WO2023215494A1 - Inhibiteurs thiophène d'ulk1/2 et leur utilisation - Google Patents

Inhibiteurs thiophène d'ulk1/2 et leur utilisation Download PDF

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WO2023215494A1
WO2023215494A1 PCT/US2023/021025 US2023021025W WO2023215494A1 WO 2023215494 A1 WO2023215494 A1 WO 2023215494A1 US 2023021025 W US2023021025 W US 2023021025W WO 2023215494 A1 WO2023215494 A1 WO 2023215494A1
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compound
cycloalkyl
heterocycloalkyl
pharmaceutically acceptable
acceptable salt
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PCT/US2023/021025
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English (en)
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Marcos GONZALEZ-LOPEZ
Jean-Michel Vernier
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Erasca, Inc.
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Publication of WO2023215494A1 publication Critical patent/WO2023215494A1/fr

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    • 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
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • R 1 is hydrogen, deuterium, halogen, C1-C4alkyl, or C1-C4haloalkyl
  • R 2 is halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl
  • R 3 is hydrogen, deuterium, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4haloalkyl
  • each R 6a is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl
  • X is O or S
  • R 5 is hydrogen
  • a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising contacting the ULK isoform with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.
  • the method inhibits ULK1 and ULK2.
  • a method of treating cancer comprising administering to a subject a compound disclosed herein, or pharmaceutically acceptable salt thereof, or pharmaceutical a composition disclosed herein.
  • Abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous).
  • Abnormal cell growth includes the abnormal growth of: (1) tumor cells (tumors) that show increased expression of ULK1 or ULK2; (2) tumors that proliferate by aberrant ULK1 or ULK2 activation; and /or (3) tumors characterized by amplification or overexpression of the genes that express ULK1 or ULK2.
  • tumor cells tumor cells
  • tumors tumors that proliferate by aberrant ULK1 or ULK2 activation
  • tumors characterized by amplification or overexpression of the genes that express ULK1 or ULK2.
  • additional anticancer agents as used herein means any one or more therapeutic agent, other than a compound of the disclosure, that is or can be used in the treatment of cancer.
  • such additional anticancer agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth.
  • Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas.
  • Cancers of the blood include, but are not limited to, leukemia, lymphoma, plasmacytoma, extramedullary plasmacytoma, and myeloma.
  • the leukemia is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML).
  • ALL acute lymphocytic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • the lymphoma is Hodgkin lymphoma, Non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the myeloma is multiple myeloma.
  • Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.
  • the term “combination therapy” refers to the administration of a compound of the disclosure together with an at least one additional pharmaceutical or medicinal agent (e.g., one or more additional anticancer agents), either sequentially or simultaneously.
  • additional pharmaceutical or medicinal agent e.g., one or more additional anticancer agents
  • subject refers to a human or animal subject. In certain preferred embodiments, the subject is a human.
  • the term “treat” or “treating” a cancer as used herein means to administer a compound of the present invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • the term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.
  • a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and
  • a numerical range such as “C1-C6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C1-10alkyl.
  • the alkyl is a C 1 - 6 alkyl.
  • the alkyl is a C 1 - 5 alkyl.
  • the alkyl is a C 1 - 4 alkyl.
  • the alkyl is a C1-3alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2.
  • alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, - CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [00032] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe.
  • alkoxy is optionally substituted with halogen.
  • Alkoxyalkyl refers to a radical of the formula -alkyleneORa where Ra is an alkyl. In some embodiments, the alkoxyalkyl is -CH2OCH3, -CH2CH2OCH3, or -CH2CH2CH2OCH3.
  • an alkoxyalkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxyalkyl is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkoxyalkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkoxyalkyl is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aromatic ring, which may be monocyclic or bicyclic (for example, phenyl or naphthyl).
  • the aryl is a 6-membered aromatic ring (phenyl).
  • Aryl radicals include, but are not limited to anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • Aryl radicals include, but are not limited to 1,2,3,5,6,7-hexahydro- s-indacene, 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]naphthalene, and 1,2,3,4,5,6,7,8-octahydroanthracene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl).
  • the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6- membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl- bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [00039] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines.
  • the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines.
  • Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums.
  • the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2.
  • the deuteroalkyl is CD3.
  • “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl).
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl or a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl or a 4- to 6- membered heterocycloalkenyl.
  • the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
  • the heteroaryl is 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepinyl, or 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, the heteroaryl is bonded through a phenyl ring atom.
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above.
  • an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl
  • R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 - C 6 heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • X is -NR 5 -.
  • X is -O-.
  • X is -S-.
  • X is -C(R 6 )2-.
  • X is null.
  • Y is -C(R 6 ) 2 -.
  • Y is -NR 5 -.
  • Y is -O-.
  • Y is null.
  • Z is -C(R 6 )2-.
  • Z is null.
  • R 4 is hydrogen. In some embodiments of a compound of Formula (I), R 4 is C1-C6alkyl.
  • R 5 is hydrogen, C1-C6alkyl, C1- C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; wherein the alkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
  • R 5 is hydrogen.
  • R 5 is C1-C6alkyl.
  • each R 6 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R; or two R 6 on the same atom are taken together to form an oxo.
  • each R 6 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), R 6 is independently hydrogen or C1- C6alkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), R 6 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), each R 6 is hydrogen.
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 8 is -CN,
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 8 is -CN,
  • R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl
  • R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl
  • R 8 is -CN, -NR c R
  • R 8 is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is independently optionally substituted with one or more R.
  • R 8 is heterocycloalkyl optionally substituted with one or more R.
  • R 9 is hydrogen, halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R 9 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 - C6haloalkyl.
  • R 9 is hydrogen or C1-C6alkyl.
  • R 9 is hydrogen.
  • R 1 is hydrogen, halogen, C1- C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen or C 1 -C 2 alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen. In some embodiments of a compound of Formula (I) or (II), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is C1-C3alkyl.
  • R 3 is hydrogen, halogen, C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (II), R 3 is hydrogen.
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is pyrazolyl.
  • Ring A is phenyl.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b .
  • each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b .
  • each R 7a is independently halogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (I) or (II), each R 7a is independently C1- C6alkyl.
  • each R 7b is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.
  • n is 1-4.
  • n is 1-3.
  • n is 1 or 2.
  • n is 1.
  • n is 2.
  • n is 3. In some embodiments of a compound of Formula (I) or (II), n is 4. [00082] wherein each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more C1-C6alkyl.
  • R 7 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more C1-C6alkyl; and R 7 is independently C1-C6alkyl, cycloalkyl, or heterocycloalkyl.
  • R 7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; or two
  • R 7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl
  • R 7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl.
  • R 7’ is hydrogen or C1-C6alkyl
  • p is 0-5
  • each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo.
  • R 7’ is hydrogen or C 1 -C 6 alkyl
  • p is 0-5
  • each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo.
  • R 7’ is hydrogen or C1-C6alkyl; and R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl.
  • R 7’ is hydrogen or C1-C6alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl.
  • R 7 is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl.
  • a and B are independently selected from CH, N, and CF, with the proviso that at least one of A or B is N or CF.
  • R 7’ is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl.
  • a and B are independently selected from CH, N, and CF, with the proviso that at least one of A or B is N or CF.
  • R 7’ is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl.
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is pyrazolyl. In some embodiments of a compound of Formula (III), Ring A is phenyl or pyridinyl. In some embodiments of a compound of Formula (III), Ring A is phenyl. In some embodiments of a compound of Formula (III), Ring A is phenyl. In some embodiments of a compound of Formula (III), Ring A is phenyl.
  • m is 1-4. In some embodiments of a compound of Formula (III), m is 1-3. In some embodiments of a compound of Formula (III), m is 1 or 2. In some embodiments of a compound of Formula (III), m is 0. In some embodiments of a compound of Formula (III), m is 1. In some embodiments of a compound of Formula (III), m is 2. In some embodiments of a compound of Formula (III), m is 3.
  • the compound is of Formula (IIIa): Formula (IIIa); wherein: R 13 is hydrogen or R 10 ; each R 14 is independently deuterium, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; and t is 0-2.
  • R 13 is R 10 .
  • each R 14 is independently deuterium, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and t is 0-2.
  • each R 14 is independently deuterium, halogen, -CN, CH3, or CF3.
  • each R 14 is independently fluorine.
  • t is 0.
  • t is 1. In some embodiments of a compound of Formula (IIIa) or (IIIb), t is 2. [000110] In some embodiments of a compound of Formula (III), the compound is of Formula (IIIc): Formula (IIIc). [000111] In some embodiments of a compound of Formula (III), the compound is of Formula (IIId): Formula (IIId). [000112] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen or C1-C2alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is hydrogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C 1 -C 3 alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C1-C2alkyl.
  • R 1 is CH3.
  • R 2 is C1-C2alkyl or C1- C2haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is CF3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C 1 -C 4 alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C3alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C2alkyl.
  • R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1- C 6 alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 - C6haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 5 is hydrogen, C1-C6alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, methyl, cyclopropyl, or oxetanyl.
  • each R 6 is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • each R 6 is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.
  • each R 6 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is hydrogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
  • two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R.
  • each R 10 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R.
  • each R 10 is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl is optionally and independently substituted with one or more R.
  • each R 10 is independently halogen, C1-C6alkyl, or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently cycloalkyl.
  • each R 12 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 - C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • each R 12 is independently halogen, -CN, -OH, -OR a , - NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 12 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl.
  • each R 12 is independently C1-C6alkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
  • two R 12 on different carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R.
  • two R 12 on different carbons are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
  • two R 12 on different carbons are taken together to form a cycloalkyl or a heterocycloalkyl.
  • two R 12 on different carbons are taken together to form a cycloalkyl.
  • two R 12 on different carbons are taken together to form a heterocycloalkyl.
  • s is 0-4.
  • s is 0-3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0-2. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0 or 1. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0. [000123] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-7. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-6.
  • s is 1-5. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-4. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1- 3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1 or 2. -In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 2.
  • s is 3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 4. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 5. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 6. [000124] In some embodiments of a compound of Formula (III) or (IIIa) In some embodiments of a compound of Formula ( , ,
  • R 11 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 11 is hydrogen, C 1 -C 6 alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 11 is hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl.
  • R 11 is C1-C6alkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is -L-cycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is -L-heterocycloalkyl optionally substituted with one or more R. [000126] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), L is absent.
  • L is C1-C3 alkylene. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), L is CH2. [000127] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH3, - . In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH3, - some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CD 3 .
  • R11 is hydrogen or -CH 3 .
  • R 11 is hydrogen.
  • R 11 is -CH3.
  • some embodiments of a compound of Formula (III) or (IIIa)-(IIId) R 11 , some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 .
  • some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 .
  • [000128] In some embodiments of a compound of Formula ( [000129] In some embodiments of a compound of Formula (III) or (IIIa)- ,
  • R 1 is hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl
  • R 2 is halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl
  • R 3 is hydrogen, deuterium, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4haloalkyl
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is pyrazolyl. In some embodiments of a compound of Formula (IV), Ring A is phenyl or pyridinyl. In some embodiments of a compound of Formula (IV), Ring A is phenyl. In some embodiments of a compound of Formula (IV), Ring A is pyridinyl. In some embodiments of a compound of Formula (IV), Ring A is a bicyclic ring.
  • Ring A is tetrahydroisoquinolinyl.
  • n is 1-4. In some embodiments of a compound of Formula (IV), n is 1-3. In some embodiments of a compound of Formula (IV), n is 1 or 2. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), n is 2. In some embodiments of a compound of Formula (IV), n is 3. In some embodiments of a compound of Formula (IV), n is 4.
  • X is -NR 5 -.
  • Y is -C(R 6b )2-.
  • Y is -O-.
  • Y is -S-.
  • p is 0-4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0-3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0-2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0 or 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa- 1), p is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 1.
  • R 7’ is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, or C1- C4alkoxyC1-C4alkyl.
  • R 7’ is hydrogen, C1-C4alkyl, C1-C4haloalkyl, or C1-C4hydroxyalkyl.
  • R 7’ is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen.
  • R 7’ is defined as above and L is absent.
  • R 7’ is defined as above and L is -CH2-.
  • R 7’ is defined as above and L is -CH2CH2-.
  • each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , - NR c R d , C1-C4alkyl, C1-C4haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a .
  • each R 7 is independently halogen, -OR a , -SR a , C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a .
  • each R 7 is independently halogen, -OR a , -SR a , C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo.
  • each R 7 is independently halogen, -OR a , C1-C4alkyl, -L-cycloalkyl, or -L- heterocycloalkyl.
  • each R 7 is independently halogen, C 1 -C 4 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen or C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen or -L-cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently C1-C4alkyl or - L-cycloalkyl.
  • each R 7 is independently C1-C4alkyl.
  • R 7 is defined as above and L is absent.
  • R 7 is defined as above and L is -CH2-.
  • R 7 is defined as above and L is -CH2CH2-.
  • R 7 is halogen, -OR a , C1- C 4 alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen, C1-C4alkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen or C1-C4alkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen or -L-cycloalkyl.
  • R 7 is C1-C4alkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is C1-C4alkyl. [000149] In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is absent. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is -CH2CH2-.
  • each R 7a is independently halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 7a is independently C1-C4alkyl. [000151] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is hydrogen or C1-C2alkyl.
  • R 1 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C3alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C2alkyl.
  • R 1 is CH3.
  • R 2 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or cycloalkyl.
  • R 2 is C1-C2alkyl, C1-C2haloalkyl, or cycloalkyl.
  • R 2 is CF3. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C3alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C2alkyl.
  • R 2 is CH3. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is cyclopropyl. [000153] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 3 is hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 3 is hydrogen.
  • R 5 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C1-C4alkyl, C1- C4haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 5 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl.
  • R 5 is hydrogen, C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, methyl, cyclopropyl, or oxetanyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen. [000155] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is defined as above and L is absent.
  • R 5 is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is defined as above and L is -CH2CH2-. [000156] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6 is independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6 is independently hydrogen or C1-C4alkyl.
  • each R 6 is hydrogen.
  • two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
  • each R 6 on adjacent carbons is taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R.
  • each R 6a is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C4heteroalkyl, or cycloalkyl.
  • each R 6a is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen or C 1 -C 4 alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen.
  • one R 6a is hydrogen and the other R 6a is C1-C4alkyl.
  • two R 6a are taken together to form a cycloalkyl.
  • two R 6a are taken together to form a cyclopropyl or a cyclobutyl.
  • each R 6b is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C4heteroalkyl, or cycloalkyl.
  • each R 6b is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), one R 6b is hydrogen and the other R 6b is C1-C4alkyl.
  • two R 6b are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), two R 6b are taken together to form a cyclopropyl or a cyclobutyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), two R 6b are taken together to form a cyclopropyl.
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl or C1-C6haloalkyl.
  • each R a is independently C1- C 6 alkyl.
  • each R b is independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl.
  • each R b is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C1-C6alkyl.
  • R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C1-C6alkyl or C1-C6haloalkyl.
  • R c and R d are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C1-C6alkyl. [000168] In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [000169] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is -CH2-.
  • L is - CH2CH2-.
  • each R is independently halogen, -CN, -OH, -OCH3, -NH2, -N(CH3)2, C1-C6alkyl, or C1- C 6 haloalkyl; or two R on the same atom form an oxo.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from: ,
  • the compound, or a pharmaceutically acceptable salt thereof is selected from:
  • the compound, or a pharmaceutically acceptable salt thereof is selected from:
  • the compound, or a pharmaceutically acceptable salt thereof is selected from: ,
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • Labeled compounds [000180] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [000183]
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Solvates [000189] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers [000191] In some situations, compounds exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Method of treatment [000192] Disclosed herein is a method of inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising contacting the ULK isoform with a compound disclosed herein or pharmaceutically acceptable salt thereof. In some embodiments, the method inhibits ULK1 and/or ULK2.
  • ULK Unc-51 like autophagy activating kinase
  • a method of selectively inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising selectively contacting the ULK isoform with a compound disclosed herein or pharmaceutically acceptable salt thereof.
  • the compounds disclosed herein or pharmaceutically acceptable salt thereof selectively inhibit Unc-51 like autophagy activating kinase (ULK) over other kinases.
  • the compounds disclosed herein or pharmaceutically acceptable salt thereof selectively inhibit Unc-51 like autophagy activating kinase (ULK) over AMP-activated protein kinase (AMPK).
  • Disclosed herein is a method of treating cancer comprising administering to a subject a compound disclosed herein or pharmaceutically acceptable salt thereof.
  • a method of treating cancer sensitive to ULK1/2 inhibition in a subject in need thereof includes methods for treating abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.
  • the abnormal cell growth is cancer
  • the cancer is lung cancer, pancreatic cancer, skin cancer, including melanoma, cancer of the head or neck, ovarian cancer, rectal cancer, colon cancer, breast cancer, cancer of the thyroid gland, chronic or acute leukaemia, and renal cell carcinoma.
  • Such cancers may be KRAS associated cancers.
  • the cancer comprises a solid tumor.
  • cancers such as lung cancer, non-small cell lung cancer, colon cancer, rectal, colorectal, gastric, stomach, oesophageal cancer, salivary gland cancer, pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC), AML, CML, and ovarian cancer.
  • PDAC pancreatic ductal adenocarcinoma
  • the method of treating cancer is a method of treating chronic myeloid leukaemia.
  • the cancer comprises a liquid tumor.
  • the cancer is chronic myeloid leukaemia.
  • one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the MAPK pathway, including cancers having alternations in one or more of the RAS, SHP2, RAF, MEK, and ERK pathways.
  • the cancer in the subject has one or more alterations in the RAS pathway.
  • the cancer in the subject has one or more alterations in the RAF pathway.
  • the cancer in the subject has one or more alterations in the MEK pathway.
  • the cancer in the subject has one or more alterations in the ERK pathway.
  • one or more compounds disclosed herein are administered to subjects having cancer that is driven by cellular signalling in the MAPK pathway.
  • one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the PI3K-AKT pathway, including cancers having alternations in one or more of the PI3K, PTEN, and AKT pathways.
  • the cancer in the subject has one or more alterations in the PI3K pathway.
  • the cancer in the subject has one or more alterations in the PTEN pathway.
  • the cancer in the subject has one or more alterations in the AKT pathway.
  • one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the mTOR pathway.
  • the cancer in the subject has one or more alterations in the RAS pathway, including mutations to KRAS, including G12C, G12D, and G12V mutations.
  • KRAS inhibitors that may be used in combination with the compounds disclosed herein include, but are not limited to, one or more of AMG 510, MRTX849, and GDC-6036.
  • the cancer in the subject has one or more alterations in the RAF pathway, including mutations to BRAF, including BRAF V600E.
  • the cancer in the subject has one or more alterations in the ERK pathway.
  • the cancer in the subject has one or more alterations in the MEK pathway.
  • beneficial or desired clinical results in a subject to which a compound of the disclosure is administered, alone or in the form of a pharmaceutically acceptable composition include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and/or prolonging survival of subjects the cancer.
  • T/C tumor growth inhibition
  • NCI National Cancer Institute
  • the treatment achieved by treatment as disclosed herein is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS).
  • PR partial response
  • CR complete response
  • OR overall response
  • PFS progression free survival
  • DFS disease free survival
  • OS overall survival
  • PFS also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time subjects have experienced a CR or PR, as well as the amount of time subjects have experienced stable disease (SD).
  • DFS refers to the length of time during and after treatment that the subject remains free of disease.
  • OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or subjects.
  • response to a combination of the disclosure is any of PR, CR, PFS, DFS, OR, or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.
  • the treatment regimen relating to a compound of the disclosure, or a pharmaceutical composition comprising a compound of the disclosure, that is effective to treat cancer in a subject may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [000207] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the dosage, or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [000213] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD10 and the ED90.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • Routes of Administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • Pharmaceutical Compositions/Formulations [000220] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof is administered to animals.
  • the compounds are administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
  • pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including compounds described herein, or a pharmaceutically acceptable salt thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
  • Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • compositions for parental use are formulated as infusions or injections.
  • the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a liquid carrier.
  • the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof.
  • the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
  • Combination [000228] Disclosed herein are methods of treating a disease or disorder associated with modulating autophagy via inhibition of ULK1 and/or ULK2,with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent.
  • the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein.
  • the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. [000230] In some embodiments, the additional therapeutic agent is an additional anticancer agent.
  • Such additional anticancer agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases and/or phosphatases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.
  • the additional anti-cancer agent is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is selected from imatinib and nilotinib.
  • the additional therapeutic agent is radiotherapy.
  • the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor.
  • PARP poly ADP ribose polymerase
  • the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib.
  • the additional therapeutic agent is a BRAF inhibitor.
  • the BRAF inhibitor is encorafenib, dabrafenib, or vemurafenib.
  • the additional therapeutic agent is an ERK inhibitor.
  • the ERK inhibitor is ulixertinib, ASN007, LY3214996, AZ13767370, MK-8353, or LTT462.
  • the additional therapeutic agent is a MEK inhibitor.
  • the MEK inhibitor is trametinib, binimetinib, cobimetinib, or selumetinib.
  • the additional therapeutic agent is mammalian target of rapamycin inhibitor (mTOR).
  • mTOR inhibitor is sirolimus, everolimus, temsirolimus, or ridaforolimus (AP23573 and MK-8669).
  • the additional therapeutic agent is an anti-angiogenesis agent.
  • the additional therapeutic agent is a VEGF inhibitor, VEGFR inhibitor, PDGFR inhibitor, sunitinib, bevacizumab, axitinib, SU 14813 (Pfizer), or AG 13958 (Pfizer).
  • the additional therapeutic agent is sorafenib.
  • the additional therapeutic agent is a so-called signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell).
  • Signal transduction inhibitors include small molecules, antibodies, and antisense molecules.
  • Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors.
  • More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, ERBB family inhibitors, IGF1R inhibitors, MEK, c-Kit inhibitors, Erk1/2 inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi-targeted kinase inhibitors.
  • the additional therapeutic agent is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is selected from imatinib and nilotinib.
  • EXAMPLES Example 1: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: N-(4-chlorophenethyl)-2,2,2-trifluoroacetamide [000239] 2-(4-Chlorophenyl)ethylamine (642 mmol) was dissolved in dichloromethane (1.2 L) and triethylamine (107 mL) was added in one portion.
  • Step 2 1-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (636.56 mmol) was suspended in acetic acid (173 mL) and paraformaldehyde (1.27 mol) was added in one portion. The mixture was cooled down to 10 °C and concentrated sulfuric acid (218 mL) was added dropwise over 85 minutes maintaining the temperature below 15 °C. The reaction mixture was stirred at 50-60 °C for 1 hour and then cooled down to room temperature and stirred for another 16 hours.
  • Step 3 1-(7-chloro-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000241] 1-(7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one (152 mmol) was dissolved in sulfuric acid (374 mL). The solution was cooled down to -20 °C and fuming nitric acid (6.5 mL) was added dropwise over 30 min while keeping the temperature at -20 °C.
  • Step 4 1-(6-amino-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000242] To a solution of 1-(7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1- one (120 mmol) in ethanol (928 mL), iron powder (608 mmol) was added in small portions. Acetic acid (14 mL) and 6N aqueous HCl (5 mL) were added and the resulting reaction mixture was heated at 70 °C for 2 hours.
  • Step 5 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000243] 1-(6-amino-7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one (34.7 mmol) was dissolved in 2,4-dichloro-5-(trifluoromethyl)pyrimidine (191 mmol) and the mixture was stirred at 70°C for 24 hours.
  • Step 6 Methyl 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000244] A solution of 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.41 mmol), triethylamine (0.83 mmol), Pd(dppf)Cl 2 (0.041 mmol) and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester (0.50 mmol) in 1,4-dioxane (2.0 mL) and water (0.4 mL)
  • Example 2 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-N,N-dimethylthiophene-3-carboxamide
  • Step 1 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylic acid
  • Step 4 [000249] A solution of tert-butyl 7-chloro-6-((4-(4-(dimethylcarbamoyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.12 mmol) in 1,4- dioxane (1.4 mL) was treated with a 4N aqueous solution of HCl (1.4 mL) and the solution was stirred at room temperature overnight. Evaporation of volatiles afforded a residue that was purified by HPLC. The title compound was isolated in 19% yield.
  • Example 3 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-N,N-dimethylthiophene-2-carboxamide
  • Step 1 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylic acid [000250] The title compound was prepared analogously to Example 1, step 6, where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was substituted with 5-carboxylthiophene-2- boronic acid pinacol ester.
  • Example 4 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000252] A solution of 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (3.26 mmol), 1,4-bis(dipheny
  • Step 2 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000253] A mixture of CuI (0.037 mmol), PdCl2(PPh3)2 (0.009 mmol), 2-bromo-6,7-dihydrothieno[3,2- C]pyridin-4(5H)-one (0.22 mmol) and 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin- 2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.18 mmol) in 1,4
  • Step 3 [000254] Potassium carbonate (0.36 mmol) was added to a stirred solution of 2-(2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one (0.073 mmol) in a mixture of ethanol (1.2 mL) and water (0.12 mL) and the reaction mixture was stirred at 70°C for 1 hour. Evaporation of volatiles afforded a residue that was purified by HPLC.
  • Step 2 [000256] A solution of tert-butyl 3-(6-((4-(4-carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)azetidine-1-carboxylate (0.071 mmol) was treated with a 4N solution of HCl in 1,4-dioxane (0.8 mL). The reaction was stirred at room temperature for 1 hour, the volatiles were removed under reduced pressure and the resulting crude material was purified by preparative HPLC to afford the title compound in 40% yield.
  • Example 7 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3- carboxamide
  • Step 1 1-(5-chloroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • 5-Chloroisoindoline (5.69 mmol) and triethylamine (2.4 mL) were dissolved in dichloromethane (28 mL). The solution was cooled down to -10°C and trifluoroacetic anhydride (8.53 mmol) was added dropwise.
  • Step 3 1-(5-amino-6-chloroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000261] 1-(5-chloro-6-nitro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one (4.23 mmol), acetic acid (0.50 mL) and iron powder (21.3 mmol) were suspended in EtOH (63.5 mL). The mixture was stirred at 80°C for 1.5 hours and the volatiles were removed under reduced pressure to afford a residue that was filtered through a pad of celite and rinsed with ethyl acetate.
  • Step 4 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000262] A mixture of 1-(5-amino-6-chloro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one (4.12 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (28.8 mmol) was stirred at 60°C overnight.
  • Step 5 Methyl-5-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate
  • the title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2- yl)-2,2,2-trifluoroethan-1-one.
  • Example 8 7-chloro-N-(4-(4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 5-bromothiophene-3-carboxylic acid
  • Methyl 2-bromothiophene-4-carboxylate (13.6 mmol) and LiOH (20.4 mmol) were dissolved in THF (30 mL) and water (30 mL) and the solution stirred at 50 ⁇ C for 2 hours.
  • Step 3 2-(5-Bromothiophen-3-yl)-4,5-dihydrooxazole [000267] 5-Bromo-N-(2-hydroxyethyl)thiophene-3-carboxamide (1.9 mmol) was suspended in dichloromethane (10 mL). Triethylamine (0.69 mL) was added and the mixture was cooled to 0 ⁇ C. Methanesulfonyl chloride (0.19 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours.
  • Step 4 1-(7-Chloro-6-((4-(4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000268]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-(5-bromothiophen-3-yl)-4,5- dihydrooxazole.
  • the title compound was isolated in 32% yield.
  • Example 9 5-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxamide
  • Step 1 7-Ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline [000270] 1-(7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one (3.24 mmol), Pd(dppf) 2 Cl 2 complex with dichloromethane (0.16 mmol), potassium phosphate tribasic (16.2 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (0.26 mmol) and ethylboronic acid (9.72 mmol) were suspended in toluene (20 mL) and water (3 mL) and the mixture was stirred at
  • Step 2 1-(7-ethyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000271] A -10°C solution of 7-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (1.96 mmol) and triethylamine (0.55 mL) in dichloromethane (9 mL) was treated with trifluoroacetic anhydride (2.94 mmol) and the resulting mixture was stirred at room temperature for one hour. The reaction was quenched with water and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 3 1-(6-Amino-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • a mixture of 1-(7-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one (1.31 mmol), iron powder (6.55 mmol) and acetic acid (0.15 mL) was suspended in ethanol (20 mL) and heated at 80°C overnight. Evaporation of volatiles under reduced pressure afforded a residue that was suspended in ethyl acetate and filtered through silica gel.
  • Step 5 Methyl 5-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000275]
  • the title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 11-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-ethyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Example 10 5-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide
  • Step 1 1-(7-Cyclopropyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000276]
  • the title compound was prepared analogously to Example 9, step 1, where ethylboronic acid was replaced with potassium cyclopropyltrifluoroborate.
  • Step 2 1-(6-Amino-7-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000277]
  • the title compound was prepared analogously to Example 9, step 3, where 1-(7-ethyl-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-cyclopropyl-6- nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 3 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-cyclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000278]
  • the title compound was prepared analogously to example 9, step 4, where 1-(6-amino-7-ethyl- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Example 11 5-(2-((7-chloro-2-(1-methylazetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide [000281] To a stirred solution of 1-methylazetidin-3-one hydrochloride (0.17 mmol) and 5-(2-((7-chloro- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide (0.14 mmol) in dichloromethane (1.4 mL), triethylamine (0.20 mL) and NaBH(OAc)3 (0.69 mmol) were added in one portion.
  • Example 12 5-(2-((6-chloro-2-(1-methylazetidin-3-yl)isoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide [000282] 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3- carboxamide (0.21 mmol), 1-methylazetidin-3-one hydrochloride (0.42 mmol) and sodium cyanoborohydride (0.42 mmol) were dissolved in methanol (2 mL).
  • Example 13 5-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide
  • Step 1 Methyl 5-(2-((7-Ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate
  • reaction mixture was stirred at room temperature for 1 hour followed by the addition of acetic acid (0.12 mL) and a 37% aqueous solution of formaldehyde (0.072mL). After 10 minutes, sodium cyanoborohydride (1.39 mmol) was added and one hour later all volatiles were removed under reduced pressure to afford a solid that was taken up in dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to afford the title compound in 84% yield.
  • Step 3 [000285] 5-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride (0.56 mmol) was dissolved in DMF (6.9 mL) and triethylamine (0.23 mL), a 0.4 N solution of ammonia in 1,4-dioxane (4.2 mL) and HATU (1.68 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, the volatiles were removed under reduced pressure and the residue was taken up in water and filtered.
  • Example 14 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide
  • Step 1 Methyl 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate
  • the title compound was prepared analogously to Example 13, step 1, where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((7-((
  • Example 15 N-(4-(4-aminothiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-7-chloro-1,2,3,4- tetrahydroisoquinolin-6-amine
  • Step 1 tert-Butyl (5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)carbamate
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(N-tert- butyloxycarbonylamino)thiophene.
  • Example 16 N-(5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)methanesulfonamide
  • Step 1 tert-butyl (5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)carbamate
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(N-tert- butyloxycarbonylamino)thiophene.
  • reaction mixture was stirred at room temperature overnight and the volatiles were removed under reduced pressure to afford a residue that was treated with a 7N solution of ammonia in methanol (1.4 mL).
  • the resulting reaction was stirred at 50°C for 2 hours, concentrated to dryness and purified by silica gel chromatography (dichloromethane with a 10% methanolic solution of ammonia) to afford the title compound in 52% yield.
  • Example 17 5-(2-((6-Chloro-2-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide
  • 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3- carboxamide (0.16 mmol) and formaldehyde (37 wt. % in water, 0.02 mL) were dissolved in methanol (2.4 mL) and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (0.33 mmol) was added and the reaction was stirred for another hour.
  • Example 18 7-Chloro-N-(4-(4-(oxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 2-(5-Bromothiophen-3-yl)oxazole [000295] 2-(5-Bromothiophen-3-yl)-4,5-dihydro-1,3-oxazole (1.08 mmol) and 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone (1.62 mmol) in 1,4-dioxane (5.0 mL) were stirred at 100 °C for 2 hours.
  • Step 2 1-(7-Chloro-6-((4-(4-(oxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000296]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-(5-bromothiophen-3-yl)oxazole.
  • Example 19 5-(2-((6-Cyclopropyl-2-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide
  • Step 1 1-(5-Cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one and ethylboronic acid were replaced with 1-(5-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one and cyclopropylboronic acid.
  • Step 2 1-(5-Cyclopropyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000299]
  • the title compound was prepared analogously to Example 1, step 3, where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-cyclopropylisoindolin-2- yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 31% yield.
  • Step 4 1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-cyclopropylisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one [000301]
  • the title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 34% yield.
  • Step 5 Methyl 5-(2-((6-cyclopropyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000302]
  • the title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Example 20 5-(2-((6-Ethyl-2-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide
  • Step 1 1-(5-Bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000304] The title compound was prepared analogously to Example 7, step 1 where 5-chloroisoindoline was replaced with 5-bromoisoindoline. The title compound was isolated in 96% yield.
  • Step 2 1-(5-Ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-bromoisoindolin-2- yl)-2,2,2-trifluoroethan-1-one.
  • Step 3 1-(5-Ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000306]
  • the title compound was prepared analogously to Example 7, step 2, where 1-(5-chloro-2,3- dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-Ethylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one.
  • Step 5 1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-ethylisoindolin-2-yl)-2,2,2- [000308]
  • the title compound was prepared analogously to Example 7, step 4, where 1-(5-amino-6- chloro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6- ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 23% yield.
  • Step 6 Methyl 5-(2-((6-ethyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000309]
  • the title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-ethylisoindolin-2- yl)-2,2,2-trifluoroethan-1-one.
  • Step 8 5-(2-((6-Ethyl-2-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene- 3-carboxylic acid [000311]
  • the title compound was prepared analogously to Example 2, step 1 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((6-ethyl-2-methylisoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate.
  • Example 21 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-Bromo-5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000313]
  • 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5h)-one (0.43 mmol
  • methyl iodide (0.14 mL) were suspended in DMF (2.0 mL) and the mixture stirred at 40 ⁇ C overnight.
  • Step 2 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one.
  • Example 22 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-ethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-bromo-5-ethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000316]
  • the title compound was prepared analogously to Example 21, step1 where methyl iodide was replaced with ethyl iodide.
  • the title compound was isolated in 45% yield.
  • Example 23 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one [000319] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromothieno[3,2-c]pyridin-4(5h)-one.
  • Example 24 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[2,3-d]pyridazin-4(5H)-one
  • Step 1 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[2,3-d]pyridazin-4(5H)-one
  • the title compound was prepared analogously to Example 4, step 2, where ethyl 2- chlorooxazole-4-carboxylate was replaced with 2-bromothieno[2,3-D]pyridazine-4(5H)-one.
  • Example 25 5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carbonitrile
  • Step 1 5-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carbonitrile [000323]
  • the title compound was prepared analogously to Example 1, step 6, where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was replaced with 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3-thiophenecarbonitrile.
  • Example 26 4-(4-Carbamoylthiophen-2-yl)-2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidine-5-carboxamide
  • Step 1 Methyl 5-(5-carbamoyl-2-chloropyrimidin-4-yl)thiophene-3-carboxylate
  • the title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 2,4- dichloropyrimidine-5-carboxamide and 4-(methoxycarbonyl)thiophene-2-boronic acid pin
  • Step 3 Methyl 5-(5-carbamoyl-2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)thiophene-3-carboxylate
  • the title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with methyl 5-(5-carbamoyl-2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiophene
  • Example 27 5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-sulfonamide
  • Step 1 Methyl 5-bromo-3-sulfamoylthiophene-2-carboxylate
  • Methyl 5-bromo-3-(chlorosulfonyl)thiophene-2-carboxylate (2.48 mmol) was dissolved in a 0.4 N solution of ammonia in 1,4-dioxane (15.5 mL) and the reaction was stirred at room temperature for 20 minutes.
  • Example 28 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
  • Step 1 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
  • the title compound was prepared analogously to Example 4, step 2, where ethyl 2- chlorooxazole-4-carboxylate was replaced with 2 ⁇ bromo ⁇ 4H,5H,6H,7H,8H ⁇ thieno[3,2 ⁇ c]azepin
  • Example 29 2-(2-((7-Cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-(2-((7-Cyclopropyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000339] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1
  • Step 2 [000340] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- (4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-cyclopropyl-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one.
  • Example 30 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[3,2-c]pyridin-4(5H)-one
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-4H,5H-thieno[3,2- c]pyridin-4-one.
  • Example 31 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one
  • Step 1 2-Bromo-5-methylthieno[2,3-d]pyridazin-4(5H)-one
  • a solution of 2-bromothieno[2,3-D]pyrazin-4(5H)-one (0.65 mmol) and dimethylformamide- dimethyl acetal (0.97 mmol) in DMF (3 mL) was stirred at 160°C for 2 hours in a sealed pressure tube.
  • Step 2 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one [000344]
  • the title compound was prepared analogously to Example 6, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-4H,5H-thieno[2,3- d]pyridazin-4-one.
  • the title compound was isolated in 72% yield.
  • Example 32 7-Chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 2-(Methoxycarbonyl)thiophene-3-sulfinic acid [000346] A suspension of Na 2 SO 3 (15 mmol) and NaHCO3 (16 mmol) in water (30.0 mL) was heated at 40 ⁇ C and methyl 3-chlorosulfonylthiophene-2-carboxylate (12 mmol) was added in small portions.
  • Step 3 Methyl 5-bromo-3-(methylsulfonyl)thiophene-2-carboxylate
  • Methyl 3-(methylsulfonyl)thiophene-2-carboxylate (1.36 mmol) was dissolved in TFA (6.0 mL) and H2SO4 (13.6 mmol). The reaction mixture was cooled down to -15°C and N-bromosuccinimide (1.49 mmol) was added in small portions over 15 minutes. The cooling bath was removed and the solution was stirred at room temperature for one hour.
  • Step 4 5-Bromo-3-(methylsulfonyl)thiophene-2-carboxylic acid
  • a 2.2 M aqueous solution of LiOH 0.5 mL was added over a solution of methyl 5-bromo-3- methanesulfonylthiophene-2-carboxylate (0.56 mmol) in methanol (3.4 mL) and the reaction was stirred at room temperature for one hour. After evaporation of volatiles under reduced pressure, the crude was dissolved in water and the pH was made acidic by the addition of a 1M aqueous solution of HCl. The precipitate was filtered affording title compound in 93% yield.
  • Step 6 1-(7-Chloro-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000351]
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(methylsulfonyl)thiophene.
  • the title compound was isolated in 44% yield.
  • Example 33 2-(2-((6-Chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-(2-((6-Chloro-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000353]
  • the title compound was prepared analogously to Example 14, step 2, where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with
  • Example 34 2-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-(2-((7-Ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000355]
  • the title compound was prepared analogously to Example 14, step 2, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-y
  • Example 35 2-(2-((7-(Methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2,2,2-Trifluoro-1-(7-(methylthio)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
  • Example 36 2-(2-((2-Cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 2-Cyclopropyl-4-(4-methylpiperazin-1-yl)aniline
  • Step 3 [000364] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 4-chloro-N-(2- cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine and dihydrothienopyridin-4-one-2-boronic acid pinacol ester, respectively.
  • Example 37 5-(2-((2-Ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxamide
  • Step 1 1-Methyl-4-(4-nitro-3-vinylphenyl)piperazine
  • Step 4 Methyl 5-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000368]
  • the title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one was substituted with 4-chloro-N-(2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)-5- (trifluoromethyl)pyrimidin-2-amine.
  • Example 38 (5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)dimethylphosphine oxide
  • Step 1 Dimethyl(thiophen-3-yl)phosphine oxide [000371] A solution of 3-iodothiophene (4.76 mmol), dimethylphosphine oxide (4.32 mmol), triethylamine (0.75 mL), Pd2(dba)3 (0.044 mmol) and Xantphos (0.044 mmol) in 1,4-dioxane (22 mL), was stirred at room temperature for 20 hours.
  • Step 2 (5-Iodothiophen-3-yl)dimethylphosphine oxide [000372] A solution of 3 ⁇ (dimethylphosphoryl)thiophene in ethanol (6.6 mL) was treated with I2 (0.94 mmol) and H5IO6 (1.09 mmol) at room temperature. The resulting mixture was stirred at 80°C for 30 minutes and at room temperature overnight. The reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography (5% methanol in dichloromethane) to afford the title compound in 55% yield.
  • Step 3 1-(7-Chloro-6-((4-(4-(dimethylphosphoryl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000373]
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 4 ⁇ (dimethylphosphoryl) ⁇ 2 ⁇ iodothiophene.
  • the title compound was isolated in 50% yield.
  • Example 39 2-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000375]
  • the title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 4-chloro-N-[2- ethyl-4-(4-methylpiperazin-1-yl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine and 2-(4,4,5,5- tetra
  • Example 43 2-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 1-(6-amino-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000376]
  • the title compound was prepared analogously to Example 1, steps 1-4, where 2-(4- chlorophenyl)ethylamine was replaced with 2-(4-fluorophenyl)ethan-1-amine in step 1.
  • Step 2 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-fluoro-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000377]
  • the title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 3 2-(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000378]
  • the title compound was prepared analogously to Example 1, step 6 where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was replaced with 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4H,5H,6H,7H-thieno[3,2-c]pyridin-4-one.
  • Example 46 2-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
  • Step 1 1-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • Trifluoroacetic anhydride 72 mmol was added over a 0°C solution of 6-chloro-1,2,3,4- tetrahydroisoquinoline (60 mmol) and triethylamine (119 mmol) in dichloromethane (300 mL) and stirred for one hour.
  • Step 2 1-(6-chloro-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 3 where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-chloro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 79% yield. MS (ESI) m/z: 307.1 [M+H] + .
  • Step 3 1-(7-amino-6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-chloro-7-nitro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 96% yield. MS (ESI) m/z: 279.1 [M+H] + .
  • Step 4 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000383]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-amino-6- chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 6 2-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one [000385]
  • the title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(6-chloro-7- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3
  • Example 48 2-(2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
  • Step 1 tert-butyl 4-(3-cyclopropyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • 3-Cyclopropyl-4-nitro-1H-pyrazole (13 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (14 mmol) and triphenylphosphine (40 mmol) were dissolved in THF (22.0 mL) and the mixture was cooled down to 0 °C.
  • Step 2 tert-butyl 4-(4-amino-3-cyclopropyl-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • a suspension of tert-butyl 4-(3-cyclopropyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (6.3 mmol) and 10% palladium on carbon (0.075 mmol) in methanol was hydrogenated at room temperature for 48 hours. The catalyst was filtered through celite and the volatiles were removed under reduced pressure to afford the title compound in 99% yield.
  • Step 3 tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropyl-1H- pyrazol-1-yl)piperidine-1-carboxylate
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 4-(4- amino-3-cyclopropyl-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the title compound was isolated in 27% yield.
  • Step 4 tert-butyl 4-(3-cyclopropyl-4-((4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate [000390]
  • the title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with tert-butyl 4-(4- ((4-chloro-5-
  • Example 49 2-(2-((6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one [000393]
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 2-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydr
  • Example 53 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,2,3,4-tetrahydro-5H-thieno[2,3-e][1,4]diazepin-5-one
  • Step 1 tert-butyl (3-(((1,3-dioxolan-2-yl)methyl)carbamoyl)-5-bromothiophen-2-yl)carbamate
  • Step 2 tert-butyl (5-bromo-3-((2-oxoethyl)carbamoyl)thiophen-2-yl)carbamate [000395] tert-butyl (3-(((1,3-dioxolan-2-yl)methyl)carbamoyl)-5-bromothiophen-2-yl)carbamate (0.88 mmol) was dissolved in methanol (20.0 mL) and 37% methanolic solution of hydrochloric acid (88 mmol).
  • reaction mixture was quenched by addition of 1M aqueous sodium hydroxide and the methanol was removed under reduced pressure.
  • the resulting aqueous solution was extracted with dichloromethane three times and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 62% yield.
  • Step 3 7-bromo-1,2,3,4-tetrahydro-5H-thieno[2,3-e][1,4]diazepin-5-one
  • tert-butyl 5-bromo-3-((2-oxoethyl)carbamoyl)thiophen-2-yl)carbamate (0.28 mmol)
  • acetic acid 0.017 ml
  • sodium cyanoborohydride 0.42 mmol
  • Step 4 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,2,3,4-tetrahydro-5H-thieno[2,3-e][1,4]diazepin-5-one [000397]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 7-bromo-1,2,3,4-tetrahydro-5H-thieno[2,3- e][1,4]diazepin-5-one.
  • Example 59 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene-2-carboxamide
  • Step 1 Methyl 3-(methylsulfonyl)thiophene-2-carboxylate [000399] To a solution of sodium bicarbonate (8.73 mmol) in water (5 mL) was added sodium sulfite (8.31 mmol).
  • Step 4 5-Bromo-3-(methylsulfonyl)thiophene-2-carboxamide
  • a solution of 5-bromo-3-methylsulfonyl-thiophene-2-carboxylic acid (0.10 mmol) in thionyl chloride (1 mL) was stirred at 60 °C for 2 hours.
  • the mixture was concentrated under reduced pressure and the resulting residue was treated with a solution of ammonium hydroxide (1.15 mmol) in THF (1 mL) precooled to 0 °C.
  • the mixture was stirred at 25 °C for 1 hour, concentrated and purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound in 61% yield.
  • Step 5 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene-2-carboxamide
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 5-bromo-3-(methylsulfonyl)thiophene-2- carboxamide.
  • Example 60 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepine 4,4-dioxide
  • Step 1 3-(thiophen-3-ylsulfanyl)propan-1-ol [000405] 3-bromothiophene (3.00 g, 1.0 eq) was dissolved in diethyl ether (21 mL) and cooled down to - 76°C.
  • Step 2 3-[(2-bromothiophen-3-yl)sulfanyl]propan-1-ol [000406] NBS (2.47 g, 1.05 eq) was added portion wise during 5 minutes to a 0°C solution of 3- (thiophen-3-ylsulfanyl)propan-1-ol (2.47 g) in dichloromethane (86 mL).
  • Step 3 5H,6H,7H-thieno[2,3-b][1,4]oxathiepine [000407]
  • a mixture of 3-(thiophen-3-ylsulfanyl)propan-1-ol (11.3 mmol), cesium carbonate (22.5 mmol), CuI (1.24 mmol) and phenanthroline (2.25 mmol) in toluene (43 mL) was heated at 110 °C for 21 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, filtered through celite, and eluted with methanol.
  • Step 5 1-(7-chloro-6-((4-(4,4-dioxido-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one [000409]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5H,6H,7H-4 ⁇ 6-thieno[2,3- b][1,4]oxathiepine-4,4-dione.
  • Example 63 5-(2-((7-Chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene-2-carboxamide
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene-2-carboxamide.
  • Example 64 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide
  • Step 1 Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2-carboxylate [000412] To a solution of sodium bicarbonate (262 mmol) and sodium sulfite (249 mmol) in water (200 mL) was added methyl 3-chlorosulfonylthiophene-2-carboxylate (125 mmol), methyl 3- chlorosulfonylthiophene-2-carboxylate (125 mmol) and ethyl alcohol (100 mL).
  • Step 2 Methyl 3-((2-aminoethyl)sulfonyl)thiophene-2-carboxylate [000413] A 10 °C solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2- carboxylate (11.5 mmol) in dichloromethane (18 mL) was treated with TFA (122 mmol) and the reaction was stirred for 1 hour. Evaporation of volatiles under reduced pressure afforded the title compound, which was used in the next step without further purification.
  • Step 3 3,4-Dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • a mixture of methyl 3-(2-aminoethylsulfonyl)thiophene-2-carboxylate (5.50 mmol) and potassium carbonate (16.5 mmol) in ethyl alcohol (10 mL) was stirred at 70°C for 12 hours.
  • the reaction mixture was filtered and concentrated under reduced pressure to afford the title compound in 88% yield which was used in the next step without further purification.
  • Step 4 2,3,4,5-Tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide
  • Step 5 1-(1,1-Dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2-trifluoroethan-1-one
  • a 0°C solution of 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide (1.67 mmol) and triethylamine (3.35 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic anhydride (2.01 mmol). The mixture was stirred at 10 °C for 1 hour and the pH adjusted to 5 by the addition of ammonium chloride.
  • Step 6 1-(7-bromo-1,1-dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2- trifluoroethan-1-one [000417] A solution of 1-(1,1-dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2- trifluoroethan-1-one (1.40 mmol), N-bromosuccinimide (1.40 mmol) and acetic acid (10 mL) was treated with sulfuric acid (19 mmol) and the mixture was stirred at 60 °C for 12 hours.
  • Step 7 1-(7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,1-dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2- trifluoroethan-1-one [000418]
  • the title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 1-(7-bromo-1,1-dioxido-2,3- dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 8 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide [000419]
  • the title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-(7-(2-((7-chloro-2-(2,2,2-trifluoro
  • Example 68 2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-7- (methylthio)-1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 2,2,2-trifluoro-1-(7-(methylthio)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
  • Step 2 1-(6-amino-7-(methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000421]
  • the title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 2,2,2-trifluoro-1-(7- (methylthio)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one.
  • the title compound was isolated in 77% yield.
  • Step 3 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-(methylthio)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000422]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- (methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 5 N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylthio)- 1,2,3,4-tetrahydroisoquinolin-6-amine epared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2,2,2-trifluoro-1-(6-((4-(4-(methylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)
  • Example 69 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide
  • Step 1 7-bromo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide
  • the title compound was prepared analogously to Example 59, step 6, where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-(7-bromo
  • Step 3 tert-butyl 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2,3-dihydrothieno[2,3-f][1,4]thiazepine-4(5H)- carboxylate 1,1-dioxide [000428] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with tert-butyl 7-bromo-2,3-dihydrothieno[2,3- f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide.
  • Example 71 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one
  • Step 1 2-(2-hydroxyethoxy)thiophene-3-carboxylic acid
  • Potassium tert-butoxide (72.4 mmol) was dissolved in ethylene glycol (11 mL) and copper(I) iodide (2.42 mmol) and 2-bromo-3-thiophenecarboxylic acid (24 mmol) were added portion-wise.
  • Step 2 2-(2-hydroxyethoxy)thiophene-3-carboxamide
  • a solution of 2-(2-hydroxyethoxy)thiophene-3-carboxylic acid (4.67 mmol), triethylamine (26.3 mmol) and HCTU (14.0 mmol) in DMF (13 ml) was treated with a 0.4 M solution of ammonia in dioxane (22.7 mmol). After 1 hour, a second portion of HCTU (14.0 mmol) and 0.4 M solution of ammonia in dioxane (22.7 mmol) was added and stirring continued overnight.
  • Step 4 3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000435] 60% Sodium hydride (2.92 mmol) was added to a solution of 2-((3-carbamoylthiophen-2- yl)oxy)ethyl methanesulfonate (2.44 mmol) in DMF (14 mL). After 12 hours, the reaction was acidified by the addition of acetic acid (0.07 mL) and the volatiles were removed under reduced pressure. The crude material was purified by silica gel chromatography to afford the title compound in 66% yield. MS (ESI) m/z: 169.9 [M+H] + .
  • Step 5 7-bromo-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000436]
  • NBS (1.52 mmol) was added to a solution of 3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one (1.60 mmol) in dichloromethane (0.3 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (0-10% methanol in 1M solution of ammonia in methanol). The title compound was isolated in 87% yield. MS (ESI) m/z: 250.4 [M+H] + .
  • Step 6 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000437]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 7-bromo-3,4-dihydrothieno[3,2- f][1,4]oxazepin-5(2H)-one.
  • Step 7 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000438]
  • the title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetra
  • Example 72 6-ethyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)isoindolin-5-amine
  • Step 1 1-(5-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • Triethylamine (76 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (50 mmol) in dichloromethane (120 mL).
  • Step 2 1-(5-ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • Step 3 1-(5-ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000441] A solution of 1-(5-ethyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one (16 mmol) in acetic anhydride (22 ml) was cooled down to -30°C.
  • Nitric acid (0.83 mL) was added slowly over 10 minutes. The reaction mixture warmed up to room temperature and stirred for 2 hours. Methanol (15 mL) was added and the mixture stirred for another 30 minutes. Evaporation of the volatiles under reduced pressure afforded a residue that was partitioned between water and dichloromethane. The organic layer was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0- 30% ethyl acetate in hexanes).
  • Step 4 1-(5-amino-6-ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000442] A solution of 1-(5-ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (7.14 mmol) in methanol (42 mL) was hydrogenated in the presence of 10% palladium on carbon (0.21 mmol) for 12 hours. The mixture was filtered through celite and the methanol was evaporated. The crude material was purified by silica gel chromatography (20-60% ethyl acetate in hexanes) to afford the title compound in 55% yield.
  • Step 5 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-ethylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000443]
  • the title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6- ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Step 6 1-(5-ethyl-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000444]
  • the title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(5-((4- chloro-5-(trifluoromethyl)pyrimidin-2-y
  • Example 73 6-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)isoindolin-5-amine [000446]
  • the title compound was prepared analogously to Example 72, where 5-bromo-2,3-dihydro-1H- isoindole was replaced with 5-chloro-2,3-dihydro-1H-isoindole in step 1.
  • Example 75 7-chloro-N-(4-(5-(3,6-dihydro-2H-pyran-4-yl)-4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 2,5-dibromo-3-(methylthio)thiophene [000447] To a solution of 3-methylsulfanylthiophene (38 mmol) in dichloromethane (50 mL) was added 1-bromopyrrolidine-2,5-dione (84 mmol).
  • Step 3 4-(5-bromo-3-(methylsulfonyl)thiophen-2-yl)-3,6-dihydro-2H-pyran [000449] A mixture of 2,5-dibromo-3-methylsulfonyl-thiophene (0.62 mmol), 2-(3,6-dihydro-2H-pyran- 4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.62 mmol), potassium phosphate (1.87 mmol) and tetrakis[triphenylphosphine]palladium(0) (0.06 mmol) in dioxane (2 mL) and water (0.4 mL) was stirred at 80 °C for 1 hour.
  • Step 4 1-(7-chloro-6-((4-(5-(3,6-dihydro-2H-pyran-4-yl)-4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one [000450] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 4-(5-bromo-3-(methylsulfonyl)thiophen-2-yl)- 3,6-dihydro-2H-pyran.
  • Example 77 6-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)isoindolin-5-amine
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 6-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)isoindolin-5-amine.
  • Example 80 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-5-amine
  • Step 1 1-(5-amino-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000453]
  • the title compound was prepared analogously to Example 72 following steps 1, 3 and 4, where 5-bromo-2,3-dihydro-1H-isoindole was replaced with 5-fluoro-2,3-dihydro-1H-isoindole in step 1.
  • Step 2 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000454]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6- fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one.
  • Step 4 2,2,2-trifluoro-1-(5-fluoro-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2-yl)ethan-1-one [000456]
  • the title compound was prepared analogously to Example 4, step 2 where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-bromo-6,7-dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 2,2,2- trifluoro-1-(5-fluoro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-y
  • Step 6 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-5-amine
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1H-isoindol-5-amine.
  • Example 82 -[2-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one
  • Step 1 8-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one
  • Step 2 7-[2-[[7-chloro-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinolin-6-yl]amino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one [000460]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 8-bromo-1,1-dioxo-3,4-dihydro-2H- thieno[2,3-f][1,4]thiazepin-5-one.
  • Example 83 7-Chloro-N-[4-(4-methylsulfonyl-5-morpholino-2-thienyl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 4-(5-bromo-3-methylsulfonyl-2-thienyl)morpholine
  • a solution of 2,5-dibromo-3-methylsulfonyl-thiophene (1.72 mmol) in 1-methyl-2- pyrrolidinone (2.5 mL) was treated with morpholine (13.7 mmol) and N,N-diisopropylethylamine (13.75 mmol).
  • Step 2 1-[7-chloro-6-[[4-(4-methylsulfonyl-5-morpholino-2-thienyl)-5-(trifluoromethyl)pyrimidin- 2-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone [000463]
  • the title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 4-(5-bromo-3-methylsulfonyl-2- thienyl)morpholine.
  • the title compound was isolated in 63% yield.
  • Step 3 7-Chloro-N-[4-(4-methylsulfonyl-5-morpholino-2-thienyl)-5-(trifluoromethyl)pyrimidin-2- yl]-1,2,3,4-tetrahydroisoquinolin-6-amine [000464]
  • the title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-[7-chloro-6-[[4-(4-methylsulfonyl-5- morpholino-2-thienyl)-5-(trifluoromethyl)pyrimidin-2-yl
  • Example 85 7-chloro-N-[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b][1,4,5]oxathiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-amine
  • Step 1 2,5-dibromo-N-(2-hydroxyethyl)thiophene-3-sulfonamide
  • Step 2 7-bromo-3,4-dihydro-2H-thieno[2,3-b][1,4,5]oxathiazepine 1,1-dioxide
  • Step 3 1-[7-chloro-6-[[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b][1,4,5]oxathiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone [000467] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 7-bromo-3,4-dihydro-2H-thieno[2,3- b][1,4,5]oxathiazepine 1,1-dioxide.
  • Example 86 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5 (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000469]
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 7-chloro-N-[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3- b][1,4,5]oxathiazepin
  • Example 88 6-cyclopropyl-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl]-2-methyl-2,3-dihydro-1H-isoindol-5-amine
  • Step 1 1-(5-amino-6-cyclopropyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 72, steps 1-4 where ethylboronic acid was replaced with cyclopropylboronic acid in step 2. The title compound was isolated.
  • Step 2 1-(5- ⁇ [4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ -6-cyclopropyl-2,3-dihydro-1H- isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000471]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6- cyclopropyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one.
  • Step 3 1-(5-cyclopropyl-6- ⁇ [5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl]amino ⁇ -2,3- dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000472]
  • the title compound was prepared analogously to Example 80, step 3 where 1-(5- ⁇ [4-chloro-5- (trifluoromethyl)pyrimidin-2-yl]amino ⁇ -6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1- one was replaced with 1-(5- ⁇ [4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ -6-cyclopropyl-2,3- dihydro-1H-is
  • Step 4 1-(5-cyclopropyl-6- ⁇ [4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl]amino ⁇ -2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000473]
  • the title compound was prepared analogously to Example 4, step 2 where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-bromo-6,7-dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 1-
  • Example 95 7-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 7-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine.
  • Example 101 N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4- tetrahydroisoquinolin-7-amine
  • Step 1 1-(7- ⁇ [4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ -1,2,3,4-tetrahydroisoquinolin-2- yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-amino- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Example 102 N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-amine
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with N-[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinolin-7-amine.
  • Example 116 7-[2-[(7-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazepin-5-one
  • Step 1 7-bromo-4-methyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazepin-5-one [000481] A 0 °C solution of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one (0.34 mmol) and DMF (3 mL) was treated with 60% sodium hydride (0.37 mmol).
  • Example 121 N-(2-chloro-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine
  • Step 1 tert-butyl 3-(2-tosylhydrazineylidene)azetidine-1-carboxylate
  • Step 2 tert-butyl 3-(3-amino-4-chlorophenyl)azetidine-1-carboxylate [000487] To a solution of tert-butyl 3-[(4-methylbenzenesulfonamido)imino]azetidine-1-carboxylate (6.00 g, 18 mmol, 1.00 eq) in anhydrous dioxane (126 mL), 3-amino-4-chlorophenylboronic acid (4.54 g, 26.516 mmol, 1.5 eq) and Cs2CO3 (8.64 g, 26.516 mmol) were added.
  • Step 3 tert-butyl 3-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate
  • a 0°C solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (0.219 mmol) in dichloroethane/t-BuOH (1.2 mL/0.2 mL) a 0.7 M solution of ZnCl2 in THF (0.69 mL) was added.
  • reaction mixture was stirred at 0°C for 1 hour and a solution of tert-butyl 3-(3-amino-4- chlorophenyl)azetidine-1-carboxylate (0.219 mmol) in dichloroethane /t-BuOH [0.31 mL/0.31 mL] was added. Over the resulting mixture, diisopropylethylamine (0.241 mmol) was added dropwise and the reaction was stirred overnight at room temperature. Water was added and the resulting solution was extracted with ethyl acetate three times.
  • Step 4 tert-butyl 3-(4-chloro-3-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)phenyl)azetidine-1-carboxylate
  • Step 5 N-(5-(azetidin-3-yl)-2-chlorophenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine
  • a 4M solution of HCl in methanol (5 mL) was added over a solution of tert-butyl 3-(4-chloro- 3-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1- carboxylate (1 mmol) in methanol (6 mL).
  • Example 122 N-(2-chloro-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000491]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with N-(5- (azetidin-3-yl)-2-chlorophenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- amine.
  • Example 123 N-(1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-(4-(methylsulfonyl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine
  • Step 1 tert-butyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate
  • a solution of 3-methyl-4-nitro-1H-pyrazole (15.7 mmol) in THF (24 mL) was treated with 1- Boc-3-hydroxyazetidine (18.9 mmol) and triphenylphosphine (6.19 mmol).
  • Step 2 tert-butyl 3-(4-amino-3-methyl-1H-pyrazol-1-yl)azetidine-1-carboxylate
  • the title compound was prepared analogously to Example 19, step 3 where 1-(5-cyclopropyl- 6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 3-(3-methyl-4-nitro-1H- pyrazol-1-yl)azetidine-1-carboxylate.
  • the title compound was isolated in 94% yield.
  • Step 3 tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1- yl)azetidine-1-carboxylate
  • the title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 3-(4-amino-3-methyl-1H- pyrazol-1-yl)azetidine-1-carboxylate.
  • Step 4 tert-butyl 3-(3-methyl-4-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate
  • the title compound was prepared analogously to Example 121, step 4 where tert-butyl 3-(4- chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate was replaced with tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol- 1-yl)azetidine-1-carboxylate.
  • Example 124 N-(3-methyl-1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine [000497]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with N-(1- (azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine.
  • Example 125 7-(2-((7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 methyl 3-((2-(tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2-carboxylate [000498] A mixture of methyl 3-chlorosulfonylthiophene-2-carboxylate (125 mmol), sodium sulfite (249 mmol), sodium bicarbonate (262 mmol) in ethanol (100 mL) and water (200 mL) was heated at 50 °C for 45 minutes.
  • Step 2 methyl 3-((2-aminoethyl)sulfonyl)thiophene-2-carboxylate
  • a 10 °C solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2- carboxylate (37 mmol) in dichloromethane (30 mL) was treated with TFA (405 mmol). Evaporation of volatiles afforded the title compound which was used in the next step without further purification.
  • Step 3 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 4 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • a solution of 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (28 mmol) in sulfuric acid (6 mL) and acetic acid (60 mL) was treated with N-bromosuccinimide (50 mmol) and the reaction was stirred at 60 °C for 12 hours. The mixture was cooled down to room temperature and the pH was neutralized by the addition of sodium bicarbonate. DMF added and the insoluble materials were filtered.
  • Step 5 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000502] A mixture of 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.68 mmol), 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.68 mmol), te
  • Step 6 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000503] A mixture of 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.16 mmol) and potassium carbonate (0.94 mmol) in ethanol (2 mL) and water was stirred at 50 °C for 12 hours.
  • Step 7 7-(2-((7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000504] Triethylamine (0.30 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.14 mmol) were added over a solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)
  • Example 126 7-(2-((7-chloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000505] A solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.07 mmol) in THF (0.3 mL) and methanol (0.3 mL) was treated with acetic acid (0.007 mmol) and (1- ethoxycyclopropoxy)
  • Example 127 8-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-amine
  • Step 1 1-(8-chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one
  • Step 2 1-(8-chloro-7-nitro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 3 where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(8-chloro-1,3,4,5-tetrahydro- 2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 97% yield.
  • Step 3 1-(7-amino-8-chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one [000508]
  • the title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(8-chloro-7-nitro- 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Step 4 1-(8-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1,3,4,5-tetrahydro-2H- benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one [000509]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-amino-8- chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Example 129 N-(3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine [000515]
  • the title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with N-(3-Cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4- (4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine.
  • Example 130 N-(1-(azetidin-3-yl)-3-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(methylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine [000516]
  • the title compound was prepared analogously to Example 123, where 3-methyl-4-nitro-1H- pyrazole was replaced with 3-cyclopropyl-4-nitro-1H-pyrazole in step 1.
  • Example 131 6-cyclopropyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)isoindolin-5-amine
  • Step 1 1-(5-cyclopropyl-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000517]
  • the title compound was prepared analogously to Example 121, step 4 where tert-butyl 3-(4- chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl
  • Example 132 7-cyclopropyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine [000519]
  • the title compound was prepared analogously to Example 131, where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 7-cyclopropyl-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine.
  • Example 133 8-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-amine
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 8-chloro-N- (4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-7-amine.
  • Example 134 7-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000521]
  • the title compound was prepared analogously to Example 4, where 1-(7-chloro-6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-fluoro-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-triflu
  • Example 135 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 7-Bromo-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 2 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000523] The title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one were
  • Example 136 N-(5-(azetidin-3-yl)-2-methylphenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000525]
  • the title compound was prepared analogously to Example 121, where 3-amino-4- chlorophenylboronic acid was replaced with 3-amino-4-methylphenylboronic acid in step 2.
  • the title compound was isolated.
  • Example 137 N-(2-Methyl-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with N-(5- (azetidin-3-yl)-2-methylphenyl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2- amine.
  • Example 138 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 1-(7-ethyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000527] A mixture of 1-(7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (2.83 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.14 mmol) in dioxane (100 mL
  • Step 2 1-(6-amino-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000528]
  • the title compound was prepared analogously to Example 19, step 3 where 1-(5-cyclopropyl- 6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-ethyl-6-nitro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 95% yield.
  • Step 3 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-ethyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Step 4 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000530]
  • the title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one (3.26 mmol), 1,4-bis(diphenylphosphino)butane was replaced with 1-(6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-7-ethyl-3,4-dihydroisoquinolin-2(1H)-y
  • Example 139 7-(2-((7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000533]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,
  • Example 140 7-(2-((7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 7-Bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000534]
  • the title compound was prepared analogously to Example 135, step 1 where ethyl iodide was replaced with methyl iodide.
  • Step 2 7-(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000535]
  • the title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced
  • Example 141 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate [000538]
  • the title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • Example 142 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000541]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6- chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiaze
  • Example 143 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide
  • Step 1 7-bromo-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000542]
  • the title compound was prepared analogously to Example 158, step 1 where bromocyclobutane was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate.
  • Example 144 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000544] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2- trifluoroethyl)-3,4-
  • Example 145 N-(3-cyclopropyl-1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine [000545]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with N-(1- (azetidin-3-yl)-3-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine.
  • Example 146 7-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000546]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)
  • Example 147 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000547]
  • the title compound was prepared analogously to Example 138, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5.
  • Example 148 7-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000548]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(
  • Example 149 7-(2-((2-chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 tert-butyl 4-(3-amino-4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • a solution of 5-bromo-2-chloroaniline (0.48 mmol)
  • tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.58 mmol)
  • bis-triphenylphosphine- palladium(II) chloride 0.05 mmol
  • Step 3 tert-butyl 4-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate
  • the title compound was prepared analogously to tert-butyl 3-(4-chloro-3-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate where tert-butyl 3-(3-amino-4- chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(3-amino-4- chlorophenyl)piperidine-1-carboxylate.
  • Step 4 tert-butyl 4-(4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate
  • the title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-on was replaced with tert-butyl 4-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate.
  • Example 150 7-(2-((2-chloro-5-(1-methylpiperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000555]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with -(2-((2- chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide.
  • Example 151 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 tert-butyl 4-(3-cyclopropyl-4-((4-(1,1-dioxido-5-oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1- [000556]
  • the title compound was prepared analogously to Example 141, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4
  • Example 152 7-(2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000558]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((3- cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5
  • Example 153 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide
  • Step 1 7-Bromo-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000559]
  • the title compound was prepared analogously to Example 135, step 1 where ethyl iodide was replaced with (bromomethyl)cyclopropane.
  • Steps 2-3 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000560]
  • the title compound was prepared analogously to Example 135, steps 2-3, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- (cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 2.
  • Example 154 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000561]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (cyclopropylmethyl)-3,4-dihydrothieno[
  • Example 155 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 2 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • a solution of 4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.85 mmol) in acetic acid (2 mL) was treated with N-bromosuccinimide (1.71 mmol) and sulfuric acid (8.6 mmol). The mixture was stirred at 60 °C for 12 hours, cooled down to room temperature and poured over ice-water.
  • Step 3 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000565] A solution of 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.03 mmol) and 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2
  • Step 4 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000566] A mixture of 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide (0.01 mmol) and potassium carbonate (0.09 mmol) in acetonitrile (2 m
  • Example 156 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000567]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3.
  • Example 157 7-(2-((6-fluoroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000568]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 2,2,2-trifluoro-1-(5-fluoro
  • Example 158 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 7-bromo-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Steps 2-3 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • the title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3.
  • Example 159 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000571]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-amino-6- chloro-3,4
  • Step 2 1-(6-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000572]
  • the title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)
  • Step 3-4 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000573]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4
  • Example 160 7-(2-((6-ethylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 4-methyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Steps 2 and 3 7-(2-((6-ethylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000575]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one were replaced with 1-(5-((4-
  • Example 161 4-methyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000576]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 4-methyl
  • Example 162 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000577]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,
  • Example 163 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide
  • Step 1 2-((3-bromothiophen-2-yl)methoxy)ethan-1-ol [000578] To a solution of ethane-1,2-diol (135 mmol) in dimethylsulfoxide (50 mL) was added potassium tert-butoxide (35 mmol) and 3-bromo-2-(chloromethyl)thiophene (27 mmol).
  • Step 2 S-(2-((3-bromothiophen-2-yl)methoxy)ethyl) ethanethioate [000579] To a 0 °C solution of triphenylphosphine (31 mmol) in THF (20 mL) was added dropwise a solution of diisopropylazodicarboxylate (31 mmol) in THF (8 mL). After 1 hour, a solution of 2-((3- bromothiophen-2-yl)methoxy)ethan-1-ol (16 mmol) in THF (8 mL) was added dropwise at 0 °C, followed by ethanethioic S-acid (31 mmol).
  • Step 3 2-((3-Bromothiophen-2-yl)methoxy)ethane-1-thiol
  • Step 5 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine
  • the title compound was prepared analogously to Example 125, step 4, where 3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 2,3-dihydro-5H-thieno[3,2- e][1,4]oxathiepine.
  • the title compound was isolated in 34% yield.
  • Step 7 and 8 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide [000584]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo- 2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide in step 3.
  • Example 164 7-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 1-(5-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)isoindolin-2- yl)-2,2,2-trifluoroethan-1-one [000585]
  • the title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-chloro-6-((4-ch
  • Example 165 7-(2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1- yl)piperidine-1-carboxylate [000587]
  • the title compound was prepared analogously to Example 123 (steps 1-3), where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl 4-hydroxypiperidine-1-carboxylate in step 1.
  • Step 2 tert-butyl 4-(3-methyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 1H-pyrazol-1-yl)piperidine-1-carboxylate
  • the title compound was prepared analogously to Example 160, step 1, where 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 4-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • Example 166 4-methyl-7-(2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000590]
  • the title compound was prepared analogously to Example 149, steps 4-5, where tert-butyl 4- (4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)phenyl)piperidine-1- carboxylate was replaced with tert-butyl 4-(3-methyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 7-bro
  • Example 167 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000591]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4
  • Example 168 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000592]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thia
  • Example 169 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000593]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thia
  • Example 170 7-(2-((4-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 1-(5-amino-4-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000594] To a 0 °C solution 1-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (27 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (27 mmol) and the reaction mixture was stirred for 2 hours.
  • Step 2 1-(5-amino-4-cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000595]
  • the title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one and ethylboronic acid were replaced with 1-(5-amino-4-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one, and potassium cyclopropyltrifluoroborate.
  • the title compound was isolated in 19% yield.
  • Step 3 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-cyclopropylisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one [000596]
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-4- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one.
  • Step 4 1-(4-cyclopropyl-5-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-cyclopropylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one.
  • Example 171 4-methyl-7-(2-((2-methyl-7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000599]
  • the title compound was prepared analogously to Example 17, where 5-(2-(6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 4-methyl-7- (2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(
  • Example 172 7-(2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000600]
  • the title compound was prepared analogously to Example 123, where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl (2-hydroxyethyl)(methyl)carbamate in step 1 and trimethyl(4-(methylsulfonyl)thiophen-2-yl)stannane with 4-methyl-7-(trimethylstannyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 4.
  • Example 173 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000601] To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (60 mmol) in dichloromethane (150 mL) was added pyridine (181 mmol), followed by dimethylaminopyridine (3.0 mmol) and trifluoroacetic anhydride (72 mmol).
  • Step 2 1-(7-bromo-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was prepared analogously to Example 1, step 3, where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-bromo-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • the title compound was isolated in 80% yield. MS (ESI) m/z: 353.09 [M+H] + .
  • Step 3 1-(7-cyclopropyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000603] A mixture of 1-(7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (8.10 mmol), cyclopropylboronic acid (32 mmol), tricyclohexylphosphane (1.61 mmol), diacetoxypalladium (0.81 mmol) and potassium phosphate (32.3 mmol) in toluene (30 mL) was stirred at 110 °C for 12 hours.
  • Step 4 1-(6-amino-7-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000604] To a solution of 1-(7-cyclopropyl-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone (1.91 mmol) in a mixture of ethanol (5.6 mL) and water (1.4 mL) was added iron powder (9.55 mmol) and ammonium chloride (9.55 mmol). The mixture was stirred at 70 °C for 2 hours, cooled down to room temperature, filtered and concentrated.
  • Step 5 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-cyclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000605] A mixture of 1-(6-amino-7-cyclopropyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone (1.23 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (6.16 mmol) was stirred at 70 °C for 12 hours.
  • Step 6 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000606]
  • the title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-cyclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one.
  • Steps 7-8 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000607]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,
  • Example 174 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)piperazine-1-carboxylate
  • the title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- ethylphenyl)piperazine-1-carboxylate.
  • Example 175 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000611] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)
  • Example 176 4-methyl-7-(2-((5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000612]
  • the title compound was prepared following the synthetic procedure described in Example 166. The title compound was isolated. MS (ESI) m/z: 556.0 [M+H] + .
  • Example 177 7-(2-((6-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000613]
  • the title compound was prepared analogously to Example 170, where 1-(5-amino-4- bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6-bromoisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one in step 2. The title compound was isolated.
  • Example 178 7-(2-((5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000614]
  • the title compound was prepared using the same synthetic procedure described in the preparation of Example 165. The title compound was isolated. MS (ESI) m/z: 542.1 [M+H] + .
  • Example 179 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 1-(5-amino-6-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000615] To a 0 °C solution 1-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (27 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (27 mmol) and the reaction mixture was stirred for 2 hours.
  • Step 2 1-(5-amino-6-methylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000616]
  • the title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one and ethylboronic acid were replaced with 1-(5-amino-6-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one and 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane.
  • the title compound was isolated in 28% yield.
  • Steps 3-5 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000617]
  • the title compound was prepared analogously to Example 170, steps 3-5, where 1-(5-amino-4- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6-methylisoindolin- 2-yl)-2,2,2-trifluoroethan-1-one.
  • Example 180 7-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000618]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 1-(5-chloro-6-((5-(trifluoromethyl
  • Example 181 7-(2-((6-chloro-2-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000619]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((6- chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide.
  • Example 182 7-(2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000620]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((3- methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-
  • Example 183 4-methyl-7-(2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000621]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 4-methyl-7- (2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-
  • Example 184 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000622]
  • the title compound was prepared analogously to Example 138, where diethylzinc was replaced with methylboronic acid in step 1 and 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one with 1-
  • Example 185 7-(2-((2-ethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000623]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5
  • Example 186 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000624]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f
  • Example 187 7-(2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000625]
  • the title compound was prepared analogously to Example 123, where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl (2-hydroxyethyl)(methyl)carbamate in step 1 and tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)azetidine-1- carboxylate in step 1 and trimethyl(4-(methylsulfonyl)thiophen-2-yl)stannane with 4-
  • Example 188 7-(2-((2-ethyl-7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000626]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-methyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][
  • Example 189 7-(2-((2-chloro-5-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000627]
  • the title compound was prepared analogously to Example 149, steps 3-6, where tert-butyl 4- (3-amino-4-chlorophenyl)piperidine-1-carboxylate was replaced with tert-butyl 4-(3-amino-4- chlorophenyl)piperazine-1-carboxylate in step 3.
  • the title compound was isolated.
  • Example 190 7-(2-((2-ethyl-6-fluoroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000628]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((6-fluoroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and ace
  • Example 191 7-(2-((4-cyclopropyl-2-ethylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000629]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((4-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1
  • Example 192 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-methyl-7-(2-((6-methylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde.
  • Example 193 7-(2-((2-chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000631]
  • the title compound was prepared analogously to Example 189, where tert-butyl 4-(3-amino-4- chlorophenyl)piperazine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- chlorophenyl)piperazine-1-carboxylate. The title compound was isolated.
  • Example 194 7-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000632]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((2- chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide.
  • Example 195 7-(2-((2-chloro-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000633]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((2-chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,
  • Example 196 7-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000634]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide was replaced with 7-(2-((2- ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide.
  • Example 197 7-(2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000635]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2
  • Example 198 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 4-ethyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • the title compound was prepared analogously to Example 160, step 1 where 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with appropriate starting material.
  • Example 199 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000638]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothien
  • Example 200 7-(2-((6-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 5-chloro-N1-methyl-4-nitrobenzene-1,2-diamine [000639] To a solution of 4-chloro-2-fluoro-5-nitroaniline (33 mmol) and methylamine hydrochloride (130 mmol) in acetonitrile (100 mL) was added triethylamine (198 mmol).
  • Step 2 6-chloro-1-methyl-5-nitro-1H-benzo[d][1,2,3]triazole [000640] To a 0 °C solution of 5-chloro-N1-methyl-4-nitrobenzene-1,2-diamine (17 mmol) in acetic acid (22 mL) and water (11 mL) was added sodium nitrite (26 mmol). After 1 hour the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 79% yield.
  • Step 4 6-chloro-N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-methyl-1H- benzo[d][1,2,3]triazol-5-amine
  • the title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 6-chloro-1- methyl-1H-benzo[d][1,2,3]triazol-5-amine.
  • the title compound was isolated in 20% yield.
  • Step 5 6-chloro-1-methyl-N-(5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)-1H- benzo[d][1,2,3]triazol-5-amine
  • the title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one (3.26 mmol), 1,4-bis(diphenylphosphino)butane was replaced with 6-chloro-N-(4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-amine.
  • Example 201 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000645]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(6-chloro-7-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-di
  • Example 202 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000646]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 1-(
  • Example 203 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000647]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-cyclobutyl-3,4-dihydrothieno
  • Example 204 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000648]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 4-eth
  • Example 205 7-(2-((2-(cyclopropylmethyl)-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000649] To a solution of 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.22 mmol) in methanol (1.2 mL) and THF (1.2 mL), acetic acid (0.026 mL) and sodium cyanoborohydride (0.33 m
  • reaction mixture was cooled down to -30 °C and cyclopropanecarboxaldehyde (0.265 mmol) was added.
  • the reaction mixture was stirred at –30 °C for 5 minutes, then the cooling bath was removed and the reaction mixture was allowed to reach room temperature and stirred for one additional hour.
  • the reaction mixture was diluted with water, extracted with dichloromethane three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 32% yield.
  • Example 206 7-(2-((2-chloro-4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000650]
  • the title compound was prepared analogously to Example 205, where 4-methyl-7-(2-((7- methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-chloro-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4
  • Example 207 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000651] To a solution of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one (1.35 mmol) and cyclopropylboronic acid (4.05 mmol) in 1,2-dichloroethane (2 mL) and DMF
  • Step 2 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000652]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin- 2-yl)amino)-3,4-di
  • Example 208 4-cyclobutyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000653]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced
  • Example 209 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000654]
  • the title compound was prepared analogously to Example 155, where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydr
  • Example 210 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 7-bromo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000655] A mixture of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one (1.02 mmol), 3-bromooxetane (1.92 mmol), cesium carbonate (2.03
  • Step 2 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000656]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3.
  • Example 211 7-(2-((6-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000657]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,
  • Example 212 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide
  • Step 1 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000658] A 0 °C solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (47 mmol) in dichloromethane (100 mL) was treated with pyridine (94 mmol), N,N-dimethylaminopyridine (2.4 mmol) and trifluoroacetic anhydride (57 mmol) and triethylamine (112 mmol).
  • Step 2 1-(6-bromo-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
  • 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (44 mmol) was dissolved in sulfuric acid (130 mL). The solution was cooled down to 0 °C and fuming nitric acid (2 mL) was added dropwise over 30 min while keeping the temperature at 0 °C.
  • Step 3 2,2,2-trifluoro-1-(7-nitro-6-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
  • a solution of 1-(6-bromo-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (17 mmol) and tributyl(vinyl)stannane (25 mmol) in dioxane (60 mL) was treated with tetrakis(triphenylphosphine) palladium(0) (1.7 mmol) and copper iodide (17 mmol).
  • Step 4 1-(7-amino-6-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000661] A solution of 2,2,2-trifluoro-1-(7-nitro-6-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (9.33 mmol) in methanol (30 mL) was hydrogenated in the presence of 10% palladium on carbon (1.0 g) for two hours. The reaction was filtered through celite and concentrated. Purification by silica gel chromatography (0-12% ethyl acetate in hexanes) afforded the title compound in 85% yield.
  • Step 5 1-(7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-ethyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000662] 1-(7-amino-6-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (7.0 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (35 mmol) were heated at 70 °C for 3 hours.
  • Step 6 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000663] To a solution of 1-[7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-ethyl-3,4-dihydro- 1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (3.1 mmol) and trimethyl(trimethylstannyl)stannane (12.4 mmol) in dioxane (10 mL) was added palladium diacetate (0.62 mmol) and 1,4- bis(diphenylphosphino)butane (0.62 mmol).
  • Steps 7-8 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 1-(
  • Example 213 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000665]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-cyclopropyl-3,4-dihydro
  • Example 214 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000666] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-
  • Example 215 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000667] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H
  • Example 216 4-methyl-7-(2-((7-methyl-2-(oxetan-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000668] To a solution of 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.22 mmol) in methanol (1.2 mL) and THF (1.2 mL), acetic Acid (0.44 mmol) and sodium cyanoborohydride
  • Example 217 7-(2-((2-chloro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000669]
  • the title compound was prepared analogously to Example 216, where 4-methyl-7-(2-((7- methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-chloro-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl
  • Example 218 4-cyclobutyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000670]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were
  • Example 219 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000671] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one
  • Example 220 4-cyclopropyl-7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000672]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced
  • Example 221 4-cyclobutyl-7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000673]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced
  • Example 222 7-(2-((2,7-diethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000674]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thi
  • Example 223 7-(2-((2-(cyclopropylmethyl)-7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000675]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3
  • Example 224 4-cyclopropyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide
  • Step 1 1-(7-amino-6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000676] To a solution of 1-(6-bromo-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one (20 mmol) in ethanol (60 mL) and water (30 mL) was added iron (99 mmol) and ammonium chloride (40 mmol).
  • Step 2 1-(7-amino-6-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000677] To a solution of 1-(7-amino-6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one (14 mmol) and cyclopropylboronic acid (58 mmol) in toluene (100 mL) was added tricyclohexylphosphane (3 mmol), potassium phosphate (58 mmol) and diacetoxypalladium (1.5 mmol).
  • Step 3-4 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000678]
  • the title compound was prepared analogously to Example 212, steps 5-6, where 1-(7-amino-6- ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone was replaced with 1-(7-amino-6- cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 4.
  • Example 5-6 4-cyclopropyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000679]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydro
  • Example 225 4-cyclobutyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000680]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were
  • Example 226 4-cyclobutyl-7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000681]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-cyclobutyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydr
  • Example 227 7-(2-((7-chloro-2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000682] To a solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.02 mmol) and 1-bromo-2-fluoroethane (0.02 mmol) in DMF (1 mL
  • Example 228 4-cyclopropyl-7-(2-((2,7-diethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000683]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3
  • Example 229 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000684] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,
  • Example 230 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000685] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1
  • Example 231 7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000686]
  • the title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide were replaced with 1-(6-
  • Example 232 7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000687] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H
  • Example 233 4-cyclopropyl-7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000688]
  • the title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothi

Abstract

L'invention concerne des composés qui sont des inhibiteurs d'ULK1/2 et leur utilisation dans le traitement de troubles tels que des cancers.
PCT/US2023/021025 2022-05-04 2023-05-04 Inhibiteurs thiophène d'ulk1/2 et leur utilisation WO2023215494A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200016567A (ko) * 2018-08-07 2020-02-17 재단법인 대구경북첨단의료산업진흥재단 치환된 n-헤테로아릴 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
WO2020257180A1 (fr) * 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Inhibiteurs de l'autophagie à base d'amide d'aminopyrimidine et leurs procédés d'utilisation
WO2022061273A1 (fr) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2023087027A1 (fr) * 2021-11-15 2023-05-19 Erasca, Inc. Inhibiteurs thiophènes de ulk1/2 et leur utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200016567A (ko) * 2018-08-07 2020-02-17 재단법인 대구경북첨단의료산업진흥재단 치환된 n-헤테로아릴 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
WO2020257180A1 (fr) * 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Inhibiteurs de l'autophagie à base d'amide d'aminopyrimidine et leurs procédés d'utilisation
WO2022061273A1 (fr) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2023087027A1 (fr) * 2021-11-15 2023-05-19 Erasca, Inc. Inhibiteurs thiophènes de ulk1/2 et leur utilisation

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