0.6 mL), K2CO3 (62 mg, 0.45 mmol, 4 equiv), H2O (0.3 mL) and 2,2-dimethyloxirane (32 mg, 0.45 mmol, 4 equiv) was irradiated with microwave radiation for 0.5 h at 110°C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 60% B in 7 min; Wave Length: 220nm nm; RT1(min): 7.5) to afford 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-2-methylpropan-2- ol (22.2 mg, 32.45%) as a white solid. LC-MS: (M+H)+ found 608.15. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 8.2 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.04 (d, J = 3.4 Hz, 2H), 4.00 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.30 (d, J = 10.8 Hz, 1H), 3.10 (s, 3H), 2.96 – 2.87 (m, 2H), 2.30 – 2.20 (m, 2H), 2.20 (s, 2H), 1.90 – 1.81 (m, 2H), 1.61 – 1.46 (m, 2H), 1.08 (s, 6H). Example 12. Synthesis of (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol
Figure imgf000330_0001
A mixture of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 equiv), EtOH (0.5 mL), K2CO3 (43 mg, 0.31 mmol, 4 equiv), H2O (0.2 mL) and (2S)-2- (methoxymethyl)oxirane (21 mg, 0.23 mmol, 3 equiv) was irradiated with microwave radiation for 0.5 h at 110°C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 52% B in 7 min; Wave Length: 220nm nm; RT1(min): 7.5) to afford (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (17.7 mg, 35.61%) as a white solid. LC-MS: (M+H)+ found 624.45.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.7 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.05 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.72 (q, J = 5.6 Hz, 1H), 3.35 (s, 1H), 3.31 – 3.27 (m, 1H), 3.25 (s, 3H), 3.24 – 3.18 (m, 1H), 3.09 (s, 3H), 2.90 – 2.79 (m, 2H), 2.31 (dd, J = 12.6, 5.1 Hz, 1H), 2.24 (dd, J = 12.7, 7.0 Hz, 1H), 2.11 (dd, J = 20.7, 10.8 Hz, 2H), 1.91 – 1.83 (m, 2H), 1.61 – 1.47 (m, 2H). Example 14. Synthesis of (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol
Figure imgf000331_0001
A mixture of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (50 mg, 0.09 mmol, 1 equiv), EtOH (0.6 mL), K2CO3 (52 mg, 0.37 mmol, 4 equiv), (2R)-2-(methoxymethyl)oxirane (33 mg, 0.37 mmol, 4 equiv) and H2O (0.3 mL) was irradiated with microwave radiation for 0.5 h at 110°C. The resulting mixture was diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 52% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.87) to afford (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (11.1 mg, 18.93%) as a white solid. LC-MS: (M+H)+ found 624.20.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.6 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.72 (m, 1H), 3.32 – 3.16 (m, 6H), 3.09 (s, 3H), 2.92 – 2.76 (m, 2H), 2.39 – 2.19 (m, 2H), 2.15 – 2.07 (m, 2H), 1.88 – 1.86 (m, 2H), 1.57 – 1.52 (m, 2H). Example 15. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1- methylpiperidin-4-amine
Figure imgf000332_0001
Step 1. Synthesis of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4- methanesulfonyl-2-methoxyaniline To a stirred solution of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (Intermediate 2; 200.0 mg, 0.56 mmol, 1 equiv) in DMSO (10 mL) were added 4-methanesulfonyl-2-methoxy-N- (prop-2-yn-1-yl)aniline (Intermediate 39; 196.3 mg, 0.82 mmol, 1.20 equiv), CuI (130.2 mg, 0.64 mmol, 1 equiv), i-Pr2NH (691.9 mg, 6.82 mmol, 10 equiv) and Pd(PPh3)4 (316.1 mg, 0.26 mmol, 0.40 equiv). The mixture was stirred for 16 h at 50oC under nitrogen atmosphere. The mixture was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4- methanesulfonyl-2-methoxyaniline (130.0 mg, 49.4%) as a yellow solid. LC-MS: (M+H)+ found 462.0. Step 2. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4- amine To a solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4- methanesulfonyl-2-methoxyaniline (130.0 mg, 0.28 mmol, 1 equiv) in 1,4-dioxane (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.3 mg, 0.36 mmol, 1.30 equiv), BrettPhosPdG4 (51.0 mg, 0.05 mmol, 0.20 equiv), RuPhos (52.5 mg, 0.11 mmol, 0.40 equiv) and Cs2CO3 (458.1 mg, 1.40 mmol, 5 equiv). The reaction mixture was heated at 100°C for 5 h under nitrogen atmosphere. The resulted solution was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude was purified using prep-HPLC with following conditions: (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 33% B to 52% B in 10min; Wave Length: 254nm/220nm; RT = 9.75 min). This resulted in (3S,4R)-N-(3-ethyl-2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin- 4-amine (8.30 mg, 5.7%) as a white solid. LC-MS: (M+H)+ found 514.10. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, 1H), 7.45-7.40 (m, 1H), 7.25 (s, 1H), 6.91-6.82 (m, 1H), 6.80-6.69 (m, 1H), 6.45 (t, 1H), 6.34-6.25 (m, 1H), 5.30-5.20 (m, 1H), 4.80 (d, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.80- 3.50 (m, 1H), 3.10 (s, 3H), 3.08-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 1H), 2.30-2.00 (m, 5H), 1.80 (s, 2H), 1.10 (t, 3H). Example 16. Synthesis of N-(3-ethyl-2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4- amine
Figure imgf000333_0001
To a stirred solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.11 mmol, 1 equiv) in 1,4-dioxane (5 mL) were added 1-methylpiperidin-4-amine (30.9 mg, 0.27 mmol, 2.50 equiv), BrettPhosPdG3 (19.6 mg, 0.02 mmol, 0.20 equiv), RuPhos (20.2 mg, 0.04 mmol, 0.40 equiv) and Cs2CO3 (176.2 mg, 0.55 mmol, 5 equiv) at room temperature. The reaction mixture was stirred at 100°C for 1 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 80% B in 30 min; 254/220 nm). The crude was purified using prep-HPLC with following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol/L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 53% B in 7 min; Wave Length: 254nm nm; RT = 7.15 min). This resulted in N-(3-ethyl-2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop- 1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (10.1 mg, 18.2%) as a yellow solid. LC-MS: (M+H)+ found 496.40.1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 6.90 (d, 1H), 6.80-6.60 (m, 1H), 6.59-6.33 (m, 1H), 6.29-6.00 (m, 1H), 5.58-5.49 (m, 1H), 4.30 (d, 2H), 3.90 (s, 3H), 3.10 (s, 3H), 3.00-2.80 (m, 2H), 2.76-2.60 (m, 2H), 2.10 (s, 3H), 2.08-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.40 (m, 3H), 1.11 (t, 3H). Example 17. Synthesis of 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000334_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide To a stirred solution of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine (Intermediate 3; 300.0 mg, 0.82 mmol, 1 equiv) in DMSO (5 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn- 1-ylamino)benzamide (Intermediate 14; 214.1 mg, 0.98 mmol, 1.20 equiv), CuI (155.7 mg, 0.82 mmol, 1 equiv), Pd(PPh3)4 (188.9 mg, 0.16 mmol, 0.20 equiv) and i-Pr2NH (827.2 mg, 8.17 mmol, 10 equiv). The resulting mixture was stirred at 30oC for 1h under nitrogen atmosphere, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 65% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3- methoxy-N-methylbenzamide (270.0 mg, 72.22%) as a brown solid. LC-MS: (M+H)+ found 457.3 Step 2. Synthesis of 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide To a stirred solution of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 equiv) in THF (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (134.5 mg, 0.66 mmol, 2 equiv), t-BuXPhosPdG3 (52.2 mg, 0.07 mmol, 0.20 equiv) and t-BuONa (252.2 mg, 2.62 mmol, 8 equiv). The resulting mixture was stirred at 65°C for 30min under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 20% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 20% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.25) to afford 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (15.1 mg, 9.05%) as a yellow solid. LC-MS: (M+H)+ found 509.35. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (q, J = 4.5 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.76-6.65 (m, 2H), 6.22 (d, J = 7.4 Hz, 1H), 5.93 (t, J = 6.4 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.80 (d, J = 49.7 Hz, 1H), 4.35-4.21 (m, 4H), 3.84 (s, 3H), 3.68 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.34-2.15 (m, 4H), 2.14-2.06 (m, 1H), 1.86-1.72 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). Example 18. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
Figure imgf000335_0001
A mixture of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 4; 60 mg, 0.18 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (116.4 mg, 0.56 mmol, 3 equiv), RuPhos (17.7 mg, 0.03 mmol, 0.2 equiv), Cs2CO3 (308.2 mg, 0.94 mmol, 5 equiv) and RuPhos Palladacycle Gen.4 (15.8 mg, 0.01 mmol, 0.1 equiv) in dioxane (3 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude was further purified using prep-HPLC with following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 52% B in 7 min; Wave Length: 254nm/220nm nm; RT(min): 6.58. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.5 mg, 7.88%) as a white solid. LC- MS: (M+H)+ found 369.15.1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 6.7 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.3 Hz, 1H), 4.96-4.65 (m, 1H), 4.12-4.07 (m, 2H), 3.74 (dt, J = 28.4, 8.5 Hz, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.78 (d, J = 11.5 Hz, 1H), 2.36-2.22 (m, 1H), 2.21 (s, 3H), 2.17-2.11 (m, 1H), 2.09 (s, 3H), 1.82 (m, 2H). Example 19. Synthesis of 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
Figure imgf000336_0001
To a stirred solution of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 4; 45 mg, 0.14 mmol, 1 equiv) in dioxane (3 mL) were added 1- methylpiperidin-4-amine (24.3 mg, 0.21 mmol, 1.5 equiv), RuPhos (13.2 mg, 0.02 mmol, 0.2 equiv), Cs2CO3 (228.2 mg, 0.70 mmol, 5 equiv) and RuPhos Palladacycle Gen.4 (11.9 mg, 0.01 mmol, 0.1 equiv). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm), then further purified by prep-HPLC with following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 7 min; Wave Length: 254nm/220nm nm; RT (min): 6.33. This resulted in 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.1 mg, 10.16%) as a white solid. LC-MS: (M+H)+ found 351.15.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 6.7 Hz, 1H), 6.87- 6.79 (m, 1H), 6.27 (d, J = 7.5 Hz, 1H), 4.09 -4.04 (m, 2H), 3.39 (td, J = 12.1, 11.6, 5.4 Hz, 1H), 2.73 (d, J = 11.4 Hz, 2H), 2.18 (s, 3H), 2.13-2.02 (m, 5H), 1.97-1.88 (m, 2H), 1.63-1.49 (m, 2H). Example 20. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine
Figure imgf000337_0001
To a solution of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5- a]pyridine (Intermediate 5; 160 mg, 0.50 mmol, 1 equiv) in THF (3 mL) was added (3S,4R)-3- fluoro-1-methylpiperidin-4-amine (133.4 mg, 1.01 mmol, 2 equiv), t-BuONa (291 mg, 3.03 mmol, 6 equiv), tBuXPhosPdG3 (25.1 mg, 0.03 mmol, 0.2 equiv). The reaction mixture was stirred at 65oC for 30 min under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude was purified using prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 53% B in 10 min; Wave Length: 220nm nm; RT(min): 9.32. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine (18.6 mg, 10.01%) as a white solid. LC-MS: (M+H)+ found 369.10.1H NMR (400 MHz, DMSO-d6) δ 7.27 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 9.1 Hz, 1H), 4.88 (d, J = 49.4 Hz, 1H), 4.00-3.60 (m, 3H), 3.07 (dt, J = 14.5, 6.8 Hz, 1H), 2.78 (d, J = 11.2 Hz, 1H), 2.41-2.04 (m, 8H), 1.89 (m, 2H). Example 21. Synthesis of N-[3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8- yl]-1-methylpiperidin-4-amine
Figure imgf000338_0001
A solution of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Intermediate 6; 100 mg, 0.38 mmol, 1 equiv), 1-methylpiperidin-4-amine (65.6 mg, 0.58 mmol, 1.5 equiv), t- BuONa (73.6 mg, 0.77 mmol, 2 equiv) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1).The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: in 7 min; Wave Length: 220nm nm; RT1(min): 7.18; Number Of Runs: 3) to afford N-[3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1- methylpiperidin-4-amine (15.0 mg, 13.30%) as a off-white solid. LC-MS: (M+H)+ found 295.10. 1H NMR (400 MHz, DMSO-d6) δ 7.87 – 7.76 (d, J = 6.8 Hz, 1H), 7.10 – 6.96 (dd, J = 12.0, 17.7 Hz, 1H), 6.84 – 6.75 (t, J = 7.1 Hz, 1H), 6.30 – 6.21 (d, J = 7.5 Hz, 1H), 6.19 – 6.09 (dd, J = 1.4, 17.6 Hz, 1H), 5.71 – 5.59 (d, J = 8.4 Hz, 1H), 5.48 – 5.37 (dd, J = 1.3, 11.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.78 – 2.65 (d, J = 11.1 Hz, 2H), 2.27 – 2.10 (d, J = 17.7 Hz, 6H), 2.09 – 1.97 (td, J = 2.5, 11.5 Hz, 2H), 1.96 – 1.83 (m, 2H), 1.65 – 1.48 (m, 2H). Example 22. Synthesis of (3S,4R)-N-[3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2- a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000338_0002
A solution of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Intermediate 6; 100 mg, 0.38 mmol, 1 equiv), t-BuONa (73.6 mg, 0.77 mmol, 2 equiv) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 15:1). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.1) to afford (3S,4R)-N- [3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (3.1 mg, 2.59%) as a off-white solid. LC-MS: (M+H)+ found 313.10.1H NMR (400 MHz, DMSO- d6) δ 7.94 – 7.85 (d, J = 6.8 Hz, 1H), 7.11 – 6.97 (dd, J = 12.0, 17.7 Hz, 1H), 6.87 – 6.78 (t, J = 7.1 Hz, 1H), 6.46 – 6.37 (d, J = 7.6 Hz, 1H), 6.21 – 6.10 (dd, J = 1.3, 17.7 Hz, 1H), 5.50 – 5.41 (dd, J = 1.4, 11.8 Hz, 1H), 5.40 – 5.31 (d, J = 9.3 Hz, 1H), 4.94 – 4.73 (d, J = 49.5 Hz, 1H), 3.82 – 3.63 (m, 1H), 3.11 – 2.98 (d, J = 11.3 Hz, 1H), 2.87 – 2.73 (d, J = 11.4 Hz, 1H), 2.37 – 2.28 (d, J = 13.4 Hz, 1H), 2.25 – 2.18 (s, 3H), 2.18 – 2.07 (s, 4H), 1.85 – 1.77 (m, 2H). Example 23. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000339_0001
Step 1. Synthesis of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate A solution of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate (Intermediate 7; 900 mg, 2.05 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 538.1 mg, 2.47 mmol, 1.2 equiv), i-Pr2NH (2.08 g, 20.54 mmol, 10 equiv), CuI (391.3 mg, 2.05 mmol, 1 equiv) and Pd(PPh3)4 (474.8 mg, 0.41 mmol, 0.2 equiv) in DMSO (9 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EA (300 mL) and washed with 5*500 mL of brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15:1) to afford tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate (900 mg, 82.90%) as a brown solid. LC-MS: (M+H)+ found 528.1. Step 2. Synthesis of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2- (3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3- yl)carbamate A solution of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate (850 mg, 1.61 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (659.9 mg, 3.22 mmol, 2 equiv), t-BuONa (773.0 mg, 8.05 mmol, 5 equiv) and tBuXphos Pd G3 (383.4 mg, 0.48 mmol, 0.3 equiv) in THF (9 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / 7 M NH3 in MeOH = 15:1 to afford tert-butyl N-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn- 1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate (670 mg, 71.85%) as a brown solid. LC-MS: (M+H)+ found 580.4. Step 3. Synthesis of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino} imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide To a stirred solution of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 2-(3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3- yl)carbamate (650 mg, 1.12 mmol, 1 equiv) and 2,6-lutidine (600.78 mg, 5.605 mmol, 5 equiv) in DCM (7 mL) was added TMSOTf (1.25 g, 5.61 mmol, 5 equiv) dropwise at 0°C. The resulting solution was stirred for 30 min at room temperature, then concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH =15:1) to afford 4-{[3-(3- amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino} imidazo[1,2-a]pyridine-2-yl)prop-2- yn-1-yl]amino}-3-methoxy-N-methylbenzamide (266 mg, 49.47%) as a brown solid. LC-MS: (M+H)+ found 480.4. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2- enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide To a stirred solution of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}imidazo[1,2-a] pyridine-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (90 mg, 0.19 mmol, 1 equiv), acrylic acid (21 mg, 0.29 mmol, 1.5 equiv) and TEA (57 mg, 0.56 mmol, 3 equiv) in THF (2 mL) was added T3P (179 mg, 0.57 mmol, 3 equiv, 50 wt% in DMF) dropwise at 0°C. The resulting mixture was stirred for 1 h at room temperature. The resulting solution was diluted with water and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 33% B to 52% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.75; Number Of Runs: 4) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (6 mg, 5.77%) as a off-white solid. LC-MS: (M+H)+ found 534.25. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 17.1, 10.3 Hz, 1H), 6.37 (d, J = 7.5 Hz, 1H), 6.34 – 6.24 (m, 1H), 5.94 (t, J = 6.1 Hz, 1H), 5.85 (d, J = 10.9 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 28.6 Hz, 1H), 3.03 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.3 Hz, 1H), 1.82 (d, J = 19.9 Hz, 2H). Example 24. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2-methylprop-2-enamido) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino} -3-methoxy- N-methylbenzamide
Figure imgf000342_0001
To a stirred solution of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (90 mg, 0.19 mmol, 1 equiv), methacrylic acid (24.2 mg, 0.28 mmol, 1.5 equiv) and TEA (57.0 mg, 0.57 mmol, 3 equiv) in THF (1 mL) was added T3P (179.1 mg, 0.57 mmol, 3 equiv, 50 wt% in DMF) at 0°C. The resulting solution was stirred for 1 h at room temperature, then diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triant C18 ExRs Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 41% B in 10 min; Wave Length: 220nm nm; RT1(min): 9.28) to afford 4-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2-methylprop-2-enamido) imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino} -3-methoxy-N-methylbenzamide (2.5 mg, 2.39%) as a white solid. LC-MS: (M+H)+ found 548.30.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.03 – 5.85 (m, 2H), 5.61 (s, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.70 (d, J = 31.1 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 10.4 Hz, 1H), 1.94 (s, 3H), 1.82 (dd, J = 11.9, 8.1 Hz, 2H). Example 25. Synthesis of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl) imidazo[1,2- a] pyridin-3-yl)-N-methylcarbamate
Figure imgf000343_0001
Step 1. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N- methylcarbamate A solution of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate (Intermediate 7; 1.6 g, 3.65 mmol, 1 equiv) in THF (15 mL) was treated with NaH (292.2 mg, 7.30 mmol, 2 equiv, 60%) at 0°C. The resulting mixture was stirred for 5 min, and then MeI (1036.85 mg, 7.304 mmol, 2 equiv) was added dropwise. The reaction was stirred for 0.5 h at room temperature, then quenched with water/ice and extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N- methylcarbamate (1.5 g, 90.91%) as a grey solid. LC-MS: (M+H)+ found 453.9. Step 2. Synthesis of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N- methylcarbamate A mixture of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N- methylcarbamate (1.5 g, 3.32mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 0.80 g, 3.65 mmol, 1.1 equiv, Pd(PPh3)4 (0.77 g, 0.66 mmol, 0.2 equiv), CuI (0.63 g, 3.31 mmol, 1 equiv), and i-Pr2NH (3.36 g, 33.20 mmol, 10.0 equiv) in DMSO (15 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EA (200mL) and washed with brine (3*200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N- methylcarbamate (1.3 g, 72.22%) as a yellow solid. LC-MS: (M+H)+ found 545.1. Step 3. Synthesis of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-2- (3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3- yl)-N-methylcarbamate A mixture of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl) imidazo[1,2-a] pyridin-3-yl]-N-methylcarbamate (1.4 g, 2.58 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.06 g, 5.16 mmol, 2 equiv), t-BuONa (1.49 g, 15.48 mmol, 6 equiv) and tBuXphos Pd G3 (0.62 g, 0.77 mmol, 0.3 equiv) in THF (14 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / 7 M NH3 in MeOH = 20:1 to afford tert-butyl N-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl] amino}-2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1- yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate (600 mg, 39.09%) as a yellow solid. LC- MS: (M+H)+ found 594.25. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- (methylamino) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide To a stirred solution of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl) imidazo[1,2-a] pyridin-3-yl)-N-methylcarbamate (600 mg, 1.01 mmol, 1 equiv) and lutidine (541.5 mg, 5.05 mmol, 5 equiv) in DCM (8 mL) was added TMSOTf (1.12 g, 5.05 mmol, 5 equiv) dropwise at 0°C. The mixture was stirred for 30 min at room temperature, then concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 67% B in 10min; RT1(min): 9) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl] amino}-3-(methylamino) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1- yl]amino}-3-methoxy-N-methylbenzamide (11.7 mg, 2.21%) as a white solid. LC-MS: (M+H)+ found 494.25. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 4.8 Hz, 1H), 7.44 – 7.27 (m, 3H), 6.72 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 7.1 Hz, 1H), 6.11 (d, J = 7.4 Hz, 1H), 5.86 (t, J = 6.3 Hz, 1H), 5.45 (m, 1H), 5.13 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 49.4 Hz, 1H), 4.22 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.73 – 3.55 (m, 1H), 3.02 (t, J = 11.8 Hz, 1H), 2.93 (d, J = 5.2 Hz, 3H), 2.75 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (d, J = 12.9 Hz, 1H), 1.78 (m, 3.8 Hz, 2H). Example 26. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide
Figure imgf000345_0001
To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (methylamino)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (150 mg, 0.30 mmol, 1 equiv), acrylic acid (33 mg, 0.45 mmol, 1.5 equiv) and TEA (92 mg, 0.90 mmol, 3 equiv) in THF (2.0 mL) was added T3P (290 mg, 0.45 mmol, 1.5 equiv, 50wt% in DMF) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3 * 100mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: YMC-Actus Triant C18 ExRs Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 17% B to 42% B in 9 min; Wave Length: 220nm nm; RT1(min): 8.12) to afford to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide (4.5 mg, 2.70%) as a white solid. LC-MS: (M+H)+ found 548.45. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.8 Hz, 1H), 7.40 (m, 2H), 7.32 (s, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 16.7 Hz, 1H), 5.93 (t, J = 6.1 Hz, 1H), 5.86 – 5.70 (m, 1H), 5.51 (m, 2H), 4.82 (d, J = 49.5 Hz, 1H), 4.22 (d, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.72 (d, J = 29.4 Hz, 1H), 3.15 (s, 3H), 3.04 (d, J = 12.4 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.81 (d, J = 19.5 Hz, 2H). Example 27. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- ol, TFA salt
Figure imgf000346_0001
trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline A solution of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 8; 760 mg, 1.63 mmol, 1 equiv), 4-methanesulfonyl-2-methoxy-N- (prop-2-yn-1-yl)aniline (Intermediate 39; 430 mg, 1.80 mmol, 1.1 equiv), Pd(PPh3)4 (755 mg, 0.65 mmol, 0.4 equiv), CuI (311 mg, 1.63 mmol, 1 equiv) and i-Pr2NH (1.65 g, 16.34 mmol, 10 equiv) in DMSO (10 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 50% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin- 2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (680 mg, 72.18%) as a brown solid. LC-MS: (M+H)+ found: 576.4. Step 2. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1- yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin- 4-amine A mixture of N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.35 mmol, 1 equiv), 1-methylpiperidin-4-amine (396 mg, 3.47 mmol, 10 equiv), BrettPhos Pd G4 (62.91 mg, 0.07 mmol, 0.2 equiv), RuPhos (64 mg, 0.14 mmol, 0.4 equiv) and Cs2CO3 (339 mg, 1.04 mmol, 3 equiv) in dioxane (5 mL) was stirred for 2h at 100 oC under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 50% to 50% gradient in 3 min; detector, UV 254 nm. This resulted in N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 47.27%) as a yellow solid. LC-MS: (M+H)+ found: 609.7. Step 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}- 8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol TFA salt To a solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}- 6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4- amine (100 mg, 0.16 mmol, 1 equiv) in MeOH (2 mL) was added con. HCl (0.5 mL) dropwise at 0 oC. The reaction solution was stirred for 1 h at 25 oC, then purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 16% B to 26% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 7.35) to afford 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1- methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (17.8 mg, 19.19%) as a yellow solid. LC-MS: (M+H)+ found: 566.20. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.32 (s, 1H), 7.43 – 7.35 (m, 1H), 7.27 – 7.17 (m, 2H), 6.90 – 6.76 (m, 1H), 6.47 (s, 1H), 6.14 (d, J = 31.5 Hz, 1H), 6.08 – 5.99 (m, 1H), 4.62 (d, J = 5.3 Hz, 1H), 4.30 (s, 2H), 4.01 – 3.93 (m, 1H), 3.90 (d, J = 1.6 Hz, 3H), 3.86 – 3.55 (m, 2H), 3.49 (d, J = 11.6 Hz, 2H), 3.10 (s, 3H), 3.05 (d, J = 11.8 Hz, 1H), 2.85 – 2.72 (m, 3H), 2.16 – 1.68 (m, 4H). Example 28. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxy-N-methylbenzamide, formic acid salt
Figure imgf000348_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridine (Intermediate 9; 150.0 mg, 0.36 mmol, 1 equiv) in DMSO (3 mL) were added 3- methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 92.9 mg, 0.43 mmol, 1.20 equiv), CuI (67.5 mg, 0.36 mmol, 1 equiv), Pd(PPh3)4 (82.0 mg, 0.07 mmol, 0.20 equiv) and i-Pr2NH (358.9 mg, 3.55 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 30°C for 1 h under nitrogen atmosphere, then purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water, 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (150.0 mg, 82.40%) as a brown solid. LC-MS: (M+H)+ found 513.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.29 mmol, 1 equiv) in THF (4.50 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (149.8 mg, 0.73 mmol, 2.50 equiv), t-BuXPhosPdG3 (116.1 mg, 0.15 mmol, 0.50 equiv) and t-BuONa (224.7 mg, 2.34 mmol, 8 equiv). The resulting mixture was stirred at 65°C for 30 min under nitrogen atmosphere, then concentrated under reduced pressure. The residue was purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (0.1% FA), 0% to 20% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 30% B in 8 min; Wave Length: 254nm/220nm; RT(min): 7.68) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (22.3 mg, 13.52%) as a light yellow solid. LC-MS: (M+H)+ found 565.20.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 0.8H), 8.11 (m, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14-2.03 (m, 1H), 1.92-1.71 (m, 2H). Example 29. Synthesis of 4-{[3-(3-cyclopropyl-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000349_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn- 1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred mixture of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine (Intermediate 10; 330.0 mg, 0.91 mmol, 1 equiv) in DMSO (10 mL) were added and 3-methoxy- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 238.1 mg, 1.09 mmol, 1.20 equiv), CuI (173.1 mg, 0.91 mmol, 1 equiv), i-Pr2NH (920.0 mg, 9.09 mmol, 10 equiv) and Pd(PPh3)4 (210.1 mg, 0.18 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 40oC for 1 h under nitrogen atmosphere, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, 0% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3- cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (331.0 mg, 80.31%) as a brown solid. LC-MS: (M+H)+ found 453.3. Step 2. Synthesis of 4-{[3-(3-cyclopropyl-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide A mixture of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 equiv) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (135.7 mg, 0.66 mmol, 2 equiv), t-BuXPhosPdG3 (42.1 mg, 0.05 mmol, 0.16 equiv) and t-BuONa (252.9 mg, 2.64 mmol, 8 equiv) was stirred for 30 min at 65°C under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (0.1% TFA), 0% to 30% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 20% B to 46% B in 8 min; Wave Length: 254nm/220nm nm; RT (min): 7.35) to afford 4-{[3-(3- cyclopropyl-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (22.9 mg, 13.58%) as a white solid. LC-MS: (M+H)+ found 505.20.1H NMR (400 MHz, DMSO-d6) δ 8.08 (m, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.43 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.83-6.72 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 5.26 (d, J = 9.3 Hz, 1H), 4.86 (d, J = 3.1 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.69 (m, 1H), 3.02 (t, J = 11.2 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.33- 2.02 (m, 5H), 1.86 (tt, J = 8.0, 5.0 Hz, 1H), 1.78 (h, J = 3.7 Hz, 2H), 0.94 (dt, J = 8.2, 3.1 Hz, 2H), 0.81-0.72 (m, 2H). Example 30. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000351_0001
Step 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine A solution of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (Intermediate 11; 230.0 mg, 0.52 mmol, 1 equiv) in DMSO (5 mL) was treated with 3-methoxy- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 227.7 mg, 1.04 mmol, 2 equiv), i-Pr2NH (527.8 mg, 5.22 mmol, 10 equiv), Pd(PPh3)4 (120.6 mg, 0.10 mmol, 0.20 equiv) and CuI (49.7 mg, 0.26 mmol, 0.50 equiv). The resulting mixture was stirred for 1h at 30oC under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine (150.0 mg, 54.5%) as a white solid. LC-MS: (M+H)+ found 528.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A solution of 4-({3-[8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (89.0 mg, 0.16 mmol, 1 equiv) in THF (5 mL) was treated with t-BuONa (96.6 mg, 1.00 mmol, 6 equiv), t-BuXPhosPdG3 (53.2 mg, 0.06 mmol, 0.40 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (68.7 mg, 0.33 mmol, 2 equiv). The resulting mixture was stirred for 30 min at 65 °C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude was purified using prep-HPLC with the following conditions Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 25% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (1.50 mg, 1.54%) as a white solid. LC-MS: (M+H)+ found 583.30. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.69 (d, J = 6.7 Hz, 1H), 7.39-7.34 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 48 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.83-3.63 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33-2.10 (m, 5H), 1.86 (tt, J = 11.9, 6.3 Hz, 1H), 1.80-1.73 (m, 1H). Example 31. Synthesis of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate
Figure imgf000352_0001
Step 1. Synthesis of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8- yl]-1-methylpiperidin-4-amine A stirred mixture of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 12; 4 g, 9.46 mmol, 1 equiv),1-methylpiperidin-4-amine (8.64 g, 75.66 mmol, 8 equiv) and DIEA (8.56 g, 66.20 mmol, 7 equiv) in DMSO (40 mL) was stirred for 16 h at 100 oC. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 20% to 40% gradient in 10 min; detector, UV 220 nm) to afford N-[6- bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8-yl]-1-methylpiperidin-4-amine (4.1 g, 85%) as an off-white solid. LC-MS: (M+H)+ found:517.1. Step 2. Synthesis of N-(6-bromo-2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8-yl)-1-methylpiperidin-4-amine A mixture of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8-yl]-1- methylpiperidin-4-amine (504 mg, 0.97 mmol, 1 equiv), CuI (185 mg, 0.97 mmol, 1 equiv), Diisopropylamine (986 mg, 9.75 mmol, 10 equiv), Pd(PPh3)4 (451 mg, 0.39 mmol, 0.4 equiv) and 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline (280 mg, 1.17 mmol, 1.2 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere before quenching with water (10 mL). The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, 0.1%TFA in water 25% to 40% gradient in 10 min; detector, UV 220 nm) to afford N-(6- bromo-2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl) imidazo[1,2-a] pyridin-8-yl)-1-methylpiperidin-4-amine (470 mg, 76.69%) as a light yellow soild. LC-MS: (M+H)+ found:628.1. Step 3. Synthesis of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate A mixture of N-(6-bromo-2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1- yn-1-yl}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.16 mmol, 1 equiv), tert-butyl carbamate (93 mg, 0.80 mmol, 5 equiv), sodium 2- methylpropan-2-olate (46 mg, 0.48 mmol, 3 equiv) and tBuXPhos Pd G3 (13 mg, 0.016 mmol, 0.1 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (Column: YMC-Actus Triart C18 150*30mm; Mobile Phase A: Water (10mmol NH4HCO3), Mobile Phase B: CAN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 25% B in 10 min; Wave Length: 254 nm; RT1(min): 8). Lyophilization yielded tert- butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-8-[(1- methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate (11.6 mg, 10.97%) as an off-white solid. LC-MS: (M+H)+ found: 655.60.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.04 (s, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.81 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 3.90 (s, 5H), 3.16 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J = 11.0 Hz, 2H), 2.17 (s, 3H), 1.97 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H), 1.56 (d, J = 11.5, 10.9 Hz, 2H), 1.47 (s, 9H). Example 32. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl}-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8- diamine
Figure imgf000354_0001
A solution of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1- yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6- yl) carbamate (100 mg, 0.15 mmol, 1 equiv) in DCM (2 mL) and TFA (1 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 62 mL/min mL/min; Gradient: 71% B to 76% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford 2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}- N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine (5.9 mg, 6.95%) as yellow solid. LC-MS: (M+H)+ found: 565.20.1H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 6.2 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.49 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.28 (d, J = 6.3 Hz, 2H), 3.89 (s, 5H), 3.22 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.75 (d, J = 11.3 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.55 (t, J = 10.0 Hz, 2H). Example 33. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine
Figure imgf000355_0001
Step 1. Synthesis of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl)-N-methylcarbamate A mixture of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1- yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate (190 mg, 0.29 mmol, 1 equiv), K2CO3 (118 mg, 0.86 mmol, 3 equiv) and MeI (48.7 mg, 0.34 mmol, 1.2 equiv) in THF (10 mL) was stirred for 1 h at room temperature. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with EA (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 20% to 40% gradient in 10 min; detector, UV 220 nm) to afford tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1- yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl)-N- methylcarbamate (130 mg, 67.01%) as black oil. LC-MS: (M+H)+ found: 679.3. Step 2. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}- N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8- diamine A mixture of tert-butyl N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1- yn-1-yl}-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6- yl)-N-methylcarbamate (130 mg, 0.19 mmol, 1 equiv) in TFA (1.5 mL) and DCM (3 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was purified by Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 2-{3-[(4- methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin- 4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine (11.2 mg, 10.11%) as a brown solid. LC-MS: (M+H)+ found: 579.30.1H NMR (400 MHz, DMSO-d6) δ 7.39 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 5.94 – 5.81 (m, 1H), 4.82 (s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.90 (s, 5H), 3.67 – 3.38 (m, 6H), 3.13 (s, 3H), 3.10 (m, 5H), 3.07 (m, 1H), 2.30 – 1.83 (m, 4H). Example 34. Synthesis of N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-6-phenyl-3-(2,2,2-trifluoroethyl)imidazo [1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine, formic acid salt
Figure imgf000356_0001
A mixture of N-(6-bromo-2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.15 mmol, 1 equiv), phenyl boronic acid (29 mg, 0.23 mmol, 1.50 equiv), Pd(dppf)Cl2.CH2Cl2 (13 mg, 0.02 mmol, 0.10 equiv) and K2CO3 (65 mg, 0.48 mmol, 3 equiv) in dioxane (2 mL) and H2O (0.5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 24% B to 28% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.8). Lyophilization yielded N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}- 6-phenyl-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine; formic acid (8.4 mg, 7.86%) as an off-white solid. LC-MS: (M+H+) found: 626.25.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.73 – 7.68 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (dd, J = 8.1, 1.9 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.51 – 6.45 (m, 2H), 5.83 (d, J = 8.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 – 4.09 (m, 2H), 3.91 (s, 3H), 3.57 – 3.51 (m, 1H), 3.11 (s, 3H), 2.75 (d, J = 11.5 Hz, 2H), 2.20 (s, 3H), 2.10 (t, J = 11.3 Hz, 2H), 1.92 (d, J = 12.2 Hz, 2H), 1.65 – 1.57 (m, 2H). Example 35. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000357_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-methylbenzamide A mixture of N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 13; 200 mg, 1.06 mmol, 1 equiv), i-Pr2NH (1.08 g, 10.63 mmol, 10 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 430 mg, 1.06 mmol, 1 equiv), Pd(PhP3)4 (246 mg, 0.21 mmol, 0.2 equiv) and CuI (202 mg, 1.06 mmol, 1 equiv) in DMSO (2 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (30:1) to afford 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop- 2-yn-1-yl}amino)-N-methylbenzamide (309 mg, 62.50%) as a brown solid. LC-MS: (M+H)+ found 467.15. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-N-methylbenzamide (60 mg, 0.13 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine.HCl (29 mg, 0.14 mmol, 1.1 equiv), t-BuONa (50 mg, 0.52 mmol, 4 equiv) and di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane; {2'-amino-[1,1'- biphenyl]-2-yl}palladio methanesulfonate (10 mg, 0.01 mmol, 0.1 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 63% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.55; Number Of Runs: 3) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (6.2 mg, 9.28%) as a white solid. LC-MS: (M+H)+ found 517.30.1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.70 – 7.61 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 – 6.66 (m, 2H), 6.59 (t, J = 6.1 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.80 – 3.65 (m, 1H), 3.03 – 3.00 (m, 1H), 2.77 – 2.72 (m, 4H), 2.32 – 2.19 (m, 4H), 2.14 – 2.05 (m, 1H), 1.88 – 1.75 (m, 2H). Example 36. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N- methylbenzamide
Figure imgf000358_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 400 mg, 0.99 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 258.7 mg, 1.19 mmol, 1.2 equiv), Pd(PPh3)4 (228.3 mg, 0.20 mmol, 0.2 equiv), i-Pr2NH (1 g, 9.88 mmol, 10 equiv) and CuI (188 mg, 0.99 mmol, 1 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford 4-({3-[8-bromo- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N- methylbenzamide (400 mg, 81.76%) as a brown solid. LC-MS: (M+H)+ found 495.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-methoxy-N-methylbenzamide (300 mg, 0.61 mmol, 1 equiv), (3S,4R)-3-fluoro- 1-methylpiperidin-4-amine dihydrochloride (248.46 mg, 1.212 mmol, 2 equiv), t-BuONa (291 mg, 3.03 mmol, 5 equiv) and tBuXphos Pd G3 (144.3 mg, 0.18 mmol, 0.3 equiv) in THF (3 mL) was stirred for 1h at 70°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH 15:1) and Prep-HPLC (Column: Xcelect CSH F-pheny OBD Column 30*150 mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 13% B to 25% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.3) to afford 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl]amino}3-methoxy-N-methylbenzamide (42.5 mg, 12.84%) as a white solid. LC-MS: (M+H)+ found 547.25.1H NMR (400 MHz, DMSO-d6) δ 8.26 – 8.03 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.1, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.71 – 4.85 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.02 (m 2H), 3.84 (s, 3H), 3.70 (d, J = 30.1 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 8.6 Hz, 1H), 1.79 (d, J = 5.6 Hz, 2H). Example 37 and 38. Synthesis of 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide (37) and 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide (38)
Figure imgf000360_0001
Step 1. Synthesis of 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-methoxy-N-methylbenzamide (150 mg, 0.30 mmol, 1 equiv), 3,3-difluoro-1- methylpiperidin-4-amine dihydrochloride (75 mg, 0.33 mmol, 1.1 equiv), BrettPhos Pd G4 (28 mg, 0.03 mmol, 0.1 equiv), RuPhos (29 mg, 0.06 mmol, 0.20 equiv) and Cs2CO3 (395 mg, 1.21 mmol, 4 equiv) in dioxane (4.5 mL) was stirred overnight at 95°C under argon atmosphere. The resulting mixture was diluted with EA (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (99:1) to afford 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (75 mg, 43.87%) as a light yellow solid. LC-MS: (M+H)+ found 565.2. Step 2. Chiral Separation The crude product 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (75 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAKIC-34.6*50mm, 3.0um; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1: 1)=65: 35; Gradient: isocratic; Injection Volume: 3.0L mL) to afford two fractions: A; (Peak 1): assigned as 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (17.9 mg, 23.58%) as a white solid. LC-MS: (M+H)+ found 565.20.1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J = 8.2, 5.6 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.6 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.60 – 3.52 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.89 (m, 1H), 1.71 – 1.68 (m, 1H). B; (Peak 2): assigned as 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (16.5 mg, 21.78%) as a white solid. LC-MS: (M+H)+ found 565.20.1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J = 8.3, 5.7 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.7 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.64 – 3.49 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.95 (m, 1H), 1.71 – 1.68 (m, 1H). Example 39. Synthesis of tert-butyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate
Figure imgf000361_0001
Step 1. Synthesis of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2- trifluoroethyl) imidazo [1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (Intermediate 14; 2.9 g, 13.29 mmol, 1.1 equiv), Diisopropylamine (12.22 g, 120.79 mmol, 10 equiv), N-[6-bromo- 2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-8-yl]-1-methylpiperidin-4-amine (6.25 g, 12.08 mmol, 1 equiv), Pd(PPh3)4 (5.58 g, 4.83 mmol, 0.4 equiv) and CuI (2.29 g, 12.08 mmol, 1 equiv) in DMSO (60 mL) was stirred for 1 h at room temperature. The resulting mixture was quenched with water (400 mL) and extracted with EtOAc (3*400 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, 0.1% TFA in water 30% to 50% gradient in 10 min; detector, UV 220 nm) to afford desired compound 4-[(3-{6-bromo-8-[(1-methylpiperidin-4- yl) amino]-3-(2,2,2-trifluoroethyl) imidazo [1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3- methoxy-N-methylbenzamide (5.3 g, 72.23%) as an off-white soild. LC-MS: (M+H)+ found:607.0. Step 2. Synthesis of tert-butyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 equiv), BocNH2 (96.4 mg, 0.83 mmol, 5 equiv), t-BuONa (47.5 mg, 0.50 mmol, 3 equiv), tBuXPhos Pd G3 (13.1 mg, 0.02 mmol, 0.1 equiv) in THF (3 mL) was stirred for 1 h at 60°C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (Column: YMC-Actus Triart C18 150*30mm; Mobile Phase A: Water (10mmol NH4HCO3), Mobile Phase B: CAN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 25% B in 10 min; Wave Length: 254 nm; RT1(min): 8) to afford tert-butyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8- [(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate (10.3 mg, 9.72%) as an off-white solid. LC-MS: (M+H)+ found: 644.35. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.14 – 7.99 (m, 2H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.95 (t, J = 6.3 Hz, 1H), 5.82 (d, J = 7.9 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.93 (m, 2H), 3.84 (s, 3H), 3.24 – 3.11 (m, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.03 – 1.93 (m, 2H), 1.89 (d, J = 12.5 Hz, 2H), 1.67 – 1.52 (m, 2H), 1.47 (s, 9H). Example 40. Synthesis of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl) amino]-3- (2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide
Figure imgf000363_0001
To a solution of tert-butyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate (100 mg, 0.16 mmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL) dropwise. The solution was stirred for 1 h at room temperature, then concentrated in vacuo. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 24% B to 28% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.8) to afford 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2- trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide (18.8 mg, 22.26%) as a yellow solid. LC-MS: (M+H)+ found:544.25.1H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.47 – 7.31 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.04 – 5.86 (m, 2H), 5.53 (d, J = 8.1 Hz, 1H), 4.76 (s, 2H), 4.23 (dd, J = 10.5, 6.2 Hz, 2H), 3.94 – 3.75 (m, 5H), 3.24 (d, J = 9.6 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.14 (d, J = 56.4 Hz, 5H), 1.90 (d, J = 13.0 Hz, 2H), 1.72 – 1.50 (m, 2H). Example 41. Synthesis of 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide
Figure imgf000364_0001
To a stirred solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (100 mg, 0.18 mmol, 1 equiv), DIEA (119 mg, 0.92 mmol, 5 equiv) and AcOH (16.6 mg, 0.28 mmol, 1.5 equiv) in DMF (2 mL) was added and HATU (105 mg, 0.28 mmol, 1.5 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O (10 mL). The mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified using prep-HPLC with following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56. The crude product was further purified using prep-HPLC with following conditions: Column: JW-CHIRALPAK IG, 20*250mm, 5um; Mobile Phase A: EtOH: DCM=1: 2--HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 23.5min; Wave Length: 220/254 nm; RT1(min): 16.33; RT2(min): 20.6; Sample Solvent: EtOH: DCM=1: 1--HPLC; Sample concentration: mg/mL; Injection Volume: 0.5 mL; Number Of Runs: 4. This resulted in 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (11.9 mg, 11.05%) as a white solid. LC-MS: (M+H)+ found: 586.25.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.37 (s, 1H), 8.15 – 8.08 (m, 1H), 7.46 – 7.38 (m, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.17 (d, J = 1.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.84 (s, 3H), 3.23 (d, J = 10.4 Hz, 1H), 2.80 (d, J = 11.3 Hz, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 2.11 – 2.01 (m, 5H), 1.94 – 1.86 (m, 2H), 1.68 – 1.55 (m, 2H). Example 42. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4- yl)amino]-6-(prop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2- yn-1-yl)amino]benzamide
Figure imgf000365_0001
To a mixture of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (100 mg, 0.18 mmol, 1.0 equiv), acrylic acid (20 mg, 0.27 mmol, 1.5 equiv) and DIEA (119 mg, 0.92 mmol, 5.0 equiv) in DMF (1 mL) was added HATU (139 mg, 0.34 mmol, 2.0 equiv). After stirring for 1 h at room temperature, the mixture was quenched with water (10 mL), and the aqueous phase was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 45% B to 49% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 5.9) to afford 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(prop-2-enamido)- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide (8.2 mg, 7.46%) as an off-white solid. LC-MS: (M+H+) found: 598.45.1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.12-8.08 (m, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.05 (s, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.17-4.09 (m, 2H), 3.84 (s, 3H), 3.24 (t, J = 7.8 Hz, 2H), 3.16 (d, J = 9.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.56 (d, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.00 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.4 Hz, 2H), 1.63 – 1.52 (m, 2H). Example 13. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4- yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]benzamide, formic acid salt
Figure imgf000366_0001
A solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (120 mg, 0.22 mmol, 1.0 equiv), methacrylic acid (38 mg, 0.44 mmol, 2.0 equiv), HATU (125 mg, 0.33 mmol, 1.5 equiv) and DIEA (142 mg, 1.10 mmol, 5.0 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 3-methoxy- N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide; Formic acid (17 mg, 11.28%) as an off-white solid. LC-MS: (M+H+) found: 612.30.1H NMR (400 MHz, DMSO- d6) δ 9.69 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.44 – 7.34 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.06 – 5.94 (m, 2H), 5.78 (d, J = 8.0 Hz, 1H), 4.30 – 4.04 (m, 4H), 3.85 (s, 3H), 3.44 (dd, J = 16.2, 6.9 Hz, 2H), 3.18 (s, 1H), 2.88 (dd, J = 16.1, 10.8 Hz, 1H), 2.76 (d, J = 4.4 Hz, 4H), 2.65 – 2.57 (m, 1H), 2.20 (s, 3H), 2.03 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.16 (d, J = 6.9 Hz, 3H). Example 43. Synthesis of 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1- methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-ylamino)-3-methoxy-N-methylbenzamide, formic acid salt
Figure imgf000367_0001
To a solution of 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1 equiv), chlorofluoroacetic acid (29.8 mg, 0.27 mmol, 1.2 equiv) and DIEA (143 mg, 1.11 mmol, 5 equiv) in DMF (3 mL) was added HATU (100 mg, 0.27 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred for 1 h at room temperature, then diluted with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 19% B to 29% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 9.15) to afford 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1- methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1- ylamino)-3-methoxy-N-methylbenzamide; formic acid (20.9 mg, 13.65%) as a yellow solid. LC- MS: (M+H)+ found: 638.25.1H NMR (400 MHz, DMSO-d6) δ 10.65 (d, J = 6.7 Hz, 1H), 9.36 (s, 1H), 8.38 – 8.23 (m, 1H), 8.18 – 8.04 (m, 1H), 7.48 – 7.30 (m, 2H), 6.93 (d, J = 48.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.48 – 6.28 (m, 2H), 5.98 (s, 1H), 4.28 (s, 2H), 4.10 – 3.93 (m, 2H), 3.85 (s, 3H), 3.78 – 3.50 (m, 3H), 3.30 – 2.99 (m, 2H), 2.77 (dd, J = 12.6, 4.0 Hz, 6H), 2.20 – 2.05 (m, 2H), 2.02 – 1.72 (m, 2H). Example 44. Synthesis of 3-methoxy-N-methyl-4-[(3-{6-[(methylcarbamoyl)amino]-8- [(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop- 2-yn-1-yl) amino] benzamide
Figure imgf000368_0001
A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide (200 mg, 0.33 mmol, 1 equiv), methylurea (48.8 mg, 0.66 mmol, 2 equiv), XantPhos (38.1 mg, 0.07 mmol, 0.2 equiv), Cs2CO3 (321.8 mg, 0.99 mmol, 3 equiv) and Pd2(dba)3 (30.2 mg, 0.03 mmol, 0.1 equiv) in dioxane (10 mL) was stirred for 16 h at 100°C.The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL/min mL/min; Gradient: 71% B to 76% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9). to afford 3-methoxy-N-methyl-4-[(3-{6-[(methylcarbamoyl)amino]-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino] benzamide (12.7 mg, 6.42%) as off-white solid. LC-MS: (M+H)+ found: 601.45. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.26 – 7.95 (m, 2H), 7.59 – 7.28 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.26 – 5.88 (m, 3H), 5.75 (d, J = 8.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (m, 5H), 3.28 – 3.14 (m, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.64 (d, J = 4.5 Hz, 3H), 2.17 (s, 3H), 2.03 – 1.83 (m, 4H), 1.71 – 1.49 (m, 2H). Example 45. Synthesis of methyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate
Figure imgf000368_0002
A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 equiv), methyl carbamate (61.8 mg, 0.83 mmol, 5 equiv), t-BuONa (47.5 mg, 0.50 mmol, 3 equiv) and tBuXPhos Pd G3 (13.1 mg, 0.02 mmol, 0.1 equiv) in THF (5 mL) was stirred for 1 h at 65°C. The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL/min mL/min; Gradient: 71% B to 76% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford methyl N-[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-8- [(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate (15.5 mg, 15.65%) as an off-white solid. LC-MS: (M+H)+ found: 602.15.1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.22 – 7.99 (m, 2H), 7.48 – 7.25 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 1.6 Hz, 1H), 6.01 – 5.81 (m, 2H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (s, 5H), 3.67 (s, 3H), 3.18 (dd, J = 12.4, 7.7 Hz, 1H), 2.76 (t, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.06 – 1.81 (m, 4H), 1.66 – 1.50 (m, 2H). Example 46. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N,N-dimethylbenzamide
Figure imgf000369_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide To a stirred solution of 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (3 mL) were added 3-methoxy-N,N- dimethyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 15; 11.8 mg, 0.05 mmol, 2 equiv), CuI (47.0 mg, 0.25 mmol, 0.50 equiv), i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv) and Pd(PPh3)4 (34.7 mg, 0.03 mmol, 0.20 equiv). The resulting mixture was stirred for 1 h at 30°C under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N- dimethylbenzamide (96.0 mg, 43.60%) as a light yellow oil. LC-MS: (M+H)+ found 510.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N- dimethylbenzamide To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide (100.0 mg, 0.20 mmol, 1 equiv) in THF (10 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (51.9 mg, 0.39 mmol, 2 equiv), t-BuONa (113.2 mg, 1.18 mmol, 6 equiv) and tBuXPhosPdG3 (62.4 mg, 0.08 mmol, 0.40 equiv) in portions at room temperature. The resulting mixture was stirred for 30 min at 65°C under nitrogen atmosphere. After removal of solvent, the residue was purified by PTLC (CH2Cl2 / MeOH 20:1) to give a crude, followed by prep-HPLC with the conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 49% B to 72% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.43; Number Of Runs: 3. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N- dimethylbenzamide (8.30 mg, 7.54%) as a white solid. LC-MS: (M+H)+ found 561.35.1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 6.95-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.79-6.72 (m, 1H), 6.45-6.35 (m, 1H), 5.85 (s, 1H), 4.81 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 4.15-3.92 (m, 2H), 3.83 (s, 3H), 3.79 (d, 1H), 3.16 (s, 1H), 2.94 (s, 2H), 2.80-2.71 (m, 1H), 2.55-2.45 (m, 1H), 2.21-2.15 (m, 3H), 2.10 (s, 1H), 1.89-1.71 (m, 1H). Example 47. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxybenzamide
Figure imgf000371_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (5 mL) were added N-ethyl-3- methoxy-4-(prop-2-yn-1-ylamino) benzamide (Intermediate 16; 229.4 mg, 0.98 mmol, 2 equiv), i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv) and CuI (47.0 mg, 0.25 mmol, 0.50 equiv). The reaction mixture was stirred for 1h at 30°C under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (250.0 mg, 99.4%) as a light yellow solid. LC-MS: (M+H)+ found 509.1. Step 2. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop- 2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (200.0 mg, 0.39 mmol, 1 equiv) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (103.8 mg, 0.79 mmol, 2 equiv), t- BuONa (226.4 mg, 2.36 mmole, 6 equiv) and tBuXPhosPdG3 (124.8 mg, 0.16 mmol, 0.40 equiv). The reaction mixture was stirred for 30min at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude was purified using Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 67% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 10.07. This resulted in N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-3-methoxybenzamide (6.50 mg, 2.8%) as a brown solid. LC-MS: (M+H)+ found 561.20. 1H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.69 (m, 2H), 6.13 (d, J = 7.5 Hz, 1H), 5.99 (s, 1H), 5.45 (d, J = 9.2 Hz, 1H), 4.91 (s, 1H), 4.79 (s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.63 (m, 2H), 3.48 (m, 3H), 3.20 (d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.5 Hz, 1H), 2.35 (s, 3H), 2.27-2.13 (m, 2H), 1.98 (m, 2H), 1.34-1.13 (t, J = 7.3 Hz, 3H). Example 48. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3- methoxybenzamide
Figure imgf000372_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 438.4 mg, 1.08 mmol, 1 equiv) in DMSO (5 mL) were added N-isopropyl-3- methoxy-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 16; 293.3 mg, 1.19 mmol, 1.10 equiv), CuI (103.1 mg, 0.54 mmol, 0.50 equiv), i-Pr2NH (75.0 mg, 0.74 mmol, 10 equiv) and Pd(PPh3)4 (17.1 mg, 0.02 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 30°C for 1h under nitrogen atmosphere, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3- methoxybenzamide (240.0 mg, 42.36%) as a light yellow solid. LC-MS: (M+H)+ found 523.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3- methoxybenzamide To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop- 2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide (180.0 mg, 0.34 mmol, 1 equiv) in THF (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (141.1 mg, 0.69 mmol, 2 equiv), t-BuXPhosPdG3 (43.7 mg, 0.06 mmol, 0.16 equiv) and t-BuONa (264.4 mg, 2.75 mmol, 8 equiv). The reaction mixture was stirred at 65°C for 30 min under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 30% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 52% B to 72% B in 10min; Wave Length: 254nm/220nm nm; RT (min): 9.65) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3- methoxybenzamide (10.5 mg, 5.08%) as a white solid. LC-MS: (M+H)+ found 575.20.1H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J = 15.8, 7.3 Hz, 2H), 7.47-7.32 (m, 2H), 6.85-6.70 (m, 2H), 6.38 (d, J = 7.5 Hz, 1H), 5.91 (t, J = 6.4 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.14-3.96 (m, 3H), 3.85 (s, 3H), 3.77-3.63 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.42-1.99 (m, 5H), 1.89-1.75 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H). Example 49. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-3-methoxybenzamide
Figure imgf000374_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (10 mL) were added N-cyclopropyl- 3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 18; 241.3 mg, 0.99 mmol, 2 equiv), iPr2NH (499.8 mg, 4.94 mmol, 10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv) and CuI (47.0 mg, 0.25 mmol, 0.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 30 °C under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 50% B in 20 min; 254/220 nm). This resulted in 4-({3- [8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N- cyclopropyl-3-methoxybenzamide (215.0 mg, 83.5%) as a yellow solid. LC-MS: (M+H)+ found 522.9. Step 2. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxybenzamide To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide (185.0 mg, 0.36 mmol, 1 equiv) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (93.8 mg, 0.71 mmol, 2 equiv), t-BuONa (204.6 mg, 2.13 mmol, 6 equiv) and tBuXPhosPdG3 (112.8 mg, 0.14 mmol, 0.40 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 65°C under nitrogen atmosphere, then cooled down to room temperature and concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 50% B in 20 min; 254/220 nm). The crude was purified using Prep-HPLC with the following conditions (Column, Xbridge BEH Shield RP18 5μm, 19*250mm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 67% B to 75% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 10.58). This resulted in N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl]amino}-3-methoxy benzamide (16.2 mg,7.9 %) as a white solid. LC-MS: (M+H)+ found 573.20.1H NMR (400 MHz, Chloroform-d) δ 7.38-7.29 (m, 2H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.45 (d, J = 9.2 Hz, 1H), 5.00-4.65 (m, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.90 (s, 3H), 3.70-3.45 (m, 3H), 3.30-3.15 (m, 1H), 2.97-2.83 (m, 2H), 2.40-2.13 (m, 5H), 2.09-1.98 (m, 2H), 0.84 (td, J = 7.0, 5.2 Hz, 2H), 0.64-0.55 (m, 2H). Example 50. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1- carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]- 1-methylpiperidin-4-amine
Figure imgf000375_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline To a stirred solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline (Intermediate 19; 800.0 mg, 3.10 mmol, 1 equiv) in DMSO (15 mL) were added 8-bromo-2-iodo- 3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine (Intermediate 1; 627.1 mg, 1.55 mmol, 0.5 equiv), i-Pr2NH (1.57 g, 15.49 mmol, 5 equiv), CuI (147.5 mg, 0.77 mmol, 0.25 equiv) and Pd(PPh3)4 (715.8 mg, 0.62 mmol, 0.2 equiv). The reaction mixture was stirred at 30°C for 1 h, then purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford N- {3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4- (pyrrolidine-1-carbonyl)aniline (700.0 mg, 42.2%) as a yellow oil. LC-MS: (M+H)+ found 535.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1- carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1- methylpiperidin-4-amine To a stirred solution of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (100 mg, 0.18 mmol, 1 equiv) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.8 mg, 0.37 mmol, 2 equiv), t-BuONa (107.7 mg, 1.122mmol, 6 equiv) and tBuXPhosPdG3 (59.4 mg, 0.08 mmol, 0.4 equiv). The reaction mixture was stirred at 65°C for 1 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude was purified using Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 72% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.38; Number Of Runs: 5) to afford (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4- (pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl]-1-methylpiperidin-4-amine (10.5 mg, 9.46%) as a white solid. LC-MS: (M+H)+ found 587.30.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.03 (m, 2H), 3.82 (s, 3H), 3.66 (t, J = 8.2 Hz, 1H), 3.61-3.38 (m, 4H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.40-1.98 (m, 5H), 2.00-1.57 (m, 6H). Example 51. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000377_0001
Step 1. Synthesis of 4-(azetidine-1-carbonyl)-N-{3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.50 mmol, 1 equiv) in DMSO (5 mL) was treated with 4-(azetidine- 1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 20; 132.7 mg, 0.54 mmol, 1.10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv), CuI (38.1 mg, 0.20 mmol, 0.40 equiv) and i- Pr2NH (499.8 mg, 4.95 mmol, 10 equiv). The resulting mixture was stirred for 1h at 30°C under N2 atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 4-(azetidine-1-carbonyl)-N-{3-[8- bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline (340.0 mg, 69.0%) as a light yellow solid. LC-MS: (M+H)+ found 521.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A solution of 4-{4-[4-bromo-1-(1,1,2,2,2-pentafluoroethyl)-7aH-inden-2-yl]but-3-yn-1- yl}-3-methoxy-N-methylbenzamide (100.0 mg, 0.20 mmol, 1 equiv) in THF (3 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.6 mg, 0.37 mmol, 2 equiv), t-BuONa (109.1 mg, 1.13 mmol, 6 equiv) and t-BuXPhosPdG3 (60.1 mg, 0.07 mmol, 0.40 equiv). The resulting mixture was stirred for 30 min at 65 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified using prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 54% B to 68% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.42; Number Of Runs: 6. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (11.5 mg, 10.43%) as a light yellow solid. LC-MS: (M+H)+ found 573.35.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, 1H), 4.52-4.19 (m, 4H), 4.02 (m, 4H), 3.83 (s, 3H), 3.77-3.63 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.32-2.18 (m, 3H), 2.19 (s, 3H), 2.09 (s, 1H), 1.88-1.75 (m, 2H). Example 52. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylpyridine-2-carboxamide
Figure imgf000378_0001
Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2- carboxamide (Intermediate 21; 168.2 mg, 0.89 mmol, 1.2 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i-Pr2NH (749.7 mg, 7.40 mmol, 10 equiv) and Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.2 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was diluted with EA (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1) to afford 5-({3-[8-bromo- 3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2- carboxamide (212 mg, 61.38%) as a light brown solid. LC-MS: (M+H)+ found 466.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2- carboxamide A solution of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-N-methylpyridine-2-carboxamide (200 mg, 0.43 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (176.0 mg, 0.86 mmol, 2 equiv), t-BuONa (206.1 mg, 2.15 mmol, 5 equiv) and tBuXPhos Pd G3 (102.2 mg, 0.13 mmol, 0.3 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN(1% 2mM NH3-MeOH); Flow rate: 25 mL/min mL/min; Gradient: 45% B to 64% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.27; Number Of Runs: 3) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylpyridine-2-carboxamide (10.1 mg, 4.50%) as a white solid. LC-MS: (M+H)+ found 518.15. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (q, J = 4.8 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 6.98 (t, J = 6.1 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 4.04 (q, J = 10.7 Hz, 2H), 3.78 – 3.62 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14 – 2.04 (m, 1H), 1.87 – 1.74 (m, 2H). Example 53. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-N-methyl-3- (trifluoromethoxy) benzamide
Figure imgf000380_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide A mixture of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide (Intermediate 22; 300 mg, 1.10 mmol, 1.30 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (Intermediate 1; 344 mg, 0.85 mmol, 1 equiv), i-Pr2NH (858 mg, 8.47 mmol, 10 equiv), CuI (162 mg, 0.84 mmol, 1 equiv) and Pd(PPh3)4 (392 mg, 0.33 mmol, 0.40 equiv) in DMSO (7 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was diluted with EtOAc (40 mL) and washed with brine (3*40 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=20:1) to afford 4-({3-[8-bromo- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3- (trifluoromethoxy)benzamide (300 mg, 59.60%) as a light yellow solid. LC-MS: (M+H)+ found 549.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2- trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-N-methyl-3- (trifluoromethoxy) benzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2- yn-1-yl} amino)-N-methyl-3-(trifluoromethoxy) benzamide (100 mg, 0.18 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (56 mg, 0.27 mmol, 1.50 equiv), BrettPhos Pd G4 (50 mg, 0.05 mmol, 0.30 equiv), RuPhos (51 mg, 0.10 mmol, 0.60 equiv) and Cs2CO3 (238 mg, 0.72 mmol, 4 equiv) in dioxane (4 mL) was stirred for 6 h at 100°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column: XBridge C18 OBD Prep Column, 100, 5 m, 19 mm X 250 mm; Mobile Phase A: water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 55% B in 7 min; Wave Length: 254 nm nm; RT1(min): 7. This resulted in 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop- 2-yn-1-yl] amino}-N-methyl-3-(trifluoromethoxy) benzamide (3.2 mg, 2.92%) as a white solid. LC-MS: (M+H)+ found 601.50.1H NMR (400 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.62 (dd, J = 8.5, 2.0 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.5 Hz, 2H), 5.54 (d, J = 8.8 Hz, 1H),5.44 (d, J = 8.8 Hz, 1H), 5.05 (s, 1H), 4.58 – 4.52 (m, 2H), 3.77-3.75 (m, 3H), 3.33 (s, 1H), 3.10 - 2.95 (m, 4H), 2.53 (s, 4H), 2.11 (s, 3H). Example 54. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3- (trifluoromethyl)benzamide
Figure imgf000381_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), N-methyl-4-(prop-2-yn-1-ylamino)-3- (trifluoromethyl)benzamide (Intermediate 23; 227.8 mg, 0.89 mmol, 1.2 equiv), i-Pr2NH (749.7 mg, 7.40 mmol, 10 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv) and Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.2 equiv) in DMSO (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) to afford 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (320 mg, 81.0%) as a brown yellow solid. LC-MS: (M+H)+ found 533.6. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3- (trifluoromethyl)benzamide A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (100 mg, 0.19 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (57.7 mg, 0.28 mmol, 1.50 equiv), t-BuONa (90.1 mg, 0.94 mmol, 5 equiv) and tBuXPhos Pd G3 (29.8 mg, 0.04 mmol, 0.2 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 52% B to 67% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.32; Number Of Runs: 3) to afford 4-{[3- (8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide (16.7 mg, 15.24%) as a off-white solid. LC-MS: (M+H)+ found 585.15.1H NMR (400 MHz, DMSO-d6) δ 8.39 – 8.27 (d, J = 4.7 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.84 – 7.76 (d, J = 6.8 Hz, 1H), 7.11 – 7.03 (d, J = 8.8 Hz, 1H), 6.89 – 6.79 (t, J = 7.2 Hz, 1H), 6.64 – 6.55 (t, J = 5.9 Hz, 1H), 6.44 – 6.34 (d, J = 7.6 Hz, 1H), 5.44 – 5.36 (d, J = 9.2 Hz, 1H), 4.93 – 4.72 (d, J = 49.4 Hz, 1H), 4.43 – 4.32 (d, J = 5.9 Hz, 2H), 4.11 – 3.94 (m, 2H), 3.81 – 3.60 (m, 1H), 3.11 – 2.95 (t, J = 11.5 Hz, 1H), 2.83 – 2.70 (d, J = 4.5 Hz, 4H), 2.37 – 2.15 (s, 4H), 2.15 – 2.03 (t, J = 10.8 Hz, 1H), 1.93 – 1.68 (dd, J = 8.1, 12.1 Hz, 2H). Example 55. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000383_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide A mixture of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 24; 400 mg, 1.80 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 606.2 mg, 150 mmol, 1 equiv), Pd(PPh3)4 (346.0 mg, 0.30 mmol, 0.2 equiv), CuI (285.1 mg, 1.50 mmol, 1 equiv) and i-Pr2NH (1.51 g, 14.97 mmol, 10 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide (354 mg, 47.32%) as a yellow oil. LC-MS: (M+H)+ found 499.1. Step 2. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-chloro-N-methylbenzamide (300 mg, 0.60 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (198.4 mg, 1.50 mmol, 2.5 equiv), t-BuONa (201.9 mg, 2.10 mmol, 3.5 equiv) and tBuXphos Pd G3 (190.8 mg, 0.24 mmol, 0.4 equiv) in THF (5 mL) was stirred for 1 h at 65 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 48% B to 67% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 10.8) to afford 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (32.1 mg, 9.65%) as a white solid. LC-MS: (M+H)+ found 551.20.1H NMR (400 MHz, DMSO- d6) δ 8.19 (d, J = 4.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.45 (t, J = 6.0 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.77 – 3.61 (m, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.19 (s, 5H), 1.79 (d, J = 5.6 Hz,2H). Example 56. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000384_0001
Step 1. Synthesis of tert-butyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate A mixture of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2-yn-1- yl)carbamate (Intermediate 25; 400 mg, 1.28 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 430.8 mg, 1.06 mmol, 1 equiv), Pd(PPh3)4 (245.9 mg, 0.21 mmol, 0.2 equiv), CuI (202.6 mg, 1.06 mmol, 1 equiv) and i-Pr2NH (1.07 g, 10.63 mmol, 10 equiv) in DMSO (2 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (2*50mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl N-{3-[8-bromo- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4- (methylcarbamoyl)phenyl]carbamate (350 mg, 55.73%) as a yellow oil. LC-MS: (M+H)+ found 590.1. Step 2. Synthesis of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl]carbamate A solution of tert-butyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (450 mg, 0.76 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (312.6 mg, 1.52 mmol, 2 equiv), t-BuONa (366.3 mg, 3.81 mmol, 5 equiv) and tBuXphos Pd G3 (181.64mg, 0.23 mmol, 0.3 equiv) in THF (5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) to afford tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl]carbamate (261 mg, 53.37%) as a brown oil. Step 3. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide To a stirred solution of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (220 mg, 0.34 mmol, 1 equiv) and 2,6-lutidine (183.7 mg, 1.72 mmol, 5 equiv) in DCM (2 mL) was added TMSOTf (381.0 mg, 1.72 mmol, 5 equiv) at 0°C. The mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 50% B to 69% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 9.52) to afford 3-cyano-4-{[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl]amino}-N-methylbenzamide (17.0 mg, 9.06%) as a white solid. LC-MS: (M+H)+ found 542.25.1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 4.8 Hz, 1H), 8.07 – 7.91 (m, 2H), 7.79 (d, J = 6.8 Hz, 1H), 7.17 (t, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.04 (m, 2H), 3.70 (s, 1H), 3.05 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.54 (s, 1H), 2.21 (s, 4H), 1.82 (d, J = 14.1 Hz, 2H). Example 57. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-N-methylbenzamide
Figure imgf000386_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), 3-cyclopropyl-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 26; 203.0 mg, 0.89 mmol, 1.2 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i-Pr2NH (749.7 mg, 7.41 mmol, 10 equiv) and Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.2 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was washed with 3*20 mL of water. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl) imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N- methylbenzamide (230 mg, 61.44%) as a brown oil. LC-MS: (M+H)+ found 505.0. Step 2. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide (200 mg, 0.40 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (162.4 mg, 0.80 mmol, 2 equiv), t-BuONa (190.2 mg, 2.00 mmol, 5 equiv) and tBuXphos Pd G3 (94.3 mg, 0.12 mmol, 0.3 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 50% B to 69% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 9.95) to afford 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide (20.5 mg, 9.11%) as a white solid. LC-MS: (M+H)+ found 557.20. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 6.86 – 6.71 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.15 (t, J = 6.1 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.79 – 3.61 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.72 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.12 – 2.02 (m, 1H), 1.89 – 1.73 (m, 2H), 1.67 (td, J = 8.3, 4.2 Hz, 1H), 0.97 – 0.84 (m, 2H), 0.60 – 0.48 (m, 2H). Example 58. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000387_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methyl benzamide A solution of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 27; 160.2 mg, 0.74 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 250 mg, 0.62 mmol, 1 equiv), CuI (117.6 mg, 0.62 mmol, 1 equiv), i-Pr2NH (624.7 mg, 6.17 mmol, 10 equiv) and Pd(PPh3)4 (214.0 mg, 0.19 mmol, 0.3 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was purified directly by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 10% to 80% gradient in 15min; detector, UV 254 nm) to afford 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-ethyl-N-methyl benzamide (170 mg, 55.82%) as a brown solid. LC-MS: (M+H)+ found 492.0. Step 2. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) prop-2-yn-1-yl]amino}-N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-ethyl-N-methylbenzamide (170 mg, 0.35 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (91.1 mg, 0.70 mmol, 2 equiv), t-BuONa (165.6 mg, 1.73 mmol, 5 equiv) and tBuXphos Pd G3 (82.1 mg, 0.10 mmol, 0.3 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 75% B in11min; Wave Length: 254nm/220nm nm; RT1(min): 9.95) to afford 3-ethyl- 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl) prop-2-yn-1-yl]amino}-N-methylbenzamide (36.2 mg, 19.14%) as a white solid. LC-MS: (M+H)+ found 544.50.1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.1 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.70 (m, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.73 (d, J = 4.5 Hz, 4H), 2.48 (s, 1H), 2.18 (s, 4H), 2.12 – 2.01 (m, 2H), 1.81 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Example 59. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-N- methylbenzamide
Figure imgf000389_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl} amino)-3-ethoxy-N-methylbenzamide A mixture of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 28; 400 mg, 1.72 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (697 mg, 1.72 mmol, 1 equiv), CuI (327 mg, 1.72 mmol, 1 equiv), Pd(PPh3)4 (796 mg, 0.69 mmol, 0.4 equiv) and bis(propan-2-yl) amine (1.74 g, 17.22 mmol, 10 equiv) in DMSO (10 mL) was stirred for 1 h at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 30% to 50% gradient in 10 min; detector, UV 220 nm) to afford 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl} amino)-3-ethoxy-N-methylbenzamide (400 mg, 45.61%) as a brown solid. LC-MS: (M+H+) found:509.1. Step 2. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-N- methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2- yn-1-yl} amino)-3-ethoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 equiv), (3S,4R)-3-fluoro- 1-methylpiperidin-4-amine (77.9 mg, 0.59 mmol, 1.5 equiv), t-BuONa (188 mg, 1.96 mmol, 5 equiv) and tBuXPhos Pd G3 (31.2 mg, 0.04 mmol, 0.1 equiv) in THF (5 mL) was stirred for 1 h at 65°C. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 30% to 50% gradient in 10 min; detector, UV 220 nm to afford the crude product (85% purity), then further purified by Pre-HPLC (Column: XBridge C18 OBD Prep Column, 100, 5 m, 19 mm X 250 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 50% B in 7 min; Wave Length: 254 nm nm; RT1(min): 7) to afford 3- ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-N-methylbenzamide (8.1 mg, 3.68%) as a off-white solid. LC-MS: (M+H)+ found: 561.40.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.86 (t, J = 6.4 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 4.14 – 3.96 (m, 4H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.39 – 2.27 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.81 (dd, J = 12.1, 8.1 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). Example 60. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-N-methylbenzamide
Figure imgf000390_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide Into a 5 mL sealed tube were added 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 29; 100 mg, 0.39 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 160 mg, 0.39 mmol, 1 equiv), Pd(PPh3)4 (91 mg, 0.08 mmol, 0.2 equiv), CuI (75 mg, 0.39 mmol, 1 equiv), i-Pr2NH (398 mg, 3.93 mmol, 10 equiv) and DMSO (2 mL) at room temperature. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3*40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N- methylbenzamide (110 mg, 52.64%) as a yellow solid. LC-MS: (M+H)+ found 533.1. Step 2. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide Into a 10 mL sealed tube were added 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 1.1 equiv), BrettPhos Pd G4 (58 mg, 0.04 mmol, 0.2 equiv), RuPhos (35 mg, 0.08 mmol, 0.4 equiv), Cs2CO3 (245 mg, 0.75 mmol, 4 equiv) and dioxane (3 mL) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3*20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1)+0.2% NH3·H2O to afford 40 mg crude product, then further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 3- (difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (15.2 mg, 13.68%) as a white solid. LC-MS: (M+H)+ found 583.45.1H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.13 (t, J = 74.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.39 (dd, J = 7.0, 3.9 Hz, 2H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.8 Hz, 1H), 4.30 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.85 – 3.57 (m, 1H), 3.10 – 2.96 (m, 1H), 2.83 – 2.65 (m, 4H), 2.35 – 2.20 (m, 1H), 2.19 (s, 3H), 2.11 – 2.06 (m, 1H), 1.89 – 1.70 (m, 2H). Example 61. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2- trifluoroethoxy)benzamide
Figure imgf000392_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy) benzamide A solution of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (Intermediate 30; 200 mg, 0.70 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 424 mg, 1.05 mmol, 1.5 equiv), DIEA (90 mg, 0.70 mmol, 1 equiv), CuI (133 mg, 0.70 mmol, 1 equiv) and Pd(PPh3)4 (161 mg, 0.14 mmol, 0.2 equiv) in DMSO (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2- trifluoroethoxy) benzamide (213 mg, 37.34%) as a brown yellow solid. LC-MS: (M+H)+ found 563.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2- trifluoroethoxy)benzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (50 mg, 0.09 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20 mg, 0.10 mmol, 1.1 equiv), tBuXPhos Pd G3 (7 mg, 0.009 mmol, 0.1 equiv) and t-BuONa (34 mg, 0.36 mmol, 4 equiv) in THF (1.5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with CH2Cl2 (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford crude product. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 51% B to 73% B in 11min; Wave Length: 254nm/220nm nm; RT1(min): 10.75) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2- trifluoroethoxy)benzamide (3.2 mg, 5.85%) as a white solid. LC-MS: (M+H)+ found 615.20.1H NMR (400 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.53 – 7.38 (m, 2H), 6.89 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 5.87 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.92 – 4.68 (m, 3H), 4.31 (d, J = 6.3 Hz, 2H), 4.02 (m, 2H), 3.76 – 3.62 (m, 1H), 3.09 – 2.96 (m, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.30 – 2.18 (m, 4H), 2.12 – 2.07 (m, 1H), 1.83 – 1.77 (m, 2H). Example 62. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2- methoxyethoxy)-N-methylbenzamide
Figure imgf000393_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a] pyridine-2- yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200 mg, 0.49 mmol, 1 equiv), 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 31; 156 mg, 0.59 mmol, 1.2 equiv), CuI (94 mg, 0.49 mmol, 1 equiv), i-Pr2NH (500 mg, 4.94 mmol, 10 equiv) and Pd(PPh3)4 (114 mg, 0.10 mmol, 0.2 equiv) in DMSO (2 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3*10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 20:1) to afford 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a] pyridine-2-yl]prop-2-yn-1- yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide (188 mg, 65.64%) as a yellow solid. LC- MS: (M+H)+ found 539.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N- methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl} amino)-3-(2-methoxyethoxy)-N-methylbenzamide (84 mg, 0.16 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (35 mg, 0.17 mmol, 1.1 equiv), RuPhos (10.2 mg, 0.02 mmol, 0.14 equiv), Cs2CO3 (203.0 mg, 0.62 mmol, 4 equiv) and Brettphos Pd G4 (17 mg, 0.01 mmol, 0.07 equiv) in dioxane (1.5 mL) was stirred overnight at 95°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 44% B to 69% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.9; Number Of Runs: 3) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N- methylbenzamide (6.3 mg, 6.78%) as a white solid. LC-MS: (M+H)+ found 591.35.1H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.39 (d, J = 9.1 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 4.14 (t, J = 4.6 Hz, 2H), 4.02 (m, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.02 (t, J = 10.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.35 – 2.04 (m, 5H), 1.91 – 1.69 (m, 2H). Example 63. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxybenzenesulfonamide
Figure imgf000395_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl}) benzenesulfonamide A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 50 mg, 0.12 mmol, 1 equiv), 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2- (trimethylsilyl)ethoxy]methyl})benzenesulfonamide (Intermediate 32; 74.2 mg, 0.15 mmol, 1.2 equiv), CuI (23.5 mg, 0.12 mmol, 1 equiv), i-Pr2NH (124.9 mg, 1.23 mmol, 10 equiv) and Pd(PPh3)4 (28.5 mg, 0.025 mmol, 0.2 equiv) in DMSO (2 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EA (50 mL) and washed with water (8*50 mL). The residue was purified by Prep-TLC (PE / EA 1:1) to afford 4- ({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3- methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl}) benzenesulfonamide (63 mg, 65.60%) as a brown oil. LC-MS: (M+H)+ found 777.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2- (trimethylsilyl)ethoxy]methyl}) benzenesulfonamide 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1- yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (200 mg, 0.26 mmol, 1 equiv), (3S,4R)-4-ammonio-3-fluoro-1-methylpiperidin-1-ium (69.0 mg, 0.51 mmol, 2 equiv), t-BuONa (98.8 mg, 1.03 mmol, 4 equiv) and tBuXphos Pd G3 (102.1 mg, 0.13 mmol, 0.5 equiv) were dissolved in THF (3 mL). The resulting mixture was stirred at 65 oC for 1h, then cooled down to room temperature, diluted with ethyl acetate (30 mL) and washed with 3*30 mL of brine. The resulting mixture was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2- (trimethylsilyl)ethoxy]methyl}) benzenesulfonamide (90 mg, 42.22%) as a white solid. LC-MS: (M+H)+ found 829.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2, 2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(tri methylsilyl) ethoxy]methyl})benzenesulfonamide (90 mg, 0.11 mmol, 1 equiv) in CH2Cl2 (2 mL) was added CF3COOH (1 mL). The resulting solution was stirred at room temperature for 1h, the n basified to pH 8 with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3*5 m L). The combined organic layers were dried with anhydrous sodium sulfate and concentrated und er vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 45% B to 60% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.75; Number Of Runs: 4) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1 -methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl] amino}-3-methoxybenzenesulfonamide (8.9 mg, 14.39%) as a white solid. LC-MS: (M+H)+ foun d 569.15.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.7 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1H), 6.99 (s, 2H), 6.87 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.20 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.88 – 4.75 ((d, J = 12.9 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2 H), 4.14 – 3.99 (m, 2H), 3.85 (s, 3H), 3.75 – 3.63 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 20.9, 4.5 Hz, 1H), 1.80 (dd, J = 12.1, 8.3 Hz, 2H). Example 64. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzenesulfonamide
Figure imgf000397_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2- (trimethylsilyl)ethoxy]methyl} benzenesulfonamide (Intermediate 33; 284.9 mg, 0.74 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i-Pr2NH (749.7 mg, 7.41 mmol, 10 equiv), and Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.2 equiv) in DMSO (2 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (230 mg, 46.93%) as a white solid. LC-MS: (M+H)+ found 661.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (100 mg, 0.15 mmol, 1 equiv), (3S,4R)-4-ammonio-3-fluoro-1-methylpiperidin-1-ium (40.6 mg, 0.30 mmol, 2 equiv), t-BuONa (58.1 mg, 0.60 mmol, 4 equiv) and tBuXphos Pd G3 (36.0 mg, 0.045 mmol, 0.3 equiv) in THF (1 mL) was stirred at 65 oC for 1h. The mixture was allowed to cool down to room temperature, then concentrated under vacuum. The residue was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (80 mg, 74.25%) as a brown solid. LC-MS: (M+H)+ found 713.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzenesulfonamide To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl- N-{[2-(trimethylsilyl)ethoxy] methyl}benzenesulfonamide (130 mg, 0.18 mmol, 1 equiv) in CH2Cl2 (2 mL) was added CF3COOH (1 mL) dropwise at room temperature. The resulting solution was stirred for 0.5 h, then basified to pH 8 with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzenesulfonamide (11.0 mg, 10.34%) as a white solid. LC-MS: (M+H)+ found 583.20. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 8.3, 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.05 (m, 1H), 6.87 – 6.79 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.32 (t, J = 6.2 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.88 (d, J = 11.2, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.06 – 4.01 (m, 2H), 3.86 (s, 3H), 3.79 – 3.58 (m, 1H), 3.04 (s, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.35 (d, J = 5.2 Hz, 4H), 2.19 (s, 3H), 2.11 (s, 1H), 1.79 (s, 2H). Example 65. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}- 3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N- dimethylbenzenesulfonamide
Figure imgf000398_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl} amino)-3-methoxy-N, N-dimethylbenzenesulfonamide A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (Intermediate 1; 150 mg, 0.37 mmol, 1.0 equiv), 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1- ylamino) benzenesulfonamide (Intermediate 34; 127.2 mg, 0.47 mmol, 1.3 equiv), i-Pr2NH (374.8 mg, 3.70 mmol, 10 equiv), CuI (70.5 mg, 0.37 mmol, 1.0 equiv) and Pd(PPh3)4 (214.0 mg, 0.18 mmol, 0.5 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water (10mmol/L NH4HCO3), 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 4-({3-[8-bromo-3- (2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl} amino)-3-methoxy-N, N- dimethylbenzenesulfonamide (120 mg, 59.41%) as a white solid. LC-MS: (M+H)+ found 545.05. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2- trifluoroethyl) imidazo[1,2-a] pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N- dimethylbenzenesulfonamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2- yn-1-yl} amino)-3-methoxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.22 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (90.2 mg, 0.44 mmol, 2 equiv), t- BuONa (126.8 mg, 1.32 mmol, 6.0 equiv) and tBuXPhos Pd G3 (87.4 mg, 0.11 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 15:1) and Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 57% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.88) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N- dimethylbenzenesulfonamide (13 mg, 9.85%) as a white solid. LC-MS: (M+H)+ found 597.30.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.45 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 2H), 3.85 (s, 3H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.56 (s, 6H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.00 (m, 1H), 1.86 – 1.72 (m, 2H). Example 66. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]- 3-fluoro-1-methylpiperidin-4-amine
Figure imgf000400_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2- yl]prop-2-yn-1-yl}-4-(ethanesulfonyl)-2-methoxyaniline A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (Intermediate 1; 150 mg, 0.37 mmol, 1.0 equiv), 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline (Intermediate 36; 150.1 mg, 0.59 mmol, 1.2 equiv), Pd(PPh3)4 (119.9 mg, 0.10 mmol, 0.2 equiv), CuI (93.1 mg, 0.49 mmol, 1.0 equiv) and i-Pr2NH (500 mg, 4.94 mmol, 10.0 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was purified directly by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water (10mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford N-{3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl]prop-2-yn-1-yl}-4-(ethanesulfonyl)-2-methoxyaniline (189 mg, 72.1%) as a yellow solid. LC-MS: (M+H)+ found 530.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4- amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-(ethanesulfonyl)-2-methoxyaniline (189 mg, 0.36 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (150 mg, 0.73 mmol, 2.0 equiv), t-BuONa (205.5 mg, 2.14 mmol, 6 equiv) and tBuXphos Pd G3 (141.5 mg, 0.18 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/7 M NH3 in MeOH = 20:1) and Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 49% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.95; Number Of Runs: 3) to afford (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3- fluoro-1-methylpiperidin-4-amine (38.9 mg, 18.73%) as a white solid. LC-MS: (M+H)+ found 582.20.1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.93 – 6.72 (m, 2H), 6.56 – 6.34 (m, 2H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 2H), 3.89 (s, 3H), 3.81 – 3.57 (m, 1H), 3.16 (m, 2H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 3.9 Hz, 1H), 1.87 – 1.71 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 67. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]- 3-fluoro-1-methylpiperidin-4-amine
Figure imgf000401_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline A mixture of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 37; 294.8 mg, 1.11 mmol, 1.5 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i-Pr2NH (749.7 mg, 7.40 mmol, 10 equiv) and Pd(PPh3)4 (171.22 mg, 0.15 mmol, 0.2 equiv) in DMSO (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 20:1) to afford N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1- yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (500 mg) as a brown solid. LC-MS: (M+H)+ found 542.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3- fluoro-1-methylpiperidin-4-amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (300 mg, 0.55 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (226. 9 mg, 1.10 mmol, 2 equiv), t-BuONa (265.8 mg, 2.76 mmol, 5 equiv) and tBuXPhos Pd G3 (219.7 mg, 0.28 mmol, 0.5 equiv) in THF (4 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1). The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN(1% 2mM NH3-MEOH); Flow rate: 25 mL/min mL/min; Gradient: 55% B to 66% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.17; Number Of Runs: 5) to afford (3S,4R)-N-[2- (3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (31.1 mg, 9.34%) as a off-white solid. LC-MS: (M+H)+ found 594.25. 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.77 (d, J = 6.7 Hz, 1H), 7.41 – 7.28 (dd, J = 2.0, 8.3 Hz, 1H), 7.25 – 7.15 (d, J = 2.0 Hz, 1H), 6.93 – 6.79 (m, 2H), 6.56 – 6.46 (t, J = 6.2 Hz, 1H), 6.45 – 6.36 (d, J = 7.6 Hz, 1H), 5.55 – 5.46 (d, J = 9.0 Hz, 1H), 5.01 – 4.81 (d, J = 48.9 Hz, 1H), 4.39 – 4.29 (d, J = 6.2 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.95 – 3.87 (s, 3H), 3.85 – 3.67 (d, J = 29.1 Hz, 1H), 3.29 – 3.15 (s, 1H), 3.00 – 2.87 (s, 1H), 2.79 – 2.68 (m, 1H), 2.64 – 2.54 (s,1H), 2.42 – 2.26 (s, 4H), 1.96 – 1.73 (m, 2H), 1.11 – 1.01 (dt, J = 3.3, 5.9 Hz, 2H), 1.01 – 0.92 (m, 2H). Example 68. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4- methanesulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo [1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine
Figure imgf000403_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 360 mg, 0.89 mmol, 1 equiv), 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1- yl)aniline (Intermediate 38; 222.2 mg, 0.98 mmol, 1.1 equiv), CuI (169.3 mg, 0.89 mmol, 1.0 equiv), Pd(PPh3)4 (513.7 mg, 0.45 mmol, 0.5 equiv) and i-Pr2NH (899.6 mg, 8.89 mmol, 10 equiv) in DMSO (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was purified directly by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (10mmol/L NH4HCO3), 0% to 100% gradient in 10 min; detector, UV 254 nm) to afford N-{3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline (490 mg) as a white solid. LC-MS: (M+H)+ found 503.9. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4- methanesulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-8- yl)-1-methylpiperidin-4-amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-2-fluoro-4-methanesulfonylaniline (200 mg, 0.40 mmol, 1 equiv), (3S,4R)-3-Fluoro-1- methyl-piperidin-4-amine dihydrochloride (162.3 mg, 0.80 mmol, 2 equiv), t-BuONa (228.69 mg, 2.38 mmol, 6 equiv), tBuXPhos Pd G3 (157.5 mg, 0.20 mmol, 0.5 equiv) in THF (2.0 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 52% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.9) to afford (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methanesulfonylphenyl)amino]prop-1-yn-1-yl}- 3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (43.3 mg, 19.53%) as a white solid. LC-MS: (M+H)+ found 556.15.1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.5 Hz, 2H), 7.08 (t, J = 8.5 Hz, 2H), 6.84 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 4.05 (m, 2H), 3.71 (dd, J = 27.0, 7.9 Hz, 1H), 3.12 (s, 3H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 7.2 Hz, 1H), 1.79 (d, J = 8.3 Hz, 2H). Example 69. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol
Figure imgf000404_0001
Step 1. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine (Intermediate 1; 300.0 mg, 0.74 mmol, 1 equiv) in DMSO (5 mL) was treated with 2-methyl-3- butyn-2-ol (124.6 mg, 1.48 mmol, 2 equiv), i-Pr2NH (749.7 mg, 7.40 mmol, 10 equiv), Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.20 equiv) and CuI (70.5 mg, 0.37 mmol, 0.50 equiv). The resulting mixture was stirred for 1h at 30oC under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol (230.0 mg, 86.0%) as a white solid. LC-MS: (M+H)+ found 361.0. Step 2. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol A solution of 4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-2- methylbut-3-yn-2-ol (150.0 mg, 0.42 mmol, 1 equiv) in THF (3 mL) was treated with (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (170.4 mg, 0.83 mmol, 2 equiv), t-BuONa (239.5 mg, 2.49 mmol, 6 equiv) and t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 equiv). The resulting mixture was stirred for 30 min at 65 °C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified using prep-HPLC with the following conditions Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 25% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2- methylbut-3-yn-2-ol (20.7 mg, 12.08%) as a white solid. LC-MS: (M+H)+ found 413.10.1H NMR (400 MHz, DMSO-d6) 7.82 (d, J = 6.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 5.40 (d, J = 8.7 Hz, 2H), 4.85 (d, J = 49.3 Hz, 1H), 4.11 (m, 2H), 3.80-3.67 (m, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.38-2.06 (m, 5H), 1.84 (s, 2H), 1.50 (s, 6H). Example 70. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol
Figure imgf000405_0001
Step 1. Synthesis of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]but-3-yn-2-ol To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 400.0 mg, 0.98 mmol, 1 equiv) in DMSO (10 mL) were added i-Pr2NH (989.8 mg, 9.80 mmol, 10 equiv), (2R)-but-3-yn-2-ol (69.2 mg, 0.98 mmol, 1 equiv), Pd(PPh3)4 (228.3 mg, 0.19 mmol, 0.20 equiv) and CuI (94.1 mg, 0.49 mmol, 0.50 equiv) at room temperature. The resulting mixture was stirred for 1 h at 30oC under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (300.0 mg, 82.5%) as a black oil. LC-MS: (M+H)+ found 347.0. Step 2. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol To a stirred mixture of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]but-3-yn-2-ol (200.0 mg, 0.58 mmol, 1 equiv) in THF (10 mL) were added (3S,4R)-3-fluoro-1- methylpiperidin-4-amine dihydrochloride (152.3 mg, 1.15 mmol, 2 equiv), t-BuONa (332.2 mg, 3.45 mmol, 6 equiv) and tBuXPhosPdG3 (183.1 mg, 0.23 mmol, 0.40 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 15 min at 65 °C under nitrogen atmosphere, then cooled down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 20% B to 47% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.22). This resulted in (2R)-4-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (27.1 mg, 11.7%) as a yellow solid. LC-MS: (M+H)+ found 399.10.1H NMR (400 MHz, DMSO- d6) δ 7.82 (d, J = 6.7 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.48 (d, J = 5.0 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 49.6 Hz, 1H), 4.68-4.57 (m, 1H), 4.17-4.05 (m, 2H), 3.95-3.60 (m, 1H), 3.04 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.35-2.18 (m, 4H), 2.11 (s, 1H), 1.87-1.77 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H). Example 71. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol
Figure imgf000407_0001
Step 1. Synthesis of 8-bromo-2-{3-[(tert-butyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (10 mL) were added (2S)-but-3-yn-2- ol (69.2 mg, 0.99 mmol, 2 equiv), i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv), CuI (47.0 mg, 0.25 mmol, 0.50 equiv) and Pd(PPh3)4 (228.3 mg, 0.20 mmol, 0.40 equiv). The resulting mixture was stirred for 1 h at 30°C under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in 8-bromo-2-{3-[(tert- butyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (94 mg, 42.54%) as a yellow solid. LC-MS: (M+H)+ found 348.1. Step 2. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol To a stirred mixture of (2S)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]but-3-yn-2-ol (143 mg, 0.41 mmol, 1 equiv) in THF (3 mL) were added (3S,4R)-3-fluoro-1- methylpiperidin-4-amine dihydrochloride (108.9 mg, 0.82 mmol, 2 equiv), t-BuONa (237.5 mg, 2.47 mmol, 6 equiv) and tBuXPhosPdG3 (126.2 mg, 0.16 mmol, 0.4 equiv) at room temperature. The resulting mixture was stirred for 30 min at 65°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (34.0 mg, 20.72%) as a yellow solid. LC-MS: (M+H)+ found 399.10. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.85 (t, 1H), 6.41 (d, J = 5.6 Hz 1H), 5.55-5.51 (m, 1H), 5.38 (d, J = 8.2 Hz 1H), 4.82 (d, J = 49.2 Hz 1H), 4.61-4.58 (m, 1H), 4.17-4.13 (m, 2H), 3.74-3.70 (m, 1H), 3.06-3.03 (m, 1H), 2.74-2.71 (m, 1H), 2.25-2.10 (m, 5H), 1.75-1.71 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). Example 72. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol
Figure imgf000408_0001
Step 1. Synthesis of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]- 1-phenylprop-2-yn-1-ol To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 1.20 g, 2.96 mmol, 1 equiv) in DMSO (10 mL) was added (1R)-1-phenylprop- 2-yn-1-ol (587.5 mg, 4.44 mmol, 1.50 equiv), diisopropylamine (899.6 mg, 8.88 mmol, 3 equiv), Pd(PPh3)4 (684.9 mg, 0.59 mmol, 0.20 equiv) and CuI (225.7 mg, 1.18 mmol, 0.40 equiv). The reaction mixture was stirred at 30oC for 1 h, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in (1S)-3-[8-bromo-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (340.0 mg, 28.04%) as a white solid. LC-MS: (M+H)+ found 409.0. Step 2. Synthesis of 8-bromo-2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn- 1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine To a solution of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo [1,2-a] pyridin-2-yl]-1- phenylprop-2-yn-1-ol (340.0 mg, 0.83 mmol, 1 equiv) in DCM (10 mL) was added imidazole (113.1 mg, 1.66 mmol, 2 equiv) and TBSCl (250.5 mg, 1.66 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was evaporated to give 8-bromo-2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1- yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (470.0 mg, 108.06%) as a white solid. LC- MS: (M+H)+ found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1- yn-1-yl]-3-(2,2,2trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine A solution of 8-bromo-2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (120.0 mg, 0.22 mmol, 1 equiv) in THF (5 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (94.0 mg, 0.45 mmol, 2 equiv), t-BuONa (132.2 mg, 1.37 mmol, 6 equiv) and t-BuXPhosPdG3 (72.8 mg, 0.09 mmol, 0.40 equiv). The resulting mixture was stirred for 30 min at 65°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in (3S,4R)-N-{2-[(3S)- 3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2trifluoroethyl)imidazo[1,2- a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 43.0%).LC-MS: (M+H)+ found 575.3. Step 4. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol A solution of (3S,4R)-N-{2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1- yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 0.17 mmol, 1 equiv) in DCM (5 mL) was treated with Et3N.3HF (1 mL, 7.36 mmol, 42.35 equiv). The resulting mixture was stirred for 1h at room temperature. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 57% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.97). This resulted in (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol (18.1 mg, 22.59%) as a white solid. LC-MS: (M+H)+ found 461.20.1H NMR (400 MHz, DMSO-d6) δ 7.89-7.82 (m, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.55-7.46 (m, 1H), 7.40 (dd, J = 8.2, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.86-4.50 (m, 2H), 4.40-4.17 (m, 2H), 3.73-3.48 (m, 1H), 3.10-2.88 (m, 1H), 2.80-2.62 (m, 1H), 2.32-2.07 (m, 4H), 2.06 (t, J = 11.4 Hz, 1H), 1.69-1.60 (m, 1H), 1.59-1.46 (m, 1H). Example 73. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol
Figure imgf000410_0001
Step 1. Synthesis of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]- 1-phenylprop-2-yn-1-ol To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 1.2 g, 2.96 mmol, 1 equiv) in DMSO (5 mL) were added (1S)-1-phenylprop-2- yn-1-ol (430.8 mg, 3.26 mmol, 1.1 equiv), diisopropylamine (899.6 mg, 8.89 mmol, 3 equiv), Pd(PPh3)4 (684.9 mg, 0.59 mmol, 0.2 equiv) and CuI (225.7 mg, 1.19 mmol, 0.4 equiv). The reaction mixture was stirred at 30oC for 1 h under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (430 mg, 35.46%) as a yellow solid. LC-MS: (M+H)+ found 409.0. Step 2. Synthesis of 8-bromo-2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn- 1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine To a solution of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1- phenylprop-2-yn-1-ol (300 mg, 0.73 mmol, 1 equiv) in DCM (10 mL) were added imidazole (99.8 mg, 1.47 mmol, 2 equiv) and TBSCl (221.0 mg, 1.47 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated to give 8-bromo-2-[(3R)-3-[(tert- butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, crude) as a yellow oil. LC-MS: (M+H)+ found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1- yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine To a solution of 8-bromo-2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1- yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, 0.76 mmol, 1 equiv) in THF (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (470.2 mg, 2.29 mmol, 3 equiv), tBuXPhosPdG3 (121.4 mg, 0.15 mmol, 0.2 equiv) and sodium 2-methylpropan-2-olate (440.6 mg, 4.58 mmol, 6 equiv). The reaction mixture was stirred at 65oC for 30 min under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. This resulted in (3S,4R)- N-{2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 22.77%) as a yellow solid. LC-MS: (M+H)+ found 575.3. Step 4. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol To a solution of (3S,4R)-N-{2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]-3-phenylprop-1-yn- 1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (80 mg, 0.14 mmol, 1 equiv) in DCM (2 mL) was added TEA.3HF (89.8 mg, 0.56 mmol, 4 equiv) and the resulting solution was stirred at room temperature for 1 h. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified using prep-HPLC with following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN (1% 2mM NH3-MeOH); Flow rate: 25 mL/min mL/min; Gradient: 52% B to 72% B in 10min; Wave Length: 254nm/220nm; RT1(min): 9.28; Number Of Runs: 3. This resulted in (1R)-3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop- 2-yn-1-ol (3.7 mg, 5.74%) as a yellow solid. LC-MS: (M+H)+ found 461.20.
Figure imgf000411_0001
(400 MHz, DMSO-d6) δ 7.90-7.82 (m, 2H), 7.74 (d, J = 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.40 (dd, J = 8.4, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.21 (d, J = 7.4 Hz, 1H), 4.79-4.56 (m, 2H), 4.28 (q, J = 10.8 Hz, 2H), 3.70-3.45 (m, 1H), 2.97 (t, J = 10.9 Hz, 1H), 2.69 (d, J = 11.0 Hz, 1H), 2.35-2.00 (m, 5H), 1.67-1.63 (m, 1H), 1.62-1.47 (m, 1H). Example 74. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000412_0001
Step 1. Synthesis of tert-butyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]but-3-yn-1-yl}carbamate A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 1 g, 2.47 mmol, 1 equiv), tert-butyl N-(but-3-yn-1-yl)carbamate (0.44 g, 2.59 mmol, 1.05 equiv), Pd(PPh3)4 (0.14 g, 0.12 mmol, 0.05 equiv), CuI (0.09 g, 0.49 mmol, 0.2 equiv) and DIEA (0.96 g, 7.41 mmol, 3 equiv) in DMSO (10 mL) was stirred at 25 °C for 1 h under nitrogen. The resulting mixture was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]but-3-yn-1-yl}carbamate (560 mg, 50.82%) as a yellow solid. LC-MS: (M+H)+ found 446.3. Step 2. Synthesis of tert-butyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate A mixture of tert-butyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]but-3-yn-1-yl}carbamate (270 mg, 0.61 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin- 4-amine dihydrochloride (186.1 mg, 0.91 mmol, 1.5 equiv), t-BuONa (232.6 mg, 2.42 mmol, 4 equiv) and tBuXPhos Pd G3 (144.2 mg, 0.18 mmol, 0.3 equiv) in THF (3 mL) was stirred at 65 oC for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford tert-butyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate (50 mg, 16.61%) as a brown solid. LC-MS: (M+H)+ found 498.2. Step 3. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine To a stirred solution of tert-butyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate (40 mg, 0.08 mmol, 1 equiv) in CH2Cl2 (0.6 mL) was added CF3COOH (0.3 mL). The reaction solution was stirred at room temperature for 1h, then concentrated under vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 17% B to 42% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.07; Number Of Runs: 3) to afford (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (10.0 mg, 30.64%) as a white solid. LC-MS: (M+H)+ found 398.10.1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 6.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 8.8 Hz,, 1H), 4.12 (m, 2H), 3.75 (d, J = 8.8 Hz, 1H), 3.56 - 2.95 (m, 4H), 2.76 (t, J = 6.8 Hz, 3H), 2.52 - 2.11 (m, 6H), 1.81 (d, J = 9.4 Hz, 2H). Example 75. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000413_0001
Step 1. Synthesis of tert-butyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}carbamate A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 500 mg, 1.24 mmol, 1 equiv), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1- yl)aniline (Intermediate 39; 70.9 mg, 0.30 mmol, 1.2 equiv), Pd(PPh3)4 (285.4 mg, 0.25 mmol, 0.2 equiv), CuI (235.2 mg, 1.24 mmol, 1 equiv) and DIEA (159.6 mg, 1.24 mmol, 1 equiv) in DMSO (5 mL) was stirred overnight at room temperature. The resulting mixture was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm )to afford tert-butyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}carbamate (274 mg, 46.21%) as a yellow solid. LC-MS: (M+H)+ found 432.0. Step 2. Synthesis of tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate A mixture of tert-butyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}carbamate (130 mg, 0.30 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin- 4-amine dihydrochloride (92.5 mg, 0.45 mmol, 1.5 equiv), t-BuONa (144.5 mg, 1.51 mmol, 5 equiv) and tBuXPhos Pd G3 (119.5 mg, 0.15 mmol, 0.5 equiv) in THF (2 mL) was stirred at 65 oC for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford tert- butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (30 mg, 20.63%) as a yellow solid. LC-MS: (M+H)+ found 484.2. Step 3. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine To a stirred solution of tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (20 mg, 0.04 mmol, 1 equiv) in CH2Cl2 (2 mL) was added CF3COOH (1 mL). The reaction solution was stirred at room temperature for 1h, then concentrated under vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 42% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.52) to afford (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl]-3-fluoro-1-methylpiperidin-4-amine (1.8 mg, 11.30%) as a white solid. LC-MS: (M+H)+ found 384.10.1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 6.8 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.90 - 4.77 (d, J = 18.0 Hz, 1H), 4.15 - 4.10 (m, 2H), 3.79 – 3.72 (m, 1H), 3.54 (s, 2H), 3.10 – 2.98 (m, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.30 - 1.97 (m, 7H), 1.81 (m, 2H). Example 76. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4- methanesulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine
Figure imgf000415_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-4-methanesulfonylaniline A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 300 mg, 0.74 mmol, 1 equiv), 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline (Intermediate 40; 232.5 mg, 1.11 mmol, 1.5 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i-Pr2NH (749.7 mg, 7.41 mmol, 10 equiv) and Pd(PPh3)4 (171.2 mg, 0.15 mmol, 0.2 equiv) in DMSO (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) to afford N-{3-[8-bromo- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline (180 mg, 49.96%) as a brown solid. LC-MS: (M+H)+ found 488.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonylphenyl)amino]prop-1- yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-4-methanesulfonylaniline (150 mg, 0.31 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine dihydrochloride (126.5 mg, 0.61 mmol, 2 equiv), t-BuONa (148.2 mg, 1.54 mmol, 5 equiv) and tBuXPhos Pd G3 (122.5 mg, 0.15 mmol, 0.5 equiv) in THF (3 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 43% B to 67% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.6; Number Of Runs: 3) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonylphenyl)amino]prop- 1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (14.4 mg, 8.68%) as a off-white solid. LC-MS: (M+H)+ found 538.15.1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.76 (d, J = 6.8 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.21 – 7.11 (t, J = 6.0 Hz, 1H), 6.90 – 6.79 (dd, J = 6.2, 8.1 Hz, 3H), 6.46 – 6.35 (d, J = 7.6 Hz, 1H), 5.45 – 5.30 (d, J = 9.2 Hz, 1H), 4.94 – 4.71 (d, J = 49.4 Hz, 1H), 4.36 – 4.22 (d, J = 6.0 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.81 – 3.62 (m, 1H), 3.13 – 2.96 (s, 4H), 2.82 – 2.71 (d, J = 11.2 Hz, 1H), 2.36 – 2.05 (m, 5H), 1.89 – 1.73 (td, J = 3.8, 9.9 Hz, 2H). Example 77. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2- sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl]- 1-methylpiperidin-4-amine
Figure imgf000416_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline (Intermediate 41; 277.3 mg, 1.04 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 1; 350 mg, 0.86 mmol, 1 equiv), CuI (136.6 mg, 0.72 mmol, 0.83 equiv), Pd(PPh3)4 (299.6 mg, 0.26 mmol, 0.3 equiv), i-Pr2NH (874.6 mg, 8.64 mmol, 10 equiv) in DMSO (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15:1) to afford N-{3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2- sulfonyl)aniline (450 mg, 95.74%) as a yellow solid. LC-MS: (M+H)+ found 544.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2- sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl]-1- methylpiperidin-4-amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.55 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (224.5 mg, 1.10 mmol, 2 equiv), t-BuONa (211.8 mg, 2.20 mmol, 4 equiv) and tBuXphos Pd G3 (131.3 mg, 0.17 mmol, 0.3 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / 7M NH3 in MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 50% B to 75% B in 11 min; Wave Length: 254nm/220nm nm; RT1(min): 10.63) to afford (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2- sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-8-yl]-1- methylpiperidin-4-amine (49 mg, 14.93%) as a white solid. LC-MS: (M+H)+ found 596.45. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.54 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 2H), 3.88 (s, 3H), 3.71 (dd, J = 28.7, 8.4 Hz, 1H), 3.27 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.30 (t, J = 12.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 6.9 Hz, 1H), 1.88 – 1.72 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 78. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2- sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl]-1-methylpiperidin-4-amine
Figure imgf000418_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline (Intermediate 41; 214.9 mg, 0.80 mmol, 2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridine (Intermediate 9;170 mg, 0.40 mmol, 1 equiv), CuI (76.5 mg, 0.40 mmol, 1 equiv), Pd(PPh3)4 (139.3 mg, 0.12 mmol, 0.3 equiv) and i-Pr2NH (406.7 mg, 4.02 mmol, 10 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20:1) to afford N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2- sulfonyl)aniline (300 mg) as a yellow oil. LC-MS: (M+H)+ found 562.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2- sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl]-1-methylpiperidin-4-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.53 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (218.3 mg, 1.07 mmol, 2 equiv), t- BuONa (256.3 mg, 2.67 mmol, 5 equiv) and tBuXphos Pd G3 (84.8 mg, 0.11 mmol, 0.2 equiv) in THF (2 mL) was stirred for 1 h at 65 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 85% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.2; Number Of Runs: 4) to afford (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1- yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (12.8 mg, 3.83%) as a white solid. LC-MS: (M+H)+ found 614.25.1H NMR (400 MHz, DMSO- d6) δ 7.86 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 – 6.53 (m, 2H), 5.59 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.8 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 3.74 (d, J = 29.9 Hz, 1H), 3.30 – 3.21 (m, 1H), 3.03 (s, 1H), 2.77 (d, J = 11.1 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.3 Hz, 1H), 1.86 (d, J = 12.0 Hz, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 79. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin- 8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000419_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin- 2-yl} prop-2-yn-1-yl)-4-(ethanesulfonyl)-2-methoxyaniline A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyridine (500 mg, 1.18 mmol, 1 equiv), 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 36; 432.9 mg, 1.42 mmol, 1.2 equiv), Pd(PPh3)4 (273.2 mg, 0.24 mmol, 0.2 equiv), CuI (225.1 mg, 1.18 mmol, 1 equiv) and i-Pr2NH (1.2 g, 11.82 mmol, 10 equiv) in DMSO (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (30:1) to afford N-(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl)-4-(ethanesulfonyl)-2- methoxyaniline (580 mg, 89.47%) as a yellow solid. LC-MS: (M+H)+ found 548.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}prop- 1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin- 4-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl)-4-(ethanesulfonyl)-2-methoxyaniline (200 mg, 0.37 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (149.0 mg, 0.73 mmol, 2 equiv), t-BuONa (175.3 mg, 1.83 mmol, 5 equiv) and tBuXphos Pd G3 (144.9 mg, 0.18 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 30:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 58% B to 78% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.12; Number Of Runs: 4) to afford (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (54.0 mg, 24.67%) as a white solid. LC-MS: (M+H)+ found 600.10.1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.10 – 6.99 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.67 – 6.49 (m, 2H), 5.60 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.82 – 3.60 (m, 1H), 3.17 (m, 2H), 3.03 (t, J = 11.6 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.2 Hz, 1H), 1.93 – 1.66 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 80. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl]-3-fluoropiperidin-4-amine
Figure imgf000420_0001
Step 1. Synthesis of tert-butyl (3S,4R)-4-((2-(3-((4-(ethylsulfonyl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8- yl)amino)-3-fluoropiperidine-1-carboxylate A mixture of N-(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl)-4-(ethanesulfonyl)-2-methoxyaniline (380 mg, 0.69 mmol, 1 equiv), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (228 mg, 1.05 mmol, 1.51 equiv), t-BuONa (136 mg, 1.42 mmol, 2.04 equiv) and tBuXphos Pd G3 (275 mg, 0.35 mmol, 0.50 equiv) in THF (4 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 50:1) to afford (3S,4R)-N-[2- (3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine (250 mg, 61.60%) as a yellow solid. LC-MS: (M+H)+ found 686.3. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}prop- 1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine To a stirred solution of tert-butyl (3S,4R)-4-{[2-(3-{[4-(ethanesulfonyl)-2-methoxyphenyl] amino} prop-1-yn-1-yl)-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-8-yl] amino}-3- fluoropiperidine-1-carboxylate (250 mg, 0.37 mmol, 1 equiv) in DCM (5 mL) was added TFA (2.5 mL, 33.66 mmol, 92.32 equiv) dropwise at 0°C. The resulting mixture was stirred for 30 min at room temperature, then diluted with water and basified to pH 8 with sat.NaHCO3. The resulting mixture was extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 57% B to 72% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.65; Number Of Runs: 7) to afford (3S,4R)-N-[2-(3-{[4-(ethanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin-8- yl]-3-fluoropiperidin-4-amine (31 mg, 14.39%) as a white solid. LC-MS: (M+H)+ found 586.15. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.54 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 4H), 3.23 – 3.05 (m, 3H), 2.94 (d, J = 13.1 Hz, 1H), 2.76 (m, 1H), 2.63 – 2.54 (m, 1H), 2.08 (s, 1H), 1.79 – 1.54 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 81. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000422_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200 mg, 0.47 mmol, 1 equiv), 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2- yn-1-yl)aniline (Intermediate 37; 250.9 mg, 0.95 mmol, 2 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd(PPh3)4 (109.3 mg, 0.09 mmol, 0.2 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford N-(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]imidazo [1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4- (cyclopropanesulfonyl) -2-methoxyaniline (350 mg) as a brown solid. LC-MS: (M+H)+ found 560.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]- 3-fluoro-1-methylpiperidin-4-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline (350 mg, 0.63 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin -4-amine (165.1 mg, 1.25 mmol, 2 equiv), tBuXPhos Pd G3 (148.8 mg, 0.19 mmol, 0.3 equiv) and t-BuONa (300.1 mg, 3.12 mmol, 5 equiv) in THF (5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 30:1) and purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 57% B to 80% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.2; Number Of Runs: 4) to afford (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl]-3-fluoro-1-methylpiperidin-4-amine (19.7 mg, 5.12%) as a light yellow solid. LC-MS: (M+H)+ found 612.15.1H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.81 (d, J = 6.6 Hz, 1H), 7.39 – 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 7.24 – 7.17 (d, J = 2.0 Hz, 1H), 7.08 – 6.98 (m, 1H), 6.91 – 6.84 (d, J = 8.4 Hz, 1H), 6.68 – 6.59 (d, J = 7.7 Hz, 1H), 6.58 – 6.49 (t, J = 6.2 Hz, 1H), 5.66 – 5.57 (d, J = 9.0 Hz, 1H), 4.94 – 4.73 (d, J = 49.5 Hz, 1H), 4.42 – 4.31 (d, J = 6.2 Hz, 2H), 3.94 – 3.86 (s, 3H), 3.85 – 3.66 (m, 1H), 3.11 – 2.96 (t, J = 11.5 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.37 – 2.24 (m, 1H), 2.24 – 2.15 (s, 3H), 2.15 – 2.04 (t, J = 11.5 Hz, 1H), 1.95 – 1.82 (dd, J = 3.6, 12.1 Hz, 1H), 1.82 – 1.71 (d, J = 12.5 Hz, 1H), 1.11 – 1.01 (m, 2H), 1.01 – 0.92 (dd, J = 2.9, 7.8 Hz, 2H). Example 82. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl)-1-methylpiperidin-4-amine
Figure imgf000423_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200.0 mg, 0.47 mmol, 1 equiv), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1- yl)aniline (Intermediate 39; 124.5 mg, 0.52 mmol, 1.10 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), Pd(PPh3)4 (109.3 mg, 0.10 mmol, 0.20 equiv) and i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) in DMSO (3 mL) was stirred at 30°C for 1 h under nitrogen atmosphere. The solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; detector, UV 254 nm) to afford N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2- methoxyaniline (150.0 mg, 59.37%) as a light yellow solid. LC-MS: (M+H)+ found 534.3. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)- 1-methylpiperidin-4-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (50.0 mg, 0.09 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (38.4 mg, 0.19 mmol, 2 equiv), t- BuXPhosPdG3 (29.8 mg, 0.04 mmol, 0.40 equiv) and t-BuONa (54.0 mg, 0.56 mmol, 6 equiv) in THF (1 mL) was stirred at 65°C for 30 min under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 30% gradient in 20 min; detector, UV 254 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05% NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT(min): 7.58) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)-1-methylpiperidin-4-amine (19.9 mg, 36.3%) as a white solid. LC-MS: (M+H)+ found 586.25. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.79-3.58 (m, 1H), 3.10 (s, 3H), 3.03 (t, J = 10.7 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.34-2.15 (m, 4H), 2.09 (dd, J = 12.6, 9.8 Hz, 1H), 1.86 (m, 1H), 1.77 (dd, J = 13.7, 3.8 Hz, 1H). Example 83. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl)piperidin-4-amine)
Figure imgf000425_0001
Step 1. Synthesis of tert-butyl (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130 mg, 0.24 mmol, 1 equiv), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (79 mg, 0.36 mmol, 1.50 equiv), [2'- (diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; {2'-amino-[1,1'-biphenyl]-2- yl}palladio methanesulfonate (48 mg, 0.05 mmol, 0.20 equiv), BINAP (60 mg, 0.10 mmol, 0.40 equiv) and Cs2CO3 (158 mg, 0.48 mmol, 2 equiv) in dioxane (10 mL) was stirred for 4 h at 100 °C under nitrogen atmosphere. The reaction was quenched with sat.NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl (3S,4R)-3- fluoro-4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (100 mg, 61.19%) as a yellow oil. LC-MS: (M+H)+ found: 672.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine) To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino] prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate (100 mg, 0.15 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0 °C . The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. NaHCO3 and extracted with DCM/MeOH (10:1) (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 40% B to 45% B in 7 min; Wave Length: 254 nm nm; RT1(min): 7) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine) (32.4 mg, 38.08%) as a white solid. LC-MS: (M+H)+ found: 572.15. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.6 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.87 - 3.78 (m, 1H), 3.19 - 3.13 (m, 1H), 3.10 (s, 3H), 2.96 - 2.91 (m, 1H), 2.83 - 2.69 (m, 1H), 2.61 – 2.55 (m, 1H), 2.07 (s, 1H), 1.73 - 1.63 (m, 2H). Example 84. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methanesulfonyl-2- methoxyphenyl) amino] prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-8-yl)-1-methylpiperidin-4-amine
Figure imgf000426_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline A solution of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline (Intermediate 42; 120 mg, 0.50 mmol, 1 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridine (212.1 mg, 0.50 mmol, 1 equiv), CuI (95.5 mg, 0.50 mmol, 1 equiv), diisopropylamine (507.5 mg, 5.01 mmol, 10 equiv) and Pd(PPh3)4 (231.8 mg, 0.20 mmol, 0.4 equiv) in DMSO (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1%NH4HCO3), 30% to 50% gradient in 10 min; detector, UV 220 nm) to afford N-(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methanesulfonyl-2- methoxyaniline (120 mg, 44.78%) as an off-white solid. LC-MS: (M+H)+ found:534.7. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-8-yl)-1- methylpiperidin-4-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (92.1 mg, 0.45 mmol, 2 equiv), Cs2CO3 (439.0 mg, 1.35 mmol, 6 equiv), BINAP (55.9 mg, 0.09 mmol, 0.4 equiv) and RAC-BINAP-PD- G3 (44.6 mg, 0.05 mmol, 0.2 equiv) in dioxane (4 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1%FA, 20% to 50% gradient in 10 min; detector, UV 220 nm) and Pre-HPLC (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 19% B to 29% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 9.35) to afford (3S,4R)-3- fluoro-N-(2-{3-[(5-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-8-yl)-1-methylpiperidin-4-amine (22.1 mg, 16.67%) as an off-white solid. LC-MS: (M+H)+ found: 586.30.1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.6 Hz, 1H), 7.32 – 7.14 (m, 2H), 7.12 – 6.97 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.4 Hz, 1H), 5.54 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.2 Hz, 1H), 4.36 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.71 (m, 1H), 3.10 (s, 3H), 3.05 (d, J = 11.6 Hz, 1H), 2.85 – 2.67 (m, 1H), 2.20 (s, 4H), 2.10 (d, J = 3.1 Hz, 1H), 1.94 – 1.72 (m, 2H). Example 85. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxybenzamide
Figure imgf000428_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200.0 mg, 0.47 mmol, 1 equiv), N-ethyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 16; 131.8 mg, 0.57 mmol, 1.20 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv), CuI (45.0 mg, 0.24 mmol, 0.50 equiv) and Pd(PPh3)4 (109.3 mg, 0.10 mmol, 0.20 equiv) in DMSO (15 mL) was stirred for 1 h at 30°C under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 4-[(3- {8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N- ethyl-3-methoxybenzamide (168.2 mg, 67.5%) as a light yellow solid. LC-MS: (M+H)+ found 529.2. Step 2. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxybenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide (50.0 mg, 0.10 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (115.1 mg, 0.56 mmol, 2 equiv), t-BuONa (161.8 mg, 1.69 mmol, 6 equiv) and tBuXPhosPdG3 (30.1 mg, 0.04 mmol, 0.40 equiv) in THF (2 mL) was stirred for 20 min at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 32% B to 60% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 7.25; Number Of Runs: 3) to afford N-ethyl-4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (19.60 mg, 12.1%) as a light yellow solid. LC- MS: (M+H)+ found 579.30.1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 5.6 Hz, 1H), 7.97-7.83 (m, 1H), 7.42 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.07-6.98 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.84-3.63 (m, 1H), 3.31-3.20 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.34-2.02 (m, 5H), 1.93-1.62 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 86. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl]amino}-3-methoxybenzamide
Figure imgf000429_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200.0 mg, 0.47 mmol, 1 equiv), N-cyclopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 18; 121.3 mg, 0.50 mmol, 1.05 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd(PPh3)4 (109.3 mg, 0.10 mmol, 0.20 equiv) in DMSO (3 mL) was stirred at 30°C for 1 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl- 3-methoxybenzamide (220 mg, 86.27%) as a light yellow solid. LC-MS: (M+H)+ found 539.4. Step 2. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy benzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide (190.0 mg, 0.35 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (144.5 mg, 0.70 mmol, 2 equiv), tBuXPhosPdG3 (111.9 mg, 0.14 mmol, 0.40 equiv) and t-BuONa (203.1 mg, 2.11 mmol, 6 equiv) in THF (3 mL) was stirred at 65°C for 15 min under nitrogen atmosphere. The solvent was removed. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 30% gradient in 10 min; detector, UV 254 nm) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 55% B in 7min; Wave Length: 254nm/220nm; RT(min): 6.42; Number Of Runs: 2) to afford N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxybenzamide (31.5 mg, 15.03%) as a white solid. LC-MS: (M+H)+ found 591.45.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.71 (dd, J = 28.2, 13.6 Hz, 1H), 3.09-2.97 (m, 1H), 2.79 (m, 2H), 2.32-1.97 (m, 5H), 1.83 (m, 2H), 0.66 (dt, J = 6.8, 3.3 Hz, 2H), 0.57-0.49 (m, 2H). Example 87. Synthesis of (3S,4R)-N-[2-(3-{[4-(azetidine-1-carbonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 8-yl]-3-fluoro-1-methylpiperidin-4-amine
Figure imgf000431_0001
Step 1. Synthesis of 4-(azetidine-1-carbonyl)-N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 340.0 mg, 0.80 mmol, 1 equiv), 4-(azetidine-1-carbonyl)-2-methoxy-N-(prop-2- yn-1-yl)aniline (Intermediate 20; 216.0 mg, 0.88 mmol, 1.10 equiv), Pd(PPh3)4 (185.0 mg, 0.16 mmol, 0.20 equiv), CuI (76.5 mg, 0.40 mmol, 0.50 equiv) and i-Pr2NH (813.4 mg, 8.04 mmol, 10 equiv) in DMSO (5 mL) was stirred for 1 h at 30°C. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 4-(azetidine-1-carbonyl)-N-(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2- methoxyaniline (390.0 mg, 89.96%) as a light yellow solid. LC-MS: (M+H)+ found 539.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(azetidine-1-carbonyl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]- 3-fluoro-1-methylpiperidin-4-amine A mixture of 4-(azetidine-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline (100.0 mg, 0.18 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin -4-amine dihydrochloride (76.1 mg, 0.37 mmol, 2 equiv), t- BuONa (106.9 mg, 1.11 mmol, 6 equiv) and t-BuXPhosPdG3 (58.9 mg, 0.07 mmol, 0.40 equiv) in THF (1 mL) was stirred for 30 min at 65°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and prep-HPLC (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 42% B to 52% B in 10 min; Wave Length: 254nm/220 nm; RT(min): 9.33; Number Of Runs) to afford (3S,4R)-N-[2-(3-{[4-(azetidine-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn- 1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4- amine (14.6 mg, 13.33%) as a white solid. LC-MS: (M+H)+ found 591.15. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.7 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 4H), 4.01 (s, 2H), 3.85 (s, 3H), 3.84-3.68 (m, 1H), 3.03 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 9.0 Hz, 1H), 2.32-2.16 (m, 6H), 2.15- 2.02 (m, 1H), 1.90-1.82 (m, 1H), 1.81-1.73 (m, 1H). Example 88. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}- 3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3- methoxy-N, N-dimethylbenzamide
Figure imgf000432_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide A solution of 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzamide (Intermediate 15; 131.8 mg, 0.57 mmol, 1.20 equiv), 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridine (200 mg, 0.47 mmol, 1 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv), Pd(PPh3)4 (218.6 mg, 0.19 mmol, 0.40 equiv) and CuI (90.0 mg, 0.47 mmol, 1 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 30% to 70% gradient in 10 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N- dimethylbenzamide (200 mg, 80.21%) as a yellow solid. LC-MS: (M+H) + found: 527.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N, N- dimethylbenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N, N-dimethylbenzamide (90 mg, 0.17 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (70.0 mg, 0.34 mmol, 2 equiv), Cs2CO3 (333.6 mg, 1.03 mmol, 6 equiv), BINAP (42.51 mg, 0.07 mmol, 0.4 equiv), RAC-BINAP- PD-G3 (33.87 mg, 0.03 mmol, 0.2 equiv) in dioxane (3 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 20% to 50% gradient in 10 min; detector, UV 220 nm) and Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 4-{[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2- yl) prop-2-yn-1-yl] amino}-3-methoxy-N, N-dimethylbenzamide (11.6 mg, 11.75%) as an off- white solid. LC-MS: (M+H)+ found: 579.15. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.95 (dd, J = 8.0, 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.90 (t, J = 6.3 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.82 (m, 4H), 3.05 (t, J = 11.7 Hz, 1H), 2.97 (s, 6H), 2.78 (d, J = 11.0 Hz, 1H), 2.37 – 2.18 (m, 4H), 2.17 – 2.05 (m, 1H), 1.96 – 1.71 (m, 2H). Example 89. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- N-isopropyl-3-methoxybenzamide
Figure imgf000434_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200.0 mg, 0.47 mmol, 1 equiv), N-isopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 17; 122.3 mg, 0.50 mmol, 1.05 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd(PPh3)4 (109.3 mg, 0.10 mmol, 0.20 equiv) in DMSO (3 mL) was stirred at 30°C for 1 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3- methoxybenzamide (177.0 mg, 69.15%) as a white solid. LC-MS: (M+H)+ found 541.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3- methoxybenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide (170.0 mg, 0.31 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.8 mg, 0.63 mmol, 2 equiv), tBuXPhosPdG3 (99.8 mg, 0.13 mmol, 0.40 equiv) and t-BuONa (181.1 mg, 1.88 mmol, 6 equiv) in THF (5 mL) was stirred at 65°C for 30 min under nitrogen atmosphere. The resulting mixture was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 40% gradient in 20 min; detector, UV 254 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 62% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.42) to afford 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide (16.9 mg, 8.90%) as a white solid. LC-MS: (M+H)+ found 593.30.1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.15-4.02 (m, 1H), 3.86 (s, 3H), 3.72 (dd, J = 26.4, 12.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.80-2.73 (m, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 12.7, 9.8 Hz, 1H), 1.87 (m, 1H), 1.80-1.73 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). Example 90. Synthesis of 4-({3-[6-(2-fluoroprop-2-enamido)-8-[(1-methylpiperidin-4- yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3- methoxy-N-methylbenzamide
Figure imgf000435_0001
To a solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (120 mg, 0.22 mmol, 1 equiv), 2-fluoroprop-2-enoic acid (23.9 mg, 0.26 mmol, 1.2 equiv) and DIEA (142.7 mg, 1.11 mmol, 5 equiv) in DMF (3 mL) was added HATU (101 mg, 0.26 mmol, 1.2 equiv). The reaction mixture was stirred for 1 h at 25oC. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 4-({3-[6-(2-fluoroprop-2-enamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N- methylbenzamide; formic acid (14 mg, 9.58%) as a yellow solid. LC-MS: (M+H)+ found 616.45. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.03 (s, 1H), 5.99 – 5.88 (m, 2H), 5.40 – 5.18 (m, 1H), 4.35 – 4.06 (m, 4H), 3.85 (s, 4H), 3.55 – 3.44 (m, 1H), 3.19 (s, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.19 (s, 3H), 2.02 (t, J = 11.2 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.60 (d, J = 11.9 Hz, 2H). Example 91. Synthesis of 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4- yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3- methoxy-N-methylbenzamide
Figure imgf000436_0001
To a stirred solution of chloroacetic acid (10.4 mg, 0.11 mmol, 1.20 equiv), DIEA (35.7 mg, 0.28 mmol, 3 equiv) and 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (50 mg, 0.09 mmol, 1 equiv) in DMF (1 mL) was added HATU (42.0 mg, 0.11 mmol, 1.20 equiv) at 0 ℃ . The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XSelect Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 19% B to 27% B in 17min; Wave Length: 254nm/220nm nm; RT1(min): 6.2) to afford 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N- methylbenzamide (9.1 mg, 15.76%) as off-white solid. LC-MS: (M+H)+ found 620.20.1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.30 (s, 1H), 8.14 – 8.02 (m, 1H), 7.34 – 7.32 (m, 1H), 7.27 (d, J = 1.9 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.12– 5.92 (m, 2H), 4.19 (d, J = 3.9 Hz, 4H), 3.92 (d, J = 10.9 Hz, 2H), 3.84 (s, 3H), 3.13(s, 1H), 2.84 (d, J = 11.1 Hz, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.14 (s, 3H), 2.08 (d, J = 11.5 Hz, 2H), 1.89 (d, J = 12.1 Hz, 2H), 1.64 (d, J = 11.8 Hz, 2H). Example 92. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N- methylpyridine-2-carboxamide
Figure imgf000437_0001
Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide A solution of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (Intermediate 43; 129.9 mg, 0.59 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200 mg, 0.49 mmol, 1 equiv), CuI (94.1 mg, 0.49 mmol, 1 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.2 equiv) and i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv) in DMSO (2 mL) was stirred for 1.5 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (50 mL) and washed with water (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 /7 M NH3 in MeOH = 15:1) to afford 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 69.36%) as a brown solid. LC-MS: (M+H)+ found 496.1. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2- carboxamide A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-y n-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.34 mmol, 1 equiv), (3S, 4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (140.5 mg, 0.69 mmol, 2 equiv), t-BuO Na (164.6 mg, 1.72 mmol, 5 equiv), tBuXphos Pd G3 (54.4 mg, 0.07 mmol, 0.2 equiv) in THF (2 mL) was stirred for 1.5 h at 65°C under nitrogen atmosphere. The resulting mixture was conc entrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in M eOH = 15:1) and Prep-HPLC (Column: YMC-Actus Triant C18 ExRs Column, 19*250 mm, 5μ m; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: MEOH; Fl ow rate: 25 mL/min mL/min; Gradient: 45% B to75% B in 9 min; Wave Length: 220nm nm; RT 1(min): 8.68) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifl uoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-ca rboxamide (9.6 mg, 5.12%) as a white solid. LC-MS: (M+H)+ found 548.20.1H NMR (400 MHz , DMSO-d6) δ 8.18 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.04 (d , J = 8.0 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 7.4 Hz, 2H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.02 (s, 5H), 3.80 – 3.60 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.18 (s, 4H), 2.11 (d, J = 14.7 Hz, 1H), 1.79 (d, J = 7.6 Hz, 2H ). Example 93. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy- N-methylpyridine-2-carboxamide
Figure imgf000438_0001
Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 170 mg, 0.40 mmol, 1 equiv), 6-methoxy-N-methyl-5-(prop-2-yn-1- ylamino)pyridine-2-carboxamide (Intermediate 43; 105.7 mg, 0.48 mmol, 1.2 equiv), Pd(PPh3)4 (92.9 mg, 0.08 mmol, 0.2 equiv), CuI (76.5 mg, 0.40 mmol, 1 equiv) and i-Pr2NH (406.7 mg, 4.02 mmol, 10 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (100mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford 5-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2- yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 82.24%) as a brown solid. LC-MS: (M+H)+ found 514.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N- methylpyridine-2-carboxamide A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.33 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (101.7 mg, 0.50 mmol, 1.5 equiv) ,t-BuONa (158.8 mg, 1.65 mmol, 5 equiv) and tBuXphos Pd G3 (52.5 mg, 0.07 mmol, 0.2 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 75% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.92; Number Of Runs: 4) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (25.3 mg, 13.53%) as a white solid. LC-MS: (M+H)+ found 566.15.1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 4.9 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.10 – 6.94 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.41 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.12 – 2.02 (m, 1H), 1.89 – 1.71 (m, 2H). Example 94. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylpyridine-2-carboxamide
Figure imgf000440_0001
Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 150 mg, 0.36 mmol, 1 equiv), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2- carboxamide (Intermediate 21; 80.5 mg, 0.43 mmol, 1.2 equiv), CuI (67.5 mg, 0.36 mmol, 1 equiv), i-Pr2NH (358.9 mg, 3.55 mmol, 10 equiv) and Pd(PPh3)4 (163.9 mg, 0.14 mmol, 0.4 equiv) in DMSO (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50mL) and washed with brine (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 30:1) to afford 5-[(3-{8-bromo-3- [(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N- methylpyridine-2-carboxamide (145 mg, 83.42%) as a brown solid. LC-MS: (M+H)+ found 485.3. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine- 2-carboxamide A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide (145 mg, 0.30 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (122.4 mg, 0.60 mmol, 2 equiv), tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 equiv) and tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 equiv) in THF (1 mL) was stirred for additional 1 h at 65°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 50% B to 75% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.67; Number Of Runs: 2) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylpyridine-2-carboxamide (10.8 mg, 6.72%) as a yellow solid. LC-MS: (M+H)+ found 536.40. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.84 (dd, J = 21.8, 7.6 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 7.02 (t, J = 7.1 Hz, 2H), 6.62 (d, J = 7.7 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.85 – 3.58 (m, 1H), 3.20 – 2.92 (m, 1H), 2.77 (d, J = 4.9 Hz, 4H), 2.35 – 2.02 (m, 5H), 1.98 – 1.65 (m, 2H). Example 95. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3- dihydroisoindol-1-one
Figure imgf000441_0001
Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one (Intermediate 44; 51 mg, 0.24 mmol, 1.19 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 80 mg, 0.20 mmol, 1 equiv), i-Pr2NH (200 mg, 1.98 mmol, 10 equiv), CuI (38 mg, 0.20 mmol, 1.01 equiv) and Pd(PPh3)4 (40 mg, 0.04 mmol, 0.18 equiv) in DMSO (2 mL) was stirred for 1 h at 65°C. The resulting solution diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 20:1) to afford 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 51.31%) as a off-white solid. LC-MS: (M+H)+ found 493.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3- dihydroisoindol-1-one A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-y n-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 0.10 mmol, 1 equiv), (3S,4R)-3-flu oro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 2.02 equiv), t-BuONa (49 m g, 0.51 mmol, 5.03 equiv) and tBuXphos Pd G3 (50 mg, 0.06 mmol, 0.62 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was concentrated un der reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 15: 1) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)i midazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one (2.8 mg , 4.92%) as a off-white solid. LC-MS: (M+H)+ found 545.25.1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.03 (s, 1H), 6.88 – 6.78 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.8 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 4.03 (m, 2H), 3.86 (s, 3H), 3.71 (d, J = 26.9 Hz, 1H), 3.02 (t, J = 11.7 Hz, 1H), 2.82 – 2.64 (m, 1H), 2.38 – 2.23 (m, 1H), 2.18 (s, 3H), 2.14 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 96. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy- 2,3-dihydroisoindol-1-one
Figure imgf000442_0001
Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one (Intermediate 44; 122.7 mg, 0.57 mmol, 1.2 equiv), 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200 mg, 0.47 mmol, 1 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd(PPh3)4 (218.6 mg, 0.19 mmol, 0.4 equiv) in DMSO (1 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) to afford 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one (150 mg, 62.0%) as a white solid. LC-MS: (M+H)+ found 512.3. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3- dihydroisoindol-1-one A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino] -6-methoxy-2,3-dihydroisoindol-1-one (160 mg, 0.31 mmol, 1 equiv) (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.62 mmol, 2 equiv), t- BuONa (150.4 mg, 1.57 mmol, 5 equiv) and tBuXPhos Pd G3 (74.6 mg, 0.09 mmol, 0.30 equiv) in THF (4 mL) was stirred for 1 h at 65°C under nitrogen at atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 50% B to 78% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.28; Number Of Runs: 3) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one (17.3 mg, 9.79%) as a yellow solid. LC-MS: (M+H)+ found 563.15.1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.08 – 6.95 (m, 2H), 6.84 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.17 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 3.80 – 3.62 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.28 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.09 (m, 1H), 1.93 – 1.69 (m, 2H). Example 97. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(trifluoromethyl)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000444_0001
Step 1. Synthesis of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop- 2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide A solution of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (Intermediate 45; 415.0 mg, 1.06 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 243.3 mg, 1.12 mmol, 1.05 equiv), CuI (202.2 mg, 1.06 mmol, 1 equiv), i- Pr2NH (25.9 mg, 0.26 mmol, 10 equiv) and Pd(PPh3)4 (5.9 mg, 0.01 mmol, 0.20 equiv) in DMSO (4 mL) was stirred at 30oC for 1 h under nitrogen atmosphere. The resulted solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 50% gradient in 10 min; detector, UV 254 nm) to afford 4-({3-[8-bromo-3- (trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N- methylbenzamide (369.0 mg, 72.22%) as a yellow solid. LC-MS: (M+H)+ found 481.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (trifluoromethyl)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A mixture of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1- yl}amino)-3-methoxy-N-methylbenzamide (200.0 mg, 0.42 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine dihydrochloride (170.5 mg, 0.83 mmol, 2 equiv), t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 equiv) and t-BuONa (239.6 mg, 2.50 mmol, 6 equiv) in THF (4 mL) was stirred at 65 oC for 30 min under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 20% gradient in 10 min; detector, UV 254 nm) and Prep- HPLC (Column: XBridge Prep OBD RP 18 Column, 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 77% B in 11 min; Wave Length: 254nm/220nm nm; RT (min): 9.7) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo [1,2- a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (10.7 mg, 4.81%) as a white solid. LC-MS: (M+H)+ found 533.20.1H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.71 (dd, J = 28.5, 13.8 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.85-2.70 (m, 4H), 2.37-2.12 (m, 4H), 2.09 (dd, J = 12.8, 10.0 Hz, 1H), 1.87 (m, 1H), 1.76 (dd, J = 13.7, 4.0 Hz, 1H). Example 98. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide
Figure imgf000445_0001
Step 1. Synthesis of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo [1,2- a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide A stirred solution of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a] pyridine (Intermediate 46; 1.34 g, 3.17 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 0.83 g, 3.80 mmol, 1.20 equiv), CuI (0.60 g, 3.17 mmol, 1 equiv), Pd(PPh3)4 (0.73 g, 0.63 mmol, 0.20 equiv) and i-Pr2NH (3.21 g, 31.68 mmol, 10 equiv) in DMSO (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) and silica gel column chromatography (PE / EA = 1:1) to afford 4-({3- [8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3- methoxy-N-methylbenzamide (880 mg, 48.16%) as a yellow solid. LC-MS: (M+H)+ found: 513.0. Step 2. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A mixture of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (161.2 mg, 0.79 mmol, 2 equiv), tBuXphos Pd G3 (154 mg, 0.20 mmol, 0.50 equiv) and t-BuONa (224 mg, 2.34 mmol, 6 equiv) in THF (3 mL) was stirred for 1 h at 65 °C under nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) ands extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 60% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (0.5 mg, 0.22%) as a yellow solid. LC-MS: (M+H)+ found: 565.40. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 6.75 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.07 (d, J = 8.6 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.25(d, J = 6.3 Hz, 2H), 4.01 – 3.95 (m, 2H), 3.82 (s, 3H), 3.50 (s, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 11.5 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H), 2.28 (d, J = 12.9 Hz, 1H), 2.24 (s, 3H), 2.19 – 2.04 (m, 1H), 1.89 – 1.85 (m, 1H), 1.74 (d, J = 11.9 Hz, 1H). Example 99. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide, formic acid salt
Figure imgf000447_0001
Step 1. Synthesis of 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide A solution of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 47; 600 mg, 1.42 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 402.5 mg, 1.85 mmol, 1.30 equiv), CuI (270.2 mg, 1.42 mmol, 1 equiv), Pd(PPh3)4 (327.9 mg, 0.28 mmol, 0.20 equiv) and i-Pr2NH (1.44 g, 14.19 mmol, 10 equiv) in DMSO (10 mL) was stirred for 2 h at room temperature under nitrogen atmosphere, then diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1%TFA) in MeCN, 25% to 40% gradient in 10 min; detector, UV 220 nm) to afford 4-({3-[8- bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3- methoxy-N-methylbenzamide (270 mg, 37.08%) as a yellow solid. LC-MS: (M+H)+ found:513.2. Step 2. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; formic acid salt A mixture of 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (270 mg, 0.53 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.63 mmol, 1.20 equiv), RuPhos (122.7 mg, 0.26 mmol, 0.50 equiv), BrettPhos Pd G4 (208.9 mg, 0.26 mmol, 0.50 equiv) and Cs2CO3 (514.2 mg, 1.58 mmol, 3 equiv) in dioxane (10 mL) was stirred for 3 h at 65°C under nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Xselect CSH PrepC18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 42% B to 50% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7) to afford 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; formic acid (9.7 mg, 3.27%) as a yellow oil. LC-MS: (M+H)+ found: 565.20. 1H NMR (400 MHz, DMSO-d6) δ 8.15 – 7.99 (m, 2H), 7.46 – 7.37 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.59 – 6.46 (m, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.09 – 3.96 (m, 2H), 3.85 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.37 – 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.96 – 1.82 (m, 1H), 1.75 (d, J = 11.6 Hz, 1H). Example 100. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000448_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 290 mg, 0.69 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (Intermediate 14; 150 mg, 0.69 mmol, 1 equiv), Pd(PPh3)4 (317 mg, 0.27 mmol, 0.4 equiv), CuI (131 mg, 0.69 mmol, 1 equiv) and i-Pr2NH (693.8 mg, 6.86 mmol, 10 equiv) in DMSO (3 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 50% to 50% gradient in 2 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (150 mg, 42.62%) as a yellow solid. LC-MS: (M+H)+ found 513.0. Step 2. Synthesis of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}piperidine-1-carboxylate A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 equiv), tert- butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (95.7 mg, 0.44 mmol, 1.5 equiv), RAC- BINAP-PD-G3 (58.0 mg, 0.06 mmol, 0.20 equiv), BINAP (72.8 mg, 0.12 mmol, 0.4 equiv) and Cs2CO3 (190.4 mg, 0.58 mmol, 2 equiv) in dioxane (3 mL) was stirred for 16 h at 100 oC under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 50% to 50% gradient in 3 min; detector, UV 254 nm) to afford tert-butyl (3S,4R)-3- fluoro-4-{[2-(3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylate (85 mg, 44.70%) as a yellow oil. LC-MS: (M+H)+ found 651.0. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}piperidine-1-carboxylate (85 mg, 0.13 mmol, 1 equiv) and TFA (0.8 mL) in DCM (3 mL) was stirred for 1 h at 0 oC. The resulting mixture was diluted with water (10 mL) and basified to pH 8 with saturated NaHCO3, then extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: Xbridge Prep Phenyl 19*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 60% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 9.4) to afford 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide (22.3 mg, 31.01%) as a white solid. LC-MS: (M+H)+ found 551.15. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.92 – 3.75 (m, 4H), 3.13 (t, J = 12.6 Hz, 1H), 2.95 (d, J = 13.1 Hz, 1H), 2.85 – 2.66 (m, 4H), 2.60 (d, J = 11.6 Hz, 1H), 1.76 – 1.60 (m, 2H). Example 101. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000450_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin- 2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide A solution of 8-bromo-2-iodo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine (1 g, 2.36 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (Intermediate 14; 0.62 g, 2.84 mmol, 1.2 equiv), i-Pr2NH (2.39 g, 23.64 mmol, 10 equiv), CuI (0.45 g, 2.36 mmol, 1 equiv) and Pd(PPh3)4 (0.55 g, 0.47 mmol, 0.2 equiv) in DMSO (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (25:1) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide (1 g, 82.40%) as a light yellow solid. LC-MS: (M+H)+ found 513.1. Step 2. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 equiv), (3R,4R)- 3-fluorooxan-4-amine hydrochloride (92.8 mg, 0.78 mmol, 2 equiv), t-BuONa (149.8 mg, 1.56 mmol, 4 equiv), tBuXphos Pd G3 (154.8 mg, 0.19 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 30:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 52% B to 72% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.5; Number Of Runs: 3) to afford 4-{[3-(8- {[(3R,4R)-3-fluorooxan-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (28.2 mg, 13.03%) as a white solid. LC-MS: (M+H)+ found 552.05.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.41 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.74 (d, J = 8.9 Hz, 1H), 4.78 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.97 (m, 10.6 Hz, 3H), 3.84 (s, 3H), 3.71 – 3.43 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 1.93 (m, 4.7 Hz, 1H), 1.76 (d, J = 12.1 Hz, 1H). Example 102. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy- N-methylbenzamide
Figure imgf000451_0001
Step 1. Synthesis of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}pyrrolidine-1-carboxylate A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide (400 mg, 0.78 mmol, 1 equiv), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (238.7 mg, 1.17 mmol, 1.5 equiv), t-BuONa (149.8 mg, 1.56 mmol, 2 equiv) and tBuXphos Pd G3 (309.5 mg, 0.39 mmol, 0.5 equiv) in THF (5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 50:1) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylate (260 mg, 52.41%) as a yellow solid. LC-MS: (M+H)+ found 637.3. Step 2. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N- methylbenzamide A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-8-yl] amino} pyrrolidine-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) and TFA (1 mL) in DCM (2 mL) was stirred for 0.5 h at room temperature. The resulting solution was basified to pH 8 with saturated NaHCO3 and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 75% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.88; Number Of Runs: 3) to afford 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3- methoxy-N-methylbenzamide (13.5 mg, 15.99%) as a white solid. LC-MS: (M+H)+ found 537.15. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.40 (m, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 5.21 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.16 – 3.96 (m, 1H), 3.84 (s, 3H), 3.32 – 3.10 (m, 3H), 2.99 (m, 1H), 2.80 (d, J = 10.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H). Example 103. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxy-N-methylbenzamide
Figure imgf000453_0001
A solution of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (100 mg, 0.19 mmol, 1 equiv) and POM (83.9 mg, 0.93 mmol, 5 equiv) in MeOH (3 mL) was treated with AcOH (1 drop) followed by the addition of NaBH3CN (35.1 mg, 0.56 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was stirred for additional 1 h at 40°C. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 55% B to 74% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.32; Number Of Runs: 3) to afford 4-{[3-(8-{[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (18.1 mg, 17.07%) as a white solid. LC-MS: (M+H)+ found 551.15.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.9 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.26 (d, J = 56.3 Hz, 1H), 4.28 (m, 3H), 3.84 (s, 3H), 3.06 m, 1H), 2.91 (t, J = 8.1 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.65 (m, 2H), 2.29 (s, 3H). Example 104. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 3-(2-methoxyethoxy)-N-methylbenzamide
Figure imgf000454_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide A solution of 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 31; 111.6 mg, 0.43 mmol, 1.2 equiv), 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 150 mg, 0.36 mmol, 1 equiv), CuI (67.5 mg, 0.36 mmol, 1 equiv), i-Pr2NH (0.50 mL, 3.55 mmol, 10 equiv), Pd(PPh3)4 (82.0 mg, 0.07 mmol, 0.2 equiv) in DMSO (1.5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. Additional 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 50mg) was added to the reaction system and mixture stirred an additional 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with DCM/MEOH=10:1 (10 mL) and washed with water (10 mL). The aqueous layer was extracted with DCM/MEOH=10:1 (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4, After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4- [(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3- (2-methoxyethoxy)-N-methylbenzamide (150 mg, 73.76%) as a brown solid. LC-MS: (M+H)+ found 557.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2- methoxyethoxy)-N-methylbenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide (60 mg, 0.11 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (24.3 mg, 0.12 mmol, 1.1 equiv), tBuXphos Pd G3 (8.6 mg, 0.01 mmol, 0.1 equiv) and t-BuoNa (31.0 mg, 0.32 mmol, 3 equiv) in THF (1 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 10:1) and reversed- phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide (16.5 mg, 25.18%) as a yellow solid. LC- MS: (M+H)+ found 609.40.1H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.87 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 4.15 (dd, J = 5.7, 3.6 Hz, 2H), 3.80 – 3.67 (m, 3H), 3.52 (s, 3H), 3.03 (t, J = 11.5 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.05 (m, 1H), 1.85 (dd, J = 12.0, 8.3 Hz, 1H), 1.79 – 1.70 (m, 1H). Example 105. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl]amino}-N-methylbenzamide
Figure imgf000455_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide A solution of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 29; 100 mg, 0.39 mmol, 1 equiv), 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 166.4 mg, 0.39 mmol, 1 equiv), CuI (74.9 mg, 0.39 mmol, 1 equiv) ,i-Pr2NH (398.0 mg, 3.93 mmol, 10 equiv) and Pd(PPh3)4 (90.9 mg, 0.08 mmol, 0.2 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 40% to 80% gradient in 10 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3- (difluoromethoxy)-N-methylbenzamide (152 mg, 66.55%) as a yellow solid. LC-MS: (M+H)+ found 549.1. Step 2. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide (20 mg, 0.04 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (8.2 mg, 0.04 mmol, 1.1 equiv), t- BuoNa (10.5 mg, 0.11 mmol, 3 equiv) and tBuXphos Pd G3 (2.9 mg, 0.004 mmol, 0.1 equiv) in THF (1 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water(10ml) and extracted with EtOAc (3*10 mL).The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 10:1) twice to afford 3- (difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide (11.3 mg, 45.68%) as a white solid. LC-MS: (M+H)+ found 601.15.1H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.21 – 6.99 (m, 2H), 6.92 (dd, J = 8.5, 4.2 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.44 (t, J = 6.1 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 2.04 (m, 1H), 1.96 – 1.71 (m, 2H). Example 106. Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy- N-methylbenzamide
Figure imgf000457_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide A solution of 8-bromo-3-[(difluoromethyl)sulfanyl]-2-iodoimidazo[1,2-a]pyridine (110 mg, 0.27 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (65 mg, 0.30 mmol, 1.1 equiv), Pd(PPh3)4 (69 mg, 0.06 mmol, 0.2 equiv), CuI (56 mg, 0.30 mmol, 1.1 equiv) and i-Pr2NH (276 mg, 2.72 mmol, 10 equiv) in DMSO (1 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with water (3 mL) and extracted with CH2Cl2 / MeOH = 10:1 (3*5 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide (127 mg, 94.51%) as a brown solid. LC-MS: (M+H)+ found 495.0. Step 2. Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide A mixture of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (102 mg, 0.21 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (84 mg, 0.42 mmol, 2 equiv), t- BuXPhos Pd G3 (81 mg, 0.10 mmol, 0.5 equiv) and t-BuONa (99 mg, 1.03 mmol, 5 equiv) in THF (1 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford 4-[(3-{3-[(difluoromethyl)sulfanyl]- 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide (8.7 mg, 7.59%) as a off-white solid. LC-MS: (M+H)+ found 547.25.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.44 – 7.13 (m, 3H), 6.96 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.52 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.84 – 3.70 (m, 4H), 3.05 (s, 1H), 2.79 – 2.74 (m, 4H), 2.20 – 2.12 (m, 4H), 1.90 – 1.76 (m, 2H), 1.24 (s, 1H). Example 107. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-4- methoxy-N-methylbenzamide
Figure imgf000458_0001
Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin- 2-yl} prop-2-yn-1-yl) amino]-4-methoxy-N-methylbenzamide A solution of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino) benzamide (Intermediate 49; 139 mg, 0.63 mmol, 0.90 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a] pyridine (300 mg, 0.71 mmol, 1 equiv), i-Pr2NH (717 mg, 7.09 mmol, 10 equiv), CuI (135 mg, 0.71 mmol, 1 equiv) and Pd(PPh3)4 (327 mg, 0.28 mmol, 0.40 equiv) in DMSO (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 30% to 40% gradient in 10 min; detector, UV 254 nm) to afford 3-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-4-methoxy-N- methylbenzamide (170 mg, 46.69%) as an off-white solid. LC-MS: (M+H)+ found:512.9. Step 2. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-4-methoxy-N- methylbenzamide A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-4-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119.9 mg, 0.58 mmol, 2 equiv), Cs2CO3 (571.2 mg, 1.75 mmol, 6 equiv), BINAP (72.8 mg, 0.12 mmol, 0.4 equiv) and RAC-BINAP-PD- G3 (58.0 mg, 0.06 mmol, 0.2 equiv) in dioxane (4 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA-water, 20% to 50% gradient in 10 min; detector, UV 220 nm) and Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 3-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-4-methoxy-N-methylbenzamide (16.7 mg, 10.12%) as an off-white solid. LC-MS: (M+H)+ found: 565.30.1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.73 – 5.49 (m, 2H), 4.83 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.83 – 3.66 (m, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.90 – 2.71 (m, 4H), 2.21 (m, 4H), 2.13 (t, J = 11.3 Hz, 1H), 1.96 – 1.83 (m, 1H), 1.77 (dd, J = 13.3, 4.0 Hz, 1H). Example 108. Synthesis of N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl] amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 4-methoxybenzamide
Figure imgf000460_0001
Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin- 2-yl} prop-2-yn-1-yl) amino]-N-ethyl-4-methoxybenzamide A solution of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (Intermediate 50; 66 mg, 0.28 mmol, 0.60 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridine (200 mg, 0.47 mmol, 1 equiv), diisopropylamine (478 mg, 4.73 mmol, 10 equiv), Pd(PPh3)4 (218 mg, 0.19 mmol, 0.40 equiv) and CuI (90 mg, 0.47 mmol, 1 equiv) in DMSO (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (10 m L) and extracted with ethyl acetate (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 40% to 60% gradient in 20 min; detector, UV 254 nm) to afford 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-N-ethyl-4-methoxybenzamide (60 mg, 24.06%) as an off-white solid. LC-MS: (M+H+) found: 527.0. Step 2. Synthesis of N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4- methoxybenzamide A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide (50 mg, 0.10 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20.4 mg, 0.10 mmol, 1 equiv), Cs2CO3 (185 mg, 0.57 mmol, 6 equiv), BINAP (23 mg, 0.04 mmol, 0.40 equiv) and BINAP Pd G3 (19 mg, 0.02 mmol, 0.20 equiv) in 1,4-dioxane (2 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl]amino}-4-methoxybenzamide (14.0 mg, 25.31%) as an off-white solid. LC-MS: (M+H+) found: 579.20.1H NMR (400 MHz, DMSO-d6) δ 8.18 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.65 – 5.58 (m, 2H), 4.83 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.72 (dd, J = 28.4, 13.8 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 1.94 – 1.71 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). Example 109. Synthesis of N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide
Figure imgf000461_0001
Step 1. Synthesis of 3-[(3-(8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide A solution of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (Intermediate 51; 115.5 mg, 0.47 mmol, 1 equiv), 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (Intermediate 9; 200 mg, 0.47 mmol, 1 equiv), Pd(PPh3)4 (218.6 mg, 0.19 mmol, 0.40 equiv), CuI (90.0 mg, 0.47 mmol, 1 equiv) and i-Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) in DMSO (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*25 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 40% to 70% gradient in 10 min; detector, UV 254 nm) to afford 3-[(3-(8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4- methoxybenzamide (200 mg, 78.42%) as a yellow solid. LC-MS: (M+H)+ found 539.1. Step 2. Synthesis of N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4- methoxybenzamide A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide (150 mg, 0.28 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.1 mg, 0.56 mmol, 2 equiv), BINAP (69.3 mg, 0.11 mmol, 0.40 equiv), Cs2CO3 (543.7 mg, 1.67 mmol, 6 equiv) and [2'- (diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; {2'-amino-[1,1'-biphenyl]-2- yl}palladio methanesulfonate (55.2 mg, 0.06 mmol, 0.20 equiv) in dioxane (2 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*15 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 20% to 50% gradient in 10 min; detector, UV 254 nm) and Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl]amino}-4-methoxybenzamide (15.0 mg, 7.62%) as a white solid. LC-MS: (M+H)+ found 591.35.1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.61 – 5.57(m, 2H), 4.88 (s, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.81 – 3.32 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.79 – 2.74(m, 2H), 2.32 (d, J = 13.0 Hz, 1H), 2.20 (s, 3H), 2.18 – 2.09 (m, 1H), 1.85 – 1.78 (m, 1H), 1.77 (dd, J = 13.2, 3.9 Hz, 1H), 0.68 – 0.63(m, 2H), 0.54 – 0.52 (m, 2H). Example 110. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7- methoxy-3,4-dihydro-2H-isoquinolin-1-one
Figure imgf000463_0001
Step 1. Synthesis of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one A solution of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one (Intermediate 52; 300 mg, 1.30 mmol, 1.3 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 406 mg, 1.00 mmol, 1 equiv), Pd(PPh3)4 (232 mg, 0.20 mmol, 0.2 equiv), CuI (191 mg, 1.00 mmol, 1 equiv) and i-Pr2NH (1.02 g, 10.02 mmol, 10 equiv) in DMSO (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with CH2Cl2/MeOH=10:1 (3*20mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford 6-({3-[8- bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy- 3,4-dihydro-2H-isoquinolin-1-one (300 mg, 59.01%) as a light yellow solid. LC-MS: (M+H)+ found 507.2. Step 2. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H- isoquinolin-1-one A mixture of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (250 mg, 0.49 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (112 mg, 0.54 mmol, 1.1 equiv), t- BuXPhos Pd G3 (196 mg, 0.25 mmol, 0.5 equiv) and t-BuONa (190 mg, 1.97 mmol, 4 equiv) in THF (5 mL) was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with CH2Cl2/MeOH = 10:1 (2* 20 mL). The combined organic layers were washed with dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( CH2Cl2 / MeOH = 10:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 49% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.72; Number Of Runs: 2) to afford 6-{[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (33.5 mg, 12.0%) as a white solid. LC- MS: (M+H)+ found 559.50.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.50 (t, J = 2.7 Hz, 1H), 7.24 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.58 (s, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.77 – 3.63 (m, 1H), 3.30 (dd, J = 8.1, 1.8 Hz, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (t, J = 6.6 Hz, 3H), 2.18 (s, 4H), 2.09 (tt, J = 8.7, 4.1 Hz, 1H), 1.90 – 1.71 (m, 2H). Example 111. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5- methoxy-N-methylbenzamide
Figure imgf000464_0001
Step 1. Synthesis of 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1- yl}amino)-2-chloro-5-methoxy-N-methylbenzamide A solution of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 53; 20 mg, 0.08 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 32.1 mg, 0.08 mmol, 1 equiv), CuI (180.9 mg, 0.95 mmol, 1 equiv), diisopropylamine (961.0 mg, 9.50 mmol, 10 equiv) and Pd(PPh3)4 (219.5 mg, 0.19 mmol, 0.2 equiv) in DMSO (6 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-({3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-2-chloro-5-methoxy-N- methylbenzamide (320 mg, 63.60%) as a yellow solid. LC-MS: (M+H)+ found 529.1. Step 2. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy- N-methylbenzamide A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}amino)-2-chloro-5-methoxy-N-methylbenzamide (150 mg, 0.28 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (64 mg, 0.31 mmol, 1.1 equiv), tBuXphos Pd G3 (113 mg, 0.14 mmol, 0.5 equiv) and t-BuONa (109 mg, 1.13 mmol, 4 equiv) in THF (5 mL) was stirred for 1 h at 65°C under argon atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with CH2Cl2/MeOH=10/1 (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10:1) and Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 49% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.72; Number Of Runs: 2) to afford 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5- methoxy-N-methylbenzamide (20.6 mg, 12.52%) as a white solid. LC-MS: (M+H)+ found 581.20. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (q, J = 4.5 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 6.92 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 6.09 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.07 (q, J = 10.6 Hz, 2H), 3.82 – 3.66 (m, 4H), 3.03 (t, J = 11.3 Hz, 1H), 2.77 – 2.72 (m, 4H), 2.3 – 2.18 (m, 4H), 2.12 – 2.06 (m, 1H), 1.83 – 1.75 (m, 2H). Example 112. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1- yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine
Figure imgf000466_0001
Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}aniline A solution of N-(prop-2-yn-1-yl)aniline (Intermediate 54; 50 mg, 0.38 mmol, 1 equiv), 8- bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 185 mg, 0.46 mmol, 1.2 equiv), CuI (72.6 mg, 0.38 mmol, 1 equiv), i-Pr2NH (0.54 mL, 3.81 mmol, 10 equiv) and Pd(PPh3)4 (88.1 mg, 0.08 mmol, 0.2 equiv) in DMSO (1.50 mL) was stirred for 1 h at 30°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE / EA 1:1) to afford N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl}aniline (137 mg, 80.92%) as a brown solid. LC-MS: (M+H)+ found 409.1 Step 2. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl}aniline (150 mg, 0.37 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82.9 mg, 0.40 mmol, 1.1 equiv), t-BuONa (105.9 mg, 1.10 mmol, 3 equiv) and tBuXphos Pd G3 (29.2 mg, 0.04 mmol, 0.1 equiv) in THF (4.50 mL) was stirred overnight at 65°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep- HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 30% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.68) to afford (3S,4R)-3-fluoro-1-methyl-N-{2-[3- (phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4- amine (4.7 mg, 2.68%) as a white solid. LC-MS: (M+H)+ found 460.15. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.9 Hz, 2H), 6.83 (t, J = 7.1 Hz, 1H), 6.71 (d, J = 7.9 Hz, 2H), 6.62 (t, J = 7.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.10 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.16 (d, J = 6.2 Hz, 2H), 4.01 (m, 2H), 3.74 – 3.70 (m, 1H), 3.05 – 3.00 (m, 1H), 2.77 – 2.67 (m, 1H), 2.32 – 2.26 (m, 1H), 2.19 (s, 3H), 2.11 – 2.05 (m, 1H), 1.79 (m, 2H). Example 124. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide
Figure imgf000467_0001
Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn- 1-yl)amino]-4-methoxy-N-methylbenzamide To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (Intermediate 57, 250.00 mg, 0.60 mmol, 1.00 equiv) in DMF (4.00 mL) were added 3-amino-4- methoxy-N-methylbenzamide (130.89 mg, 0.73 mmol, 1.20 equiv) and K2CO3 (250.95 mg, 1.81 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70°C for 1 h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 48.37%) as a white solid. LC-MS: (M+H)+ found 512.15. Step 2. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 0.29 mmol, 1.00 equiv) and (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (120.09 mg, 0.59 mmol, 2.00 equiv) in 1,4- dioxane (4.00 mL) were added Cs2CO3 (572.34 mg, 1.76 mmol, 6.00 equiv), BINAP (18.23 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (29.05 mg, 0.03 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C for 4 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm). The crude was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7 min; Wave Length: 220 nm; RT: 6.53 min). This resulted in 3-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (41.70 mg, 25.22%) as an off-white solid. LC-MS: (M+H)+ found 564.35.1H NMR (400 MHz, DMSO-d6) δ 8.11 (q, J = 4.5 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.20-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.79 (d, J = 8.2 Hz, 1H), 5.48 (t, J = 6.4 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.07-2.97 (m, 1H), 2.80 (d, J = 9.8 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.18 (s, 4H), 2.12-1.93 (m, 2H), 1.68 (d, J = 11.7 Hz, 1H). Example 125. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide
Figure imgf000468_0001
1-yl)amino]-4-methoxy-N-methylbenzamide To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (Intermediate 57, 200.00 mg, 0.48 mmol, 1.00 equiv) in DMF (4.00 mL) were added 3-amino-4-methoxy-N-methylbenzamide (104.71 mg, 0.58 mmol, 1.20 equiv) and K2CO3 (200.76 mg, 1.45 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70°C for 1 hour. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 60.46%) as a white solid. LC-MS: (M+H)+ found 512.10. Step 2. Synthesis of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)amino]-4-methoxy-N-methylbenzamide (130.00 mg, 0.25 mmol, 1.00 equiv) and tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (83.07 mg, 0.38 mmol, 1.50 equiv) in 1,4- dioxane (4.00 mL) were added Cs2CO3 (248.01 mg, 0.76 mmol, 3.00 equiv) and Pd-PEPPSI- IHeptCl 3-chloropyridine (24.71 mg, 0.03 mmol, 0.10 equiv) at room temperature. The reaction mixture was stirred at 100°C for 4 h under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (120.00 mg, 72.79%) as a brown solid. LC-MS: (M+H)+ found 650.15. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (100.00 mg, 0.15 mmol, 1.00 equiv) in DCM (1.50 mL) / TFA (0.50 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 3x3 mL of DCM. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254 nm/220 nm; RT: 7.78 min) to afford 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (39.90 mg, 47.12%) as a white solid. LC-MS: (M+H)+ found 550.20.1H NMR (400 MHz, DMSO- d6) δ 8.14 (q, J = 4.5 Hz, 1H), 7.84 (t, J = 6.7 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.22-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.1 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.54 (t, J = 6.5 Hz, 1H), 4.71 (d, J = 50.8 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.98-3.55 (m, 4H), 3.10 (t, J = 12.3 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.96-2.64 (m, 4H), 2.63-2.52 (m, 1H), 1.85-1.68 (m, 1H), 1.65-1.57 (m, 1H). Example 126. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000470_0001
Step 1. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop- 2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (Intermediate 58, 100.00 mg, 0.19 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.02 mg, 0.29 mmol, 1.50 equiv) in 1,4-dioxane (2.00 mL) were added Cs2CO3 (317.97 mg, 0.98 mmol, 5.00 equiv), BINAP (12.15 mg, 0.02 mmol, 0.10 equiv) and BINAP-Pd-G3 (19.37 mg, 0.02 mmol, 0.10 equiv) at room temperature. The reaction mixture was stirred at 100°C for 4 h under nitrogen atmosphere. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 70% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 7 min; Wave Length: 220 nm; RT: 7.15 min) to afford 4-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (19.60 mg, 17.82%) as a white solid. LC-MS: (M+H)+ found 564.20.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 6.76 (t, J = 8.5 Hz, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.1 Hz, 1H), 5.86 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 48.8 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.90-2.62 (m, 4H), 2.32-2.18 (m, 4H), 2.17-1.92 (m, 2H), 1.71-1.63 (m, 1H). Example 132. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzenesulfonamide
Figure imgf000471_0001
Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn- 1-yl)-4-methanesulfonyl-2-methoxyaniline To a stirred mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (Intermediate 57, 300.00 mg, 0.73 mmol, 1.00 equiv) and tert-butyl N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (Intermediate 60, 324.39 mg, 0.73 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs2CO3 (165.88 mg, 2.17 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm). This resulted in tert-butyl N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl} carbamate (350.00 mg, 61.9%) as a yellow oil. LC-MS: (M+H)+ found 778.12. Step 2. Synthesis of tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate To a stirred mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (300.00 mg, 0.39 mmol, 1.00 equiv), Cs2CO3 (627.56 mg, 1.92 mmol, 5.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (158.02 mg, 0.77 mmol, 2.00 equiv) in dioxane (10.00 mL) were added BINAP (95.95 mg, 0.15 mmol, 0.40 equiv) and BINAP-Pd-G3 (76.46 mg, 0.07 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50.00 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (2 x 50.00 mL). The combined organic layers were washed with water (3 x 50.00 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm). This resulted in tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-N-{2- methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (200.00 mg, 62.5%) as a yellow solid. LC-MS: (M+H)+ found 830.30. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzenesulfonamide A mixture of tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2- (trimethylsilyl) ethoxy]methyl})sulfamoyl]phenyl}carbamate (100.00 mg, 0.12 mmol, 1.00 equiv) in HCl (4M in MeOH, 10.00 mL) was stirred for 0.5 h at 70 °C. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10.00 mL). The filtrate was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford 3-{[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-4-methoxy-N-methylbenzenesulfonamide (12.8 mg, 17.7%) as a white solid. LC-MS: (M+H)+ found 600.20.1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 7.14-7.03 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.88-4.76 (m, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.88 (s, 3H), 3.67-3.50 (m, 1H), 3.02 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.34 (d, J = 5.1 Hz, 3H), 2.30-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J = 12.0 Hz, 1H). Example 135. Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide
Figure imgf000473_0001
Step 1. Synthesis of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn- 1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(difluoromethyl)sulfanyl]indolizine (Intermediate 64, 350.00 mg, 0.89 mmol, 1.00 equiv) and 4- amino-3-methoxy-N-methylbenzamide (159.65 mg, 0.89 mmol, 1.00 equiv) in DMF (5.00 mL) was added K2CO3 (367.32 mg, 2.66 mmol, 3.00 equiv). The reaction mixture was stirred at 70°C for 1 h. The resulted solution was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (220.00 mg, 50.23%) as a light yellow solid. LC-MS: (M+H)+ found 494.00. Step 2. Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide To a stirred solution of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop- 2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200.00 mg, 0.40 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (124.26 mg, 0.61 mmol, 1.50 equiv) in 1,4-dioxane (3.00 mL) were added BINAP (25.20 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (40.16 mg, 0.04 mmol, 0.10 equiv) and Cs2CO3 (658.08 mg, 2.02 mmol, 5.00 equiv). The resulting mixture was stirred at 100°C for 5 h under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, ACN in Water (0.1% FA), 0% to 30% gradient in 15 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 58% B in 7 min; Wave Length: 254nm/220nm; RT: 7.5 min) to afford 4-[(3-{3- [(difluoromethyl)sulfanyl]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (76.1 mg, 34.48%) as a white solid. LC-MS: (M+H)+ found 546.40.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.29-6.93 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.1 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J = 29.6 Hz, 1H), 3.10-2.95 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.34-2.18 (m, 4H), 2.16-1.89 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 139. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide
Figure imgf000475_0001
Step 1. Synthesis of 4-[(3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn- 1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred solution of 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine (Intermediate 68, 120 mg, 0.326 mmol, 1 equiv) in DMF (1.2 mL) were added 4-amino-3-methoxy-N-methylbenzamide (70.40 mg, 0.391 mmol, 1.2 equiv) and K2CO3 (89.99 mg, 0.652 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 70°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (2 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 / MeOH 10:1 (3 x 5mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2 / MeOH 10:1) to afford 4-[(3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 68.93%) as a yellow solid. LC-MS: (M+H)+ found 468. Step 2. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide A mixture of 4-[(3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 0.224 mmol, 1 equiv) and Cs2CO3 (365 mg, 1.120 mmol, 5 equiv) in dioxane (1 mL) was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at 0°C. The resulting mixture was extracted with CH2Cl2 / MeOH 10:1 (3 x 5mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2 / MeOH 10:1) to afford 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (33.1 mg, 25.25%) as a brown solid. LC-MS: (M+H)+ found 564.30.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.09 (t, J = 4.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.8, 7.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.94 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 3.84 (s, 4H), 3.07 (s, 1H), 2.85 (s, 1H), 2.77 – 2.65 (m, 3H), 2.33 (m, 3H), 2.09 (d, J = 11.3 Hz, 2H), 1.73 (d, J = 9.9 Hz, 1H). Example 154. Synthesis of 3-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4- methoxy-N-methylbenzamide
Figure imgf000476_0001
Step 1. Synthesis of ethyl 8-bromo-6-fluoroimidazo[1,2-a] pyridine-2-carboxylate To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.00 g, 26.17 mmol, 1.00 equiv) in dioxane (20 mL) were added NaHCO3 (4.40 g, 52.35 mmol, 2.00 equiv) and ethyl 3- bromo-2-oxopropanoate (10.21 g, 52.35 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 100 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in ethyl 8-bromo-6-fluoroimidazo[1,2-a] pyridine-2-carboxylate (5.3 g, 70.52%) as a light yellow solid. LC-MS: (M+H)+ found:287. Step 2. Synthesis of ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a] pyridine-2-carboxylate To a stirred solution of ethyl 8-bromo-6-fluoroimidazo[1,2-a] pyridine-2-carboxylate (6.40 g, 22.29 mmol, 1.00 equiv) in MeCN (60 mL) were added NIS (10.03 g, 44.58 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 1 h at 80 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a] pyridine-2-carboxylate (2.9 g, 31.50%) as a light yellow solid. LC-MS: (M+H)+ found:413. Step 3. Synthesis of 8-bromo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2- carboxylate To a stirred mixture of [(trifluoromethyl)sulfanyl] silver (2.70 g, 12.90 mmol, 1.90 equiv) and copper(I) iodide (2.57 g, 13.46 mmol, 1.90 equiv) in ACN (20 mL) dropwise at - 30°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at - 30°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. To the above mixture was added ethyl 8-bromo-3- iodoimidazo[1,2-a] pyridine-2-carboxylate (2.80g, 7.08 mmol, 1.00 equiv) and 1,10- phenanthroline (140.52 mg, 0.78 mmol, 0.11 equiv) in DMF (10 mL) at room temperature. The resulting mixture was stirred for 16 h at 60°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 8-bromo- 3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2-carboxylate (600 mg, 22.93%) as a yellow solid. LC-MS: (M+H+) found:387. Step 4. Synthesis of 8-bromo-6-fluoro-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2-carboxylic acid To a stirred solution of ethyl 8-bromo-6-fluoro-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2-carboxylate (550 mg, 1.42 mmol, 1.00 equiv) and lithiumol (51 mg, 2.13 mmol, 1.50 equiv) in H2O (3 mL) were added lithiumol (51mg, 2.13 mmol, 1.50 equiv) and water (39 mg, 2.13 mmol, 1.5 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with conc. HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 8-bromo-6-fluoro-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2-carboxylic acid (470 mg, 92.13%) as a off-white solid. LC- MS: (M+H)+ found: 359. Step 5. Synthesis of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine To a stirred solution of 8-bromo-6-fluoro-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine-2-carboxylic acid (460 mg, 1.28 mmol, 1.00 equiv) in DMSO (5 mL) were added I2 (650 mg, 2.56 mmol, 2.00 equiv) and K3PO4 (544 mg, 2.56 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 1 h at 150 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine (220 mg, 38.94%) as a light yellow solid. LC-MS: (M+H+) found:441. Step 6. Synthesis of 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)sulfanyl] imidazo[1,2- a] pyridin-2-yl} prop-2-yn-1-yl) amino]-4-methoxy-N-methylbenzamide A mixture of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridine (200 mg, 0.45 mmol, 1.00 equiv), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino) benzamide (44.54 mg, 0.20 mmol, 0.45 equiv), i-Pr2NH (230 mg, 2.27 mmol, 5.00 equiv), CuI (17 mg, 0.09 mmol, 0.20 equiv) and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.10 equiv) in DMSO (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 35:1) to afford 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn-1-yl) amino]-4-methoxy-N-methylbenzamide (100 mg, 39.76%) as a yellow solid. LC-MS: (M+H)+ found: 531. Step 6. Synthesis of 3-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide A mixture of 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (95 mg, 0.17 mmol, 1.00 equiv) ,(3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55 mg, 0.27 mmol, 1.50 equiv), Cs2CO3 (291 mg, 0.90 mmol, 5.00equiv) ,BINAP (45 mg, 0.07 mmol, 0.40 equiv) and [2'- (diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; {2'-amino-[1,1'-biphenyl]-2- yl}palladio methanesulfonate (36 mg, 0.03 mmol, 0.20 equiv) in dioxane (3 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 3-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide (14.2 mg, 13.59%) as a off-white solid. LC-MS: (M+H)+ found: 583.05. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 4.5 Hz, 1H), 7.99 (s, J = 4.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (s, J = 8.3, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.74 (dd, J = 2.1 Hz, 1H), 6.11 (d, J = 8.9 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.89- 4.77 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.80-3.73 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (s, 4H), 2.23 (s, 4H), 2.10 (t, J = 11.5 Hz, 1H), 1.95 (qd, J = 12.0, 3.7 Hz, 1H), 1.74 (d, J = 11.5 Hz, 1H). Example 155. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-7-yl) prop-2-yn-1-yl] amino}-3- methoxy-N-methylbenzamide; formic acid
Figure imgf000480_0001
Step 1. Synthesis of 7-bromo-1-chloro-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazine To a stirred mixture of 7-bromo-1-chloropyrrolo[1,2-a] pyrazine (500 mg, 2.16 mmol, 1.00 equiv) and 2-[(trifluoromethyl)sulfanyl] isoindole-1,3-dione (694.11 mg, 2.81 mmol, 1.30 equiv) in DMF (5.00 mL) was added NaCl (63.12 mg, 1.08 mmol, 0.50 equiv). The resulting mixture was stirred at 90°C for 16 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%TFA in water 25% to 40% gradient in 10 min; detector, UV 220 nm to afford desired compound 7-bromo-1-chloro-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazine (480 mg, 67.03%) as a yellow soild. LC-MS: (M+H) + found:331. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine A stirred mixture of 7-bromo-1-chloro-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazine (500.00 mg, 1.51 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (299.02 mg, 2.26 mmol, 1.50 equiv), RAC-BINAP-PD-G3 (299.34 mg, 0.30 mmol, 0.20 equiv), BINAP (375.63 mg, 0.60 mmol, 0.40 equiv) in dioxane (5.00 mL) was added Cs2CO3 (2.95 g, 9.05 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at 100°C before quenching with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%TFA in water 25% to 40% gradient in 10 min; detector, UV 220 nm to afford desired compound (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-1- yl}-3-fluoro-1-methylpiperidin-4-amine (350.00 mg, 54.3%) as a light yellow soild. LC-MS: (M+H) + found:427. Step 3. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-6- [(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-7-yl) prop-2-yn-1-yl] amino}-3-methoxy-N- methylbenzamide; formic acid To a stirred mixture of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.23 mmol, 1 equiv), diisopropylamine (236.83 mg, 2.34 mmol, 10 equiv), CuI (22.29 mg, 0.12 mmol, 0.5 equiv), DavePhos (36.84 mg, 0.1 mmol, 0.4 equiv), DavePhos Pd G3 (35.73 mg, 0.05 mmol, 0.2 equiv) in DMSO (3 mL) was added a solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (61.30 mg, 0.28 mmol, 1.2 equiv) in DMSO (0.5 mL) dropwise at 100°C under nitrogen atmosphere. The mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EtOAc (100 mL) twice times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-TLC (DCM/MeOH=15:1) to afford product (90% purity), the resulting crude material was purified by Pre-HPLC (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 8% B to 18% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 9.35). Lyophilization yielded 4-{[3-(1-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl] amino}-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a] pyrazin-7-yl) prop-2- yn-1-yl] amino}-3-methoxy-N-methylbenzamide; formic acid (21.3 mg, 14.77%) as an off-white solid. LC-MS: (M+H) + found: 565.25.1H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.30 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.19 (d, J = 30.4 Hz, 1H), 3.84 (s, 3H), 3.09 (t, J = 11.7 Hz, 1H), 2.87 (d, J = 10.9 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.22 (m, 6H), 1.68 (d, J = 12.2 Hz, 1H). Example 156. Synthesis of 3-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide
Figure imgf000482_0001
A stirred mixture of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (synthesized according to Example 154, 100 mg, 0.23 mmol, 1.00 equiv) and 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (51.08 mg, 0.23 mmol, 1.00 equiv) in DMSO (3.00 mL) were added DIPA (236.84 mg, 2.34 mmol, 10.00 equiv), CuI (22.29 mg, 0.12 mmol, 0.50 equiv), DavePhos Pd G3 (35.73 mg, 0.05 mmol, 0.20 equiv) and DavePhos (36.84 mg, 0.09 mmol, 0.40 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 100°C before quenching with water (10 m L). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%FA in water 50% to 60% gradient in 10 min; detector, UV 220 nm. The crude was purified using prep-HPLC with following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 50% B to 62% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56. This resulted in 3-{[3- (1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (11.7 mg, 8.8%) as a yellow solid. LC-MS: (M+H)+ found: 565.30.1H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.08 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 11.5, 3.5 Hz, 2H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.28 (d, J = 6.4 Hz, 2H), 4.24 – 4.08 (m, 1H), 3.84 (s, 3H), 3.11 – 3.00 (m, 1H), 2.87 – 2.80 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.28 – 1.88 (m, 6H), 1.67 (dd, J = 9.8, 4.9 Hz, 1H). Example 185 Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphoryl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid
Figure imgf000483_0001
Step 1. Synthesis of 4-(dimethylphosphoryl)-2-methoxy-N-(prop-2-yn-1-yl) aniline A solution of 4-(dimethylphosphoryl)-2-methoxyaniline (95 mg, 0.48 mmol, 1.00 equiv) in DMF (3 mL) was treated with propargyl bromide (85 mg, 0.72 mmol, 1.50 equiv) at room temperature followed by the addition of K2CO3 (132 mg, 0.95 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for additional 3 h at 100°C. The reaction was monitored by LCMS. The reaction was quenched with Water and extracted with CH2Cl2 (3 x20 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to afford 4- (dimethylphosphoryl)-2-methoxy-N-(prop-2-yn-1-yl) aniline (40 mg, 35.35%) as a yellow oil. LC- MS: (M+H) + found:238.05. Step 2. Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphoryl)-2- methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-1-yl]- 3-fluoro-1-methylpiperidin-4-amine; formic acid A solution of (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl}-1-methylpiperidin-4-amine (80 mg, 0.17 mmol, 1.00 equiv) in DMSO (2 mL) was treated with 4-(dimethylphosphoryl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (40 mg, 0.17 mmol, 1.00 equiv) and DIPA (85 mg, 0.85 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere followed by the addition of Pd(PPh3)4 (20 mg, 0.02 mmol, 0.10 equiv) and CuI (6 mg, 0.03 mmol, 0.20 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1h at 70°C. The reaction was monitored by LCMS. The reaction was quenched with Water and extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford (3S,4R)-N-[7-(3-{[4- (dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6- [(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid (15.8 mg, 14.76%) as a white solid. LC-MS: (M+H) + found: 584.25.1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.22-7.17 (m, 1H), 7.13 (dd, J = 11.9, 1.6 Hz, 1H), 6.83 (dd, J = 8.0, 3.0 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (dd, J = 31.3, 7.2 Hz, 1H), 3.84 (s, 3H), 3.33 – 3.05 (m, 1H), 2.84 – 2.67 (m, 1H), 2.18 (s, 4H), 2.14 – 2.01 (m, 2H), 1.67 (dd, J = 9.6, 5.1 Hz, 1H), 1.58 (d, J = 13.1 Hz, 6H). Example 186 Synthesis of 8-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}- N-methylimidazo[1,2-a]pyridine-6-carboxamide
Figure imgf000484_0001
Step 1. Synthesis of methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6- carboxylate A solution of methyl 8-aminoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 5.23 mmol, 1 equiv), propargyl bromide (933 mg, 7.84 mmol, 1.50 equiv) and DIEA (2.73 mL, 15.69 mmol, 3.00 equiv) in DMF (10 mL) was stirred for 16h at 70 °C. The reaction was quenched with Water at 0 °C. The precipitated solids were collected by filtration and washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 40% to 60% gradient in 20 min; detector, UV 254 nm to afford methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 29.19%) as a brown solid which combined with the precipitated solids. LC-MS: (M+H+) found: 230.10. Step 2. Synthesis of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid A mixture of methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 1.53 mmol, 1.00 equiv) and LiOH.H2O (192 mg, 4.58 mmol, 3.00 equiv) in solvent [H2O (1 mL), MeOH (1 mL), THF (1 mL)] was stirred overnight at 50 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20mL) and acidified to pH 5 with 4M HCl (aq.). The precipitated solids were collected by filtration and dried under vacuum to afford 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (300 mg, 91.30%) as a light brown solid. LC-MS: (M+H+) found: 216.05 Step 3. Synthesis of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6- carboxamide To a stirred solution of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (250 mg, 1.16 mmol, 1.00 equiv)8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6- carboxylic acid (250 mg, 1.16 mmol, 1 equiv)methanamine hydrochloride (94mg, 1.39 mmol, 1.20 equiv) and DIEA (600 mg, 4.65 mmol, 4.00 equiv) in DMF (3 mL) was added HATU (883 mg, 2.32 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with Water. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL) to afford N-methyl-8-(prop-2-yn-1- ylamino)imidazo[1,2-a]pyridine-6-carboxamide (200 mg, 75.43%) as a light yellow solid. LC- MS: (M+H+) found: 228.95 Step 4. Synthesis of 8-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6- [(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-N- methylimidazo[1,2-a]pyridine-6-carboxamide A mixture of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide (58 mg, 0.25 mmol, 1.20 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6- [(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (100 mg, 0.21 mmol, 1.00 equiv), Pd(PPh3)4 (49 mg, 0.042 mmol, 0.20 equiv), CuI (4 mg, 0.021 mmol, 0.10 equiv) and DIPA (64 mg, 0.63 mmol, 3.00 equiv) in DMSO (1 mL) was stirred for 2 h at 70°C under nitrogen atmosphere. The reaction was quenched with Water. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH=10/1) to afford the crude product (100 mg). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 31% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 9.25) to afford 8-{[3-(1-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn- 1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide (51.6 mg, 42.04%) as an off-white solid. LC-MS: (M+H+) found: 575.20.1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 1.4 Hz, 1H), 8.40 – 8.37 (m, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.39 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.65 (t, J = 6.4 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.42 (d, J = 6.4 Hz, 2H), 4.17 (d, J = 31.2 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.88 – 2.77 (m, 4H), 2.27 – 1.93 (m, 6H), 1.69 – 1.62 (m, 1H). Example 196 Synthesis of 4-[(3-{6-[(difluoromethyl)sulfanyl]-1-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3- methoxy-N-methylbenzamide; formic acid
Figure imgf000487_0001
Step 1. Synthesis of 7-bromo-1-chloro-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazine A solution/mixture of 7-bromo-1-chloropyrrolo[1,2-a]pyrazine (400 mg, 1.73 mmol, 1.00 equiv), 2-[(difluoromethyl)sulfanyl]isoindole-1,3-dione (475 mg, 2.07 mmol, 1.20 equiv) and TMSCl (206 mg, 1.90 mmol, 1.10 equiv) in DCE (10 mL) was stirred for overnight at 90 °C under nitrogen atmosphere. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford 7-bromo-1-chloro-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazine (500 mg, 92.28%) as an off-white solid. LC-MS: (M+H+) found: 312.85. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine A mixture of 7-bromo-1-chloro-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazine (200 mg, 0.64 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (196 mg, 0.96 mmol, 1.50 equiv), BINAP (79 mg, 0.13 mmol, 0.20 equiv), RAC-BINAP-PD-G3 (63 mg, 0.06 mmol, 0.10 equiv) and Cs2CO3 (1039 mg, 3.19 mmol, 5.00 equiv) in dioxane (5 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford (3S,4R)-N-{7-bromo-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2-a]pyrazin- 1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 38.30%) as a light yellow solid. LC-MS: (M+H+) found: 408.95. Synthesis of 4-[(3-{6-[(difluoromethyl)sulfanyl]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; formic acid To a stirred mixture of (3S,4R)-N-{7-bromo-6-[(difluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.244 mmol, 1 equiv), DavePhos (38.46 mg, 0.098 mmol, 0.4 equiv), DavePhos Pd G3 (37.30 mg, 0.049 mmol, 0.2 equiv), CuI (23.27 mg, 0.122 mmol, 0.5 equiv)CuI (23.27 mg, 0.122 mmol, 0.5 equiv) DIPA (123.63 mg, 1.220 mmol, 5 equiv) in DMSO (3 mL) was added the solution of 3-methoxy-N-methyl-4-(prop- 2-yn-1-ylamino)benzamide (63.99 mg, 0.293 mmol, 1.2 equiv) in DMSO(1 mL) dropwise at 100 °C under nitrogen atmosphere. The reaction mixture was stirred for 5 h at 100 °C. The reaction was quenched with Water. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 12:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 30% B to 60% B in 12min; Wave Length: 254nm/220nm nm; RT1(min): 9.35) to afford 4-[(3-{6-[(difluoromethyl)sulfanyl]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; formic acid (14.6 mg, 9.99%) as a light yellow solid. LC-MS: (M+H+) found: 547.25.
Figure imgf000488_0001
NMR (400 MHz, DMSO-d6) δ 8.14 – 8.06 (m, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.39 – 7.06 (m, 5H), 6.77 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.1 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.17 (d, J = 30.4 Hz, 1H), 3.85 (s, 3H), 3.11 – 3.01 (m, 1H), 2.88 – 2.80 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.30 – 2.08 (m, 4H), 2.08 – 1.93 (m, 2H), 1.66 (dd, J = 9.8, 4.9 Hz, 1H). Example 206 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxy-N-methylbenzamide
Figure imgf000489_0001
Step 1. Synthesis of methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate 3-chloropyrazin-2-amine (5 g, 38.6 mmol, 1 equiv) methyl 3-bromo-2-oxopropanoate (4.93 mL, 46.3 mmol, 1.2 equiv) and NaHCO3 (3.89 g, 46.3 mmol, 1.2 equiv) were mixed in ACN (75 mL). The reaction mixture was stirred at 80 oC for 4h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (2200 mL). The mixture was stirred at room temperature for 1h. The precipitated solids were collected by filtration and washed with water (2x300 mL). The resulting solid was air-dried under vacuum to give methyl 8- chloroimidazo[1,2-a]pyrazine-2-carboxylate (6 g, 73.47%) as a beige solid. LC-MS: (M+H)+ found 212.00. Step 2. Synthesis of methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate Methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol, 1 equiv) NBS (9.58 g, 53.8 mmol, 1.15 equiv) and BPO (0.12 g, 0.468 mmol, 0.01 equiv) were mixed in ACN (100 mL). The reaction mixture was stirred at 80 oC for 1h. The resulting mixture was diluted with water (300 mL). The precipitated solids were collected by filtration and washed with water (1x100 mL), air-dried to give methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (10 g, 73.58%) as a white solid. LC-MS: (M+H)+ found 290.80. Step 3. Synthesis of methyl 8-chloro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine- 2-carboxylate CuI (2.62 g, 13.8 mmol, 2 equiv) and silver(1+) (trifluoromethyl)sulfanide (2.88 g, 13.8 mmol, 2 equiv) were mixed in ACN (20 mL). The reaction mixture was stirred at -30 oC to 0 oC for 3h. DMF (20 mL), methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (2 g, 6.89 mmol, 1 equiv) and 1,10-phenanthroline (0.25 g, 1.38 mmol, 0.2 equiv) were added successively. The reaction mixture was stirred at 100 oC for 4h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (2x100 mL). The filtrate was washed with brine (2x200 mL). The resulting organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 8-chloro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2- carboxylate (560 mg, 26.10%) as a yellow solid. LC-MS: (M+H)+ found 311.85. Step 4. Synthesis of methyl 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2-carboxylate Methyl 8-chloro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2-carboxylate (1.5 g, 4.81 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.09 g, 5.29 mmol, 1.1 equiv) and Et3N (2.44 g, 24.1 mmol, 5 equiv) were mixed in DMSO (20 mL). The reaction mixture was stirred at 150 oC for 4h. The resulting mixture was diluted with ethyl acetate (200 mL). The resulting mixture was washed with 3x200 mL of brine. The organic phase was dried with anhydrous sodium sulfate and concentrated under vaccum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (30:1) to afford methyl 8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2- carboxylate (1.2 g, 61.20%) as a white solid. LC-MS: (M+H)+ found 408.1. Step 5. Synthesis of 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2-carboxylic acid Tert-butyl (3S,4R)-3-fluoro-4-{[2-(methoxycarbonyl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-8-yl]amino}pyrrolidine-1-carboxylate (1.3 g, 2.71 mmol, 1 equiv) and LiOH (0.65 g, 27.1 mmol, 10 equiv) were mixed in H2O (10 mL) and THF (10 mL). The reaction mixture was stirred at room temperature for 1h. The mixture was acidified to pH 7 with 2M HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to give 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2-carboxylic acid (1.2 g, 121.15%) as a white solid. LC-MS: (M+H)+ found 394.1 Step 6. Synthesis of tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)carbamate 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2-carboxylic acid (300 mg, 0.763 mmol, 1 equiv) was dissolved in t-BuOH (3 mL), DPPA (524 mg, 1.91 mmol, 2.5 equiv) and Et3N (231 mg, 2.29 mmol, 3 equiv) were added successively. The reaction mixture was stirred at 85 oC for 1h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (20 mL). The resulting mixture was washed with 3x20 mL of sat. aq. NaHCO3. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to afford tert-butyl N-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2- yl)carbamate (150 mg, 42.34%) as a white solid. LC-MS: (M+H)+ found 465.20 Step 7. Synthesis of N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazine-2,8-diamine Tert-butyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)carbamate (150 mg, 0.323 mmol, 1 equiv) was dissolved in CF3COOH (1 mL) and CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 1h. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (3x10 mL). The resulting mixture was washed with 3x30 mL of brine. The organic phase was dried with anhydrous sodium sulfate and concentrated under vaccum to give N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyrazine-2,8-diamine (100 mg, 84.98%) as a brown oil. LC-MS: (M+H)+ found 365.10 Step 8. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyrazin-8-yl}-1-methylpiperidin-4-amine N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyrazine-2,8-diamine (300 mg, 0.823 mmol, 1 equiv), CH2I2 (3.3 g, 12.3 mmol, 15 equiv) and 3-methylbutyl nitrite (241 mg, 2.06 mmol, 2.5 equiv) were mixed in ACN (3 mL). The reaction mixture was stirred at 40 oC for 5h. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to give (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine (150 mg, 38.33%) as a brown oil. LC-MS: (M+H)+ found 476.00 Step 9. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-8-yl}-1- methylpiperidin-4-amine (60 mg, 0.126 mmol, 1 equiv), 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (86.5 mg, 0.396 mmol, 1.2 equiv), CuI (62.9 mg, 0.330 mmol, 1 equiv), Pd(PPh3)4 (76.3 mg, 0.066 mmol, 0.2 equiv) and i-Pr2NH (334 mg, 3.30 mmol, 10 equiv) were mixed in DMSO (1 mL). The reaction mixture was stirred at room temperature for 1h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (8.5 mg, 11.87%) as a white solid. LC-MS: (M+H)+ found 566.25. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.2H), 8.12 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.52 (dd, J = 18.4, 6.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.90 (d, J = 18.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 (d, J = 8.3 Hz,, 1H), 3.84 (s, 3H), 3.04 (t, J = 11.8 Hz, 1H), 2.78 (dd, J = 21.2, 6.5 Hz, 4H), 2.22 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (p, J = 13.9, 13.2 Hz, 2H), 1.66 (d, J = 9.9 Hz, 1H). Example 214 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1- yl]amino}-3-methoxy-N-methylbenzamide
Figure imgf000492_0001
Step 1. Synthesis of ethyl 3-[2-(methylsulfanyl) pyrimidin-4-yl]-2-oxopropanoate To a stirred solution of 4-methyl-2-(methylsulfanyl) pyrimidine (10 g, 71 mmol, 1.00 equiv) and ethyl oxalate (52.12 g, 356.63 mmol, 5.00 equiv) in THF (100 mL) was added t-BuOK (16.01 g, 142.65 mmol, 2.00 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 15 min at room temperature under air atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (100 mL). This resulted in ethyl 3-[2-(methylsulfanyl) pyrimidin-4-yl]-2- oxopropanoate (15 g, 87.52%) as a yellow solid. LC-MS: (M+H) + found:241.05. Step 2. Synthesis of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylsulfanyl) pyrimidin-4-yl] propanoate To a stirred solution of ethyl 3-[2-(methylsulfanyl) pyrimidin-4-yl]-2-oxopropanoate (15 g, 62.42 mmol, 1.00 equiv) and NH2OH.HCl (4.77 g, 68.67 mmol, 1.10 equiv) in EtOH (100 mL) was added NaOAc (7.68 g, 93.64 mmol, 1.50 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2h at 80°C under air atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with Water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (100 mL). This resulted in ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylsulfanyl) pyrimidin-4- yl] propanoate (15 g, 94.12%) as a yellow solid. LC-MS: (M+H) + found:256.00. Step 3. Synthesis of ethyl 7-(methylsulfanyl) pyrazolo[1,5-c]pyrimidine-2-carboxylate To a stirred solution of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylsulfanyl) pyrimidin- 4-yl] propanoate (1.00 g, 3.91 mmol, 1.00 equiv) and TEA (11.89 g, 117.51 mmol, 2.00 equiv) in ACN (150 mL) was added TsCl (11.20 g, 58.75 mmol, 1.00 equiv) in portions at 0°C under air atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under air atmosphere. To the above mixture was added ferrous chloride (2.23 g, 17.62 mmol, 0.30 equiv) in portions over 1 min at room temperature. The resulting mixture was stirred for additional overnight at 80°C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of Water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (25:1) to afford ethyl 7-(methylsulfanyl) pyrazolo[1,5-c]pyrimidine-2-carboxylate (3 g, 21.52%) as a yellow solid. LC-MS: (M+H) + found:238.00. Step 4. Synthesis of 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine-2-carboxylic acid A solution of ethyl 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine-2-carboxylate (2.00 g, 8.42 mmol, 1.00 equiv) in MeOH (5 mL) and H2O (10 mL) was treated with NaOH (1.06 g, 25.28 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was neutralized to pH 6 with HCl (2 M, aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine-2-carboxylic acid (1.38 g, 78.25%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS:(M+H) + found 210.20. Step 5. Synthesis of tert-butyl N-[7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-yl] carbamate A solution of 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine-2-carboxylic acid (1.38 g, 6.59 mmol, 1.00 equiv) in t-BuOH (15 mL) was treated with TEA (1.00 g, 9.89 mmol, 1.50 equiv) at room temperature followed by the addition of DPPA (2.18 g, 7.91 mmol, 1.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was quenched with NaHCO3 at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30:1) to afford tert-butyl N-[7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-yl] carbamate (710 mg, 38.40%) as a yellow oil. LCMS:(M+H) + found 281.10. Step 6. Synthesis of 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine A solution of tert-butyl N-[7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-yl] carbamate (620 mg, 2.21 mmol, 1.00 equiv) in DCM (7.50 mL) was treated with TFA (2.50 mL) at 0°C. The resulting mixture was stirred for overnight at room temperature. The mixture was neutralized to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 7- (methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine (370 mg, 92.83%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS:(M+H) + found 181.05. Step 7. Synthesis of 7-(methylsulfanyl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidin-2-amine To a stirred solution of 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine (360 mg, 1.99 mmol, 1.00 equiv) and N-(TRIFLUOROMETHYLTHIO)SACCHARIN (565 mg, 1.99 mmol, 1.00 equiv) in DCM (5.00 mL) was added TMSCl (282 mg, 2.59 mmol, 1.30 equiv) dropwise at room temperature . The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford 7-(methylsulfanyl)-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidin-2-amine (510 mg, 91.09%) as a white solid. LCMS:(M+H) + found 280.90. Step 8. Synthesis of 72-iodo-7-(methylsulfanyl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- c] pyrimidine To a stirred solution of 7-(methylsulfanyl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidin-2-amine (510 mg, 1.82 mmol, 1.00 equiv) and isoamyl nitrite (639 mg, 5.46 mmol, 3.00 equiv) in ACN (8 mL) was added CH2I2 (4.87 g, 18.20 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred for 1h at 40°C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 15:1) to afford 2-iodo-7-(methylsulfanyl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidine (470 mg, 58.11%) as a yellow solid. LCMS:(M+H) + found 391.85. Step 9. To a stirred solution of 2-iodo-7-(methylsulfanyl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidine (200 mg, 0.51 mmol, 1.00 equiv) in DCM (4.00 mL) was added m- CPBA (114 mg, 0.66 mmol, 1.30 equiv) in portions at 0°C. The resulting mixture was stirred for 1 h at room temperature . The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS:(M+H) + found 407.85. Step 10. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine To a stirred solution of 2-iodo-7-methanesulfinyl-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidine (180 mg, 0.44 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136 mg, 0.66 mmol, 1.50 equiv) in DMA (3.00 mL) was added DIEA (285 mg, 2.21 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 1 h at 50°C. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH=20/1) to afford (3S,4R)-3-fluoro-N-{2-iodo- 3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine (140 mg, 66.64%) as a yellow solid. LCMS:(M+H) + found 476.00 Step 11. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide To a stirred solution of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-c] pyrimidin-7-yl}-1-methylpiperidin-4-amine (130 mg, 0.27 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (59 mg, 0.27 mmol, 1.00 equiv) in DMSO (2.00 mL) were added i-Pr2NH (138 mg, 1.37 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd(PPh3)4 (31 mg, 0.02 mmol, 0.100 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford crude product (150 mg) as a yellow oil. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 63% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 7.82) to afford 4-{[3-(7- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (78.7 mg, 50.87%) as a white solid. LCMS:(M+H) + found 566.15. 1H NMR (400 MHz, DMSO-d6) 8.11-8.08 (m, 1H), 7.95 - 7.73 (m, 2H), 7.46 - 7.38 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 4.88 (d, J = 49.3 Hz, 1H), 4.37 (d, J = 6.3 Hz, 2H), 4.28 - 3.93 (m, 1H), 3.85 (s, 3H), 3.11 - 2.99 (m, 1H), 2.86 - 2.79 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 - 1.98 (m, 6H), 1.78 - 1.64 (m, 1H). Example 215 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(1-fluoroethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1- yl]amino}-3-methoxy-N-methylbenzamide
Figure imgf000497_0001
Step 1. Synthesis of 3-[(difluoromethyl)sulfanyl]-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine To a stirred solution of 7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine (500 mg, 2.77 mmol, 1.00 equiv) and 2-[(difluoromethyl)sulfanyl] isoindole-1,3-dione (763 mg, 3.33 mmol, 1.20 equiv) in DCE (5.00 mL) were added TMSCl (452 mg, 4.16 mmol, 1.50 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (15:1) to afford 3- [(difluoromethyl)sulfanyl]-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine (600 mg, 82.45%) as a yellow solid. LCMS:(M+H) + found 262.95 Step 2. Synthesis of 3-[(difluoromethyl)sulfanyl]-2-iodo-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine To a stirred solution of 3-[(difluoromethyl)sulfanyl]-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidin-2-amine (600 mg, 2.28 mmol, 1.00 equiv) and (3-methylbutyl) nitrite (804 mg, 6.86 mmol, 3.00 equiv) in ACN (8.00 mL) was added CH2I2 (6.13 g, 22.87 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred for 1 h at 40 °C. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford 3-[(difluoromethyl)sulfanyl]-2- iodo-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine (330 mg, 36.65%) as a white solid. LCMS:(M+H) + found 373.85 Step 3. To a stirred solution of 3-[(difluoromethyl)sulfanyl]-2-iodo-7-(methylsulfanyl) pyrazolo[1,5-c] pyrimidine (160 mg, 0.43 mmol, 1.00 equiv) in DCM (3.00 mL) was added m- CPBA (96 mg, 0.56 mmol, 1.30 equiv) in portions at 0°C. The resulting mixture was stirred for 1 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20.00mL). The resulting mixture was extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS:(M+H) + found 389.85. Step 4. Synthesis of (3S,4R)-N-{3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5-c] pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine To a stirred solution of 3-[(difluoromethyl)sulfanyl]-2-iodo-7- methanesulfinylpyrazolo[1,5-c] pyrimidine (250 mg, 0.64 mmol, 1.00 equiv) and (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (145 mg, 0.71 mmol, 1.10 equiv) in DMA (3.00 mL) was added DIEA (415 mg, 3.21 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 2h at 50°C.The resulting mixture was diluted with water (20.00mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford (3S,4R)-N-{3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5-c] pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 40.85%) as a yellow solid. LCMS:(M+H) + found 457.95. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1- fluoroethyl)sulfanyl]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide To a stirred solution of (3S,4R)-N-{3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5-c] pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 0.26 mmol, 1.00 equiv) and 3- methoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (57 mg, 0.26 mmol, 1.00 equiv) in DMSO (3.00 mL) were added i-Pr2NH (132 mg, 1.31 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd(PPh3)4 (30 mg, 0.02 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH=20/1) to afford crude product (120 mg) as a yellow oil. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 51% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 7.98) to afford 4-{[3- (7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)sulfanyl]pyrazolo[1,5- c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (26.8 mg, 18.77%) as an off-white solid. LCMS:(M+H) + found 548.15.1H NMR (400 MHz, DMSO-d6) 8.16 - 8.01 (m, 1H), 7.82 - 7.64 (m, 2H), 7.43 - 7.38 (m, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 55.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.24 - 4.02 (m, 1H), 3.85 (s, 3H), 3.15 - 2.98 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.30 - 1.99 (m, 6H), 1.76 - 1.63 (m, 1H). Example 216 Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1- yl]amino}-4-methoxy-N-methylbenzamide
Figure imgf000500_0001
Step 1. Synthesis of 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine A round bottomed flask was charged with2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (4 g, 17.207 mmol, 1 equiv), NIS (15.48 g, 68.828 mmol, 4 equiv) and a stirbar. ACN (50 mL) was added, and the solution was stirred for 2 h at 25 °C. The mixture was quenched with saturated Na2CO3(aq.). The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with DCM (40 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following condition: column, C18 silica gel; mobile phase, MeCN in water, 0%to 100% gradient in 10min; detector, UV 220 nm. Concentration in vacuo resulted in to afford 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (5 g, 81.09%) solid. LC-MS: (M+H)+ found:358.0. Step 2. Synthesis of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro- 1-methylpiperidin-4-amine A round bottomed flask was charged with 2-bromo-7-chloro-3-iodopyrazolo[1,5- a]pyrimidine (1 g, 2.790 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (0.55 g, 4.185 mmol, 1.5 equiv), TEA (1.69 g, 16.740 mmol, 6 equiv) and a stirbar. DMSO (15 mL) was added, and the solution was stirred for 1 h at 100 °C. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with DCM (50mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following condition: column, C18 silica gel; mobile phase, MeCN in water, 0%to 100% gradient in 10min; detector, UV 220 nm. Concentration in vacuo resulted in (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5- a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (1.26 g, 99.44%) as a yellow solid. LC-MS: (M+H)+ found:453.95. Step 3. Synthesis of (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine To a mixture of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1- methylpiperidin-4-amine (1.3 g, 2.863 mmol, 1 equiv) and (Trifluoromethylthio) silver(I) (1803.11 mg, 8.589 mmol, 3 equiv) in ACN (90 mL) was added 2,2'-Dipyridyl (894.28 mg, 5.726 mmol, 2 equiv) and CuI (1090.48 mg, 5.726 mmol, 2.00 equiv) at 25 °C under nitrogen atmosphere. The mixture was stirred for 16 h at 90 °C. The mixture was quenched with water and NH3.H2O. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was purified by Prep- TLC (DCM/MeOH; ratio:20/1) to afford (3S,4R)-N-{2-bromo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (600 mg, 48.94%) as a yellow solid. LC-MS: (M+H)+ found:428.00. Step 3. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine A resealable reaction vial was charged with (3S,4R)-N-{2-bromo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (300 mg, 0.701 mmol, 1 equiv), NaI (1.05 g, 7.010 mmol, 10 equiv), NaI (1.05 g, 7.010 mmol, 10 equiv), CuI (40.02 mg, 0.210 mmol, 0.3 equiv), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2- diamine (49.82 mg, 0.350 mmol, 0.5 equiv) and a stirbar before being evacuated and purged with nitrogen three times. DMF (1 mL) was added, and the mixture was stirred for 16 h at 110 °C. The reaction mixture was filtered (through a pad of Celite), the pad was washed with EA, and the filtrate was concentrated in vacuo. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with EA (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-TLC (DCM/MeOH; ratio:20/1) to afford (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (200 mg, 60.07%) as a yellow solid. LC-MS: (M+H)+ found:476.00. Step 4. Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide A resealable reaction vial was charged with (3S,4R)-3-fluoro-N-{2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (100 mg, 0.210 mmol, 1 equiv), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (68.89 mg, 0.315 mmol, 1.5 equiv), DIPA (85.17 mg, 0.840 mmol, 4 equiv), CuI (4.01 mg, 0.021 mmol, 0.1 equiv), Pd(PPh3)4 (48.63 mg, 0.042 mmol, 0.2 equiv) and a stirbar before being evacuated and purged with nitrogen three times. DMSO (2 mL) was added, and the mixture was stirred for 1 h at 70 °C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56). Lyophilization yielded 3-{[3-(7-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyrimidin-2-yl)prop- 2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (24 mg, 20.17%) as an off-white solid. LC- MS: (M+H)+ found: 566.30.1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.5 Hz, 1H), 8.14 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.35 (d, J = 6.5 Hz, 2H), 4.00 (d, J = 25.1 Hz, 1H), 3.85 (s, 3H), 3.04 (t, J = 11.5 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.37 – 2.23 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.71 (d, J = 12.2 Hz, 1H). Example 219 Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-7-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3- methoxy-N-methylbenzamide
Figure imgf000503_0001
Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine BF3.Et2O (11.80 mL, 93.116 mmol, 1.10 equiv) was added to a solution of pyrazolo[1,5- a]pyridine (10 g, 84.646 mmol, 1 equiv) in THF (100 mL) at 0 °C and stirred for 10 min. The mixture was cooled to -78 °C and 1-(chloromagnesio)-2,2,6,6-tetramethylpiperidine; chlorolithium (102 mL, 101.580 mmol, 1.20 equiv) was added dropwise and the mixture stirred for 15 min, before a solution of I2 (32.23 g, 126.969 mmol, 1.5 equiv) in THF (100 mL) was added dropwise and the mixture allowed to slowly warm to ambient temperature overnight. The mixture quenched by addition of saturated aqueous Na2S2O3 (50 mL) and saturated aqueous NH4Cl (50 mL), extracted with EtOAc (3x80 mL), the combined organics washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 38.24%) as a light yellow oil. LC-MS: (M+H)+ found 245. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine A solution of 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 32.372 mmol, 1 equiv) in THF (100 mL) was cooled to -78 °C, before 1-(chloromagnesio)-2,2,6,6-tetramethylpiperidine; chlorolithium (32 mL, 32.372 mmol, 1 equiv) was added dropwise and the mixture stirred for 20 min. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (15.81 g, 48.558 mmol, 1.5 equiv) in THF (10 mL) was added dropwise and the mixture allowed to warm to ambient overnight. The mixture quenched by addition of saturated aqueous NH4Cl (50 mL), extracted with EtOAc (2x80 mL), the combined organics washed with brine (90 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford 7-bromo-2-iodopyrazolo[1,5-a]pyridine (4 g, 38.26%) as a light yellow solid. LC-MS: (M+H)+ found 323, 325. Step 3. Synthesis of 7-bromo-3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5-a]pyridine To a stirred mixture of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (2 g, 6.19 mmol, 1 equiv) and 2-[(difluoromethyl)sulfanyl]isoindole-1,3-dione (1.56 g, 6.81 mmol, 1.1 equiv) in DCE (30 mL) was added TMSCl (1.35 g, 12.386 mmol, 2 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 7-bromo-3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5-a]pyridine (1.6 g, 63.79%) as a light yellow solid. LC-MS: (M+H)+ found 405, 407. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(difluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred mixture of 7-bromo-3-[(difluoromethyl)sulfanyl]-2-iodopyrazolo[1,5- a]pyridine (1 g, 2.469 mmol, 1 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (0.67 g, 3.086 mmol, 1.25 equiv) in 1,4-dioxane (10 mL) were added Pd(PPh3)2Cl2 (0.17 g, 0.247 mmol, 0.1 equiv) and CuI (0.47 g, 2.469 mmol, 1 equiv), K3PO4 (3.14 g, 14.814 mmol, 6 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with water (2x120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 40% gradient in 30 min; detector, UV 254 nm. This resulted in 4-[(3-{7-bromo-3-[(difluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (207.4 mg, 11.94%) as a brown solid. LC-MS: (M+H)+ found 495, 497. Step 5. Synthesis of 4-[(3-{3-[(difluoromethyl)sulfanyl]-7-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide To a stirred mixture of 4-[(3-{7-bromo-3-[(difluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (180 mg, 0.254 mmol, 1 equiv, 70%) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (105 mg, 0.508 mmol, 2 equiv) in THF (3 mL) were added 3rd t-BuXPhos generation precatalyst (41 mg, 0.051 mmol, 0.2 equiv) and t-BuONa (123 mg, 1.270 mmol, 5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 65°C under nitrogen atmosphere. The resulting mixture was extracted with CH2Cl2/MeOH (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-[(3-{3-[(difluoromethyl)sulfanyl]-7-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy- N-methylbenzamide (45.2 mg, 31.44%) as a yellow solid. LC-MS: (M+H)+ found 547.15. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (q, J = 4.5 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.34 (d, J = 1.9 Hz, 1H), 7.16 (t, J = 55.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.44 – 6.38 (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.91 – 3.82 (m, 4H), 3.06 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33 – 2.12 (m, 5H), 2.01 – 1.74 (m, 2H). Example 223 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-3-methoxy-N-methylbenzamide
Figure imgf000506_0001
Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine BF3.Et2O (3.96 g, 27.93 mmol, 1.10 equiv) was added to a solution of pyrazolo[1,5- a]pyridine (3.00 g, 25.39 mmol, 1.00 equiv) in THF (20.00 mL) at 0 °C and it was stirred for 10 min. The mixture was cooled to -78 °C and then, TMPMgCl.LiCl (1M, 30.47 mL, 30.47 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 15 min, a solution of I2 (9.67 g, 38.09 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise under nitrogen atmosphere and the reaction mixture was allowed to slowly warm to ambient temperature overnight. The resulted mixture was quenched by addition of saturated aqueous Na2S2O3 (20.00 mL) and saturated aqueous NH4Cl (20.00 mL). It was extracted with EtOAc (3x40.00 mL) and the combined organics were washed with brine (2x40.00 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 2-iodopyrazolo[1,5-a]pyridine (1.6 g, 25.82%) as a light brown oil. LC-MS: (M+H)+ found 244.95. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine A solution of 2-iodopyrazolo[1,5-a]pyridine (1.60 g, 6.56 mmol, 1.00 equiv) in THF (15.00 mL) was cooled to -78°C, and then, TMPMgCl.LiCl (1M, 7.87 mL, 7.87 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 20 min, a solution of 1,2-dibromo- 1,1,2,2-tetrachloroethane (3.20 g, 9.83 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The resulted mixture was quenched by addition of saturated aqueous NH4Cl (30 mL) and it was extracted with EtOAc (3x40 mL). The combined organics were washed with brine (2x40 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.3 g, 61.40%) as a light yellow solid. LC-MS: (M+H)+ found 322.86. Step 3. Synthesis of 7-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine To a stirred solution of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.35 g, 4.18 mmol, 1.00 equiv) in DMF (15.00 mL) were added 2-[(trifluoromethyl)sulfanyl]isoindole-1,3-dione (1.24 g, 5.02 mmol, 1.20 equiv) and NaCl (24.43 mg, 0.42 mmol, 0.10 equiv). The resulting mixture was stirred at 90°C for 16 h under nitrogen atmosphere. The resulted solution was purified by reversed- phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 7-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine (820.00 mg, 46.37%) as a light yellow solid. LC-MS: (M+H)+ found 422.82. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin- 2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide To a stirred solution of 7-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridine (300.00 mg, 0.71 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (193.49 mg, 0.89 mmol, 1.25 equiv) in 1,4-dioxane (2.00 mL) were added CuI (135.07 mg, 0.71 mmol, 1.00 equiv) and K3PO4 (903.28 mg, 4.25 mmol, 6.00 equiv). The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The solvent was removed under vacuum and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 55% gradient in 40 min; detector, UV 254 nm. This resulted in 4-[(3-{7-bromo-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (45.00 mg, 12.36%) as a light yellow solid. LC-MS: (M+H)+ found 513.01. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide To a stirred solution of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (70.00 mg, 0.14 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55.94 mg, 0.27 mmol, 2.00 equiv) in THF (1.00 mL) were added tBuXPhosPd G3 (43.33 mg, 0.05 mmol, 0.40 equiv) and t-BuONa (78.63 mg, 0.82 mmol, 6.00 equiv). The resulting mixture was stirred at 60°C for 20 min under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 30% gradient in 20 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 7min; Wave Length: 254nm/220 nm; RT(min): 6.67) to afford 4-{[3-(7-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl]amino}-3-methoxy-N-methylbenzamide (16.1 mg, 20.91%) as a white solid. LC-MS: (M+H)+ found 565.30.1H NMR (400 MHz, DMSO-d6) δ 8.11 (q, J = 4.4 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 8.3, 5.4 Hz, 2H), 6.03 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.05 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.35-2.05 (m, 5H), 2.04-1.90 (m, 1H), 1.81 (d, J = 11.7 Hz, 1H). Example 251 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop- 2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide
Figure imgf000508_0001
Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene- 9-carboxylate To a mixture of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 equiv) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 equiv) drop wise at -78°C under nitrogen atmosphere. The mixture was stirred for 1 h at -78°C.And then chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 equiv) was added at -78°C. The mixture was stirred for 2 h at -10°C. The mixture was quenched with NaHCO3(10% a.q.).and the aqueous phase was extracted with EA (300 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Resulted in tert-butyl 7- [(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene-9-carboxylate (3 g, 72.71%) (crude)as yellow oil. Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 equiv) in ACN (50 mL) was added tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 equiv) drop wise at -30°C under nitrogen atmosphere. The mixture was stirred for 30 min at -30°C. And then the mixture was stirred for 30 min at 10°C.The mixture was quenched with water. And the aqueous phase was extracted with EA (300 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1%TFA, 35% to 60% gradient in 10 min; detector, UV 220 nm to afford tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (2 g, 91.42%) as light yellow solid. LC-MS: (M-t-Bu+) found:204.10. Step 3. Synthesis of tert-butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate A mixture of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (500 mg, 1.93 mmol, 1 equiv) and NH4OAc (1.04 g, 13.50 mmol, 7 equiv) in MeOH (10 mL) was stirred for 2 h at room temperature, and then NaBH3CN (181.77 mg, 2.89 mmol, 1.5 equiv) was added, the mixture was stirred for 16 h at 60°C. The reaction mixture was quenched with water (10 mL), and the mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1%FA, 20% to 40% gradient in 10 min; detector, UV 200 nm to afford tert-butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (400 mg, 79.68%) as off-white oil. LC-MS: (M+H+) found:261.10. Step 4. Synthesis of tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 equiv), tert- butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (219.07 mg, 0.84 mmol, 1.2 equiv), Cs2CO3 (685.49 mg, 2.103 mmol, 3 equiv), Pd-PEPPSI-IHeptCl 3- chloropyridine (34.15 mg, 0.04 mmol, 0.05 equiv) in dioxane (8 mL) was stirred for 16 h at 100° C under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (100 mL) twice times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was purified by Prep-TLC (DCM/MeOH=20:1) to afford tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3- {[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane- 9-carboxylate (380 mg, 78.22%) as light yellow solid. LC-MS: (M+H+) found:693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan- 7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}- 3-methoxy-N-methylbenzamide A mixture of tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4- (methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-8-yl] amino}-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (160 mg, 0.23 mmol, 1 equiv) in DCM (3 mL) and TFA (1.5 mL) was stirred for 1 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The resulting crude material was purified by Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56). Lyophilization yielded 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro- 3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H+) found:593.20. Step 5. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide The resulting 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3- methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equiv) was purified Chiral Pre-HPLC (Column: CHIRALPAKIF3; Mobile Phase A: Hex(0.1%DEA): EtOH=50: 50; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 2uL mL). Lyophilization yielded rel- 4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N- methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H)+ found: 593.20. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H). Example 275 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-3-methoxy-N-methylbenzamide
Figure imgf000511_0001
Step 1. Synthesis of tert-butyl 3-[5-(methylcarbamoyl)-2-(prop-2-yn-1- ylamino)phenoxy]azetidine-1-carboxylate To a stirred solution of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (204 mg, 0.99 mmol, 1.00 equiv) and tert-butyl 3-iodoazetidine-1-carboxylate (311 mg, 1.09 mmol, 1.10 equiv) in DMF (4.00 mL) was added Cs2CO3 (976 mg, 2.99 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 3-[5-(methylcarbamoyl)- 2-(prop-2-yn-1-ylamino)phenoxy]azetidine-1-carboxylate (200 mg, 55.71%) as a yellow oil. LC- MS: (M+H)+ found: 360.15. Step 2. Synthesis of tert-butyl 3-{2-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5- (methylcarbamoyl)phenoxy}azetidine-1-carboxylate To a stirred solution of tert-butyl 3-[5-(methylcarbamoyl)-2-(prop-2-yn-1- ylamino)phenoxy]azetidine-1-carboxylate (230 mg, 0.64 mmol, 1.00 equiv) and 8-bromo-2-iodo- 3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (270 mg, 0.64 mmol, 1.00 equiv) in DMSO (4.00 mL) were added Pd(PPh3)4 (36 mg, 0.032 mmol, 0.05 equiv) and CuI (12 mg, 0.064 mmol, 0.10 equiv) and i-Pr2NH (161 mg, 1.60 mmol, 2.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 3-{2-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5- (methylcarbamoyl)phenoxy}azetidine-1-carboxylate (380 mg, crude). The crude was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford tert-butyl 3-{2- [(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5- (methylcarbamoyl)phenoxy}azetidine-1-carboxylate (250 mg, 59.69%) as a yellow solid. LC-MS: (M+H)+ found: 654.15. Step 3. Synthesis of tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5- (methylcarbamoyl)phenoxy)azetidine-1-carboxylate To a stirred solution of tert-butyl 3-{2-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5- (methylcarbamoyl)phenoxy}azetidine-1-carboxylate (270 mg, 0.41 mmol, 1.00 equiv) and (3R,4R)-3-fluorooxan-4-amine (73 mg, 0.61 mmol, 1.50 equiv) in dioxane (8.00 mL) were added Pd-PEPPSI-IHeptCl 3-chloropyridine (40 mg, 0.041 mmol, 0.10 equiv) and Cs2CO3 (672 mg, 2.06 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with NaHCO3 aq. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3- fluorooxan-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-5-(methylcarbamoyl)phenoxy)azetidine-1-carboxylate (270 mg, 94.48%) as a yellow solid. LC-MS: (M+H)+ found: 693.25. Step 4. Synthesis of 3-(azetidin-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide To a stirred solution of tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5- (methylcarbamoyl)phenoxy)azetidine-1-carboxylate (150 mg, 0.21 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00 mL) dropwise at 0 °C . The resulting mixture was stirred for 0.5 h at room temperature. The mixture/residue was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2/MeOH (10:1, 5 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-(azetidin-3-yloxy)-4-{[3-(8-{[(3R,4R)-3- fluorooxan-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-N-methylbenzamide (120 mg, 93.52%) as a yellow solid. LC-MS: (M+H)+ found: 593.20. Step 5. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1- methylazetidin-3-yl)oxy]benzamide To a stirred solution of 3-(azetidin-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxan-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide (115 mg, 0.19 mmol, 1.00 equiv) and POM (11 mg, 0.38 mmol, 2.00 equiv) in MeOH (5.00 mL) were added HOAc (11 mg, 0.19 mmol, 1.00 equiv) and NaBH3CN (36 mg, 0.58 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 50 °C. The reaction was quenched with NaHCO3 aq. The resulting mixture was extracted with CH2Cl2 / MeOH (10:1, 4 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (110 mg) was purified by Prep-HPLC with the following conditions (Column: xBridge Prep Phenyl 5μm OBD 19*250mm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min mL/min; Gradient: isocratic 35%B - 65%B IN 20 MIN; Wave Length: 220/254 nm; RT1(min): 14) to afford 4-{[3-(8-{[(3R,4R)-3-fluorooxan-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1- methylazetidin-3-yl)oxy]benzamide (50.7 mg, 42.34%) as a white solid. LC-MS: (M+H)+ found: 607.10.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.4, 1.6 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.04 (t, J = 6.3 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 4.86 - 4.73 (m, 2H), 4.34 (d, J = 6.2 Hz, 2H), 4.05 - 3.90 (m, 3H), 3.79 – 3.75 (m, 2H), 3.67 -3.33 (m, 2H), 3.06 – 3.03 (m, 2H), 2.75 - 2.65 (m, 3H), 2.31 (s, 3H), 1.93 -1.92 (m, 1H), 1.83 -1.78 (m, 1H). Example 308 Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl]-5- methoxy-2H-indazol-6-amine
Figure imgf000514_0001
Step 1. Synthesis of 5-methoxy-6-nitro-2-(oxan-2-yl)indazole To a stirred solution of 5-methoxy-6-nitro-2H-indazole (1 g, 5.17 mmol, 1.00 equiv) and DHP (650 mg, 7.76 mmol, 1.50 equiv) in DCM (10 mL) was added TsOH (90 mg, 0.51 mmol, 0.10 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred overnight at 50°C under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-methoxy-6-nitro-2-(oxan-2-yl)indazole (1.20 g, 83.60%) as a yellow solid. LC-MS: (M+H)+ found:278. Step 2. Synthesis of 5-methoxy-2-(oxan-2-yl) indazol-6-amine To a stirred solution of 5-methoxy-6-nitro-2-(oxan-2-yl)indazole (1.10 g, 3.96 mmol, 1.00 equiv) and Fe (2.22 g, 39.67 mmol, 10.00 equiv) in MeOH (10 mL) was added NH4Cl (4.24 g, 79.34 mmol, 20.00 equiv) in portions at room temperature under air atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This resulted in 5-methoxy-2-(oxan-2-yl) indazol-6-amine (0.8 g, 81.54%) as a yellow solid. LC-MS: (M+H)+ found:248. Step 3. Synthesis of 5-methoxy-2-(oxan-2-yl)-N-(prop-2-yn-1-yl) indazol-6-amine To a stirred solution of 5-methoxy-2-(oxan-2-yl) indazol-6-amine (1.00 g, 4.04 mmol, 1.00 equiv) and propargyl bromide (0.53 g, 4.44 mmol, 1.10 equiv) in DMF (10 mL) was added K2CO3 (1.68 g, 12.13 mmol, 3.00 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 70°C under air atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-methoxy-2-(oxan-2-yl)-N-(prop-2-yn-1-yl) indazol-6-amine (0.8 g, 69.33%) as a brown solid. LC-MS: (M+H+) found:286. Step 4. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin- 2-yl} prop-2-yn-1-yl)-5-methoxy-2-(oxan-2-yl) indazol-6-amine) To a stirred solution of 5-methoxy-2-(oxan-2-yl)-N-(prop-2-yn-1-yl) indazol-6-amine (135 mg, 0.47 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridine (200 mg, 0.47 mmol, 1.00 equiv) in DMSO (4 mL) were added CuI (90 mg, 0.47 mmol, 1.00 equiv) and i-Pr2NH (479 mg, 4.73 mmol, 10.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added Pd(PPh3)4 (219 mg, 0.18 mmol, 0.40 equiv) in portions over 1min at room temperature. The resulting mixture was stirred for additional 1h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl} prop-2-yn- 1-yl)-5-methoxy-2-(oxan-2-yl) indazol-6-amine) (190 mg, 65.74%) as a yellow solid. LC-MS: (M+H)+ found: 580. Step 5. Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2 -yn-1-yl]-5-methoxy-2-(oxan-2-yl) indazol-6-amine A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)-5-methoxy-2-(oxan-2-yl)indazol-6-amine (186 mg, 0.32 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (131 mg, 0.64 mmol, 2.00 equiv) ,Cs2CO3 (626mg, 1.92 mmol, 6.00 equiv), BINAP (80 mg, 0.12 mmol, 0.40 equiv) and [2'- (diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; {2'-amino-[1,1'-biphenyl]-2- yl}palladio methanesulfonate (64 mg, 0.06 mmol, 0.20 equiv) in 1,4-dioxane (4 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 28% to 30% gradient in 5 min; detector, UV 254 nm. This resulted in N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2 -yn-1-yl]-5-methoxy-2-(oxan-2-yl) indazol-6-amine (110 mg, 54.12%) as a yellow solid. LC-MS: (M+H+) found:632. Step 6. Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl]-5-methoxy-2H-indazol- 6-amine To a stirred mixture of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl]-5-methoxy-2-(oxan-2-yl) indazol-6-amine (100 mg, 0.15 mmol, 1.00 equiv) in MeOH (2.5 mL) were added HCl (0.65 mL) dropwise at 0°C. The mixture was stirred for 4 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (2x20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 50% B to 60% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl) sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl]-5-methoxy- 2H-indazol-6-amine (33.2 mg, 38.22%) as a white solid. LC-MS: (M+H)+ found: 548.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.67 (d, J = 1.0 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.84 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.89-4.76 (s, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.85 (m, 3H), 3.77-3.68 (s, 1H), 3.08- 2.77 (m, 2H), 2.29 - 2.19 (m, 1H), 2.19 (m, 3H), 2.14 – 2.05 (m, 1H), 1.94 – 1.73 (m, 2H). Example 322 Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4- yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide
Figure imgf000518_0001
Step 1. Synthesis of 4-[(3-{8-[(1,1-dioxo-1lambda6-thiolan-3-yl)amino]-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide To a solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (500.00 mg, 0.97 mmol, 1.00 equiv) and 3-amino-1lambda6-thiolane-1,1-dione hydrochloride (167.18 mg, 0.97 mmol, 1.00 equiv) in dioxane (8.00 mL) were added BINAP (130.30 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (952.07 mg, 2.92 mmol, 3.00 equiv) and BINAP-Pd-G3 (96.66 mg, 0.10 mmol, 0.10 equiv). After stirring at 100°C for 12 h under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 65 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) to afford 4-[(3-{8-[(1,1-dioxo-1lambda6-thiolan-3-yl)amino]-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (360.00 mg, 65.1%) as a yellow oil. LC-MS: (M+H)+ found 568.10. Step 2. Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide The 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide (360.00 mg, 0.64 mmol, 1.00 equiv) was purified by CHIRAL-HPLC with the following conditions (Column: CHIRALPAK IH-3 4.6*50mm, 3.0um; Mobile Phase A: Hex (0.2% DEA) : (MeOH : DCM=1:1)=70:30; Gradient: isocratic; Injection Volume: 3.0 mL) to afford 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide (24.3 mg, 6.7%) as a white solid. LC-MS: (M+H)+ found 568.10.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 9.6 Hz, 1H), 7.34 (s, 1H), 7.04-7.00 (m, 1H), 6.79-6.73 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.03-6.00 (m, 1H), 4.45-4.41 (m, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 3.61-3.56 (m, 1H), 3.38-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.75 (s, 3H), 2.51-2.47 (m, 1H), 2.28-2.23 (m, 1H). Example 324 Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
Figure imgf000519_0001
Step 1. Synthesis of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate To a stirred solutionof 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.292 mmol, 1.00 equiv) and tert-butyl (1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate (4.76 mg, 0.02 mmol, 2.00 equiv) in 1,4-dioxane (3 mL) was added Cs2CO3 (286 mg, 0.876 mmol, 3 equiv), BINAP (73 mg, 0.12 mmol, 0.40 equiv) and RAC-BINAP-PD-G3 (58 mg, 0.06 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 4h at 100°C. The reaction was monitored by LCMS. The reaction was quenched by the addition of Water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (25:1) to afford tert-butyl (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn- 1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}-8- azabicyclo[3.2.1]octane-8-carboxylate as a brown solid. LC-MS: (M+H)+ found:677.50. Step 2. Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide A solution of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.077 mmol, 1.00 equiv) in TFA (0.3 mL) /DCM (0.9 mL) (3:1) at room temperature . The resulting mixture was stirred for additional 1h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with Water and extracted with CH2Cl2 (3 x10 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro- 8-azabicyclo[3.2.1]octan-3-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.5 mg, 22.30%) as an off-white solid.LC-MS: (M+H) + found:577.10.1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 0H), 8.10 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 6.3 Hz, 1H), 5.47 (d, J = 9.4 Hz, 1H), 4..52 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.98 (s, 1H), 3.84 (s, 3H), 3.58 -3.44 (m, 3H), 2.75 (d, J = 4.5 Hz, 3H), 1.83-1.69 m, 6H). Example 329 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop- 2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide
Figure imgf000521_0001
Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene- 9-carboxylate To a mixture of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 equiv) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 equiv) drop wise at -78°C under nitrogen atmosphere. The mixture was stirred for 1 h at -78°C.And then chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 equiv) was added at -78°C. The mixture was stirred for 2 h at -10°C. The mixture was quenched with NaHCO3(10% a.q.).and the aqueous phase was extracted with EA (300 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Resulted in tert-butyl 7- [(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene-9-carboxylate (3 g, 72.71%) (crude)as yellow oil. Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 equiv) in ACN (50 mL) was added tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo [3.3.1] non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 equiv) drop wise at -30°C under nitrogen atmosphere. The mixture was stirred for 30 min at -30°C. And then the mixture was stirred for 30 min at 10°C.The mixture was quenched with water. And the aqueous phase was extracted with EA (300 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1%TFA, 35% to 60% gradient in 10 min; detector, UV 220 nm to afford tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (2 g, 91.42%) as light yellow solid. LC-MS: (M-t-Bu+) found:204.10. Step 3. Synthesis of tert-butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate A mixture of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (500 mg, 1.93 mmol, 1 equiv) and NH4OAc (1.04 g, 13.50 mmol, 7 equiv) in MeOH (10 mL) was stirred for 2 h at room temperature, and then NaBH3CN (181.77 mg, 2.89 mmol, 1.5 equiv) was added, the mixture was stirred for 16 h at 60°C. The reaction mixture was quenched with water (10 mL), and the mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1%FA, 20% to 40% gradient in 10 min; detector, UV 200 nm to afford tert-butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (400 mg, 79.68%) as off-white oil. LC-MS: (M+H+) found:261.10. Step 4. Synthesis of tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 equiv), tert- butyl (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (219.07 mg, 0.84 mmol, 1.2 equiv), Cs2CO3 (685.49 mg, 2.103 mmol, 3 equiv), Pd-PEPPSI-IHeptCl 3- chloropyridine (34.15 mg, 0.04 mmol, 0.05 equiv) in dioxane (8 mL) was stirred for 16 h at 100° C under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (100 mL) twice times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was purified by Prep-TLC (DCM/MeOH=20:1) to afford tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3- {[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane- 9-carboxylate (380 mg, 78.22%) as light yellow solid. LC-MS: (M+H+) found:693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan- 7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}- 3-methoxy-N-methylbenzamide A mixture of tert-butyl (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4- (methylcarbamoyl) phenyl] amino} prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-8-yl] amino}-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (160 mg, 0.23 mmol, 1 equiv) in DCM (3 mL) and TFA (1.5 mL) was stirred for 1 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The resulting crude material was purified by Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56). Lyophilization yielded 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro- 3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H+) found:593.20. Step 6. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N-methylbenzamide The resulting 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3-[(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3- methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equiv) was purified Chiral Pre-HPLC (Column: CHIRALPAKIF3; Mobile Phase A: Hex(0.1%DEA): EtOH=50: 50; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 2uL mL). Lyophilization yielded rel- 4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl] amino}-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a] pyridin-2-yl) prop-2-yn-1-yl] amino}-3-methoxy-N- methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H)+ found: 593.20. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H). Compounds of Formula (I) in Table 2 below can be prepared analogously to examples 124- 126, 128, 132, 135, 154-156, 185-186, 196, 206, 214-216, 219, 223, 251, 275, 286-287, 308, 315, 322, 324, and 329. Table 2. Compounds of Formula (I) S
Figure imgf000524_0001
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Figure imgf000551_0001
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Figure imgf000560_0001
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Figure imgf000571_0001
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Figure imgf000576_0001
Figure imgf000577_0001
Figure imgf000578_0001
Figure imgf000579_0001
Example 416 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R)-2- hydroxypropyl]-3-methoxybenzamide
Figure imgf000580_0001
Step 1: A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (700.0 mg, 1.70 mmol, 1.00 equiv), methyl 5-amino-6- methoxypyridine-3-carboxylate (370.5 mg, 2.03 mmol, 1.20 equiv) and K2CO3 (702.7 mg, 5.09 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred for 2 h at 70°C. The resulting mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford methyl 4-[(3- {8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3- methoxybenzoate (450.0 mg, 51.73%) as a brown solid. LC-MS: (M+H)+ found 513.1. Step 2. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxybenzoate (450.0 mg, 0.88 mmol, 1.00 equiv) and aq. NaOH (350.6 mg, 8.77 mmol, 10.00 equiv, 5.00 mL H2O) in MeOH (10.00 mL) was stirred for 1 day at 70°C. The mixture was acidified to pH 5 with 1 M HCl. The precipitated solids were collected by filtration and washed with H2O to afford 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (400.0 mg, 91.39%) as a brown yellow solid. LC-MS: (M+H)+ found 499.1. Step 3. To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (260.0 mg, 0.52 mmol, 1.00 equiv) in DMF (4.00 mL) were added HATU (297.0 mg, 0.78 mmol, 1.50 equiv) and Et3N (158.1 mg, 1.56 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (R)-1-amino-2-propanol (46.9 mg, 0.63 mmol, 1.20 equiv). The resulting solution was stirred for additional 1 h at room temperature. The resulted solution was purified using C18 chromatography (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3- methoxybenzamide (200.0 mg, 69.03%) as a brown solid. LC-MS: (M+H)+ found 556.1. Step 4. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (160.0 mg, 0.29 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (117.9 mg, 0.58 mmol, 2.00 equiv), Cs2CO3 (562.2 mg, 1.73 mmol, 6.00 equiv), BINAP (17.9 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (28.5 mg, 0.03 mmol, 0.10 equiv) in 1,4-dioxane (3.00 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 chromatography (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) and Prep-HPLC (Column: RP Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 61% B in 8 min; Wave Length: 220nm nm; RT: 8.25 min) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R)-2-hydroxypropyl]-3- methoxybenzamide (23.6 mg, 13.14%) as an off-white solid. LC-MS: (M+H)+ found 608.40.1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.92-4.67 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dt, J = 11.8, 6.0 Hz, 1H), 3.65-3.50 (m, 1H), 3.17 (td, J = 6.0, 2.7 Hz, 2H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.32-2.14 (s, 4H), 2.12-1.92 (m, 2H), 1.72-1.64 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 475 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2- hydroxypropyl]-3-methoxybenzamide
Figure imgf000582_0001
Step 1: To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (300.0 mg, 0.60 mmol, 1.00 equiv) in DMF (6.00 mL) were added HATU (342.7 mg, 0.90 mmol, 1.50 equiv) and Et3N (182.4 mg, 1.80 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (2S)-1-aminopropan-2-ol (54.2 mg, 0.72 mmol, 1.20 equiv) and the solution was stirred for 1 h at room temperature. The resulted solution was purified using C18 chromatography (Mobile Phase A: water; Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25min; 254/220 nm) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3- methoxybenzamide (200.0 mg, 59.83%) as a brown solid. LC-MS: (M+H)+ found 556.1. Step 2. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (150.0 mg, 0.27 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (110.6 mg, 0.54 mmol, 2.00 equiv), Cs2CO3 (527.0 mg, 1.62 mmol, 6.00 equiv), BINAP (16.8 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (26.8 mg, 0.03 mmol, 0.10 equiv) in 1,4-dioxane (3.00 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 chromatography (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) and Prep-HPLC (Column: RP Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220 nm; RT: 7.95 min) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2-hydroxypropyl]-3- methoxybenzamide (65.3 mg, 39.14%) as an off-white solid. LC-MS: (M+H)+ found 608.45.1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.65 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.58 (d, J = 28.5 Hz, 1H), 3.17 (td, J = 6.0, 3.2 Hz, 2H), 3.08-2.97 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.35-2.10 (m, 4H), 2.09- 1.87 (m, 2H), 1.72-1.63 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 419 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1- hydroxycyclopropyl)methyl]-3-methoxybenzamide
Figure imgf000583_0001
Step 1: To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoic acid (80 mg, 0.15 mmol, 1 equiv), DIEA (112.68 mg, 0.870 mmol, 6 equiv), 1- (aminomethyl)cyclopropan-1-ol (25.3 mg, 0.29 mmol, 2 equiv) in DMF (2 mL) was added HATU (82.9 mg, 0.22 mmol, 1.5 equiv) at 0oC. The solution was stirred for 1 h at 25°C, then diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide (23.2 mg, 25.77%) as an off-white solid. LC-MS: (M-H+) found: 620.35.1H NMR (400 MHz, DMSO-d6) δ 8.10 (t, J = 5.7 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.82 – 6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 5.42 (s, 1H), 4.84 (d, J = 49.2 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 1H), 3.42 (d, J = 5.7 Hz, 2H), 3.05 (d, J = 12.0 Hz, 1H), 2.84 (d, J = 10.8 Hz, 1H), 2.22 (s, 4H), 2.14 (t, J = 11.7 Hz, 1H), 2.00 (m, 1H), 1.70 (d, J = 12.5 Hz, 1H), 0.54 (m, 4H). Example 430 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1- hydroxycyclopropyl)methyl]-3-methoxybenzamide
Figure imgf000584_0001
Step 1: To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}benzoic acid (60 mg, 0.12 mmol, 1 equiv), 2-methanesulfonylethanamine (18.5 mg, 0.15 mmol, 1.3 equiv) and DIEA (89.4 mg, 0.69 mmol, 6 equiv) in DMF(1mL) were added HATU (65.7 mg, 0.17 mmol, 1.5 equiv) and the resulting solution was stirred for 1 h at room temperature. The mixture was diluted with water (20 mL) and extracted with EtOAc (2*20mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 57% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 8.1) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2- methanesulfonylethyl)benzamide (17.2 mg, 23.28%) as a white solid. LC-MS: (M+H)+ found: 626.25.1H NMR (400 MHz, DMSO-d6) δ8.15 (d, J = 4.7 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 4.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 – 6.93 (m, 4H), 6.85 – 6.63 (m, 1H), 5.86 (d, J = 55.8 Hz, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 2.90 – 2.83 (m, 1H), 2.81 – 2.79 (m, 4H), 2.76 (d, J = 4.5 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.23 – 2.13 (m, 3H), 2.10 – 1.93 (m, 3H), 1.82 – 1.79 (m, 1H). Example 406 Synthesis of 1-(4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoyl)-3- methylazetidin-3-ol
Figure imgf000585_0001
Step 1: To a stirred solution of 4-{[3-(8-{[(3S,4R)-1-(tert-butoxycarbonyl)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxybenzoic acid (300.0 mg, 0.47 mmol, 1.00 equiv), DIEA (304.5 mg, 2.35 mmol, 5.00 equiv) and 3-methylazetidin-3-ol hydrochloride (87.4 mg, 0.70 mmol, 1.50 equiv) in DMF (3.00 mL) was added HATU (268.8 mg, 0.70 mmol, 1.50 equiv) at room temperature. The solution was stirred for 1 h at room temperature. The resulting solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3- hydroxy-3-methylazetidine-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizin -8-yl]amino}piperidine-1-carboxylate (270 mg, 81.19%) as a yellow solid. LC-MS: (M+H)+ found 706.3. Step 2. To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3-hydroxy-3- methylazetidine-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizin-8-yl]amino}piperidine-1-carboxylate (70.0 mg, 0.09 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (0.50 mL) at 0 °C. The resulting solution was stirred for 30 min at room temperature, then neutralized to pH 8 with saturated NaHCO3 and extracted with EA (3*50 mL). The organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 58% B in 8 min; Wave Length: 220 nm; RT: 6.6 min) to afford 1-(4-{[3-(8-{[(3S,4R)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 3-methoxybenzoyl)-3-methylazetidin-3-ol (18.4 mg, 28.76%) as a white solid. LC-MS: (M+H)+ found 606.20.1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 6.8 Hz, 1H), 7.22 (s, 1H), 7.17 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 4.72 (d, J = 50.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 4.22-3.53 (m, 8H), 3.11 (td, J = 12.1, 11.2, 5.9 Hz, 1H), 2.97 (d, J = 13.1 Hz, 1H), 2.76 (dd, J = 39.0, 14.4 Hz, 1H), 2.58 (t, J = 12.2 Hz, 1H), 1.79 (m, 1H), 1.62 (dd, J = 12.5, 4.1 Hz, 1H), 1.37 (s, 3H). Example 492 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
Figure imgf000586_0001
Step 1: A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N-methylbenzamide (185 mg, 0.38 mmol, 1 equiv), tert-butyl (3S,4R)-4-amino- 3-fluoropiperidine-1-carboxylate (125.6 mg, 0.58 mmol, 1.5 equiv), RAC-BINAP-Pd-G3 (76.1 mg, 0.08 mmol, 0.2 equiv), BINAP (119.4 mg, 0.19 mmol, 0.5 equiv) and Cs2CO3 (249.9 mg, 0.77 mmol, 2 equiv) in dioxane (2 mL) was stirred for 1h at 100℃ under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (65 mg, 27.35%) as a yellow solid. LC-MS: (M+H)+ found 620.3. Step 2. A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[4- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (50 mg, 0.08 mmol, 1 equiv) and TFA (0.2 mL) in DCM (1 mL) was stirred for 1 h at room temperature. The solution was basified to pH 8 with saturated NaHCO3 and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μ m; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 29% B to 54% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.58) to afford 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (14.8 mg, 34.99%) as a light yellow solid. LC-MS: (M+H)+ found 520.10.1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 4.7 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.73 – 7.55 (m, 2H), 7.21 (d, J = 13.5 Hz, 1H), 6.90 – 6.41 (m, 4H), 6.17 (dd, J = 13.6, 7.6 Hz, 1H), 5.89 (dd, J = 28.6, 8.3 Hz, 1H), 4.72 (d, J = 50.8 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.69 (d, J = 29.3 Hz, 1H), 3.15 – 2.78 (m, 3H), 2.78 – 2.64 (m, 4H), 2.64 – 2.54 (m, 1H), 1.85 – 1.72 (m, 1H), 1.61 (d, J = 12.2 Hz, 1H). Example 504 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000587_0001
Step 1: To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (200.0 mg, 0.40 mmol, 1.00 equiv) and HATU (228.5 mg, 0.60 mmol, 1.50 equiv) in DMF (3.00 mL) were added TEA (121.6 mg, 1.20 mmol, 3.00 equiv) and CH3NH2.HCl (40.6 mg, 0.60 mmol, 1.50 equiv) at room temperature. The reaction was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] indolizin-2- yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110 mg, 53.60%) as a light yellow solid. LC-MS: (M+H)+ found: 511.9. Step 2. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110.0 mg, 0.22 mmol, 1.00 equiv), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (70.3 mg, 0.32 mmol, 1.50 equiv), Cs2CO3 (279.8 mg, 0.86 mmol, 4.00 equiv), BINAP (26.7 mg, 0.04 mmol, 0.20 equiv) and BINAP-Pd-G3 (42.6 mg, 0.04 mmol, 0.20 equiv) in 1,4-dioxane (1.50 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3- {[2-methoxy-4-(methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizin-8-yl]amino} piperidine-1-carboxylate (110 mg, 78.86%) as a yellow solid. LC-MS: (M+H)+ found: 650.2. Step 3. To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino} prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (100.0 mg, 0.15 mmol, 1.00 equiv) in DCM (1.20 mL) was added TFA (0.40 mL) dropwise at room temperature. The resulting solution was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum to afford 4-{[3-(8- {[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn- 1-yl]amino}-3-methoxy-N-methylbenzamide trifluoroacetate (80 mg, 94.57%) as a brown solid. LC-MS: (M+H)+ found: 550.3. Step 4. A mixture of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide trifluoroacetate (70.0 mg, 0.13 mmol, 1.00 equiv), 3-oxetanone (45.9 mg, 0.64 mmol, 5.00 equiv) and NaOAc (31.4 mg, 0.38 mmol, 3.00 equiv) in MeOH (1.50 mL) was stirred for 1 h at room temperature. Then NaBH3CN (24.0 mg, 0.38 mmol, 3.00 equiv) was added and the solution was stirred for additional 2 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 60% B in 30min; Wave Length: 254 nm/220 nm; RT: 7.73 min) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxetan-3- yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-3- methoxy-N-methylbenzamide (33.1 mg, 42.57%) as an off-white solid. LC-MS: (M+H)+ found: 606.20.1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45- 7.30 (m, 2H), 7.21 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.95 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.85 (d, J = 49.4 Hz, 1H), 4.54 (td, J = 6.4, 2.9 Hz, 2H), 4.42 (dt, J = 24.8, 6.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 28.8 Hz, 1H), 3.49 (m, 1H), 2.96 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (dd, J = 37.5, 12.8 Hz, 1H), 2.00 (m, 2H), 1.72 (d, J = 11.9 Hz, 1H). Example 436 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy- N-methylbenzamide
Figure imgf000589_0001
Step 1: To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (2 g, 10.92 mmol, 1 equiv), CH3NH2.HCl (1.11 g, 16.38 mmol, 1.50 equiv), DIEA (2.38 mL) in DMF (20 mL) was added HATU (6.23 g, 16.38 mmol, 1.50 equiv) in portions over at 0 °C. The reaction was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 3-hydroxy-N-methyl-4-nitrobenzamide (1.8 g, 84.02%) as a yellow solid. LC-MS: (M+H)+ found 197.1. Step 2. A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (600 mg, 3.06 mmol, 1 equiv), bromofluoromethane (0.39 mL, 6.118 mmol, 2 equiv) and K2CO3 (845 mg, 6.12 mmol, 2.00 equiv) in DMF (6 mL) was stirred for 1 h at room temperature. The resulting mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 93.13%) as a light yellow solid. LC-MS: (M+H)+ found 229.3. Step 3. A mixture of 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 2.85 mmol, 1 equiv), Fe (735 mg, 13.15 mmol, 5 equiv) and NH4Cl (762 mg, 14.25 mmol, 5 equiv) in EtOH (5 mL) / H2O (1 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4- amino-3-(fluoromethoxy)-N-methylbenzamide (550 mg, 97.42%) as a colorless oil. LC-MS: (M+H)+ found 199.4. Step 4. A mixture of 4-amino-3-(fluoromethoxy)-N-methylbenzamide (96 mg, 0.48 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (200 mg, 0.48 mmol, 1.00 equiv) and K2CO3 (201 mg, 1.45 mmol, 3 equiv) in ACN (2 mL) was stirred overnight at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-[(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(fluoromethoxy)-N- methylbenzamide (130 mg, 50.62%) as a light yellow solid. LC-MS: (M+H)+ found 530.2. Step 5. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-(fluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (58 mg, 0.28 mmol, 1.5 equiv), Pd-PEPPSI- IHeptCl 3-chloropyridine (37 mg, 0.04 mmol, 0.2 equiv) and Cs2CO3 (308 mg, 0.95 mmol, 5 equiv) in dioxane (1.5 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 8 min; Wave Length: 220nm nm; RT1(min): 6.53) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 3-(fluoromethoxy)-N-methylbenzamide (40.7 mg, 37.11%) as a white solid. LC-MS: (M+H)+ found 582.40.1H NMR (400 MHz, DMSO-d6) δ 8.15 (m, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.55 (m, 2H), 7.28 – 7.15 (m, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.25 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.90 (s, 1H), 5.85 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.58 (d, J = 28.8 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 10.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.00 (m, 2H), 1.67 (d, J = 12.1 Hz, 1H). Example 469 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N- methylbenzamide
Figure imgf000591_0001
Step 1: A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1.00 equiv), Cs2CO3 (4.98 g, 15.29 mmol, 3.00 equiv) and bromo(methoxy)methane (960.3 mg, 7.65 mmol, 1.50 equiv) in DMF (10.00 mL) was stirred for 2 h at 0°C. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1% FA) in ACN, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (1.00 g, 81.7%) as a yellow solid. LC-MS: (M+H)+ found:241.0. Step 2. A mixture of solution of 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (950 mg, 3.96 mmol, 1.00 equiv), Fe (2.21 g, 39.55 mmol, 10.00 equiv) and NH4Cl (1.06 g, 19.78 mmol, 5.00 equiv) in EtOH (10.00 mL)/H2O (0.50 mL) was stirred for 2 h at 80°C. The resulting mixture diluted with water (50 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-amino-3-(methoxymethoxy)-N-methylbenzamide (700 mg, 84.19%) as a brown oil. LC-MS: (M+H)+ found:211.0. Step 3. A mixture of 4-amino-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.95 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (196.5 mg, 0.48 mmol, 0.50 equiv) and K2CO3 (394.4 mg, 2.85 mmol, 3.00 equiv) in ACN (6.00 mL) was stirred overnight at 70°C. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE: EA= 1:1) to afford 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 38.76%) as a yellow oil. LC- MS: (M+H+) found:542.0. Step 4. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.37 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (113.5 mg, 0.55 mmol, 1.50 equiv), RAC-BINAP-PD-G3 (36.6 mg, 0.04 mmol, 0.10 equiv), BINAP (45.9 mg, 0.07 mmol, 0.20 equiv) and Cs2CO3 (720.9 mg, 2.21 mmol, 6.00 equiv) in 1,4-dioxane (3.00 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-3-(methoxymethoxy)-N-methylbenzamide (180 mg, 82.2%) as a yellow solid. LC-MS: (M+H)+ found:551.2. Step 5. To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3- (methoxymethoxy)-N-methylbenzamide (70 mg, 0.12 mmol, 1 equiv) in MeOH (6 mL, 148.193 mmol, 1256.76 equiv) was added 1M HCl (0.5 mL) at 0°C. The resulting mixture was stirred for 6 h at room temperature, then basified to pH 8 with sat.NaHCO3 (10 mL) and extracted with CH2Cl2 (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 2% B to 24% B in 8 min; Wave Length: 254 nm/220 nm; RT1(min): 8.1) to afford 4-{[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-3-hydroxy-N-methylbenzamide (12.8 mg, 19.67%) as a off-white solid. LC-MS: (M+H)+ found:550.20.1H NMR (400 MHz, DMSO-d6) δ 9.51 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.29–7.16 (m, 3H), 6.80–6.66 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 5.73–5.62 (m, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.60 (d, J = 29.1 Hz, 1H), 3.04 (s, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.09 (dd, J = 12.8, 10.1 Hz, 1H), 2.00 (d, J = 11.8 Hz, 1H), 1.69 (d, J = 12.2 Hz, 1H). Example 455 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N- methylbenzamide
Figure imgf000593_0001
Step 1: A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (150 mg, 0.28 mmol, 1 equiv), tert- butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (72.4 mg, 0.33 mmol, 1.2 equiv), Cs2CO3 (270.3 mg, 0.83 mmol, 3 equiv), BINAP (17.2 mg, 0.03 mmol, 0.1 equiv) and RAC-BINAP-PD- G3 (17.2 mg, 0.03 mmol, 0.1 equiv) in 1,4-dioxane (1 mL) was stirred for 2 h at 100°C. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=1:1) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-(methoxymethoxy)-4-(methylcarbamoyl)phenyl] amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8-yl]amino}piperidine-1- carboxylate (160 mg, 76.60%) as a light yellow solid. LC-MS: (M+H)+ found:680.0. Step 2. To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2- (methoxymethoxy)-4-(methylcarbamoyl) phenyl]amino}prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizin-8-yl]amino}piperidine-1-carboxylate (150 mg, 0.22 mmol, 1 equiv) in MeOH (5 mL) was added 2 M HCl (1 mL) at 0°C. The resulting solution was stirred for 5 h at room temperature, then basified to pH 8 with sat. NaHCO3 (8 mL) and extracted with CH2Cl2 (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 53% B in 10 min; Wave Length: 254 nm/220 nm; RT1(min): 7.92) to afford 4-{[3-(8-{[(3S,4R)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 3-hydroxy-N-methylbenzamide (9 mg, 7.61%) as a off-white solid. LC-MS: (M+H)+ found:536.15. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.24 (m, J = 14.6, 5.9 Hz, 3H), 6.80–6.65 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.1 Hz, 1H), 5.67 (t, J = 6.2 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.70 (d, J = 29.7 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.98 (d, J = 13.0 Hz, 1H), 2.86–2.68 (m, 4H), 2.60 (d, J = 12.0 Hz, 1H), 2.04 (d, J = 33.5 Hz, 1H), 1.88–1.71 (m, 1H), 1.62 (d, J = 12.4 Hz, 1H). Example 466. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000594_0001
Step 1. To a stirred solution of 4-amino-3-chlorobenzoic acid (1 g, 5.84 mmol, 1 equiv), CH3NH2.HCl (511 mg, 7.58 mmol, 1.3 equiv), DIEA (3.01 g, 23.31 mmol, 4 equiv) in DMF (10 mL) was added HATU (2.66 g, 6.99 mmol, 1.2 equiv) at 0 oC. The resulting mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-amino-3-chloro-N- methylbenzamide (1 g, 92.94%) as a yellow oil. LC-MS: (M+H)+ found 185.0. Step 2. A mixture of 4-amino-3-chloro-N-methylbenzamide (200 mg, 1.08 mmol, 1 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (447 mg, 1.08 mmol, 1 equiv) and K2CO3 (449 mg, 3.25 mmol, 3 equiv) in ACN (1.5 mL) was stirred overnight at 70 °C. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-chloro-N- methylbenzamide (70 mg, 12.50%) as a white solid. LC-MS: (M+H)+ found 516.1. Step 3. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-chloro-N-methylbenzamide (60 mg, 0.12 mmol, 1 equiv), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (23 mg, 0.17 mmol, 1.5 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (33 mg, 0.04 mmol, 0.3 equiv) and Cs2CO3 (189 mg, 0.58 mmol, 5 equiv) in dioxane (1.5 mL) was stirred for 5 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 67%B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.92) to afford 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (5.3 mg, 7.90%) as a light yellow solid. LC-MS: (M+H)+ found 568.35.1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 7.21 (d, J = 0.9 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.58 (d, J = 29.5 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.07 (s, 3H), 1.68 (d, J = 12.3 Hz, 1H). Example 446. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-6-[(trifluoromethyl)sulfanyl] pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}- 3-hydroxy-N-methylbenzamide
Figure imgf000596_0001
Step 1. To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (500 mg, 2.29 mmol, 1 equiv) in DCM(5mL) was added BBr3 (4.58 mL, 4.58 mmol, 2 equiv) at 0°C. The resulting mixture was stirred for 1 h at 0°C. The reaction was quenched by the addition of sat.NaHCO3 (30 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-hydroxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (250 mg, 53.43%) as a yellow solid. LC-MS: (M+H)+ found: 204.9. Step 2. A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (50 mg, 0.25 mmol, 1.2 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)sulfanyl]pyrrolo[1,2- a]pyrazin-1-yl}-1-methylpiperidin-4-amine (96.8 mg, 0.20 mmol, 1 equiv), DIEPA (103.2 mg, 1.02 mmol, 5 equiv), CuI (3.89 mg, 0.02 mmol, 0.1 equiv) and Pd(PPh3)4 (23.6 mg, 0.02 mmol, 0.1 equiv) in DMSO (2 mL) was stirred for 1 h at 70°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6- [(trifluoromethyl)sulfanyl] pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N- methylbenzamide (10.2 mg, 8.68%) as a white solid. LC-MS: (M+H)+ found: 551.30. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.26 (dd, J = 8.2, 2.0 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.68 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 50.0 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (d, J = 34.7 Hz, 1H), 3.31 (m, 1H), 3.07 (d, J = 11.9 Hz, 1H), 2.83 (s, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 3H), 2.16 – 1.87 (m, 3H), 1.67 (d, J = 11.4 Hz, 1H). Example 450. Synthesis of 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-N-methylbenzamide
Figure imgf000597_0001
Step 1. To a stirred solution of methyl 3-formyl-4-nitrobenzoate (2 g, 9.56 mmol, 1 equiv) in DCM (20 mL) was added DAST (1.85 g, 11.474 mmol, 1.2 equiv) dropwise at 0℃. The solution was stirred for 1 h at room temperature, then quenched with water at room temperature. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 3-(difluoromethyl)-4-nitrobenzoate (2.42 g) as a yellow oil. Step 2. A mixture of methyl 3-(difluoromethyl)-4-nitrobenzoate (2.4 g, 10.38 mmol, 1 equiv) and NaOH (2.08 g, 51.92 mmol, 5 equiv) in MeOH (12 mL)/H2O (12 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 6 with 1 M HCl and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(difluoromethyl)-4- nitrobenzoic acid (1.976 g, 87.65%) as a light yellow solid. LC-MS: (M-H)- found 216.0. Step 3. To a stirred solution of 3-(difluoromethyl)-4-nitrobenzoic acid (1.8 g, 8.29 mmol, 1 equiv), methanamine, hydrochloride (0.67 g, 9.95 mmol, 1.2 equiv) and DIEA (4.29 g, 33.16 mmol, 4 equiv) in DMF (20 mL) was added HATU (4.73 g, 12.44 mmol, 1.5 equiv) at 0℃. The mixture was stirred for 1 h at room temperature, then diluted with EA (50 mL) and washed with 3*50 mL of brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1.19 g, 62.26%) as a light yellow solid. LC-MS: (M-H)- found 229.1. Step 4. A mixture of 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1 g, 4.35 mmol, 1 equiv) and Pd/C (2.31 g, 21.73 mmol, 5 equiv) in MeOH (10 mL) was stirred for 1h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 50 min; detector, UV 254 nm) to afford 4-amino- 3-(difluoromethyl)-N-methylbenzamide (750 mg, 86.23%) as a yellow oil. LC-MS: (M+H)+ found 201.1. Step 5. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (200 mg, 0.48 mmol, 1 equiv), K2CO3 (200.7 mg, 1.45 mmol, 3 equiv) and 4-amino-3-(difluoromethyl)-N-methylbenzamide (116.3 mg, 0.58 mmol, 1.2 equiv) in ACN (2 mL) was stirred for 4 h at 70℃. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=1:1) to afford 4-[(3-{8-bromo-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3- (difluoromethyl)-N-methylbenzamide (42 mg, 16.29%) as a brown solid. LC-MS: (M+H)+ found 532.1. Step 6. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-3-(difluoromethyl)-N-methylbenzamide (40 mg, 0.08 mmol, 1 equiv), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine dihydrochloride (23.1 mg, 0.11 mmol, 1.5 equiv), Pd-PEPPSI- IHeptCl 3-chloropyridine (14.6 mg, 0.02 mmol, 0.2 equiv) and Cs2CO3 (97.9 mg, 0.30 mmol, 4 equiv) in 1,4-dioxane (1 mL) was stirred for 0.5 h at 100℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 7min; Wave Length: 254 nm/220 nm; RT1(min): 6.62; Number Of Runs: 2) to afford 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide (4.5 mg, 9.77%) as a dark yellow solid. LC-MS: (M+H)+ found 584.15. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 4.6 Hz, 1H), 8.01 – 7.70 (m, 3H), 7.22 (d, J = 2.8 Hz, 1H), 7.09 (s, 1H), 7.01 – 6.93 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.57 (t, J = 5.9 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.34 (d, J = 5.8 Hz, 2H), 3.59 (d, J = 29.7 Hz, 1H), 3.08 – 2.98 (m, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.09 – 1.92 (m, 2H), 1.68 (d, J = 11.8 Hz, 1H). Example 502. Synthesis of 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000599_0001
Step 1. To a stirred mixture of 4-amino-3-fluorobenzoic acid (2.00 g, 12.89 mmol, 1.00 equiv), CH3NH2.HCl (1.75 g, 25.91 mmol, 2.00 equiv) and NaHCO3 (5.42 g, 64.46 mmol, 5.00 equiv) in DMF (20.00 mL) was added HATU (7.35 g, 19.34 mmol, 1.50 equiv) in portions at 0oC. The solution was stirred for 2 h at room temperature. The resulting solution was purified using C18 flash chromatography (Column: C18 column; Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford 4-amino-3-fluoro-N-methylbenzamide (1.50 g, 68.80%) as a yellow solid. LC-MS: (M+H)+ found 169.1. Step 2. To a stirred mixture of 4-amino-3-fluoro-N-methylbenzamide (1.00 g, 5.94 mmol, 1.00 equiv) and (Boc)2O (1.29 g, 5.94 mmol, 1.00 equiv) in dioxane (20.00 mL) was added DMAP (720.0 mg, 5.94 mmol, 1.00 equiv) at 0 °C. The resulting mixture was stirred for 2 h at 60 °C. After removal of solvent, the residue was purified using C18 flash chromatography (Column: C18 column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford tert-butyl N-[2-fluoro- 4-(methylcarbamoyl)phenyl]carbamate (0.50 g, 31.41%) as a white solid. LC-MS: (M+H)+ found 269.1. Step 3. A mixture of tert-butyl N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamate (200.0 mg, 0.74 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (307.9 mg, 0.74 mmol, 1.00 equiv) and Cs2CO3 (728.7 mg, 2.23 mmol, 3.00 equiv) in DMF (5.00 mL) was stirred for 2 h at room temperature. The resulting mixture was filtered and the filtrate was purified using C18 flash chromatography (Column: C18 column; Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford tert-butyl N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-fluoro-4- (methylcarbamoyl)phenyl]arbamate (300.0 mg, 67.25%) as a yellow solid. LC-MS: (M+H)+ found 600.0. Step 4. A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamate (200.0 mg, 0.33 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (66.0 mg, 0.50 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (32.4 mg, 0.03 mmol, 0.10 equiv) and Cs2CO3 (542.6 mg, 1.66 mmol, 5.00 equiv) in 1,4-dioxane (5.00 mL) was stirred for 3 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using C18 flash chromatography (Column: C18 column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4- (methylcarbamoyl)phenyl]carbamate (150.0 mg, 69.10%) as a yellow oil. LC-MS: (M+H)+ found 652.2. A solution of tert-butyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4- (methylcarbamoyl)phenyl]carbamate (150.0 mg, 0.23 mmol, 1.00 equiv) in 4M HCl (g) in 1,4- dioxane (5.00 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 39% B to 64% B in 8 min; Wave Length: 220 nm; RT: 7.17 min) to afford 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- N-methylbenzamide (53.2 mg, 33.88%) as a grey solid. LC-MS: (M+H)+ found 552.15.1H NMR (400 MHz, DMSO-d6) δ 8.17 (m, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.63-7.51 (m, 2H), 7.21 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.57 (td, J = 6.2, 2.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.74 (m, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.67-3.51 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.85-2.72 (m, 4H), 2.32-1.92 (m, 6H), 1.68 (d, J = 11.6 Hz, 1H). Example 432. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylbenzamide
Figure imgf000601_0001
Step 1. A solution of methyl 4-amino-3-cyanobenzoate (1 g, 5.67 mmol, 1 equiv), (Boc)2O (1.49 g, 6.81 mmol, 1.2 equiv) and DMAP (2.08 g, 17.03 mmol, 3 equiv) in 1,4-dioxane (15 mL) was stirred overnight at 100°C. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford methyl 4-[(tert- butoxycarbonyl)amino]-3-cyanobenzoate (780 mg, 49.74%) as a off-white solid. LC-MS: (M-H)- found 275.2. Step 2. A mixture of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate (240.8 mg, 0.87 mmol, 1.2 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (300 mg, 0.72 mmol, 1 equiv) and Cs2CO3 (709.9 mg, 2.18 mmol, 3 equiv) in DMF (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (3*200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)(tert-butoxycarbonyl)amino]-3-cyanobenzoate (580 mg) as a brown yellow oil. LC-MS: (M+H)+ found 607.9. Step 3. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)(tert-butoxycarbonyl)amino]-3-cyanobenzoate (580 mg, 0.95 mmol, 1 equiv) and NaOH (190.6 mg, 4.76 mmol, 5 equiv) in MeOH (4.5 mL)/H2O (1.5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with citric acid and extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)(tert-butoxycarbonyl)amino]-3- cyanobenzoic acid (550 mg, 97.07%) as a Brown yellow oil. LC-MS: (M+H)+ found 596.0. Step 4. A solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)(tert-butoxycarbonyl)amino]-3-cyanobenzoic acid (550 mg, 0.92 mmol, 1 equiv), methanamine, hydrochloride (93.7 mg, 1.39 mmol, 1.5 equiv), HATU (351.8 mg, 0.92 mmol, 1 equiv) and DIEA (597.9 mg, 4.62 mmol, 5 equiv) in DMF (6 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 67.96%) as a light brown solid. LC-MS: (M+H)+ found 608.9. Step 5. A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 0.62 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (256.6 mg, 1.25 mmol, 2 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (243.7 mg, 0.25 mmol, 0.4 equiv) and Cs2CO3 (1.02 g, 3.13 mmol, 5 equiv) in dioxane (5 mL) was stirred for 3 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (150 mL) and extracted with CH2Cl2 (3 *100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=10:1) to afford tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]carbamate (320 mg, 77.66%) as a brown solid. LC-MS: (M+H)+ found 659.4. Step 6. A solution of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]carbamate (200 mg, 0.30 mmol, 1 equiv) and 4 M HCl (gas) in 1,4-dioxane (0.8 mL) in DCM (4 mL) was stirred for 1h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3 and extracted with CH2Cl2 (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 8.27) to afford 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (71.5 mg, 40.43%) as a off-white solid. LC-MS: (M+H)+ found 559.15.1H NMR (400 MHz, DMSO- d6) δ 8.28 (d, J = 4.7 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 13.7 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.59 (d, J = 30.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 (t, J = 14.0 Hz, 1H), 2.18 (s, 3H), 2.17 – 1.92 (m, 2H), 1.68 (d, J = 12.4 Hz, 1H). Example 495. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6- dimethylpyridine-2,6-dicarboxamide
Figure imgf000603_0001
Step 1. A mixture of 2,6-dibromo-3-nitropyridine (200.0 mg, 0.71 mmol, 1.00 equiv), Fe (158.5 mg, 2.84 mmol, 4.00 equiv) and NH4Cl (151.8 mg, 2.84 mmol, 4.00 equiv) in EtOH (4.00 mL)/H2O (1.00 mL) was stirred at 70℃ for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was diluted with water (50.00 mL) and extracted with EtOAc (3*50.00 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2,6-dibromopyridin-3-amine (180.00 mg, crude) as a light green solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found 252.9. Step 2. To a solution of 2,6-dibromopyridin-3-amine (180.0 mg, 0.72 mmol, 1.00 equiv) in THF (4.00 mL) were added Boc2O (467.9 mg, 2.15 mmol, 3.00 equiv), DMAP (8.7 mg, 0.07 mmol, 0.10 equiv) and Et3N (216.9 mg, 2.15 mmol, 3.00 equiv). The mixture was stirred at 80℃ for 1 h. After removal of solvent, the residue was purified using C18 chromatography (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 65 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) to afford tert-butyl N-(tert-butoxycarbonyl)-N-(2,6-dibromopyridin-3- yl) carbamate (270.00 mg, 83.57%) as a white solid. LC-MS: (M+H)+ found 453.0. Step 3. A mixture of tert-butyl N-(tert-butoxycarbonyl)-N-(2,6-dibromopyridin-3-yl) carbamate (290.0 mg, 0.64 mmol, 1.00 equiv), Pd(dppf)Cl2 (140.8 mg, 0.19 mmol, 0.30 equiv), TEA (1.95 g, 19.23 mmol, 30.00 equiv) and MeNH2.HCl (173.2 mg, 2.56 mmol, 4.00 equiv) in DMA (10.00 mL) was stirred for 16 h at 100℃ under CO atmosphere (10 atm). The resulted mixture was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford tert- butyl N-[2,6-bis(methylcarbamoyl)pyridin-3-yl] carbamate (190.0 mg, 96.07%) as a light yellow solid. LC-MS: (M+H)+ found 309.2. Step 4. To a solution of tert-butyl N-[2,6-bis(methylcarbamoyl)pyridin-3-yl] carbamate (190.0 mg, 0.62 mmol, 1.00 equiv) in MeOH (1.00 mL) was added 4 M HCl (g) in 1,4-dioxane (1.00 mL). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under vacuum to afford 3-amino-N2,N6-dimethylpyridine-2,6-dicarboxamide hydrochloride (130.0 mg, 101.32%) as a light yellow solid. LC-MS: (M+H)+ found 209.1. Step 5. A solution of 3-amino-N2,N6-dimethylpyridine-2,6-dicarboxamide (130.0 mg, 0.62 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (257.9 mg, 0.62 mmol, 1.00 equiv) and 4-methylbenzene-1- sulfonic acid (43.0 mg, 0.25 mmol, 0.40 equiv) in ACN (3.00 mL) was stirred for 16 h at 80℃ under N2 atmosphere. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6 dicarboxamide (40.0 mg, 11.86%) as an off-white solid. LC-MS: (M+H)+ found 540.0. Step 6. A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6-dicarboxamide (40.0 mg, 0.05 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (22.8 mg, 0.11 mmol, 2.00 equiv), Cs2CO3 (108.5 mg, 0.34 mmol, 6.00 equiv), BINAP (3.5 mg, 0.01 mmol, 0.10 equiv) and BINAP- Pd-G3 (5.5 mg, 0.01 mmol, 0.10 equiv) in dioxane (2.00 mL) was stirred for 16 h at 100℃ under N2 atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 61% B in 8 min; Wave Length: 220 nm; RT: 7.58 min) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6-dimethylpyridine-2,6- dicarboxamide (5.80 mg, 20.96%) as a yellow solid. LC-MS: (M+H)+ found 592.20. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.46 (s, 2H), 3.64-3.57 (m, 1H), 3.05 (t, J = 11.0 Hz, 1H), 3.03-2.71 (m, 7H), 2.35-2.06 (m, 5H), 2.00 (d, J = 13.0 Hz, 1H), 1.81-1.66 (m, 1H). Example 433. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy- N-methylpyridine-2-carboxamide
Figure imgf000605_0001
Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (250 mg, 0.61 mmol, 1 equiv), 5-amino-6-methoxy-N- methylpyridine-2-carboxamide (219.3 mg, 1.21 mmol, 2 equiv) and K2CO3 (250.9 mg, 1.82 mmol, 3 equiv) in ACN (6 mL) was stirred for 2 days at 70°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=20:1) to afford 5-[(3-{8-bromo-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine- 2-carboxamide (150 mg, 47.80%) as a yellow solid. LC-MS: (M+H)+ found 514.3. Step 2. A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (76 mg, 0.15 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.7 mg, 0.30 mmol, 2 equiv), Cs2CO3 (241.2 mg, 0.74 mmol, 5 equiv) and 1-methyl-4-(propan-2-yl)benzene; N-[(1R,2R)-2- amino-1,2-diphenylethyl]-N-(chlororuthenio)-4-methylbenzene-1-sulfonamide (18.8 mg, 0.03 mmol, 0.2 equiv) in 1,4-dioxane (1.5 mL) was stirred for additional 2 h at 100°C. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=20:1) to afford 5-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 6-methoxy-N-methylpyridine-2-carboxamide (24.3 mg, 28.98%) as a white solid. LC-MS: (M+H)+ found 565.35.1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 4.9 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.37 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.09 – 2.95 (m, 1H), 2.80 (d, J = 4.9 Hz, 4H), 2.18 (s, 4H), 2.16 – 1.91 (m, 2H), 1.73 – 1.57 (m, 1H). Example 493. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3- dimethylbenzene-1,3-dicarboxamide
Figure imgf000607_0001
Step 1. A solution of 4-aminobenzene-1,3-dicarboxylic acid (600 mg, 3.31 mmol, 1 equiv), methanamine, hydrochloride (447.3 mg, 6.62 mmol, 2 equiv), HATU (2.52 g, 6.62 mmol, 2 equiv) and DIEA (1.71 g, 13.25 mmol, 4 equiv) in DMF (7 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (10 mmol/L NH4HCO3), 0% to 50% gradient in 15 min; detector, UV 254 nm) to afford 4-amino-N1,N3-dimethylbenzene-1,3-dicarboxamide (480 mg, 69.93%) as a light yellow solid. LC-MS: (M-H)-found 206.1. Step 2. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (200 mg, 0.48 mmol, 1 equiv), 4-amino-N1,N3- dimethylbenzene-1,3-dicarboxamide (110.4 mg, 0.53 mmol, 1.1 equiv) and K2CO3 (200.8 mg, 1.45 mmol, 3 equiv) in DMF (3 mL) was stirred for 2 h at 70°C. The resulting mixture was diluted with CH2Cl2 (20 mL) and washed with water (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3- dicarboxamide (145 mg, 55.52%) as a Brown yellow solid. LC-MS: (M+H)+ found 539.1. Step 3. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3-dicarboxamide (140 mg, 0.26 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (79.9 mg, 0.39 mmol, 1.5 equiv), RAC-BINAP-PD-G3 (51.5 mg, 0.05 mmol, 0.2 equiv), BINAP (32.3 mg, 0.05 mmol, 0.2 equiv) and Cs2CO3 (422.9 mg, 1.30 mmol, 5 equiv) in 1,4-dioxane (2 mL) was stirred for 1h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with CH2Cl2 (3 *15 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 /MeOH=10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 59% B in 8 min; Wave Length: 220 nm; RT1(min): 7.25) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3- dimethylbenzene-1,3-dicarboxamide (5.5 mg, 3.51%) as a off-white solid. LC-MS: (M+H)+ found 591.20.1H NMR (400 MHz, DMSO-d6) δ 8.47 – 8.36 (d, J = 4.7 Hz, 1H), 8.34 – 8.23 (t, J = 5.8 Hz, 1H), 8.13 – 8.02 (dd, J = 3.5, 9.3 Hz, 2H), 7.90 – 7.83 (d, J = 6.9 Hz, 1H), 7.83 – 7.76 (dd, J = 2.1, 8.8 Hz, 1H), 7.29 – 7.18 (s, 1H), 6.96 – 6.87 (d, J = 8.8 Hz, 1H), 6.81 – 6.72 (t, J = 7.2 Hz, 1H), 6.19 – 6.11 (d, J = 7.6 Hz, 1H), 5.89 – 5.80 (d, J = 8.3 Hz, 1H), 4.94 – 4.74 (d, J = 49.4 Hz, 1H), 4.47 – 4.31 (d, J = 5.8 Hz, 2H), 3.69 – 3.49 (d, J = 28.2 Hz, 1H), 3.10 – 2.97 (s, 1H), 2.89 – 2.79 (s, 2H), 2.79 – 2.73 (d, J = 4.5 Hz, 6H), 2.23 – 2.16 (s, 3H), 2.14 – 1.95 (m, 2H), 1.73 – 1.65 (d, J = 12.2 Hz, 1H). Example 481. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy- N-methylbenzamide
Figure imgf000608_0001
Step 1 A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (1.00 g, 2.42 mmol, 1.00 equiv), 3-amino-4-methoxy-N- methylbenzamide (523.5 mg, 2.91 mmol, 1.20 equiv) and K2CO3 (1.00 g, 7.26 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 70°C for 1 h. The resulted mixture was filtered and the filtrate was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 3-[(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N- methylbenzamide (650.0 mg, 52.4%) as a white solid. LC-MS: (M+H)+ found 512.0. Step 2. A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-4-methoxy-N-methylbenzamide (640.0 mg, 1.25 mmol, 1.00 equiv), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (408.9 mg, 1.87 mmol, 1.50 equiv), Cs2CO3 (1.22 g, 3.75 mmol, 3.00 equiv), BINAP (77.8 mg, 0.12 mmol, 0.10 equiv) and BINAP-Pd-G3 (123.9 mg, 0.12 mmol, 0.10 equiv) in 1,4-dioxane (10.00 mL) was stirred for 3 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino} piperidine-1-carboxylate (630.0 mg, 77.6%) as a light brown solid. LC-MS: (M+H)+ found 650.2. Step 3. To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl] amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino}piperidine-1-carboxylate (620.0 mg, 0.95 mmol, 1.00 equiv) in DCM (9.00 mL) were added TFA (3.00 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The resulting solution was concentrated under vacuum to afford 3-{[3-(8-{[(3S,4R)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- 4-methoxy-N-methylbenzamide trifluoroacetate (1.08 g, crude) as a dark green semi-solid. LC- MS: (M+H)+ found 550.2. Step 4. A solution of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide trifluoroacetate (100.0 mg, 0.18 mmol, 1.00 equiv), 3-oxetanone (65.6 mg, 0.91 mmol, 5.00 equiv) and NaOAc (44.8 mg, 0.55 mmol, 3.00 equiv) in MeOH (3.00 mL) was stirred at room temperature for 1 h. Then NaBH3CN (34.3 mg, 0.55 mmol, 3.00 equiv) was added at room temperature. The reaction was stirred for additional 3 h at room temperature. The resulting solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 59% B in 7 min; Wave Length: 254 nm/220 nm; RT: 7.67 min) to afford 3-{[3-(8- {[(3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (21.0 mg, 18.8%) as a white solid. LC-MS: (M+H)+ found 606.20.1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.21-7.13 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.2 Hz, 1H), 4.54 (td, J = 6.5, 2.7 Hz, 2H), 4.45 (t, J = 6.1 Hz, 1H), 4.39 (t, J = 6.1 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.83-3.58 (m, 1H), 3.48 (m, 1H), 2.96 (t, J = 10.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.24 (d, J = 12.8 Hz, 1H), 2.02 (td, J = 21.0, 19.7, 9.4 Hz, 2H), 1.71 (d, J = 11.9 Hz, 1H). Example 477. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N- methylbenzamide
Figure imgf000610_0001
Step 1 To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizin-8- yl]amino} piperidine-1-carboxylate (200.0 mg, 0.31 mmol, 1.00 equiv) in DCM (10.00 mL) was added BBr3 (1M in DCM, 5.00 mL) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for 2 h at room temperature, then quenched with MeOH at 0°C. The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150 mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 30% B in 7 min; Wave Length: 254nm/220nm; RT: 6.4 min) to afford 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N-methylbenzamide (18.40 mg, 11.16%) as a grey solid. LC-MS: (M+H)+ found 536.15.1H NMR (400 MHz, DMSO- d6) δ 8.27 (s, 1H), 8.06 (m, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.25-7.18 (m, 2H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.80-6.67 (m, 2H), 6.17 (d, J = 7.6 Hz, 1H), 5.93 (d, J = 8.1 Hz, 1H), 5.26 (s, 1H), 4.86 (d, J = 48.8 Hz, 1H), 4.26 (d, J = 4.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.29 (t, J = 12.2 Hz, 1H), 3.08 (dd, J = 26.6, 13.5 Hz, 2H), 2.99-2.76 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 1.99-1.85 (m, 1H), 1.77- 1.69 (m, 1H). Example 489. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2- hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2- yn-1-yl]amino}-4-methoxy-N-methylbenzamide
Figure imgf000611_0001
Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and K2CO3 (301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100°C for 16 h. The mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% NH3.H2O), 0% to 60% gradient in 20 min; detector, UV 254 nm) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2- hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then it was separated by Prep-SFC (Column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 100 mL/min; Gradient: isocratic 20% B; Column Temperature(oC): 25; Back Pressure(bar): 100; Wave Length: 220 nm; RT(min): 1.7; Sample Solvent: MeOH; Injection Volume: 1.5 mL; Number Of Runs: 30) to afford 3-{[3-(8-{[(3S,4R)- 3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H)+ found 606.40.1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 480. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2R*)-2- hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2- yn-1-yl]amino}-4-methoxy-N-methylbenzamide
Figure imgf000612_0001
Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and K2CO3 (301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100°C for 16 h. The mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water (0.1% NH3.H2O), 0% to 60% gradient in 20 min; detector, UV 254 nm) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2- hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then it was separated by Prep-SFC (Column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 100 mL/min; Gradient: isocratic 20% B; Column Temperature(oC): 25; Back Pressure(bar): 100; Wave Length: 220 nm; RT(min): 1.7; Sample Solvent: MeOH; Injection Volume: 1.5 mL; Number Of Runs: 30) to afford 3-{[3-(8-{[(3S,4R)- 3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H)+ found 606.40.1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 459. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2- hydroxy-2-methylpropyl)-4-(oxetan-3-yloxy)benzamide
Figure imgf000613_0001
Step 1 A mixture of methyl 4-hydroxy-3-nitrobenzoate (3.00 g, 15.21 mmol, 1.00 equiv), 3-iodooxetane (8.40 g, 45.65 mmol, 3.00 equiv) and Cs2CO3 (14.87 g, 45.65 mmol, 3.00 equiv) in DMF (30 mL) was stirred for 24 h at 100°C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-nitro-4-(oxetan-3-yloxy) benzoate (930 mg, 24.14%) as a brown solid. LC-MS: (M+H) + found 254.2. Step 2. A mixture of methyl 3-nitro-4-(oxetan-3-yloxy) benzoate (930 mg, 3.67 mmol, 1.00 equiv), NH4Cl (1.18 g, 22.04 mmol, 6.00 equiv) and Fe (1.23 g, 22.03 mmol, 6.00 equiv) in EtOH (15 mL)/H2O (5 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (12:1) to afford methyl 3-amino-4-(oxetan-3- yloxy) benzoate (800 mg, 97.58%) as a yellow solid. LC-MS: (M+H) + found 224.1. Step 3. A mixture of methyl 3-amino-4-(oxetan-3-yloxy) benzoate (486 mg, 2.18 mmol, 1.50 equiv), K2CO3 (602 mg, 4.36 mmol, 3.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl] indolizine (600 mg, 1.45 mmol, 1.00 equiv) in ACN (8 mL) was stirred overnight at 70°C. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=2 / 1) to afford methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl} prop-2- yn-1-yl) amino]-4-(oxetan-3-yloxy) benzoate (520 mg, 64.46%) as a brown solid. LC-MS: (M+H) + found 555.1. Step 4. A mixture of methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl} prop-2-yn-1-yl) amino]-4-(oxetan-3-yloxy) benzoate (530 mg, 0.95 mmol, 1.00 equiv), (3S,4R)- 3-fluoro-1-methylpiperidin-4-amine dihydrochloride (391 mg, 1.91 mmol, 2.00 equiv), Cs2CO3 (1.87 g, 5.72 mmol, 6.00 equiv), BINAP (237 mg, 0.38 mmol, 0.40 equiv) and RAC-BINAP-PD- G3 (189 mg, 0.19 mmol, 0.20 equiv) in dioxane (10 mL) was stirred overnight at 100°C under nitrogen atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 /MeOH=20/1) to afford methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl) prop-2-yn-1-yl] amino}-4-(oxetan-3-yloxy) benzoate (340 mg, 58.73%) as a brown solid. LC-MS: (M+H) + found 607.3. Step 5. To a stirred solution of methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl) prop-2-yn-1-yl] amino}-4-(oxetan-3- yloxy) benzoate (330 mg, 0.54 mmol, 1.00 equiv) in MeOH (3 mL)/THF (3 mL) /H2O (3 mL) was added NaOH (217 mg, 5.44 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60°C. The mixture was acidified to pH 5 with 1 M HCl, then extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found 593.0. Step 6. To a stirred mixture of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl) sulfanyl] indolizin-2-yl) prop-2-yn-1-yl] amino}-4-(oxetan-3-yloxy) benzoic acid (70 mg, 0.11 mmol, 1.00 equiv), 1-amino-2-methylpropan-2-ol (12.6 mg, 0.14 mmol, 1.2 equiv) and DIEA (46 mg, 0.35 mmol, 3.00 equiv) in DMF (1 mL) was added HATU (54 mg, 0.14 mmol, 1.20 equiv) at 0°C. The mixture was stirred for 1 h at room temperature. The reaction was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254 nm/220 nm; RT1 (min): 6.56) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-hydroxy-2-methylpropyl)- 4-(oxetan-3-yloxy)benzamide (26.5 mg, 33.50%) as a off-white solid. LC-MS: (M+H)+ found: 664.35.1H NMR (400 MHz, DMSO-d6) δ7.95 (d, J = 6.8 Hz, 1H), 7.81 (dd, J = 12.2, 8.1 Hz, 1H), 7.35 (s, 1H), 7.2 (dd, J = 8.1, 2.1 Hz, 1H),7.1 (s,1H), 6.86 (t, J = 7.2 Hz, 1H), 6.54 (s,1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (s, 2H), 5.45 (s,1H), 4.97 (d, J = 6.2 Hz, 2H), 4.91-4.80 (m,1H), 4.63 (s, 3H), 4.3 (s, 2H), 3.81 (d, J = 10.8 Hz, 1H), 3.3 (s, 2H), 3.12 (t, J = 11.5 Hz, 1H), 2.88 (s, 1H), 2.31-2.15 (m,4H),2.12 (s,1H),1.99 (d, J = 13.3 Hz, 1H),1.75-1.64 (m,1H),1.15(s,6H). Example 413. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4- [(1s,3s)-3-hydroxycyclobutoxy]benzamide
Figure imgf000615_0001
Step 1. To a stirred solution of cyclobutane-1,3-diol (444.6 mg, 5.05 mmol, 1 equiv) in DMF (2 mL) was added NaH (403.7 mg, 10.09 mmol, 2 equiv, 60%) at 0°C. The resulting mixture was stirred for 5 min at room temperature. Then 4-fluoro-N-methyl-3-nitrobenzamide (1 g, 5.047 mmol, 1 equiv) was added and the reaction was stirred for 1 h at room temperature. The reaction was quenched with water at 0°C and extracted with EtOAc (2*50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 254 nm) to afford 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (300 mg, 13.40%) as a yellow oil. LC-MS: (M+H)+ found 267.1. Step 2. A mixture of 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (100 mg, 0.30 mmol, 1 equiv), Fe (83.9 mg, 1.50 mmol, 5 equiv), NH4Cl (32.1 mg, 0.60 mmol, 2 equiv), H2O (1 mL) and EtOH (1 mL) was stirred for 1 h at 70 °C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 3- amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 70.43%) as a yellow solid. LC- MS: (M+H)+ found 237.1. Step 3. A mixture of 3-amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 0.42 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (174.8 mg, 0.42 mmol, 1 equiv), and K2CO3 (175.5 mg, 1.27 mmol, 3 equiv) in acetonitrile (2 mL) was stirred for 3 h at 70 °C. The mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(3- hydroxycyclobutoxy)-N-methylbenzamide (80 mg, 33.25%) as a yellow solid. LC-MS: (M+H)+ found 568.0. Step 4. A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (120 mg, 0.21 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (41.9 mg, 0.32 mmol, 1.5 equiv), t-BuONa (101.5 mg, 1.06 mmol, 5 equiv) and tBuXPhos Pd G3 (50.3 mg, 0.06 mmol, 0.3 equiv) in THF (2 mL) was stirred for 1 h at 65 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N- methylbenzamide (40 mg, 30.58%) as a yellow solid. LC-MS: (M+H)+ found 620.3. Step 5. The 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N- methylbenzamide (40 mg, 0.07 mmol, 1 equiv) was separated by chiral-HPLC (Column: CHIRALPAKIF-34.6*50 mm, 3.0 um; Mobile Phase A: MtBE (0.2% DEA): (EtOH: DCM=1: 1)=70: 30; Flow rate: 1.0 ml/min mL/min; Gradient: isocratic; Injection Volume: 5.0L mL) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1s,3s)-3-hydroxycyclobutoxy]benzamide (1.1 mg, 2.74%) as a white solid. LC-MS: (M+H)+ found 620.35.1H NMR (400 MHz, DMSO- d6) δ 8.12 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J = 8.2, 2.1 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.14 (d, J = 7.7 Hz, 1H), 5.87 (s, 1H), 5.53 (t, J = 6.4 Hz, 1H), 5.18 (d, J = 5.5 Hz, 1H), 4.86 (dt, J = 6.6, 3.1 Hz, 2H), 4.40 (m, 1H), 4.28 (d, J = 6.4 Hz, 2H), 3.65 (d, J = 5.5 Hz, 1H), 3.1 (d, J = 5.5 Hz, 1H),2.84 (s, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.43 – 2.18 (m, 8H), 2.09 – 1.95 (m, 2H), 1.71 (s, 1H). Example 497. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4- [(1r,3r)-3-hydroxycyclobutoxy] benzamide
Figure imgf000617_0001
Step 1. The 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N- methylbenzamide (40 mg, 0.07 mmol, 1 equiv) was separated by chiral-HPLC (Column: CHIRALPAKIF-34.6*50 mm, 3.0 um; Mobile Phase A: MtBE (0.2% DEA): (EtOH: DCM=1: 1)=70: 30; Flow rate: 1.0ml/min mL/min; Gradient: isocratic; Injection Volume: 5.0 L mL) to afford 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1r,3r)-3-hydroxycyclobutoxy] benzamide (9.8 mg, 24.38%) as a white solid. LC-MS: (M+H)+ found 620.30.1H NMR (400 MHz, DMSO- d6) δ 8.12 (m, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 0.9 Hz, 1H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.50 (t, J = 6.4 Hz, 1H), 5.21 (d, J = 6.3 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (dd, J = 11.0, 6.6 Hz, 3H), 3.85 (m, 1H), 3.59 (d, J = 29.2 Hz, 1H), 3.04 (s, 1H), 2.83 (m, 3H), 2.74 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.08 (d, J = 6.3 Hz, 1H), 2.05 – 1.87 (m, 3H), 1.68 (d, J = 12.2 Hz, 1H). Example 503. Synthesis of 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylimidazo[1,2-a]pyridine-6-carboxamide
Figure imgf000618_0001
Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (500.0 mg, 1.21 mmol, 1.00 equiv), methyl 8- aminoimidazo[1,2-a]pyridine-6-carboxylate (277.7 mg, 1.45 mmol, 1.20 equiv) and K2CO3 (836.5 mg, 6.06 mmol, 5.00 equiv) in ACN (8.00 mL) was stirred for 2 h at 90°C. The resulting mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)amino]imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 28.41%) as a brown solid. LC-MS: (M+H)+ found 523.1. Step 2. A solution of methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino] imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 0.34 mmol, 1.00 equiv) and aq.NaOH (137.6 mg, 3.44 mmol, 10.00 equiv, 5.00 mL H2O) in MeOH (5.00 mL) was stirred overnight at 70°C. The resulted mixture was acidified to pH 5 with 1 M HCl. The precipitated solids were collected by filtration and washed with H2O, then dried under vacuum to afford 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1- yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (130.0 mg, 74.21%) as a brown solid. LC-MS: (M+H)+ found 509.1. Step 3. To a stirred solution of 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (120.0 mg, 0.24 mmol, 1.00 equiv) in DMF (3.00 mL) were added HATU (134.4 mg, 0.35 mmol, 1.50 equiv) and Et3N (71.5 mg, 0.71 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 10 min at room temperature. Then CH3NH2.HCl (19.1 mg, 0.28 mmol, 1.20 equiv) was added and the resulting mixture was stirred for additional 1 hour at room temperature. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 8-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylimidazo[1,2- a]pyridine-6-carboxamide (80.0 mg, 65.00%) as a light brown solid. LC-MS: (M+H)+ found 522.1. Step 4. A mixture of 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N-methylimidazo[1,2-a]pyridine-6-carboxamide (80.0 mg, 0.15 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (47.1 mg, 0.23 mmol, 1.50 equiv), Cs2CO3 (249.5 mg, 0.77 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (29.8 mg, 0.03 mmol, 0.20 equiv) in 1,4-dioxane (2.00 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 chromatography (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 55% B in 7min; Wave Length: 254 nm/220 nm; RT: 7.63 min) to afford 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N- methylimidazo[1,2-a]pyridine-6-carboxamide (17.0 mg, 19.25%) as an off-white solid. LC-MS: (M+H)+ found 574.20.1H NMR (400 MHz, DMSO-d6) δ 8.43-8.35 (m, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.19 (s, 1H), 6.78-6.70 (m, 2H), 6.63 (t, J = 6.4 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 6.3 Hz, 2H), 3.58 (d, J = 28.6 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.79 (d, J = 4.4 Hz, 4H), 2.31-2.14 (m, 4H), 2.13-1.86 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 439. Synthesis of 2-(3-{[6-(dimethylphosphoryl)-4-methoxypyridin-3- yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine
Figure imgf000620_0001
Step 1. A solution of 6-chloro-4-methoxypyridin-3-amine (2 g, 12.61 mmol, 1 equiv), Dppf (2.79 g, 5.04 mmol, 0.4 equiv), Pd(OAc)2 (283.1 mg, 1.26 mmol, 0.1 equiv), DIEA (0.88 mL, 5.04 mmol, 0.4 equiv) and (methylphosphonoyl)methane (1.48 g, 18.92 mmol, 1.5 equiv) in DMF (20 mL) was stirred for 2 h at 120°C under nitrogen atmosphere. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford 6- (dimethylphosphoryl)-4-methoxypyridin-3-amine (1.36 g, 53.87%) as a white solid. LC-MS: (M+H)+ found 201.1. Step 2. To a stirred solution of 6-(dimethylphosphoryl)-4-methoxypyridin-3-amine (1.16 g, 5.80 mmol, 1 equiv) and DMAP (141.6 mg, 1.16 mmol, 0.2 equiv) in 1,4-dioxane (12 mL) was added (Boc)2O (2.48 mL, 11.59 mmol, 2 equiv) dropwise at room temperature. The resulting solution was stirred for 0.5 h at 70°C, then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 0% to 90% gradient in 15 min; detector, UV 254 nm) to afford tert- butyl N-(tert-butoxycarbonyl)-N-[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]carbamate (1.45 g, 62.49%) as a white solid. LC-MS: (M+H)+ found 401.2. Step 3. A mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[6-(dimethylphosphoryl)-4- methoxypyridin-3-yl]carbamate (1.5 g, 3.75 mmol, 1 equiv) and K2CO3 (1.55 g, 11.24 mmol, 3.00 equiv) in MeOH (15 mL) was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert-butyl N-[6- (dimethylphosphoryl)-4-methoxypyridin-3-yl]carbamate (1.1 g, 97.78%) as a white solid. LC-MS: (M+H)+ found 301.1. Step 4. A mixture of tert-butyl N-[6-(dimethylphosphoryl)-4-methoxypyridin-3- yl]carbamate (200 mg, 0.67 mmol, 1 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (275.1 mg, 0.67 mmol, 1 equiv) and Cs2CO3 (651.0 mg, 2.00 mmol, 3 equiv) in DMF (2 mL) was stirred for 1.5 h at 70°C. The mixture was diluted with water (30 mL) and extracted with CH2Cl2 (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N- [6-(dimethylphosphoryl) -4-methoxypyridin-3-yl]carbamate (320 mg, 59.26%) as a brown yellow solid. LC-MS: (M+H)+ found 632.1. Step 5. A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]carbamate (150 mg, 0.24 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine.2HCl (72.6 mg, 0.34 mmol, 1.5 equiv), Cs2CO3 (386.4 mg, 1.19 mmol, 5 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (46.2 mg, 0.05 mmol, 0.2 equiv) in dioxane (1.5 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford tert-butyl N-[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]carbamate (130 mg, 80.17%) as a brown yellow solid. LC-MS: (M+H)+ found 684.3. Step 6. To a stirred solution of tert-butyl N-[6-(dimethylphosphoryl)-4-methoxypyridin-3- yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]carbamate (130 mg, 0.19 mmol, 1 equiv) in DCM (1.5 mL) was added 4M HCl (gas) in 1,4-dioxane (0.3 mL, 9.87 mmol, 51.93 equiv) dropwise at 0°C. The resulting mixture was stirred for 1 h at room temperature, then concentrated under vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 8 min; Wave Length: 220 nm nm; RT1(min): 7.75) to afford 2-(3-{[6-(dimethylphosphoryl)-4-methoxypyridin- 3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine (47.6 mg, 42.81%) as a pink solid. LC-MS: (M+H)+ found 584.15.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.23 (s, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.19 – 6.09 (m, 2H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.59 (d, J = 29.1 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.86 – 2.76 (m, 1H), 2.35 – 2.13 (m, 4H), 2.12 – 1.92 (m, 2H), 1.73 – 1.64 (m, 1H), 1.58 (d, J = 13.4 Hz, 6H). Example 420. Synthesis of 2-(3-{[6-(dimethylphosphoryl)pyridin-3-yl]amino}prop- 1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine
Figure imgf000622_0001
Step 1. A solution of 6-bromopyridin-3-amine (1.50 g, 8.67 mmol, 1.00 equiv), (methylphosphonoyl)methane (1.69 g, 21.67 mmol, 2.5 equiv), Pd(OAc)2 (291.9 mg, 1.30 mmol, 0.15 equiv), Xantphos (1.00 g, 1.73 mmol, 0.20 equiv) and DIEA (3.36 g, 26.01 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred for 2 h at 130°C. The resulted solution was purified by reversed- phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 6-(dimethylphosphoryl)pyridin-3-amine (850 mg, 57.35%) as a pink solid. LC-MS: (M+H)+ found 171.1. Step 2. To a stirred solution of 6-(dimethylphosphoryl)pyridin-3-amine (850.0 mg, 4.99 mmol, 1.00 equiv) in DMF (5.00 mL) were added Boc2O (1.09 g, 4.99 mmol, 1.00 equiv), DMAP (305.2 mg, 2.50 mmol, 0.50 equiv) and Et3N (1.52 g, 14.99 mmol, 3.00 equiv) at room temperature. The reaction was stirred for 1 h at 100°C. The resulted solution was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford tert-butyl N-[6-(dimethylphosphoryl)pyridin-3-yl]carbamate (295 mg, 21.85%) as a brown yellow solid. LC-MS: (M+H)+ found 271.1. Step 3. A mixture of tert-butyl N-[6-(dimethylphosphoryl)pyridin-3-yl]carbamate (275.0 mg, 1.02 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (420.3 mg, 1.02 mmol, 1.00 equiv) and Cs2CO3 (994.6 mg, 3.05 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred for 16 h at room temperature. The mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[6- (dimethylphosphoryl)pyridin-3-yl]carbamate (291 mg, 47.47%) as a white solid. LC-MS: (M+H)+ found 602.0. Step 4. A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphoryl)pyridin-3-yl]carbamate (80.0 mg, 0.13 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (54.5 mg, 0.27 mmol, 2.00 equiv), Cs2CO3 (216.3 mg, 0.66 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (12.9 mg, 0.01 mmol, 0.10 equiv) in dioxane (2.00 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford tert-butyl N-[6-(dimethylphosphoryl)pyridin- 3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]carbamate (80 mg, 92.16%) as a yellow solid. LC-MS: (M+H)+ found 654.2. Step 5: To a stirred solution of tert-butyl N-[6-(dimethylphosphoryl)pyridin-3-yl]-N-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]carbamate (70.0 mg, 0.10 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (0.50 mL). The resulting mixture was stirred for 1 h at room temperature. The mixture was neutralized with sat.NaHCO3 and extracted with EA. The combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 49% B in 7 min; Wave Length: 254 nm/220 nm; RT(min): 7.73) to afford 2-(3-{[6-(dimethylphosphoryl)pyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (38.1 mg, 64.21%) as a white solid. LC-MS: (M+H)+ found 554.25.1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.68 (dd, J = 8.4, 4.9 Hz, 1H), 7.23 (s, 1H), 7.16 (dt, J = 8.5, 2.8 Hz, 1H), 6.96 (t, J = 6.2 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 3.59 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.85-2.77 (m, 1H), 2.41-1.89 (m, 6H), 1.68 (d, J = 12.0 Hz, 1H), 1.56 (d, J = 13.4 Hz, 6H). Example 428. Synthesis of 2-(3-{[5-(dimethylphosphoryl)pyridin-2-yl]amino}prop- 1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine
Figure imgf000624_0001
Step 1. A mixture of 5-bromopyridin-2-amine (2 g, 11.56 mmol, 1 equiv), (methylphosphonoyl)methane (1.80 g, 23.12 mmol, 2.00 equiv), Pd(OAc)2 (779 mg, 3.47 mmol, 0.3 equiv), XantPhos (1.34 g, 2.31 mmol, 0.2 equiv) and DIEA (6.04 mL, 34.68 mmol, 3 equiv) in DMF (20 mL) was stirred for 2 h at 120°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford crude 5-(dimethylphosphoryl)pyridin-2-amine (2 g) as a yellow oil which was used in the next step directly without further purification. LC-MS: (M+H)+ found 171.2. Step 2: To a stirred solution of 5-(dimethylphosphoryl)pyridin-2-amine (2.7 g, 15.87 mmol, 1 equiv) and di-tert-butyl dicarbonate (6.93 g, 31.74 mmol, 2 equiv) in dioxane (30 mL) were added DMAP (194 mg, 1.59 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The reaction was stirred for 1 h at 100°C. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert- butyl N-(tert-butoxycarbonyl)-N-[5-(dimethylphosphoryl)pyridin-2-yl]carbamate (1.7 g, 28.92%) as a yellow solid. LC-MS: (M+H)+ found 371.1. Step 3: A mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[5- (dimethylphosphoryl)pyridin-2-yl]carbamate (1.2 g, 3.240 mmol, 1 equiv) and K2CO3 (1.34 g, 9.72 mmol, 3 equiv) in MeOH (10 mL) was stirred for 1 h at room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford tert- butyl N-[5-(dimethylphosphoryl)pyridin-2-yl]carbamate (700 mg, 79.94%) as a white solid. LC- MS: (M+H)+ found 271.3. Step 4: A mixture of tert-butyl N-[5-(dimethylphosphoryl)pyridin-2-yl]carbamate (131 mg, 0.48 mmol, 1 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (200 mg, 0.48 mmol, 1.00 equiv) and K2CO3 (201 mg, 1.45 mmol, 3.00 equiv) in ACN (2 mL) was stirred for 2 h at 70°C. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford tert-butyl N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphoryl)pyridin-2- yl]carbamate (170 mg, 58.28%) as a light brown solid. LC-MS: (M+H)+ found 602.2. Step 5: A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphoryl)pyridin-2-yl]carbamate (160 mg, 0.27 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82 mg, 0.40 mmol, 1.5 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (52 mg, 0.05 mmol, 0.2 equiv) and Cs2CO3 (433 mg, 1.33 mmol, 5 equiv) in dioxane (2 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 0% to 80% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl N-[5- (dimethylphosphoryl)pyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]carbamate (100 mg, 57.60%) as a yellow solid. LC-MS: (M+H)+ found 654.0. Step 6: To a stirred solution of tert-butyl N-[5-(dimethylphosphoryl)pyridin-2-yl]-N-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]carbamate (80 mg, 0.12 mmol, 1 equiv) in DCM (2 mL) was added HCl (gas)in 1,4-dioxane (0.4 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 51% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78) to afford 2-(3- {[5-(dimethylphosphoryl)pyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (23.7 mg, 34.98%) as a light yellow solid. LC-MS: (M+H)+ found 554.20.1H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J = 6.6, 2.2 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.72 (m, 1H), 7.55 (t, J = 5.9 Hz, 1H), 7.23 (s, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.66 (dt, J = 8.6, 1.4 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.70 – 3.50 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.81 (d, J = 10.6 Hz, 1H), 2.19 (s, 4H), 2.14 – 1.91 (m, 2H), 1.74 – 1.62 (m, 1H), 1.59 (d, J = 13.3 Hz, 6H). Example 402. Synthesis of 2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridin-2- yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine
Figure imgf000627_0001
Step 1. A mixture of 5-bromo-3-methoxypyridin-2-amine (2 g, 9.85 mmol, 1 equiv), (methylphosphonoyl)methane (2.31 g, 29.55 mmol, 3 equiv), DIEA (3.82 g, 29.55 mmol, 3 equiv), Pd(OAc)2 (442.3 mg, 1.97 mmol, 0.2 equiv) and XantPhos (1.71 g, 2.96 mmol, 0.3 equiv) in DMF (10 mL) was stirred for 24 h at 120°C. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 5-(dimethylphosphoryl)-3- methoxypyridin-2-amine (1.5 g, 76.07%) as a yellow oil. LC-MS: (M+H)+ found 201.0. Step 2: To a stirred solution of 5-(dimethylphosphoryl)-3-methoxypyridin-2-amine (1.40 g, 6.99 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added di-tert-butyl dicarbonate (6.11 g, 27.98 mmol, 4 equiv) and DMAP (256.3 mg, 2.10 mmol, 0.3 equiv) at 0°C. The reaction was stirred at 100°C for 1.5h. The resulting solution was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-(tert-butoxycarbonyl)-N-[5- (dimethylphosphoryl)-3-methoxypyridin-2-yl]carbamate (1.80 g, 64.28%) as a yellow oil. LC- MS: (M+H)+ found 401.1. Step 3: A mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[5-(dimethylphosphoryl)-3- methoxypyridin-2-yl]carbamate (1.80 g, 4.49 mmol, 1 equiv) and K2CO3 (1.86 g, 13.48 mmol, 3 equiv) in MeOH (15 mL) was stirred for 12 h at 25°C.The resulting mixture was diluted with water (100 mL) and extracted with DCM (3* 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-[5- (dimethylphosphoryl)-3-methoxypyridin-2-yl]carbamate (1.30 g, 96.30%) as a yellow oil. LC-MS: (M+H)+ found 301.3. Step 4: A mixture of tert-butyl N-[5-(dimethylphosphoryl)-3-methoxypyridin-2- yl]carbamate (300 mg, 1.00 mmol, 1 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (412.6 mg, 1.00 mmol, 1 equiv) and Cs2CO3 (976.5 mg, 3.00 mmol, 3 equiv) in MeCN (4 mL) was stirred for 3 h at 70°C. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-(3- {8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphoryl) -3-methoxypyridin-2-yl]carbamate (400 mg, 63.31%) as a yellow solid. LC-MS: (M+H)+ found 631.9. Step 5: A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphoryl)-3-methoxypyridin-2-yl]carbamate (150 mg, 0.24 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (72.9 mg, 0.36 mmol, 1.5 equiv), Cs2CO3 (386.4 mg, 1.19 mmol, 5 equiv) and Pd-PEPPSI-IHeptCl 3- chloropyridine (46.2 mg, 0.05 mmol, 0.2 equiv) in 1,4-dioxane (3 mL) was stirred at 100°C for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (5* 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-[5-(dimethylphosphoryl)-3-methoxypyridin- 2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 86.33%) as a yellow solid. LC-MS: (M+H)+ found 684.4. Step 6: To a stirred solution of tert-butyl N-[5-(dimethylphosphoryl)-3-methoxypyridin-2- yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 0.21 mmol, 1 equiv) in DCM (1.5 mL) was added 4 M HCl(gas)in 1,4-dioxane (1.02 mL, 4.10 mmol, 20 equiv) at 0°C. The reaction was stirred at 25°C for 1 h. The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 29% B to 54% B in 7min; Wave Length: 254 nm/220 nm; RT1(min): 7.52) to afford 2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridin-2- yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine (73.6 mg, 61.53%) as an off-white solid. LC-MS: (M+H)+ found 584.45.1H NMR (400 MHz, DMSO-d6) 7.98 (dd, J = 6.7, 1.6 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.29-7.17 (m, 2H), 7.07 (t, J = 6.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.59 (d, J = 28.9 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.19 (m, 4H), 2.13-1.92 (m, 2H), 1.64 (s, 4H), 1.60 (s, 3H). Example 445. Synthesis of 2-(3-{[2-(dimethylphosphoryl)-4-methoxypyrimidin-5- yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine
Figure imgf000629_0001
Step 1. A mixture of 2-chloro-4-methoxypyrimidin-5-amine (500.0 mg, 3.13 mmol, 1.00 equiv), (methylphosphonoyl) methane (317.9 mg, 4.07 mmol, 1.30 equiv), DIEA (162.0 mg, 1.25 mmol, 0.40 equiv), DPPF (692.3 mg, 1.25 mmol, 0.40 equiv) and Pd(OAc)2 (70.4 mg, 0.31 mmol, 0.10 equiv) in DMF (5.00 mL) was stirred at 120℃ for 1 h under nitrogen atmosphere. The resulted mixture was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 2-(dimethylphosphoryl)-4-methoxypyrimidin-5-amine (380.0 mg, 60.29%) as a light brown solid. LC-MS: (M+H)+ found 202.1. Step 2: A mixture of 2-(dimethylphosphoryl)-4-methoxypyrimidin-5-amine (370.0 mg, 1.84 mmol, 1.10 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl] indolizine (690.7 mg, 1.67 mmol, 1.00 equiv) and K2CO3 (693.3 mg, 5.01 mmol, 3.00 equiv) in DMF (2.00 mL) was stirred for 2 h at 70℃. The mixture was filtered and the filtrate was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford tert-butyl N-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl} prop-2-yn-1-yl)-N-[2-(dimethylphosphoryl)-4- methoxypyrimidin-5-yl] carbamate (240.0 mg, 22.66%) as a white solid. LC-MS: (M+H)+ found 533.0. Step 3: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)-7-(dimethylphosphoryl)-1,3-dihydro-2-benzofuran-4-amine (100.0 mg, 0.18 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (76.9 mg, 0.37mmol, 2.00 equiv), Cs2CO3 (366.6 mg, 1.13 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (18.3 mg, 0.02 mmol, 0.10 equiv) in 1,4-dioxane (2.00 mL) was stirred for 16 h at 100oC under N2 atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 16% B to 30% B in 7 min; Wave Length: 254nm/220 nm; RT: 7.82 min) to afford 2-(3-{[2-(dimethylphosphoryl)-4-methoxypyrimidin-5-yl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine; FA salt (20.40 mg, 17.70%) as a white solid. LC-MS: (M+H)+ found 585.35. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 71.6 Hz, 2H), 7.90 (d, J = 6.9 Hz, 1H), 7.15 (s, 1H), 6.81 (t, J = 7.2 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 48.2 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.78 (dd, J = 29.1, 11.7 Hz, 1H), 3.44 (t, J = 11.8 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.89 (dd, J = 38.9, 13.8 Hz, 1H), 2.70 (t, J = 11.7 Hz, 1H), 2.53 (s, 3H), 2.10 (dt, J = 17.5, 9.3 Hz, 1H), 1.88 (d, J = 13.4 Hz, 1H), 1.72 (d, J = 13.5 Hz, 6H). Example 429. Synthesis of 2-(3-{[6-(dimethylphosphoryl)pyridazin-3- yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl] indolizin-8-amine
Figure imgf000631_0001
Step 1. A mixture of 6-bromopyridazin-3-amine (500 mg, 2.87 mmol, 1 equiv), (methylphosphonoyl)methane (672.9 mg, 8.62 mmol, 3 equiv), XantPhos (665.1 mg, 1.15 mmol, 0.4 equiv), Pd(AcO)2 (129.0 mg, 0.58 mmol, 0.2 equiv) and DIEA (1.00 g, 7.76 mmol, 2.7 equiv) in DMF (3 mL) was stirred for 3 h at 130 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2/MeOH=10:1 (5*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-(dimethylphosphoryl)pyridazin-3-amine (450 mg, 91.50%) as a brown solid. LC-MS: (M+H)+ found 172.3. Step 2: A solution of 6-(dimethylphosphoryl)pyridazin-3-amine (1 g, 5.84 mmol, 1 equiv), di-tert-butyl dicarbonate (2.55 g, 11.69 mmol, 2 equiv) and DMAP (71.4 mg, 0.58 mmol, 0.1 equiv) in dioxane (8 mL) was stirred for 2 h at 100 °C. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=2:1) to afford tert-butyl N-(tert-butoxycarbonyl)-N-[6- (dimethylphosphoryl)pyridazin-3-yl]carbamate (1 g, 46.08%) as a brown solid. LC-MS: (M+H)+ found 372.2. Step 3: A mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[6- (dimethylphosphoryl)pyridazin-3-yl]carbamate (900 mg, 2.42 mmol, 1 equiv) and K2CO3 (1.00 g, 7.27 mmol, 3 equiv) in MeOH (10 mL) was stirred for 2 h at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=1:1) to afford tert-butyl N-[6-(dimethylphosphoryl)pyridazin-3-yl]carbamate (550 mg, 83.67%) a brown solid. LC-MS: (M+H)+ found 272.1. Step 4: A mixture of tert-butyl N-[6-(dimethylphosphoryl)pyridazin-3-yl]carbamate (150 mg, 0.55 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (228.4 mg, 0.55 mmol, 1.00 equiv) and Cs2CO3 (540.5 mg, 1.66 mmol, 3 equiv) in MeCN (5 mL) was stirred for 2 h at 70 °C. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=2:1) to afford tert-butyl N-(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[6- (dimethylphosphoryl)pyridazin-3-yl]carbamate (240 mg, 71.93%) as a brown solid. LC-MS: (M+H)+ found 603.1. Step 5: A mixture of tert-butyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphoryl)pyridazin-3-yl]carbamate (140 mg, 0.23 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (71.4 mg, 0.35 mmol, 1.5 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (45.2 mg, 0.05 mmol, 0.2 equiv) and Cs2CO3 (378.0 mg, 1.16 mmol, 5.00 equiv) in 1,4-dioxane (2 mL) was stirred for 5 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=2:1) to afford tert-butyl N-[6-(dimethylphosphoryl)pyridazin-3-yl]-N-[3-(8-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1- yl]carbamate (120 mg, 79.00%) as a brown solid. LC-MS: (M+H)+ found 655.4. Step 6: To a solution of tert-butyl N-[6-(dimethylphosphoryl)pyridazin-3-yl]-N-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)prop-2-yn-1-yl]carbamate (120 mg, 0.18 mmol, 1 equiv) in DCM (2 mL) was added 4M HCl (gas) in 1,4-dioxane (0.4 mL) at room temperature. The reaction was stirred at room temperature for 30 min. The resulting solution was concentrated under reduced pressure. The residue was purified using C18 flash chromatography (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 47% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.85; Number Of Runs: 3) to afford 2-(3-{[6- (dimethylphosphoryl)pyridazin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (57.1 mg, 56.17%) as an off-white solid. LC-MS: (M+H)+ found 555.25.1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 7.0 Hz, 2H), 7.73 (dd, J = 9.1, 4.1 Hz, 1H), 7.25 (s, 1H), 7.02 (dd, J = 9.2, 2.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.60 (d, J = 28.6 Hz, 1H), 3.02 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.19 (s, 4H), 2.12 – 1.93 (m, 2H), 1.69 (d, J = 13.6 Hz, 7H). Example 437. Synthesis of 7-(dimethylphosphoryl)-N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]- 1,3-benzoxazol-4-amine
Figure imgf000633_0001
Step 1. To a solution of 1,3-benzoxazol-4-amine (1.00 g, 7.45 mmol, 1.00 equiv) in DMF (10.00 mL) was added a solution of NIS (1.30 g, 5.78 mmol, 0.78 equiv) in DMF (10.00 mL) dropwise at -40°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 50% B in 20 min; 254/220 nm) to afford 7-iodo-1,3-benzoxazol-4-amine (1.83 g, 94.40%) as a yellow solid. LC-MS: (M+H)+ found 261.0. Step 2: A solution of 7-iodo-1,3-benzoxazol-4-amine (1.00 g, 3.85 mmol, 1.00 equiv), palladium acetate (207.2 mg, 0.92 mmol, 0.24 equiv), XantPhos (400.5 mg, 0.69 mmol, 0.18 equiv), DIEA (1.09 g, 8.46 mmol, 2.20 equiv) and (methylphosphonoyl)methane (900.5 mg, 11.54 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred for 1 h at 80°C under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 10% B in 20 min; 254/220 nm) to afford 7-(dimethylphosphoryl)-1,3-benzoxazol-4-amine (300.0 mg, 37.12%) as a green solid. LC-MS: (M+H)+ found 211.2. Step 3: A mixture of 7-(dimethylphosphoryl)-1,3-benzoxazol-4-amine (106.8 mg, 0.51 mmol, 1.05 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]indolizine (200.0 mg, 0.48 mmol, 1.00 equiv) and K2CO3 (200.8 mg, 1.45 mmol, 3.00 equiv) in ACN (3.00 mL) was stirred at 70°C for 8 h. The mixture was filtered and the filtrate was purified using C18 flash chromatography (Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 70% B in 20 min; 254/220 nm) to afford N-(3-{8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphoryl) -1,3- benzoxazol-4-amine (100.0 mg, 38.08%) as a yellow solid. LC-MS: (M+H)+ found 542.1. Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)-7-(dimethylphosphoryl)-1,3-benzoxazol-4-amine (85.0 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.2 mg, 0.24 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (15.3 mg, 0.02 mmol, 0.10 equiv) and Cs2CO3 (306.4 mg, 0.94 mmol, 6.00 equiv) in 1,4-dioxane (2.00 mL) was stirred at 100°C for 16 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 30% B in 20 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 55% B in 8 min; Wave Length: 220 nm; RT: 7.27 min) to afford 7-(dimethylphosphoryl)-N-[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-1,3- benzoxazol-4-amine (11.20 mg, 12.01%) as a white solid. LC-MS: (M+H)+ found 594.25. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.54 (dd, J = 11.8, 8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.4, 1.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.89 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.59 (d, J = 29.4 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.27-1.99 (m, 6H), 1.70 (d, J = 13.4 Hz, 7H). Example 389. Synthesis of 7-(dimethylphosphoryl)-N-[3-(8-{[(3R,4S)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]- 1,3-benzothiazol-4-amine; formic acid
Figure imgf000635_0001
Step 1. To a stirred mixture of 1,3-benzothiazol-4-amine (1 g, 6.65 mmol, 1.00 equiv) in ACN (15 mL, 285.36 mmol, 42.86 equiv) was added NIS (1.50 g, 6.65 mmol, 1.00 equiv) in portions at 0℃ under. The mixture was stirred for 1 h at room temperature. The reaction was quenched with water at room temperature and extracted with CH2Cl2/MEOH (10/1). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford 7-iodo-1,3-benzothiazol-4-amine (1.7 g, 87.30%) as a yellow solid. LC-MS: (M+H)+ found:277.1. Step 2: A mixture of 7-iodo-1,3-benzothiazol-4-amine (850 mg, 3.07 mmol, 1.00 equiv), (methylphosphonoyl)methane (601 mg, 7.69 mmol, 2.50 equiv), Pd(OAc)2 (104 mg, 0.46 mmol, 0.15 equiv), XantPhos (267 mg, 0.46 mmol, 0.15 equiv) and DIEA (796mg, 6.15 mmol, 2.00 equiv) in DMF (10 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The reaction was quenched with water at room temperature and extracted with CH2Cl2/MeOH (10/1). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (60:1) to afford 7-(dimethylphosphoryl)-1,3- benzothiazol-4-amine (640 mg, 87.76%) as a yellow solid. LC-MS: (M+H)+ found:227.2. Step 3: A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl) sulfanyl] indolizine (200 mg, 0.48 mmol, 1.00 equiv), 7-(dimethylphosphoryl)-1,3-benzothiazol-4-amine (131 mg, 0.58 mmol, 1.20 equiv) and K2CO3 (201 mg, 1.45 mmol, 3.00 equiv) in MeCN (5 mL) was stirred overnight at 70℃. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2/MeOH=20:1) to afford N-(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] indolizin-2-yl} prop-2-yn-1-yl)-7-(dimethylphosphoryl)-1,3-benzothiazol-4-amine (100 mg, 34.14%) as a yellow oil. LC-MS: (M+H)+ found:558.1. Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl) sulfanyl] indolizin-2-yl} prop-2- yn-1-yl)-7-(dimethylphosphoryl)-1,3-benzothiazol-4-amine (90 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (50 mg, 0.24 mmol, 1.50 equiv), Cs2CO3 (263 mg, 0.80 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (31 mg, 0.03 mmol, 0.20 equiv) in 1,4-dioxane (3 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.56) to afford 7-(dimethylphosphoryl)-N-[3-(8-{[(3R,4S)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]-1,3- benzothiazol-4-amine; formic acid (36 mg, 36.31%) as a light brown solid. LC-MS: (M+H)+ found: 610.15.1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.61 (dd, J = 12.2, 8.1 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.63 (s, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.5 Hz, 1H), 1.98 (s, 1H), 1.69 (d, J = 13.3 Hz, 7H). Example 483. Synthesis of 8-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl- [1,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000636_0001
Step 1. To a stirred solution of 6-chloro-5-nitropyridine-3-carboxylic acid (2 g, 9.87 mmol, 1 equiv), CH3NH2.HCl (1.33 g, 19.75 mmol, 2 equiv) and DIEA (6.38 g, 49.37 mmol, 5 equiv) in DMF (20 mL) was added T3P (9.43 g, 14.81 mmol, 1.5 equiv, 50% in DMF) at room temperature. The reaction was stirred at 25°C for 1 h. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.6 g, 75.16%) as a yellow solid. LC-MS: (M+H)+ found 216.0. Step 2: To a stirred solution of 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.4 g, 6.49 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added NH2NH2.H2O (1.63 g, 32.47 mmol, 5 equiv) at room temperature. The reaction mixture was stirred at 60°C for 1.5 h. The precipitated solids were collected by filtration and washed with DCM to afford 6-hydrazinyl-N-methyl-5- nitropyridine-3-carboxamide (1 g, 72.92%) as a purple solid. LC-MS: (M+H)+ found 212.2. Step 3: To a stirred solution of 6-hydrazinyl-N-methyl-5-nitropyridine-3-carboxamide (900 mg, 4.26 mmol, 1 equiv) in DMF (10 mL) was added trimethyl orthoformate (4.52 g, 42.62 mmol, 10 equiv) followed by catalytic amount of PTSA (293.6 mg, 1.71 mmol, 0.4 equiv) at room temperature. The reaction mixture was stirred at 65°C for 3 h. The precipitated solids were collected by filtration and washed with DCM to afford N-methyl-8-nitro-[1,2,4]triazolo[4,3- a]pyridine-6-carboxamide (600 mg, 63.65%) as a yellow solid. LC-MS: (M+H)+ found 220.0. Step 4: A mixture of N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (600 mg, 2.71 mmol, 1 equiv), Fe (1.21 g, 21.70 mmol, 8 equiv) and NH4Cl (1.45 g, 27.13 mmol, 10 equiv) in EtOH (3 mL)/water (1 mL) was stirred at 70°C for 1.5 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (250 mg, 48.20%) as a yellow solid. LC-MS: (M+H)+ found 192.1. Step 5: A mixture of 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.52 mmol, 1 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (216.0 mg, 0.52 mmol, 1 equiv) and K2CO3 (216.9 mg, 1.57 mmol, 3 equiv) in DMF (2 mL) was stirred at 70°C for 3h. The resulting mixture was filtered and the filtrate was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, 0% to 50% gradient in 30 min; detector, UV 254 nm) to afford 8-[(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methyl- [1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (60 mg, 9.86%) as a yellow solid. LC-MS: (M+H)+ found 522.8. Step 6: A mixture of 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-1-yl)amino]-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (60 mg, 0.05 mmol, 1 equiv, 45%), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (15.9 mg, 0.08 mmol, 1.5 equiv), Cs2CO3 (67.24 mg, 0.208 mmol, 4 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (10.0 mg, 0.01 mmol, 0.2 equiv) in 1,4-dioxane (2 mL) was stirred at 100°C for 6 h. The resulting mixture diluted with water (20 mL) and extracted with DCM (3* 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 55% B in 7 min; Wave Length: 254 nm/220 nm; RT1(min): 7.53) to afford 8-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}- N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (7 mg, 23.61%) as an off-white solid. LC-MS: (M+H)+ found 575.35.1
Figure imgf000638_0001
8.68 (d, J = 1.4 Hz, 1H), 8.58- 8.51 (m, 1H), 8.47 (s, 1H), 7.82 (d, J = 6.9 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.06 (t, J = 6.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 49.4 Hz, 1H), 4.44 (d, J = 6.3 Hz, 2H), 3.58 (d, J = 30.5 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.13-1.91 (m, 2H), 1.67 (d, J = 11.8 Hz, 1H). Example 491. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2- hydroxy(2-2H)propyl]-3-methoxybenzamide
Figure imgf000639_0001
Step 1. To a stirred solution of 3-methoxy-4-nitrobenzoic acid (1.00 g, 5.07 mmol, 1.00 equiv) in DMF (10.00 mL) were added α-aminoacetone hydrochloride (666.82 mg, 6.09 mmol, 1.20 equiv), DIEA (3.27 g, 25.36 mmol, 5.00 equiv) and HATU (2.89 g, 7.61 mmol, 1.50 equiv) in portions at 0°C under air atmosphere. The mixture was stirred at room temperature for 1 h. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 40% B in 20 min; 254/220 nm). This resulted in 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (750.00 mg, 58.62%) as a yellow oil. LC-MS: (M-H)- found 251.0. Step 2: To a stirred solution of 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (740.00 mg, 2.93 mmol, 1.00 equiv) in MeOH (8.00 mL) was added sodium borodeuteride (245.61 mg, 5.87 mmol, 2.00 equiv) in portions at 0°C under air atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (2.00 mL) at 0°C. The resulted mixture was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 30% B in 20 min; 254/220 nm). This resulted in N-[2-hydroxy(2-2H)propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 74.78%) as a yellow oil. LC-MS: (M+H)+ found 256.1. Step 3: To a stirred solution of N-[2-hydroxy(2-2H)propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 2.19 mmol, 1.00 equiv) in i-PrOH (6.00 mL) was added Pd/C (100.00 mg) under nitrogen atmosphere. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulted mixture was filtered and the filter cake was washed with i-PrOH (3x2.00 mL). The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-[2- hydroxy(2-2H)propyl]-3-methoxybenzamide (440.00 mg, 89.03%) as a grey oil. LC-MS: (M+H)+ found 226.1. Step 4: To a stirred mixture of 4-amino-N-[2-hydroxy(2-2H)propyl]-3-methoxybenzamide (200.00 mg, 0.89 mmol, 1.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl]indolizine (293.38 mg, 0.71 mmol, 0.80 equiv) in DMF (2.00 mL) was added K2CO3 (368.11 mg, 2.66 mmol, 3.00 equiv) at room temperature. The mixture was stirred at 70°C for 1 h. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 75% B in 20 min; 254/220 nm). This resulted in 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2-2H)propyl]-3- methoxybenzamide (245.00 mg, 49.51%) as a white solid. LC-MS: (M+H)+ found 557.0. Step 5: To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2-2H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) were added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and Cs2CO3 (841.73 mg, 2.59 mmol, 6.00 equiv) at room temperature. The mixture was stirred at 100°C for 3 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by Prep-Chiral-HPLC with the following conditions (Column: Lux3umCellulose2; Mobile Phase A: Hex (0.2% DEA): EtOH=80: 20; Flow rate: 1 mL/min; Gradient: isocratic; Injection Volume: 1 mL) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- 2H)propyl]-3-methoxybenzamide (35.6 mg, 13.50%) as a white solid. LC-MS: (M+H)+ found 609.2.1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 5.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.19 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.60 (d, J = 29.6 Hz, 1H), 3.23-3.12 (m, 2H), 3.05 (s, 1H), 2.83 (d, J = 10.9 Hz, 1H), 2.36-2.19 (m, 4H), 2.18-2.05 (m, 1H), 1.99 (d, J = 12.5 Hz, 1H), 1.68 (d, J = 12.4 Hz, 1H), 1.04 (s, 3H). Example 487. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2- hydroxy(2-2H)propyl]-3-methoxybenzamide
Figure imgf000641_0001
Step 1. To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2-2H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) were added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and Cs2CO3 (841.73 mg, 2.59 mmol, 6.00 equiv) at room temperature. The reaction mixture was stirred at 100°C for 3 h under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by Prep-Chiral-HPLC with the following conditions (Column: Lux3umCellulose2; Mobile Phase A: Hex (0.2% DEA): EtOH=80: 20; Flow rate: 1 mL/min; Gradient: isocratic; Injection Volume: 3 mL) to afford 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- 2H)propyl]-3-methoxybenzamide (39.8 mg, 15.05%) as a white solid. LC-MS: (M+H)+ found 609.2.1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 0.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 49.0 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (d, J = 29.1 Hz, 1H), 3.23-3.12 (m, 2H), 3.08 (s, 1H), 2.85 (s, 1H), 2.40-2.10 (m, 5H), 2.00 (d, J = 11.6 Hz, 1H), 1.70 (d, J = 12.3 Hz, 1H), 1.04 (s, 3H). Example 476. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide
Figure imgf000642_0001
Step 1. To a solution of ethyl 8-brmoimidazo[1,2-a]pyridine-2-carboxylate (200 g, 743.23 mmol, 1 eq), andammonia; thiocyanic acid (113.15 g, 1.49 mol, 113.15 mL, 2 eq) in MeOH (2000 mL) was added NCS (200.00 g, 1.50 mol, 2.02 eq). The mixture was stirred at 20 °C for 2 hr. (5 batches) LCMS showed that reactant 1 was consumed and the desired mass (M+1 = 327 Rt = 0.483 min) was given. The reaction mixture was concentrated under vacuum, DCM (3 L) was added. The resulting mixture was stirred for 30 min and filtered, filter cake was washed with DCM (1 L), filtrate was collected, filtrate was washed with 10% NH4Cl (4L), organic phase was filtered with silica gel, filtrate was washed with 10% NH4Cl (4L), Na2SO4 dried and filtered. The residue was triturated with MTBE (1 L) at 25 °C for 1 hour and filtered to get the yellow solid. ethyl 8- bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (900 g, 2.76 mol, 74.25% yield) was obtained as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.82 - 8.66 (m, 1H), 8.08 -7.92 (m, 1H), 7.25 (t, J = 7.2 Hz, 1H), 4.52 - 4.33 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H). Step 2: To a solution of ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (225 g, 689.83 mmol, 1 eq) and Cs2CO3 (337.50 g, 1.04 mol, 1.5 eq) in ACN (1500 mL) and DMF (500 mL) was added TMSCF3 (117.71 g, 827.79 mmol, 1.2 eq). The mixture was stirred at 20 ° C for 2 hr. (4 batches) LCMS showed that ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine- 2-carboxylat consumed and the desired mass (M+1 = 371 Rt = 0.556 min) was given. The reaction mixture was concentrated under vacuum, diluted with H2O (2000 mL), extracted with EA (1000 mL ×3). The organic layer was washed with brine (3000 mL), dried over Na2SO4 and filtered. The crude product was dissolved by DCM (500 mL) and filtered through silica gel. The filtrate was concentrated in vacuo. ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2- carboxylate (660 g, 1.79 mol, 64.79% yield) was obtained as yellow solid. Which was confirmed HNMR. 1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 6.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.23 (t, J = 7.2 Hz, 1H), 4.50 - 4.29 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). Step 3: To a solution of ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2- carboxylate (350.00 g, 948.11 mmol, 1 eq) in MeOH (2500 mL) was added LiOH.H2O (79.57 g, 1.90 mol, 2 eq) in H2O (350 mL). The mixture was stirred at 20 °C for 1 hr. (2 batches) LCMS showed that ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate consumed and the desired mass (M+1 = 341 Rt = 0.452 min) was given. The reaction mixture was adjusted to pH = 1~2 with 6N HCl (350 mL). The mixture was filtered and the filter cake was washed with MeOH (200 mL). The crude product was used for next step directly. 8-bromo-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (520 g, 1.52 mol, 80.40% yield) was obtained as yellow solid, which was confirmed HNMR.1H NMR (400 MHz, DMSO-d6) δ = 8.77 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H). Step 4: To a solution of 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2- carboxylic acid (100 g, 293.17 mmol, 1 eq) and tripotassium; phosphate (130.00 g, 612.44 mmol, 2.09 eq) in DMF (1500 mL) was added I2 (450 g, 1.77 mol, 357.14 mL, 6.05 eq). The mixture was stirred at 140 ° C for 8 hr. (4 batches) LCMS showed that 8-bromo-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid consumed and the desired mass (M+1 = 423 Rt = 0.591 min) was given. The reaction mixture was cooled to 20°C, then poured into 10% sodium sulfite solution (6 L), stirred for 0.5 hr and filtered. The cake was collected and diluted with EA (2000 mL). The organic layer was washed with saturated NaHCO3 (2000 mL) and then with brine (2000 mL). The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was triturated with MTBE: PE = 1: 1 (100 mL) at 20 °C for 1 hour and filtered to get the Off-White solid. 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridine (370 g, 813.49 mmol, 69.37% yield, 93% purity) was obtained as off-white solid, which was confirmed HNMR, FNMR HPLC and LCMS. MS (ESI): 422.8 (M+H) +.1H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J = 6.8 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.12 (t, J = 7.2 Hz, 1H). Step 5: To a solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (28.0 g, 128 mmol, 1.00 eq) and 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine (54.3 g, 128 mmol, 1.00 eq) in DMSO (250 mL) was added CuI (2.44 g, 12.8 mmol, 0.10 eq), DIPA (38.9 g, 385 mmol, 54.4 mL, 3.00 eq) and Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.01 eq), the mixture was degassed and purged with N2 for 3 times, after stirring several minutes the temperature rised to 40°C, stirred at ambient temperature (25°C) under N2 for 16h, a dark brown clear solution was observed. LCMS showed 87% desired mass was detected. To a stirring water (1.0 L) was poured the reaction solution, lots of gray precipitate was formed, the solid was collected by filtration and washed by water (300 mL × 3). The crude product was triturated with MTBE (1.0 L), the filter cake was washed with MTBE (300 mL) and then dried under vacuum to give 65 g gray powder, the resulting solid was diluted with MeCN/water (v/v=1:6, 600 mL) and lyophilized. TLC (EA) showed three spots were observed. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20~100% Ethyl acetate/Petroleum ether, 7~15% MeOH/DCM gradient @ 80 mL/min). 4-((3-(8-bromo-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide (47.2 g, 91.95 mmol, 71.67% yield) was obtained as a gray solid which was determined by HNMR. MS (ESI): 513.0 (M+H) +.1H NMR (400 MHz, DMSO-d6) δ = 8.64 (d, J = 6.8 Hz, 1H),8.10 (br d, J = 4.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.44 -7.38 (m, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz,1H), 6.76 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.34 (d,J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.33 (s, 4H), 2.75 (d, J = 4.4 Hz,3H), 2.54 (s, 2H). Step 6: To a suspension of 4-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (9.20 g, 17.9 mmol, 1.00 eq) and tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (4.69 g, 21.5 mmol, 1.20 eq) in dioxane (180 mL) was added Cs2CO3 (11.7 g, 35.8 mmol, 2.0 eq), BINAP (1.12 g, 1.79 mmol, 0.1 eq) and rac-BINAP-Pd-G3 (889 mg, 896 μmol, 0.05 eq), the resulting mixture was degassed and purged with N2 for 3 times, then stirred at 100°C under N2 for 16h, a dark brown suspension was observed. LCMS showed most reactant was consumed and main peak with desired mass was detected. Four batches was combined, diluted with water (1 L) and extracted with EA (500 mL × 3), organic layer was washed withe brine (400 mL × 3) and dried over Na2SO4, concentrated under vacuum. TLC showed four spots (Rf=0.7, 0.5, 0.55, 0.15) were observed. The residue was purified by flash silica gel chromatography (ISCO®; 120 g × 2 SepaFlash® Silica Flash Column, Eluent of 0~ 85% Ethyl acetate/Petroleum ethergradient @ 90 mL/min), eluent (Rf=0.5) was concentrated under vacuum. tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-8-yl)amino)piperidine-1-carboxylate (25 g, 29.78 mmol, 41.54% yield, 77.50% purity) was obtained as a yellow solid (Rf=0.5) which was determined by LCMS. MS (ESI): 651.4 (M+H) +. Step 7: To a solution of tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-8-yl)amino)piperidine-1-carboxylate (25 g, 29.58 mmol, 1 eq) in MeOH (200 mL) was added HCl/MeOH (4 M, 100 mL), the mixture was stirred at 25°C for 1h, a yellow suspension was observed. TLC (EA) showed reactant (Rf=0.5) was consumed and a new main spot (Rf=0.01) was observed. The mixture was concentrated under vacuum.4-((3-(8-(((3S,4R)-3-fluoropiperidin- 4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide (25.9 g, crude, HCl) was obtained as a yellow solid (Rf=0.01) which was determined by LCMS. MS (ESI): 551.3 (M+H) +. Step 8: To a solution of 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide (400 mg, 726.52 μmol, 1 eq) in CD3OD (5 mL) was added AcOK (713.02 mg, 7.27 mmol, 10 eq) and (CD2O)n (235.39 mg, 13.08 mmol, 18 eq). The mixture was stirred at 25 °C for 1 hour. Then NaBD4 (137.42 mg, 3.63 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 0.5 hour. LCMS (EW44940-43-P1A) showed that 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide consumed and the desired mass (M+1 = 568.3 Rt = 0.457 min) was given. The reaction mixture is concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:28%-58% B over 15 min). 4-((3-(8-(((3S,4R)-3- fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (160 mg, 277.60 μmol, 38.21% yield, 98.48% purity) was obtained as a white solid. LCMS (ESI): Retention time: 0.460 min, [M+H+] =568.4.1H NMR (400 MHz, DMSO-d6 ) δ = 8.10 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.40 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.59 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.64 (m, 1H), 3.05 - 2.99 (m, 1H), 2.76 – 2.73 (m, 4H), 2.30 - 2.16 (m, 1H), 2.11 - 2.06 (m, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.72 (m, 1H). Example 442. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)- N-methylbenzamide
Figure imgf000646_0001
Step 1. To a solution of 3-fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol, 1 eq) in DMF (50 mL) was added HATU (15.41 g, 40.52 mmol, 1.5 eq), DIPEA (10.47 g, 81.03 mmol, 14.11 mL, 3 eq) and methanamine; hydrochloride (2.19 g, 32.41 mmol, 1.2 eq), the reaction mixture was stirred at 25 °C for 2 hours. TLC (PE/EA = 1/1) indicated Reactant 1 (Rf = 0) was consumed completely and one new spot (Rf = 0.5) formed. The reaction was clean according to TLC. LCMS (EW47880- 16-P1A) showed the reactant was consumed completely and one main peak with desired mass. The reaction mixture was diluted with H2O 100 mL and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL * 3), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 36 mL/min). 3-fluoro-N-methyl-4- nitrobenzamide (5 g, 22.67 mmol, 83.94% yield, 89.85% purity) was obtained as a yellow solid. MS (ESI): 198.9 (M+H) +. Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (5 g, 25.23 mmol, 1 eq) in DMF (50 mL) was added Cs2CO3 (24.66 g, 75.70 mmol, 3 eq) and CD3OD (2.73 g, 75.70 mmol, 3.07 mL, 3 eq), the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the reactant was consumed completely and one main peak with desired mass. The reaction mixture was diluted with H2O 80 mL and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used for next step without purification. 3-(methoxy-d3)-N-methyl-4-nitrobenzamide (5 g, 23.45 mmol, 92.94% yield, 100% purity) was obtained as a yellow solid. MS (ESI): 214.0 (M+H) +. Step 3: To a solution of 3-(methoxy-d3)-N-methyl-4-nitrobenzamide (4 g, 18.76 mmol, 1 eq) in MeOH (40 mL) was added Pd/C (400 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 for 3 times. The mixture was stirred under H2 (15psi) at 25 °C for 2 hours. LCMS showed the reactant was consumed completely and one main peak with desired mass. The reaction mixture was filtered and the filtrate was concentrated. The crude product was used for next step without purification.4-amino-3-(methoxy-d3)-N-methylbenzamide (3.2 g, 16.62 mmol, 88.58% yield, 95.15% purity) was obtained as a white solid. MS (ESI): 184.0 (M+H) +. Step 4: To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (130 g, 371.27 mmol, 1 eq) in DCM (1500 mL) was added PPh3 (146.07 g, 556.90 mmol, 1.5 eq) and CBr4 (147.75 g, 445.52 mmol, 1.2 eq) at 10 °C. The mixture was stirred at 25 °C for 2 hr under N2. TLC (PE: EA = 10: 1) showed compound 1 (Rf = 0.2) consumed and a new spot (Rf = 0.4) was formed. LCMSshowed the reactant consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 3000 g SepaFlash® Silica Flash Column, Eluent of 0~16% Ethyl acetate/Petroleum ether gradient @ 500 mL/min).8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (160 g, 356.61 mmol, 96.05% yield, 92.06% purity) was obtained as a yellow oil. MS (ESI): 413.9 (M+H) +.1H NMR: 400 MHz, CHLOROFORM-d δ = 8.37 (d, J = 7.2Hz, 1H), 7.22 - 7.18 (m, 1H), 6.87 (s, 1H), 6.66 (t, J = 7.2 Hz, 1H), 4.23 (s, 2H). Step 5: To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- ((trifluoromethyl)thio)indolizine (2.5 g, 6.05 mmol, 1 eq) and 4-amino-3-(methoxy-d3)-N- methylbenzamide (1.33 g, 7.26 mmol, 1.2 eq) in DMF (30 mL) was added K2CO3 (1.67 g, 12.11 mmol, 2 eq) and KI (1.51 g, 9.08 mmol, 1.5 eq). The mixture was stirred at 80 °C for 1 hr. LCMS (EW47880-23-P1A) showed 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- ((trifluoromethyl)thio)indolizine consumed completely and several new peaks were shown on LC- MS and 47.86% of desired compound was detected. TLC (PE: EA = 1: 1) showed 8-bromo-2-(3- bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine(Rf = 0.8) consumed and a new spot (Rf = 0.2) was formed. The reaction mixture was diluted with H2O 50 mL and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~67% Ethyl acetate/Petroleum ethergradient @ 36 mL/min). 4-((3-(8-bromo-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N- methylbenzamide (1.7 g, 3.18 mmol, 52.55% yield, 96.42% purity) was obtained as a yellow solid. MS (ESI): 517.0 (M+H) +. Step 6: To a solution of 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn- 1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (600 mg, 1.16 mmol, 1 eq) and (3S,4R)-3- fluoro-1-methylpiperidin-4-amine (235.60 mg, 1.40 mmol, 1.2 eq, HCl) in 2-methylbutan-2-ol (8 mL) was added Cs2CO3 (1.90 g, 5.82 mmol, 5 eq), dicyclohexyl-[3, 6-dimethoxy-2-(2, 4, 6- triisopropylphenyl) phenyl]phosphane; methanesulfonate; [2-[2-(methylamino) phenyl]phenyl]palladium (1+) (107.17 mg, 116.42 μmol, 0.1 eq). The mixture was stirred at 100 °C for 16 h under N2. LC-MS (EW47880-15-P1A) showed 4-((3-(8-bromo-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N- methylbenzamide consumed completely, several new peaks were shown on LC-MS and 57.90% of desired mass was detected. The reaction mixture was partitioned between water 20 mL and EA (20 mL*3). The organic phase was separated, washed with saturated aqueous NaCl (20 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10um; mobile phase: [water (TFA) -ACN]; gradient: 26%-56% B over 9 min). 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- (methoxy-d3)-N-methylbenzamide (103.86 mg, 152.59 μmol, 13.11% yield, 98.19% purity, TFA salt) was obtained as a yellow solid. MS (ESI): 568.1 (M+H) +.1H NMR: 400 MHz, DMSO-d6 δ = 9.87 - 9.73 (m, 1H), 8.17 -8.08 (m, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 - 7.33 (m, 1H), 7.19 (s, 1H), 6.83 - 6.75 (m, 2H), 6.22 -6.16 (m, 1H), 6.08 (br d, J = 7.2 Hz, 1H), 5.25 - 5.07 (m, 1H), 4.28 (s, 2H), 3.97 - 3.77 (m, 2H), 3.53 - 3.50 (m, 2H), 3.22 -3.12 (m, 1H), 2.83 (br s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.26 -2.10 (m, 1H), 2.04 - 1.91 (m, 1H). Example 505. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}- 3-(2H3)methoxy-N-methylbenzamide
Figure imgf000649_0001
Step 1. A mixture of 3-fluoro-4-nitrobenzoic acid (6.00 g, 32.41 mmol, 1.00 equiv) and HATU (18.49 g, 48.61 mmol, 1.50 equiv) in DMF (50.00 mL) was stirred for 0.5 h at room temperature under air atmosphere. To the above mixture was added CH3NH2HCl (2.63 g, 38.89 mmol, 1.20 equiv) and NaHCO3 (8.17 g, 97.23 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1.5 h at room temperature. The resulted solution was purified by C18 chromatography with the following conditions (Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; Wave Length: 254; 220 nm) to afford 3-fluoro-N-methyl-4-nitrobenzamide (5.40 g, 84.08%) as a white solid. LC-MS: (M+H)+ found 199.10. Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (1.10 g, 5.55 mmol, 1.00 equiv) in DMF (10.00 mL) were added Cs2CO3 (5.43 g, 16.65 mmol, 3.00 equiv) and CD3OD (600.64 mg, 16.65 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with H2O (30.00 mL) and extracted with EA (20 mLx3). The combined organic layers were washed with saturated brine (20 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-(2H3)methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a yellow solid. The crude product was used for next step without purification. LC- MS: (M+H)+ found 214.15. Step 3: To a solution of 3-(2H3)methoxy-N-methyl-4-nitrobenzamide (1.10 g, 5.15 mmol, 1.00 equiv) in IPA (20.00 mL) was added Pd/C (110.00 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon. And then, the resulted solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford 3-(2H3)methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a pink solid. The crude product was used for next step without purification. LC-MS: (M+H)+ found 184.20. Step 4: To a stirred solution of 4-amino-3-(2H3)methoxy-N-methylbenzamide (700.00 mg, 3.82 mmol, 1.00 equiv) in DMF (10.00 mL) were added propargyl bromide (545.38 mg, 4.58 mmol, 1.20 equiv) and DIEA (1.97 g, 15.28 mmol, 4.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 70°C. The resulted solution was purified by C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm). This resulted in 3- (2H3)methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (490.00 mg, 57.96%) as a yellow solid. LC-MS: (M+H)+ found 222.15. Step 5: To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridine (170.00 mg, 0.40 mmol, 1.00 equiv) and 3-(2H3)methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (106.72 mg, 0.48 mmol, 1.20 equiv) in DMSO (2.00 mL) were added CuI (76.54 mg, 0.40 mmol, 1.00 equiv), i-Pr2NH (406.70 mg, 4.02 mmol, 10.00 equiv) and Pd(PPh3)4 (46.44 mg, 0.04 mmol, 0.10 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulted mixture was purified by C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 25 min; 254/220 nm). This resulted in 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]- 3-(2H3)methoxy-N-methylbenzamide (140.00 mg, 67.46%) as a light brown solid. LC-MS: (M+H)+ found 516.10. Step 6: To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2H3)methoxy-N-methylbenzamide (140.00 mg, 0.27 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (111.22 mg, 0.54 mmol, 2.00 equiv) in 1,4-dioxane (2.00 mL) were added Cs2CO3 (530.04 mg, 1.626 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (26.40 mg, 0.02 mmol, 0.10 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified by C18 chromatography with the following conditions (Mobile Phase A: Water (0.1% NH3.H2O + 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 70% B in 30 min; 254/220 nm). This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2H3)methoxy- N-methylbenzamide (65.90 mg, 42.56%) as an off-white solid. LC-MS: (M+H)+ found 568.15.1H NMR (400 MHz, DMSO-d6) δ 8.09 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.99 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.88 - 3.61 (m, 1H), 3.07 (t, J = 11.4 Hz, 1H), 2.88-2.70 (m, 4H), 2.42- 2.10 (m, 5H), 1.88 (qd, J = 12.0, 3.7 Hz, 1H), 1.83-1.72 (m, 1H). Example 470. Synthesis of 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- (methoxy-d3)-N-methylbenzamide
Figure imgf000651_0001
Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and tert-butyl (3S, 4R) -4-amino-3-fluoro-piperidine-1-carboxylate (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140°C for 3 hrs. LCMS (EW46021-6-P1A) showed 7-bromo-1-chloro- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine consumed completely and one main peak with desired m/z was detected. The mixture was added to H2O (20 mL), some solid was observed. The mixture was filtered. The cake was washed with H2O (5 mL), then was dried to give a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was combined with the filter cake and purified together. The combined crude was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). tert-butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3- fluoropiperidine-1-carboxylate (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +.1H NMR: 400 MHz, DMSO-d6 δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H). Step 2: To a solution of 4-fluoro-N-methyl-3-nitrobenzamide (4 g, 20.19 mmol, 1 eq) in DMF (60 mL) was added Cs2CO3 (19.73 g, 60.56 mmol, 3 eq) and CD3OD (2.18 g, 60.56 mmol, 2.46 mL, 3 eq). The mixture was stirred at 25°C for 2 hrs. LCMS (EW46021-9-P1A) showed 4- fluoro-N-methyl-3-nitrobenzamide consumed completely and one main peak with desired m/z was detected. The mixture was added H2O (300 mL), then was extracted with EA (100 mL * 5). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. Without further purification. 4-(methoxy-d3)-N-methyl-3-nitrobenzamide (5.6 g, crude) was obtained as a yellow solid, which was checked by HNMR. MS (ESI): 214.2 (M+H) +.1H NMR: 400 MHz, DMSO-d6 δ = 8.60 (br d, J = 4.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.20 - 8.09 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H). Step 3: To a solution of 4-(methoxy-d3)-N-methyl-3-nitrobenzamide (5 g, 23.45 mmol, 1 eq) in EtOH (100 mL) and H2O (30 mL) was added Fe (5.24 g, 93.81 mmol, 4 eq) and NH4Cl (6.27 g, 117.26 mmol, 5 eq). The mixture was stirred at 80°C for 1 h. TLC (PE/EA = 0:1) showed 4-(methoxy-d3)-N-methyl-3-nitrobenzamide (Rf = 0.55) consumed completely and one main new spot formed (Rf = 0.45). The mixture was worked up. The mixture was filtered and the cake was washed with EA (150 mL) and DCM (150 mL). The filtrate was concentrated to remove EtOH. Then the aqueous phase was extracted with DCM (100 mL * 3) and EA (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. 3- amino-4-(methoxy-d3)-N-methylbenzamide (5 g, crude) was obtained as a brown oil, which was checked by HNMR.1HNMR: 400 MHz, CHLOROFORM-d, δ = 7.17 (d, J = 2.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.15 (brs, 1H), 2.96 (d, J =5.2 Hz, 3H). Step 4: To a solution of 3-amino-4-(methoxy-d3)-N-methylbenzamide (4.5 g, 24.56 mmol, 1 eq) in ACN (90 mL) was added Cs2CO3 (16.00 g, 49.12 mmol, 2 eq) and 3-bromoprop-1-yne (5.84 g, 49.12 mmol, 4.23 mL, 2 eq). The mixture was stirred at 60°C for 5 hrs. LCMS (EW46021- 14-P1A) showed 15% of 43-amino-4-(methoxy-d3)-N-methylbenzamide remained and 53% of desired m/z was detected. TLC (PE/EA = 0:1) showed 3-amino-4-(methoxy-d3)-N- methylbenzamide remained (Rf = 0.5) and one new spot formed (Rf = 0.6). The mixture was filtered and the cake was washed with EA (200 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). 4-(methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (3.3 g, 12.45 mmol, 50.70% yield, 83.50% purity) was obtained as a yellow oil, which was checked by LCMS and HNMR.4-(methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (1.86 g, 10.15 mmol, 41.33% yield) was recycled as a yellow oil. MS (ESI): 222.0 (M+H) +. 1HNMR: 400 MHz, CHLOROFORM-d, δ = 7.16 - 7.10 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.12 (br s, 1H), 4.53 (br s, 1H), 4.01 (d, J = 1.6 Hz, 2H), 2.99 (d, J = 4.8 Hz, 3H), 2.27 - 2.21 (m, 1H). Step 5: A mixture of tert-butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylate (100 mg, 194.80 μmol, 1 eq), 4- (methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (92.92 mg, 350.64 μmol, 1.8 eq), [2- (2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methane sulfonate (14.19 mg, 19.48 μmol, 0.1 eq), Cs2CO3 (126.94 mg, 389.60 μmol, 2 eq) in DMSO (2.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 3 hrs under N2 atmosphere in 5 batches. LCMS showed tert-butyl (3S,4R)-4-((7-bromo-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylate consumed completely and 46% of desired m/z was detected. TLC (PE/EA = 0:1) showed tert- butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3- fluoropiperidine-1-carboxylate (Rf = 0.75) was consumed and one main new spot formed (Rf = 0.5). The reaction was worked up. The mixture was filtered and the cake was washed with EA (50 mL). The filtrate was added to 50 mL H2O and extracted with EA (30 mL *3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). tert-butyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy-d3)-5-(methylcarbamoyl)phenyl)amino)prop- 1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylate (270 mg, 349.05 μmol, 35.84% yield, 84.51% purity) was obtained as a yellow solid, which was checked by LCMS. MS (ESI): 654.3 (M+H) +. Step 6: To a solution of tert-butyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy-d3)-5- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin- 1-yl)amino)piperidine-1-carboxylate (270 mg, 413.03 μmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 3 mL, 29.05 eq). The mixture was stirred at 25°C for 0.5 hr. LCMS (EW46021-21-P1A) showed tert-butyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy-d3)-5- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin- 1-yl)amino)piperidine-1-carboxylate consumed and 68% of desired m/z was detected. The mixture was concentrated to give a residue. Compound 3-[3-[1-[[(3S, 4R)-3-fluoro-4- piperidyl]amino]-6-(trifluoromethylsulfanyl)pyrrolo[1, 2-a]pyrazin-7-yl]prop-2-ynylamino]-N- methyl-4-(trideuteriomethoxy)benzamide (284 mg, crude, HCl) was obtained as a yellow solid. MS (ESI): 554.2 (M+H) +. To a solution of 3-[3-[1-[[ (3S, 4R) -3-fluoro-4-piperidyl]amino]-6- (trifluoromethylsulfanyl) pyrrolo[1, 2-a]pyrazin-7-yl]prop-2-ynylamino]-N-methyl-4- (trideuteriomethoxy) benzamide (340 mg, 576.22 μmol, 1 eq, HCl) in MeOH (15 mL) was added KOAc (565.52 mg, 5.76 mmol, 10 eq) and (HCHO)n (172.87 mg, 5.76 mmol, 10 eq). The mixture was stirred at 25°C for 0.5 h. Then NaBH(OAc)3 (366.38 mg, 1.73 mmol, 3 eq) was added, the mixture was stirred at 25°C for 1 hr. LCMS showed starting material consumed and 63% of desired m/z was detected. TLC (DCM:MeOH = 10:1) showed one main new spot formed (Rf = 0.3). NH3. H2O (37%, 0.5 mL) was added to the mixture. Then 50 mL H2O was added and extracted with EA (30 mL *3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE, 0~10% MeOH/DCM gradient @ 50 mL/min) to give 180 mg crude, which was checked by LCMS and HPLC. The crude was further purified by Prep-HPLC (column: Welch Ultimate XB-CN 250*50*10um;mobile phase: [Hexane-EtOH];gradient:10%-50% B over 15 min). The title compound (102 mg, 175.13 μmol, 30.39% yield, 97.46% purity) was obtained as a white solid, which was checked LCMS, HPLC, HNMR, FNMR, and SFC. MS (ESI): 568.1 (M+H) +.1HNMR: 400 MHz, DMSO-d6, δ = 8.18 - 8.08 (m, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.29 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.92 - 4.77 (m, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.23 - 4.06 (m, 1H), 3.09 - 2.98 (m, 1H), 2.82 (br d, J = 7.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.23 -1.97 (m, 6H), 1.65 (br d, J = 12.4 Hz, 1H). Example 506. Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl]amino}-4-(2H3)methoxy-N-methylbenzamide
Figure imgf000655_0001
Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and tert-butyl (3S, 4R) -4-amino-3-fluoro-piperidine-1-carboxylate (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140°C for 3 hrs. LCMS (EW46021-6-P1A) showed 7-bromo-1-chloro- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine consumed completely and one main peak with desired m/z was detected. The mixture was added to H2O (20 mL), some solid was observed. The mixture was filtered. The cake was washed with H2O (5 mL), then was dried to give a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was combined with the filter cake and purified together. The combined crude was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). tert-butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3- fluoropiperidine-1-carboxylate (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +.1H NMR: 400 MHz, DMSO-d6 δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H). Assays Surface Plasmon Resonance (SPR) Assay Protocol SPR experiments were performed on a Biacore 8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) was immobilized onto a streptavidin sensor chip (Sensor Chip SA), by flowing the protein solution through the sensor chip at typically 10 ^g/mL concentration, 5 ^L/min flow rate for 70 seconds. Compounds were 2-fold, 7-point serial diluted; the top concentration varied depending on the potency. Compound binding affinities were measured in the multi-cycle kinetics mode, at 30 μL/min flow rate with 60 seconds association time and 120 seconds dissociation time. The running buffer contained 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20 and 1% DMSO. The assay temperature was maintained at 16 or 20oC and data were fit into the 1:1 binding model using the Biacore Insight Evaluation software. Thermal shift assay (TSA) protocol 5 ^M recombinant p53 Y220C mutant protein (amino acid residues 94-293) was incubated with 10 ^M or 100 ^M compound for 3 hours at 20oC in buffer containing 20 mM HEPES, pH7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific catalog number 4461146), on a 384-well PCR plate (Applied Biosystems catalog number 4483285). The volume was 5 ^L/well. The sealed plate was then loaded onto a QuantStudio 7 Flex instrument for melting temperature (TM) measurement. The temperature was increased from 30 oC to 50oC, at a rate of 0.03oC/second. Data were fit into a Boltzmann two-state model to determine the TM. Luciferase reporter assay protocol Luciferase reporter (Luc) driven by p53 response element (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and inducible p53 Y220C construct (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter assay. 5,000 cells were seeded in each well of 384 plate and cultured in 0.5 ug/mL doxycycline (D3072; Sigma) containing medium for 24 hours before compound treatment. After 6 hour of compound treatment, equal volume of One-Glo reagent (E6110; Promega) was added to each well and the plate was incubated for 5 minutes with shaking at room temperature. The luciferase activity was immediately measured with PheraStar microplate reader. Luciferase activity was stimulated by 10 uM of a tool compound as positive control and AC50 was calculated. Cell proliferation assay Inducible p53 Y220C and R273H constructs (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299-inducible p53 Y220C, and NCIH1299-inducible p53 R273H cell lines were used for cell proliferation assay. 250-500 cells were seeded in each well of 384 plate and then compounds were dispensed into each well using Echo or Tecan. After 5 days of incubation, equal volume of CellTiter-Glo reagent (G7570; Promega) was added into each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescent signal was measured by PheraStar microplate reader and IC50 was calculated. Table A shows results of the SPR p53 Y220C Kd_kinetic (nM), TSA p53 Y220C dTM (deg C), Luc p53 Y220C AC50 (nM), CTG H1299 p53 Y220C IC50 (nM), CTG H1299 p53 R273H IC50 (nM), and CTG NUGC3 p53 Y220C IC50 (nM) assays. Activity categories are as follows: • SPR p53 Y220C Kd_kinetic (nM): D ≥ 1000 > C ≥ 100 > B ≥ 10 > A • TSA p53 Y220C dTM (deg C, 100 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D • TSA p53 Y220C dTM (deg C, 10 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D • CTG NUGC3 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 R273H IC50 (nM): A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D • CTG H1299 p53 Parent IC50 (nM): A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D • Luc p53 Y220C AC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • Luc p53 Y220C Emax (nM): A ≥ 90 > B ≥ 80 > C ≥ 70 > D Table A.
Figure imgf000658_0001
Figure imgf000659_0001
Figure imgf000660_0001
Figure imgf000661_0001
Figure imgf000662_0001
Figure imgf000663_0001
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
Figure imgf000667_0001
Figure imgf000668_0001
Figure imgf000669_0001
Figure imgf000670_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I)
Figure imgf000671_0001
or a pharmaceutically acceptable salt thereof, wherein: X1 is CR1 or N; R1 is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5 are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N; RA is hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each R2 is
Figure imgf000672_0001
Z1 is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent; when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent; R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
2. The compound of Claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000673_0001
C), or a pharmaceutically acceptable salt of any of the foregoing.
3. The compound of Claim 1 or 2, wherein one of X2, X3, X4, and X5 is N.
4. The compound of Claim 1 or 2, wherein two of X2, X3, X4, and X5 are N.
5. The compound of any one of Claims 1-4, wherein X1 is CR1.
6. The compound of any one of Claims 1-5, wherein R1 is hydrogen.
7. The compound of any one of Claims 1-5, wherein R1 is halogen.
8. The compound of any one of Claims 1-5, wherein R1 is cyano.
9. The compound of any one of Claims 1-5, wherein R1 is –OR4.
10. The compound of any one of Claims 1-5, wherein R1 is -NR4R5.
11. The compound of any one of Claims 1-5, wherein R1 is -C(=O)R4.
12. The compound of any one of Claims 1-5, wherein R1 is -OC(=O)R4.
13. The compound of any one of Claims 1-5, wherein R1 is –C(=O)OR4.
14. The compound of any one of Claims 1-5, wherein R1 is –C(=O)NR4R5.
15. The compound of any one of Claims 1-5, wherein R1 is –SR4.
16. The compound of any one of Claims 1-5, wherein R1 is –S(=O)R4.
17. The compound of any one of Claims 1-5, wherein R1 is –S(O2)R4.
18. The compound of any one of Claims 1-5, wherein R1 is -NR4C(=O)R5.
19. The compound of any one of Claims 1-5, wherein R1 is –R4C(=O)R5.
20. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted C1-C6 alkyl.
21. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted C2-C6 alkenyl.
22. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted C2-C6 alkynyl.
23. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted C3-C10 cycloalkyl.
24. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted phenyl.
25. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted 4- 12 membered heterocyclyl.
26. The compound of any one of Claims 1-5, wherein R1 is an optionally substituted 5- 10 membered heteroaryl.
27. The compound of any one of Claims 1-4, wherein X1 is N.
28. The compound of any one of Claims 1-27, wherein RA is hydrogen.
29. The compound of any one of Claims 1-27, wherein RA is –OR6.
30. The compound of any one of Claims 1-27, wherein RA is -NR6R7.
31. The compound of any one of Claims 1-27, wherein RA is -C(=O)R6.
32. The compound of any one of Claims 1-27, wherein RA is -R6C(=O)R7.
33. The compound of any one of Claims 1-27, wherein RA is -OC(=O)R6.
34. The compound of any one of Claims 1-27, wherein RA is -OC(=O)NR6.
35. The compound of any one of Claims 1-27, wherein RA is –C(=O)OR6.
36. The compound of any one of Claims 1-27, wherein RA is –NR6C(=O)OR7.
37. The compound of any one of Claims 1-27, wherein RA is –C(=O)NR6R7.
38. The compound of any one of Claims 1-27, wherein RA is –SR6.
39. The compound of any one of Claims 1-27, wherein RA is –S(=O)R6.
40. The compound of any one of Claims 1-27, wherein RA is –S(O2)R6.
41. The compound of any one of Claims 1-27, wherein RA is –S(O2)NR6.
42. The compound of any one of Claims 1-27, wherein RA is –NR6S(O2)R7.
43. The compound of any one of Claims 1-27, wherein RA is -NR6C(=O)R7.
44. The compound of any one of Claims 1-27, wherein RA is -NR6C(=O)NR7.
45. The compound of any one of Claims 1-27, wherein RA is -SiR6R7R8.
46. The compound of any one of Claims 1-27, wherein RA is an optionally substituted C1-C6 alkyl.
47. The compound of any one of Claims 1-27, wherein RA is an optionally substituted C2-C6 alkenyl.
48. The compound of any one of Claims 1-27, wherein RA is an optionally substituted C2-C6 alkynyl.
49. The compound of any one of Claims 1-27, wherein RA is an optionally substituted C3-C10 cycloalkyl.
50. The compound of any one of Claims 1-27, wherein RA is an optionally substituted phenyl.
51. The compound of any one of Claims 1-27, wherein RA is an optionally substituted 4-12 membered heterocyclyl.
52. The compound of any one of Claims 1-27, wherein RA is an optionally substituted 5-10 membered heteroaryl.
53. The compound of any one of Claims 1-52, wherein RB is halogen.
54. The compound of any one of Claims 1-52, wherein RB is cyano.
55. The compound of any one of Claims 1-52, wherein RB is hydroxyl.
56. The compound of any one of Claims 1-52, wherein RB is –NR8R9.
57. The compound of any one of Claims 1-52, wherein RB is -OR8.
58. The compound of any one of Claims 1-52, wherein RB is –C(=O)NR8R9.
59. The compound of any one of Claims 1-52, wherein RB is –C(=O)R8.
60. The compound of any one of Claims 1-52, wherein RB is -C(=O)OR8.
61. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)OR9
62. The compound of any one of Claims 1-52, wherein RB is –OC(=O)R8.
63. The compound of any one of Claims 1-52, wherein RB is –OC(=O)NR8.
64. The compound of any one of Claims 1-52, wherein RB is –C(=O)NR8R9.
65. The compound of any one of Claims 1-52, wherein RB is –NR8C(=O)R9.
66. The compound of any one of Claims 1-52, wherein RB is –NR8C(=O)NR9.
67. The compound of any one of Claims 1-52, wherein RB is –SR8.
68. The compound of any one of Claims 1-52, wherein RB is –S(=O)R8.
69. The compound of any one of Claims 1-52, wherein RB is –S(O2)R8.
70. The compound of any one of Claims 1-52, wherein RB is –S(O2)NR8.
71. The compound of any one of Claims 1-52, wherein RB is –NR8S(O2)R9.
72. The compound of any one of Claims 1-52, wherein RB is -R8C(=O)R9.
73. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)R9.
74. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)NR9.
75. The compound of any one of Claims 1-52, wherein RB is an optionally substituted C1-C6 alkyl.
76. The compound of any one of Claims 1-52, wherein RB is C1-C6 haloalkyl.
77. The compound of any one of Claims 1-52, wherein RB is an optionally substituted C2-C6 alkenyl.
78. The compound of any one of Claims 1-52, wherein RB is an optionally substituted C2-C6 alkynyl.
79. The compound of any one of Claims 1-52, wherein RB is an optionally substituted C3-C10 cycloalkyl.
80. The compound of any one of Claims 1-52, wherein RB is an optionally substituted phenyl.
81. The compound of any one of Claims 1-52, wherein RB is an optionally substituted 3-12 membered heterocyclyl.
82. The compound of any one of Claims 1-52, wherein RB is an optionally substituted 5-10 membered heteroaryl.
83. The compound of any one of Claims 1-82, wherein each
Figure imgf000679_0001
.
84. The compound of any one of Claims 1-83, wherein one of X2, X3, X4, and X5 is CR2 and the remaining X2, X3, X4, and X5 are CH, N, or CR3.
85. The compound of any one of Claims 1-84, wherein Z1 is a bond.
86. The compound of any one of Claims 1-84, wherein Z1 is -C=O-.
87. The compound of any one of Claims 1-84, wherein Z1 is -S(O2)-.
88. The compound of any one of Claims 1-84, wherein Z1 is an optionally substituted C1-C6 alkylene.
89. The compound of any one of Claims 1-84, wherein Z1 is an optionally substituted C2-C6 alkenylene.
90. The compound of any one of Claims 1-84, wherein Z1 is an optionally substituted C2-C6 alkynylene.
91. The compound of any one of Claims 1-84, wherein Z1 is an optionally substituted C3-C4 cycloalkylene.
92. The compound of any one of Claims 1-91, wherein Z2 is N.
93. The compound of any one of Claims 1-91, wherein Z2 is O and R2B is absent.
94. The compound of any one of Claims 1-91, wherein Z2 is a bond.
95. The compound of any one of Claims 1-91, wherein Z2 is CR2C.
96. The compound of any one of Claims 1-91 or 95, wherein R2C is hydrogen.
97. The compound of any one of Claims 1-91 or 95, wherein R2C is halogen.
98. The compound of any one of Claims 1-91 or 95, wherein R2C is C1-C6 alkyl.
99. The compound of any one of Claims 1-84, wherein Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1.
100. The compound of any one of Claims 1-99, wherein R2A is hydrogen.
101. The compound of any one of Claims 1-99, wherein R2A is -C(=O)R10.
102. The compound of any one of Claims 1-99, wherein R2A is –C(=O)OR10.
103. The compound of any one of Claims 1-99, wherein R2A is –C(=O)NR10R11.
104. The compound of any one of Claims 1-99, wherein R2A is –S(=O)R10.
105. The compound of any one of Claims 1-99, wherein R2A is –S(O2)R10.
106. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted C1-C6 alkyl.
107. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted C2-C6 alkenyl.
108. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted C2-C6 alkynyl.
109. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted C3-C10 cycloalkyl.
110. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted phenyl.
111. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted 4-12 membered heterocyclyl.
112. The compound of any one of Claims 1-99, wherein R2A is an optionally substituted 5-10 membered heteroaryl.
113. The compound of any one of Claims 1-98 and 100-112, wherein R2B is hydrogen.
114. The compound of any one of Claims 1-98 and 100-112, wherein R2B is -C(=O)R10.
115. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –C(=O)OR10.
116. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –C(=O)NR10R11.
117. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –S(=O)R10.
118. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –S(O2)R10.
119. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted C1-C6 alkyl.
120. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted C2-C6 alkenyl.
121. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted C2-C6 alkynyl.
122. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted C3-C10 cycloalkyl.
123. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted phenyl.
124. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted 4-12 membered heterocyclyl.
125. The compound of any one of Claims 1-98 and 100-112, wherein R2B is an optionally substituted 5-10 membered heteroaryl.
126. The compound of any one of Claims 1-98, wherein one of R2A and R2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2A and R2B is hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.
127. The compound of any one of Claims 1-98, wherein R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.
128. The compound of any one of Claims 1-127, wherein one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH or N.
129. The compound of any one of Claims 1-2 or 5-127, wherein one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH.
130. The compound of any one of Claims 1-129, wherein R3 is halogen.
131. The compound of any one of Claims 1-129, wherein R3 is cyano.
132. The compound of any one of Claims 1-129, wherein R3 is –NR12R13.
133. The compound of any one of Claims 1-129, wherein R3 is -OR12.
134. The compound of any one of Claims 1-129, wherein R3 is –C(=O)NR12R13.
135. The compound of any one of Claims 1-129, wherein R3 is –C(=O)R12.
136. The compound of any one of Claims 1-129, wherein R3 is -C(=O)OR12.
137. The compound of any one of Claims 1-129, wherein R3 is –OC(=O)R12.
138. The compound of any one of Claims 1-129, wherein R3 is –NR12(C=O)NR12R13.
139. The compound of any one of Claims 1-129, wherein R3 is –SR12.
140. The compound of any one of Claims 1-129, wherein R3 is –S(=O)R12.
141. The compound of any one of Claims 1-129, wherein R3 is –S(O2)R12.
142. The compound of any one of Claims 1-129, wherein R3 is –S(O2)NR12R13.
143. The compound of any one of Claims 1-129, wherein R3 is –NR12S(O2)NR13R14.
144. The compound of any one of Claims 1-129, wherein R3 is -R12C(=O)R13.
145. The compound of any one of Claims 1-129, wherein R3 is -NR12C(=O)R13.
146. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted C1-C6 alkyl.
147. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted C2-C6 alkenyl.
148. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted C2-C6 alkynyl.
149. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted C3-C6 cycloalkyl.
150. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted phenyl.
151. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted 4-6 membered heterocyclyl.
152. The compound of any one of Claims 1-129, wherein R3 is an optionally substituted 5-6 membered heteroaryl.
153. The compound of any one of Claims 1-152, wherein m is 0.
154. The compound of any one of Claims 1-152, wherein m is 1.
155. The compound of any one of Claims 1-152, wherein m is 2.
156. The compound of any one of Claims 1-155, wherein L is an optionally substituted C2-C6 alkynylene.
157. The compound of any one of Claims 1-156, wherein L is a C2-C6 alkynylene.
158. The compound of any one of Claims 1-157, wherein L is a C2-C3 alkynylene.
159. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in List 1 or Table A, or a pharmaceutically acceptable salt of any of the foregoing.
160. A pharmaceutical composition comprising a compound of any one of Claims 1- 159, or a pharmaceutically acceptable salt thereof.
161. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.
162. A method of treating cancer in a subject previously identified as having one or more p53 mutations, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.
163. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has one or more p53 mutations, and (b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.
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WO2025077778A1 (en) * 2023-10-12 2025-04-17 上海宇道生物技术有限公司 Carboxylic acid compound and preparation method therefor and use thereof
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