THIAZOLO[5,4-b]PYRIDINE MALT-1 INHIBITORS

Abstract

To provide compounds that inhibit the MALT-1 protease activity.SOLUTION: The present disclosure provides compounds of the general formula (I), where R1a, R1b, R2, R3, R4, R5, R6, R7, R8 and ring A have any of the values defined in the specification, and pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to compounds that inhibit the activity of mucosal-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1), and compositions containing such compounds. [Background technology]

[0002] Adaptive immune system B and T cells utilize the multifaceted NF-κB signaling pathway to transmit extracellular signals via cognitive antigen receptors to enhance viability and proliferation. This signaling leads to rapid nuclear localization of NF-κB and activation of target genes, including inflammatory cytokines and negative regulators of apoptosis. A key downstream signaling hub of the NF-κB pathway is the CARD11-BCL10-MALT1 (CBM) complex, which plays an essential regulatory role. When B cell and T cell receptors are stimulated, the CBM complex is formed, recruiting multiple signaling proteins and triggering canonical NF-κB activation.

[0003] Paracaspase MALT1 is an essential regulator within the CBM complex. MALT1 not only acts as a scaffold for assembling protein complexes for NF-κB activation, but also as a protease that cleaves negative regulators of the NF-κB pathway for signal reinforcement.

[0004] In activated B-cell-like subtype diffuse large B-cell lymphoma (ABC-DLBCL), abnormal activation of NF-κB signaling occurs. ABC-DLBCL tumors possess gene expression signature characteristics of B cells activated through the B-cell receptor. In the case of DLBCL, gain-of-function alterations in the BCR pathway are frequently detected, and these mutations induce constitutive NF-κB activation required for tumor cell survival. [Overview of the project] [Problems that the invention aims to solve]

[0005] Considering the role of MALT-1 as a regulator of the NF-κB pathway, which plays a central role in diseases including ABC-DLBCL, compounds that inhibit MALT-1 protease activity are needed for use as anti-ABC-DLBCL therapies. Specifically, there is a need for MALT-1 compounds that inhibit MALT-1 protease activity and have improved pharmaceutical properties.

Means for Solving the Problems

[0006] (Summary of the Invention) In one aspect, the present disclosure provides a compound of formula (I)

[0007]

Chemical formula

[0008]

Chemical formula

[0009] In another embodiment, ring A is

[0010] [ka] In another embodiment, R 2 is H. In another embodiment, R 3 is H. In another embodiment, R 1a is OCH3. In another embodiment, R 1b is CHF2. In another embodiment, R 5 It is methyl.

[0011] In another embodiment, ring A is

[0012] [ka] In another embodiment, R 1a is OCH3. In another embodiment, R 1b is CHF2. In another embodiment, R 6 is a C1-C4 alkyl group. In another embodiment, R 5 These are C1-C4 alkyl groups.

[0013] In another embodiment, the compound is: N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-ethyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[3,5-difluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[3-fluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1S)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-[(1S)-1-(4-{[7-(1,1-difluoropropan-2-yl)-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)-3-fluorophenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; 1-Acetyl-N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide; 1-Acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide; 1-(3-hydroxypropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-(2-hydroxy-2-methylpropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-(2,3-dihydroxypropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-[(2R)-2-hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-[(2S)-2-hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-[(2R)-2,3-dihydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide; 1-Acetyl-N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide; 1-[(2S)-2,3-dihydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide; 1-Acetyl-N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide; 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; 1-Acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide; 1-Acetyl-N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide; N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2R)-1,1,1-trifluoropropan-2-yl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiane-4-carboxamide; and N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2S)-1,1,1-trifluoropropan-2-yl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiane-4-carboxamide; or selected from the group consisting of pharmaceutically acceptable salts thereof.

[0014] In another embodiment, the compound is N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0015] In another embodiment, the compound is N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 It is -Chiang-4-carboxamide.

[0016] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in any of the prior embodiments, in combination with a pharmaceutically acceptable carrier.

[0017] In another embodiment, the present disclosure provides a method for treating activated B-cell-like subtype diffuse large B-cell lymphoma (ABC-DLBCL) in a subject, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any of the preceding embodiments, to a subject in need thereof.

[0018] In another aspect, this disclosure relates to formula (1G)

[0019] [ka] The compound is given by formula (2G)

[0020] [ka] The compound is reacted with the solvent in the presence of a base and a catalyst to produce formula (3A).

[0021] [ka] (In the formula: R 1a It is selected from the group consisting of OCH3 and CH3, R 1b It is selected from the group consisting of CH3, CHF2, and CF3. R 2 It is selected from the group consisting of H and F, R 3 It is selected from the group consisting of H and F, R 4 It is selected from the group consisting of CHF2 and CF3, R 5 These are C1-C4 alkyl groups, Ring A is,

[0022] [ka] A ring selected from the group consisting of, R 6 It is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl, R 7 It is selected from the group consisting of H and C1-C4 alkyl groups, R 8 The present invention provides a method for synthesizing the compound of formula (3A) described in claim 1 by forming a compound of ( ), which is selected from the group consisting of CHF2 and CH3. [Modes for carrying out the invention]

[0023] This disclosure describes compounds that inhibit the activity of MALT-1.

[0024] Equation (I)

[0025] [ka] (In the formula: R 1aIt is selected from the group consisting of OCH3 and CH3, R 1b It is selected from the group consisting of CH3, CHF2, and CF3. R 2 It is selected from the group consisting of H and F, R 3 It is selected from the group consisting of H and F, R 4 It is selected from the group consisting of CHF2 and CF3, R 5 These are C1-C4 alkyl groups, Ring A is,

[0026] [ka] A ring selected from the group consisting of, R 6 It is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl, R 7 It is selected from the group consisting of H and C1-C4 alkyl groups, R 8 Compounds of which are selected from the group consisting of CHF2 and CH3 are disclosed herein.

[0027] definition Certain terms used herein are intended to refer to the following definitions, as detailed below.

[0028] It should be noted that the singular forms “a,” “an,” and “the” used herein and in the claims refer to multiple entities unless the context clearly indicates otherwise. Therefore, for example, a reference to “a compound” includes a single compound, as well as one or more identical or different compounds.

[0029] As used herein and in the appended claims, unless otherwise specified, the following terms have the meanings given: As used herein, the term "alkyl" refers to a saturated, linear, or branched hydrocarbon chain group. Typical examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0030] As used herein, the term "hydroxyalkyl" refers to one or more hydroxyl groups (OH) added to the parent molecule through an alkyl group as defined herein. Unless otherwise specified, a hydroxyalkyl group may have one, two, three, or four carbon atoms. Typical examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.

[0031] In some examples, the number of carbon atoms in a part is determined by the prefix "C". x ~C y This is indicated by ", where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Therefore, for example, "C1~C6 alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C1~C3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms.

[0032] In this disclosure (including the claims), the use of the words “comprise,” “comprises,” or “comprising” is, unless otherwise required by context, based on the principle and clear understanding that such words are to be interpreted comprehensively, not exclusively.

[0033] The term "pharmaceutical composition" refers to a composition suitable for administration in pharmaceutical use.

[0034] The term "pharmaceutically acceptable carrier" refers to a single pharmaceutically acceptable carrier, as well as one or more pharmaceutically acceptable carriers.

[0035] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-to-risk ratio.

[0036] The term “stable” refers to a compound that possesses sufficient stability to enable manufacturing and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein.

[0037] As used herein, the term “subject” refers to a human being. The terms “human being,” “patient,” and “subject” are used interchangeably herein.

[0038] The term "therapeutic dose" refers to the amount of a compound or a pharmaceutically acceptable salt thereof that is sufficient to treat one or more symptoms of the condition or disorder being treated when administered for the treatment of a particular subject or population.

[0039] As used herein, the terms “treat,” “treating,” and “treatment” refer to methods of reducing or suppressing a disease and / or its associated symptoms. compound The compounds of this disclosure have the general formula (I) described herein.

[0040] In embodiments, this disclosure relates to formula (I)

[0041] [ka] (In the formula: R 1a It is selected from the group consisting of OCH3 and CH3, R 1b It is selected from the group consisting of CH3, CHF2, and CF3. R 2 It is selected from the group consisting of H and F, R 3It is selected from the group consisting of H and F, R 4 It is selected from the group consisting of CHF2 and CF3, R 5 These are C1-C4 alkyl groups, Ring A is,

[0042] [ka] A ring selected from the group consisting of, R 6 It is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl, R 7 It is selected from the group consisting of H and C1-C4 alkyl groups, R 8 The present invention provides compounds or pharmaceutically acceptable salts thereof (selected from the group consisting of CHF2 and CH3).

[0043] The specific values ​​of the variable group in the compound of formula (I) are as follows. Such values ​​may be used, where appropriate, in conjunction with any of the other values, definitions, claims, or embodiments defined herein.

[0044] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a R is selected from the group consisting of OCH3 and CH3. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a It is CH3.

[0045] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b is selected from the group consisting of CH3, CHF2, and CF3. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b R is selected from the group consisting of CH3 and CHF2. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1bis selected from the group consisting of CH3 and CF3. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b is selected from the group consisting of CHF2 and CF3. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b is CH3. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b is CHF2. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1b is CF3.

[0046] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, and R 1b is CHF2.

[0047] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is selected from the group consisting of H and F. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is H, or a pharmaceutically acceptable salt thereof. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is F.

[0048] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, R 1b is CHF2, and R 2 is H.

[0049] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 3 is selected from the group consisting of H and F. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 3 is H. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 3 is F.

[0050] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, and R1b is CHF2, and R 2 is H, and R 3 is H.

[0051] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 4 is selected from the group consisting of CHF2 and CF3. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 4 is CHF2. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 4 is CF3.

[0052] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, R 1b is CHF2, R 2 is H, R 3 is H, R 4 is CF3.

[0053] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C1-C4 alkyl. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 5 is methyl. In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 5 is ethyl.

[0054] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, R 1b is CHF2, R 2 is H, R 3 is H, R 4 is CF3, R 5 is methyl.

[0055] In certain embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3, R 1b is CHF2, R 2 is H, R 3 is H, R4 CF3 and R 5 H is H.

[0056] In formula (I), or in some embodiments of its pharmaceutically acceptable salts, ring A is

[0057] [ka] Selected from the group consisting of: In one embodiment of formula (I), or a pharmaceutically acceptable salt thereof, ring A is

[0058] [ka] In formula (I), or in some embodiments of its pharmaceutically acceptable salts, ring A is

[0059] [ka] That is the case.

[0060] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 6 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 6 is a C1-C4 alkyl group. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 6 These are C1-C4 hydroxyalkyl groups.

[0061] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a It is OCH3, and R 1b It is CHF2, and R 2 H is R 3 H is R 4 CF3 and R 5 H is H, and ring A is,

[0062] [ka] That is the case.

[0063] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 7 R is selected from the group consisting of H and C1-C4 alkyl groups. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 7 is H. In some embodiments of formula (I), or its pharmaceutically acceptable salt, R 7 is a C1-C4 alkyl group. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 7 It is methyl.

[0064] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a It is OCH3, and R 1b It is CHF2, and R 2 H is R 3 H is R 4 CF3 and R 5 H is H, and ring A is,

[0065] [ka] And R 7 H is H.

[0066] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 8 is selected from the group consisting of CHF2 and CH3. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 8 is CHF2. In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 8 It is CH3.

[0067] In some embodiments of formula (I), or a pharmaceutically acceptable salt thereof, R 1a It is OCH3, and R 1b It is CHF2, and R 2 H is R 3 H is R 4 CF3 and R5 H is H, and ring A is,

[0068] [ka] And R 7 H is R 8 It is CH3.

[0069] The compounds disclosed herein may contain one or more variable compounds appearing more than once in any of the substituents or formulas herein. The definition of a variable compound is independent of its definition in each occurrence. Furthermore, a combination of substituents is permitted only if such a combination results in a stable compound.

[0070] The compounds and intermediates of this disclosure were named using the ACD / Name 2021.1.3 (file version N15E41, build 123232, July 7, 2021) software program and / or using the Struct=Name naming algorithm as part of CHEMDRAW® Professional v.15.0.0.106.

[0071] The compounds of exemplary formula (I) include, but are not limited to, the compounds shown in Table 1 below, and their pharmaceutically acceptable salts. In the event of any discrepancy between the names of compounds found herein and the structures found in Table 1, it should be understood that the structures in Table 1 shall prevail.

[0072] [Table 1] TIFF2023152927000020.tif231169TIFF2023152927000021.tif228170TIFF2023152927000022.tif118167

[0073] The compound of formula (I) may be used in the form of a pharmaceutically acceptable salt.

[0074] The compound of formula (I) may contain a basic or acidic functional group, or both, and may be converted to a pharmaceutically acceptable salt by using a suitable acid or base, if desired.

[0075] Method for creating exemplary compounds The compounds of this disclosure can be better understood with the following synthetic schemes and methods illustrating means by which the compounds can be prepared. The compounds of this disclosure can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in schemes 1 to 8, but are not limited thereto. Variable R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 8 And A are defined as detailed herein.

[0076] The abbreviations used in the scheme and its description have the following meanings: BOC stands for tert-butyloxycarbonyl protecting group.

[0077] Exemplary intermediates and representative schemes for synthesizing compounds of formula (I):

[0078] [ka]

[0079] Scheme 1 describes the synthesis of the intermediate of formula (1G). Formula (1A) (wherein R 1A , R 1B and R 8The compound (as described herein) can be converted to the compound of formula (1B) by reacting the former and (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. The reaction is typically carried out at ambient temperature in a solvent, for example, but not limited to dichloromethane. Separation of the compound of formula (1B) into the compounds of formulas (1C) and (1D) can be carried out via precipitation techniques described herein. The compound of formula (1D) can be hydrolyzed using a base, for example lithium hydroxide, followed by the addition of an acid, for example hydrochloric acid, to obtain the compound of formula (1E). The reaction is typically carried out in an aqueous environment and may be carried out at an elevated temperature, where the elevated temperature is above ambient temperature, for example, above 20°C. The compound of formula (1F) can be prepared by reacting the compound of formula (1E) with diphenyl azidophosphate in tert-butanol in the presence of a base, such as triethylamine. The reaction is typically carried out at an increasing temperature. The compound of formula (1G) can be prepared by treating the compound of formula (1F) with an acid in a solvent, such as dichloromethane, such as 2,2,2-trifluoroacetic acid. The reaction can be carried out at a low temperature.

[0080] [ka]

[0081] As shown in Scheme 2, equation (2A) (where R 2 , R 3 and R 4 The compound of formula (2B) (as described herein) can be reacted with (R)-2-methylpropane-2-sulfinamide and tetraisopropoxytitanium at increasing temperatures, followed by treatment with lithium trisec-butylborohydride at low temperatures to obtain the compound of formula (2B). The reaction is typically carried out in a solvent, such as tetrahydrofuran. The compound of formula (2D) can be obtained by treating the compound of formula (2B) with sodium hydride at low temperatures, followed by treatment with formula (2C) (wherein R 5 and X1 Compounds of formula (2D) (wherein A is as described herein) can be prepared by adding them to a solvent, for example, tetrahydrofuran, but not limited to tetrahydrofuran. Compounds of formula (2D) can be treated with hydrochloric acid in a solvent, for example, 1,4-dioxane, methanol, or a mixture thereof, to obtain compound (2E). Compounds of formula (2F) (wherein A is as described herein) can be treated with oxalyl chloride at ambient temperature to obtain an intermediate acid chloride, which is then reacted with compound (2E) and a base, for example, N,N-diisopropylethylamine, but not limited to tetrahydrofuran, to obtain compound (2G). The reaction is typically carried out in a solvent, for example, dichloromethane, N,N-dimethylformamide, or a mixture thereof.

[0082] [ka]

[0083] Scheme 3 describes the synthesis of the compound of formula (3A), which is representative of the compound of formula (I). Formula (1G) (wherein R 1A , R 1B and R 8 The compounds of formula (2G) (wherein R are as described herein) are: 2 , R 3 , R 4 , R 5 Compounds of formula (3A) can be obtained by coupling the compounds of (and A as described herein) under Buchwald coupling conditions, which may include the use of a base, for example but not limited to cesium carbonate, and a catalyst, for example but not limited to XantPhos Pd G3. The reaction is typically carried out at an increasing temperature in a solvent, for example but not limited to 1,4-dioxane.

[0084] [ka]

[0085] As shown in Scheme 4, equation (4A) (where R 1a and R 1b The compound of formula (as described herein) can be treated with iodomethane in the presence of a base, for example, potassium carbonate, to obtain the compound of formula (4B). The reaction is typically carried out at ambient temperature in a solvent, for example, N,N-dimethylformamide, to example. The compound of formula (4B) can be treated with selenium dioxide to obtain the compound of formula (4C). The reaction is typically carried out at an increasing temperature in a solvent, for example, 1,4-dioxane, to example. The compound of formula (4D) can be prepared by treating the compound of formula (4C) with [bis(2-methoxyethyl)amino]sulfur trifluoride at a low temperature, followed by heating. The reaction is typically carried out in a solvent, for example, toluene, to example. The compound of formula (4D) can be treated with a base, for example, sodium carbonate, at ambient temperature in a solvent, for example, methanol, to obtain the compound of formula (4E). The compound of formula (4F) can be prepared by reacting the compound of formula (4E) with diphenyl azidophosphate in tert-butanol in the presence of a base, such as triethylamine. The reaction is typically carried out at an increasing temperature. The compound of formula (4F) can be used as described in Scheme 3 to obtain the compound of formula (I).

[0086] [ka]

[0087] Scheme 5 describes the synthesis of compound (5C), which is representative of compound (I). Formula (5A) (wherein R 8 , R 1a and R 1bThe compound (as described herein) can be coupled to (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine under Buchwald coupling conditions, which may include the use of a base, e.g., cesium carbonate, and a catalyst, e.g., XantPhos Pd G3 XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g. XantPhos Pd G3, e.g

[0088] [ka]

[0089] As shown in Scheme 6, equation (6A) (where R 8The compound of formula (as described herein) can be treated with a base, for example, LiOH, but not limited to, to obtain the compound of formula (6B). The reaction is typically carried out at ambient temperature in an aqueous solvent system, for example, a mixture of water and 1,4-dioxane, but not limited to. The compound of formula (6C) can be prepared by reacting the compound of formula (6B) with diphenyl azidophosphate in tert-butanol in the presence of a base, for example, triethylamine. The reaction is typically carried out at rising temperatures. The compound of formula (6C) can be treated with sodium iodide and acetyl chloride to obtain the compound of formula (6D). The reaction is typically carried out at low temperatures in a solvent, for example, acetonitrile, but not limited to. Compounds of formula (6E) can be prepared by reacting compound (6D) with 4,4,6-trimethyl-2-(3,3,3-trifluoropropane-1-en-2-yl)-1,3,2-dioxaborinane in the presence of a base, such as but not limited to cesium carbonate, and a catalyst, such as but not limited to [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane. The reaction is typically carried out at an increasing temperature, via microwave irradiation, and may also be heated in a solvent, such as 1,2-dimethoxyethane, water, or a mixture thereof. Compounds of formula (6E) can be treated with hydrogen gas and palladium (5% by weight on carbon) to obtain compound (6F). The reaction is typically carried out at an increasing temperature in a solvent, such as but not limited to ethanol. The compound of formula (6G) can be prepared by treating the compound of formula (6F) with 2,2,2-trifluoroacetic acid in dichloromethane at ambient temperature. The compound of formula (6G) can be used as described in Scheme 3 to obtain the compound of formula (I).

[0090] [ka]

[0091] Scheme 7 describes the synthesis of a compound of formula (7B) that can be used as an intermediate in the synthesis of a compound of formula (I). A compound of formula (7A) (where R 4 is as described herein) can be reacted with 1-acetylpiperidine-4-carbonyl chloride in the presence of pyridine and N,N-dimethylpyridin-4-amine to obtain a compound of formula (7B).

[0092]

Chemical formula

[0093] 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid is treated with oxalyl chloride at ambient temperature to obtain an intermediate acid chloride, followed by a compound of formula (7A) (where R 4Compound (8A) can be obtained by reacting a compound of formula (8A) (as described herein) with a base, for example, but not limited to N,N-diisopropylethylamine. The reaction is typically carried out at low temperatures in a solvent, for example, dichloromethane, N,N-dimethylformamide, or a mixture thereof. Compound (8A) can be obtained by reacting a compound of formula (5A) with a compound of formula (5A) under Buchwald coupling conditions, including the presence of a base, for example, but not limited to cesium carbonate, and a catalyst, for example, but not limited to XPhos Pd G3. The reaction is typically carried out at rising temperatures in a solvent, for example, but not limited to dioxane. Compound (8C) can be prepared by treating compound (8B) with an acid, for example, 2,2,2-trifluoroacetic acid, in a solvent, for example, dichloromethane. The compound of formula (8D), which is representative of the compound of formula (I), can be prepared by reacting the compound of formula (8C) with 2-hydroxyacetic acid, a coupling agent, for example but not limited to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, and a base, for example but not limited to N,N-diisopropylethylamine. The reaction is typically carried out at ambient temperature in a solvent, for example but not limited to N,N-dimethylformamide.

[0094] It should be recognized that the synthesis schemes and specific examples illustrated in the Synthesis Examples section are illustrative and should not be construed as limiting the scope of the attached claims. All substitutes, modifications, and equivalents in the synthesis methods and specific examples are included within the scope of the claims.

[0095] The optimal reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in them. Specific procedures are shown in the Synthesis Examples section. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.

[0096] Pharmaceutical composition When used as a pharmaceutical, the compounds of this disclosure may be administered in the form of a pharmaceutical composition. Such a composition may contain a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

[0097] How to use Compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising compound (I) or pharmaceutically acceptable salts thereof, may be administered to subjects suffering from ABC-DLBCL. The term "administer" refers to the method by which the compound is brought into contact with the subject requiring it.

[0098] In another embodiment, the compounds of the Disclosure, or pharmaceutical compositions comprising the compounds of the Disclosure, may be used for drug use. In a particular embodiment, the compounds of the Disclosure, or pharmaceutical compositions comprising the compounds of the Disclosure, may be used for the treatment of diseases or disorders described above herein, including ABC-DLBCL.

[0099] This disclosure also covers the use of the compound according to formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of ABC-DLBCL. [Examples]

[0100] The following embodiments may be used for illustrative purposes and should not be considered to limit the scope of this disclosure.

[0101] All reagents were commercial grade and, unless otherwise specified, were used as received without further purification. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. Reagent-grade solvents were used in all other cases unless otherwise specified. 1 The chemical shift (δ) of the 1H NMR spectrum is reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal standard, or to a suitable residual solvent peak, i.e., CHCl3 (δ 7.27).

[0102] The following abbreviations have the meanings indicated unless otherwise specified: NMR is nuclear magnetic resonance; s is singleline; br s is broad singleline; d is doublet or doubleline; m is multiline; t is tripleline; q is quadrupleline; LC / MS or LCMS is liquid chromatography-mass spectrometry; min is minute; mL is milliliter; μL is microliter; L is liter; g is gram; mg is milligram; mmol is millimoles; HPLC is high-pressure liquid chromatography; ppm is parts per million; DCI is desorption chemical ionization; DSI is droplet spray ionization; ESI is electrospray ionization; M is molar concentration (moles / liter); N is normality (equivalents / liter); and APCI is atmospheric pressure chemical ionization.

[0103] [Example 1] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0104] [Example 1A] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate N,N'-dicyclohexylcarbodiimide (175 g) and 4-dimethylaminopyridine (9.44 g) were added to a solution of 7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid (195 g, WO2018020474A1) in dichloromethane (2 L), and the reaction mixture was stirred at 20°C for 10 minutes. (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (101 g) was added, and the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was pulverized with tetrahydrofuran (2.5 L) at 50°C for 30 minutes. The reaction mixture was concentrated under vacuum to reduce the volume to approximately 400 mL, and stirred at 20°C for 30 minutes. The precipitate was collected by filtration to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.78 (s, 0.2H), 8.70 (s, 1H), 5.67 (s, 1H), 5.63 (s, 0.2H), 5.45 - 5.39 (m, 0.2H), 5.36 (q, 1H), 4.12 (s, 2H), 3.30 (s, 3H), 3.30 - 3.29 (m, 0.7H), 2.90 (s, 3H), 1.78 (d, 0.7H), 1.74 (d, 3H), 1.36 (s, 3H), 1.35 (br s, 0.7H), 1.25 (s, 3H), 1.19 (s, 0.7H).

[0105] [Example 1B] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate; and

[0106] [Example 1C] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate Example 1A (370g) in tetrahydrofuran (3L) was stirred at 70°C for 30 minutes. The mixture was concentrated under vacuum to reduce its volume to approximately 1L, and then stirred at 25°C for 30 minutes. The resulting precipitate was collected by filtration to obtain the crude product. The process was repeated three times, and the precipitate was collected by filtration to obtain Example 1B. The mother liquor from the first filtration was concentrated under vacuum to obtain Example 1C. Example 1B: 1 ¹H NMR (400 MHz, CDCl3) δ ppm 8.70 (s, 1H), 5.68 (s, 1H), 5.37 (q, 1H), 4.12 (s, 2H), 3.30 (s, 3H), 2.90 (s, 3H), 1.75 (d, 3H), 1.36 (s, 3H), 1.25 (s, 3H). Combined chiral purity of Example 1B: 97.66% de. Chiral purity of Example 1C: 92% de.

[0107] [Example 1D] (S)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid A mixture of Example 1B (230 g) and lithium hydroxide hydrate (79 g) in water (1.2 L) was stirred at 80°C for 1.5 hours. The reaction mixture was filtered, and the filtrate was diluted with water (2 L). A 6 M HCl aqueous solution was added to adjust the pH to 1.57. The mixture was heated to 100°C for 50 minutes, and then stirred at 100°C for 30 minutes. The mixture was cooled to 25°C for 5 hours and stirred for 30 minutes. The precipitate was collected by filtration to obtain the crude product, which was ground in water (2 L) at 25°C for 30 minutes. The precipitate was collected by filtration, air-dried for 3 hours, and then dried under vacuum at 50°C for 6 hours to obtain the title compound. 1 ¹H NMR (400 MHz, CDCl3) δ ppm 9.13 (s, 1H), 5.91 - 5.83 (m, 1H), 3.47 (s, 3H), 2.89 (s, 3H), 1.73 (d, 3H). No single exchangeable proton was observed.

[0108] [Example 1E] tert-Butyl (S)-(7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate To a solution of Example 1D (20 g) in tert-butanol (305 mL) at 40 °C under a nitrogen atmosphere, triethylamine (14.36 mL) was added. The mixture was heated to 60 °C and diphenyl azidophosphate (18.79 mL) was added dropwise over about 6 minutes. The reaction mixture was stirred at 60 °C for 5 hours. After cooling to ambient temperature, sodium hydroxide (5 wt% in water, 60 mL) was added to the reaction mixture, which was then concentrated in vacuo. Water (200 mL) was added and the suspension was stirred for 15 minutes. The precipitate was collected by filtration, washed with water (2 × 200 mL) and air dried for 1 hour. Ethyl acetate (600 mL) was added to the precipitate and the resulting suspension was warmed to about 40 °C and stirred until a slightly turbid solution was formed. The solution was cooled to ambient temperature, stirred for 30 minutes and filtered. The filtrate was concentrated in vacuo to give the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 9.30 (s, 1H), 8.40 (s, 1H), 5.57 (q, 1H), 3.38 (s, 3H), 2.81 (s, 3H), 1.56 (d, 9H). MS(ESI) m / z 324.3(M+H) + 。

[0109] [Example 1F] (S)-7-(1-Methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine To a solution of Example 1E (22.9 g) in anhydrous dichloromethane (201 mL), 2,2,2-trifluoroacetic acid (46.4 mL) was added over 7 minutes at 10°C. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. Dichloromethane (100 mL) was added, and disodium hydrogen phosphate (1 M in water) was added to adjust the pH to neutral. The phases were separated, the organic layer was washed with brine, dehydrated with sodium sulfate, and filtered. The filtrate was concentrated under vacuum. Ethyl acetate (150 mL) was added, and the resulting suspension was stirred for 5 minutes and filtered. The filtrate was diluted with heptane (150 mL), stirred for 5 minutes, and filtered. The filtrate was concentrated under vacuum to approximately 80 mL. Heptane (150 mL) was added, and the mixture was stirred at 70°C for 5 minutes. The mixture was cooled to ambient temperature, and the precipitate was collected by filtration to obtain the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 7.99 (s, 1H), 5.50 (q, 1H), 4.16 (s, 2H), 3.35 (s, 3H), 2.79 (s, 3H), 1.57 (d, 3H).MS(ESI)m / z 224.2(M+H) + .

[0110] [Example 1G] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide A mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (3.01 mL), (R)-2-methylpropane-2-sulfinamide (2.99 g), and tetraisopropoxytitanium (14.63 mL) was dissolved in tetrahydrofuran (200 mL) and stirred overnight at 50°C. The reaction mixture was cooled to -78°C, lithium trisec-butylbohydride (1 M in tetrahydrofuran, 59.3 mL) was added, and the reaction mixture was stirred at -78°C for 3 hours. Brine (50 mL) was added to the reaction mixture and warmed to ambient temperature. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate (200 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The crude substance was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.58 - 7.52 (m, 2H), 7.33 - 7.30 (m, 2H), 4.80 (p, 1H), 3.59 (d, 1H), 1.25 (s, 9H).MS(ESI)m / z 358 / 360(M+H) + .

[0111] [Example 1H] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-2-dimethylpropane-2-sulfinamide At 0°C, sodium hydride (0.475 g) was gradually added to the solution of Example 1G (3.73 g) in tetrahydrofuran (50 mL), and the reaction mixture was stirred at 0°C for 2 hours. Iodomethane (3.26 mL) was added to the reaction mixture and stirred at 0°C for 10 minutes, and then at ambient temperature for another 10 minutes. Saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dehydrated with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The crude substance was purified by chromatography on silica gel (0-60% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.56 - 7.49 (m, 2H), 7.39 - 7.30 (m, 2H), 5.05 (q, 1H), 2.45 (s, 3H), 1.25 (s, 9H).MS(ESI)m / z 372.1 / 374.2(M+H) + .

[0112] [Example 1I] (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethaneamine In Example 1, 1.90 g of H was dissolved in 15 mL of 1,4-dioxane and 15 mL of methanol. 4 M HCl in 5.10 mL of 1,4-dioxane was added to the solution, and the reaction mixture was stirred at ambient temperature for 2 hours. The solution was concentrated under vacuum, and 80 mL of 0.5 M aqueous HCl solution was added. The aqueous layer was extracted with ethyl acetate (3 × 30 mL). Sodium hydroxide (2 M in water) was added to the aqueous layer to adjust the pH to 14, and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 - 7.58 (m, 2H), 7.47 - 7.38 (m, 2H), 4.30 (p, 1H), 2.87 (dq, 1H), 2.20 (d, 3H).MS(ESI)m / z 268.1 / 270.1(M+H) + .

[0113] [Example 1J] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.83 g) in dichloromethane (20 mL), oxalyl chloride (0.41 mL) and N,N-dimethylformamide (0.014 mL) were added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under vacuum. The residue was dissolved in dichloromethane (10 mL) and added to a solution of Example 1I (0.96 g) and N,N-diisopropylethylamine (1.876 mL) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 90 minutes and dichloromethane (20 mL) and brine (30 mL) were added. The phases were separated, and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (2 × 30 mL), dehydrated with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The crude substance was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (d, 2H), 7.32 (d, 2H), 6.54 (q, 1H), 3.31 - 3.00 (m, 5H), 2.88 (s, 3H), 2.18 - 1.89 (m, 4H).MS(ESI)m / z 428 / 430(M+H) + .

[0114] [Example 1K] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide To a degassed mixture of Example 1F (60 mg), Example 1J (127 mg), and cesium carbonate (263 mg) in 1,4-dioxane (6 mL), XantPhos Pd G3 ([(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate) (25.5 mg) was added, and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth, washed with ethyl acetate (20 mL), and concentrated under vacuum. The crude substance was purified by chromatography on silica gel (0-80% ethyl acetate-ethanol (3:1) / 2-methylpentane), and the residue was precipitated from dichloromethane / 2-methylpentane to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6, 90℃) δ ppm 8.48 (s, 1H), 7.57 (s, 1H), 7.25 (d, 2H), 7.10 - 7.01 (m, 2H), 6.42 (s, 1H), 5.39 (q, 1H), 3.27 (s, 3H), 3.24 - 3.03 (m, 5H), 2.91 (s, 3H), 2.83 (s, 3H), 2.10 (td, 4H), 1.54 (d, 3H).MS(ESI)m / z 571.2(M+H) + .

[0115] [Example 2] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide Example 11G (50 mg, 0.180 mmol), Example 1J (85 mg, 0.198 mmol), XPhos Pd G2 (14.19 mg, 0.018 mmol), and cesium carbonate (176 mg, 0.541 mmol) were mixed in 1,4-dioxane (0.9 mL). The mixture was sparged with nitrogen for 10 minutes, and the reaction vial was sealed. The reaction was stirred at 95°C for 16 hours. After cooling, the reaction mixture was loaded directly onto a 40 g silica gel column. The crude product was purified by flash chromatography (0-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 7.60 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.46 (q, J = 9.3 Hz, 1H), 5.93 (q, J = 7.6 Hz, 1H), 3.52 (s, 3H), 3.30 - 3.07 (m, 5H), 2.91 (s, 3H), 2.86 (s, 3H), 2.16 - 1.97 (m, 4H).MS(APCI)m / z 625.3(M+H) + .

[0116] [Example 3] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0117] [Example 3A] Ethyl 2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-carboxylate To a mixture of ethyl 7-chloro-2-methylthiazolo[5,4-b]pyridine-6-carboxylate (60 g, 234 mmol, WO2018020474A1, Example 16, Step 2) in 1,4-dioxane (600 mL) and water (100 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (72.0 g, 467 mmol), tetrakis(triphenylphosphine)palladium(0) (27.0 g, 23.37 mmol), and Na2CO3 (61.9 g, 584 mmol) were added. The mixture was stirred at 100°C for 12 hours, then 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (14.4 g, 93.4 mmol), tetrakis(triphenylphosphine)palladium(0) (5.4 g, 4.67 mmol), and Na2CO3 (12.4 g, 116.8 mmol) from a separate batch were added, and the mixture was stirred at 100°C for a further 4 hours. After cooling to 25°C, the reaction was quenched with water (500 mL) and extracted with ethyl acetate (3 × 1500 mL). The combined organic phase was washed with brine (300 mL), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J = 7.1 Hz, 3H), 2.85 (s, 3H), 4.30-4.42 (m, 2H), 5.89-5.97 (m, 1H), 6.63-6.74 (m, 1H), 7.27-7.39 (m, 1H), 8.82 (s, 1H).LCMS(ES)m / z(M+H) + 249.2.

[0118] [Example 3B] 2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-carboxylic acid To the solution of 1,4-dioxane (120 g, 483 mmol) in 1,4-dioxane (960 mL) and water (720 mL) of Example 3A, lithium hydroxide (17.36 g, 725 mmol) was added, and the reaction was stirred at 20°C for 2 hours. The mixture was concentrated under vacuum to remove most of the 1,4-dioxane. The pH was adjusted to approximately 3 with 2 M aqueous HCl, and the mixture was filtered. The filtered cake was washed with water (1000 mL), dissolved in tetrahydrofuran (1000 mL), dehydrated with MgSO4, filtered, and concentrated to obtain the title compound. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.87 (s, 3H), 5.95 (dd, J = 11.7, 2.1 Hz, 1H), 6.74 (dd, J = 17.6, 2.1 Hz, 1H), 7.45 (dd, J = 17.6, 11.7 Hz, 1H), 8.87 (s, 1H), 13.62 (s, 1H).LCMS(ES)m / z 221(M+H) + .

[0119] [Example 3C] tert-butyl(2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-yl)carbamate Diphenyl phosphoryl azide (137 g, 497 mmol) was added to a mixture of Example 3B (73 g, 331 mmol, oven-dried) and triethylamine (138 mL, 994 mmol, molecularly dried) in toluene (1095 mL, dried on a molecular sieve). After stirring at 20°C for 1 hour, tert-butanol (91 mL, 994 mmol, molecularly dried) was added, and the mixture was stirred at 90°C for 2 hours. After cooling, the mixture was concentrated to a small amount. The residue was poured into water (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layer was washed with brine (500 mL), dehydrated with Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (1:3 ethyl acetate / petroleum ether) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 9H), 2.86 (s, 3H), 5.89 (d, J = 11.5 Hz, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.93-7.06 (m, 1H), 8.43 (s, 1H), 9.09 (s, 1H).LCMS(ES)m / z 292.25(M+H) + .

[0120] [Example 3D] tert-butyl(7-formyl-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate Example 3C (50 g, 172 mmol) was dissolved in acetonitrile (750 mL), water (750 mL), and tetrahydrofuran (750 mL), and treated with potassium osmium(VI) dihydrate (6.32 g, 17.16 mmol), followed by sodium periodate (110 g, 515 mmol) at 0°C. The reaction was warmed to 20°C and stirred overnight. The mixture was filtered, and the filtered cake was dissolved in dichloromethane (2500 mL) and water (2000 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 1000 mL). The combined organic layers were washed with brine (800 mL), dehydrated with MgSO4, filtered, and concentrated to obtain the title compound. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.53 (s, 9H), 2.93 (s, 3H), 9.41 (s, 1H), 10.17 (s, 1H), 10.81 (s, 1H).LCMS(ES)m / z 294.05(M+H) + .

[0121] [Example 3E] tert-butyl(7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate To a suspension of Example 3D (50 g, 170 mmol) and triphenylphosphine (71.5 g, 273 mmol) in N,N-dimethylformamide (350 mL), (bromodifluoromethyl)trimethylsilane (42.4 mL, 273 mmol) was added, and the reaction mixture was stirred at 25°C for 3 hours. 1.5 M potassium hydroxide (352 mL, 528 mmol) was slowly added, and the reaction mixture was stirred at 0°C for a further 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution (400 mL), and the mixture was extracted with ethyl acetate (4 × 800 mL). The organic layers were combined, washed with brine (700 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (3:7 ethyl acetate / petroleum ether) to obtain tert-butyl(7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate (50 g, purity 83%, containing POPh3) and tert-butyl(7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate (265 g, purity 65%, containing POPh3). POPh3 was removed in the following step. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 9H), 2.82 (s, 3H), 5.75 (s, 1H), 6.39 (t, J = 55.2 Hz, 1H), 7.28 -7.43 (m, 1H), 8.87 (s, 1H), 8.98 (s, 1H).LCMS(ES)m / z 346.25(M+H) + .

[0122] [Example 3F] 1-(6-amino-2-methylthiazolo[5,4-b]pyridine-7-yl)-2,2-difluoroethane-1-ol The solution of Example 3E (50 g, 145 mmol) in 1,4-dioxane in 4 M HCl (500 mL, 2000 mmol) was stirred at 25°C for 4 hours and then filtered. The filtered cake was dissolved in ethyl acetate, basicized to approximately pH 8 with saturated sodium carbonate aqueous solution, and extracted with ethyl acetate (4 × 600 mL). The combined organic extracts were washed with water (800 mL), saturated sodium bicarbonate solution (800 mL), and brine (800 mL). The organic layer was dehydrated with Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The crude product was purified by column chromatography (2:3 ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.74 (s, 3H), 5.58 (d, J = 26.5 Hz, 3H), 6.12-6.49 (m, 1H), 6.74 (s, 1H), 8.05 (s, 1H).LCMS(ES)m / z 346.01(M+H) + .

[0123] [Example 3G] (R)-7-(2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine

[0124] [Example 3H] (S)-7-(2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine To a solution of Example 3E (25 g, 102 mmol) in N,N-dimethylformamide (500 mL), sodium hydride (4.89 g, 122 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 20 minutes. Iodomethane (15.92 g, 112 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with a semi-saturated brine solution (1000 mL), and the mixture was extracted with ethyl acetate (4 × 600 mL). The organic layers were combined, washed with water (3 × 600 mL) and brine (3 × 500 mL), dehydrated with Na₂SO₄, and filtered. The filtrate was concentrated under vacuum. The crude racemic mixture was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to obtain the desired product as a mixture of enantiomers (49.3 g). Enantiomers were separated by preparative chiral SFC using a CHIRAL ART Cellulose-SB, 5 × 25 cm, 10 μm column. The conditions used were as follows: Mobile phase A: CO2, Mobile phase B: Isopropyl alcohol (0.5% 2M ammonia solution in methanol); Flow rate: 200 mL / min; Gradient: Isocratic 20% B; Column temperature: 35°C; Back pressure: 100 bar; Wavelength: 220 nm. Retention time for Example 3G: 6.93 min; Retention time for Example 3H: 8.25 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3H), 3.32 (s, 3H), 5.34-5.45 (m, 1H), 5.59 (s, 2H), 6.36-6.65 (m, 1H), 8.09 (s, 1H).LCMS(ES)m / z 260(M+H) + .

[0125] [Example 3I] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide To a degassed mixture of 1,4-dioxane (2 mL), Example 3 G (39 mg), Example 1 J (85 mg), and cesium carbonate (147 mg), XantPhos Pd G3 (14.26 mg) was added, and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth, washed with ethyl acetate (20 mL), and concentrated under vacuum. The crude substance was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 8.00 (s, 1H), 7.20 (d, 2H), 6.97 (d, 2H), 6.89 - 6.62 (m, 1H), 5.31 (dt, 1H), 6.43 (q, 1H), 3.28 (s, 3H), 3.25 - 3.04 (m, 5H), 2.90 (s, 3H), 2.86 (s, 3H), 2.10 - 1.95 (m, 4H).MS(ESI)m / z 607.2(M+H) + .

[0126] [Example 4] N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0127] [Example 4A] 1-(4-bromophenyl)-2,2-difluoroethane-1-one 1-Bromo-4-iodobenzene (50 g, 177 mmol) was dissolved in tetrahydrofuran (500 mL), to which n-butyllithium (78 mL, 194 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes. Ethyl 2,2-difluoroacetate (24.12 g, 194 mmol) was added dropwise over 1 hour at -78°C. The reaction mixture was stirred at -78°C for a further 1 hour, then at 0°C for 1 hour. The reaction was quenched with 1N aqueous HCl (15 mL) and extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography using ethyl acetate / petroleum ether to obtain the title compound. 1 H NMR (400 MHz, DMSO) δ ppm 7.16 (t, 1H), 7.80-7.89 (m, 2H), 7.94- 8.01 (m, 2H).

[0128] [Example 4B] (S)-1-(4-bromophenyl)-2,2-difluoro-N-methylethaneamine In Example 4A (30 g, 128 mmol), sodium cyanoborate (16.04 g, 255 mmol) was gradually added to a solution of methaneamine (39.6 g, 383 mmol) and titanium(IV) isopropoxide (72.6 g, 255 mmol) in ethyl alcohol and dichloromethane (450 mL). The reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was quenched with ammonium hydroxide (33% in water), and the solvent was removed under vacuum. The residue was purified by flash chromatography (1:1 petroleum ether / dichloromethane). The enantiomers were separated by normal-phase HPLC using a CHIRALPAK® OD-H column (20 × 250 mm, 5 micron) with hexane (0.1% diethylamine) / isopropanol, 20 mL / min; elution in 10 minutes, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3H), 2.54 (d, J = 3.2 Hz, 1H), 3.79-3.94 (m, 1H), 5.89-6.25 (m, 1H), 7.33-7.40 (m, 2H), 7.55-7.61 (m, 2H).MS(ESI)m / z 250(M+H) + . [α] 22.7 D = +50.67(C 0.01 CH3OH).

[0129] [Example 4C] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine Example 1F (152 mg, 0.682 mmol), Example 4B (155 mg, 0.620 mmol), XPhos Pd G2 (48.8 mg, 0.062 mmol), and cesium carbonate (606 mg, 1.859 mmol) were mixed in 1,4-dioxane (8.9 mL). The mixture was sparged with nitrogen for 5 minutes, and the container was sealed. The reaction was stirred at 90°C for 16 hours. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography (40 g silica gel, 0-70% ethyl acetate / heptane) to obtain the title compound. MS(ESI) m / z 393.0(M+H) + .

[0130] [Example 4D] N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide Tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (113 mg, 0.633 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (142 mg, 0.791 mmol), and N-methylmorpholine (87 μL, 0.791 mmol) were mixed in dichloromethane (2.7 mL) and stirred at ambient temperature for 1 hour. The mixture of Example 4C (207 mg, 0.527 mmol) in dichloromethane (2.7 mL) was added, and the mixture was stirred overnight at ambient temperature. The mixture was concentrated and directly purified by reverse-phase HPLC (C18 Phenomenex® LUNA®, 250 × 50 mm, 10-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The fraction containing the product was concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1g SiliCycle SiliaPrep carbonate cartridge to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.49 (s, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.66 (t, J = 54.9 Hz, 1H), 5.70 (s, 1H), 5.40 (q, J = 6.7 Hz, 1H), 3.28 (s, 3H), 3.25 - 3.06 (m, 5H), 2.93 (s, 3H), 2.83 (s, 3H), 2.09 (q, J = 7.1, 5.4 Hz, 4H), 1.54 (d, J = 6.6 Hz, 3H).MS(APCI)m / z 553.2(M+H) + .

[0131] [Example 5] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0132] [Example 5A] 7-((S)-2,2-difluoro-1-methoxyethyl)-2-methyl-N-(4-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)phenyl)thiazolo[5,4-b]pyridine-6-amine Example 3H (1.00 g, 3.86 mmol), Example 1I (1.29 g, 4.24 mmol), and cesium carbonate (3.77 g, 11.6 mmol) were sparged with N2 for 2 minutes in 1,4-dioxane (19 mL). XPhos Pd G4 (methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(ii), 0.33 g, 0.39 mmol) was added, and the reaction mixture was heated at 95°C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated. The material was purified on silica gel (0-70% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 7.84 (s, 1H), 7.29 (d, J = 8.3 Hz, 3H), 6.95 (d, J = 8.6 Hz, 2H), 6.75 (ddd, J = 57.6, 54.5, 5.9 Hz, 1H), 5.34 (dt, J = 13.9, 5.7 Hz, 1H), 4.10 (q, J = 8.1 Hz, 1H), 3.29 (s, 3H), 2.86 (s, 3H), 2.22 (d, J = 5.8 Hz, 3H).MS(ESI)m / z 447.7(M+H) + .

[0133] [Example 5B] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide Tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.60 g, 3.36 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (0.65 g, 3.58 mmol), CH2Cl2 (50 mL), and N-methylmorpholine (0.394 mL, 3.58 mmol) were stirred at ambient temperature for 1 hour. Example 5A (1.00 g, 2.24 mmol) was added to this solution, and the combined solution was stirred at ambient temperature for 15 hours. After evaluation by LC-MS, the reaction mixture was concentrated. The residue was purified on silica gel (0-100% ethyl acetate / heptane) to obtain the residue. The residue was further purified by reverse-phase chromatography (C18 250×50 mm C18 Phenomenex® LUNA® HPLC column, eluted with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated to remove acetonitrile. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate aqueous solution to obtain the desired product, the free base. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was freeze-dried to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.99 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.01 6.92 (m, 2H), 6.75 (ddd, J = 57.7, 54.3, 5.9 Hz, 1H), 6.44 (q, J = 9.3 Hz, 1H), 5.31 (dt, J = 14.1, 5.5 Hz, 1H), 3.28 (s, 3H), 3.26 3.06 (m, 4H), 2.91 (s, 3H), 2.86 (s, 3H), 2.17 1.91 (m, 4H).MS(ESI+)m / z 607.3(M+H) + .

[0134] [Example 6] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0135] [Example 6A] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine The title compound (235 mg, 86%) was prepared using the conditions described in Example 4C, with Example 3G replaced by Example 1F. MS(APCI)m / z 429.3(M+H) + .

[0136] [Example 6B] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide The title compound (145 mg, 45%) was prepared using the conditions described in Example 4D, with Example 6A replaced by Example 6A4C. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 7.61 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.07 - 6.89 (m, 2H), 6.66 (ddd, J = 56.8, 54.8, 5.5 Hz, 2H), 5.70 (s, 1H), 5.40 (ddd, J = 13.0, 7.3, 5.5 Hz, 1H), 3.37 (s, 3H), 3.32 - 3.04 (m, 5H), 2.93 (s, 3H), 2.85 (s, 3H), 2.21 - 1.95 (m, 4H).MS(APCI)m / z 589.3 (M+H)+ .

[0137] [Example 7] N-ethyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0138] [Example 7A] (S)-1-(4-bromophenyl)-N-ethyl-2,2,2-trifluoroethaneamine To a solution of Example 1I (0.4 g, 1.575 mmol) in methanol (5.3 mL), acetaldehyde (0.088 mL, 1.575 mmol) was added dropwise. The mixture was stirred at ambient temperature for 1 hour, followed by the addition of sodium borohydride (0.119 g, 3.15 mmol). Stirring was continued for 18 hours. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was concentrated and purified by reverse-phase HPLC (250 × 50 mm Phenomenex® LUNA® C18, 10-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to obtain the title compound (100 mg, 16.03%). MS (APCI) m / z 282.2 (M+H) + .

[0139] [Example 7B] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-ethyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.084 g, 0.47 mmol) in dichloromethane (1.880 mL), oxalyl chloride (0.470 mL, 0.940 mmol) and N,N-dimethylformamide (3.64 μL, 0.047 mmol) were added at 0°C. The mixture was stirred for 1 hour while being warmed to ambient temperature. The reaction was concentrated to obtain crude tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide, which was mixed in dichloromethane (0.8 mL). The suspension was added dropwise to a solution of Example 7A (66.3 mg, 0.235 mmol) and triethylamine (0.07 mL, 0.470 mmol) in dichloromethane (0.8 mL). The reaction was stirred at ambient temperature for 20 hours. The mixture was directly purified by flash chromatography (12g silica gel, 0-70% acetone / heptane) to obtain the title compound (15mg, 14.43%). MS(APCI)m / z 442.1(M+H) + .

[0140] [Example 7C] N-ethyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide Example 1F (19.69 mg, 0.088 mmol), Example 7B (30 mg, 0.068 mmol), XPhos Pd G2 (5.34 mg, 6.78 μmol), and cesium carbonate (66.3 mg, 0.203 mmol) were mixed in 1,4-dioxane (1.0 mL). The mixture was sparged with nitrogen for 5 minutes and the container was sealed. The reaction was stirred at 90°C for 16 hours. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The collected fraction containing the product was concentrated and re-purified by flash chromatography (12 g silica gel, 0-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.57 (s, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.33 (s, 1H), 5.38 (q, J = 6.7 Hz, 1H), 3.51 - 3.04 (m, 10H), 2.83 (s, 3H), 2.27 - 1.95 (m, 4H), 1.53 (d, J = 6.6 Hz, 3H), 0.88 (m, 3H).MS(APCI)m / z 585.2(M+H) + .

[0141] [Example 8] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0142] [Example 8A] (R)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid Example 1C (20 g, 54.9 mmol), lithium hydroxide-H2O (11.52 g, 274 mmol), tetrahydrofuran (80 mL), and water (40 mL) were stirred at ambient temperature for 24 hours. After completion, the tetrahydrofuran was removed under reduced pressure, the mixture was filtered, and the filter cake was washed with water. The aqueous filtrate was acidified to pH 1 with concentrated HCl (37 wt%). The mixture was filtered, the filter cake was washed with water, and dried under vacuum at 60°C for 24 hours. The aqueous filtrate was concentrated under reduced pressure and ground with water. The mixture was filtered, and the filter cake was dried under vacuum at 60°C for 24 hours. After drying, the title compound was obtained from the combined filter cakes. 1 H NMR (500 MHz, DMSO-d6) δ ppm 13.36 (s, 1H), 8.62 (s, 1H), 5.31 (q, J = 6.7 Hz, 1H), 3.13 (s, 3H), 2.88 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H).MS(ESI)m / z 253.4(M+H) + .

[0143] [Example 8B] (R)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine Example 8A (11.6 g, 46.2 mmol), tert-butanol (300 mL), N,N-diisopropylethylamine (40 mL, 231 mmol), and diphenyl azidophosphate (11.9 mL, 55.4 mmol) were heated at 90°C for 90 minutes. After completion, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine, dehydrated with magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel (0-40% ethyl acetate / heptane) to obtain boc-protected aniline. The boc-protected aniline was dissolved in a 1:1 mixture of trifluoroacetic acid and CH2Cl2 and stirred at ambient temperature for 1 hour. After completion, the solution was concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel (0-80% ethyl acetate / heptane) to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.04 (s, 1H), 5.40 (s, 2H), 5.37 (q, J = 6.7 Hz, 1H), 3.22 (s, 3H), 2.75 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 224.4(M+H) + .

[0144] [Example 8C] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide Example 8B (5.65 g, 3.86 mmol), Example 1I (12.5 g, 29.1 mmol), and cesium carbonate (24.8 g, 11.6 mmol) were sparged with N2 for 5 minutes in 1,4-dioxane (507 mL). XPhos Pd G4 (3.27 g, 3.80 mmol) was added, and the reaction mixture was heated at 95 °C for 16 hours. The solution was cooled to 50 °C. Pyrrolidine-1-carbodithioic acid, ammonia salt (2.08 g, 12.7 mmol) and water (5 mL) were added to the reaction mixture. The solution was stirred at ambient temperature for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter pad was washed with ethyl acetate. The filtrate was concentrated. The residue was purified on silica gel (0-100% ethyl acetate / heptane). The residue was further purified by reverse-phase chromatography (C18 HPLC, eluted with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate aqueous solution to obtain the desired product, the free base. To improve the diastereoisomer purity to >99%, the material was subjected to chiral supercritical fluid chromatography (SFC) using a CHIRALPAK® OJ-H column (30 × 250 mm, 5 microns) eluted at 35°C with 20% methanol in CO2, 150 mL / min, 120 bar, to obtain the title compound.1 H NMR (500 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 7.73 (d, J = 15.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.10 7.02 (m, 2H), 6.45 (q, J = 9.3 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 3.24 (dd, J = 13.3, 3.5 Hz, 1H), 3.21 (s, 3H), 3.21 3.15 (m, 1H), 3.17 3.07 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.14 1.95 (m, 5H), 1.52 (d, J = 6.7 Hz, 3H).MS(ESI+)m / z 571.7(M+H) + .

[0145] [Example 9] N-{(1S)-1-[3,5-difluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0146] [Example 9A] (R,E)-N-(4-bromo-3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide To a mixture of (R)-2-methylpropane-2-sulfinamide (16.4 g, 136 mmol) and 4-bromo-3,5-difluorobenzaldehyde (10 g, 45.2 mmol) in dichloroethane (200 mL), copper(II) sulfate (21.7 g, 136 mmol) was added at 20 °C under N2. The mixture was stirred at 85 °C for 12 hours. The mixture was filtered through a diatomaceous earth pad. The filtrate was purified by column chromatography on silica gel (10:1 to approximately 5:1 petroleum ether:ethyl acetate) to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (s, 1H), 7.45 (d, J = 6.5 Hz, 2H), 1.28 (s, 9H).LCMS m / z 324.0(M+H) + .

[0147] [Example 9B] (R)-N-((S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide To a mixture of tetrabutylammonium acetate (4.65 g, 15.4 mmol) and Example 9A (5 g, 15.4 mmol) in N,N-dimethylformamide (100 mL), (trifluoromethyl)trimethylsilane (4.93 mL, 30.8 mmol) was added under N2 at -55°C. The mixture was stirred at -20°C for 0.5 hours. The reaction was quenched with NH4Cl solution at -40°C and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (2 × 50 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (10:1-3:1 petroleum ether / ethyl acetate) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.09 (d, J = 6.8 Hz, 2H), 4.81 (t, J = 7.2 Hz, 1H), 3.65 (br d, J = 7.3 Hz, 1H), 1.27 (s, 9H).LCMS m / z 394.0(M+H) + .

[0148] [Example 9C] (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethane-1-amine To a solution of Example 9B (7.5 g, 19.0 mmol) in ethyl acetate (10 mL), a solution of 4N HCl in ethyl acetate (100 mL) was added. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was diluted with methyl tert-butyl ether. The mixture was stirred at 20°C for 2 hours, then filtered to obtain (S)-1-(4-bromo-3,5-difluorophenyl)2,2,2-trifluoroethaneamine hydrochloride. The hydrochloride was dissolved in water (20 mL), neutralized with NaHCO3 solution (50 mL), and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (30 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethaneamine (5.2 g, 92%), which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 7.16 - 7.05 (m, 2H), 4.41 (q, J = 7.0 Hz, 1H), 1.78 (br d, J = 2.2 Hz, 2H).LCMS m / z 290.0(M+H) + .

[0149] [Example 9D] (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoro-N-methylethane-1-amine To a mixture of Example 9C (2.5 g, 8.62 mmol) in methanol (50 mL), formaldehyde (0.839 g, 10.3 mmol) was added at 20°C, and the resulting mixture was stirred at 20°C for 12 hours. NaBH4CN (1.63 g, 25.9 mmol) was added, and the mixture was stirred at 20°C for 2 hours. The combined mixture was poured into ice water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layer was washed with brine (20 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20:1-5:1 petroleum ether / ethyl acetate) to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.08 (d, J = 7.1 Hz, 2H), 4.03 (q, J = 6.9 Hz, 1H), 2.40 (s, 3H), 1.69 (br s, 1H).LCMS m / z 304.0(M+H) + .

[0150] [Example 9E] (S)-N-(1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide To a solution of Example 9D (1 g, 3.29 mmol) and triethylamine (1.38 mL, 9.87 mmol) in dichloromethane (10 mL), tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (1.75 g, 8.88 mmol) was added at 0°C. The mixture was stirred at 25°C for 12 hours, poured into ice water (20 mL), and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine (10 mL), dehydrated with Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 to approximately 1:1 petroleum ether / ethyl acetate) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 6.99 (br d, J = 7.1 Hz, 2H), 6.61 (q, J = 8.6 Hz, 1H), 3.58 - 3.39 (m, 1H), 3.39 - 3.24 (m, 1H), 3.08 - 2.84 (m, 6H), 2.53 - 2.18 (m, 4H).LCMS m / z 464.0(M+H) + .

[0151] [Example 9F] N-{(1S)-1-[3,5-difluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6-Chiang-4-carboxamide To a solution of Example 9E (200 mg, 0.431 mmol), Example 1F (106 mg, 0.474 mmol), and Cs2CO3 (421 mg, 1.29 mmol) in 1,4-dioxane (4 mL), methanesulfonate (2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (111 mg, 0.129 mmol) was added under N2 conditions. The reaction was stirred at 90°C for 3 hours and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (instrument: Shimadzu LC-8A preparative HPLC; column: 150 × 40 mm × 10 μm, Waters® Xbridge Prep OBD C18, 10 mM NH4HCO3 in 40-70% acetonitrile / water for 10 minutes) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.96 (t, J = 2.6 Hz, 1H), 7.58 (s, 1H), 7.02 (br d, J = 8.6 Hz, 2H), 6.63 (q, J = 8.6 Hz, 1H), 5.62 (q, J = 6.7 Hz, 1H), 3.56 - 3.48 (m, 1H), 3.45 (s, 3H), 3.33 (ddd, J = 3.5, 7.4, 10.8 Hz, 1H), 3.10 - 2.90 (m, 6H), 2.84 (s, 3H), 2.54 - 2.25 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H).LCMS m / z 607.1(M+H) + .

[0152] [Example 10] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[3-fluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0153] [Example 10A] 1-(4-bromo-3-fluorophenyl)-2,2,2-trifluoroethanol 4-bromo-3-fluorobenzaldehyde (5 g) and cesium fluoride (0.075 g) were dissolved in tetrahydrofuran (50 mL), to which trimethyl(trifluoromethyl)silane (14.59 mL) was added at 0°C. The reaction mixture was slowly warmed to ambient temperature and stirred over the weekend. 1 M aqueous HCl (30 mL) was added, and the mixture was stirred at ambient temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 80 mL). The combined organic extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The crude product was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (dd, 1H), 7.47 (dd, 1H), 7.31 (dt, 1H), 7.08 (d, 1H), 5.32 - 5.19 (m, 1H).

[0154] [Example 10B] 1-(4-bromo-3-fluorophenyl)-2,2,2-trifluoro-N-methylethaneamine To a solution of Example 10A (1.3 g) in dichloromethane (30 mL), 2,6-dimethylpyridine (1.109 mL) and anhydrous trifluoromethanesulfone (1 M in dichloromethane, 7.14 mL) were added at -30°C. The reaction mixture was stirred for 2.5 hours and slowly warmed to ambient temperature. Methaneamine (33% by weight in ethanol, 15 mL) was added, and the reaction mixture was stirred at 45°C for 4 hours. The reaction mixture was left to stand overnight at ambient temperature. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The crude product was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (dd, 1H), 7.53 (dd, 1H), 7.30 (dd, 1H), 4.39 (p, 1H), 2.97 (dq, 1H), 2.20 (d, 3H).MS(ESI)m / z 286.0 / 288.0(M+H) + .

[0155] [Example 10C] N-(1-(4-bromo-3-fluorophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (530 mg) in dichloromethane (25 mL), 4-methylmorpholine (0.359 mL) and 2,4-dichloro-6-methoxy-1,3,5-triazine (588 mg) were added. The reaction mixture was stirred at ambient temperature for 90 minutes. A solution of Example 10B (850 mg) in dichloromethane (1.5 mL) was added, and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was concentrated under vacuum on silica gel. The crude product was purified by chromatography on silica gel (0-70% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.86 - 7.77 (m, 1H), 7.35 (dd, 1H), 7.18 (dd, 1H), 6.56 (q, 1H), 3.17 (dddd, 5H), 2.92 (s, 3H), 2.14 - 1.89 (m, 4H).MS(ESI)m / z 447.8(weak ionization)(M+H) + .

[0156] [Example 10D] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[3-fluoro-4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide To a degassed suspension of Example 1F (125 mg), Example 10C (250 mg), and cesium carbonate (548 mg) in 1,4-dioxane (5 mL), XPhos Pd G4 (145 mg) was added at ambient temperature, and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was filtered through diatomaceous earth and washed with dichloromethane (10 mL). Water (5 mL) and saturated ammonium chloride aqueous solution (5 mL) were added to the filtrate, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dehydrated with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% ethyl acetate-ethanol (3:1) / 2-methylpentane, then 0-80% ethyl acetate-ethanol (3:1) / 2-methylpentane) to obtain the product as a mixture of diastereoisomers. A mixture of diastereoisomers was separated by chiral supercritical fluid chromatography (SFC) at 40°C using a CHIRALPAK® IC column (10 × 250 mm, 5 microns) eluted with 40% methanol (0.1% ammonia) in CO2 at 15 mL / min and 120 bar, to obtain the title compound as individual diastereoisomers. The absolute stereochemistry of these title compounds was arbitrarily assigned. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.76 (d, 1H), 7.28 (t, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 6.49 (q, 1H), 5.39 (q, 1H), 3.26 (s, 3H), 3.24 - 3.06 (m, 4H), 2.93 (s, 3H), 2.84 (s, 3H), 2.14 - 1.88 (m, 5H), 1.51 (d, 3H).MS(ESI)m / z 589.3(M+H) + .

[0157] [Example 11] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1S)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0158] [Example 11A] Ethyl 2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-carboxylate Ethyl-7-chloro-2-methylthiazolo[5,4-b]pyridine-6-carboxylate (30 g, 117 mmol, WO2018020474A1, Example 16), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (27 g, 175 mmol), and Na2CO3 (24.8 g, 234 mmol) were dissolved in a mixture of 1,4-dioxane (300 mL) and water (30 mL). The solution was purged with nitrogen, and tetrakis(triphenylphosphine)palladium (6.75 g, 5.84 mmol) was added. The resulting solution was heated at 110°C for 16 hours under a nitrogen atmosphere. After cooling to ambient temperature, 1,4-dioxane was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with water (2 × 300 mL). The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on silica gel (10% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300 MHz, CD3OD) δ ppm 1.44 (t, J = 7.1 Hz, 3H), 2.89 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H), 5.94 (dd, J = 11.7, 1.8 Hz, 1H), 6.70 (dd, J = 17.6, 1.8 Hz, 1H), 7.47 (dd, J = 17.6, 11.7 Hz, 1H), 8.87 (s,1H).MS(ESI+)m / z 249(M+H) + .

[0159] [Example 11B] 2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-carboxylic acid Example 11A (18.5 g, 74.5 mmol) and lithium hydroxide (3.57 g, 149 mmol) were dissolved in a mixture of 1,4-dioxane (180 mL) and water (100 mL). The reaction mixture was stirred at ambient temperature for 2 hours. After complete hydrolysis, 1,4-dioxane was removed under reduced pressure. The resulting aqueous solution was adjusted to pH 2 with 1 M HCl aqueous solution. The mixture was filtered, and the filtered cake was dried under vacuum to obtain the title compound (15 g, 91%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.89 (s, 3H), 5.96 (dd, J = 11.7, 2.1 Hz, 1H), 6.75 (dd, J = 17.6, 2.1 Hz, 1H), 7.46 (dd, J = 17.6, 11.7 Hz, 1H), 8.88 (s, 1H), 13.61 (s, 1H)

[0160] [Example 11C] tert-butyl(2-methyl-7-vinylthiazolo[5,4-b]pyridine-6-yl)carbamate Example 11B (15 g, 68 mmol) and triethylamine (19 mL, 136 mmol) were dissolved in tert-butanol (300 mL) and treated with diphenyl phosphoryl azide (28.1 g, 102 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, and then refluxed overnight at 95°C. After cooling, the resulting solution was concentrated under reduced pressure. The residue was purified on silica gel (10% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300 MHz, CDCl3) δ ppm 2.85 (s, 3H), 5.95 (dd, J = 11.7, 1.6 Hz, 1H), 6.37 - 6.49 (m, 1H), 6.62 (s, 1H), 7.03 (dd, J = 17.9, 11.7 Hz, 1H), 8.92 (s, 1H).MS(ESI+)m / z 292(M+H) + .

[0161] [Example 11D] tert-butyl(7-formyl-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate Example 11C (15 g, 51.5 mmol), potassium osmium(VI) dihydrate (1.90 g, 5.15 mmol), and sodium periodate (33 g, 154 mmol) were dissolved in a mixture of acetonitrile (150 mL), water (150 mL), and tetrahydrofuran (150 mL). The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on silica gel (20% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300 MHz, CDCl3) δ ppm 1.59 (s, 9H), 2.92 (s, 3H), 9.82 (s, 1H), 10.34 (s, 1H), 11.10 (d, J = 0.8 Hz, 1H).MS(ESI+)m / z 294(M+H) + .

[0162] [Example 11E] tert-butyl(2-methyl-7-(2,2,2-trifluoro-1-hydroxyethyl)thiazolo[5,4-b]pyridine-6-yl)carbamate A mixture of Example 11D (26 g, 89 mmol), a 4 Å molecular weight sieve (10 g), and dimethyl sulfoxide (250 mL) was treated with (trifluoromethyl)trimethylsilane (15.1 g, 106 mmol). The resulting mixture was stirred under a nitrogen atmosphere at ambient temperature for 12 hours. Potassium carbonate (12.3 g, 89 mmol) and dichloromethane (250 mL) were added, and the combined solution was stirred at ambient temperature. After 2 hours, the mixture was filtered, and the filtrate was diluted with water (1.2 L). The aqueous layer was extracted with dichloromethane (3 × 800 mL). The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (20% ethyl acetate / petroleum ether) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 9H), 2.85 (s, 3H), 6.08 - 6.25 (m, 1H), 8.29 (d, J = 6.2 Hz, 1H), 8.62 (s, 1H), 9.07 (s, 1H).

[0163] [Example 11F] tert-butyl(2-methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-yl)carbamate Potassium carbonate (12.3 g, 89 mmol) and methyl iodide (5.6 mL, 89 mmol) were added to the solution of Example 11E (29.4 g, 81 mmol) in N,N-dimethylformamide (500 mL). The resulting heterogeneous mixture was stirred at ambient temperature for 12 hours and then diluted with water (1000 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (0-100% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 9H), 2.87 (s, 3H), 3.54 (s, 3H), 5.98 (q, J = 7.6 Hz, 1H), 8.28 (s, 1H), 8.97 (s, 1H).MS(ESI+)m / z 378(M+H) + .

[0164] [Example 11G] (R)-2-methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-amine; and

[0165] [Example 11H] (S)-2-methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-amine Example 11F (35.2 g, 93.3 mmol) was dissolved in 4 M HCl in ethyl acetate (200 mL, 800 mmol) and stirred at ambient temperature for 2 hours. After completely consuming the starting material as determined by LC-MS, the reaction mixture was filtered, and the filtered cake was washed with ethyl acetate (80 mL). The filtered cake was dispersed in water (80 mL), and the resulting suspension was adjusted to pH 9 with 15% sodium carbonate aqueous solution and filtered. The filtered cake was washed with water (80 mL) and dried under vacuum to obtain a 1:1 mixture of Example 11G and 11H. The racemic material was subjected to chiral SFC (supercritical fluid chromatography) at 35°C using a CHIRALPAK® AD-H column (5 × 25 cm, 5 microns) with elution at 150 mL / min of 15% methanol (2 mM ammonia) in CO2 to obtain the title compound (Example 11G: retention time 5.14 min and Example 11H: retention time 5.95 min). Example 11G: 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.77 (s, 3H), 3.44 (s, 3H), 5.64 (s, 2H), 5.83 (q, J = 7.8 Hz, 1H), 8.12 (s, 1H).MS(ESI+)m / z 278(M+H) + Example 11H: 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.77 (s, 3H), 3.44 (s, 3H), 5.64 (s, 2H), 5.83 (q, J = 7.8 Hz, 1H), 8.12 (s, 1H).MS(ESI+)m / z 278(M+H) + .

[0166] [Example 11I] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1S)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide 1,4-Dioxane (10 mL) was spagged with N2 for 2 minutes with Example 11H (0.15 g, 0.54 mmol), Example 1I (0.24 g, 0.57 mmol), and Cesium Carbonate (0.53 g, 1.6 mmol). XPhos Pd G4 (70 mg, 0.081 mmol) was added, and the reaction mixture was heated at 95°C for 16 hours. The solution was cooled to ambient temperature, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by reverse-phase chromatography (C18 HPLC, eluted with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated to remove acetonitrile. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate aqueous solution to the desired product, the free base. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and concentrated. The residue was freeze-dried to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 7.62 (d, J = 18.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.46 (q, J = 9.2 MS(ESI+)m / z 626.0(M+H) + .

[0167] [Example 12] N-{(1S)-2,2-difluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0168] [Example 12A] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine Examples 8B (0.500 g, 2.24 mmol), 4B (0.588 g, 2.35 mmol), and cesium carbonate (2.19 g, 6.72 mmol) were sparged with N2 for 2 minutes in 1,4-dioxane (25 mL). XPhos Pd G4 (0.39 g, 0.45 mmol) was added, and the reaction mixture was heated at 95 °C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified on silica gel (0-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 7.55 (s, 1H), 7.29 - 7.22 (m, 2H), 7.07 - 6.99 (m, 2H), 6.00 (d, J = 4.3 Hz, 1H), 5.37 (q, J = 6.6 Hz, 1H), 3.70 (d, J = 13.9 Hz, 1H), 3.24 (s, 3H), 2.83 (s, 3H), 2.34 (s, 1H), 2.19 (d, J = 3.2 Hz, 3H), 1.52 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 393.2(M+H) + .

[0169] [Example 12B] N-{(1S)-2,2-difluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide Example 12B was prepared according to the procedure used for the preparation of Example 5B, with Example 12A replaced by Example 5A, to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.49 (d, J = 2.6 Hz, 1H), 7.62 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.08 - 7.01 (m, 2H), 6.73 (dd, J = 12.3, 5.3 Hz, 0H), 5.80 - 5.72 (m, 1H), 5.34 (q, J = 6.7 Hz, 1H), 3.22 (d, J = 2.9 Hz, 4H), 3.13 - 3.06 (m, 3H), 2.93 (s, 3H), 2.83 (d, J = 1.5 Hz, MS(ESI)m / z 553.6(M+H) + .

[0170] [Example 13] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0171] [Example 13A] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-amine 1,4-Dioxane (30 mL) was sparged with N2 for 2 minutes with Example 3H (0.500 g, 2.24 mmol), Example 4B (0.506 g, 2.03 mmol), and Cesium Carbonate (2.19 g, 6.72 mmol). XPhos Pd G4 (0.17 g, 0.19 mmol) was added, and the reaction mixture was heated at 95°C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified on silica gel (0-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 7.77 (s, 1H), 7.39 - 7.11 (m, 2H), 7.10 - 6.93 (m, 2H), 6.74 (ddd, J = 57.5, 54.5, 5.8 Hz, 1H), 5.99 (td, J = 56.3, 4.3 Hz, 1H), 5.36 (dt, J = 13.8, 5.9 Hz, 1H), 3.71 (t, J = 12.8 Hz, 1H), 3.31 (s, 3H), 2.85 (s, 3H), 2.32 (s, 1H), 2.19 (s, 3H).MS(ESI)m / z 429.8(M+H) + .

[0172] [Example 13B] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide Example 13B was prepared according to the procedure used for the preparation of Example 5B, with Example 13A replaced by Example 5A, to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.51 (d, J = 3.3 Hz, 1H), 7.88 (s, 1H), 7.22 - 7.16 (m, 2H), 7.00 - 6.91 (m, 2H), 6.87 - 6.56 (m, 2H), 5.75 (td, J = 13.3, 5.3 Hz, 1H), 5.33 (dt, J = 14.0, 5.5 Hz, 1H), 3.29 (d, J = 2.3 Hz, 3H), 3.27 - 3.04 (m, 5H), 2.93 (s, 3H), 2.86 (d, J = 1.9 Hz, 3H), 2.16 - 1.87 (m, 4H).MS(ESI)m / z 589.5(M+H) + .

[0173] [Example 14] N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0174] [Example 14A] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-amine Example 14A (345.2 mg, 97%) was prepared using the conditions described in Example 4C, with Example 11G replaced by Example 1F. MS(APCI)m / z 447.3(M+H) + .

[0175] [Example 14B] N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ6 -Chiang-4-carboxamide Example 14B (75.4 mg, 51%) was prepared using the conditions described in Example 4D, with Example 14A replaced by Example 4C. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.88 - 6.46 (m, 1H), 5.94 (q, J = 7.7 Hz, 1H), 5.72 (s, 1H), 3.56 (s, 3H), 3.28 - 3.04 (m, 5H), 2.94 (s, 3H), 2.85 (s, 3H), 2.20 - 1.98 (m, 4H).MS(APCI)m / z 607.3(M+H) + .

[0176] [Example 15] N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0177] [Example 15A] Methyl(S)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate To a solution of Example 1D (1 g, 3.96 mmol) in N,N-dimethylformamide (12 mL), potassium carbonate (1.096 g, 7.93 mmol) and iodomethane (0.296 mL, 4.76 mmol) were added. The resulting suspension was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water (40 mL) and ethyl acetate (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic extract was washed with water (30 mL) and saturated sodium chloride solution (30 mL), dehydrated with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by chromatography on Companion (24 g column, 10-50% ethyl acetate / 2-methylpentane) to obtain the title compound (980 mg, 3.68 mmol, 93%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 5.25 (q, J = 6.7 Hz, 1H), 3.86 (s, 3H), 3.14 (s, 3H), 2.89 (s, 3H),1.59 (d, J = 6.6 Hz, 3H).MS(ESI)m / z 267.1(M+H) + .

[0178] [Example 15B] Methyl(S)-2-formyl-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylate A mixture of Example 15A (15 g, 56.3 mmol) and selenium dioxide (25.00 g, 225 mmol) in 1,4-dioxane (210 mL) was stirred at 93°C for 8 hours. After cooling, the reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with ethyl acetate / petroleum (1:4) to obtain the title compound (2.808 g, 9.66 mmol, 17.15%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.90 (s, 1H), 5.30-5.43 (m, 1H), 3.90 (s, 3H), 3.18 (s, 3H),1.65 (d, J = 6.7 Hz, 3H).LCMS(ESI)m / z 281(M+H) + .

[0179] [Example 15C] Methyl(S)-2-(difluoromethyl)-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylate To a solution of Example 15B (1.2 g, 4.28 mmol) in toluene (36 mL), [bis(2-methoxyethyl)amino]sulfur trifluoride (5.21 g, 23.55 mmol) was added at 0°C. The reaction mixture was stirred overnight at 50°C. After cooling, the reaction mixture was partitioned between saturated sodium bicarbonate aqueous solution (50 mL) and dichloromethane (3 × 100 mL). The combined organic layer was washed with sodium bicarbonate solution (50 mL), dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC using ethyl acetate / petroleum ether (1 / 1) to obtain the title compound (812.4 mg, 2.63 mmol, 61.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (d, J = 1.4 Hz, 1H), 5.27 (q, J = 6.6 Hz, 1H), 3.86 (s, 3H), 3.13 (s, 3H), 1.58 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 303(M+H) + .

[0180] [Example 15D] (S)-2-(difluoromethyl)-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylic acid A mixture of Example 15C (0.3 g, 0.992 mmol) and sodium carbonate (0.526 g, 4.96 mmol) in methanol (10 mL) was stirred overnight at ambient temperature. The solvent was removed, and the residue was redissolved in ethyl acetate and 0.1 N HCl aqueous solution. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC on a C18 column eluted with 20-100% acetonitrile in 0.1% trifluoroacetic acid aqueous solution to obtain the title compound (0.082 g, 0.284 mmol, 28.7%). 0.10 g of Example 15C was also recovered. 1 H NMR (600 MHz, DMSO-d6) δ ppm 13.60 (s, 1H), 8.86 (s, 1H), 7.63-7.45 (m, 1H), 5.35 (q, J = 6.6 Hz, 1H), 3.15 (s, 3H), 1.64 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 289.0(M+H) + .

[0181] [Example 15E] A mixture of Example 15D (0.07 g, 0.243 mmol), diphenyl azidophosphate (0.080 g, 0.291 mmol), and triethylamine (0.203 mL, 1.457 mmol) in tert-butyl alcohol (3 mL) was heated overnight at 80 °C. The solvent was removed, and the residue was purified by flash column chromatography on silica gel eluted with 50% ethyl acetate in heptane to obtain the title compound (0.017 g, 0.066 mmol, 27.0%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.42 (t, J = 53.9 Hz, 1H), 5.67 (s, 2H), 5.37 (q, J = 6.7 Hz, 1H), 3.24 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 261.0(M+H) + .

[0182] [Example 15F] N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide A mixture of Example 15E (0.018 g, 0.070 mmol), Example 1J (0.03 g, 0.070 mmol), and cesium carbonate (0.068 g, 0.210 mmol) in 1,4-dioxane (1.5 mL) was degassed and refilled with nitrogen several times. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (5.51 mg, 7.01 μmol) was added to this reaction mixture. The reaction vessel was re-lidded, then degassed and refilled with nitrogen several times. The reaction mixture was heated overnight at 95°C. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase preparative HPLC on a C18 column eluted with 20-100% acetonitrile in 0.1% aqueous trifluoroacetic acid to obtain the title compound (0.031 g, 0.051 mmol, 73.0%). 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 7.88 (s, 1H), 7.50 (t, J = 53.8 Hz, 1H)., 7.24 (d, J = 8.4 Hz, 2H), 7.14 - 7.07 (m, 2H), 6.45 (q, J = 9.3 Hz, 1H), 5.32 (q, J = 6.7 Hz, 1H), 3.21 (s, 3H), 3.29 - 3.07 (m, 4H), 2.91 (s, 3H), 2.13 - 2.07 (m, 1H), 2.05 (dq, J = 8.7, 3.3 Hz, 2H), 2.05 - 1.96 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 608.0(M+H)+ .

[0183] [Example 16] N-[(1S)-1-(4-{[7-(1,1-difluoropropan-2-yl)-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide

[0184] [Example 16A] tert-butyl(7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate To a suspension of Example 11D (4 g) in N,N-dimethylformamide (40 mL), (bromodifluoromethyl)trimethylsilane (4.24 mL) and triphenylphosphine (7.15 g) were added, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0°C, and potassium hydroxide (2 M in water, 13.64 mL) was slowly added. The reaction mixture was stirred at this temperature for 1 hour, and then saturated ammonium chloride aqueous solution (50 mL) was added. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 70 mL), and the combined organic extract was washed with water / brine (1:1, 3 × 50 mL), dehydrated with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-60% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 8.88 (s, 1H), 7.35 (d, 1H), 6.40 (td, 1H), 5.82 - 5.72 (m, 1H), 2.84 (s, 3H), 1.48 (s, 9H).MS(ESI)m / z 345.8(M+H) + .

[0185] [Example 16B] tert-butyl(7-(2,2-difluoroacetyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate To a solution of Example 16A (500 mg) in dichloromethane (15 mL), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (Dess-Martin periodinane) (921 mg) and sodium bicarbonate (243 mg) were added. The reaction mixture was stirred at ambient temperature for 45 minutes, filtered, and the filter cake was washed with dichloromethane (10 mL). The filtrate was washed with saturated sodium bicarbonate aqueous solution (10 mL), dehydrated with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.51 (s, 1H), 6.82 (t, 1H), 2.85 (s, 3H), 1.45 (s, 9H).MS(ESI)m / z 362.4(M+H3O) + .

[0186] [Example 16C] tert-butyl(7-(3,3-difluoropropane-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate Potassium tert-butoxide (1M in tetrahydrofuran, 3.23 mL) was slowly added at 0°C to a suspension of methyltriphenylphosphonium bromide (1270 mg) in tetrahydrofuran (15 mL). The reaction was stirred at this temperature for 40 minutes. To a solution of Example 16B (370 mg) in tetrahydrofuran (10 mL), a portion of the pre-formed ylide solution (6 mL) was added at -10°C, and the reaction mixture was stirred for 30 minutes. An additional ylide solution (6 mL) was added, and the reaction mixture was stirred overnight and slowly warmed to ambient temperature. The reaction mixture was stirred at 50°C for 1 hour, then at 70°C for 12 hours, and left at ambient temperature for 3 days. A saturated aqueous solution of ammonium chloride (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H), 8.57 (s, 1H), 6.86 (t, 1H), 6.16 (q, 1H), 5.76 (s, 1H), 2.82 (s, 3H), 1.43 (s, 9H).MS(ESI)m / z 342.2(M+H) + .

[0187] [Example 16D] tert-butyl(7-(3,3-difluoropropane-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate To a solution of Example 16C (130 mg) in tetrahydrofuran (3 mL), palladium (5% by weight on carbon, 130 mg) was added. The reaction mixture was stirred at ambient temperature for 3 hours under a hydrogen atmosphere (3 bar). The reaction mixture was filtered through a glass microfiber pad, washed with methanol (5 mL), and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1H), 8.43 (s, 1H), 6.98 - 6.61 (m, 1H), 3.72 (dp, 1H), 2.86 (s, 3H), 1.48 (d, 3H), 1.46 (s, 9H).MS(ESI)m / z 344.2(M+H) + .

[0188] [Example 16E] 7-(1,1-difluoropropan-2-yl)-2-methylthiazolo[5,4-b]pyridine-6-amine To a solution of Example 16D (1.1 g) in dichloromethane (20 mL), 2,2,2-trifluoroacetic acid (4.90 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours. Toluene (10 mL) was added, and the reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate aqueous solution (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (s, 1H), 6.85 (ddd, 1H), 5.53 (s, 2H), 3.86 - 3.67 (m, 1H), 2.76 (s, 3H), 1.39 (d, 3H).MS(ESI)m / z 244.2(M+H) + .

[0189] [Example 16F] N-[(1S)-1-(4-{[7-(1,1-difluoropropan-2-yl)-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide To a degassed suspension of Example 16E (150 mg), Example 1J (396 mg), and potassium phosphate (262 mg) in 1,4-dioxane (5 mL), XPhos Pd G4 (106 mg) was added, and the reaction mixture was stirred at 70°C for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered through diatomaceous earth and washed with dichloromethane (15 mL). The filtrate was concentrated under vacuum, and the residue was purified by chromatography on silica gel (0-80% ethyl acetate / 2-methylpentane). The product was dissolved in tetrahydrofuran (5 mL) and pyrrolidine-1-carbodithioic acid, and ammonia salt (APDTC) was added. The resulting suspension was stirred at 40°C for 3 hours and then filtered. The filtrate was concentrated under vacuum on silica gel, and the residue was purified by chromatography on silica gel (0-80% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1H), 8.13 (s, 1H), 7.16 (d, 2H), 6.84 (td, 1H), 6.78 (d, 2H), 6.41 (q, 1H), 3.88 (dq, 1H), 3.30 - 3.06 (m, 5H), 2.90 (s, 3H), 2.87 (s, 3H), 2.11 - 1.94 (m, 4H), 1.45 (d, 3H).MS(ESI)m / z 591.1(M+H) + .

[0190] [Example 17] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)-3-fluorophenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide XPhos Pd G4 (77 mg) was added to a degassed suspension of Example 3G (116 mg), Example 10C (200 mg), and potassium phosphate (95 mg) in 1,4-dioxane (2 mL) and the reaction mixture was stirred at 70°C for 16 hours. After cooling to ambient temperature, the reaction mixture was filtered through diatomaceous earth and washed with dichloromethane (10 mL). The filtrate was concentrated under vacuum, and the residue was purified by chromatography on silica gel (0-100% ethyl acetate-ethanol (3:1) / 2-methylpentane) to obtain the product as a mixture of diastereoisomers. The mixture of diastereoisomers was separated at 40°C by chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® IC column (10 × 250 mm, 5 microns) eluted at 35% methanol (0.1% ammonia) in CO2, 15 mL / min, and 120 bar to obtain the title compound as individual diastereoisomers. The absolute stereochemistry of these title compounds was arbitrarily assigned. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.84 (s, 1H), 7.21 (d, 1H), 7.15 - 7.04 (m, 2H), 6.72 (td, 1H), 6.48 (q, 1H), 5.41 (dt, 1H), 3.34 (s, 3H), 3.28 - 3.05 (m, 5H), 2.93 (s, 3H), 2.86 (s, 3H), 2.14 - 1.93 (m, 4H).MS(ESI)m / z 625.1(M+H) + .

[0191] [Example 18] 1-Acetyl-N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide

[0192] [Example 18A] (S)-1-acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide 1-Acetylpiperidine-4-carbonyl chloride (0.747 g, 3.94 mmol) was added to a 40 mL vial containing the hydrochloride salt of Example 1I (1.0 g, 3.28 mmol) in dichloromethane (3 mL), pyridine (1.328 mL, 16.42 mmol), and N,N-dimethylpyridine-4-amine (0.401 g, 3.28 mmol). The reaction was stirred at ambient temperature for 30 minutes and diluted with dichloromethane (20 mL). The organic layer was washed with saturated ammonium chloride aqueous solution (20 mL), dehydrated with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated. The residue was purified by automated flash chromatography (ISCO, SiO2, ethyl acetate / hexane) to obtain the title compound.

[0193] [Example 18B] 1-Acetyl-N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide Example 18A (125 mg, 0.297 mmol), Example 3G (70 mg, 0.270 mmol), Pd-Xphos-G2 (21.24 mg, 0.027 mmol), and Cs2CO3 (264 mg, 0.810 mmol) were placed in vials. The contents were evacuated and the vials were refilled with nitrogen twice. 1,4-Dioxane was added, and the mixture was stirred overnight at 90°C under nitrogen. The crude mixture was filtered on diatomaceous earth and concentrated under vacuum. The crude residue was purified using reverse-phase chromatography (C18 HPLC, eluted with 20-70% acetonitrile / 0.1% formic acid in water) to obtain the title compound. 1H NMR (500 MHz, CDCl3) 8.61 (s, 1H), 7.26 (t, J = 8.5 Hz, 2H), 7.08-7.02 (m, 2H), 6.59 (q, J = 9.0 Hz, 1H), 6.12 (td, J = 55 Hz, 1H), 5.57 (m, 1H), 4.61 (t, J = 12.1 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.57 (s, 3H), 3.14 (m, 1H), 2.93 (d, J = 2.4 Hz, 3H), 2.83 (s, 3H), 2.82-2.67 (m, 3H), 2.11 (s, 3H), 1.92-1.70 (m, 4H).MS(ESI)m / z 600.4(M+H) + .

[0194] [Example 19] 1-Acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 18A (83 mg, 0.197 mmol), Example 1F (40 mg, 0.179 mmol), Pd-Xphos-G2 (14.09 mg, 0.018 mmol), and Cs2CO3 (175 mg, 0.537 mmol) were placed in vials. The contents were evacuated and the vials were refilled with nitrogen twice. 1,4-Dioxane was added, and the mixture was stirred overnight at 90°C under nitrogen. The mixture was filtered on diatomaceous earth and concentrated under vacuum. The residue was purified using automated flash chromatography (ISCO, SiO2, ethyl acetate / hexane) to obtain the title compound. 1H NMR (500 MHz, CDCl3) 8.60 (s, 1H), 7.46 (s, 1H), 7.26 (t, J = 7.4 Hz, 2H), 7.16-7.05 (m, 2H), 6.59 (q, J = 9.0 Hz, 1H), 5.57 (q, J = 6.7 Hz, 1H), 4.61 (t, J = 12.1 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.41 (s, 3H), 3.14 (ddd, J = 17.2, 9.8, 4.4 Hz, 1H), 2.94 (d, J = 2.4 Hz, 3H), 2.83 (s, 3H), 2.82 (s, 1H), 2.81-2.68 (m, 1H), 2.11 (s, 3H), 1.92-1.70 (m, 3H), 1.56 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 564.0(M+H) + .

[0195] [Example 20] 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0196] [Example 20A] (S)-tert-butyl4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (459 mg, 2.00 mmol) in dichloromethane (10 mL), 2.0 M oxalyl chloride (2.00 mL, 4.00 mmol) in dichloromethane was added at 0°C, followed by the addition of a small amount of N,N-dimethylformamide. The reaction mixture was stirred at 5°C for 3 hours, concentrated, and azeotropically mixed twice with toluene. The residue was dissolved in dichloromethane (5.0 mL) and slowly added at 0°C to a mixture of the hydrochloride salt of Example 1I (305 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.875 mL, 5.01 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at 5°C for 1 hour and partitioned with dichloromethane and water. The organic layer was washed with 5% aqueous sodium bicarbonate and saturated aqueous sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, heptane, 10-50% 3:1 ethyl acetate / ethanol) to obtain the title compound. MS(ESI+)m / z 479.1, 481.0(M+H) + .

[0197] [Example 20B] tert-butyl 4-(methyl((S)-2,2,2-trifluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate Example 1F (179 mg, 0.800 mmol), Example 20A (383 mg, 0.800 mmol), XPhos Pd G3 (67.7 mg, 0.0800 mmol), and cesium carbonate (782 mg, 2.40 mmol) were combined in dioxane (5.0 mL). The reaction mixture was purged with nitrogen for 10 minutes, stirred at 90°C for 2 hours, cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and concentrated. The residue was purified by flash chromatography (silica gel, heptane, 20-60% ethyl acetate) to obtain the title compound. MS(ESI+)m / z 622.3(M+H) + .

[0198] [Example 20C] N-methyl-N-((S)-2,2,2-trifluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)piperidine-4-carboxamide Trifluoroacetic acid (2.50 mL, 32.4 mmol) was added to a mixture of Example 20B (410 mg, 0.659 mmol) in dichloromethane (7.5 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10-100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to obtain the title compound as trifluoroacetate. MS(ESI+)m / z 522.3(M+H) + .

[0199] [Example 20D] 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide In Example 20, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (34 mg, 0.088 mmol) was gradually added to a solution of 20C (51 mg, 0.080 mmol), 2-hydroxyacetic acid (6.7 mg, 0.088 mmol), and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at ambient temperature for 2 hours and purified by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10-100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The fractions containing the product were combined, and acetonitrile was removed by evaporation. The solution was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was freeze-dried with acetonitrile / water to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.6 Hz, 1H), 4.50 (s, 1H), 4.35 (d, J = 13.1 Hz, 1H), 4.16 - 4.01 (m, 2H), 3.71 (d, J = 13.4 Hz, 1H), 3.21 (s, 3H), 3.09 - 2.97 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.76 - 2.65 (m, 1H), 1.80 - 1.66 (m, 2H), 1.66 - 1.37 (m, 5H).MS(ESI+)m / z 580.2(M+H) + .

[0200] [Example 21] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0201] [Example 21A] tert-butyl4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate Example 21A was prepared according to the procedure used for the preparation of Example 20B, with Example 3G replaced by Example 1F, to obtain the title compound. MS(ESI+)m / z 658.6(M+H) + .

[0202] [Example 21B] N-((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide, trifluoroacetic acid Example 21B was prepared according to the procedure used for the preparation of Example 20C, with Example 21A replaced by Example 20B, to obtain the title compound. MS(ESI+)m / z 558.4(M+H) + .

[0203] [Example 21C] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide Example 21C was prepared according to the procedure used for the preparation of Example 20D, with Example 21B replaced by Example 20C, to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.99 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.75 (ddd, J = 57.6, 54.4, 5.9 Hz, 1H), 6.45 (q, J = 9.4 Hz, 1H), 5.31 (dt, J = 14.0, 5.6 Hz, 1H), 4.49 (s, 1H), 4.35 (d, J = 13.1 Hz, 1H), 4.15 - 4.01 (m, 2H), 3.70 (d, J = 13.2 Hz, 1H), 3.28 (s, 3H), 3.08 - 2.97 (m, 2H), 2.91 (s, 3H), 2.86 (s, 3H), 2.77 - 2.65 (m, 1H), 1.80 - 1.59 (m, 2H), 1.59 - 1.35 (m, 2H).MS(ESI+)m / z 615.9(M+H) + .

[0204] [Example 22] 1-(3-hydroxypropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 22 was prepared according to the procedure used for the preparation of Example 20D, in which 30% 3-hydroxypropionic acid in water was replaced with 2-hydroxyacetic acid to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.48 (t, J = 5.4 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 3.92 (d, J = 13.5 Hz, 1H), 3.63 (td, J = 6.5, 5.3 Hz, 2H), 3.21 (s, 3H), 3.12 - 2.98 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.69 - 2.57 (m, 2H), 2.50 - 2.41 (m, 1H), 1.80 - 1.61 (m, 2H), 1.58 - 1.45 (m, 4H), 1.43 - 1.33 (m, 1H).MS(ESI+)m / z 594.3(M+H) + .

[0205] [Example 23] 1-(2-hydroxy-2-methylpropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 23 was prepared using the same procedure as for the preparation of Example 20D, in which 2-hydroxy-2-methylpropanoic acid was replaced with 2-hydroxyacetic acid, to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.38 (s, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.81 (s, br, 1H), 4.43 (s, br, 1H), 3.21 (s, 3H), 3.10 - 2.96 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.64 (s, 1H), 1.78 - 1.43 (m, 7H), 1.31 (s, 6H).MS(ESI+)m / z 608.3(M+H) + .

[0206] [Example 24] 1-(2,3-dihydroxypropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 24 was prepared according to the procedure used for the preparation of Example 20D, in which 20% 2,3-dihydroxypropanoic acid in water was replaced with 2-hydroxyacetic acid to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.3 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.90 - 4.81 (m, 1H), 4.74 - 4.62 (m, 1H), 4.42 - 4.30 (m, 2H), 4.10 - 4.03 (m, 1H), 3.55 - 3.48 (m, 1H), 3.47 - 3.41 (m, 1H), 3.21 (s, MS(ESI+)m / z 610.2(M+H) + .

[0207] [Example 25] 1-[(2R)-2-hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 25 was prepared by following the procedure used for the preparation of Example 20D, in which (R)-2-hydroxypropionic acid was replaced with 2-hydroxyacetic acid, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.87 - 4.80 (m, 1H), 4.47 - 4.31 (m, 2H), 4.01 (d, J = 12.9 Hz, 1H), 3.21 (s, 3H), 3.13 - 2.99 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.77 - 2.65 (m, 1H), 1.81 - 1.66 (m, 2H), 1.60 - 1.35 (m, 5H), 1.21 - 1.12 (m, 3H).MS(ESI+)m / z 594.2(M+H) + .

[0208] [Example 26] 1-[(2S)-2-hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 26 was prepared by following the procedure used for the preparation of Example 20D, in which (S)-2-hydroxypropionic acid was replaced with 2-hydroxyacetic acid, to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.84 (d, J = 6.9 Hz, 1H), 4.46 - 4.34 (m, 2H), 4.02 (d, J = 13.2 Hz, 1H), 3.21 (s, 3H), 3.14 - 2.99 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.73 - 2.64 (m, 1H), 1.82 - 1.66 (m, 2H), 1.63 - 1.37 (m, 5H), 1.20 - 1.15 (m, 3H).MS(ESI+)m / z 594.2(M+H) + .

[0209] [Example 27] 1-[(2R)-2,3-dihydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0210] [Example 27A] (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid A solution of (R)-methyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 6.24 mmol) in tetrahydrofuran (10 mL) was mixed with lithium hydroxide (0.299 g, 12.5 mmol) in water (10 mL). The reaction mixture was stirred at ambient temperature for 2 hours and partitioned with ethyl acetate and water. The organic layer was discarded. The aqueous layer was adjusted to pH 3 by adding 2 M aqueous HCl and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound.

[0211] [Example 27B] 1-[(2R)-2,3-dihydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide To a solution of Example 20C (153 mg, 0.240 mmol), Example 27A (35.1 mg, 0.240 mmol), and N,N-diisopropylethylamine (0.126 mL, 0.720 mmol) in N,N-dimethylformamide (2.0 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (100 mg, 0.264 mmol) was gradually added. The reaction mixture was stirred at ambient temperature for 2 hours and purified by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA, 10-100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to obtain the title compound and the protecting intermediate. The fraction of the protecting intermediate was concentrated, dissolved in a mixture of acetic acid (1.0 mL) / water (0.50 mL), stirred at 70°C for 15 minutes, cooled to ambient temperature, and concentrated. The residue was purified by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10-100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The combined fraction of the title compound was concentrated, acetonitrile was removed, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was freeze-dried with acetonitrile / water to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.92 - 4.81 (m, 1H), 4.72 - 4.62 (m, 1H), 4.43 - 4.29 (m, 2H), 4.11 - 4.03 (m, 1H), 3.56 - 3.48 (m, 1H), 3.47 - 3.40 (m, 1H), 3.21 (s, 3H), 3.14 - 3.00 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.76 - 2.65 (m, 1H), 1.80 - 1.65 (m, 2H), 1.63 - 1.53 (m, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.48 - 1.37 (m, 1H).MS(ESI+)m / z 610.3(M+H) + .

[0212] [Example 28] N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0213] [Example 28A] tert-butyl 4-(((S)-2,2-difluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)(methyl)carbamoyl)piperidine-1-carboxylate 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (73.6 mg, 0.321 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (69.3 mg, 0.385 mmol), and N-methylmorpholine (42.4 μL, 0.385 mmol) were mixed in dichloromethane (1.6 mL) and stirred at ambient temperature for 1 hour. The resulting suspension was added dropwise to a solution of Example 4C (126 mg, 0.321 mmol) in dichloromethane (1.6 mL), and the mixture was stirred overnight at ambient temperature. The reaction was concentrated and directly purified by flash chromatography (0-70% ethyl acetate / heptane) to obtain the title compound. MS(ESI) m / z 604.4(M+H) + .

[0214] [Example 28B] N-((S)-2,2-difluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)-N-methylpiperidine-4-carboxamide Trifluoroacetic acid (0.67 mL, 8.61 mmol) was added to a mixture of Example 28A (104 mg, 0.172 mmol) in dichloromethane (3.5 mL). The mixture was stirred at ambient temperature for 1 hour and concentrated. The residue was purified by flash chromatography (12 g silica gel, 2-10% methanol / dichloromethane and 3% NH4OH) to obtain the title compound. MS(ESI) m / z 504.4(M+H) + .

[0215] [Example 28C] N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide To a solution of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (41.5 mg, 0.109 mmol)) in N,N-dimethylformamide (1.0 mL) containing (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (41.5 mg, 0.109 mmol)) in N,N-dimethylformamide (1.0 mL), the mixture was added dropwise. The mixture was stirred at ambient temperature for 2 hours and then subjected to reverse-phase HPLC (250 × 50 mm C18). The compound was directly purified using Phenomenex® LUNA® (10-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The fraction containing the product was concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1g SiliCycle SiliaPrep carbon dioxide cartridge to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.48 (s, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.64 (td, J = 55.0, 5.1 Hz, 1H), 5.70 (s, 1H), 5.40 (q, J = 6.6 Hz, 1H), 4.40 - 3.65 (m, 5H), 3.28 (s, 3H), 3.05 - 2.85 (m, 6H), 2.83 (s, 3H), 1.71 (d, J = 10.4 Hz, 2H), 1.54 (m, 5H).MS(APCI)m / z 562.3(M+H) + .

[0216] [Example 29] 1-Acetyl-N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide To a solution of Example 28B (45 mg, 0.089 mmol) and triethylamine (31.1 μL, 0.223 mmol) in N,N-dimethylformamide (0.9 mL), acetyl chloride (7.62 μL, 0.107 mmol) was added dropwise. The mixture was stirred at ambient temperature for 2 hours and purified directly by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The desired fraction was concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1 g SiliCycle SiliaPrep carbon dioxide cartridge to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.48 (s, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.64 (td, J = 55.2, 5.1 Hz, 1H), 5.70 (s, 1H), 5.40 (q, J = 6.6 Hz, 1H), 4.50 - 3.60 (m, 2H), 3.28 (s, 3H), 3.12 - 2.85 (br, 6H), 2.83 (s, 3H), 1.99 (s, 3H), 1.70 (d, J = 11.4 Hz, 2H), 1.63 - 1.41 (m, 5H).MS(APCI)m / z 546.4(M+H) + .

[0217] [Example 30] 1-[(2S)-2,3-dihydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 30 was prepared according to the procedure used for the preparation of Example 20D, in which (S)-2,3-dihydroxypropanoic acid was replaced with 2-hydroxyacetic acid, to obtain the title compound (26 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.89 - 4.80 (m, 1H), 4.72 - 4.59 (m, 1H), 4.42 - 4.30 (m, 2H), 4.12 - 4.02 (m, 1H), 3.57 - 3.47 (m, 1H), 3.47 - 3.40 (m, 1H), 3.21 (s, MS(ESI+)m / z 610.3(M+H) + .

[0218] [Example 31] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0219] [Example 31A] tert-butyl4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2-difluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate The title compound (100 mg, 45%) was prepared using the conditions described in Example 28A, with Example 6A replaced by Example 4C. MS(APCI)m / z 640.4(M+H) + .

[0220] [Example 31B] N-((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2-difluoroethyl)-N-methylpiperidine-4-carboxamide The title compound (70 mg, 83%) was prepared using the conditions described in Example 28B, with Example 31A replaced by Example 28A. MS(APCI)m / z 540.4(M+H) + .

[0221] [Example 31C] N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2-difluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide The title compound (33.4 mg, 43%) was prepared using the conditions described in Example 28C, with Example 31B replaced by Example 28B. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 7.60 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 6.85 - 6.41 (m, 2H), 5.70 (s, 1H), 5.40 (ddd, J = 13.1, 7.3, 5.5 Hz, 1H), 4.38 - 3.56 (m, 5H), 3.36 (s, 3H), 3.00 - 2.96 (m, 3H), 2.92 (s, 3H), 2.85 (s, 3H), 1.71 (d, J = 8.3 Hz, 2H), 1.54 (d, J = 12.9 Hz, 2H).MS(APCI)m / z 598.4(M+H) + .

[0222] [Example 32] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0223] [Example 32A] (S)-tert-butyl4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.45 g, 10.7 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (1.77 g, 9.85 mmol), CH2Cl2 (50 mL), and N-methylmorpholine (1.08 mL, 9.85 mmol) were stirred at ambient temperature for 1 hour. Example 1I (2.50 g, 8.21 mmol) was added to this solution, and the combined solution was stirred at ambient temperature for 15 hours. After determination by LC-MS, the reaction mixture was concentrated. The residue was purified on silica gel (0-100% ethyl acetate / heptane). The residue was further purified by reverse-phase chromatography (C18 HPLC, eluted with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate solution to obtain the desired product, a free base. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.61 (m, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.55 (q, J = 9.2 Hz, 1H), 3.96 (d, J = 13.3 Hz, 2H), 3.08 - 2.67 (m, 6H), 1.70 (t, J = 16.9 Hz, 2H), 1.40 (s, 11H).MS(ESI+)m / z 479.6 and 481.7(M+H) + .

[0224] [Example 32B] tert-butyl4-(((S)-1-(4-((7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate 1,4-Dioxane (30 mL) was sparged with N2 for 2 minutes with Example 3H (0.500 g, 2.24 mmol), Example 32A (0.75 g, 1.57 mmol), and Cesium Carbonate (1.51 g, 4.63 mmol). XPhos Pd G4 (0.20 g, 0.23 mmol) was added, and the reaction mixture was heated at 95°C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated. The material was purified on silica gel (0-70% ethyl acetate / heptane) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.99 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.01 - 6.91 (m, 2H), 6.76 (ddd, J = 57.7, 54.3, 6.0 Hz, 1H), 6.46 (q, J = 9.3 Hz, 1H), 5.32 (dt, J = 14.2, 5.5 Hz, 1H), 3.99 (dd, J = 39.7, 10.1 Hz, 2H), 3.28 (s, 3H), 2.88 (d, J = 20.3 Hz, 9H), 1.68 (dd, J = 34.8, 12.9 Hz, 2H), 1.40 (s, 11H).MS(ESI)m / z 658.7(M+H) + .

[0225] [Example 32C] N-((S)-1-(4-((7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide Example 32B (0.95 g, 1.45 mmol) was dissolved in a 1:1 mixture of dichloromethane (3 mL) and trifluoroacetic acid (3 mL, 38.9 mmol). The solution was allowed to stand at ambient temperature for 30 minutes. After the starting material was completely consumed, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 8.00 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 - 6.94 (m, 2H), 6.75 (ddd, J = 57.8, 54.3, 5.9 Hz, 1H), 6.44 (q, J = 9.3 Hz, 1H), 5.31 (dt, J = 14.1, 5.5 Hz, 1H), 3.28 (s, 3H), 3.11 - 2.83 (m, 11H), 1.94 - 1.56 (m, 5H).MS(ESI)m / z 558.3(M+H) + .

[0226] [Example 32D] N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide To a solution of 2-hydroxyacetic acid (0.033 g, 0.43 mmol), Example 32C (0.20 g, 0.36 mmol), N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (0.31 mL, 1.79 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (0.15 g, 0.40 mmol) was added in three portions over 10 minutes. The combined solution was stirred at ambient temperature for 1 hour. After the starting materials were completely consumed, the crude substance was directly purified by reverse-phase chromatography (C18 HPLC, eluted with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate solution to obtain the desired product, the free base. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was freeze-dried to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.99 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.02 - 6.94 (m, 2H), 6.75 (ddd, J = 57.8, 54.3, 5.9 Hz, 1H), 6.45 (q, J = 9.3 Hz, 1H), 5.32 (dt, J = 14.1, 5.5 Hz, 1H), 4.49 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 12.9 Hz, 1H), 4.23 - 4.01 (m, 2H), 3.70 (d, J = 13.8 Hz, 1H), 3.28 (s, 3H), 3.03 (tq, J = 11.1, 3.6 Hz, 1H), 2.92 (s, 3H), 2.86 (s, 3H), 2.71 (dt, J = 24.0, 13.0 Hz, 1H), 1.84 - 1.32 (m, 5H).MS(ESI)m / z 616.0(M+H) + .

[0227] [Example 33] 1-Acetyl-N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide A solution of acetic acid (0.097 g, 1.6 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.31 g, 0.81 mmol), N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) was added to the solution of N,N-dimethylformamide (1.0 mL) in Example 32C (0.30 g, 0.54 mmol). The combined mixture was stirred at ambient temperature for 20 minutes. LC-MS showed complete conversion. After the starting materials were completely consumed, the crude substance was directly purified by reverse-phase chromatography (C18 HPLC, eluted with 20-80% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. The clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate solution to obtain the desired product, the free base. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was freeze-dried to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 8.00 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.07 - 6.94 (m, 2H), 6.92 - 6.58 (m, 1H), 6.44 (t, J = 9.4 Hz, 1H), 5.31 (dt, J = 13.8, 5.6 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.83 (d, J = 13.4 Hz, 1H), 3.28 (s, 3H), 3.05 (dt, J = 41.6, 11.7 Hz, 1H), 2.91 (s, MS(ESI)m / z 600.5(M+H) + .

[0228] [Example 34] 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0229] [Example 34A] tert-butyl 4-(methyl((S)-2,2,2-trifluoro-1-(4-((7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate Example 34A was prepared according to the procedure used for the preparation of Example 32B, with Example 8B replaced by Example 3H, to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.09 - 6.99 (m, 2H), 6.45 (t, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 3.95 (s, 2H), 3.21 (s, 3H), 2.87 (d, J = 43.2 Hz, 7H), 1.68 (dd, J = 42.3, 13.3 Hz, 2H), 1.52 (d, J = 6.7 Hz, 3H), 1.40 (m, 13H).MS(ESI)m / z 622.4(M+H) + .

[0230] [Example 34B] N-methyl-N-((S)-2,2,2-trifluoro-1-(4-((7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)piperidine-4-carboxamide Example 34B was prepared according to the procedure used for the preparation of Example 32C, in which Example 34A was replaced with Example 32B, to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.72 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.06 - 6.97 (m, 2H), 6.45 (q, J = 9.3 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 3.21 (s, 3H), 3.12 - 2.87 (m, 8H), 2.84 (s, 3H), 1.95 - 1.66 (m, 4H), 1.52 (d, J = 6.6 Hz, 3H).MS(ESI)m / z 522.4(M+H) + .

[0231] [Example 34C] 1-(hydroxyacetyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 34C was prepared according to the procedure used for the preparation of Example 32D, with Example 34B replaced by Example 32C, to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.09 - 7.03 (m, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.32 (q, J = 6.7 Hz, 1H), 4.49 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 12.9 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.70 (d, J = 13.6 Hz, 1H), 3.21 (s, 3H), 3.10 - 2.98 (m, 1H), 2.92 (s, 3H), 2.84 (s, 3H), 2.71 (dt, J = 24.4, 12.5 Hz, 1H), 1.82 - 1.33 (m, 8H).MS(ESI)m / z 580.4(M+H) + .

[0232] [Example 35] 1-Acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 35 was prepared according to the procedure used for the preparation of Example 33, with Example 34B replaced by Example 32C, to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.10 - 7.02 (m, 2H), 6.46 (q, J = 9.4 Hz, 1H), 5.33 (q, J = 6.7 Hz, 1H), 4.40 - 4.33 (m, 1H), 3.86 - 3.79 (m, 1H), 3.21 (s, 3H), 3.16 - 2.96 (m, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.64 (d, J = 7.1 Hz, 1H), 2.00 (d, J = MS(ESI)m / z 564.7(M+H) + .

[0233] [Example 36] N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0234] [Example 36A] tert-butyl4-(((S)-2,2-difluoro-1-(4-((2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)(methyl)carbamoyl)piperidine-1-carboxylate The title compound (175.7 mg, 51%) was prepared using the conditions described in Example 28A, with Example 14A replaced by Example 4C. MS(APCI)m / z 640.4(M+H) + .

[0235] [Example 36B] N-((S)-2,2-difluoro-1-(4-((2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridine-6-yl)amino)phenyl)ethyl)-N-methylpiperidine-4-carboxamide The title compound (149.9 mg, 100%) was prepared using the conditions described in Example 28B, with Example 36A replaced by Example 28A. MS(APCI)m / z 558.4(M+H) + .

[0236] [Example 36C] N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide The title compound (58.6 mg, 71%) was prepared using the conditions described in Example 28C, with Example 36B replaced by Example 28B. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.66 (td, J = 55.2, 5.1 Hz, 1H), 5.94 (q, J = 7.7 Hz, 1H), 5.72 (s, 1H), 4.36 - 3.70 (m, 5H), 3.56 (s, 3H), k 2.85 (s, 3H), 1.72 (dd, J = 13.0, 6.8 Hz, 2H), 1.55 (d, J = 12.9 Hz, 2H).MS(APCI)m / z 616.0(M+H) + .

[0237] [Example 37] 1-Acetyl-N-{(1S)-2,2-difluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro-1-methoxyethyl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide The title compound was prepared using the conditions described in Example 29, with Example 36B replaced by Example 28B. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.66 (td, J = 55.1, 5.1 Hz, 1H), 5.94 (q, J = 7.7 Hz, 1H), 5.72 (s, 1H), 4.57 - 3.65 (m, 2H), 3.56 (s, 3H), 2.99 - 2.87 (m, 6H), 2.85 (s, 3H), 1.99 (s, 3H), 1.78 - 1.65 (m, 2H), 1.63 - 1.39 (m, 2H).MS(APCI)m / z 600.3(M+H) + .

[0238] [Example 38] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2R)-1,1,1-trifluoropropan-2-yl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide

[0239] [Example 38A] Ethyl 7-chloro-2-methylthiazolo[5,4-b]pyridine-6-carboxylate (50 g, 195 mmol) was dissolved in 1,4-dioxane (600 mL) and water (500 mL), to which LiOH (4.66 g, 195 mmol) was added. The reaction mixture was stirred at 20°C for 3 hours. The resulting solution was acidified to pH 2 with 1 M HCl aqueous solution, filtered, and the crude title compound was obtained. The crude substance was used directly in the next step. LC-MS (ESI) m / z 375 (M+H) + .

[0240] [Example 38B] tert-butyl(7-chloro-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate A mixture of Example 38A (30 g, 131 mmol) and triethylamine (54.9 mL, 394 mmol) in tert-butanol (600 mL) was mixed with diphenyl phosphoryl azide (43.3 g, 157 mmol), and the mixture was stirred at 90°C for 12 hours. Next, the reaction mixture was concentrated to remove the tert-butanol, and the resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (s, 9H), 2.87 (s, 3H), 8.62 (s, 1H), 9.21 (s, 1H).LCMS(ESI)m / z 300(M+H) + .

[0241] [Example 38C] tert-butyl(7-iodo-2-methylthiazolo[5,4-b]pyridine-6-yl)carbamate Example 38B (12.5 g, 41.7 mmol) was dissolved in acetonitrile (180 mL) and treated with sodium iodide (18.75 g, 125 mmol). The mixture was cooled to 0°C, and then acetyl chloride (3.56 mL, 50.0 mmol) was added. The reaction was stirred at 0°C for 3 hours. The reaction mixture was poured into a stirred, cooled (10°C) saturated solution of sodium bicarbonate (500 mL). Then, a 1 M sodium thiosulfate solution (100 mL) was added, the suspension was stirred for 5 minutes, filtered, and washed with water (100 mL). The filtrate was collected, ground with ethyl acetate (500 mL), and filtered again. The residue was dried overnight in a desiccator to obtain the title compound. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (s, 9H), 2.86 (s, 3H), 8.32 (s, 1H), 9.00 (s, 1H).LCMS(ES)m / z 392(M+H) + .

[0242] [Example 38D] tert-butyl(2-methyl-7-(3,3,3-trifluoropropane-1-en-2-yl)thiazolo[5,4-b]pyridine-6-yl)carbamate In Example 38C (2.4g), a degassed suspension of 4,4,6-trimethyl-2-(3,3,3-trifluoropropane-1-en-2-yl)-1,3,2-dioxaporinane (2.043g) and cesium carbonate (6.00g) in 1,2-dimethoxyethane (20mL) and water (2mL) was prepared, to which [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (0.501g) was added. The reaction mixture was stirred at 110°C for 90 minutes under microwave irradiation. The reaction mixture was cooled to ambient temperature, degassed again, and [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (0.250g) was added. The reaction mixture was stirred at 110°C for 90 minutes under microwave irradiation. The reaction mixture was cooled to ambient temperature and partitioned between water (30 mL) and ethyl acetate (80 mL). The aqueous layer was adjusted to pH 7 by adding 1 M HCl aqueous solution and extracted with ethyl acetate (50 mL). The combined organic extract was dehydrated with magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to obtain the title compound. MS(ESI)m / z 360.2(M+H) + .

[0243] [Example 38E] tert-butyl(2-methyl-7-(1,1,1-trifluoropropan-2-yl)thiazolo[5,4-b]pyridine-6-yl)carbamate To a solution of Example 38D (200 mg) in ethanol (10 mL), palladium (5% by weight on carbon, 59.2 mg) was added. The reaction mixture was stirred overnight at 50°C under a hydrogen atmosphere (5 bar). The reaction mixture was cooled to ambient temperature, diluted with ethanol (10 mL), and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to obtain the title compound. MS(ESI)m / z 362.1(M+H) + .

[0244] [Example 38F] 2-Methyl-7-(1,1,1-trifluoropropan-2-yl)thiazolo[5,4-b]pyridine-6-amine To a solution of Example 38E (175 mg) in dichloromethane (5 mL), 2,2,2-trifluoroacetic acid (1.119 mL) was added. The reaction mixture was stirred overnight and then concentrated under vacuum. The residue was dissolved in dichloromethane (15 mL) and washed with saturated sodium bicarbonate aqueous solution (20 mL). The aqueous layer was further extracted with dichloromethane (5 mL). The combined organic extract was concentrated under vacuum. The crude product was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to obtain the title compound. MS(ESI) m / z 262.1(M+H) + .

[0245] [Example 38G] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2R)-1,1,1-trifluoropropan-2-yl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide and

[0246] [Example 39] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2S)-1,1,1-trifluoropropan-2-yl][1,3]thiazolo[5,4-b]pyridine-6-yl}amino)phenyl]ethyl}-1λ 6 -Chiang-4-carboxamide To a degassed mixture of Example 38F (65 mg), Example 1J (107 mg), and cesium carbonate (243 mg) in 1,4-dioxane (2 mL), XantPhos Pd G3 (23.59 mg) was added, and the mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth, washed with dichloromethane (12 mL), and the filtrate was concentrated under vacuum. The crude product was purified by chromatography on silica gel (0-25% acetonitrile / dichloromethane) to obtain the title compound as a mixture of diastereoisomers. A mixture of diastereoisomers was separated at 40°C by chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® IG column (10 × 250 mm, 5 microns) eluted at 40% ethanol (0.1% ammonia) in CO2, 15 mL / min, 120 bar, to obtain the title compound as individual diastereoisomers. The absolute stereochemistry of these title compounds was arbitrarily assigned. The rapidly eluting diastereoisomer corresponds to Example 38G, and the slowly eluting diastereoisomer corresponds to Example 39. Example 38G: 1 H NMR (400 MHz, DMSO-d6, 90℃) δ ppm 8.43 (s, 1H), 7.77 (s, 1H), 7.19 (d, 2H), 6.88 - 6.73 (m, 2H), 6.40 (s, 1H), 4.52 (dd, 1H), 3.26 - 3.05 (m, 5H), 2.90 (s, 3H), 2.86 (s, 3H), 2.18 - 2.00 (m, 4H), 1.77 (d, 3H).MS(ESI)m / z 609.4(M+H) + Example 39: 1H NMR (400 MHz, DMSO-d6, 90℃) δ ppm 8.43 (s, 1H), 7.77 (s, 1H), 7.19 (d, 2H), 6.85 - 6.75 (m, 2H), 6.39 (s, 1H), 4.53 (dd, 1H), 3.27 - 3.04 (m, 5H), 2.90 (s, 3H), 2.86 (s, 3H), 2.16 - 2.01 (m, 4H), 1.77 (d, 3H).MS(ESI)m / z 609.4(M+H) + .

[0247] Comparative example A N-{(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]pyrazolo[1,5-α]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide Comparative Example A was prepared according to the procedure used for the preparation of Example 1K, with (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-α]pyrimidine-6-amine replaced in Example 1J, to obtain the title compound. (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-α]pyrimidine-6-amine was obtained as described in WO2018226150, Intermediate I-2b, page 87. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 7.81 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.98 - 6.90 (m, 3H), 6.44 (q, J = 9.3 Hz, 1H), 5.29 (q, J = 6.7 Hz, 1H), 3.30 - 3.07 (m, 7H), 2.91 (s, 3H), 2.15 - 1.96 (m, 5H), 1.60 (d, J = 6.7 Hz, 3H).MS(ESI)m / z 574.1(M+H) + .

[0248] Comparative example B (S)-1-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-yl)-3-(7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)urea Comparative Example B was prepared as described in WO2018020474, Compound 142.

[0249] Biological assays MALT-1 Biochemical Assay Examples 1 through 39, which are exemplary MALT-1 inhibitors, were tested using a quenching fluorescence resonance energy transfer (quenching-FRET) enzyme assay to test their ability to inhibit the cleavage of the sequence MALT1-specific quenching fluorescent substrate [TAMRA-PEG2-Leu-Val-Ser-Arg-Gly-Ala-Ala-Ser-PEG2-K(QSY7)] by human MALT-1 protein; TAMRA is 6-carboxytetramethylrhodamine, PEG2 is 2-(2-(2-aminoethoxy)ethoxyamide linker, and QSY7 is a non-fluorescent quenching dye (Thermo-Fisher catalog #Q10193). The assay was performed by pre-dispensing the compounds into 384-well Proxiplates™ (PE 6008289). Human MALT-1 (6nM) was quenched in assay buffer (25mM HEPES). A solution was prepared using pH 7.5, 1 mM ethylenediaminetetraacetic acid, 0.8 M sodium citrate, 0.005% bovine serum albumin (BSA), and 2 mM dithiothreitol (DTT), and added to a compound plate. The plate was incubated at room temperature for 40 minutes. The reaction was carried out by adding the substrate (2 μM) to the plate and incubating at room temperature for 60 minutes. Fluorescence readings were then measured using a PE EnVision® reader (Ex.535 / Em.590). The results of the enzyme assay are subsequently shown in Table 2, demonstrating the ability of the compounds disclosed herein to inhibit MALT-1 protease activity. EC 50 This is defined as the semi-maximal effective concentration at which the compound inhibits MALT-1 protease activity.

[0250] [Table 2]

[0251] MALT-1 cell IL-6 AlphaLISA assay The following MALT-1 cell interleukin-6 (IL-6) AlphaLISA assay was performed using the Perkin Elmer® IL-6 AlphaLISA® detection kit (PE AL223). The IL-6 detection assay is a homogeneous immunoassay for detecting human IL-6 present in cell culture media in the MALT-1-dependent human ABC-DLBCL cell line, OCI-LY3. 30 μM to 1.5 nM of the compound was pre-dispensed into Black 384w microtiter plates (Greiner, 781090). Viable OCI-LY3 cells were then seeded on top of the compound at a seeding density of 50,000 cells / mL. The plates were then incubated in a 37°C incubator for 48 hours. After 48 hours of incubation, 2 μL of cell medium was transferred from each well to white ProxiPlates® (PE 6008289). A novel mix of AlphaLISA receptor beads (10 μg / mL) and biotinylated IL-6 antibody (1 nM) was prepared in AlphaLISA immunoassay buffer and added to all wells (4 μL). The plates were incubated at room temperature for 60 minutes. Streptavidin donor beads (40 μg / mL) were prepared using assay buffer and added to all wells (5 μL). The plates were incubated at room temperature for 30 minutes and read using a PE EnVision® reader. The results are shown in Table 3.

[0252] [Table 3]

[0253] Cardiovascular assay The following cardiovascular assays were performed using male Sprague-Dawley rats anesthetized with Inactin (thiobutabarbital), measured (catheter insertion into both femoral artery and vein; catheter insertion into the left ventricle), and stabilized. After a 30-minute baseline period, each compound was infused at low, medium, and high doses over 30 minutes. Plasma samples were taken at the end of each injection. If the mean arterial pressure (MAP) of an animal fell below 70 mmHg at any point, the injection was immediately stopped, a final blood sample was taken, and the hemodynamic data of that animal was removed from the group mean at all subsequent time points. A 15% change from the vehicle in either MAP or heart rate (HR) was considered biologically relevant. A 20% change from the vehicle in dP / dt@50 was considered biologically relevant. The results are shown in Table 4.

[0254] [Table 4]

[0255] CYP3A4 induction assay CYP induction by the compounds in the examples was evaluated in vitro by determining the expression level of CYP 3A4 mRNA using a qPCR (quantitative polymerase chain reaction) assay. On day 1, cryopreserved human hepatocytes were thawed in pre-warmed (37°C) thawing medium (cryopreserved hepatocyte recovery medium, Gibco® CM 7000; Thermo Fisher Scientific), centrifuged (1000 g, 10 min), and resuspended in plate medium (Gibco® CM3000, Williams medium E supplemented with a serum-containing hepatocyte plating supplement pak; Thermo Fisher Scientific). Cells were counted using a hemocytometer by trypan blue exclusion, yielding 1.2 × 10⁶ cells. 6The cell density was adjusted to cells / μL. Then, 0.05 μL of the cell suspension was added as an aliquot to each well of a 96-well plate to obtain 60,000 cells / well. The plate was shaken in north-south and east-west directions during plate culture. The plate-cultured cells were incubated in a humidified cell culture incubator at 37°C / 5%CO2 for 4-6 hours. During this time, incubation medium (Gibco® CM4000, cell maintenance supplement pack; Thermo Fisher Scientific) was mixed with Gibco® Geltrex® (Thermo Fisher Scientific) at an appropriate Geltrex® protein concentration. After harvesting, the medium was removed from the cells and replaced with freshly prepared incubation medium. The cells were incubated overnight in a cell culture incubator (37°C / 5%CO2).

[0256] The following day, incubation medium was prepared by combining the hepatocyte maintenance supplement pack with Williams medium E. The medium was warmed to 37°C. A 1000× dimethyl sulfoxide stock of the compound of the example was prepared to the desired concentration. The 10 mM compound stock in dimethyl sulfoxide was diluted (1 μL to 1 mL CM4000; final concentration = 10 μM). The stratified medium was aspirated, and 0.1 μL dose solutions were added to the desired labeled 96-well plate. The cells were then administered the compound (10 μM) to induce prototypes at target concentrations of 50 μM with omeprazole (Sigma 0104 / lot BCBF-2161V) or 10 μM with rifampicin (Sigma R3501 / lot 011M1159V). Probenecid, a negative control, was administered at 10 μM (Sigma P8761 / lot 013K0148).

[0257] On day 3, RNA isolation was performed. All surfaces were cleaned using RNase RNAy. The entire RNA was isolated using the MagMAX Express 96 RNA Isolation System (Life Technologies, AM1830). Briefly, hepatocytes were washed once with 1×PBS (phosphate-buffered saline). 145 μL of RNA lysis buffer was added to each well, and each well was mixed several times by pipetting. The lysates were then transferred to the wells of a 96-well bound plate. The samples were then mixed with 20 μL of magnetic beads from the kit. The RNA bound to the beads was then captured using a magnetic tip manifold, and the beads were washed with the washing solution. The samples were treated with TURBO® DNase. After TURBO® DNase treatment, the RNA was re-bound to the beads and washed two more times with the prepared washing buffer. The beads were then dried, and the RNA was eluted with 50 μL of elution buffer. The eluted mRNA was transferred from the wells to an RNase-free, sealable microtiter plate and stored at -80°C until use.

[0258] After mRNA isolation, reverse transcription (RT) was performed using Taqman® reverse transcription reagent (ThermoFisher Scientific). The RT master mix consisted of 2.5 μL of 10× RT buffer and 5.5 μL of 25 mM MgCl. 2、 The RT mix was prepared by mixing 5 μL of deoxy-NTP mixture, 1.25 μL of 50 mM random hexamer, 0.5 μL of 2× RNAse inhibitor, 0.625 μL of multiscript RTase (50 U / μL), and 0.625 μL of water. Aliquots of the RT mix (16 μL) and the mRNA sample (9 μL) were added to each well of a 96-well plate. A SimpliAmp® thermal cycler PCR system VIIA7 from Applied Biosystems was used for reverse transcription under the following conditions: Segment 1: 25°C, 10 min; Segment 2: 45°C, 45 min; Segment 3: 95°C, 5 min; and Segment 4: Hold at 4°C; one cycle per segment.

[0259] Subsequently, TaqMan® qPCR was performed using the Applied Biosystems QuantStudio 7 Flex System (Applied Biosystems, Foster City, CA). TaqMan® Fast Advanced Master Mix and gene expression assay primers (HS00604506_m1 (ThermoFisher) for CYP3A4 and HS02758991_g1 hGAPDH (ThermoFisher) as a control, glyceraldehyde-phosphate dehydrogenase) were purchased from Applied Biosystems. The PCR reaction mix contained diluted cDNA (2 μL) and 18 μL of TaqMan® qPCR master mix (10 μL TaqMan® Fast Advanced Master Mix, 1 μL gene expression primer probe mix, and 7 μL nuclease-free water). qPCR thermal cycling conditions: Segment 1: Hold at 50°C for 10 minutes; Segment 2: Hold at 95°C for 3 minutes; followed by 40 cycles of Segment 3: 95°C for 15 seconds and Segment 4: 60°C for 1 minute.

[0260] The induction ratios in CYP isoform mRNA induced by compound treatment were determined using comparative quantitative real-time polymerase chain reaction (qPCR). This method calculated the CYP induction ratio as a percentage of the response to the vehicle (0.1% DMSO), the positive control, and rifampicin. Induction ratio = ratio of treated sample / ratio of vehicle control. Percentage of positive control = (induction ratio of treated sample - 1) / (induction ratio of rifampicin - 1).

[0261] [Table 5]

[0262] It is understood that the above-mentioned detailed description and accompanying examples are illustrative only and should not be construed as limiting the scope of this disclosure as defined solely by the accompanying claims and equivalents. Various variations and modifications of the disclosed embodiments will be apparent to those skilled in the art. Such variations and modifications may be made without departing from their spirit and scope. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for any purpose.

Claims

【Request 1】 N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide; or a pharma- ceutically acceptable salt thereof. 【Request 2】 N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide.