QUINAZOLINE COMPOUND, ITS USE AND PHARMACEUTICAL COMPOSITION

专利摘要:
the present invention relates to a compound that is useful as an active ingredient in a pharmaceutical composition for the treatment of lung cancer. the present inventors have studied a compound useful as an active ingredient in a pharmaceutical composition for the treatment of lung cancer, and as a result, a quinazoline compound has been found to have excellent kras mutation activity in g12c, and that it can be used as a therapeutic agent for lung cancer, and so the present invention has been completed. the quinazoline compound of the present invention and the salt thereof can be used as the therapeutic agent for lung cancer.
公开号:BR112019015364A2
申请号:R112019015364-0
申请日:2018-02-01
公开日:2020-03-10
发明作者:Kuramoto Kazuyuki；Akaiwa Michinori；Abe Tomoaki；Araki Takanobu；Yamaki Susumu；Kunikawa Shigeki；Imaizumi Tomoyoshi；Nigawara Takahiro；Arakawa Keisuke；Shimada Itsuro；Shimazaki Masashi；Satake Yoshiki；Watanabe Kazushi；Koike Takanori
申请人:Astellas Pharma Inc.；
IPC主号:

专利说明:

Descriptive Report of the Invention Patent for QUINAZOLINE COMPOUND, ITS USE AND PHARMACEUTICAL COMPOSITION.
Technical Field [001] The present invention relates to a quinazoline compound that is useful as a pharmaceutical composition and a G12C mutation KRAS inhibitor, and is expected to be useful as an active ingredient in a pharmaceutical composition, for example example, a pharmaceutical composition for the treatment of lung cancer. Background to the Technique [002] It has been reported that the number of lung cancer deaths is the highest, as 19% of all cancer deaths, and 1.8 million new cases per year in the world are newly affected (GLOBOCAN , 2012). In non-small cell lung cancer (NSCLC), which is defined to occupy about 80% of lung cancer, (American Cancer Society. Cancer Facts and Figures, 2016), although surgical therapy has been considered to a certain extent , and after this phase, chemotherapy or radiotherapy is used as an important treatment without having to undergo surgery. Based on cell morphology, adenocarcinoma and squamous cell carcinoma are classified as the most common type of NSCLC. The clinical course of these tumors is similar, however, adenocarcinoma is characterized by the peripheral location of the lungs.
[003] Ras protein is a small binding molecule to small molecule guanosine triphosphate (GTP) of approximately 21 kDa consisting of 188 to 189 amino acids, and there are four main proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) generated from three genes, such as KRAS gene, NRAS gene and HRAS gene. The RAS protein has two types of a type of binding to GTP, which is an active form and a type of binding to guanosine diphosphate (GDP), which
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2/265 is an inactive form. The RAS protein is activated by exchanging GDP for GTP by stimulating a ligand to the cell membrane receptor, such as EGFR. The active form of RAS binds to about 20 types of effector proteins, such as RAF, PI3K and RALGDS, and activates a signal cascade downstream. On the other hand, the active form RAS becomes inactive due to the conversion of GTP to GDP by the hydrolysis activity of endogenous GTP (GTPase). This GTPase activity is enhanced by GAP (GTPase activating protein). From this, RAS plays an important molecular shift function in the intracellular signaling pathway such as EGFR and plays an important role in the progress of cell growth, proliferation, and blood vessel formation (Nature rev. Cancer, 11, 761, 2011, Nature rev. drug discovery, 13, 828, 2014, Nature rev. drug discov., 15, 771,2016).
[004] When amino acid substitution occurs due to a mutation of the RAS gene, the proportion of the active form is considered to increase due to a decrease in endogenous GTPase activity or a decrease in affinity for GAP. The resulting excessive signal transmission is thought to cause carcinogenesis and proliferation of cancer growth. In lung cancer, the RAS gene mutation was seen in 32% of lung adenocarcinoma. It has been solidly reported that the disruption frequency of the mutation is 96% of the KRAS gene, 3% of the NRAS gene, and 1% of the HRAS gene, and there are many point mutations of KRAS exon 2 (codon 12, codon 13). In particular, the G12C mutation in which the glycine at codon 12 is replaced with cysteine is a frequent mutation in the KRAS gene and occupies the largest proportion of 44% of the KRAS gene mutation seen in pulmonary adenocarcinoma (Nature rev. Drug discov., 13,828, 2014).
[005] In creating a KRAS inhibitor, it is ideal to selectively inhibit a function of the KRAS mutant protein. On the other hand, a
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3/265 Since a resulting mutation site is distal from an effector binding site, obtaining a compound having selectivity for both a mutant and a wild type inhibitory activity is generally considered difficult (Bioorg. Med. Chem Lett., 22, 5766, 2012). In recent years, a compound that is irreversibly linked to the G12C KRAS mutation (Nature, 503, 548, 2013, Angew. Chem., Int. Ed. Engl., 53, 199, 2014, Cancer Discov., 6, 316, 2016) by forming a covalent bond with respect to a mutation cysteine has been solidly reported together with the existence of an allosteric pouch in the vicinity of a region called change II being shown (Nature, 503, 548, 2013) against the mutation of G12C KRAS. A selective KRAS inhibitor of the G12C mutation inhibits the conversion of the inactive form to the active form by covalently binding to the G12C KRAS mutation and induces cancer cell death, blocking the downstream signal. Consequently, a compound with this mechanism of action has been reported to be useful for the treatment of lung cancer positive for G12C KRAS mutation.
[006] It has been reported that the compounds represented by Formula (A) and Formula (B) have binding capacity for the G12C KRAS mutation (Patent Documents 1, 2, and 3), and Patent Document 2 describes a compound of Example I-59 (hereinafter also referred to as Compound C).
Chemical Formula 1

(B) (The meanings of the symbols in the formula refer to
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Patent)
Related Technique Document
Patent Document [007] [Patent Document 1]
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Publication
International No. WO 2015/054572 [008] [Patent Document 2]
Flyer
Publication
International No. WO 2016/164675 [009] [Patent Document 3]
Flyer
Publication
International No. WO 2017/087528
Description of the Invention
Problems to be Resolved by the Invention [0010] A compound is provided which is useful as a pharmaceutical composition, such as a KRAS inhibitor of G12C mutation, and is expected to be useful as an active ingredient of a pharmaceutical composition for treatment of lung cancer and lung cancer positive for KRAS G12C mutation.
Means for Solving Problems [0011] The present inventors have intensively studied with useful ranks as an active ingredient in a pharmaceutical composition for the treatment of lung cancer, and as a result, it has been found that a quinazoline compound of Formula ( I) has excellent KRAS inhibitory activity of G12C mutation, and thus the present invention has been completed.
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5/265 [0012] That is, the present invention relates to a compound of
Formula (I) or its salt and a pharmaceutical composition containing the compound of Formula (I) or its salt, and an excipient.
Chemical Formula 2 [0013]
[0014] R ¹ is vinyl, (E) -l-propenyl or cyclopropyl, [0015] R ² is Formula (II) or (III),
Chemical Formula 3
[0016] R ³ is C3-4 alkyl, methyl or n-propyl each of which is substituted with two or more F's, ethyl or C3-4 cycloalkyl each of which can be substituted with F, benzyl which can be substituted with C1 -3 alkyl, benzyl that can be substituted with -O-C1-3 alkyl, or benzyl that can be substituted with -O- (C1-3 alkyl which is substituted with F), [0017] R ⁴ is -O-C3 -5 substitutable alkyl, -O substitutable cycloalkyl, or Formula (IV), (V), (VI), or (VII),
Chemical Formula 4
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6/265
(IV) (V) (VI) (VII) [0018] R ⁵ is H or CF ₃ , [0019] R ^{a is} HouF, [0020] R ^b is H or F, [0021] R ^c is H, methyl, vinyl, or Cl, [0022] R ^d is H or Cl, [0023] R ^and is CO2Me, COMe, CON (Me) 2, SO2Me, C3-4 cycloalkyl, a non-aromatic heterocyclic group having 4 to 6 ring members substitutable, or C1-3 alkyl which can be substituted with a group selected from Group G, [0024] 0 Group G is -O-C1-3 alkyl, -O- (C1-3 alkyl which is substituted with F or C3-4 cycloalkyl), C3-4 cycloalkyl, -F, -CN, -SO2Me, and aromatic heterocyclic group, a non-aromatic heterocyclic group having 4 to 6 ring members, -N (C1-3 alkyl> 2, and -C (Me) 2OH, [0025] R ^f is H, methyl, or F, [0026] R ^g is H, methyl, or ethyl, [0027] R ^h is substituted C1-3 alkyl with -OMe, [0028] X is O, NH, S, or methylene, [0029] Y is a bond or methylene, [0030] Z is a bond, methylene, or ethylene, [0031] Q is methylene or ethylene, [0032] n is an integer of 1 or 2, and [0033] m is an integer in a range of 1 to 3).
[0034] Unless otherwise specified, the same symbols have the same meaning in the case of symbols in certain chemical formulas in this specification.
[0035] Furthermore, the present invention relates to a pharmaceutical composition for the treatment of lung cancer, which contains
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7/265 has a compound of Formula (I) or its salt, and particularly, refers to a pharmaceutical composition for the treatment of lung cancer positive for G12C KRAS mutation. Note that the pharmaceutical composition includes a therapeutic agent for lung cancer, particularly lung cancer positive for G12C KRAS mutation, which contains the compound of Formula (I) or the salt thereof.
[0036] In addition, the present invention relates to a compound of Formula (I) or its salt, which is a KRAS inhibitor of G12C mutation; the compound of Formula (I) or its salt for use as the KRAS inhibitor of G12C mutation; the KRAS inhibitor of G12C mutation containing the compound of Formula (I) or its salt; use of the compound of Formula (I) or its salt to manufacture a pharmaceutical composition for the treatment of lung cancer, particularly lung cancer positive for KRAS G12C mutation; use of the compound of Formula (I) or its salt for the treatment of lung cancer, in particular, lung cancer positive for KRAS G12C mutation; the Formula (I) compound or its salt, for use in the treatment of lung cancer, particularly KRAS G12C mutation positive lung cancer; and a method of treating lung cancer, in particular, lung cancer positive for KRAS G12C mutation including administering an effective dose of the Formula (I) compound or its salt to a target. Note that the target is a human being or other animals in need of treatment, and as a modality, the target is a human being in need of prevention or treatment.
Effects of the Invention [0037] The compound of Formula (I) or its salt has a KRAS inhibitory activity on the G12C mutation, and can be used as a
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8/265 therapeutic agent for lung cancer.
Modalities of the Invention [0038] In the following, the present invention will be described in detail.
[0039] In this specification, the phrase can be replaced by means to have no substituted group or 1 to 3 substituents.
[0040] Substituted means having 1 to 5 substituents, and substituted with two or more F's means having 2 to 5 F atoms.
[0041] C1-3 alkyl represents straight or branched alkyl having 1 to 3 carbon atoms, and examples include methyl, ethyl, n-propyl, and isopropyl. As a modality, C1-3 alkyl is methyl, ethyl, or n-propyl, as a modality, it is methyl or ethyl, as a modality, it is methyl or n-propyl, as a modality, it is ethyl or n-propyl, as a modality, it is methyl, as a modality, it is ethyl and, as a modality, it is n-propyl.
[0042] C3-4 alkyl means straight or branched alkyl having 4 carbon atoms, and examples include n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. As a modality, C3-4 alkyl is n-propyl or isobutyl and, as a modality, it is isobutyl.
[0043] C3-5 alkyl means straight or branched alkyl having 5 carbon atoms, and examples include n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl. As a modality, C3-5 alkyl is n-propyl, n-butyl, or n-pentyl, as a modality, it is n-propyl or n-butyl, and as a modality, it is npropyl.
[0044] Cycloalkyl means a saturated hydrocarbon ring group having 3 to 10 members in the ring which may have a crosslink, and its examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl. As a modality, cycloalkyl is cyclopentyl, cyclohexyl, or cycloheptyl, and as a
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9/265 modality, is cyclohexyl.
[0045] C3-4 cycloalkyl means cycloalkyl having 3 to 4 members in the ring. As a modality, C3-4 cycloalkyl is cyclopropyl or cyclobutyl, as a modality, it is cyclopropyl, and as a modality, it is cyclobutyl.
[0046] A non-aromatic heterocyclic group with 4 to 6 ring members means a monovalent group of a non-aromatic heterocyclic group having 4 to 6 ring members, which has 1 to 2 equal or different hetero atoms selected from the group consisting of N, O, and S, and examples of these include azetidinyl, oxetanil, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydrothienyl, and tetrahydrothiopyranyl. As a modality, the non-aromatic heterocyclic group having 4 to 6 ring members is oxetanil, tetrahydropyranyl, piperidinyl, pyrrolidinyl, or morpholinyl; , as a modality, it is oxetanil and, as a modality, it is tetrahydropyranyl.
[0047] An aromatic heterocyclic group means a monovalent group of an aromatic heterocycle having 5 to 10 members in the ring having 1 to 4 identical or different heteroatoms, selected from the group consisting of N, O and S, and their examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl, and 1,2,4-oxadiazolyl, as a modality, is an aromatic heterocyclic group having 5 to 6 members in the ring having 1 to 1 2 N atoms and, as a modality, is pyridyl.
[0048] G12C mutation indicates a mutation in the wild-type gene in which the residue corresponding to position 12 is converted from glycine to cysteine.
[0049] Mutation of G12C KRAS means KRAS having the mutationPetition 870190100577, of 10/8/2019, p. 13/278
10/265 tion of G12C described above in the gene encoding wild-type KRAS.
[0050] Lung cancer is, for example, small cell lung cancer and non-small cell lung cancer, and as a modality, it is non-small cell lung cancer, as a modality, it is lung adenocarcinoma, as a modality, it is positive lung cancer for G12C KRAS mutation, as a modality, it is non-small cell lung cancer positive for G12C KRAS mutation, and as a modality, it is positive lung adenocarcinoma for G12C KRAS mutation.
[0051] An embodiment of the compound of formula (I) of the present invention or its salt will be described below.
[0052] (1) A compound or a salt thereof where R ¹ is vinyl, (E) -1-propenyl or cyclopropyl. As a modality, a compound or a salt thereof where R ¹ is vinyl or cyclopropyl. As a modality, a compound or a salt thereof in which R ¹ is vinyl. As an embodiment, a compound or a salt thereof wherein R ¹ is cyclopropyl.
[0053] (2) A compound or a salt thereof where R ² is Formula (II) or Formula (III). As a modality, a compound or a salt thereof where R ² is Formula (II). As a modality, a compound or a salt thereof where R ² is Formula (III).
[0054] (3) A compound or a salt thereof where R ^a is H or F in Formula (II). As an embodiment, a compound or a salt thereof where R ^a is H in Formula (II). As an embodiment, a compound or a salt thereof where R ^a is F in Formula (II).
[0055] (4) A compound or a salt thereof where R ^b is H or F in Formula (II). As an embodiment, a compound or a salt thereof where R ^b is H in Formula (II). As a modality, a
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11/265 compound or a salt thereof where R ^b is F in Formula (II).
[0056] (5) A compound or a salt thereof in which R ^c is methyl, vinyl or Cl in Formula (II). As an embodiment, a compound or a salt thereof wherein R ^c is methyl or Cl in Formula (II). As a modality, a compound or a salt thereof where R ^c is methyl or vinyl in Formula (II). As an embodiment, a compound or a salt thereof wherein R ^c is methyl in Formula (II). As a modality, a compound or a salt thereof in which R ^c is vinyl in Formula (II). As an embodiment, a compound or a salt thereof wherein R ^c is Cl in Formula (II).
[0057] (6) A compound or a salt thereof where R ^d is H or Cl in Formula (II). As a modality, a compound or a salt thereof where R ^d is H in Formula (II). As an embodiment, a compound or a salt thereof where R ^d is Cl in Formula (II).
[0058] (7) A compound or a salt thereof where R ³ is C3-4 alkyl, methyl or n-propyl each of which is replaced with two or more F, ethyl or C3-4 cycloalkyl each of which can be substituted with F, benzyl which can be substituted with C1-3 alkyl, benzyl which can be substituted with -O-C1-3 alkyl, or benzyl which can be substituted with -O- (C1-3 alkyl which is substituted with F). As an embodiment, a compound or a salt thereof where R ³ is C3-4 alkyl, methyl or n-propyl each of which is replaced with two or more F's, or ethyl or C3-4 cycloalkyl each of which may be substituted with F. As a modality, a compound or a salt thereof where R ³ is C3-4 alkyl, methyl or n-propyl, each of which is replaced with two or more F's. As a modality, a compound or a salt thereof where R ³ is ethyl, cyclopropyl, or cyclobutyl each of which can be replaced with F's. As a modality, a compound or a salt thereof where R ³ is ethyl which can be substituted with F. As a modality, a compound or
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12/265 a salt of the same where R ³ is ethyl, difluoroethyl or trifluoroethyl. As an embodiment, a compound or a salt thereof where R ³ is ethyl or difluoroethyl. As a modality, a compound or salt thereof where R ³ is ethyl or trifluoroethyl. As a modality, a compound or a salt thereof where R ³ is ethyl or 2,2,2-trifluoroethyl. As an embodiment, a compound or a salt thereof wherein R ³ is difluoroethyl or trifluoroethyl. As a modality, a compound or salt thereof where R ³ is ethyl. As a modality, a compound or salt thereof where R ³ is difluoroethyl. As an embodiment, a compound or a salt thereof where R ³ is 2,2difluoroethyl. As an embodiment, a compound or a salt thereof where R ³ is trifluoroethyl. As a modality, a compound or a salt thereof where R ³ is 2,2,2-trifluoroethyl. As an embodiment, a compound or a salt thereof wherein R ³ is C 3-4 alkyl. As a modality, a compound or a salt thereof where R ³ is isobutyl. As a modality, a compound or a salt thereof where R ³ is methyl or n-propyl, each of which is replaced with two or more F's. As a modality, a compound or a salt thereof where R ³ is C3-4 cycloalkyl that can be substituted with F. As a modality, a compound or a salt thereof where R ³ is cyclobutyl that can be substituted with F As a modality, a compound or a salt thereof in which R ³ is cyclobutyl. As a modality, a compound or a salt thereof where R ³ is ethyl or cyclobutyl each of which can be replaced by F.
[0059] (8) A compound or a salt thereof in which R ⁴ is -O-C3-5 substitutable alkyl, -O substitutable -O-cycloalkyl, or Formula (IV), (V), ( VI), or (VII). As an embodiment, a compound or a salt thereof in which R ⁴ is -O-C3-5 alkyl which can be substituted or is -O-cycloalkyl which can be substituted. As a modality, a compound or a salt thereof in which R ⁴ is
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Formula (IV). As a modality, a compound or a salt thereof where R ⁴ is Formula (V). As a modality, a compound or a salt thereof where R ⁴ is Formula (VI). As an embodiment, a compound or a salt thereof where R ⁴ is Formula (VII).
[0060] (9) A compound or a salt thereof in which R ^e in Formula (IV) is a non-aromatic heterocyclic group having 4 to 6 members in the ring that can be substituted, or C1-3 alkyl that can be substituted with a substituent selected from Group G. As a modality, a compound or a salt thereof in which R ^e in Formula (IV) is oxetanyl, tetrahydropyranyl or C1-3 alkyl which can be substituted with a substituent selected from of the group consisting of -O-C1-3 alkyl and -C (Me) 2OH. As an embodiment, a compound or a salt thereof in which R ^and in formula (IV) is oxetanyl, tetrahydropyranyl or C1-3 alkyl which can be substituted with a substituent selected from the group consisting of -OMe, -OEt and -C (Me) 2OH. As an embodiment, a compound or a salt thereof in which R ^e in Formula (IV) is C1-3 alkyl which can be substituted with -OMe. As an embodiment, a compound or a salt thereof in which R ^e in Formula (IV) is C1-3 alkyl which can be substituted with -OEt. As an embodiment, a compound or a salt thereof in which R ^e in Formula (IV) is C1-3 alkyl which can be substituted with -C (Me) ₂ OH. As an embodiment, a compound or a salt thereof, wherein R ^e in Formula (IV) is C1-3 alkyl. As a modality, a compound of formula (IV) is methyl or ethyl. As a modality, a compound of formula (IV) is methyl. As a modality, a compound or a salt thereof in which R ^e in Formula (IV) is ethyl. As an embodiment, a compound or a salt thereof in which R ^e in Formula (IV) is methoxyethyl. As an embodiment, a compound or a salt thereof in which R ^e in Formula (IV) is ethoxyethyl. As a modality, a compound or a salt thereof in which R ^e in Formula
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14/265 (IV) is methoxypropyl.
[0061] (10) A compound or a salt of the same where R ^f in Formula (IV) is H, methyl or F. As an embodiment, a compound or a salt of the same where R ^f in Formula (IV) is H. As an embodiment, a compound or a salt thereof in which R ^f in Formula (IV) is methyl. As an embodiment, a compound or a salt thereof where R ^f in Formula (IV) is F.
[0062] (11) A compound or a salt thereof where X in formula (IV) is O, NH, S or methylene. As a modality, a compound or a salt of the same where X in Formula (IV) is O. As a modality, a compound or a salt of the same where X in Formula (IV) is NH. As a modality, a compound or a salt of the same where X in Formula (IV) is S. As a modality, a compound or a salt of the same where X in Formula (IV) is methylene.
[0063] (12) A compound or a salt thereof where Y in Formula (IV) is a bond or methylene. As an embodiment, a compound or a salt thereof where Y in Formula (IV) is a bond. As an embodiment, a compound or a salt thereof where Y in Formula (IV) is methylene.
[0064] (13) A compound or a salt thereof where Z in Formula (IV) is a bond, methylene or ethylene. As an embodiment, a compound or a salt thereof where Z in Formula (IV) is a bond. As an embodiment, a compound or a salt thereof where Z in Formula (IV) is methylene. As an embodiment, a compound or a salt thereof where Z in Formula (IV) is ethylene.
[0065] (14) A compound or a salt thereof where Q in Formula (IV) is methylene or ethylene. As an embodiment, a compound or a salt thereof where Q in Formula (IV) is methylene. As an embodiment, a compound or a salt thereof where Q in Formula (IV) is ethylene.
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15/265 [0066] (15) A compound or a salt thereof where R ⁵ is H or
CF3. As a modality, a compound or a salt thereof where R ⁵ is H. As a modality, a compound or a salt thereof where R ⁵ is CF3.
[0067] (16) A compound or a salt thereof that is a combination of two or more arbitrary that are not contradictory, among the modalities described in (1) to (15) above.
[0068] Examples of the modalities described in (16) above include the following compounds or salts thereof.
[0069] (17) A compound or a salt thereof where R ¹ is vinyl, (E) -1-propenyl or cyclopropyl, R ² is Formula (II) or (III), R ³ is C2-4 alkyl, methyl or n-propyl each of which is replaced by two or more F's, ethyl or C3-4 cycloalkyl each of which can be replaced with F, benzyl which can be replaced with C1-3 alkyl, benzyl which can be replaced with -O-C1-3 alkyl or benzyl that can be substituted with -O- (C1-3 alkyl substituted with F), R ⁴ is -O-C3-5 alkyl that can be substituted, -O-cycloalkyl that can be substituted , or Formula (IV), (V), (VI) or (VII), R ⁵ is H or CF ₃ , R ^a is H or F, R ^b is H or F, R ^c is H, methyl, vinyl or Cl, R ^d is H or Cl, R ^and is CO2Me, COMe, CON (Me) 2, SO2Me or C3-4 cycloalkyl, a non-aromatic heterocyclic group having 4 to 6 members in the ring that can be substituted, C1-3 alkyl which can be substituted with a group selected from Group G where Group G is -O-C1-3 alkyl, -O- (Ci-3 al alkyl substituted with F or C3-4 cycloalkyl), C3-4 cycloalkyl, -F, -CN, -SO2Me, an aromatic heterocyclic group, a non-aromatic heterocyclic group having 4 to 6 ring members, -N (C1-3 alkyl ) 2, and -C (Me) 2OH, R ^f is H, methyl or F, R ^g is H, methyl or ethyl, R ^h is C1-3 alkyl which can be replaced with -OMe, X is O, NH, S or methylene, Y is a bond or methylene, Z is a bond, methylene or ethylene, Q is methylene or ethylene, n is an integer of 1 or 2 and n is an integer in the range of 1
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16/265 to 3.
[0070] (18) The compound or salt thereof described in (17) where R ² is Formula (II).
[0071] (19) The compound or salt thereof described in (18) where R ⁴ is Formula (IV).
[0072] (20) The compound or salt thereof described in (19), where X is O.
[0073] (21) The compound or salt thereof described in (20), where R ⁵ is H.
[0074] (22) The compound or salt thereof described in (21) where R ¹ is vinyl or cyclopropyl.
[0075] (23) The compound or salt thereof described in (22) where R ^a is H, R ^b is H or F, R ^c is methyl or Cl, and R ^d is H.
[0076] (24) The compound or salt thereof described in (23) where R ³ is C3-4 alkyl, methyl or n-propyl, each of which is replaced with two or more F's, or ethyl or C3 -4 cycloalkyl, each of which can be replaced by F.
[0077] (25) The compound or 0 salt thereof described in (24) where R ^e is a non-aromatic heterocyclic group having 4 to 6 members on the ring that can be substituted, or C1-3 alkyl that can be substituted with a substituent selected from Group G.
[0078] (26) The compound or 0 salt thereof described in (25) where R ^e is oxetanyl, tetrahydropyranyl or C1-3 alkyl which can be substituted with a substituent selected from the group consisting of -OMe , -OEt and -C (Me) 2OH.
[0079] (27) The compound or 0 salt thereof described in (25) or (26) where R ^f is H.
[0080] (28) The compound or 0 salt thereof described in (27), where Y is a bond.
[0081] (29) The compound or salt thereof described in (28) where
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Z is ethylene.
[0082] (30) The compound or its salt described in (29) where Q is methylene.
[0083] As the combination of the modalities described in (16) above, the specific examples are as follows.
[0084] (31) A compound of Formula (I) or a salt thereof, where R ¹ is vinyl or cyclopropyl, R ² is Formula (II), R ³ is ethyl, cyclopropyl, or cyclobutyl each of which is replaced with F, R ⁴ is Formula (IV), R ⁵ is H, R ^a is H, R ^b is H or F, R ^c is methyl or Cl, R ^d is H, R ^and is oxetanyl, tetrahydropyranyl , or C1-3 alkyl that can be substituted with a substituent selected from the group consisting of OMe, -OEt, and -C (Me) 2OH, R ^f is Η, X is O, Y is a bond or methylene, Z is a bond, methylene or ethylene, Q represents methylene or ethylene.
[0085] (32) A compound of Formula (I) or a salt thereof where R ¹ is vinyl or cyclopropyl, R ² is Formula (II), R ³ is ethyl, cyclopropyl, or cyclobutyl each of which can be substituted with F, R ⁴ is Formula (IV), R ⁵ is H, R ^a is H, R ^b is H or F, R ^c is methyl or Cl, R ^d is H, R ^and is C1-3 alkyl which can be replaced with -OMe, R ^f is Η, X is O, Y is a bond or methylene, Z is a bond, methylene or ethylene, Q is methylene or ethylene.
[0086] (33) A compound of Formula (I) or a salt thereof where R ¹ is vinyl or cyclopropyl, R ² is Formula (II), R ³ is ethyl or 2,2,2trifluoroethyl, R ⁴ is Formula (IV), R ⁵ is H, R ^a is H, R ^b is H, R ^c is methyl, R ^d is H, R ^and is C1-3 alkyl that can be replaced with -OMe, R ^f is Η, X is O, Y is a single bond, Z is ethylene, Q is methylene.
[0087] As an example of the specific compounds included in the present invention, the following compounds can be exemplified as an embodiment.
[0088] 1 - (7- {8- (2,2-difluoroethoxy) -7- (5-methyl-1 H-indazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] - 6-vinylquinazolin-4-yl} -2,7-diazospiro [3.5] non-2
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18/265 yl) prop-2-en-1-one, [0089] 1 - (7- {6-cyclopropyl-8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2- [(1 methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] non-2-yl) prop2-en-1-one, [0090] 1 - (7- {6 -cyclopropyl-8- (2,2-d ifl uoroethoxy) -7- (5-methyl-1Hindazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} - 2,7diazaespiro [3.5] non-2-yl) prop-2-en-1-one, [0091] 1 - {7- [6-cyclopropyl-8- (2,2-difluoroethoxy) -7- (5- methyl-1 Hindazol-4-yl) -2 - {[(2S) -1-methylpyrrolidin-2-yl] methoxy} quinazolin-4-yl] -2,7diazaospiro [3.5] non-2-yl} prop-2 -en-1-one, and [0092] 1 - (7- {8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 -methyl I pi perid i n4- il) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2-yl) prop-2-en-1ona, and a salt thereof.
[0093] As an example of the specific compounds included in the present invention, the following compounds can be exemplified as another embodiment.
[0094] 1 - (7- {8- (2,2-d if fluoroethoxy) -7- (5-methyl I-1 H-indazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2il) prop-2-en-1-one, [0095] 1 - (7- {6-cyclopropyl-8-ethoxy -7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] non-2-yl ) prop2-en-1-one, [0096] 1 - (7- {6-cyclopropyl-8- (2,2-d ifl uoroethoxy) -7- (5-methyl-1Hindazol-4-yl) -2- [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 diazospiro [3.5] non-2-yl) prop-2-en-1-one, [0097] 1 - {7- [ 6-cyclopropi 1-8- (2,2-d ifluoroethoxy) -7- (5-methyl I-1Hindazol-4-yl) -2 - {[(2S) -1-methylpyrrolidin-2-yl] methoxy} quinazolin -4-yl] -2,7 diazaespiro [3.5] non-2-yl} prop-2-en-1-one, [0098] 1 - (7- {8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1-methyl pi perid i n4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2-yl) prop- 2-en-1Petition 870190100577, of 10/8/2019, p. 22/278
19/265 ona, [0099] (+) - 1 - (7- {8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxide ] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2il) prop-2-en-1-one, [00100] 1 - {7- [6-cyclopropyl l-2- { [1 - (2-methoxyethyl) piperidin n-4-yl] oxy} -7- (5methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4 -il] -2,7 diazaespiro [3.5] non-2-yl} prop-2-en-1-one, [00101] 1 - {7- [6-cyclopropyl l-2 - {[1 - (3-methoxy propi I) pi peridi n-4-yl] oxy} -7 (5-methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2 , 7diazaespiro [3.5] non-2-il} prop-2-en-1-one, and a salt thereof.
[00102] Furthermore, as an example of the specific compounds included in the present invention, the following compounds can be exemplified as another embodiment.
[00103] (+) - 1 - (7- {8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] -6-vinylquinazolin -4-il} -2,7-diazaespiro [3.5] non-2il) prop-2-en-1-one, [00104] (+) - 1 - {7- [6-cyclopropyl l-2 - {[ 1 - (2-methoxyethyl) piperidin n-4-yl] oxy} -7 (5-methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4 -il] -2,7 diazaespiro [3.5] non-2-yl} prop-2-en-1-one, [00105] (+) - 1 - {7- [2 - {[1 - (2-methoxy ) pi perid i n-4-yl] oxy} -7- (5-methyl I-1Hindazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2 , 7diazaespiro [3.5] non-2-yl} prop-2-en-1-one, [00106] (+) - 1 - {7- [2 - {[1 - (2-ethoxyethyl) pi peridin-4 -yl] oxy} -7- (5-methyl I-1Hindazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazospiro [3.5] non- 2-yl} prop-2-en-1-one, [00107] (+) - 1 - {7- [6-cyclopropyl 1-2 - {[1 - (3-methoxy propyl I) pi perid i n- 4-yl] oxy} 7- (5-methyl-1H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] non-2- il} prop-2-en-1-one, [00108] (+) - 1 - {7- [7- (5-methyl-1 H-indazol-4-yl) -2 - {[1 - (tetra -hi dro-2Hpiran-4-yl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] Petition 870190100577, of 10/8/2019, p. 23/278
20/265
2,7-diazospiro [3.5] non-2-yl} prop-2-en-1-one, and [00109] (+) - 1 - {7- [2 - {[1 - (2-h id roxy -2-methyl I propi I) pi perid i n-4-yl] oxy} -7- (5methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin -4-il] -2,7diazaespiro [3.5] non-2-il} prop-2-en-1-one, and a salt thereof.
[00110] A tautomer or geometric isomer may be present in the compound of Formula (I) depending on the type of substituent. In the present description, the compound of Formula (I) is described in only one embodiment of the isomer; however, the present invention includes other isomers, separate isomers or a mixture thereof.
[00111] Additionally, the compound of Formula (I) may have an asymmetric carbon atom and a chirality of the axis, and based on it, there may be an optical isomer. The present invention also includes separate forms of optical isomers of the compound of Formula (I), or a mixture thereof.
[00112] The present invention further includes a pharmaceutically acceptable prodrug of the compounds of Formula (I). A pharmacologically acceptable prodrug is a compound with a group that can be converted to an amino group, a hydroxyl group, a carboxyl group or the like by solvolysis or under physiological conditions. Examples of a group forming a prodrug include groups described in Prog. Med., 5, 2157-2161 (1985) and Development of pharmaceuticals (Hirokawa Shoten, 1990), Volume 7, Molecular Design 163198.
[00113] Additionally, the salt of the compound of Formula (I) is a pharmaceutically acceptable salt of the compound of Formula (I), and depending on the type of substituent, it can form an acid addition salt or a salt with a base. Specifically, its examples include an acid addition salt of an inorganic acid such as a hydrochloric acid, a hydrobromic acid, a hydroiodic acid, a sulfuric acid, a
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21/265 nitric acid, and a phosphoric acid, and an organic acid, such as a formic acid, an acetic acid, a propionic acid, an oxalic acid, a malonic acid, a succinic acid, a fumaric acid, a maleic acid , a lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, aspartic acid, and a glutamic acid, a salt with inorganic metal such as sodium, potassium, magnesium, calcium, and aluminum, a salt with an organic base such as methylamine, ethylamine, ethanolamine and, various amino acids such as acetyl leucine, lysine, and ornithine, a salt with an amino acid derivative, and an ammonium salt.
[00114] In addition, the present invention also includes various hydrates and solvates of the compound of Formula (I) and its salts, and crystalline polymorphism substances. In addition, the invention also includes compounds labeled with various radioactive or non-radioactive isotopes. (Preparation method) [00115] The compound of Formula (I) and its salt can be prepared by applying various known synthetic methods using characteristics based on its basic structure or type of substituent. Depending on the type of functional group, it may be effective to replace a functional group with a suitable protecting group (a group that can easily be converted into a functional group) at a stage from a starting material to the intermediate. As such a protective group, for example, a protective group described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) written by Wuts (PGM Wuts) and Greene (TW Greene) can be exemplified, and can be selected appropriately and used according to these reaction conditions. In such a method, the desired compound can
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22/265 be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as needed.
[00116] In addition, similar to the protective group described above, the prodrug of the compound of Formula (I) can be prepared by introducing a specific group in the starting material stage to the intermediate or by carrying out the reaction using the compound obtained from Formula (I). The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
[00117] Hereinafter, a typical method of preparing the compound of Formula (I) will be described. Each preparation method can also be performed with reference to the references attached to the explanation. The method of preparing the present invention is not limited to the examples described below.
[00118] In the present specification, the following abbreviations can be used.
[00119] TEA: triethylamine, DIPEA: N, N-diisopropylethylamine, NMO: N-methylmorpholine, DABCO: 1,4-diazabicyclo [2.2.2] octane, THF: tetrahydrofuran, DMF: Ν, Ν-dimethylformamide, DMSO : dimethylsulfoxide
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Chemical Formula 5
(in the formula, PG ¹ represents a protecting group, and PG ² represents a protecting group or a hydrogen atom.) [00120] A compound of Formula (l) -1 representing the compound of Formula (I) can be obtained by submitting the compound (1) to a deprotection reaction in order to obtain a compound (2), and then undergoing an acylation reaction. Here, examples of the protecting group include a tert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, an ethoxymethyl (trimethylsilyl) group, a trifluoroacetyl group, an ally group, and a tetrahydro-2H-pyran2-yl group.
[00121] The deprotection reaction carried out with reference to Protective Groups in Organic Synthesis written by Greene and Wuts, 5 ^a
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Edition, published by John Wiley & Sons Inc., 2014.
[00122] In the acylation reaction, an equivalent amount of the compound (2) obtained in the previous step and an acylation reagent, or an excess amount of one of these is used, the mixture is reacted in a solvent inert to the reaction, in the presence of a base, and the mixture was stirred under cooling to heating, preferably at a temperature of -20 ° C to 80 ° C usually for 0.1 hour to 1 day. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, acetonitrile, water and a mixture thereof. In addition, examples of the base used herein include an inorganic base, such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or an organic base, such as TEA, DIPEA and NMO. In addition, examples of the acylating reagent include an acyl halide and an acid anhydride. Examples of the acyl halide include such as acryloyl chloride and 3-chloropropanoyl chloride. In addition, a method of reacting the mixture obtained using an equivalent amount of the compound (2) and a carboxylic acid, or an excess amount of one of these, in the presence of a condensing agent can be used. The condensing agent is not particularly limited, and examples of these include 1- (3-dimethylaminopropyl) -3ethylcarbodiimide, dicyclohexylcarbodiimide, 1, T-carbonyldiimidazole, azide diphenylphosphate, and phosphorus oxychloride.
[00123] Note that the present reaction can be carried out after isolating the compound (2) which is an amine compound obtained by deprotection reaction.
[00124] It may also be necessary to remove the acyl reagentPetition 870190100577, from 10/8/2019, p. 28/278
25/265 excessively reacted in the presence of an inorganic base, such as an aqueous solution of sodium carbonate.
[00125] Furthermore, in order to obtain the compound of Formula (l) -1, it may be necessary to subject a compound obtained by the acylation reaction with 3-chloropropanoyl chloride or similar to an elimination reaction in the presence of a base in a solvent inert to the reaction. The solvent used here is not particularly limited and its examples include alcohols such as isopropyl alcohol, water and a mixture thereof. In addition, examples of the base include an inorganic base such as sodium hydroxide.
[00126] In addition, the compound of Formula (l) -1 can have axial chirality, and can be obtained in the form of a mixture of atropisomers, but the respective atropisomers can be isolated by performing the normal resolution operation, for example, at optical resolution using chiral column chromatography of supercritical fluid.
Reference
J. Med. Chem. 43, 2591-2600, 2000
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(Overview of starting material 1)
Chemical Formula 6

(In the formula, A represents a boronic acid, boronate ester or a trifluoroborate salt. In addition, X ⁺ represents a metal cation, such as Na ⁺ , K ⁺ and Cs ⁺ .) [00127] The present method of preparation it is a first method of preparing a starting compound (1).
(First step) [00128] This step is a method of preparing the compound (5) by substitution reaction of ipso between the compound (3) and the compound (4).
[00129] In the present reaction, an equivalent amount of the compound (3) and the compound (4), or an excess amount of one of the
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27/265 is used, and its mixture is stirred in a solvent inert to the reaction, or under the absence of solvent, under cooling to heating reflux, preferably at a temperature of 0 ° C to 80 ° C, normally during 0, 1 hour to 5 days. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, acetonitrile and a mixture thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, NMO, DABCO, and an inorganic base such as potassium carbonate, sodium carbonate, and cesium carbonate, in order to smoothly progress the reaction. (Second step) [00130] This step is a method of preparing the compound (7) by an ipso substitution reaction between the compound (5) and the compound (6).
[00131] The reaction conditions are similar to the first step of Synthesis of the starting material 1.
(Third step) [00132] This step is a method of preparing the compound (9) by substitution reaction of ipso between the compound (7) and the compound (8).
[00133] The reaction conditions are similar to the first step of Synthesis of the starting material 1.
[00134] The compound (8) used in the present reaction can be prepared by stirring the corresponding alcohol with a base in a reaction-inert solvent under cooling to room temperature generally for 0.1 hour to 1 hour. The solvent to be used here is not particularly limited, and its examples include ethers such as
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28/265 as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF,
DMSO, and a mixture thereof. In addition, examples of the base used herein include an inorganic base, such as sodium hydride and cesium carbonate, or an organic base, such as potassium tert-butoxide.
(Fourth step) [00135] This step is a method of preparing the compound (11) by Suzuki coupling reaction between the compound (9) and the compound (10).
[00136] In the present reaction, an equivalent amount of the compound (9) and the compound (10), or an excess amount of one of them is used, and its mixture is stirred in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature at heating reflux, usually for 0.1 hour to 5 days. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, alcohols, such as methanol, ethanol, isopropyl alcohol and butanol, DMF, DMSO, acetonitrile, 1,3-dimethylimidazolidin-2-one, water, and a mixture thereof. Examples of the base include an inorganic base such as tripotassium phosphate, sodium carbonate, potassium carbonate and sodium hydroxide. Examples of a palladium catalyst include tetracis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (ll) dichloride, [1,1'-bis (diphenylphosphine) ferrocene] palladium (ll) dichloromethane and (1E , 4E) -1,5-diphenylpenta-1,4-dien-3-one / palladium (3: 2). It may be advantageous to carry out the reaction in the presence of a binder, such as dicyclohexyl (2 ', 6'-dimethoxybiphenyl-2-yl) phosphine, in order to smoothly advance the reaction. It may be advantageous to heat the mixture for
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29/265 microwave irradiation in order to smoothly progress the reaction.
Reference
J. Am. Chem. Soc. 127, 4685-4696 (2005) (Fifth step) [00137] This step is a method of preparing the compound (1) by Suzuki coupling reaction between the compound (11) and the compound (12).
[00138] The reaction conditions are similar to the fourth step of Synthesis of the starting material 1.
(Overview of starting material 2)
Chemical Formula 7
first step
F (14) second stage

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30/265 [00139] The present method of preparation is a second method of preparing a starting compound (1).
(First stage) [00140] This stage is a method of preparing a compound (14) by subjecting the compound (13) to an iodination reaction.
[00141] In the present reaction, an equivalent amount of the compound (13) and an iodination reagent are used, or an excess amount of one of them, and its mixture is stirred in a solvent inert to the reaction at room temperature at reflux heating for 0.1 hour to 5 days. The solvent to be used here is not particularly limited, and examples thereof include halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane and chloroform, ethers, such as diethyl ether, THF, 1,4-dioxane and 1,2- dimethoxyethane, alcohols such as methanol, ethanol, isopropyl alcohol and butanol, DMF, DMSO and a mixture thereof. As the iodination reagent, Niosuccinimide or similar is preferable.
Reference
J. Med. Chem. 58, 3548-3571,2015 (Second step) [00142] In this step, the cyclization reaction of the compound (14) with urea is carried out and then the resulting cyclized compound is subjected to the chlorination reaction to prepare the compound (15).
[00143] In the present reaction, an equivalent amount of the compound (14) and urea is used, or an excess amount of one of them, and its mixture is stirred in a solvent inert to the reaction or in the absence of solvent, under temperature heating reflux, generally for 0.1 hour to 1 day, and an equivalent amount of the product obtained cyclized and chlorinating reagent, or an excess amount of one of them is used, and the mixture is stirred in a solvent inert to the reaction, or in the absence of sun Petition 870190100577, of 10/8/2019, p. 34/278
31/265 at room temperature at reflux of heating, generally for 0.1 hour to 1 day. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF, DMSO and a mixture thereof. With the chlorination reagent, phosphorus oxychloride, thionyl chloride and the like are preferable. It may be advantageous to carry out the reaction in the presence of the organic base, such as DIPEA, in order to smoothly progress the reaction.
[00144] The cyclized product as an intermediate in this step can be obtained by subjecting the compound (14) to a condensation reaction with aqueous ammonia in a solvent inert to the reaction in the presence of the condensing agent, and then reacting the obtained amide product. with 1, T-carbonyldiimidazole in a solvent inert to the reaction in the presence of a base. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF, DMSO and a mixture thereof. In addition, as the condensing agent, 1H-benzotriazole-1-ol, 1- (3-dimethylaminopropyl) -3ethylcarbodiimide and the like are preferred. In addition, examples of the base include an inorganic base, such as potassium carbonate, sodium carbonate and cesium carbonate, and an organic base, such as TEA, DIPEA and NMO.
[00145] Note that it is advantageous to carry out the following reaction after the isolation of the intermediate amide and cyclized products, respectively, in order to smoothly progress the reaction.
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Reference
J. Med. Chem. 58, 3548-3571,2015 (Third step) [00146] This step is a method of preparing the compound (16) by an ipso substitution reaction between the compound (15) and the compound (4).
[00147] The reaction conditions are similar to the first step of Synthesis of the starting material 1.
(Fourth step) [00148] This step is a method of preparing the compound (17) by an ipso substitution reaction between the compound (16) and the compound (6).
[00149] The reaction conditions are similar to the second step of Synthesis of the starting material 1.
(Fifth step) [00150] This step is a method of preparing the compound (18) by an ipso substitution reaction between the compound (17) and the compound (8).
[00151] The reaction conditions are similar to the third step of Synthesis of the starting material 1.
(Sixth step) [00152] This step is a method of preparing the compound (19) by Suzuki coupling reaction between the compound (18) and the compound (12).
[00153] The reaction conditions are similar to the fifth step of Synthesis of the starting material 1.
(Seventh step) [00154] This step is a method of preparing the compound (1) by Suzuki coupling reaction between the compound (19) and the compound (10).
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33/265 [00155] The reaction conditions are similar to the fourth stage of the
Synthesis of starting material 1. (Synthesis of starting material 3) Chemical formula 8
(in the formula, PG ³ represents a protecting group, and L represents an leaving group.) [00156] The present method of preparation is a third method of preparation
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34/265 preparation of a starting compound (1).
(First step) [00157] This step is a method of preparing the compound (21) by an ipso substitution reaction between the compound (16) and the compound (20).
[00158] The reaction conditions are similar to the second step of Synthesis of the starting material 1.
(Second step) [00159] This step is a method of preparing the compound (22) by an ipso substitution reaction between the compound (21) and the compound (8).
[00160] The reaction conditions are similar to the third step of Synthesis of the starting material 1.
(Third step) [00161] This step is a method of preparing the compound (23) by Suzuki coupling reaction between the compound (22) and the compound (12).
[00162] The reaction conditions are similar to the fifth step of Synthesis of the starting material 1.
(Fourth step) [00163] This step is a method of preparing the compound (24) by Suzuki coupling reaction between the compound (23) and the compound (10).
[00164] The reaction conditions are similar to the fourth step of Synthesis of the starting material 1.
(Fifth step) [00165] This step is a method of preparing a compound (25) by subjecting the protective group represented by PG ³ of the compound (24) to a selective deprotection reaction. Here, examples of PG ³ include a 2- (trimethylsilyl) ethoxycarbonyl group, a tertiary group 870190100577, from 10/8/2019, p. 38/278
35/265 butoxycarbonyl, a benzyl group, a benzyloxycarbonyl group, a (trimethylsilyl) ethoxymethyl group, a trifluoroacetyl group, and an allyl group. The deprotection reaction carried out with reference to Protective
Groups in Organic Synthesis written by Greene and Wuts, 5th Edition, published by John Wiley & Sons Inc., 2014.
(Sixth step) [00166] This step is a method of preparing the compound (1) by reaction between the compound (25) and the compound (26). Here, examples of the leaving group include halogen, methanesulfonyloxy and ptoluenesulfonyloxy. It is possible to obtain a desired compound (1) by reacting an epoxy compound such as 2,2-dimethyloxirane instead of compound (26).
[00167] In the present reaction, an equivalent amount of compound (25) and compound (26) is used, or an excess amount of one of them, and their mixture is stirred in a solvent inert to the reaction or in the absence of solvent , under cooling to heating reflux, preferably at a temperature of 0 ° C to 120 ° C, normally for 0.1 hour to 5 days. The solvent to be used here is not particularly limited, and its examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, alcohols, such as methanol, ethanol, isopropyl alcohol and butanol, DMF, DMSO, ethyl acetate, acetonitrile, water, and a mixture thereof. It may be advantageous to carry out the reaction in the presence of the organic base, such as TEA, DIPEA, or NMO, or the inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, or potassium hydroxide, in order to smoothly progress the reaction. It may be advantageous to heat the mixture by microwave irradiation in order to smoothly progress the reaction.
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36/265 [00168] The compound of Formula (I) is isolated and purified as a free compound, a salt thereof, a hydrate, a solvate or a crystalline polymorphism substance. The salt of the compound of Formula (I) can also be prepared by subjecting it to a conventional salt formation reaction.
[00169] Isolation and purification are carried out by applying common chemical operations such as extraction, fractional crystallization, various fractionation chromatography and the like.
[00170] Various types of isomers can be prepared by selecting a suitable starting compound or can be separated using a difference in physicochemical properties between isomers. For example, the optical isomer can be obtained by a method of general optical resolution of the racemic compound (for example, fractional crystallization leading to a diastereomeric salt with an optically active base or with an acid, chromatography using a chiral column or the like), and it can also be prepared from a suitably optically active starting compound.
[00171] The pharmacological activity of the compound of Formula (I) was confirmed by the following test.
Test Example 1
Evaluation of the inhibitory action of the formation of the KRAS G12C / SOS / c-Raf complex [00172] KRAS G12C, SOS, and Human Recombinant c-Raf protein were used, and with regard to the formation of the complex of these proteins, an inhibitory action of Test compound was examined using a time-resolved fluorescence resonance energy transfer method (TR-FRET).
[00173] Biotinylated AviTag-KRAS G12C (amino acid region 1185, GDP) (2.5 μΙ_; 400 nM) dissolved in assay buffer (50 mM HEPES, 150 mM NaCI, 5 mM MgCb, 0.05% Tween 20, pH 7.4)
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37/265 and test compound were added in a 2.5 μΙ volume of 4,000 nM to 4 nM were added to the 384 well plate (Corning Inc.). Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μΙ_; 1.3 μΜ) and c-Raf (amino acid region 51-131) GST containing GTP (Sigma-Aldrich Co. LLC) (2, 5 gL, 130 nM and 4 μΜ each) were added to the above mixture, and the resultant was left to stand for one hour at room temperature. Then, a mixed solution (10 pL) of LANCE Ulight-anti-GST (120 nM, PerkinElmer. Co., Ltd) and Streptoavidin labeled with LANCE Eu-W1024 (100 ng / mL, PerkinElmer. Co., Ltd) added, and a fluorescence intensity at the 620 nm and 665 nm wavelength condition was measured using the EnVision 2103 Multilabel Reader (Perkin Elmer Co., Ltd.) at the 337 nm excitation wavelength conditions. After a fluorescence intensity value at the 620 nm reference wavelength was normalized, when a signal value in a solvent treatment was set to 0% inhibition, and a signal value without GTP addition was set to 100% inhibition, the 50% inhibitory concentration (IC50) was calculated by non-linear Sigmoid-Emax regression analysis. The results of various test compounds of Formula (I) are shown in Table 1. In the Tables, Ex represents Example numbers described later. In addition, in Tables, Compound C represents a test compound of Example I-59 described in International Publication No. WO 2016/164675, and the structures of Reference Example 1 and Reference Example 2 are shown in Table 168 described below (0 same applies below)
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Table 1
Ex IC ₅ o (nM) Ex IC50 (nM) Ex IC50 (nM) 1 34 33 44 65 46 2 37 34 36 66 47 3 29 35 17 67 43 4 35 36 21 68 45 5 31 37 17 69 50 6 37 38 15 70 79 7 33 39 14 71 40 8 32 40 15 72 41 9 55 41 42 73 44 10 34 42 44 74 50 11 38 43 50 75 51 12 23 44 41 76 43 13 37 45 38 77 56 14 50 46 48 78 47 15 52 47 43 79 57 16 45 48 54 80 166 17 34 49 41 81 41 18 46 50 50 82 43 19 48 51 59 83 108 20 32 52 56 84 43 21 65 53 37 85 56 22 39 54 60 86 72 23 39 55 83 87 39 24 21 56 63 88 148 25 48 57 52 89 53 26 41 58 57 90 55 27 40 59 63 91 42 28 38 60 98 Reference example 1 37 29 49 61 56 Reference example 2 35 30 45 62 37 Compound C 68 31 45 63 53 32 39 64 32
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Test Example 2
Evaluation of the inhibitory action of ERK phosphorylation with respect to the non-small cell lung cancer strain positive for human KRAS G12C mutation, NCI-H1373.
[00174] The inhibitory action of ERK phosphorylation by the test compound was assessed by measuring threonine phosphorylation 202th (Thr 202) and tyrosine 204th (Tyr 204) of ERK downstream of the KRAS signal by Cell ELISA.
[00175] NCI-H1373 cells (ATCC, CRL-5866) were seeded in 384 well plates (Greiner bio-one) in 36 pL / well, each to be 2 x 10 ⁴ cells per well. Cell culture was performed under conditions of 37 ° C in the presence of 5% CO2 using RPMI 1640 medium (Sigma-Aldrich Co. LLC) containing 10% fetal bovine serum (GE Life Sciences).
[00176] The next day, test compounds (six points in a final concentration range of 1,000 nM to 0.3 nM), final concentration 1 μΜ of Trametinib (GlaxoSmithKline Inc; MEK inhibitor) as a positive control, and DMSO , which is a solvent of the test compound as a negative control, was diluted 100 times with fresh medium, 4 pL each was added to each well and then cultured for 2 hours. Immediately after culture, 30 pL of 30% glyoxal solution (Wako; 40% glyoxal diluted with Phosphate Buffered Saline (PBS; Wako)) was added to each well, and the cells were allowed to stand at room temperature for an hour to be fixed. Then, the supernatant was removed by centrifuging the plate (110 xg for 7 seconds, unless otherwise indicated below under the same conditions), and 20 µl of PBS containing 0.1% Triton X-100 (Amersham Biosciences Corp.) were added to each well. After being allowed to stand at room temperature for 10 minutes, the supernatant was removed
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40/265 by centrifugation and the same operation was repeated. Then, 20 µl of PBS containing 0.5% SDS (Invitrogen) was added to each well, and the mixture was left to stand at room temperature for 30 minutes, and then centrifuged to remove the supernatant. Subsequently, 20 μΙ_ of a blocking solution (ODYSSEY Blocking Buffer; LI-COR Biosciences) was added to each well and left to stand at room temperature for one hour. The supernatant was removed by centrifugation, and 10 µl of a blocking solution prepared by diluting ERK (Thr 202 / Tyr 204) of a phosphorylation antibody (Cell Signaling Technology, Inc.) as a primary antibody to be 1/2, 500 µl of the stock in relation to the stock solution was added to each well and left to stand at 4 ° C overnight.
[00177] The following day, a reaction liquid is removed by centrifuging the plate, 20 μΙ_ of 0.05% PBS containing Tween-20 (Thermo Scientific; 20 x PBS, Tween-20 diluted 20 times with ion exchange water ) was added to each well and each well was washed by removing the supernatant by centrifugation. The washing was carried out three times in total. After washing, 10 µl of a blocking solution prepared by diluting goat anti-Rabbit IgG IRDye 800CW (LI-COR Biosciences) as a secondary antibody to be 1 / 1,000 amount with respect to a stock solution was added to each cavity and was left to stand at room temperature for one hour. The reaction liquid was removed by centrifuging the plate, and each well was washed three times with PBS containing 0.05% Tween-20, in the same way as after the reaction of the primary antibody. The centrifugation after the third wash was 171 x g for 17 seconds. After removing the cleaning solution, the plate was allowed to air dry at room temperature for three hours or more and the fluorescent signal at 800 nm was measured by Aerius (LI-COR
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Biosciences).
[00178] When a signal value at the time of adding DMSO was set to 0% inhibition, and a signal value at the time of adding 1 μ of Trametinib was set to 100% inhibition, an inhibition value of 50 % (IC50) was calculated using Sigmoid-Emax nonlinear regression analysis. The results of various test compounds of Formula (I) are shown in Table 2.
Table 2
Ex IC ₅ o (nM) Ex IC50 (nM) Ex IC50 (nM) 1 6.4 33 4.6 65 9.3 2 4.4 34 5.8 66 9.7 3 3.3 35 2.5 67 11 4 2.9 36 3.0 68 12 5 4.7 37 2.5 69 12 6 3.5 38 3.4 70 18 7 8.8 39 3.0 71 14 8 2.6 40 3.1 72 14 9 3.8 41 6.2 73 15 10 5.7 42 4.4 74 15 11 10 43 5.0 75 15 12 6.7 44 5.1 76 15 13 11 45 5.2 77 16 14 6.1 46 5.5 78 16 15 11 47 5.6 79 16 16 9.1 48 5.9 80 16 17 4.9 49 2.9 81 16 18 5.9 50 6.4 82 16 19 4.5 51 8.9 83 16 20 6.5 52 6.7 84 17 21 14 53 6.8 85 17 22 4.6 54 7.2 86 12 23 4.9 55 7.4 87 18
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Ex IC ₅ o (nM) Ex IC50 (nM) Ex IC50 (nM) 24 3.7 56 7.7 88 19 25 2.5 57 8.2 89 19 26 3.3 58 8.4 90 22 27 3.3 59 8.4 91 22 28 3.5 60 8.8 Reference example 1 22 29 4.2 61 8.8 Reference example 2 17 30 3.1 62 8.8 Compound C 210 31 6.3 63 6.6 32 5.7 64 9.1
Test Example 3
Evaluation of the inhibitory action of cell proliferation independent of anchorage in relation to lung cancer of non-small cells positive for a G12C mutation of KRAS, NCI-H1373.
[00179] An inhibitory action of cell proliferation independent of anchoring by the test compound was evaluated by a three-dimensional spheroid culture.
[00180] NCI-H1373 cells were seeded in 384-well plates with low cell adsorption U-base (Prime Surface: Sumitomo Bakelite Co., Ltd.) at 36 pL / well each, to be 5 x 10 ² cells per well. Cell culture was performed under the same conditions as in Test Example 2.
[00181] The following day, the test compounds (six points in a final concentration range of 1,000 nM to 0.3 nM) and DMSO, which is a solvent of the test compound as a negative control, were diluted 100 times with fresh medium, 4 pL each were added to each well. After culturing at 37 ° C in the presence of 5% CO2 for six days, 20 µl of CelITiter Glo or CelITiter Glo 2.0 (Promega Corporation) was added to each well. After stirring for one hour at room temperature using a plate mixer (FlPetition 870190100577, of 10/8/2019, page 46/278
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NEPCR), an emission signal was measured with ARVO X3 (PerkinElmer
Co., Ltd.).
[00182] When a signal value in a DMSO treatment was defined as 0% inhibition, and a signal value in the cell-free medium was only defined as 100% inhibition, a value of 50% inhibition (IC50) was calculated using the non-linear regression analysis model Sigmoid-Emax. The results of various test compounds of Formula (I) are shown in Table 3.
Table 3
Ex IC ₅ o (nM) Ex IC50 (nM) Ex IC50 (nM) 1 12 33 8.7 65 27 2 6.2 34 7.5 66 39 3 4.7 35 2.5 67 18 4 3.4 36 3.2 68 16 5 8.1 37 8.8 69 17 6 12 38 2.5 70 71 7 11 39 4.3 71 10 8 3.5 40 5.1 72 24 9 5.5 41 14 73 28 10 10 42 13 74 21 11 12 43 6.0 75 43 12 11 44 7.6 76 25 13 13 45 7.3 77 32 14 8.8 46 8.1 78 24 15 14 47 17 79 43 16 10 48 15 80 75 17 12 49 4.6 81 26 18 7.3 50 16 82 62 19 15 51 24 83 51 20 11 52 16 84 33 21 27 53 9.8 85 27 22 15 54 6.8 86 37
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Ex IC ₅ o (nM) Ex IC50 (nM) Ex IC50 (nM) 23 5.9 55 43 87 35 24 6.1 56 21 88 90 25 5.2 57 39 89 40 26 8.6 58 17 90 53 27 6.5 59 26 91 39 28 5.8 60 35 Reference example 1 32 29 10 61 17 Reference example 2 22 30 5.4 62 14 Compound C 320 31 8.3 63 14 32 7.1 64 15
Test Example 4
Evaluation of the inhibitory action of intratumoral pERK [00183] The amount of ERK phosphorylation in a tumor sample after administration of the test compound was examined using the pERK measurement kit (Advanced ERK phospho-T202 / Y204 kit, Cisbio co., Ltd .) through a TR-FRET method.
[00184] 2.0 to 5.0 x 10 ⁶ NCI-H1373 cells were prepared using a solution in which an equivalent amount of Matrigel (Becton, Dickinson and Company) was added to PBS, were injected subcutaneously in a volume of 100 pL and planted in 4-5 week old male nude mice (CAnN.Cg-Foxn 1 nu / CrlCrlj (nu / nu), from Charles River Laboratories Japan, Inc.), and then the nude mice, males, were used for the test 15 to 26 days later. The test was conducted with three mice in a solvent group and three mice in a test compound administration group, and the test compounds were prepared using a solvent such that its dosage is as indicated in Table 4. The test compound was administered subcutaneously or orally. For subcutaneous administration, physiological saline solution suPetition 870190100577, of 10/8/2019, p. 48/278
45/265 supplemented with equimolar hydrochloric acid was added as a solvent. For oral administration, 6% 2-hydroxypropyl-p-cyclodextrin (Sigma-Aldrich Co. LLC) was used as a solvent. Six hours after administration, a tumor was excised from a dislocated cervical mouse under isoflurane anesthesia, and part of it was placed in a 2 ml Eppendorf tube and frozen using liquid nitrogen. The tumor sample was stored in a deep freezer at -80 ° C until it was subjected to the pERK measurement test. [00185] 500 pL of a lysis buffer (Phospholysis buffer [Cisbio
Co., Ltd.], Free EDTA Complete [Roche Diagnostics KK], Phosphatase 2 inhibitor cocktail [Sigma-Aldrich Co. LLC]) and one bead (5 mm YTZ sphere [Nikkato Corp.]) were added to the sample. tumor and ground (frequency 25 / s for 3 minutes) using Tissue Lyser II (QIAGEN GmbH). The total amount was transferred to a new tube and centrifuged (20,400 xg for 10 minutes, 4 ° C) using a high velocity of micro quantity in order to obtain a tumor lysate that is a supernatant. The protein quantification of the tumor lysate was performed using a protein quantification kit (Pierce 660 nm Potein Assay Kit [Thermo Fisher Scientific Inc.]) , and each sample was diluted using lysis buffer 2 (Phosphorysis buffer [Cisbio Co., Ltd.], Blocking Agent [attached to the pERK measurement kit]) so that the amount is a final concentration of 0.5 pg / pL.
[00186] Each of P-ERK1 / 2 cryptate antibody and p-ERK1 / 2 d2 antibody (attached to the pERK measurement kit) was diluted 20 times with each of the detection buffers (attached to the measurement of pERK), and thus a mixed solution of these two types of antibodies was prepared. A mixed solution of the antibody was added to a 384 well plate at a volume of 4 pL / well. In addition, the tumor lysate diluted in 0.5 pg / L was added to a
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46/265 volume of 16 pL / well. After standing at room temperature in a humid box for about 17 hours, the fluorescence intensity at 620 nm and 665 nm was measured under the 337 nm excitation wavelength condition using the EnVision 2103 Multilabel Reader (Perkin Elmer Co ., Ltd.). After normalizing the value with the fluorescence intensity at the 620 nm reference wavelength, the vehicle administration group count was set to 0% inhibition, the count without added lysate was set to 100% inhibition, and an inhibition value of the test compound administration sample was the% calculated by inhibition rate. The results of various test compounds of Formula (I) are shown in Table 4.
Table 4
Ex Administration routine Dosage (mg / kg) PERK inhibition (%) 2 Subcutaneous administration 1 54 3 Subcutaneous administration 1 57 4 Subcutaneous administration 1 58 5 Subcutaneous administration 3 72 7 Subcutaneous administration 3 59 15 Subcutaneous administration 3 53 16 Subcutaneous administration 3 51 24 Oral administration 40 72 25 Oral administration 10 66 26 Oral administration 10 50 28 Oral administration 10 46 29 Oral administration 10 62 30 Oral administration 10 56 31 Oral administration 10 51 32 Oral administration 10 55 33 Oral administration 10 71 34 Oral administration 10 54
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Ex Administration routine Dosage (mg / kg) PERK inhibition (%) 35 Oral administration 10 68 36 Oral administration 10 46 37 Oral administration 10 63 38 Oral administration 10 66 39 Oral administration 10 43 40 Oral administration 10 58 50 Oral administration 10 63 52 Oral administration 10 68 56 Oral administration 10 53 65 Oral administration 10 68 Compound C Subcutaneous administration 30 54
Test Example 5
Evaluation of the antitumor effect in mice carrying a tumor of the non-small cell lung cancer strain NCI-H1373 positive for human KRAS G12C mutation [00187] A cell suspension prepared by 3.0 x 10 ⁷ / mL, suspending the cells NCI-H1373 in PBS, an equivalent amount of Matrigel (Becton, Dickinson and Company) was added to this, and the cell suspension was planted subcutaneously in a volume of 100 μΙ_ for 4-5 week old male nude mice (CAnN .Cg-Foxnlnu / CrCrlj (nu / nu), Charles River Laboratories Japan, Inc.). Approximately 2 weeks after planting, the groups were divided so that the tumor volume and body weight between the groups were almost equivalent to each other, and the administration of the test compound started from the following day. The test was conducted with five mice in a solvent group and five mice in a test compound administration group, and a 6% aqueous solution of 2-hydroxypropyl-p-cyclodextrin (Sigma-Aldrich Co. LLC) was administered orally to the solvent group and a 6% aqueous solution of 2-hydroxypropyl-p-cyclodextrin in which the compound
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48/265 test (10 or 40 mg / kg) was mixed, it was administered orally to the test compound administration group. Administration was performed once a day for 13 or 14 days and the tumor diameter and volume were measured twice a week. For the calculation of tumor volume, the following formula was used.
[tumor volume (mm ³ )] = [largest diameter (mm) of the tumor] x [smallest diameter (mm) of the tumor] ² x 0.5 [00188] The rate of inhibition of tumor growth (%) by the compound The test was calculated by adjusting the tumor volume of the test compound administration group on the day before solid administration started as 100% inhibition, and the tumor volume of the solvent group on the last day of administration as 0% inhibition. In addition, in a case where the tumor volume of the test compound administration group was less than the tumor volume on the day before administration started solid, the tumor regression rate (%) of the test compound was calculated adjusting the tumor volume the day before the solid administration started as 0% regression, and the tumor volume 0 as 100% regression. The results of various test compounds of Formula (I) are shown in Table 5.
Table 5
Ex Dosage (mg / kg) Anti-tumor effect 24 40 48% regression 35 10 72% regression 36 10 43% regression 37 10 58% regression 38 10 58% regression 39 10 96% inhibition 40 10 15% regression [00189] How to resull side of the tests above, the inhibitory action of
KRAS of the G12C mutation has been confirmed in several compounds of
Formula (I). Consequently, the compound of Formula (I) can be
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49/265 used for the treatment of lung cancer, lung cancer positive for the K12 G12C mutation and the like.
[00190] A pharmaceutical composition containing the compound of Formula (I) or one or more types of salts as active ingredients can be prepared using an excipient commonly used in this field, that is, an excipient for pharmacists and a carrier for pharmaceutical products through of the methods generally used.
[00191] Administration can be any of oral administration with tablets, pills, capsules, granules, powders, solutions, and the like, and parenteral administration with injections, such as intraarticular, intravenous, intramuscular, and the like, suppositories, eye drops, ointment ointments , transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches and inhalants.
[00192] As a solid composition for oral administration, tablets, powders, granules and the like are used. In such a solid composition, one or more active ingredients are mixed with at least one type of inert excipient. The composition can contain an inert additive such as a lubricant, an integral d, a stabilizer and a solubilizing agent according to the conventional method. Tablets or pills can be coated with a sugar coating or a film of gastric or enteric substance, if necessary.
[00193] The liquid composition for oral administration includes a pharmaceutically acceptable emulsion, a solution, a suspension, a syrup, an elixir, and the like, and further includes an inert diluent generally used such as purified water or ethanol. The liquid composition can include a solubilizing agent, a wetting agent, an adjuvant such as a suspending agent, a sweetening agent, a flavoring agent, an aromatic, and a preservative, in addition to
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[00194] An injection for parenteral administration includes a sterile aqueous or non-aqueous solution, a suspension or an emulsion. Examples of an aqueous solvent include distilled water for injection or physiological saline. Examples of a non-aqueous solvent include alcohols such as ethanol. Such a composition may further include an isotonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These compositions are sterilized, for example, by filtration through a bacteria retention filter, mixing a sterilizing or irradiating agent. In addition, these compositions are used to prepare a sterile solid composition and can be used by being dissolved or suspended in sterile water or in a sterile injectable solvent before use.
[00195] A transmucosal agent, such as an inhalation agent and a transnasal agent, is in a solid, liquid or semi-solid state and can be prepared according to conventionally known methods. For example, in addition to the well-known excipient, a pH adjuster and preservatives and a surfactant and lubricant, a stabilizer and a thickener can be added appropriately. For administration, a suitable inhalation or insufflation device can be used. For example, using a device known as a calibrated inhalation delivery device or a nebulizer, the compound can be administered alone or as a powder of the formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler or the like can be used for single or multiple administrations, and dry powder or powder containing capsules can be used. Alternatively, an agent can be used
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51/265 of suitable ejection, for example, a pressurized aerosol spray using suitable gases such as chlorofluoroalkane or carbon dioxide.
[00196] In a case of common oral administration, an adequate dosage per day is approximately in the range of 0.001 to 100 mg / kg by body weight, preferably in the range of 0.1 to 30 mg / kg, and even more preferably in a range of 0.1 to 10 mg / kg, and administration is carried out one or two to four divided dosages. In a case of intravenous administration, an adequate dosage per day is approximately in the range of 0.0001 to 10 mg / kg by body weight, and the administration is carried out once a day to several times a day. In addition, as a transmucosal agent, approximately 0.001 to 100 mg / kg by body weight is administered once to several times a day. The dosage is appropriately decided according to the individual cases in consideration of symptoms, age, sex and the like.
[00197] Depending on the route of administration, the dosage form, the site of administration, the type of excipients and additives, the pharmaceutical composition of the present invention contains one or more types of compounds of Formula (I) or their salts having ingredients active in a range of 0.01% to 100% by weight and, as a modality, active ingredients in the range of 0.01% to 50% by weight.
[00198] The compound of Formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases in which the compound of Formula (I) is considered to exhibit efficacy. The combination can be administered simultaneously or separately in succession or at a desired time. The co-administered preparation can be a compositional agent or formulated separately.
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Examples [00199] Hereinafter, the method of preparing the compound of Formula (I) will be described in more detail in the Example. It should be noted that the present invention is not limited to the compounds described in the following Examples. In addition, the method of preparing the starting compound is described in the Preparation Examples, respectively. In addition, the method of preparing the compound of Formula (I) is not limited only to methods that are prepared from the specific examples described below, and the compound of Formula (I) can be prepared by combining these preparation methods or can be prepared by methods obvious to those skilled in the art.
[00200] In the present specification, there are cases where naming software, such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) is used to name compounds.
[00201] In addition, for convenience, the mol / L concentration is represented by M. For example, 1 M aqueous sodium hydroxide solution means 1 mol / L aqueous sodium hydroxide solution. Preparation Example 1 [00202] A mixture of 4-bromo-3-fluorobenzoic acid (4.0 g), Niodosuccinimide (4.0 g) and Ν, Ν-dimethylformamide (hereinafter abbreviated as DMF) (40 ml) it was stirred at 50 ° C for 2 hours under argon flow. N-iodosuccinimide (1.5 g) was added to the reaction mixture at 50 ° C and the mixture was stirred at the same temperature for 1.5 hours. N-iodosuccinimide (1.5 g) was added to the reaction mixture at 50 ° C and the mixture was stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, then water was added and the mixture was stirred at room temperature for 5 hours. The precipitated solid was collected by filtration and air dried at room temperature. The obtained solid was suspended
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53/265 in water and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water and dried at 50 ° C under reduced pressure to obtain 2-amino-4-bromo-3-fluoro-5-iodobenzoic (5.6 g) as a solid.
Preparation Example 2 [00203] A mixture of 2-amino-4-bromo-3-fluoro-5iodobenzoic acid (5.6 g) and urea (4.7 g) was stirred at 200 ° C for 3 hours. The reaction mixture was cooled to room temperature, then water was added and the mixture was stirred at room temperature for 15 minutes. The solid was collected by filtration, washed with water and dried at 50 ° C under reduced pressure. The obtained solid was ground into powder, then it was mixed with phosphorus oxychloride (80 ml), cooled in an ice bath, and N, N-diisopropylethylamine dropwise (hereinafter, abbreviated as DIPEA) (8 , 0 mL) was added to the mixture in a nitrogen flow atmosphere. The reaction mixture was stirred at 150 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure and ethyl acetate was added to the obtained residue. The reaction mixture was poured into ice water, then an insoluble material was filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate to concentrate the solution under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to produce 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (3.6 g) as a solid.
Preparation Example 3 [00204] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6iodoquinazoline (3.6 g) and 1,4-dioxane (35 ml) was cooled in an ice bath and then DIPEA 2,7-diazaespiro [3.5] nonano-2 Petition 870190100577, of 10/8/2019, p. 57/278
54/265 carboxylate (2.0 g) to the mixture in a nitrogen stream and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / ethyl acetate) to obtain tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl) -2, 7diazaespiro [3.5] nonane-2-carboxylate (4.6 g) as a solid.
Preparation Example 4 [00205] 1-methylpiperidin-4-ol (3.5 ml), cesium carbonate (9.6 g) and
1,4-diazabicyclo [2.2.2] octane (hereinafter abbreviated as DABCO) tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl) -2,7 diazaospiro [ 3.5] nonane-2-carboxylate (6.0 g) (hereinafter, abbreviated as THF) (60 mL) under an argon atmosphere and then stirred at room temperature for 14 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The obtained residue was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water) to produce tert-butyl 7- {7-bromo-8-fluoro-6-iodo-2 [(1-methylpiperidin-4 -yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2carboxylate (6.3 g).
Preparation Example 5 [00206] A mixture of 2,2-difluoroethanol (0.37 mL) and DMF (20 mL) was cooled in an ice bath, and the mixture was stirred at the same temperature for 5 minutes under an argon atmosphere. , and then stirred at room temperature for 20 minutes (mixture A). A mixture of tert-butyl 7- {7-bromo-8-fluoro-6-iodo-2 - [(1-methylpiperidin-4yl) oxy] quinazolin-4-yl} -2,7-diazospiro [3.5] nonane- 2-carboxylate (2.0 g) and THF (40 ml) were cooled in an ice bath, the mixture was
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55/265 added dropwise to the mixture, stirred at the same temperature for 1 hour under an argon atmosphere, and then stirred at room temperature for 2 hours. Under the argon atmosphere, a mixture of 2,2-difluoroethanol (92 μΙ_) and DMF (5 mL) was cooled in an ice bath, sodium hydride (55%, liquid paraffin dispersion, 63 mg) was added to the mixture, stirred at the same temperature for 5 minutes and then stirred at room temperature for 20 minutes (mixture B). The reaction mixture was cooled in an ice bath, then mixture B was added and the mixture was stirred at room temperature for 3 hours. Water and a saturated aqueous solution of sodium chloride were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {7-bromo-8- (2, 2-difluoroethoxy) -6-iodo-2 - [(1-methylpiperidin-4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (2.0 g). Preparation Example 6 [00207] Potassium carbonate (1.1 g) and adduct of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) - dichloromethane (hereinafter, abbreviated as PdCb (dppf ^ dichloride CHzCb) (210 mg) were added to a mixture of tert-butyl 7- {7-bromo-8- (2,2-difluoroethoxy) -6-iodo2 - [(1-methylpiperidin-4-yl) oxy] quinazolin- 4-yl} -2,7-diazaspiro [3.5] nonane2-carboxylate (2.0 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.88 mL) , 1.4 - 4.0 ml), and the mixture was stirred at 80 ° C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate and a saturated aqueous solution of sodium chloride were added to the reaction mixture. Insoluble material was filtered off, then the filtrate was extracted with ethyl acetate
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56/265 and an organic layer was dried with anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). The purified product obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Ethyl acetate and hexane were added to the obtained purified product, the solvent was evaporated under reduced pressure to obtain tert-butyl 7- {7-bromo-8- (2,2-difluoroethoxy) -2 - [(1 methylpiperidin-4-yl ) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (1.4 g).
Preparation Example 7 [00208] A mixture of tert-butyl 7- {7-bromo-8- (2,2-difluoroethoxy) -2 [(1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4- il} -2,7 diazaespiro [3.5] nonane-2-carboxylate (1.4 g), boronic acid (5-methyl-1Hindazol-4-yl) (760 mg), 1,4-dioxane (17 mL) and water (1.7 mL) was bubbled under argon, then tripotassium phosphate (2.3 g), dicyclohexyl (2 ', 6'-dimethoxybiphenyl-2-yl) phosphine (hereinafter, abbreviated as SPhos) ( 270 mg), and (1E, 4E) -1,5-diphenylpenta-1,4-dien-3-one / palladium (3: 2) (hereinafter, abbreviated as Pd2 (dba) s) (400 mg) were added to the mixture, and the mixture was stirred at 120 ° C for 1 hour under microwave irradiation. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). The obtained purified product was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water), to obtain tert-butyl 7- {8- (2,2difluoroethoxy) -7- (5-methyl-1 H- indazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] -6vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (290 mg).
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Preparation Example 8 [00209] Sodium ethoxide (390 mg) was added to a mixture of tert-butyl 7- {7-bromo-8-fluoro-6-iodo-2 - [(1-methyl I pi perid i n- 4il) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (3.3 g) and THF (65 ml), and the mixture was stirred at 40 ° C overnight. Sodium ethoxide (390 mg) was added to the reaction mixture, and the mixture was stirred at 40 ° C overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl 7- {7-bromo-8-ethoxy-6-iodo-2 - [(1-methylpiperidin -4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (1.3 g) as a solid.
Preparation Example 9 [00210] A mixture of tert-butyl 7- {7-bromo-8-ethoxy-6-iodo-2 - [(1methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 -diazaespiro [3.5] nonane-2carboxylate (1.3 g), 1,4-dioxane (25 ml), water (5.0 ml), cyclopropylboronic acid (160 mg), tripotassium phosphate (1.4 g), PdCb (dppf) * CH2Cl2 (150 mg) was stirred at 100 ° C overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl 7 {7-bromo-6-cyclopropyl-8-ethoxy- 2 - [(1-methylpiperidin- 4-yl) oxy] quinazolin-4yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (800 mg).
Preparation Example 10
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58/265 [00211] Under the argon atmosphere, tert-butyl 7- {7-bromo-6cyclopropyl-8-ethoxy-2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2 , 7 diazaespiro [3,5] nonane-2-carboxylate (420 mg), boronic acid (5-methyl-1Hindazol-4-yl) (230 mg), Pd2 (dba) s (61 mg), SPHos (55 mg) , tripotassium phosphate (500 mg), 1,4-dioxane (10 ml) and water (1.0 ml) were mixed, and the mixture was stirred at 120 ° C for 2 hours under microwave irradiation. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl 7- {6-cyclopropyl-8-ethoxy-7- (5-methyl-1H-indazole- 4il) -2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (180 mg).
Preparation Example 11 [00212] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diaza-spiro [3.5] nonane-2-carboxylate (5.0 g), benzyl 4-hydroxypiperidine-1-carboxylate (3.7 ml), DMF (75 ml), cesium carbonate (8.0 g) and DABCO (140 mg) was stirred at room temperature for 16 hours under argon atmosphere. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to produce tert-butyl 7- [2 - ({1 [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -7-bromine -8-fluoro-6iodoquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate (4.1 g). Preparation Example 12 [00213] A mixture of 2,2-difluoroethanol (0.42 ml) and DMF (30 ml)
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59/265 was cooled in an ice bath and to the mixture was added sodium hydride (55%, liquid paraffin dispersion, 290 mg) and stirred at room temperature for 5 minutes under an argon atmosphere. The reaction mixture was cooled in an ice bath, and then a mixture of tert-butyl 7- [2 - ({1 - [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -7bromo-8-fluoro -6-iodoquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (2.7 g) and DMF (15 ml) was added to this. The reaction mixture was stirred at the same temperature for 10 minutes and then it was stirred at room temperature for 4 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel to produce tert-butyl 7- [2 - ({1 - [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -7-bromo-8 (2, 2-difluoroethoxy) -6-iodoquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (2.7 g) as a solid.
Preparation Example 13 [00214] Cyclopropylboronic acid (290 mg), tripotassium phosphate (2.3 g) and PdCb (dppf ^ CFLCb (250 mg) were added to a mixture of tert-butyl 7- [2 - ({1 - [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -7bromo-8- (2,2-difluoroethoxy) -6-iodoquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (2 , 6 g), 1,4-dioxane (52 ml) and water (10 ml), and the mixture was stirred at 90 ° C for 14 hours under an argon atmosphere, a cyclopropylboronic acid (100 mg) was added to the mixture reaction mixture, and the mixture was stirred at 90 ° C for 8 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulphate and then concentrated under reduced pressure.The residue obtained was purified. 870190100577, from 10/8/2019, page 63/278
60/265 using column chromatography on silica gel (hexane I ethyl acetate) to obtain tert-butyl 7- [2 - ({1 - [(benzyloxy) carbonyl] piperidin-4yl} oxy) -7-bromo -6 -cyclopropyl-8- (2,2-difluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (1.4 g) as a solid.
Preparation Example 14 [00215] A mixture of tert-butyl 7- [2 - ({1 - [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -7-bromo-6-cyclopropyl-8- (2, 2difluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate (1.4 g), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -4 - (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -1H-indazole (700 mg), tripotassium phosphate (1.2 g), SPhos (140 mg), Pd2 (dba ) s (160 mg), 1,4-dioxane (30 ml) and water (3.0 ml) were divided in equal amounts and, under an argon atmosphere, the mixture was stirred at 120 ° C for 1 hour under irradiation of microwave. The reaction mixture was mixed, and the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {2 - ({1 - [(benzyloxy) carbonyl] piperidin-4yl} oxy) - 6-cyclopropyl-8- (2,2-difluoroethoxy) -7- [5-methyl-1- (tetrahydro-2Hpyran-2-yl) -1H-indazol-4-yl] quinazolin-4-yl} - 2,7-diazaspiro [3.5] nonane-2carboxylate (820 mg) as a solid.
Preparation Example 15 [00216] Formaldehyde (37% aqueous solution, 0.40 mL) and 10% palladium on carbon (moistened with about 50% water, 180 mg) were added to a mixture of tert-butyl 7 - {2-tert-butyl - ({1 [(benzyloxy) carbonyl] piperidin-4-yl} oxy) -6-cyclopropyl-8- (2,2-difluoroethoxy) 7- [5-methyl-1- (tetra -hydro-2H-pyran-2-yl) -1H-indazol-4-yl] quinazolin-4-yl} -
2,7-diazaspiro [3.5] nonane-2-carboxylate (820 mg) and methanol (16 ml). The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / acetate of
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61/265 ethyl) to obtain tert-butyl 7- {6-cyclopropyl-8- (2,2-difluoroethoxy) -2 - [(1 methylpiperidin-4-yl) oxy] -7- [5-methyl-1- ( tetrahydro-2H-pyran-2-yl) -1Hindazol-4-yl) quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (530 mg) as a solid.
Preparation Example 16 [00217] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (3 , 0 g), [(2S) -1-methylpyrrolidin-2-yl] methanol (2.4 ml), acetonitrile (30 ml), and potassium carbonate (2.1 g) was stirred at 80 ° C for 18 hours under argon atmosphere. [(2S) -1-Methylpyrrolidin-2-yl] methanol (0.60 ml) was added to the reaction mixture, and the mixture was stirred at 80 ° C for 5 hours. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- (7-bromo-8-fluoro-
6-iodo-2 - {[(2S) -1-methylpyrrolidin-2-yl] methoxy} quinazolin-4-yl) -2,7 diazaospiro [3.5] nonane-2-carboxylate (2.8 g).
Preparation Example 17 [00218] A mixture of 2,2-difluoroethanol (600 mg) and DMF (30 ml) was cooled in an ice bath, sodium hydride (55%, dispersion in paraffin oil, 310 mg) was added to the mixture, and stirred at room temperature for 5 minutes under an argon atmosphere (mixture C). Then, the mixture of tert-butyl 7- (7-bromo-8-fluoro-6-iodo2- {[(2S) -1-methyl Pyrol id i n-2-yl] methoxy} chi-nazol i n- 4-yl) -2,7 diazaospiro [3.5] nonane-2-carboxylate (2.8 g), and THF (30 ml) was cooled in an ice bath, mixture C was added to the mixture, the mixture was stirred at the same temperature for 10 minutes, and then
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62/265 was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried with anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [7-bromo-8- (2, 2difluoroethoxy) -6-iodo-2 - {[(2S) -1-methylpyrrolidin-2-yl] methoxy} quinazolin-4yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate (2.3 g).
Preparation Example 18 [00219] A mixture of tert-butyl 7- [7-bromo-8- (2,2-difluoroethoxy) -6iodo-2 - {[(2S) -1-methylpyrrolidin-2-yl] methoxy} quinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (2.2 g), 1,4-dioxane (45 ml), water (4.5 ml), cyclopropylboronic acid (280 mg), tripotassium phosphate (2.3 g), and PdCI ₂ (dppf) -CH ₂ CI ₂ (240 mg) was stirred at 95 ° C for 8 hours under an argon atmosphere and then stirred at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl
7- [7-bromo-6-cyclopropyl-8- (2,2-difluoroethoxy) -2 - {[(2S) -1-methylpyrrolidin-2yl] methoxy} quinazolin-4-yl] -2,7-diazaospiro [ 3.5] nonane-2-carboxylate (980 mg).
Preparation Example 19 [00220] Under the argon atmosphere, tert-butyl 7- [7-bromo-6cyclopropyl-8- (2,2-difluoroethoxy) -2 - {[(2S) -1-methylpyrrolidin-2yl] methoxy } quinazolin-4-yl] -2,7-diazaospiro [3.5] nonane-2-carboxylate (520 mg), Pd ₂ (dba) 3, SPhos (120 mg), tripotassium phosphate (1.1 g), 1 , 4
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63/265 dioxane (15 ml) and water (1.2 ml) were mixed, and the mixture was stirred at 120 ° C for 2 hours under microwave irradiation. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl 7 [6-cyclopropyl-8- (2,2-difluoroethoxy) -7- (5-methyl -1H-indazol-4-yl) -2 - {[(2S) -1methylpyrrolidin-2-yl] methoxy} quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (470 mg).
Preparation Example 20 [00221] A mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (30 g) and 1,4-dioxane (300 ml) was cooled in an ice bath, then DIPEA (85 mL) and tert-butyl 2,7-diazaospiro [3.5] nonane-2carboxylate (21 g) were added to the mixture in a stream of nitrogen, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water and then washed with hexane / ethyl acetate (4: 1). The obtained solid was dried at 50 ° C under reduced pressure to obtain tert-butyl 7- (7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl) -
2,7-diazaspiro [3.5] nonane-2-carboxylate (47 g) as a solid.
Preparation Example 21 [00222] A mixture of tert-butyl 7- (7-bromo-2,6-dichloro-8fluoroquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (5.0 g), 1-methylpiperidin-4-ol (2.8 ml), DMF (50 ml) and cesium carbonate (11 g) and DABCO (160 mg) was stirred at room temperature for 3 days. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate 870190100577, from 10/8/2019, p. 67/278
64/265 droso. The resulting residue was purified by column chromatography on silica gel to produce tert-butyl 7- (7-bromo-6-chloro-8-fluoro-2 - [(1methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2carboxylate (4.9 g) as a solid.
Preparation Example 22 [00223] Sodium ethoxide (830 mg) was added to a mixture of tert-butyl 7- {7-bromo-6-chloro-8-fluoro-2 - [(1-methyl I pi perid i n -4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (4.9 g) and THF (100 ml), and the mixture was stirred at room temperature for 1 day. Sodium ethoxide (830 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane I ethyl acetate) to produce tert-butyl 7- {7-bromo-6-chloro-8-ethoxy-2 - [(1-methylpiperidin-4 -il) oxy] quinazolin4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (3.8 g) as a solid.
Preparation Example 23 [00224] A mixture of tert-butyl 7- {7-bromo-6-chloro-8-ethoxy-2 - [(1methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 -diazaespiro [3.5] nonyl-2carboxylate (3.8 g), boronic acid (5-methyl-1H-indazol-4-yl) (1.6 g), Pdz (dba) s (1.1 g), SPhos (1.0 g), 1,4-dioxane (60 ml), tripotassium phosphate (6.5 g) and water (15 ml) were stirred at 115 ° C for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on
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65/265 silica gel (chloroform I methanol). The obtained purified product was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). The purified product obtained was purified by column chromatography on silica gel to produce tert-butyl 7- {6chloro-8-ethoxy-7- (5-methyl-1H-indazol-4-yl) -2 - [(1-methylpiperidin -4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (1.0 g) as a solid.
Preparation Example 24 [00225] A mixture of tert-butyl 7- {6-chloro-8-ethoxy-7- (5-methyl-1Hindazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 diazospiro [3.5] nonane-2-carboxylate (1.0 g), 1,4-dioxane (12 ml), 4,4,5,5-tetramethyl-2-vinyl -1,3,2-dioxaborolane (1.3 mL), Pd2 (dba) s (140 mg), SPhos (180 mg), tripotassium phosphate (1.6 g), and water (3.0 mL) were stirred at 150 ° C for 1.5 hours under microwave irradiation. 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.25 mL), Pd2 (dba) s (140 mg) and SPhos (180 mg), tripotassium phosphate (1, 6 g) and water (3.0 ml) were stirred at 150 ° C for 30 minutes under microwave irradiation and stirred again at the same temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol). The obtained purified product was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {8-ethoxy-7- (5-methyl-1H-indazol-4-yl ) -2 - [(1methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (360 mg).
Preparation Example 24-2 [00226] A mixture of tert-butyl 7- {7-bromo-8-ethoxy-2 - [(1
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66/265 methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (5.7 g), acid (5-methyl-1Hindazol-4-yl ) boronic acid (2.4 g), Pd2 (dba) s (850 mg), SPhos (60 ml), tripotassium phosphate (10 g) and water (12 ml) were stirred at 120 ° C for 4 hours under an atmosphere of argon. Then the reaction mixture was cooled to room temperature, ethyl acetate and a saturated aqueous solution of sodium chloride were added to the reaction mixture and an insoluble material was filtered off. The filtrate was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product and then the mixture was stirred at room temperature for 6 hours. The precipitated solid was collected by filtration to obtain tert-butyl 7- {8-ethoxy-7- (5-methyl1 H-indazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] -6 -vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (2.2 g) as a solid.
Preparation Example 28 [00227] A trifluoroacetic acid (hereinafter abbreviated as TFA) (5.0 mL) was added to a mixture of tert-butyl 7- {8 (cyclobutyloxy) -6-cyclopropyl 1-2- [(1-methylpiperidin-4-i) oxy] -7- [5-methyl-1 (tetrahydro-2H-pyran-2-yl) -1 H-indazol-4-yl] quinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (540 mg) and dichloromethane (10 ml), and the mixture was stirred at room temperature for 4 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water) in order to obtain 8- (cyclobutyloxy) -6-cyclopropyl-4- (2,7diazaospiro [3.5] non-7-il ) -7- (5-methyl-1H-indazol-4-yl) -2 - [(1-methylpiperidin4-yl) oxy] quinazoline (310 mg) as a solid.
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Preparation Example 33 [00228] TFA (1.0 ml) was added to a mixture of tert-butyl 7 {8-ethoxy-2 - [(1-ethylpiperidin-4-yl) oxy] -7- (5-methyl -1 H-indazol-4-yl) -6vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (560 mg) and dichloromethane (1.0 ml), and the mixture was stirred in room temperature for 1 hour. After concentrating the reaction under reduced pressure, the residue obtained was purified by column chromatography on silica gel (hereinafter, abbreviated as ODS) silica gel, water / acetonitrile / TFA). A saturated aqueous solution of sodium hydrogen carbonate and water was added to the obtained purified product, and the mixture was extracted with chloroform / methanol (4: 1), and an organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to produce 4- (2,7diazaespiro [3.5] non-7-yl) -8-ethoxy-2 - [(1-ethylpiperidine- (5-methyl-1H-indazol4-yl) -6 -vinylquinazoline (370 mg).
Preparation Example 34 [00229] After cooling in an ice bath, a mixture of 3bromo-5-fluoro-2,4-dimethylaniline (1.1 g), hydrochloric acid 12M (6.0 ml) and water (4, 0 ml) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes. 12M hydrochloric acid (2.0 ml) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. Sodium tetrafluoroborate (720 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. The precipitated solid was collected by filtration, washed with cold water and then dried in air to produce a solid (solid A). A mixture of potassium acetate (670 mg), 1,4,7,10,13,16-hexaoxycyclooctadecane (47 mg), and chloroform (44 ml) was added to a solid, and the mixture was stirred at room temperature. room for 5 hours. After an insoluble material was separated by filtration, the filtrate was washed with an aqueous solution saPetição 870190100577, of 10/8/2019, p. 71/278
68/265 cloudy with sodium chloride and dried by anhydrous magnesium sulfate.
The resulting residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to produce 4-bromo-6-fluoro-5methyl-1H-indazole (240 mg).
Preparation Example 35 [00230] 3,4-dihydro-2H-pyran (0.24 mL) and 940 mg ptoluenesulfonic acid monohydrate) were added to a mixture of (4bromo-6-fluoro-5-methyl -1H-indazole (240 mg) and dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was cooled in an ice bath, a saturated aqueous solution of hydrogen carbonate was added. sodium to the reaction mixture, and the reaction mixture was extracted with chloroform.The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The resulting residue was purified by column chromatography on silica gel (hexane / acetate) ethyl) to produce 4-bromo-6-fluoro-5-methyl-1- (tetrahydro2H-pyran-2-yl) -1H-indazole as an oil.
Preparation Example 36 [00231] Potassium acetate (310 mg) and PdCb (dppf / CEECb (68 mg) were added to a mixture of 4-bromo-6-fluoro-5-methyl-1- (tetrahydro-2H-pyran -2-yl) -1H-indazole (330 mg), 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl2,2'-bi-1,3,2-dioxaborolane (320 mg), 4-dioxane (7.0 mL), and the mixture was stirred at 100 ° C for 3 hours under an argon atmosphere, the reaction mixture was cooled to room temperature, then ethyl acetate was added and an insoluble material was filtered off The resulting residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to yield 6-fluoro-5-methyl-1 (tetrahydro-2H-pyran-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 Hindazol (220 mg) as an oil.
Preparation Example 39
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69/265 [00232] A mixture of tert-butyl 7- {7-bromo-6-chloro-2 - [(1 ethylpiperidin-4-yl) oxy] -8-fluoroquinazolin-4-yl} -2,7 diazaospiro [3.5 ] nonane-2-carboxylate (2.5 g), 2,2,2-trifluoroethanol (0.59 ml), cesium carbonate (2.7 g) and DMF (25 ml) was stirred at room temperature under argon for 3 days. Water was added to the reaction mixture, the mixture was stirred at room temperature for 10 minutes and then the precipitated solid was collected by filtration. The obtained solid was dissolved in dichloromethane, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {7bromo-6-chloro-2 - [(1-ethylpiperidine-4-yl) oxide ] -8- (2,2,2trifluoroethoxy) quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (2.4 g).
Preparation Example 94 [00233] Potassium carbonate (5.5 g) and PdCb (dppf) * CH2Cl2 (1.1 g) were added to a mixture of 7- {7-bromo-8-ethoxy-6iodo tert-butyl -2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 diazospiro [3.5] nonane-2-carboxylate (9.5 g), 4,4,5,5-dioxaborolane (4 , 5 ml), 1,4-dioxane (100 ml) and water (10 ml), and the mixture was stirred at 80 ° C for 1 hour under an argon atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate, a saturated aqueous solution of sodium chloride and celite were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 10 minutes. Insoluble material was filtered off, then the filtrate was extracted with ethyl acetate and an organic layer was dried with anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to produce tert-butyl 7- {7-bromo-8
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70/265 ethoxy-2 - [(1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate as a solid.
Preparation Example 95 [00234] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (8 , 1 g), 1 (2-methoxyethyl) piperidin-4-ol (5.3 g), cesium carbonate (13 g), DABCO (220 mg), DMF (65 ml) and THF (65 ml) was stirred at room temperature for 3 days under an argon atmosphere. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane I ethyl acetate) to obtain tert-butyl 7- (7bromo-8-fluoro-6-iodo-2 - {[1- (2- methoxyethyl) piperidin-4-yl] oxy} quinazolin-4yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (7.9 g).
Preparation Example 96 [00235] A mixture of tert-butyl 7- (7-bromo-8-fluoro-6-iodo-2 - {[1 (2-methoxyethyl) piperidin-4-yl] oxy} quinazolin-4- il) -2,7 diazaospiro [3.5] nonane-2-carboxylate (3.8 g), 2,2,2-trifluoroethanol (0.75 ml), cesium carbonate (3.4 g), and DMF (40 ml ) was stirred at room temperature for 20 hours under an argon atmosphere. 2,2,2trifluoroethanol (0.40 ml) and cesium carbonate (1.7 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration, then chloroform / methanol (9: 1) was added, and the obtained solution was dried with anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [7-bromo-6-iodine-2 - {[1- (2Petition 870190100577, de 10/8/2019, page 74/278
71/265 methoxyethyl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate as a solid.
Preparation Example 99 [00236] Potassium carbonate (1.5 g) and PdCb (dppf) * CH2Cl2 (30 mg) were added to a mixture of tert-butyl 7- [7-bromo-6-iodine-2 { [1- (2-methoxyethyl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -
2,7-diazaspiro [3.5] nonane-2-carboxylate (3.0 g), potassium vinyltrifluoroborate (640 mg), 1,4-dioxane (30 ml) and water (3.0 ml), and the mixture was stirred at 50 ° C for 2 hours under a nitrogen atmosphere. PdCb (dppfJ-ChLCb (150 mg) was added to the reaction mixture and the mixture was stirred at 60 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then acetate was added. ethyl and water An insoluble material was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica. gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [7-bromo-2 - {[1- (2-methoxyethyl) piperidin4-yl] oxy} -8- (2,2,2 -trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (2.2 g).
Preparation Example 100 [00237] Boronic acid (5-methyl-1H-indazol-4-yl) (490 mg), Pd2 (dba) s (130 mg) and SPhos (120 mg) were added to a mixture of tercbutil 7 - [7- bromo-2 - {[1 - (2-methoxyethyl) piperidin n-4-yl] oxy} -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2 , 7-diazaspiro [3.5] nonane-2carboxylate (1.0 g), tripotassium phosphate (900 mg), 1,4-dioxane (10 ml), and water (2.0 ml), and the mixture was stirred at 130 ° C for 4 hours, under the argon atmosphere. The reaction mixture was cooled to room temperature, then ethyl acetate and water were added. An insoluble material was separated by filtration, and the filtrate was
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72/265 extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). The purified product obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). Acetonitrile was added to the obtained solid, and the mixture was stirred at room temperature. The precipitated solid was collected to obtain tert-butyl 7- [2 - {[1- (2methoxyethyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4-yl) -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (630 mg) as a solid.
Preparation Example 101 [00238] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (9 , 5 g), 1 (260 mg), DMF (76 ml) and THF (76 ml) was stirred at room temperature overnight under an argon atmosphere. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, diisopropyl ether was added to the obtained solid, and the mixture was stirred at room temperature. The solid was collected by filtration, and dried at 50 ° C under reduced pressure to obtain tert-butyl 7- (7-bromo-8-fluoro-6-iodo-2 - {[1- (3-methoxypropyl) piperidin-4 -il] oxy} -quinazolin-4-yl) -2,7 diazaospiro [3.5] nonane-2-carboxylate (9.1 g) as a solid.
Preparation Example 102 [00239] A mixture of tert-butyl 7- (7-bromo-8-fluoro-6-iodo-2 - {[1 (3-methoxypropyl) piperidin-4-yl] oxy} quinazolin-4- il) -2,7 diazospiro [3.5] nonane-2-carboxylate (5.0 g), 2,2,2-trifluoroethanol (1.4 ml), cesium carbonate (6.5 g), and DMF (50 mL) was stirred in time
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73/265 room temperature for 5 hours. The reaction mixture was stirred at 50 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane I ethyl acetate) to obtain tert-butyl 7- [7-bromo-6-iodo-2 - {[1- (3-methoxypropyl) piperidin- 4-yl] oxy} -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate.
Preparation Example 105 [00240] A mixture of tert-butyl 7- [7-bromo-6-iodo-2 - {[1- (3methoxypropyl) piperidin-4-yl] oxy} -8- (2,2,2 -trifluoroethoxy) quinazolin-4-yl] -
2,7-diazaspiro [3.5] nonane-2-carboxylate (2.7 g), cyclopropylboronic acid (560 mg), tripotassium phosphate (2.5 g), PdCh (dppfFChhCh (270 mg), 1,4-dioxane (20 ml), acetonitrile (20 ml) and water (8.6 ml) were stirred at 100 ° C for 4 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, an aqueous solution was added saturated sodium chloride to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel ( amino silica gel, hexane I ethyl acetate) to obtain tert-butyl 7- [7-bromo-6-cyclopropyl-2 - {[1- (3methoxypropyl) piperidin-4-yl] oxy} -8- (2,2 , 2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (1.9 g).
Preparation Example 106 [00241] Under the argon atmosphere, tert-butyl 7- [7-bromo-6cyclopropyl-2 - {[1- (3-methoxypropyl) piperidin-4-yl] oxy} -8- (2, 2,2trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate
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74/265 (1.9 g), (5-methyl-1H-indazol-4-yl) boronic acid (230 mg), SPhos (210 mg), tripotassium phosphate (2.2 g), 1,4- dioxane (15 ml), and water (2.8 ml) were mixed, and the mixture was stirred at 120 ° C for 70 minutes under microwave irradiation. After concentrating the reaction mixture under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). Acetonitrile was added to the obtained purified product and then the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain tert-butyl 7- [6cyclopropyl-2 - {[1- (3-methoxypropyl) piperidin-4-yl] oxy} -7- (5-methyl-1H-indazol4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane2-carboxylate (630 mg) as a solid.
Preparation Example 111 [00242] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (4 , 5 g), 1 (tetrahydro-2H-pyran-4-yl) piperidin-4-ol (4.1 g), cesium carbonate (7.2 g), DABCO (120 mg), DMF (45 ml) and THF (45 ml) were stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (hexane / ethyl acetate, then chloroform / methanol / 28% ammoniacal water). The purified product obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain 7- (7-bromo-8-fluoro-
6-iodo-2-tetrahydro-2H-pyran-4-yl) piperidin-4-yl] oxy} -quinazolin-4-yl) -2,7 diazaospiro [3.5] nonane-2-carboxylate as a solid.
Preparation Example 112 [00243] A mixture of tert-butyl 7- (7-bromo-8-fluoro-6-iodo-2 - {[1
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75/265 (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] oxy} quinazolin-4-yl) -2,7 diazaospiro [3.5] nonane-2-carboxylate (5.2 g), 2 , 2,2-trifluoroethanol (1.5 ml), cesium carbonate (6.7 g) and DMF (50 ml) was stirred at 50 ° C overnight. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). Diisopropyl ether was added to the obtained solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to obtain tert-butyl 7- [7-bromo-6-iodine-2 - {[1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] oxy} 8- ( 2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (4.1 g) as a solid.
Preparation Example 113 [00244] Potassium carbonate (740 mg) and PdCb (dppf) * CH2Cl2 (15 mg) were added to a mixture of tert-butyl 7- [7-bromo-6-iodine-2 {[1 - (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] oxy} -8- (2,2,2trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2 -carboxylate (1.5 ml), potassium vinyltrifluoroborate (290 mg), 1,4-dioxane (15 ml) and water (1.5 ml), and the mixture was stirred at 40 ° C for 18 hours under an atmosphere of argon. After the reaction mixture was cooled to room temperature, ethyl acetate, water and a saturated aqueous solution of sodium chloride were added to the reaction mixture. An insoluble material was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by chromatography on
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76/265 column on silica gel (amino silica gel, hexane I ethyl acetate). Diisopropyl ether was added to the obtained solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to obtain tert-butyl 7- [7-bromo-2 - {[1- (tetrahydro-2H-pyran-4yl) piperidin-4-yl] oxy} -8- (2,2 , 2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (940 mg) as a solid. Preparation Example 114 [00245] Pd2 (dba) s (120 mg) and SPhos (110 mg) were added to a mixture of tert-butyl 7- [7-bromo-2-tert-butyl - {[1- (tetra -hydro-2Hpiran-4-yl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -
2,7-diazaspiro [3.5] nonane-2-carboxylate (940 mg) methyl-1Hindazol-4-yl) boronic acid (330 mg), tripotassium phosphate (1.3 g), 1.4 dioxide (10 ml), water (2.0 mL) for 4 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate, water and a saturated aqueous solution of sodium chloride were added to the reaction mixture. An insoluble material was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). Acetonitrile was added to the obtained solid and the mixture was then stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to obtain tert-butyl 7- [7 (5-methyl-1H-indazol-4-yl) -2 - {[1- (tetrahydro-2H-pyran-4-yl) piperidin-4yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (610 mg) as a solid. Preparation Example 115 [00246] 2- (Trimethylsilyl) ethyl 4-hydroxypiperidine-1-carboxylate (1.0 g), cesium carbonate (2.7 g) and DABCO (31 mg) were added to a mixture of tert- butyl 7- (7-bromo-2-chloro 6-iodoquinazolin-4-yl) -2,7
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77/265 diazaespiro [3.5] nonane-2-carboxylate (1.7 g), DMF (5.0 mL) at room temperature for 16 hours under an argon atmosphere. 2.2,2 Trifluoroethanol (0.60 ml) and cesium carbonate (1.8 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration to obtain tert-butyl 7- {7-bromo-6-iodo-8 (2,2,2-trifluoroethoxy) -2 - [(1 - {[2- (trimethylsilyl) ethoxy] carbonyl } piperidin-4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (2.7 g) as a solid.
Preparation Example 118 [00247] Tetrabutylammonium fluoride (1M THF solution, 3.6 mL) was added dropwise to a mixture of 7- {7- [5-methyl-1 (tetrahydro-2H) tert-butyl -pyran-2-yl) -1 H-indazol-4-yl] -8- (2,2,2-trifluoroethoxy) -2 - [(1 {[2- (trimethylsilyl) ethoxy] carbonyl} piperidin-4- il) oxy] -6-vinylquinazolin-4-yl} -
2,7-diazaspiro [3.5] nonane-2-carboxylate (1.7 g) and THF (25 ml), and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed with water and a saturated aqueous solution of sodium chloride. An organic layer was dried using anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure to obtain tert-butyl 7- {7- [5-methyl-1- (tetrahydro-2H-pyran- 2-yl) 1H-indazol-4-yl] -2- (piperidin-4-yloxy) -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl} -2,7-diazospiro [3.5] nonane-2-carboxylate (1.3 g). Preparation Example 119 [00248] tert-butyl 7- {7- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1 Hindazol-4-yl] -2- (piperidin-4 -yloxy) -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (500 mg), 2,2-dimethyloxirane (68 pL) , triethylamine (0.18 ml) and ethanol (4.0 ml) were
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78/265 were mixed, and the mixture was stirred at 80 ° C for 30 minutes under microwave irradiation. The reaction mixture was stirred at 100 ° C for 30 minutes under microwave irradiation. 2.2 Dimethyloxyrane (28 μΙ_) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 1 hour under microwave irradiation. The reaction mixture was stirred at 120 ° C for 1 hour under microwave irradiation. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol). The purified product obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [2 - {[1- (2-hydroxy-2methylpropyl) piperidin-4-yl ] oxy} -7- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1Hindazol-4-yl] -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin- 4-yl] -2,7 diazospiro [3.5] nonane-2-carboxylate (450 mg).
Preparation Example 132 [00249] A mixture of 2,2,6,6-tetramethylpiperidine (4.3 ml) and THF (50 ml) was cooled to -70 ° C, followed by n-butyl lithium (solution in hexane to 1.6 M, 16 ml) was added dropwise to the mixture under an argon atmosphere, and the mixture was stirred at the same temperature for 10 minutes. A mixture of 1-bromo-4,5-difluoro-2-methylbenzene (5.0 g) and THF (25 ml) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 2 hours. After adding DMF (2.0 mL) to the reaction mixture, the temperature of the reaction mixture was raised to -20 ° C. 1 M hydrochloric acid was added dropwise to the reaction mixture, and the reaction mixture was extracted with diethyl ether. An organic layer was washed with 1M hydrochloric acid and a saturated aqueous sodium chloride solution, and
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79/265 then dried with anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure to obtain 2-bromo-5,6-difluoro-3methylbenzaldehyde (5.2 g) as a solid.
Preparation Example 133 [00250] O-methylhydroxylamine hydrochloride (2.2 g) was added to a mixture of 2-bromo-5,6-difluoro-3-methylbenzaldehyde (5.2 g), potassium carbonate ( 3.9 g), and 1,2-dimethoxyethane (25 ml), and the mixture was stirred at room temperature for 3 days. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (hexane / ethyl acetate). Hydrazine monohydrate (20 ml) was added to a mixture of obtained oil (4.2 g) and 1.2 dimethoxyethane (20 ml), and the mixture was stirred at 100 ° C for 20 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium chloride. An organic layer was dried using anhydrous magnesium sulfate, and then a solvent was evaporated under reduced pressure to obtain 4-bromo-7-fluoro-5-methyl-1H-indazole (3.6 g) as a solid.
Preparation Example 136 [00251] Potassium carbonate (3.0 g) and PdCb (dppf ^ ChLCb (580 mg) were added to a mixture of 5-bromo-4-chloro-1- (tetrahydro-2H-pyran-2 -yl) -1H-indazole (2.3 g), trivinylboroxine / pyridine (1: 1) (1.4 g), 1,4-dioxane (22 mL), and water (4.5 mL), and The mixture was stirred at 70 ° C for 15 hours under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, then ethyl acetate and water were added, and an insoluble material was filtered off. with ethyl acetate, the organic layer was washed with a saturated aqueous solution of
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80/265 sodium and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to obtain 4-chloro-1- (tetrahydro-2H-pyran-2-yl) 5- 1H-indazole (1.6 g ) as a solid.
Preparation Example 137 [00252] Potassium acetate (720 mg), palladium acetate (26 mg), and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (120 mg) were added to a mixture of 4-chloro-1- (tetrahydro-2H-pyran-2-yl) -5-vinyl-1Hindazole (630 mg), 4.4.4 ', 4', 5.5.5 ' , 5'-octamethyl-2,2'-bi-1,3,2dioxaborolane (1.0 g) and 1,4-dioxane (6.0 ml), and the mixture was stirred at 100 ° C for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then ethyl acetate was added and an insoluble material was filtered off. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate) to obtain 1- (tetrahydro-2H-pyran-2-yl) -4- (4.4,5, 5tetramethyl-1,3 , 2-dioxaborolan-2-yl) -5-vinyl-1H-indazole (390 mg) as an oil.
Preparation Example 138 [00253] 4,4,4 ', 4', 5,5,5 ', 5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane (720 mg), acetate potassium (700 mg) (dpptyChkCb (190 mg) was added to a mixture of 7-bromo-6-methyl-1H-indazole (500 mg) and 1,4-dioxane (8.0 mL) for 18 hours under an argon atmosphere The reaction mixture was cooled to room temperature, then ethyl acetate and water were added, and an insoluble material was separated by filtration. After extracting the filtrate with ethyl acetate, the organic layer was washed with an aqueous solution. saturated with sodium chloride and then dried with anhydrous sodium sulfate.After concentration of the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (hexane / ethyl acetate) to obtain 6-methyl-7 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 HPetition 870190100577, of 10/8/2019, page 84/278
81/265 indazole (350 mg) as a solid.
Preparation Example 139 [00254] 1 - ({[2- (T rimethylsilyl) ethoxy] carbonyl} oxy) pyrrolidine-2,5-dione (4.0 g) was added to a mixture of methyl piperidin-4ylacetate hydrochloride ( 3.0 g), triethylamine (5.4 ml) and DMF (15 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate / hexane (10: 1). The organic layer was washed with 1 M aqueous sodium hydroxide solution, 1 M hydrochloric acid and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 2 (trimethylsilyl) ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1-carboxylate (4.7 g) as an oil.
Preparation Example 140 [00255] 1M aqueous sodium hydroxide solution (31 ml) was added to 2- (trimethylsilyl) ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1carboxylate (4.7 g) and methanol (23 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (31 ml) was added to the reaction mixture and then extracted with chloroform. An organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain (1 - {[2 (trimethylsilyl) ethoxy] carbonyl} piperidin-4-yl) acetic acid (4.2 g) as a solid. Preparation Example 141 [00256] 1,3-Difluoropropan-2-yl p-toluenesulfonate (13 g) was added to a mixture of piperidine-4-ol (5.0 g), potassium iodide (1.6 g) , potassium carbonate (13 g) and DMF (40 ml), and the mixture was stirred at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature and an insoluble material was separated by filtration. The resulting residue was purified by column chromatography on silica
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82/265 gel (amino silica gel, hexane I ethyl acetate) to obtain 1- (1,3difluoropropan-2-yl) piperidin-4-ol (5.0 g) as an oil.
Preparation Example 142 [00257] A mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic (1.0 g), 1H-benzotriazol-1-ol (450 mg), 1- (3dimethylaminopropyl hydrochloride) ) -3-ethylcarbodiimide (640 mg) and DMF (5.0 ml) was stirred at room temperature for 30 minutes. 28% ammoniacal water (0.28 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 1.5 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, and washed with water, and the obtained solid was dried at 50 ° C under reduced pressure to obtain 2-amino-4-bromo-3-fluoro-5-iodobenzamide (1.0 g) as solid.
Preparation Example 143 [00258] 1,1'-carbonyldiimidazole (920 mg) was added to a mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzamide (1.0 g), potassium carbonate (1.0 g) and DMF (5.0 ml), and the mixture was stirred at room temperature for 30 minutes. 1,1'-carbonyldiimidazole (1.4 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water and 1M hydrochloric acid were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water and dried at 50 ° C under reduced pressure to obtain tert-butyl 7-bromo-8-fluoro-6-iodoquinazoline-2,4 (1H, 3H) dione as a solid.
Preparation Example 144 [00259] 2-Bromoethyl cyclopropylmethyl ether (170 mg) was added to a mixture of 7- {7- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) tert-butyl) 1 H-indazol-4-yl] -2- (piperidin-4-yloxy) -8- (2,2,2-trifluoroethoxy) -6Petition 870190100577, from 10/8/2019, p. 86/278
83/265 vinylquinazolin-4-yl} -2,7-diazaospiro [3.5] nonane-2-carboxylate (500 mg), DIPEA (0.33 ml) and DMF (5.0 ml), and the mixture was stirred at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [2 - ({1- [2- (cyclopropylmethoxy) ethyl] piperidin-4-yl } oxy) -
7- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl] -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (470 mg).
Preparation Example 155 [00260] Sodium triacetoxyborohydride (180 mg) was added to a mixture of tert-butyl 7- [7- (5-methyl-1 H-indazol-4-yl) -2- (piperidine -4yloxy) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (310 mg), tetrahydro-2H-pyran4-carbaldehyde (100 mg), acetic acid (0.12 ml) and dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 18 hours. A saturated solution of sodium hydrogen carbonate and water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water) to obtain tert-butyl 7- [7- (5-methyl-1 Hi ndazol-4-yl) -2 - {[ 1 - (tetrahydro-2H-pyran-4ylmethyl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazospiro [3,5 ] nonane-2-carboxylate (300 mg) as an oil.
Preparation Example 175 [00261] A mixture of tert-butyl 7- {7-bromo-8-fluoro-6-iodo-2 - [(1methylpiperidin-4-yl) sulfanyl] quinazolin-4-yl} -2,7 -diazaespiro [3.5] nonane-2carboxylate (180 mg), 2,2,2-trifluoroethanol (92 mL), cesium carbonate
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84/265 (420 mg) and DMF (5.0 ml) was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with chloroform and an organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). Potassium carbonate (60 mg) and PdCb (dppf ^ CFLCb (10 mg) were added to a mixture of the purified product obtained (100 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3, 2dioxaborolane (50 ml), 1,4-dioxane (5.0 ml) and water (0.50 ml), and the mixture was stirred at 60 ° C for 2 hours After the reaction mixture was cooled to room temperature , a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with chloroform An organic layer was dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {7-bromo-2 - [(1-methylpiperidin-4yl) sulfanyl] -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin- 4-yl} -2,7 diazospiro [3.5] nonane-2-carboxylate (73 mg).
Preparation Example 181 [00262] Cesium carbonate (1.0 g) and sodium chlorine (difluoro) acetate (490 mg) were added to a mixture of tert-butyl 7- {7-bromo-8hydroxy-6-iodine- 2 - [(1 - {[2- (trimethylsilyl) ethoxy] carbonyl} piperidin-4yl) oxy] quinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (1.1 g), DMF 1.0 ml), and the mixture was stirred at 100 ° C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (hexane / ethyl acetate) to
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85/265 obtain tert-butyl 7- {7-bromo-8- (difluoromethoxy) -6-iodine-2 - [(1 - {[2 (trimethylsilyl) ethoxy] carbonyl} piperidin-4-yl) oxy] quinazolin- 4-yl} -2,7 diazospiro [3.5] nonane-2-carboxylate (1.0 g).
Preparation Example 227 [00263] A mixture of tert-butyl 7- (7-bromo-2-chloro-8-fluoro-6iodoquinazolin-4-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylate (2 , 0 g), 1 methylpiperidine-4-amine (750 mg), DIPEA (1.7 ml) and 1-methylpyrrolidin-2one (20 ml) was stirred at 100 ° C overnight. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- {7-bromo-8-fluoro-6-iodo2 - [(1-methylpiperidin-4 -yl) amino] quinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (730 mg).
Preparation Example 235 [00264] A mixture of tert-butyl 7- [7- (5-methyl-1H-indazol-4-yl) -2 (piperidin-4-yloxy) -8- (2,2,2- trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (300 mg), triethylamine (0.18 ml), and dichloromethane (6.0 ml) was cooled in an ice bath , and then, dimethylcarbamoyl chloride (39 µl) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on silica gel, to obtain tert-butyl 7- [2 - {[1- (dimethylcarbamoyl) piperidin-4yl] oxy} -7- (5-methyl-1H-indazole-4 -yl) -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl] -2,7-diazaospiro [3.5] nonane-2-carboxylate (290 mg). Preparation Example 253 [00265] N-chlorosuccinimide (32 mg) was added to a mixture of tert-butyl 7- [2 - {[1- (2-methoxyethyl) piperidin-4-yl] oxy} -7- ( 5-methyl-1 HPetition 870190100577, of 10/8/2019, page 89/278
86/265 indazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin] -2,7 diazaospiro [3.5] nonane-2-carboxylate (150 mg), aqueous sodium hydroxide solution 1M (1.6 ml) and ethanol (3.0 ml), and the mixture was stirred at room temperature for 30 minutes. Nchlorosuccinimide (16 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of sodium sulfite was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate) to obtain tert-butyl 7- [7- (3-chloro-5-methyl-1 Hi ndazol-4-yl) -2 - {[1 - (2-methoxyethyl) piperidin-4yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] nonane-2-carboxylate (130 mg) as a solid. Preparation Example 283 [00266] Thionyl chloride (2.0 ml) was added to a mixture of (1 - {[2- (trimethylsilyl) ethoxy] carbonyl} piperidin-4-yl) acetic acid (1.9 g ) and toluene (20 ml) at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure. The residue obtained was azeotroped with toluene. 2 amino-4-bromo-3-fluoro-5-iodobenzamide (2.0 g) and pyridine (2.0 ml) were added to a mixture of the obtained residue and dichloromethane (20 ml) and then the mixture was stirred in room temperature overnight. After concentrating the reaction mixture under reduced pressure, 1,4-dioxane (30 ml) and 1 M aqueous sodium hydroxide solution (30 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. . 1 M hydrochloric acid (30 mL) was added to the reaction mixture, and then the precipitated solid was collected by
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87/265 filtration. The obtained solid was purified by column chromatography on silica gel to obtain 2- (trimethylsilyl) ethyl 4 - [(7-bromo-8-fluoro-6-iodo-4oxo-3,4-d ih id roq uz nazol i n -2-yl) methyl I] piperidine-1-carboxylate (3.5 g) as a solid.
Preparation Example 284 [00267] (1 H-Benzotriazol-1-yloxy) hexafluorophosphate [tri (pyrrolidin-1yl)] phosphonium (4.4 g) was added to a mixture of 2- (trimethylsilyl) ethyl 4 [(7 -bromo-8-fluoro-6-iodo-4-oxo-3,4-dihydroquinazolin-2yl) methyl] piperidine-1 - carboxylate (3.5 g), tert-butyl 2,7 diazaospiro [3,5] nonane-2-carboxylate (1.9 g), 1.8-diazabicyclo [5.4.0] -7undecene (1.7 ml) and acetonitrile (50 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. An organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (hexane / ethyl acetate) to obtain tert-butyl 7- {7-bromo-8-fluoro-6-iodo-2- [(1 - {[2 (trimethylsilyl) ethoxy] carbonyl} piperidin-4-yl) methyl] quinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (3.7 g).
[00268] The compounds listed in Tables 6 to 118 below were prepared in the same way as the methods of preparation in the Preparation Examples described above. The preparation method, structure and physicochemical data of the compounds in the respective Preparation Examples are shown in Tables 6 to 118.
Example 1 [00269] A mixture of tert-butyl 7- {8- (2,2-difluoroethoxy) -7- (5-methyl1H-i ndazol-4-yl) -2 - [(1-methyl I pi perid i n-4-yl) oxy] -6-vi ni Iq ui nazol i n-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (290 mg), and dichloromethane (6.0
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88/265 ml) was cooled in an ice bath, then TFA (3.0 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the reaction mixture was azeotroped with toluene and then azeotroped with THF. After a mixture of the obtained residue and THF (6.0 mL) had cooled solid in an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (3.0 mL) and acryloyl chloride (35 mL) was added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride were added to the reaction mixture, and were extracted with chloroform / isopropyl alcohol (hereinafter abbreviated as IPA) (4: 1). The organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product, and then the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain 1- (7- {8- (2,2-difluoroethoxy) -7- (5-methyl-1H-indazol-4yl) -2 - [(1-methylpiperidin-4- il) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] non-2-yl) prop-2-en-1-one (77 mg).
Example 2 [00270] A mixture of tert-butyl 7- {6-cyclopropyl-8-ethoxy-7- (5-methyl1 Hi ndazol-4-yl) -2 - [(1-methyl I pi perid i n-4 -il) oxy] chi-nazol i n-4 -yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (180 mg) and dichloromethane (3.0 mL) was cooled in an ice bath, then TFA (3 , 0 mL) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the reaction mixture was azeotroped with toluene. After a mixture of the obtained residue and THF (5.0 mL) was cooled in a
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89/265 ice, 1M sodium hydrogen carbonate solution (5.0 ml) and acryloyl chloride (24 pL) was added to the mixture, and the mixture was stirred at the same temperature for 3 hours. After concentrating the reaction mixture, the residue obtained was purified by column chromatography on silica gel (ODS silica gel, water / acetonitrile). Hexane and ethyl acetate were added to the purified product obtained and sonicated. The precipitated solid was collected by filtration to obtain 1- (7- {6-cyclopropyl-
8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1-methyl Peripid n-4yl) oxy] quinazolin-4-yl} -2,7-diazospiro [ 3.5] non-2-yl) prop-2-en-1-one (62 mg) as a solid.
Example 3 [00271] TFA (5.0 ml) was added to a mixture of tert-butyl 7- {6cyclopropyl-8- (2,2-difluoroethoxy) -2 - [(1-methylpiperidin-4-yl) oxy] -7- [5-methyl-1 (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl] quinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate ( 530 mg) and dichloromethane (10 ml) and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture under reduced pressure, the reaction mixture was azeotroped with toluene. After a mixture of the obtained residue and THF (10 mL) had cooled solid in an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (4.0 mL) and acryloyl chloride (55 mL) were added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was extracted with chloroform / IPA (4: 1). The organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (ODS silica gel, water / methanol). The purified product obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Hexane was added to the purified product obtained and sonicated. The precipitated solid was collected by filtration to obtain 1- (7- {6Petition 870190100577, from 10/8/2019, page 93/278
90/265 cyclopropi 1-8- (2,2-difluoroethoxy) -7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] quinazolin-4-yl } -2,7-diazaespiro [3.5] non-2-yl) prop2-en-1-one (120 mg) as a solid.
Example 4 [00272] TFA (2.5 ml) was added to a mixture of tert-butyl 7 [6-cyclopropyl-8- (2,2-difluoroethoxy) -7- (5-methyl-1H-indazol-4- il) -2 - {[(2S) -1methylpyrrolidin-2-yl] methoxy} quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (470 mg), dichloromethane (9.0 mL), and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the reaction mixture was azeotroped with THF. After a mixture of the obtained residue and THF (9.0 ml) had cooled solid in an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (4.0 ml) and a solution of THF (2.0 ml) of acryloyl chloride (63 µl) were added to the mixture, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with chloroform / IPA (4: 1). The organic layer was dried over anhydrous sodium sulfate, and then a solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ODS silica gel, water / acetonitrile) to obtain 1- {7- [6-cyclopropyl-
8- (2,2-difluoroethoxy) -7- (5-methyl-1 H-indazol-4-yl) -2 - {[(2S) -1-methylpyrrolidin2-yl] methoxy} quinazolin-4-yl] - 2,7-diazaespiro [3.5] non-2-yl} prop-2-en-1-one (88 mg) as a solid.
Example 5 [00273] TFA (1.0 ml) was added to a mixture of tert-butyl 7- {8ethoxy-7- (5-methyl-1 H-indazol-4-yl) -2 - [(1-methylpiperidin -4-yl) oxy] -6vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] nonane-2-carboxylate (360 mg) and dichloromethane (6.0 ml), and the mixture was stirred at room temperature for 1 hour. After the concentration of the reaction mixture under reduced pressure, the reaction mixture was azeotroped with chloroforPetition 870190100577, of 10/8/2019, p. 94/278
91/265 mio. After THF (3.0 mL), water (3.0 mL) and sodium hydrogen carbonate (740 mg) were added to the residue obtained, and cooled in an ice bath, THF solution (1.0 mL) of acryloyl (54 pL) was added to the mixture. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture and the mixture was stirred for 10 minutes. Water was added to the reaction mixture and extracted with chloroform. An organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol). Hexane was added to the purified product obtained and sonicated. The precipitated solid was collected by filtration to obtain 1- (7- {8-ethoxy-7- (5-methyl-1H-indazol4yl) -2 - [(1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin- 4-yl} -2,7 diazaespiro [3.5] non-2-yl) prop-2-en-1-one (85mg) as a solid. Example 5-2 [00274] A mixture of tert-butyl 7- {8-ethoxy-7- (5-methyl-1H-indazol-4yl) -2 - [(1-methylpiperidine-4-yl) oxide] -6 -vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] nonane-2-carboxylate (1.3 g) and 1M hydrochloric acid (13 ml) was stirred at room temperature for 18 hours. After the reaction mixture was cooled in an ice bath, dichloromethane (6.5 mL), 3-chloropropanoyl chloride (0.41 mL), sodium hydrogen carbonate (1.6 g) were added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes. IPA (13 ml) and 4 M aqueous sodium hydroxide solution (4.9 ml) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled in an ice bath, 1M hydrochloric acid (6.4 ml), 5% aqueous sodium hydrogen carbonate solution (26 ml), and chloroform (39 ml) were added to the reaction mixture, and the mixture was stirred
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92/265 at room temperature for 10 minutes. The reaction mixture was filtered through celite and the filtrate was extracted with chloroform. An organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product, and then the precipitated solid was collected by filtration. The obtained solid was dried at 50 ° C under reduced pressure to obtain 1- (7- {8-ethoxy-7- (5-methyl-1H-indazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaospiro [3.5] non-2il) prop-2-en-1-one (980mg) as a solid.
Example 6 [00275] After a mixture of DIPEA (0.22 ml) and THF (3.0 ml) was cooled in an ice bath, acryloyl chloride (0.10 ml) was added to the mixture. THF solution (6.0 mL) of 8- (cyclobutyloxy) -6cyclopropyl-4- (2,7-diazaspiro [3.5] non-7-yl) -7- (5-methyl-1H-indazol-4-yl ) -2 [(1-methylpiperidin-4-yl) oxy] quinazoline (310 mg) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes. Aqueous 1M sodium hydroxide solution (3.0 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour. Water and a saturated aqueous solution of sodium chloride were added to the reaction mixture, and the mixture was extracted with chloroform / IPA (4: 1). An organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (ODS silica gel, water / methanol). Hexane and ethyl acetate were added to the obtained purified product and ground. The precipitated solid was collected by filtration to obtain 1- (7- {8- (cyclobutyloxy) -6-cyclopropyl-7Petition 870190100577, from 10/8/2019, page 96/278
93/265 (5-methyl-1 H-indazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] quinazolin-4-yl} -2,7 diazospiro [3.5] non-2il) prop -2-en-1-one as a solid.
Example 7 [00276] A mixture of 4- (2,7-diazaspiro [3.5] non-7-yl) -8-ethoxy-2 [(1-ethylpiperidin-4-yl) oxy] -7- (5-methyl -1 H-indazol-4-yl) -6-vinylquinazoline (150 mg), sodium hydrogen carbonate (320 mg), THF (1.5 ml), and water (1.5 ml) was cooled in an ice bath, and a solution of THF (0.50 ml) of acryloyl chloride (21 ml) was added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. After the concentration of the reaction mixture, the residue obtained was purified by column chromatography on silica gel (ODS silica gel, water / acetonitrile). Acetonitrile was added to the obtained purified product, and a solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to obtain 1- (7- {8-ethoxy-2 - [(1-ethylpiperidin-4-yl) oxy] -7- (5-methyl-1 H-indazol-4-yl) -6-vinylquinazolin-4-yl} -2,7 diazaespiro [3.5] non-2-yl) prop-2-en-1-one as a solid.
Example 24 [00277] 1 - (7- {8-Ethoxy-7- (5-methyl-1 H-indazol-4-yl) -2 - [(1-methyl Piperidin n4-yl) oxy] - 6-vinylquinazolin-4-yl} -2,7-diazaespiro [3.5] non-2-yl) prop-2-en-1ona (1.5 g) was fractionated by supercritical fluid chromatography (chiral column, carbon dioxide / ethanol / triethylamine). Hexane and ethyl acetate were added to the fractionated product obtained and crushed. The precipitated solid was collected by filtration to obtain (+) - 1- (7- {8-ethoxy7- (5-methyl-1 H-indazol-4-yl) -2 - [(1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin4-yl} -2,7-diazaospiro [3.5] non-2-yl) prop-2-en-1-one as a solid.
[00278] A solid (3.0 g) obtained by carrying out the method described above was purified several times by column chromatography on silica gel (ODS silica gel, water / methanol). Acetonitrile was added to the obtained purified product, and then the mixture was stirred at room temperature. The precipitated solid was collected by filtration, and the
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94/265 of the obtained was dried at 40 ° C under reduced pressure to obtain (+) - 1- (7 {8-ethoxy-7- (5-methyl-1 Hi ndazol-4-yl) -2 - [(1 -methyl I pi perid i n-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2-yl) prop-2-en-1-one (2, 0 g) as a crystal.
Example 25 [00279] A mixture of tert-butyl 7- [6-cyclopropyl-2 - {[1- (2methoxyethyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4- il) -8- (2,2,2trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate (800 mg) and dichloromethane (4.0 ml) was cooled in an ice bath , TFA (1.2 ml) was added to the mixture, and the mixture was stirred at room temperature for 6 hours. Chloroform / IPA (4: 1) and 2M aqueous potassium carbonate solution (11 mL) were added to the reaction mixture. An aqueous layer was extracted with chloroform / IPA (4: 1), and an organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure (residue A). After a mixture of DIPEA (0.45 ml) and THF (16 ml) was cooled in an ice-methanol bath, acryloyl chloride (0.20 ml) was added to the mixture. To this mixture, a solution of THF (12 ml) of residue A was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. Aqueous 1M sodium hydroxide solution (5.0 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the purified product obtained and sonicated. The precipitated solid was collected by filtration to obtain
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- {7- [6-cyclopropyl I-2- {[1 - (2-methoxyethyl I) pi peridi n-4-yl] oxy} -7- (5-methyl I-1Hindazol-4-yl) -8 - (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazaospiro [3.5] non-2-yl} propan-2-in-1-one (410 mg) as a solid.
Example 26 [00280] A mixture of tert-butyl 7- [2 - {[1- (2-methoxyethyl) piperidin-4yl] oxy} -7- (5-methyl-1H-indazol-4-yl] oxy} - 7- (5-methyl-1H-indazol-4-yl) -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaospiro [3.5] nonane-2carboxylate (470 mg) , and 1M hydrochloric acid (4.1 ml) was stirred for 1 hour, after the reaction mixture was cooled in an ice bath, dichloromethane (2.3 ml), 3-chloropropanoyl chloride (0.13 ml), sodium hydrogen carbonate (520 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour IPA (4.7 mL) and 4 M aqueous sodium hydroxide solution (2.3 mL) were added. added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried by anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product, and then the mixture was stirred at room temperature for 5 minutes. The precipitated solid was collected by filtration, and dried at 30 ° C under reduced pressure to obtain 1- {7- [2 - {[1- (2methoxyethyl) piperidin-4-yl] oxy} -7- (5-methyl- 1 H-indazol-4-yl) -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-en-1-one (320 mg) like a solid.
Example 28 [00281] A mixture of tert-butyl 7- [6-cyclopropyl-2 - {[1- (3methoxypropyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4- il) -8- (2,2,2Petition 870190100577, of 10/8/2019, page 99/278
96/265 trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2carboxylate (630 mg) and 1M hydrochloric acid (5.5 mL) was stirred at 50 ° C for 1 hour under an argon atmosphere . After the reaction mixture was cooled in an ice bath, dichloromethane (3.2 ml), 3-chloropropanoyl chloride (0.17 ml), sodium hydrogen carbonate (670 mg) were added to the reaction mixture, and the mixture was stirred. at the same temperature for 30 minutes. IPA (9.3 ml) and 4M aqueous sodium hydroxide solution (3.0 ml) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was cooled in an ice bath, then 1M hydrochloric acid (10 mL), a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was extracted with ethyl acetate, and then an organic layer was washed with a saturated aqueous solution of sodium chloride. An organic layer was dried over anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (chloroform / methanol). Acetonitrile was added to the obtained purified product, and then the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain 1- {7- [6cyclopropyl-2 - {[1 - (3-methoxypropyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol4-yl ) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] non-2il} prop-2-in-1-one (230 mg) as a solid.
Example 30 [00282] A mixture of tert-butyl 7- [7- (5-methyl-1 H-indazol-4-yl) -2 - {[1 (tetrahydro-2H-pyran-4-yl) piperidin -4-yl] oxy} -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane-2-carboxylate (610 mg), and 1M hydrochloric acid ( 5.2 ml) was stirred at 50 ° C for 30 minutes.
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After the reaction mixture was cooled in an ice bath, dichloromethane (3.0 ml), 3-chloropropanoyl chloride (0.17 ml), sodium hydrogen carbonate (650 mg) were added to the reaction mixture, and the mixture it was stirred at the same temperature for 1 hour. IPA (6.0 mL) and 4M aqueous sodium hydroxide solution (3.0 mL) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled in an ice bath, then 1M hydrochloric acid (7.0 mL), a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was extracted with ethyl acetate, and an organic layer was dried with anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product, and the precipitated solid was collected by filtration to obtain 1- {7- [7- (5-methyl-1H-indazol-4-yl) -2 - {[1- (tetrahydro -2Hpiran-4-yl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -
2,7-diazaespiro [3.5] non-2-yl} prop-2-en-1-one (420 mg) as a solid. Example 31 [00283] A mixture of 1- (4 - {[4- (2,7-diazaspiro [3.5] non7-yl) -7- (5methyl-1H- indazol-4-yl) -8- (2, 2,2-trifluoroethoxy) -6-vinylquinazolin-2yl] oxy} piperidin-1-yl) -2-methylpropan-2-ol (290 mg), 1M hydrochloric acid (3.0 mL), and dichloromethane (1.5 ml) was cooled in an ice bath, and then 3-chloropropanoyl chloride (90 pL) was added to it. Sodium hydrogen carbonate (430 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 15 minutes. IPA (3.0 mL) and 4 M aqueous sodium hydroxide solution (1.6 mL) were added to the reaction mixture at the same temperature, and
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The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. An organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water). Hexane and ethyl acetate were added to the obtained purified product and ground. The precipitated solid was collected by filtration to obtain 1- {7- [2 - {[1- (2-hydroxy-2methylpropyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4 -il) -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaospiro [3.5] non-2-yl} prop-2en-1-one (110 mg) as a solid.
Example 36 [00284] 1 - {7- [2 - {[1 - (2-methoxyethyl) pi peridi n-4-yl] oxy} -7- (5-methyl I-1Hindazol-4-yl) - 8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] non-2-yl} propan-2-en-1-one (2.0 g) was fractionated by supercritical fluid chromatography (chiral column, carbon dioxide / methanol / triethylamine, carbon dioxide / ethanol / triethylamine). The fractionated material obtained was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water) to obtain (+) 1 - {7- [2 - {[1 - (2-methoxyethyl) pi perid i na-i l] oxy} -7- (5-methyl I-1 H-indazol-4-yl) -8 (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7- diazaespiro [3,5] non-2il} prop-2-en-1-one (810 mg).
Example 38 [00285] 1 - {7- [6-C iclopropyl 1-2 - {[1 - (3-methoxy propyl I) pi peridi n-4-yl] oxide} -7 (5-methyl-1 H -indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7diazaespiro [3.5] non-2-yl} propan-2-in-1-one 2,2 g) was fractionated by supercritical fluid chromatography (chiral column, carbon dioxide / ethanol / triethylamine). The fractionated material obtained was purified by column chromatography on silica gel to obtain (+) - 1- {7- [6-cyclopropylPetition 870190100577, from 10/8/2019, p. 102/278
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2 - {[1 - (3-methoxypropyl) piperidin-4-oxy] -7- (5-methyl-1 H-indazol-4-yl) -8 (2,2,2-trifluoroethoxy) quinazolin-4-yl ] -2,7-diazaespiro [3.5] non-2-yl} prop-2en-1-one (1.1 g).
Example 39 [00286] 1 - {7- [7- (5-methyl I-1 H-indazol-4-yl) -2 - {[1 - (tetrahydro-2H-pyran4-yl) piperidin-4- il] oxy} -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] non-2-yl} propan-2-in-1-one (2, 0 g) was fractionated by high performance liquid chromatography (chiral column, hexane / ethanol / triethylamine). The fractionated material obtained was purified by column chromatography on silica gel to obtain (+) - 1 - {7- [7- (5-methyl1H-indazol-4-yl) -2 - {[1- (tetrahydro- 2H-pyran-4-yl) piperidin-4-yl] oxy} -8 (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2il} prop -2-en-1-one (930 mg).
Example 41 [00287] A mixture of 7- [2 - ({1 - [2- (cyclopropylmethoxy) ethyl] piperidin4-yl} oxy) -7- [5-methyl-1 - (tetrahydro-2H-pyran -2-yl) -1 H-indazol-4-yl] -8 (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] nonane2-carboxylate (470 mg ), 1M hydrochloric acid (4.0 ml) and THF (2.0 ml) was stirred at room temperature for 6 days. After the reaction mixture was cooled in an ice bath, dichloromethane (3.0 mL), 3-chloropropanoyl chloride (0.12 mL), sodium hydrogen carbonate (450 mg) were added to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes. IPA (5.0 ml) and 4M aqueous sodium hydroxide solution (2.0 ml) were added to the reaction mixture at the same temperature and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by chromatography on
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100/265 column on silica gel (chloroform / methanol / 28% ammoniacal water). Acetonitrile was added to the obtained purified product, and then the precipitated solid was collected by filtration. The obtained solid was dried at 50 ° C under reduced pressure to obtain 1- {7- [2 - ({1- [2 (cyclopropylmethoxy) ethyl] piperidin-4-yl} oxy) -7- (5-methyl-1 H-indazol-4-yl) -8 (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaospiro [3.5] non-2il} prop-2-en-1-one (82 mg) as a solid.
Example 51 [00288] Tripotassium phosphate (120 mg), Pd2 (dba) s (30 mg) and SPhos (30 mg) were added to a mixture of tert-butyl 7- {7-bromo-2 [(1-methylpiperidin- 4-yl) sulfanyl] -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4il} -2,7-diazaspiro [3.5] nonane-2-carboxylate (73 mg), acid (5-methyl- 1Hindazol-4-yl) boronic acid (28 mg), 1,4-dioxane (5.0 ml), water (1.0 ml) and the mixture was stirred at 120 ° C for 4 hours. The reaction mixture was cooled to room temperature, and an insoluble material was separated by filtration. After concentrating the filtrate under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, hexane / ethyl acetate). A mixture of the obtained purified product (40 mg) and 1M hydrochloric acid (2.0 ml) was stirred at 60 ° C or 1 hour. After the reaction mixture was cooled in an ice bath, dichloromethane (0.80 mL), 3-chloropropanoyl chloride (12 pL), sodium hydrogen carbonate (180 mg) were added to the reaction mixture, and the mixture was stirred. at the same temperature for 30 minutes. IPA (2.4 ml) and 4M aqueous sodium hydroxide solution (0.80 ml) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled in an ice bath, then 1M hydrochloric acid (1.7 mL) and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. . The organic layer has been
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101/265 each with anhydrous magnesium sulfate, and then a solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform / methanol / 28% ammoniacal water) to obtain 1- {7- [7- (5-methyl-1H-indazol-4-yl) -2- [ (1methylpiperidin-4-yl) sulfanyl] -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] 2-7-diazaospiro [3.5] non-2-yl} prop-2-en- 1-one (10 mg).
Example 82 [00289] A mixture of 6-cyclopropyl-4- (2,7-diazaspiro [3.5] non-7il) -8- (2,2-difluoroethoxy) -2 - {[1 - (2-methoxyethyl) piperidin -4-yl] oxy} -7- (5-methyl1H-indazol-4-yl) quinazoline (100 mg), (2E) -4,4,4 trifluorobut-2enoic acid (33 mg), O- (hexafluorophosphate) 7-azabenzotriazol-1-yl) Ν, Ν, Ν ', Ν'-tetramethyluronium (89 mg), DIPEA (80 pL), and DMF (2.0 ml) was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. An organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the residue obtained was purified by column chromatography on silica gel (amino silica gel, chloroform / methanol) to obtain (2E) -1- {7- [6-cyclopropyl-8- (2 , 2difluoroethoxy) -2 - {[1- (2-methoxyethyl) piperidin-4-yl] oxy} -7- (5-methyl-1H-indazol4-yl) quinazolin-4-yl] -2,7-diazaospiro [ 3.5] non-2-yl} -4,4,4-trifluorobut-2-en1-one (25 mg) as a solid.
[00290] The compounds shown in Tables 119 to 160 below were prepared in the same way as the methods of preparation of the Examples described above. In addition, the structures of the compounds in the respective Examples are shown in Tables 119 to 160 described below, and the methods of preparation and physico-chemical data of the compounds in the respective Examples are shown in Tables 161 to 167.
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102/265 [00291] In the tables described below, the following abbreviations can be used.
[00292] PEx: the number of Preparation Examples, Ex: the number of Examples, PSyn: the number of Preparation Examples prepared using the similar mode, Syn: the number of Examples prepared using the similar mode (for example, E1 represents o Example 1), Str: chemical structural formula (Me: methyl, Et: ethyl, Boc: tert-butoxycarbonyl, THP: tetrahydro-2H-pyran-2-yl, Cbz: benzyloxycarbonyl, and Teoc: 2- (trimethylsilyl) ethoxycarbonyl Note that a compound denoted by in a chemical structural formula indicates that the compound is an isomer having a stereochemistry of the notation structure. In addition, a compound denoted by # represents a single optical isomer based on axial chirality), Dat: data physicochemical, ESI +: m / z value in mass spectrometry (ESI ionization method, unless otherwise [M + H] ⁺ ), ESI-: m / z value in mass spectrometry (ESI ionization method, a unless otherwise [M + H]), Cl ⁺ : m / z value in spect mass rometry (Cl ionization method, unless otherwise [M + H] ⁺ , NMR: a δ (ppm) value of a signal in ¹ H-NMR in DMSO-d6, s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), [q] d ²⁰ : specific rotation at 20 ° C, c: concentration in the measurement of specific rotation (g / 100 mL).
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Table 6
PEx PSyn Str Dice 1 1 H0 ₂ C — Br h ₂ nf ESI-; 359.8 2 2 ‘Χά,F CI +; 422.9 3 3 BocI'rò. Br ^ y ^ N ^ CI F ESI +; 611.2,613.2 4 4 Çocll ΐ I t Br ^ y ^ lxXcG ^^F ESI +; 692.3
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Table 7
PEx PSyn Str Dice 5 5 Boc 1 Cr k 1 JVIe I t Br ^ Y ^ N ^ O ^^ o chf ₂ ESI +; 754.3 6 6 Boc 1 ch ₂ VA ΓΥ ^Μ θ Br ^ y ^ N ^ O ^^ ° Ί chf ₂ ESI +; 654.4
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Table 8
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Table 9
PEx PSyn Str Dice 9 9 Boc I A ry ^Me X ESI +; 632.5 10 10 BocIΛHN X k II A 1 ^ A 7le ° Et ESI +; 682.7 11 11 Boc1k 1, / CbzγΥγ ΓτF ESI +; 810.3
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Table 10
PEx PSyn Str Dice 12 12 Boc I k 1 ^^ .. ^ Cbz Γ τ o chf ₂ ESI +; 874.4 13 13 Boc 1 γ rf ^bz o CHF ₂ ESI +; 788.5
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Table 11
PEx PSyn Str Dice 14 14 Boc IN _Λ 1 Cbz 7i-ip ^ n V JL JI -I 1 L o chf ₂ ESI +; 922.8 15 15 Boc 1 λ ΐγΐ ^τΗρ ^ γΜγννΜ L JL ci ^^ T / le 's chf ₂ ESI +; 802.7
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Table 12
PEx PSyn Str Dice 16 16 Boc INQ *f Ly ESI +; 690.3 17 17 Boc IN Cp * ^Br ^ chf ₂ ESI +; 754.4
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Table 13
PEx PSyn Str Dice 18 18 Boc I N * Μθ 'chf ₂ ESI +; 668.5 19 19 Boc I N II * Λ Μθ γγ ^ ΝΛτΑΔ L JL A Lv ^^ Me chf ₂ ESI +; 718.6
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Table 14
PEx PSyn Str Dice 20 20 Çoc Nχτχ Bry'T'CI F ESI +; 521.2 21 21 BocICl JLγΎύ I t Br ^ yXxXcGXXF ESI +; 598.2,600.2 22 22 BocIll t I t% t ESI +; 624.1,626.1
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Table 15
PEx PSyn Str Dice 23 23 Boc1Crhn 1 JL 1 JL 1 J^^ TVIe ^ Et ESI +; 676.3 24 2424-2 Boc 1 ch ₂ Cr / ^ν = λ γ ^ ϊΓ ^ HN _X xk 1/1 1 J γΥγ ^ Ν ^{/ Χ} 0 ^Ζχ / L JL cl ^^ iVle Et ESI +; 668.3 25 5 Boc 1 Cp k JL ^^ _K JVIe Γτ ESI +; 744.3
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Table 16
PEx PSyn Str Dice 26 9 Boc 1 pf ^e ESI +; 658.5 27 7 Boc 1 λ N = n rA 'thp-n ^ L ^ _n A ₀ A ^ J ESI +; 792.7
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Table 17
PEx PSyn Str Dice 28 28 H A Tf HN _X λ k 1 zl 1 J ESI +; 608.6 29 4 Boc 1 ÇP ^cl Ykíi Cf F ESI +; 612.4,614.4 30 8 Boc1Çr% t ESI +; 638.4,640.4
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Table 18
PEx PSyn Str Dice 31 23 Boc I hn X k XA 1 ^ A _M e ° ^x Et ESI +; 690.7 32 24 Boc 1 ch ₂ Çr hn X k XAX γγγ ^ Ν ^ ο ^ ^ A _Me ° - _Et ESI +; 682.6 33 33 H çh ₂ N = n hn _k X k XAXJ ^ A _Me ° - _Et ESI +; 582.6
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Table 19
PEx PSyn Str Dice 34 34 Brà Me όγτ ESI +; 231.0 35 35 ^THP ^ ^N vV ^Br ^ 'ψΊνΐβ F ESI +; 313.1 36 36 Me Me γ ^ τ <V Me ^L '''y ^x Me F ESI +; 361.3 37 7 Boc 1 κ, ^ .xEt μ—. yY ^ i ί ψ “rup ^ -NV JU JL J Y / T ^^ Me ^O ^ Et F ESI +; 792.7
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Table 20
PEx PSyn Str Dice 38 24 Boc 1 N G ^H 2 Y -ri_ip_-N JL <JL JL J YYY ^ I ^ O ^^ y ^ Me ° ^ Et F ESI +; 784.7 39 39 Boc Çr ^0Ι ΥΎ ^ ϊ cf ₃ ESI +; 692.5,694.4
Petition 870190100577, of 10/08/2019, p. 121/278
118/265
Table 21
PEx PSyn Str Dice 40 7 Boc I HNX k 1 zl 1 J Me Μ cf ₃ ESI +; 744.6,746.5 41 24 Boc 1 CH ₂ ζρ HN 1 k 1 zl 1 J Me M cf ₃ ESI +; 736.6
Petition 870190100577, of 10/08/2019, p. 122/278
119/265
Table 22
Petition 870190100577, of 10/08/2019, p. 123/278
120/265
Table 23
PEx PSyn Str Dice 44 24 Boc 1 N ch ₂ hn X JL 1 JL 1 J LI ° chf ₂ ESI +; 718.7 45 5 Boc 1 Υ · Τ ^c 'Tl Ϊ Pf ^Et L - - F F ESI +; 700.2,702.2
Petition 870190100577, of 10/08/2019, p. 124/278
121/265
Table 24
PEx PSyn Str Dice 46 7 Boc 1 Çr ^cl yv ^ N ΚΎ ^Εί HN _v 1 k 1 zl 1 J ^ Μθ ° νΛ νγ-F F ESI +;752.6,754.5 47 24 Boc 1 CH ₂ TT N = n HN.kk 1/1 1 γγγ ^ Ν '^ Ο''^ / ^ Me ° VA νγ-F F ESI +;744.6
Petition 870190100577, of 10/08/2019, p. 125/278
122/265
Table 25
PEx PSyn Str Dice 48 4 Boc1MeF ESI +;628.2 49 8 Boc 1 Cr Me Pl. 1 . 1 r ^ íl Me ° ^x Et ESI +;652.2,654.2 50 7 Boc1MePl. 1 - 11X1 = 3 Τιίν A'N MehnA L 1 zl 1 J^^ Me ° ^ Et ESI +;704.4
Petition 870190100577, of 10/08/2019, p. 126/278
123/265
Table 26
PEx PSyn Str Dice 51 24 Boc I çh ₂ N = a AAl ^ iVIe hn XL II JIJ L jl cl ^^ T / le Et ESI +;696.3 52 4 Boc 1NÇrF ESI +;644.1 53 8 Boc 1 CL js ^ M / m / / 0sm ll γ | γ Me Br ^ y ^ N ^ O ^ AA ° ^x Et ESI +; 668.2, 670.2
Petition 870190100577, of 10/08/2019, p. 127/278
124/265
Table 27
PEx PSyn Str Dice 54 7 Boc IHN k k J1 A 1 JL 1 hey^ -X / le Et ESI +;720.5 55 24 Boc 1 ch ₂ Çr HN kk 1 A 1 JL k (Ύ Et ESI +;712.6 56 16 Boc 1 N * Ίγ η ϊ Βγ ^ Υ ^ Ν ^ Ο ^ < ^Ν f Ly ESI +;598.3,600.3
Petition 870190100577, of 10/08/2019, p. 128/278
125/265
Table 28
PEx PSyn Str Dice 57 5 Boc 1 N * Y Ύ ϊ Μθ θΊ chf ₂ ESI +; 660.4, 662.4 58 7 Boc 1 N * ri 1 νγ * «Me ^ Μβ ° _Ί ^U chf ₂ ESI +;796.6
Petition 870190100577, of 10/08/2019, p. 129/278
126/265
Table 29
PEx PSyn Str Dice 59 24 Boc 1 N ch ₂ * Me ^> ^ S / le η chf ₂ ESI +;788.8 60 5 Boc 1 N Cr * ^Cl x ^ Ai li ty® ESI +; 650.5, 652.5
Petition 870190100577, of 10/08/2019, p. 130/278
127/265
Table 30
PEx PSyn Str Dice 61 7 Boc IN γ * M CL JL, N ^ FIi Me ^H nr ^νΛ ° υ $ ESI +;702.4 62 24 Boc IN CH ₂ τψ *, ^N = Me hn A JL 1 A n JL cr Ly ESI +;694.6 63 8 Boc I N LJ * ^ i r II I Br ^ Y ^ N ^ ^x O ^ Y ' ^N ° ^ Et ESI +; 624.4, 626.4
Petition 870190100577, of 10/08/2019, p. 131/278
128/265
Table 31
PEx PSyn Str Dice 64 23 Boc 1 N Sr * N = n ^C SXVl ^Μ θ ^ T / leSt ESI +;676.6,678.6 65 24 Boc 1 N cjH ₂ * N = x SXy ^ N Me ^HN vÁÀÂX / KN L 1 cl '- / ^^ T / le Et ESI +;668.5 66 6 Ejtoc ch ₂ Çk Υ> Λ P ^ ^Me Br ^ X ^ lxXo ^ S ^ ° Λ3 ESI +;644.4
Petition 870190100577, of 10/08/2019, p. 132/278
129/265
Table 32
PEx PSyn Str Dice 67 7 Boc 1 N CH ₂ Ck hn V JL Jk JL J ^ Ανΐθ ^Ο -> θ ESI +;694.6 68 4 Boc 1 Cp 'V ^ A | ^^ ^Et Br ^ Y ^ N ^ O ^^ F ESI +;706.3 69 8 Boc 1 AT ^Et % t ESI +;732.3
Petition 870190100577, of 10/08/2019, p. 133/278
130/265
Table 33
Petition 870190100577, of 10/08/2019, p. 134/278
131/265
Table 34
PEx PSyn Str Dice 73 9 Boc 1 ύγϊ rr ^Et ESI +;670.5 74 7 Boc Λ THP'N_kkJI. _N A ₀ AJ ESI +;806.8
Petition 870190100577, of 10/08/2019, p. 135/278
132/265
Table 35
PEx PSyn Str Dice 75 6 Boc 1 CH ₂ Ar ^Et ESI +;658.4 76 7 Boc 1 ch ₂ Yv ¹ ; ¹ THP-N ^ k ^ L _N A _o AJ ESI +;792.7 77 35 THETHP-NyA ^ Br ESI +;317.1
Petition 870190100577, of 10/08/2019, p. 136/278
133/265
Table 36
PEx PSyn Str Dice 78 36 ^M ^ Me ÇrAMe ΤΗ P- ^ ^{N Me} ESI +;363.3 79 6 Boc 1 ch ₂ Br ^ y ^ ixr ^ o ^ AA ° 'Et ESI +;632.5 80 7 Boc 1 çh ₂ p ~ ^ rp ^Et τηραΛΑΡΑΑ ^ ¹ ^ x ^ CI ° -Et ESI +;786.6
Petition 870190100577, of 10/08/2019, p. 137/278
134/265
Table 37
Petition 870190100577, of 10/08/2019, p. 138/278
135/265
Table 38
PEx PSyn Str Dice 83 7 Boc 1 Λ C ^ chf ₂ ESI +;816.6 84 28 H N Λ HN 1 k 11 A 1 I ^ A Zle °> CHF ₂ ESI +;632.5 85 8 Boc 1 N 0 * ^Ιχ Α | lyie Βϊ ^ζ γ ^ Αθ ^/ Α ° 'Et ESI +;718.3
Petition 870190100577, of 10/08/2019, p. 139/278
136/265
Table 39
Petition 870190100577, of 10/08/2019, p. 140/278
137/265
Table 40
Petition 870190100577, of 10/08/2019, p. 141/278
138/265
Table 41
PEx PSyn Str Dice 92 7 Boc 1 N * ri 1 Me thpAaAÂ. ν LX o _x LJ Me ESI +;746.4 93 24 Boc 1 N CH ₂ TT * Me Thp-N Αϊν A. / X. N Ο ^ _Λ Me Me ESI +;738.4
Petition 870190100577, of 10/08/2019, p. 142/278
139/265
Table 42
PEx PSyn Str Dice 94 94 Boc o ch ₂ ° 'Et ESI +;618.3 95 95 SoeGQF ESI +;734.3 96 96 Bgg N δ ^k 'Y ::> - y * C _N ESI +;814.2
Petition 870190100577, of 10/08/2019, p. 143/278
140/265
Table 43
PEx PSyn Str Dice 97 9 N δ A 'Y _b YYYY èp ₅ ESI +;730.4 98 7 ΛΛZA 1st<br MéHebrew 1 L jl J 1 Jk X 0. ESI +;780.6
Petition 870190100577, of 10/08/2019, p. 144/278
141/265
Table 44
PEx PSyn Str Dice 8qc4 Ύ. rj ESI +; 99 99 ÇH>THE 716.4 100 100 BsçTHEM Sr ESI +;766.5 Hrí l · L 1 J * 1 J L JL _S 2nd. - Me CF _S
Petition 870190100577, of 10/08/2019, p. 145/278
142/265
Table 45
PEx PSyn Str Dice 101 101 BocOi 1 λ λ λ Me'·, - ·· - ·> Η Z' N · '' - ·· 'O ESI +;748.3 102 102 Bog.i.N8'Mά. ESI +;830.2 103 6 BoC I Λ, jx cX CH _S , _{ J Ü. ... I ·., J XJ AIJ ^Br J ^- hr O ' ESI +;730.4
Petition 870190100577, of 10/08/2019, p. 146/278
143/265
Table 46
PEx PSyn Str Dice 104 23 X CF _S ESI +;780.6 105 105 to A BRAjAAo-A ^ X èp ₃ ESI +;744.3
Petition 870190100577, of 10/08/2019, p. 147/278
144/265
Table 47
PEx PSyn Str Dice 106 106 IL Jl àCR ESI +;794.5 107 4 Bõs A δ γ-THE ESI +;750.3 108 39 Bc-CίΜu%THE ESI +;830.3
Petition 870190100577, of 10/08/2019, p. 148/278
145/265
Table 48
PEx PSyn Str Dice 109 6 Boc ή δ Ί cf ₃ ESI +;728.4,730.3 110 23 Boc A Çh ₂ nr L IL A Me y A ESI +;780.6 111 111 B © cHW Α ^ θglAA ^ AgAy ESI +;760.3,762.4
Petition 870190100577, of 10/08/2019, p. 149/278
146/265
Table 49
PEx PSyn Str Dice Bce 112 112 0 § ESI +;/ vkz 840.3 ^z A, 7 Ί cf ₃ Boc <5 çH _g Υγ ESI +; 113 113 γγγγ> Ν Br- ^ γΑ ⁵ ^ cf ₃ 740.6
Petition 870190100577, of 10/08/2019, p. 150/278
147/265
Table 50
PEx PSyn Str Dice 114 114 Λδ ~CH · / SsK f 0 ESI +;792.6 X cf ₃ 115 115 X, Λ ò w vSArx ^ ÒF _â ESI +; 900.4, 902.4
Petition 870190100577, of 10/08/2019, p. 151/278
148/265
Table 51
PEx PSyn Str Dice 116 6 Sõíí Λ ii 1 f Ν 'I .1 ^{: Ô} W-. CF ₃ ESI +; 800.5, 802.5 117 23 Béx δ><! - ·· Lm òf ₃ ESI +;936.6
Petition 870190100577, of 10/08/2019, p. 152/278
149/265
Table 52
PEx PSyn Str Dice 118 118 fee ή δ ch ₂ SA í '... i UWs àp ₃ ESI +;792.5 119 119 .... 1. J ifei a ^ iA cf ₃ ESI +;864.6
Petition 870190100577, of 10/08/2019, p. 153/278
150/265
Table 53
PEx PSyn Str Dice 120 28 H N LJ Me ÇHg pQH ^H „À ... 7 V 'N Ό ^v L [ò CF ₃ ESI +;680.5 121 39 Spleen 0 LI j I j 0HF _s ESI +;798.3
Petition 870190100577, of 10/08/2019, p. 154/278
151/265
Table 54
PEx PSyn Str Dice 122 9 BocNQA 7AM ''Br ESI +;712.5 123 23 S »X HN 1 j LX JL J '/ GV o ^{x /} ESI +;762.6 124 4 Çoc à 8 X r- ^ Β _Γ -ΧΧ | ^ Χθ> χΧ ESI +;732.2
Petition 870190100577, of 10/08/2019, p. 155/278
152/265
Table 55
PEx PSyn Str Dice 125 39 BoW pp0¾ ESI +;812.3,814.3 126 6 Soc o T JX ^h í ^{c! #} YYí f T Ò X ESI +;712.4,714.4
Petition 870190100577, of 10/08/2019, p. 156/278
153/265
Petition 870190100577, of 10/08/2019, p. 157/278
154/265
Table 57
PEx PSyn Str Dice 130 7 Soc-* SF -spZ 1yy'W [-'N '··AJ X AJwXJk J ESI +;724.7 131 33 HN zx _Λ 1 / r> XX Á X Ã J XXteXt ESI +;624.5
Petition 870190100577, of 10/08/2019, p. 158/278
155/265
Table 58
PEx PSyn Str Dice 132 132 MrK A AHO XTHE CI +; 235.0 133 133 BrMsl A..T HF ESI +; 228.9 134 35ESI +; 313.0 135 36 Me Ma X. oX jHp-H I ⁰ Me F ' ^- ' A 'Me ESI +; [M + Na] +383.3 136 136 Τι 1 ckAA ^ thp Mi ESI +; 263.2
Petition 870190100577, of 10/08/2019, p. 159/278
156/265
Table 59
PEx PSyn Str Dice 137 137 CH ₂ A _TU n Me Kfe ESI +; 355.3 138 138 _H Me Me A οΛ x Ag y. Yyv Me ESI +; 259.2 139 139 Λ χ'χ AMΓ J | T N J OTeoc ESI +; [M + Na] +324.2 140 140 .χχ. XX jO H OkrTeçç ESI +;[M + Na] +310.1
Petition 870190100577, of 10/08/2019, p. 160/278
157/265
Table 60
PEx PSyn Str Dice 141 141 HO'AA ESI +; 180.1 142 142ESI +; 359.0 143 143 btAAAq£ H ESI +; 385.0,386.9 144 144 Boc ch ₂ sr x ° Μ ™, / y ôf ₃ ESI +; 890.7
Petition 870190100577, of 10/08/2019, p. 161/278
158/265
Petition 870190100577, of 10/08/2019, p. 162/278
159/265
Table 62
PEx PSyn Str Dice 147 6 Soç A IJ yyS A Αγ® cf ₃ ώβ ESI +; 683.4 148 7 CH ₂ ^H TA * ' ESI +; 735.5 149 4 phytosδk I Yγγγ-Ν γΎTHE ESI +; 718.1
Petition 870190100577, of 10/08/2019, p. 163/278
160/265
Table 63
PEx PSyn Str Dice 150 8 BocTHEÇ ΛδΑ ESI +; 744.1 151 9 BocN δA V AAt ESI +; 658.3 152 7 Boc ΛA V/ J. ·· 'hxí 1 L H J 1 J’Êt ESI +; 708.4
Petition 870190100577, of 10/08/2019, p. 164/278
161/265
Table 64
PEx PSyn Str Dice Boc153 23 ch ₂ Q ESI +; 852.6 YjC, X. 154 118 v Soc / iê pA. _N pNH ESI +; 708.5 JL Y'-Y'O '- ’kA
Petition 870190100577, of 10/08/2019, p. 165/278
162/265
Table 65
PEx PSyn Str Dice 155 155 Bac Λ Ns », SaA S ΙλΙI 1 J γχ 'y' γ Ν'Ό 'òf ₃ ESI +; 806.6 156 4 Theδτ ί ΐ 1 ϊ 1 J ESI +; 791.3 157 39 Boc ιίι δ ESI +; 871.2
Petition 870190100577, of 10/08/2019, p. 166/278
163/265
Table 66
PEx PSyn Str Dice 158 9 A <*> Zk XJ g _f A- ^ iÀo '''J% 6f _s ESI +; 785.5 159 23 Boc <^> L jl Λ ^ '^ OileS cf ₃ ESI +; 835.6
Petition 870190100577, of 10/08/2019, p. 167/278
164/265
Table 67
PEx PSyn Str Dice 160 155 BOC N L 1 t ' Μ γ «tóXt O Ms η òf ₃ ESI +; 762.4 161 4 P0 ESI +; 762.4 162 39 Boc ôTHEX ESI +; 844.3
Petition 870190100577, of 10/08/2019, p. 168/278
165/265
Table 68
PEx PSyn Str Dice 163 6 Boc N γγ> Ν f iy γ ^ô i cf ₃ ESI +; 744.4 164 23 Çoc ή <Q>vfc VAYXaak L Y ESI +; 794.6 165 4 NδΎ γί <f ^ sF ESI +; 706.2
Petition 870190100577, of 10/08/2019, p. 169/278
166/265
Table 69
PEx PSyn Str Dice 166 39 ÇccOώ «1CF-, ESI +; 786.2 167 6 It's J-OQ. & X ck _s y .... 1,> mrj ar 'ò X ESI +; 686.4 168 23 çHj ‘y’UMs “· ESI +; 736.5
Petition 870190100577, of 10/08/2019, p. 170/278
167/265
Table 70
PEx PSyn Str Dice 169 23 BoeTHE<: y..X. MeOVER THEREMm AYTHP- ’’UJk A ESI +; [M + Na] +884.8 BosΝHERE170 4 0 k χχ M, k jTY βγ ^ Ύ W ^{> x} f L fG Me ESI +; 677.2 171 39 K LA àF ₃ ESI +; 757.2
Petition 870190100577, of 10/08/2019, p. 171/278
168/265
Table 71
PEx PSyn Str Dice 172 6 Boc A CLa ά ΙΑ. cf ₃ ESI +; 657.3 173 7 BOC A o η A .. * 1 ώ cf ₃ ESI +; 707.5 174 4 Boc S <^ 'γγΧ »xnr ^Me ESI +; 706.2
Petition 870190100577, of 10/08/2019, p. 172/278
169/265
Table 72
PEx PSyn Str Dice 175 175 S & c & X gh ₂ çj ESI +; 688.3. II I I176 4 BX THEδVrX '’F £ ESI +; 708.2,710.2 177 39 Soe& ObrCL £ ESI +; 790.2
Petition 870190100577, of 10/08/2019, p. 173/278
170/265
Table 73
PEx PSyn Str Dice 178 6 Bcc A / X CH ₂ U 0 1, χ-χ,. Me 'Ν' F ESI +; 690.3 179 23 Çoc.ΝJ 1 JL J1 1 JCF j ESI +; 740.5 180 115 BocsJA A A 1 jOH ESI +; 818.3,820.2
Petition 870190100577, of 10/08/2019, p. 174/278
171/265
Table 74
PEx PSyn Str Dice 181 181 IN<>Q XHFà ESI +; 868.3,870.3 182 6 Scc-OΥΗΓ “2 ESI +; 768.5,770.4 183 118 BscCH ·· ,. 'Ν'I ‘1L h j 1 íόOHFg ESI +; 624.4
Petition 870190100577, of 10/08/2019, p. 175/278
V12I2S5
Table 75
PEx PSyn Str Dice 184 144 Soc A CH ₂ SY X BrXjXíYxAX À XHF, • K · ESI +; 684.4 185 23 &> cY X Ms ESI +; 734.6 186 4 Boc8BrX ^ XXoX ^ ESI +; 731.0
Petition 870190100577, of 10/08/2019, p. 176/278
173/265
Table 76
PEx PSyn Str Dice 187 8 N Q Χχγ-Μ χγχ ^ χ · ^0Ν XXJ 1 J Ò 'Et ESI +; 755.1 188 9 Boc x ^ er ^ ^CN 1 h „1 1 1 grVSfMbX ^ X ^Ò 'Et ESI +; 671.2 189 7 BoçTHEA YMMe Έί ESI +; 721.4
Petition 870190100577, of 10/08/2019, p. 177/278
174/265
Table 77
PEx PSyn Str Dice 190 4 BccTheOT r.F ESI +; 756.2 191 39 Etoc. Is 8 7 Α'Ίϊ A ft 1f ₃ ESI +; 836.3 192 6 BóçÇH, M V ESI +; 736.3
Petition 870190100577, of 10/08/2019, p. 178/278
175/265
Table 78
PEx PSyn Str Dice 193 23 Boc JX 'ij J hn ik IJL JI i' tf- Ό ···· ^χ ·· - '·' JL ó. 0f ₃ ESI +; 786.5 194 155 Boc ri Γ1 | H ₂ W * fe-- r ^ hr HM 1 kl 4 LJ 'γΧγ γ ¹ ^ W O' · · '''-··' ESI +; 799.5
Petition 870190100577, of 10/08/2019, p. 179/278
176/265
Table 79
PEx PSyn Str Dice 195 5 BocairX ESI +; 810.3 BôcN196 6 Λχ 1 MonthYY AYk .kL ™ JVte'-Q- ESI +; 710.5
Petition 870190100577, of 10/08/2019, p. 180/278
177/265
Table 80
PEx PSyn Str Dice 197 23 ch ₂ S ''' ESI +; 760.7 198 5 BogK. .. · χ X eTie ESI +; 794.3
Petition 870190100577, of 10/08/2019, p. 181/278
178/265
Table 81
PEx PSyn Str Dice 199 6 B & c A ÇH ₂ 'hT L .-' x À. _b ,: çkaa> ά _χ Me ESI +; 694.4 200 23 Bos ώ Ο ch ₂ XX 0 ώβ ESI +; 744.7
Petition 870190100577, of 10/08/2019, p. 182/278
179/265
Table 82
PEx PSyn Str Dice 201 4 NV ESI +; 721.3 202 39 Bíjc 8 ήί A · Α · - _o ·· ^ · ESI +; 801.3 203 6 φοε N X CH ₂ Wx. Br- CL CF ₃ ESI +; 699.4
Petition 870190100577, of 10/08/2019, p. 183/278
180/265
Table 83
PEx PSyn Str Dice 204 7 Boc 8 ch, Sr V 1 tu. YYy 1 LJJ ~ 'ΥΥΥV xy cf ₃ ESI +; 751.5 205 4 BocTHEThe x ESI +; 772.2,774.2 206 39 Boe '^ s t J Y'G Yr Γ LIJ O _v X ESI +; 854.4
Petition 870190100577, of 10/08/2019, p. 184/278
181/265
Table 84
PEx PSyn Str Dice THE207 6 YCR} ESI +; 752.3,754.3 208 23 Boe Jsí Ο CH ₃ X ΫΥΥ ' ¹ ^^ ESI +; 804.5 ÜFg
Petition 870190100577, of 10/08/2019, p. 185/278
182/265
Table 85
PEx PSyn Str Dice 209 5 Bss Λ WyX / A ^and o (ίη ESI +; 778.3 210 6 SockÇH · »u ESI +; 678.4,680.3
Petition 870190100577, of 10/08/2019, p. 186/278
183/265
Table 86
PEx PSyn Str Dice 211 23 S O CH ₂ N hn 'VL Jh j 1 j At f''Ν··''Ό' · Mws ò ESI +; 730.7 212 23 Bce N CH ₂ Ν ' ² hb J ESI +; 766.6
Petition 870190100577, of 10/08/2019, p. 187/278
184/265
Table 87
PEx PSyn Str Dice 213 175 BocA çr, YrTHE^ Me ESI +; 668.3 214 7 Boc _CHl ^HNJ 0 x ^ fJ SifeXs JVT Γ ' ESI +; [M + Na] +740.5
Petition 870190100577, of 10/08/2019, p. 188/278
185/265
Table 88
PEx PSyn Str Dice 215 4 BogNMr * ESI +; 718.2,720.2 216 39 BocSr y®TheTHE ESI +; 800.2 217 6 Soe N ò çh ₂ γτ IVte A ESI +; 700.5
Petition 870190100577, of 10/08/2019, p. 189/278
186/265
Table 89
PEx PSyn Str Dice 218 23 Boc o 1 M Jísrí r '' Ύ Ate HH. 1 K to J 1] yX · Y no * ^ '' · '······' · L Jl □ „--- / Me h èF ₃ ESI +; 750.6 219 4 Bcc k 0To LM · j & e ESI +; 677.2 220 39 Boc ky ^k yk'yk _{f; {} A 's, N 1 í CF ₃ Me ESI +; 757.3
Petition 870190100577, of 10/08/2019, p. 190/278
187/265
Table 90
PEx PSyn Str Dice 221 6 Bocò 'XyM. ESI +; 657.3 222 7 With Mr/χ/'ίί UX 'X.- CF _â Ms ESI +; 707.6
Petition 870190100577, of 10/08/2019, p. 191/278
188/265
Petition 870190100577, of 10/08/2019, p. 192/278
189/265
Table 92
PEx PSyn Str Dice 225 23 ^<: 'k .k X Λ J -S]' £ Ή1 ₂ ESI +; 796.6 226 144 N 8 «s Y r * ® _w Jh kôkl fj V * Ms p ESI +; 891.7
Petition 870190100577, of 10/08/2019, p. 193/278
190/265
Table 93
PEx PSyn Str Dice 227 227 BocTHEThe ESI +; 689.2,691.2 228 39 Boe χΥχ Aj ò ^H cA ESI +; 769.3,771.3 229 6 δ _Λ .1 JWe X ['y c ^H ESI +; 671.3
Petition 870190100577, of 10/08/2019, p. 194/278
191/265
Table 94
PEx PSyn Str Dice 230 23 Boc A u ^K CG JL Κ A 1. LAA ^H CF ₃ ESI +; 721.5 231 4 ^ ocΛ δ γβΑΑΑοΆΥ £ ESI +; 704.2,706.2 232 39 Sec A L i yrr. ry ¹ 'CF. _s ESI +; 784.3
Petition 870190100577, of 10/08/2019, p. 195/278
192/265
Table 95
PEx PSyn Str Dice 233 6 Boc Λ cH _a . Sr à 1 Λ. 1 / Br γ''ίΝ '0 ESI +; 684.5 234 23 Boc A O ch ₂ w 'HN Λ L | , 1 1 / YYΎ 'U CFj ESI +; [M + Na] +758.5
Petition 870190100577, of 10/08/2019, p. 196/278
193/265
Table 96
PEx PSyn Str Dice 235 235 9oc CH ₂ Sp ^h % aPUwAAj CF, _S ESI +; 779.6 236 4 Bcç δ ^v rr ΑρΛι r Me ESI +; 680.2 237 39 ROC. K δ Αζχ Αν 8r '^ f' y Fite èf _s ESI +; 760.2
Petition 870190100577, of 10/08/2019, p. 197/278
194/265
Table 97
PEx PSyn Str Dice 238 6 ώ Q ch ₂ kA VA, ó ftfe · CF _S ESI +; 660.3 239 23 Boc ch> Cr 'U £ ^M V>Ar'Ww * Mws è ₃ ESI +; 710.5
Petition 870190100577, of 10/08/2019, p. 198/278
195/265
Table 98
PEx PSyn Str Dice 240 155 A ÇHí pr * Y ^; · X z Xf Yr kJLA 'Μ'. ' X ESI +; 805.5 241 141 Boc A rS r ch ₂ V., Έ λ λ J L-ϊ V'yX X'n- cf ₃ ESI +; 889.5
Petition 870190100577, of 10/08/2019, p. 199/278
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Table 99
PEx PSyn Str Dice 242 5 ήKThe ESI +; 746.3 243 6 Boc & Y U çh ₂ Sr ύ γ <n Jl A 1. J I àte ' ESI +; 646.4
Petition 870190100577, of 10/08/2019, p. 200/278
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Table 100
PEx PSyn Str Dice 244 23 Ete, the CM y hk αΛλ Á a J ιΓ τ ' ^N ' Me i ESI +; 696.6 245 4 BtwΛδí> xTx O ESI +; 727.2 246 39 Boü CC γ ^ Ά ^ο ò X ESI +; 805.2,807.2
Petition 870190100577, of 10/08/2019, p. 201/278
198/265
Table 101]
PEx PSyn Str Dice 247 6 0 & C-j 1 0 ESI +; 705.3,707.3 248 23 So<>Ϋ jYÇÇvvm ESI +; 757.5 249 4 Ete Λ<AΑαχ-λ ESI +; 691.2
Petition 870190100577, of 10/08/2019, p. 202/278
199/265
Table 102
PEx PSyn Str Dice 250 39 BocTHEXCF; j ESI +; 771.3 251 6 Boc à O yr 'bcxjx η cf ₃ ESI +; 671.4
Petition 870190100577, of 10/08/2019, p. 203/278
200/265
Table 103
PEx PSyn Str Dice 252 23 çh ₃ sr h .ik L. Ϊ V '' Ν '' NV .. j JI Ws O A ESI +; 721.5 253 253 8oc ÇHj RfX 9't, _x Jk o Hf / i LIJI i CF _{; S} ESI +; 800.4,802.5
Petition 870190100577, of 10/08/2019, p. 204/278
201/265
Table 104
PEx PSyn Str Dice ή254 7 y. 1 ~ .0 f '' Me THP-X <X XPl X _n .AJ 1Π ⁰ F - U «4 ESI +; 868.5 H, .. n IA.255 28 ί ΊiF T _ □hi4 i k 1 J 1 JyYí 'V' N- · '0' '· - ·^ e · XCFi ESI +; 684.5
Petition 870190100577, of 10/08/2019, p. 205/278
202/265
Table 105
PEx PSyn Str Dice 256 39 BocÇ ,s ESI +; 864.4,866.4 257 6 Boc CH _to XK _D AA 4. - A j Br γ N xr x. F'Jxt'3 ESI +; 764.4,766.3
Petition 870190100577, of 10/08/2019, p. 206/278
203/265
Table 106
PEx PSyn Str Dice 258 23 1¾ 7 N => ^: Ύ <. F'f0P _s ESI +; 816.5 259 4 Soe&δΥγΥ Yy ^ cf ,. ESI +; 758.3,760.3 260 39 Yes Ιγ δ Ύ γ ΥγΥ Αγ G óf ₃ ESI +; 838.2,840.2
Petition 870190100577, of 10/08/2019, p. 207/278
204/265
Table 107
PEx PSyn Str Dice 261 6 BOC N VXi S ' ¹ ÚF- ^ ESI +; 740.3 262 23 BOC oh ₂ cf ₃ .γ VY γΜ ^:: γ ^λ ·, .ΑAr · -o ^l -J cf ₃ ESI +; 790.6 263 4 Boc x Al y ^{si i} ESI +; 784.0
Petition 870190100577, of 10/08/2019, p. 208/278
205/265
Table 108
PEx PSyn Str Dice 264 39 Soc<>Xy S iPThe ESI +; 864.0 265 6 BftC ώ Q F * V pp sr-X .xxX. · AWj èr ₃ ESI +; 764.2
Petition 870190100577, of 10/08/2019, p. 209/278
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Table 109
PEx PSyn Str Dice 266 23 N„ΠL A 2ndÒFj ESI +; 814.3 267 23 Boc X Λ .. ζΛ. _Λ JL XX '··.> Yc N Me Me -í ESI +; 846.6
Petition 870190100577, of 10/08/2019, p. 210/278
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Table 110
PEx PSyn Str Dice 268 28 HN <<> UA Ν 'CHFj. ESI +; 662.5 269 144 BügTHE, - ’Ύ çAYchí w y ηχχχΧΑSA.AMe xCFa ESI +; 918.5
Petition 870190100577, of 10/08/2019, p. 211/278
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Table 111
PEx PSyn Str Dice 270 24 l J TT <JJjua j Ύ sfY 'N ^; rr · y CHFj ESI +; 732.7 271 4 3ocOL1Τ 'Cf ..i '...I ΪF X, Ò ESI +; 628.4,630.4 272 8 Bôc rA -'jy Ύο k,. ^! i 'Et ESI +; 654.4,656.4
Petition 870190100577, of 10/08/2019, p. 212/278
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Table 112
PEx PSyn Str Dice 273 7 0QQkY'XxAy. Μ ESI +; 706.5,708.5 274 24 Boc χYrthere is ITYA. M ESI +; 698.7 275 235 BoeÇ>nXkX0¾ ESI +; 786.5
Petition 870190100577, of 10/08/2019, p. 213/278
210/265
Table 113
PEx PSyn Str Dice 276 7 8thN £ . TheA 1 nhA 1 A 1 A J I w% ESI +; 766.5 277 235 Çoc A- ^J O- ^Me NMr ·. ^H A A''tAoAS cf ₃ ESI +; 766.4
Petition 870190100577, of 10/08/2019, p. 214/278
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Table 114
PEx PSyn Str Dice 278 4 BíKΛTheF ESI +; 705.2 279 39 Bcc â δ Υτδ, Ε · AA% _and A ESI +; 783.3
Petition 870190100577, of 10/08/2019, p. 215/278
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Table 115
PEx PSyn Str Dice 280 6 Boc ώ CHj Y ÒF _S ESI +; 685.4 281 23 Bo-s to F Ç Ϋ / ΑΑγ CF _S ESI +; 735.5
Petition 870190100577, of 10/08/2019, p. 216/278
213/265
Table 116
PEx PSyn Str Dice 282 235 8th there CHj π Ni »Me A 1 A £ A £ jr YT ⁰ cf ₃ ESI +; 750.5 283 283 9 WS _Bf > yAAAA ESI-; 608.2 284 284 8oe lOX ESI +; 818.3,820.3
Petition 870190100577, of 10/08/2019, p. 217/278
214/265
Table 117
PEx PSyn Str Dice 285 39 Sos N A γ YjPsxAkí zM® ⁰⁸ À À ESI +; 898.3,900.4 286 6 φοο ... s, -YJIIG áF _s ESI +; 798.5,800.5
Petition 870190100577, of 10/08/2019, p. 218/278
215/265
Table 118
PEx PSyn Str Dice 287 118 Soc ·N p o y -K ·· VyS ry ESI +; 656.3 288 144 Boc ò '> Me LJ ò çh ₂ yy ypyY py ESI +; 714.4 289 23 Ç 7 to 1. U. $ Ã i 1 yyV Tó '- • Xz ¹ k A „ò, X' V ey cf ₃ ESI +; 764.5
Petition 870190100577, of 10/08/2019, p. 219/278
216/265
Table 119
Petition 870190100577, of 10/08/2019, p. 220/278
217/265
Table 120
Ex Str 3 ° YAh ₂ Λ ρΧγγΧι zy ¹ 'ην 1 k JI Λ 1 chf ₂ 4 y ^ CH ₂ N LJ * Λ ^N Ny ^ ppp ^ N Me ^H Vpp Ayk ^ ASviep chf ₂
Petition 870190100577, of 10/08/2019, p. 221/278
218/265
Table 121
Ex Str 5 Ck Y ^x ch ₂ çh ₂ ü 1 .Me HN X k Λ 1 L JL ci ^^ Tvie ^ Et 6 ° YA Λ μ / x JL / ^ν = λ [Y Η Ν Α 1 zl 1 J 7 ° Y ^ CH ₂ ch ₂ δγΎΥ | ^ Y ^Et hn _v X k J1 Λ 1 J Ax ^ Me ° Et
Petition 870190100577, of 10/08/2019, p. 222/278
219/265
Table 122
Petition 870190100577, of 10/08/2019, p. 223/278
220/265
Table 123
Ex Str ch ₂ 10ÇH ₂ Mr , Et MX^X N ^Z _HN ΛMriVIe chf ₂ • ch ₂ GH ₂ 11 FM ^X N ' xEtHN Ϊ IL Í iVIe F F
Petition 870190100577, of 10/08/2019, p. 224/278
221/265
Table 124
Ex Str ch ₂ 12çh ₂ SrMe GO'NTWlehn i ryS Αθ ° Έί ° V ^ c h ₂ 13h ₂ Υτΐ i ^ N ^x ^^ ^Ox MeHNT. 'ySS' 'Me ° Et 0. Άη ₂ * 14 N ₌ / çh ₂ Sr N MeHN Ti ^{N <} / Ak _Me ^u | CHF; >
Petition 870190100577, of 10/08/2019, p. 225/278
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Table 125
Ex Str Ckch ₂ N * 15 N = n / QH ₂ k _N - ii ^x > NMeΗΝΪ ^ Me II ^ N ^;/ ά ^ν Ck ^> CH ₂ N, 16ÇH ₂ ^ N- * > NMehn 1 Yà Ύ | | ''0 ^ / * A ^N 0 ^ Me ^x Et ch ₂ 17ÇH ₂ y Me N ^HN A iL í 0 ^ iVIe
Petition 870190100577, of 10/08/2019, p. 226/278
223/265
Table 126
Ex Str 18 ° Y ^ ch ₂ Λ í ^ N ^ ^Et η ν A k Jl AL 1 J ^N ^^ Me ° Et 19 ° YXh ₂ A | <= ΓγΥ * Ν Y ' ⁸ hn AL Η Λ 1
Petition 870190100577, of 10/08/2019, p. 227/278
224/265
Ex Table 127Str 20 Y ^ CH ₂ ch ₂ N = n tYAn ΥΆ hn A k II A 1 21 V * CH ₂ çh ₂ H-aul Xf A _C | ° -Et
Petition 870190100577, of 10/08/2019, p. 228/278
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Table 128
Ex Str 22 ° Y> CH ₂ λ X-Λ r ^x N ^Et hn kk 11 A 1 ^ A ^ Me ⁰ ^ chf ₂ 23 CK Y ^x ch ₂ N II * A ^N XaXxAn Me k JL cl ky ^^ ríVIe Et
Petition 870190100577, of 10/08/2019, p. 229/278
226/265
Table 129
Petition 870190100577, of 10/08/2019, p. 230/278
227/265
Table 130
Petition 870190100577, of 10/08/2019, p. 231/278
228/265
Table 131
Petition 870190100577, of 10/08/2019, p. 232/278
229/265
Table 132
Petition 870190100577, of 10/08/2019, p. 233/278
230/265
Table 133
Petition 870190100577, of 10/08/2019, p. 234/278
231/265
Table 134
Petition 870190100577, of 10/08/2019, p. 235/278
232/265
Table 135
Petition 870190100577, of 10/08/2019, p. 236/278
233/265
Table 136
Petition 870190100577, of 10/08/2019, p. 237/278
234/265
Table 137
Petition 870190100577, of 10/08/2019, p. 238/278
235/265
Table 138
Petition 870190100577, of 10/08/2019, p. 239/278
236/265
Table 139
Ex Str 46 N IJ A Sy v ÒF ₃ 47 ° V ^ ch _k / • í C j çíh _s sr nSAWXfArX ôf ₃
Petition 870190100577, of 10/08/2019, p. 240/278
237/265
Table 140
Petition 870190100577, of 10/08/2019, p. 241/278
238/265
Table 141
Petition 870190100577, of 10/08/2019, p. 242/278
239/265
Table 142
Ex Str 52 O. V Ahή, ô $ h ₂ 'Ύ ppàzf 53 V * ch, A YY w çh, yp hf! «Tf ALXXI j X f T ⁰ 54 G- Άί-ij<5y Y There is A LJ A I J
Petition 870190100577, of 10/08/2019, p. 243/278
240/265
Table 143
Petition 870190100577, of 10/08/2019, p. 244/278
241/265
Table 144
Petition 870190100577, of 10/08/2019, p. 245/278
242/265
Table 145
Petition 870190100577, of 10/08/2019, p. 246/278
243/265
Table 146
Petition 870190100577, of 10/08/2019, p. 247/278
244/265
Table 147
Petition 870190100577, of 10/08/2019, p. 248/278
245/265
Table 148
Ex Str 65 ch ₂ G'- ' ^: íYçíX, CF ₃ ώβ 66 V -cx ri X çh ₂ yr 'ν = ^ ZXr ^{M6 H} ' χΑγΑγΑ, Χ.J Sx,
Petition 870190100577, of 10/08/2019, p. 249/278
246/265
Table 149
Petition 870190100577, of 10/08/2019, p. 250/278
247/265
Table 150
Petition 870190100577, of 10/08/2019, p. 251/278
248/265
Table 151
Petition 870190100577, of 10/08/2019, p. 252/278
249/265
Table 152
Petition 870190100577, of 10/08/2019, p. 253/278
250/265
Table 153
Ex Str 75 CK ΛΥ Χ.Ηχy πΜ X / A A J V XΥ'Ή 'Ό' '· -' ··X 76 0 <ΛIOMr«Αχό 'Πτγ ^ -γ w, Y>. O
Petition 870190100577, of 10/08/2019, p. 254/278
251/265
Table 154
Petition 870190100577, of 10/08/2019, p. 255/278
252/265
Table 155
Petition 870190100577, of 10/08/2019, p. 256/278
253/265
Table 156
Petition 870190100577, of 10/08/2019, p. 257/278
254/265
Table 157
Petition 870190100577, of 10/08/2019, p. 258/278
255/265
Table 158
Ex Str 85 N o O GH ;, Sr Hf · / 1 k (1 J 'AV ¥ <XA-A AU jí o L o V' · ^x Me Et 86 Οχ - <x Ί 'CH _S , ίζ FV _h Ai ΎΥϊ PrS''crxmws 87 CL V'CH ^ à V A 9 Μ P CF _{: i}
Petition 870190100577, of 10/08/2019, p. 259/278
256/265
Table 159
Petition 870190100577, of 10/08/2019, p. 260/278
257/265
Table 160
Petition 870190100577, of 10/08/2019, p. 261/278
258/265
Table 161
Ex Syn Dice 1 E1 ESI +; 658.5NMR (400 MHz): 1.63 - 1.80 (2 H, m) 1.91 - 2.22 (8 H, m) 2.04 (3 H, s) 2.17 (3 H, s) 2.59 - 2.79 (2 H, m)3.65 - 3.84 (4 H, m) 3.75 (2 H, s) 4.00 - 4.17 (1 H, m) 4.04 (2 H, s) 4.25 - 4, 44 (1 H, m) 4.92 - 5.11 (2 H, m) 5.72 (1 H, tt, J = 55.3, 4.0 Hz) 5.65 - 5.71 (2 H , m) 5.99 - 6.18 (2 H, m) 6.34 (1 H, dd, J = 17.0, 10.4 Hz) 7.33 (1 H, d, J = 8.6 Hz) 7.38 - 7.45 (1 H, m) 7.50 (1 H, d, J = 8.4 Hz) 7.96 (1 H, s) 13.03 (1 H, s) 2 E2 ESI +; 636.6NMR (500 MHz): 0.42 - 0.71 (4 H, m) 0.83 (3 H, t, J = 7.0 Hz) 1.23 - 1.36 (1 H, m) 1, 59 - 1.79 (2 H, m) 1.90 - 1.98 (4 H, m) 1.99-2.25 (4 H, m) 2.11 (3 H, s) 2.18 ( 3 H, s) 2.65 - 2.77 (2 H, m) 3.57 - 3.68 (4 H, m) 3.75 (2 H, s) 3.77 - 3.87 (1 H , m) 3.98 - 4.12 (1 H, m) 4.03 (2 H, s) 4.92 - 5.03 (1 H, m) 5.68 (1 H, dd, J = 10 , 3, 2.3 Hz) 6.12 (1 H, dd, J = 17.0, 2.3 Hz)6.34 (1 H, dd, J = 17.0, 10.3 Hz) 7.14 (1 H, s) 7.33 (1 H, d, J = 8.6 Hz) 7.41 - 7 , 44 (1 H, m) 7.46 (1 H, d, J = 8.6 Hz) 12.96 (1 H, s) 3 E3 ESI +; 672.6NMR (500 MHz): 0.46 - 0.73 (4 H, m) 1.24 - 1.37 (1H, m) 1.62 - 1.80 (2 H, m) 1.89 - 2.23 (8 H, m) 2.11 (3 H, s) 2.17 (3 H, s) 2, 60 - 2.76 (2 H, m) 3.57 -3.69 (4 H, m) 3.75 (2 H, s) 3.97 - 4.15 (1 H, m) 4.03 (2 H, s) 4.22 - 4.48 (1 H , m) 4.87 - 5.03 (1 H, m)5.72 (1 H, tt, J = 55.2, 3.8 Hz) 5.68 (1 H, dd, J = 10.3, 2.3 Hz) 6.12 (1 H, dd, J = 17.0, 2.3 Hz) 6.34(1 H, dd, J = 16.8, 10.3 Hz) 7.20 (1 H, s) 7.34 (1 H, d, J = 8.4 Hz) 7.43 - 7.52 ( 2 H, m) 12.99 (1 H, s)
Petition 870190100577, of 10/08/2019, p. 262/278
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Table 162
Ex Syn Dice 4 E4 ESI +; 672.6NMR (400 MHz): 0.46 - 0.76 (4 H, m) 1.21 - 1.45 (1 H, m) 1.57 - 3.01 (14 H, m) 2.11 (3 H, s) 3.58 - 3.83 (4 H, m) 3.76 (2 H, s) 3.95 - 4.19 (1 H, m) 4.04 (2 H, s) 4, 21 -4.65 (3 H, m) 5.72 (1 H, tt, J = 55.1.3.7Hz) 5.69 (1 H, dd, J = 10.1.2.2 Hz) 6.12 (1 H, dd, J = 16.8, 2.2 Hz) 6.34 (1 H, dd , J = 17.0, 10.1 Hz)7.22 (1 H, s) 7.35 (1 H, d, J = 8.6 Hz) 7.44 - 7.48 (1 H, m) 7.49 (1 H, d, J = 8 , 6 Hz) 13.01 (1 H, s) 5 E5E5-2 ESI +; 622.5NMR (400 MHz): 0.83 (3 H, t, J = 7.1 Hz) 1.62 -1.83 (2 H, m) 1.87-2.27 (8 H, m) 2.04 (3 H, s) 2.18 (3 H, s) 2.62 - 2.78 (2 H , m) 3.63 - 3.80 (4 H, m)3.76 (2 H, s) 3.78 - 3.91 (1 H, m) 3.98 - 4.16 (1 H, m) 4.04 (2 H, s) 4.93 - 5, 08 (2 H, m) 5.60 - 5.74 (2 H, m) 6.00 - 6.17 (2 H, m) 6.34 (1 H, dd, J = 17.0, 10, 4 Hz) 7.32 (1 H, d, J = 8.6 Hz) 7.36 - 7.41 (1 H, m) 7.49 (1 H, d, J = 8.4 Hz) 7, 90 (1 H, s) 13.01 (1 H, s) 6 E6 ESI +; 662.5 7 E7 ESI +; 636.5 8 E3 ESI +; 654.6 9 E1 ESI +; 690.6 10 E1 ESI +; 672.6 11 E1 ESI +; 698.6 12 E1 ESI +; 650.6 13 E1 ESI +; 666.6 14 E3 ESI +; 658.6 15 E1 ESI +; 648.6 16 E1 ESI +; 622.6 17 E1 ESI +; 648.6 18 E3 ESI +; 650.5
Petition 870190100577, of 10/08/2019, p. 263/278
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Table 163
Ex Syn Dice 19 E3 ESI +; 676.5 20 E3 ESI +; 662.6 21 E3 ESI +; 656.5 22 E6 ESI +; 686.5 23 E1 ESI +; 636.5 24 E24 ESI +; 622.4NMR (500 MHz): 0.83 (3 H, t, J = 7.0 Hz) 1.64 -1.79 (2 H, m) 1.90-2.23 (8 H, m) 2.04 (3 H, s) 2.17 (3 H, s) 2.65 - 2.75 (2 H , m) 3.67 - 3.75 (4 H, m)3.76 (2 H, s) 3.79 - 3.88 (1 H, m) 4.00 - 4.13 (1 H, m) 4.04 (2 H, s) 4.94 - 5, 07 (2 H, m) 5.62 - 5.72 (2 H, m) 6.06 (1 H, dd, J = 17.5, 10.9 Hz) 6.12 (1 H, dd, J = 17.0, 2.3 Hz) 6.35 (1 H, dd, J = 17.1, 10.3 Hz) 7.32 (1 H, d, J = 8.6 Hz) 7.35 - 7.41 (1 H, m)7.49 (1 H, d, J = 8.6 Hz) 7.90 (1 H, s) 13.01 (1 H, s)[a] D20 +39.6 (c 0.35, MeOH) 25 E25 ESI +; 734.5 26 E26 ESI +; 720.5NMR (500 MHz): 1.63 - 1.76 (2 H, m) 1.91 - 2.11 (6 H, m) 2.05 (3 H, s) 2.12 - 2.22 (2 H, m) 2.47 (2 H, t, J = 5.8 Hz) 2.75 - 2.87 (2 H, m) 3.22 (3 H, s) 3.42 (2H, t, J = 5.8 Hz) 3.68 - 3.82 (4 H, m) 3.76 (2 H, s) 4.04 (2 H, s) 4.42 - 4.54 ( 1 H, m) 4.70 - 4.85 (1 H, m) 4.92 - 5.03 (1 H, m) 5.07 (1 H, d, J = 11.8 Hz) 5.64 - 5.75 (2 H, m) 6.02 - 6.18 (2 H, m) 6.35 (1 H, dd, J = 17.0, 10.3 Hz) 7.32 (1 H, d, J = 8.7 Hz) 7.38- 7.42 (1 H, m) 7.49 (1 H, d, J = 8.6 Hz) 7.98 (1 H, s) 13.00 (1 H, s) 27 E5-2 ESI +; 734.5
Petition 870190100577, of 10/08/2019, p. 264/278
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Table 164
Ex Syn Dice 28 E28 ESI +; 748.5NMR (400 MHz): 0.46 - 0.78 (4 H, m) 1.24 - 1.41 (1 H, m) 1.58 - 1.77 (4 H, m) 1.87 - 2 , 16 (8 H, m) 2.11 (3 H, s) 2.25 - 2.36 (2 H, m) 2.70 - 2.84 (2 H, m)3.21 (3 H, s) 3.27 - 3.37 (2 H, m) 3.59 - 3.72 (4 H, m) 3.75 (2 H, s) 4.03 (2 H , s) 4.38 - 4.53 (1 H, m)4.69 - 4.84 (1 H, m) 4.89 - 5.03 (1 H, m) 5.68 (1 H, dd, J = 10.1.2.2 Hz) 6.12 ( 1 H, dd, J = 17,1,2,3 Hz)6.34 (1 H, dd, J = 17.0, 10.1 Hz) 7.22 (1 H, s) 7.33 (1 H, d, J = 8.6 Hz) 7.42 - 7 , 51 (2 H, m) 12.96 (1 H, s) 29 E5-2 ESI +; 734.5 30 E30 ESI +; 746.6NMR (500 MHz): 1.34-1.50 (2 H, m) 1.59 - 1.76 (4 H, m) 1.90 - 2.13 (6 H, m) 2.05 (3 H, s) 2.22 - 2.33 (2 H, m) 2.38 - 2.50 (1 H, m) 2.80 - 2.92 (2 H, m)3.20 - 3.33 (2 H, m) 3.69 - 3.81 (4 H, m) 3.76 (2 H, s) 3.82 - 3.92 (2 H, m) 4, 04 (2 H, s) 4.42 - 4.54 (1H, m) 4.72 - 4.84 (1 H, m) 4.93 - 5.01 (1 H, m) 5.06 (1 H, d, J = 11.9 Hz) 5.65- 5.74 (2 H, m) 6.03-6.17 (2 H, m) 6.35 (1 H, dd, J = 17.0, 10.4 Hz) 7.32 (1 H, d , J = 8.7 Hz) 7.37 - 7.43 (1 H, m) 7.49 (1 H, d, J =8.9 Hz) 7.98 (1 H, s) 12.74 - 13.27 (1 H, m) 31 E31 ESI +; 734.5 32 E5-2 ESI +; 716.6 33 E5-2 ESI +; 718.5 34 E31 ESI +; 678.5
Petition 870190100577, of 10/08/2019, p. 265/278
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Table 165
Ex Syn Dice 35 E24 ESI +; 734.5[a] D20 +19.7 (c0.35, MeOH) 36 E36 ESI +; 720.5NMR (400 MHz): 1.62 - 1.77 (2 H, m) 1.91 - 2.09 (6 H, m) 2.05 (3 H, s) 2.11 - 2.23 (2 H, m) 2.45 - 2.52 (2 H, m) 2.75 - 2.89 (2 H, m) 3.22 (3 H, s) 3.42 (2 H, t, J = 5.8 Hz) 3.69 - 3.81 (4 H, m) 3.76 (2 H, s) 4.04 (2 H, s) 4.41 - 4.54 (1 H, m) 4 , 71 - 4.84 (1 H, m) 4.92 - 5.03 (1 H, m) 5.06 (1 H, d, J = 11.7 Hz) 5.64 5.76 (2 H , m) 6.01 - 6.19 (2 H, m) 6.34 (1 H, dd, J = 17.0, 10.4 Hz) 7.32 (1 H, d, J = 8.6 Hz) 7.37 - 7.43 (1 H, m) 7.49 (1 H, d, J = 8.6 Hz) 7.98 (1 H, s) 12.94-13.06 (1 H , m)[a] D20 +33.2 (c 0.35, MeOH) 37 E24 ESI +; 734.5[a] D20 +34.2 (c 0.35, MeOH) 38 E38 ESI +; 748.5NMR (400 MHz): 0.48 - 0.74 (4 H, m) 1.27 - 1.40 (1 H, m) 1.58 - 1.75 (4 H, m) 1.88 - 2 , 16 (8 H, m) 2.11 (3 H, s) 2.24 - 2.38 (2 H, m) 2.71 - 2.83 (2 H, m)3.21 (3 H, s) 3.27 - 3.36 (2 H, m) 3.51 - 3.71 (4 H, m) 3.75 (2 H, s) 4.03 (2 H , s) 4.35 - 4.55 (1 H, m) 4.67 - 4.85 (1 H, m) 4.88-5.06 (1 H, m) 5.68 (1 H, dd ,J = 10.1, 2.2 Hz) 6.12 (1 H, dd, J = 17.0, 2.2 Hz) 6.34 (1 H, dd, J = 17.0, 10.1 Hz ) 7.22 (1 H, s) 7.33 (1 H, d, J = 8.6 Hz) 7.42-7.52 (2 H, m) 12.96 (1 H, s)[a] D20 +20.0 (c 0.35, MeOH)
Petition 870190100577, of 10/08/2019, p. 266/278
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Table 166
Ex Syn Dice 39 E39 ESI +; 746.5NMR (500 MHz): 1.35 - 1.49 (2 H, m) 1.60 - 1.75 (4 H, m) 1.91 - 2.12 (6 H, m) 2.05 (3 H, s) 2.23 - 2.34 (2 H, m) 2.38 - 2.54 (1 H, m) 2.80 - 2.92 (2 H, m)3.19 - 3.35 (2 H, m) 3.69 - 3.81 (4 H, m) 3.76 (2 H, s) 3.82 - 3.91 (2 H, m) 4, 04 (2 H, s) 4.42 - 4.53 (1H, m) 4.72 - 4.85 (1 H, m) 4.92 - 5.02 (1 H, m) 5.06 (1 H, d, J = 11.8 Hz) 5.64- 5.75 (2 H, m) 6.02-6.17 (2 H, m) 6.35 (1 H, dd, J = 17.1, 10.3 Hz) 7.32 (1 H, d , J = 8.7 Hz) 7.38 - 7.43 (1 H, m) 7.49 (1 H, d, J =8.7 Hz) 7.98 (1 H, s) 12.76 - 13.18 (1 H, m) [a] D20 +32.7 (c 0.35, MeOH) 40 E39 ESI +; 734.5[a] D20 +31.2 (c0.35, MeOH) 41 E41 ESI +; 760.5 42 E5-2 ESI +; 689.5 43 E25 ESI +; 662.5 44 E5-2 ESI +; 760.5 45 E5-2 ESI +; 789.5 46 E5-2 ESI +; 716.5 47 E5-2 ESI +; 748.5 48 E5-2 ESI +; 690.5 49 E41 ESI +; 732.5 50 E5-2 ESI +; 661.5 51 E51 ESI +; 692.4 52 E5-2 ESI +; 694.4 53 E5-2 ESI +; 688.5 54 E25 ESI +; 675.6 55 E5-2 ESI +; 740.5 56 E5-2 ESI +; 753.5 57 E5-2 ESI +; 714.5 58 E5-2 ESI +; 698.5
Petition 870190100577, of 10/08/2019, p. 267/278
264/265
Table 167
Ex Syn Dice 59 E5-2 ESI +; 705.5 60 E5-2 ESI +; 758.4 61 E5-2 ESI +; 684.5 62 E5-2 ESI +; 720.5 63 E5-2 ESI +; 672.5 64 E5-2 ESI +; 704.5 65 E5-2 ESI +; 661.5 66 E5-2 ESI +; 750.5 67 E41 ESI +; 761.5 68 E5-2 ESI +; 675.5 69 E5-2 ESI +; 690.5 70 E5-2 ESI +; 733.5 71 E5-2 ESI +; 664.4 72 E5-2 ESI +; 759.5 73 E41 ESI +; 759.5 74 E5-2 ESI +; 650.4 75 E5-2 ESI +; 711.4 76 E5-2 ESI +; 675.5 77 E5-2 ESI +; 754.5 78 E31 ESI +; 738.5 79 E5-2 ESI +; 770.5 80 E5-2 ESI +; 744.5 81 E5-2 ESI +; 768.4 82 E82 ESI +; 784.5 83 E41 ESI +; 788.5 84 E1 ESI +; 686.6 85 E1 ESI +; 652.5 86 E5-2 ESI +; 740.4 87 E5-2 ESI +; 720.4 88 E5-2 ESI +; 720.5 89 E5-2 ESI +; 689.5 90 E5-2 ESI +; 704.5 91 E5-2 ESI +; 718.5
Petition 870190100577, of 10/08/2019, p. 268/278
265/265
Table 168
Reference example 1 ⁿ = to hi Í 1 c Ml ^C O. / X Syn: E3Data: ESI +;642.5 N'Me ' ^C CH ₂ Ν Y Ck Mh ₂ Λ ExampleSyn: E3 referenceQh ₂ Sj ·* Data: ESI +; reference 2 PM 'N lyieN 608.6 ^hn A ^} 'Me
Industrial Applicability [00293] The compound of the present invention and its salt are useful as a G12C mutation KRAS inhibitor, and can be used as a pharmaceutical composition, for example, an active ingredient of a pharmaceutical composition for the treatment of cancer lung.

权利要求:
Claims (22)
[1]
1. Compound, characterized by the fact that it has Formula (I) or a salt thereof:
Chemical Formula 9

[2]
2/5

[3]
A compound or 0 salt thereof according to claim 2, characterized by the fact that R ⁴ is Formula (IV).
[4]
4. Compound or salt thereof according to claim
Petition 870190100577, of 10/08/2019, p. 271/278
3/5 cation 3, characterized by the fact that X is O.
[5]
5. Compound or salt thereof according to claim 4, characterized by the fact that R ⁵ is H.
[6]
A compound or its salt according to claim 5, characterized by the fact that R ¹ is vinyl or cyclopropyl.
[7]
Compound or salt thereof according to claim 6, characterized in that R ^a is H, R ^b is H or F, R ^c is methyl or Cl, and R ^d is H.
[8]
A compound or salt thereof according to claim 7, characterized in that R ³ is C3-4 alkyl, methyl or npropyl each of which is replaced with two or more F's, or ethyl or C3-4 cycloalkyl each of which can be replaced with F.
[9]
A compound or salt thereof according to claim 8, characterized by the fact that R ^e is a non-aromatic heterocyclic group having 4 to 6 members in the ring that can be substituted, or C1-3 alkyl that can be substituted with a group selected from Group G.
[10]
A compound or 0 salt thereof according to claim 9, characterized by the fact that R ^e is oxetanil, tetrahydropyranyl, or C1-3 alkyl that can be substituted with a group selected from the group consisting of -OMe, - OEt, and C (Me) ₂ OH.
[11]
11. Compound or 0 salt thereof according to claim 1, characterized in that the compound is selected from the group consisting of (+) - 1 - (7- {8-ethoxy-7- (5-methyl -1 Hi ndazol-4-yl) -2 - [(1 methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7-diazaspiro [3.5] non-2il) prop-2-en -1-one, (+) - 1- {7- [6-cyclopropyl-2 - {[1- (2-methoxyethyl) piperidin-4-yl] oxy} -7 (5-methyl-1 H-indazole- 4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 Petition 870190100577, of 10/8/2019, p. 272/278
4/5 diazaespiro [3.5] non-2-il} prop-2-en-1-one, (+) - 1 - {7- [2 - {[1 - (2-methoxyethyl) pi perid i n- 4-yl] oxy} -7- (5-methyl I-1Hindazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaespiro [3.5] non -2-yl} prop-2-en-1-one, (+) - 1 - {7- [2 - {[1 - (2-ethoxyethyl) pi peridin-4-yl] oxy} -7- ( 5-methyl I-1Hindazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] non-2-yl} prop-2-en -1-one, (+) - 1 - {7- [6-cyclopropyl-2 - {[1 - (3-methoxypropyl) piperidin-4-yl] oxy} 7- (5-methyl-1H-indazol-4 -il) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7 diazospiro [3.5] non-2-yl} prop-2-en-1-one, (+) - 1 - {7- [7- (5-methyl-1 H-indazol-4-yl) -2 - {[1 - (tetrahydro-2Hpyran-4-yl) piperidin-4-yl] oxy} -8- ( 2,2,2-trifluoroethoxy) -6-vinylquinazolin-4-yl] 2,7-diazaospiro [3.5] non-2-yl} prop-2-en-1 -one, and (+) - 1 - {7 - [2 - {[1 - (2-hydroxy-2-methylpropyl) piperidin-4-yl] oxy} -7- (5methyl-1 H-indazol-4-yl) -8- (2,2,2- trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7 diazaospiro [3.5] non-2-yl} prop-2-en-1-one.
[12]
12. Pharmaceutical composition, characterized by the fact that it comprises:
the compound or its salt as defined in claim 11; and a pharmaceutically acceptable excipient.
[13]
Pharmaceutical composition according to claim 12, characterized in that it is a pharmaceutical composition for the treatment of lung cancer.
[14]
14. Use of the compound or its salt as defined in claim 1, characterized by the fact that it is for the manufacture of a pharmaceutical composition for the treatment of lung cancer.
[15]
15. Compound or its salt according to claim 1, characterized by the fact that it is for use in the treatment of lung cancer.
Petition 870190100577, of 10/08/2019, p. 273/278
5/5
[16]
16. A compound or its salt according to claim 11, characterized in that it is (+) - 1- (7- {8-ethoxy-7- (5-methyl-1Hindazol-4-yl) -2- [ (1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl} -2,7 diazaospiro [3.5] non-2-yl) prop-2-en-1-one.
[17]
17. A compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [6-cyclopropyl-2 - {[1- (2methoxyethyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4-yl) -8- (2,2,2trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl} prop- 2-en-1ona.
[18]
18. A compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [2 - {[1- (2-methoxyethyl) piperidin4-yl] oxy} -7- ( 5-methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl} prop-2 -en-1-one.
[19]
19. A compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [2 - {[1- (2-ethoxyethyl) piperidin-4yl] oxy} -7- ( 5-methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) -6vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl} prop-2 -en-1-one.
[20]
20. The compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [6-cyclopropyl-2 - {[1- (3methoxypropyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl} prop-2-en-1-one.
[21]
21. The compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [7- (5-methyl-1 H-indazol-4-yl) 2 - {[1 - (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] oxy} -8- (2,2,2-trifluoroethoxy) 6-vinylquinazolin-4-yl] -2,7-diazaospiro [3.5 ] non-2-il} prop-2-en-1-one.
[22]
22. The compound or its salt according to claim 11, characterized in that it is (+) - 1- {7- [2 - {[1- (2-hydroxy-2methylpropyl) piperidin-4-yl] oxy} -7- (5-methyl-1 H-indazol-4-yl) -8- (2,2,2trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl } prop-2en-1-one.

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法律状态:
2021-04-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 3A ANUIDADE. |

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2021-08-10| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2624 DE 20/04/2021. |

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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