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

[0002] B and T cells of the adaptive immune system utilize the multifaceted NF-κB signaling pathway to transduce extracellular signals from their cognate antigen receptors to enhance survival and proliferation. This signaling leads to the rapid nuclear localization of NF-κB and the 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. Upon stimulation of the B cell receptor and T cell receptor, the CBM complex forms and recruits multiple signaling proteins, leading to canonical NF-κB activation.

[0003] The paracaspase MALT1 is an essential regulator within the CBM complex, which not only acts as a scaffold to assemble the protein complex for NF-κB activation but also as a protease to cleave negative regulators of the NF-κB pathway for signal reinforcement.

[0004] Aberrant activation of NF-κB signaling occurs in diffuse large B-cell lymphoma with an activated B-cell-like subtype (ABC-DLBCL). ABC-DLBCL tumors have a gene expression signature characteristic of B cells activated through the B-cell receptor. Gain-of-function alterations in the BCR pathway are frequently detected in DLBCL cases, and these mutations induce constitutive NF-κB activation, which is required for tumor cell survival. Summary of the Invention [Problem to be solved by the invention]

[0005] Given the role of MALT-1 as a regulator of the NF-κB pathway, which plays a central role in diseases including ABC-DLBCL, there is a need for compounds that inhibit MALT-1 protease activity for use as anti-ABC-DLBCL therapeutics. In particular, there is a need for MALT-1 compounds that inhibit MALT-1 protease activity with improved pharmaceutical properties. [Means for solving the problem]

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

[0007] [ka] (In the formula: R 1a is selected from the group consisting of OCH3 and CH3; R 1b is selected from the group consisting of CH3, CHF2, and CF3; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H and F; R 4 is selected from the group consisting of CHF2 and CF3; R 5 is C1-C4 alkyl, Ring A is

[0008] [ka] is a ring selected from the group consisting of R 6 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from the group consisting of H and C1-C4 alkyl; R 8is selected from the group consisting of CHF2 and CH3, or a pharmaceutically acceptable salt thereof.

[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 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 C1-C4 alkyl. In another embodiment, R 5 is C1-C4 alkyl.

[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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide; 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; N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-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; 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-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide; N-{(1S)-1-[3,5-difluoro-4-({7-[(1S)-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; 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide; N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][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; N-[(1S)-1-(4-{[7-(1,1-difluoropropan-2-yl)-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; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)-3-fluorophenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide; 1-acetyl-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-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide; or a pharmaceutically acceptable salt 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide.

[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding aspects, in combination with a pharmaceutically acceptable carrier.

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

[0018] In another aspect, the present disclosure provides a compound of formula (1G):

[0019] [ka] with a compound of formula (2G)

[0020] [ka] in a solvent in the presence of a base and a catalyst to obtain a compound of formula (3A)

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

[0022] [ka] is a ring selected from the group consisting of R 6 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from the group consisting of H and C1-C4 alkyl; R 8 is selected from the group consisting of CHF2 and CH3. DETAILED DESCRIPTION OF THE INVENTION

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

[0024] Formula (I)

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

[0026] [ka] is a ring selected from the group consisting of R 6 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from the group consisting of H and C1-C4 alkyl; R 8 is selected from the group consisting of CHF2 and CH3.

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

[0028] It is noted that as used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds.

[0029] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated: The term "alkyl," as used herein, refers to a saturated, straight or branched hydrocarbon chain group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0030] The term "hydroxyalkyl," as used herein, refers to one or more hydroxy groups (OH) appended to the parent molecular moiety through an alkyl group, as defined herein. The hydroxyalkyl group can have 1, 2, 3, or 4 carbons, unless otherwise specified. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

[0031] In some instances, the number of carbon atoms in the moiety is indicated by the prefix "C x ~C y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms, and "C1-C3 alkyl" means an alkyl substituent containing from 1 to 3 carbon atoms.

[0032] With respect to the use of the words "comprise" or "comprises" or "comprising" in this disclosure (including the claims), unless the context otherwise requires, such words are used based on the principle and clear understanding that they are interpreted in an inclusive rather than exclusive manner.

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

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

[0035] The phrase "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio.

[0036] The term "stable" refers to a compound that possesses sufficient stability to allow for manufacture and maintains the integrity of the compound 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. The terms "human," "patient," and "subject" are used interchangeably herein.

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

[0039] As used herein, the terms "treat," "treating," and "treatment" refer to a method of alleviating or arresting a disease and / or its attendant symptoms. compound The compounds of the present disclosure have the general formula (I) described herein.

[0040] In embodiments, the present disclosure provides a compound of formula (I):

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

[0042] [ka] is a ring selected from the group consisting of R 6 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from the group consisting of H and C1-C4 alkyl; R 8 is selected from the group consisting of CHF2 and CH3), or a pharmaceutically acceptable salt thereof.

[0043] Particular values ​​for variables in compounds 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 certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 1a is selected from the group consisting of OCH3 and CH3. In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 1a is OCH3. In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 1a is CH3.

[0045] In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 1b is selected from the group consisting of CH3, CHF2, and CF3. In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 1b is selected from the group consisting of CH3 and CHF2. In certain 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 and 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 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 and R 1b is CHF2 and R 2 is H and R 3 is H and 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 and R 1b is CHF2 and R 2 is H and R 3 is H and R 4 is CF3 and R 5 is methyl.

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

[0056] In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is

[0057] [ka] In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is selected from the group consisting of:

[0058] [ka] In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is:

[0059] [ka] is.

[0060] In certain 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 certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is C1-C4 alkyl. In certain embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is C1-C4 hydroxyalkyl.

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

[0062] [ka] is.

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

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

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

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

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

[0068] [ka] and R 7 is H and R 8 is CH3.

[0069] The compounds disclosed herein may contain one or more variables that occur more than once in any substituent or formula herein. The definition of a variable at each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds.

[0070] The compounds and intermediates of the present disclosure were named using the ACD / Name 2021.1.3 (file version N15E41, build 123232, July 07, 2021) software program and / or by using the Struct=Name naming algorithm as part of CHEMDRAW® Professional v.15.0.0.106.

[0071] Exemplary compounds of Formula (I) include, but are not limited to, the compounds set forth below in Table 1, and pharmaceutically acceptable salts thereof. It should be understood that if a discrepancy exists between the name of a compound found herein and the structure found in Table 1, the structure in Table 1 shall control.

[0072] [Table 1] TIFF2025156455000020.tif231169TIFF2025156455000021.tif228170TIFF2025156455000022.tif118167

[0073] The compounds of formula (I) may be used in the form of pharmaceutically acceptable salts.

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

[0075] Methods of Making Exemplary Compounds The compounds of the present disclosure may be better understood with reference to the following synthetic schemes and methods that illustrate the means by which the compounds can be prepared. The compounds of the present disclosure may be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in, but not limited to, Schemes 1-8. 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 schemes and their descriptions have the following meanings: BOC is a tert-butyloxycarbonyl protecting group.

[0077] Representative schemes for synthesizing exemplary intermediates and compounds of formula (I):

[0078] [ka]

[0079] Scheme 1 describes the synthesis of an intermediate of formula (1G). 1A , R 1B and R 8(wherein R is as described herein) can be converted to a compound of formula (1B) by reacting the former with (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 in a solvent such as, but not limited to, dichloromethane at ambient temperature. Separation of the compound of formula (1B) into compounds of formula (1C) and (1D) can be carried out via precipitation techniques described herein. The compound of formula (1D) can be hydrolyzed using a base such as lithium hydroxide followed by the addition of an acid such as hydrochloric acid to give a compound of formula (1E). The reaction is typically carried out in an aqueous environment and can be carried out at elevated temperatures, where the elevated temperature is above ambient temperature, for example, above 20°C. Compounds of formula (1F) can be prepared by reacting compounds 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 elevated temperatures. Compounds of formula (1G) can be prepared by treating compounds of formula (1F) with an acid, such as 2,2,2-trifluoroacetic acid, in a solvent, such as dichloromethane. The reaction can be carried out at low temperatures.

[0080] [ka]

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

[0082] [ka]

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

[0084] [ka]

[0085] As shown in Scheme 4, a compound of formula (4A) (wherein R 1a and R 1b A compound of formula (4B) can be treated with iodomethane in the presence of a base, such as, but not limited to, potassium carbonate, to give a compound of formula (4B). The reaction is typically carried out in a solvent, such as, but not limited to, N,N-dimethylformamide, at ambient temperature. A compound of formula (4B) can be treated with selenium dioxide to give a compound of formula (4C). The reaction is typically carried out in a solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature. A compound of formula (4D) can be prepared by treating a compound of formula (4C) with [bis(2-methoxyethyl)amino]sulfur trifluoride at low temperature, followed by heating. The reaction is typically carried out in a solvent, such as, but not limited to, toluene. Treatment of a compound of formula (4D) with a base, such as, for example, sodium carbonate, in a solvent, such as methanol, at ambient temperature gives a compound of formula (4E). Compounds of formula (4F) can be prepared by reacting compounds 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 elevated temperatures. Compounds of formula (4F) can be utilized as described in Scheme 3 to obtain compounds of formula (I).

[0086] [ka]

[0087] Scheme 5 describes the synthesis of compounds of formula (5C), which are representative of compounds of formula (I). 8 , R 1a and R 1bA compound of formula (2F) (where A is as described herein) can be coupled to (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine under Buchwald coupling reaction conditions, which may include the use of a base, such as, but not limited to, cesium carbonate, and a catalyst, such as, but not limited to, XantPhos Pd G3, to provide a compound of formula (5B). The reaction is typically carried out in a solvent, such as, but not limited to, 1,4-dioxane, at elevated temperatures. A compound of formula (2F) (where A is as described herein) can be treated with 2,4-dichloro-6-methoxy-1,3,5-triazine and N-methylmorpholine in dichloromethane at ambient temperature, followed by the addition of a compound of formula (5B), to provide a compound of formula (5C), which is representative of a compound of formula (I).

[0088] [ka]

[0089] As shown in Scheme 6, a compound of formula (6A) (wherein R 8A compound of formula (6B) can be treated with a base, such as, but not limited to, LiOH, to give a compound of formula (6B). The reaction is typically carried out in an aqueous solvent system, such as, but not limited to, a mixture of water and 1,4-dioxane, at ambient temperature. A compound of formula (6C) can be prepared by reacting a compound of formula (6B) with diphenyl azidophosphate in tert-butanol in the presence of a base, such as triethylamine. The reaction is typically carried out at elevated temperatures. A compound of formula (6C) can be treated with sodium iodide and acetyl chloride to give a compound of formula (6D). The reaction is typically carried out at low temperatures in a solvent, such as, but not limited to, acetonitrile. Compounds of formula (6E) can be prepared by reacting compounds of formula (6D) with 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-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 elevated temperatures and can be heated via microwave irradiation and in solvents such as 1,2-dimethoxyethane, water, or mixtures thereof. Compounds of formula (6E) can be treated with hydrogen gas and palladium (5 wt. % on carbon) to give compounds of formula (6F). The reaction is typically carried out at elevated temperatures in solvents such as, but not limited to, ethanol. Compounds of formula (6G) can be prepared by treating compounds of formula (6F) with 2,2,2-trifluoroacetic acid in dichloromethane at ambient temperature. Compounds of formula (6G) can be utilized as described in Scheme 3 to provide compounds of formula (I).

[0090] [ka]

[0091] Scheme 7 describes the synthesis of compounds of formula (7B), which can be used as intermediates in the synthesis of compounds of formula (I). 4 (wherein R 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 provide a compound of formula (7B).

[0092] [ka]

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

[0094] It will be appreciated that the synthetic schemes and specific examples illustrated in the Synthetic Examples section are illustrative and should not be construed as limiting the scope of the appended claims. All alternatives, modifications, and equivalents in the synthetic methods and specific examples are included within the scope of the claims.

[0095] Optimum reaction conditions and reaction times for each of the individual steps may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Synthetic Examples section. Unless otherwise noted, starting materials and reagents are commercially available or can be prepared from commercially available materials by one skilled in the art using methods described in the chemical literature.

[0096] Pharmaceutical Composition When employed as pharmaceuticals, the compounds of the present disclosure may be administered in the form of a pharmaceutical composition, which may comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0097] How to use The compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, can be administered to a subject suffering from ABC-DLBCL. The term "administering" refers to the method of contacting a compound with a subject in need thereof.

[0098] In another embodiment, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure may be for use in medicine. In certain embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure may be for use in treating a disease or disorder described herein above, including ABC-DLBCL.

[0099] The present disclosure is also directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating ABC-DLBCL. [Example]

[0100] The following examples may be used for illustrative purposes and should not be construed as narrowing the scope of the present disclosure.

[0101] All reagents were of commercial grade and were used as received without further purification unless otherwise specified. 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 Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal standard or relative to the appropriate residual solvent peak, i.e., CHCl3 (δ 7.27).

[0102] The following abbreviations have the indicated meanings unless otherwise specified: NMR is nuclear magnetic resonance; s is singlet; br is broad singlet; d is doublet or doublet; m is multiplet; t is triplet; q is quartet; 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 millimole; 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide

[0104] Example 1A (R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl 7-(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 in vacuo to give a residue, which was triturated with tetrahydrofuran (2.5 L) at 50°C for 30 minutes. The reaction mixture was concentrated in vacuo to reduce the volume to approximately 400 mL and stirred at 20°C for 30 minutes. The precipitate was collected by filtration to give 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-yl 7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate; and

[0106] Example 1C (R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl 7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylate Example 1A (370 g) in tetrahydrofuran (3 L) was stirred at 70° C. for 30 minutes. The mixture was concentrated in vacuo to reduce the volume to approximately 1 L, and then stirred at 25° C. for 30 minutes. The resulting precipitate was collected by filtration to give the crude product. The process was repeated three times, and the precipitate was collected by filtration to give Example 1B. The mother liquor from the first filtration was concentrated in vacuo to give Example 1C. Example 1B: 1 H NMR (400 MHz, CDCl) 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). 6 M aqueous HCl was added to adjust the pH to 1.57. The mixture was heated to 100° C. over 50 minutes and then stirred at 100° C. for 30 minutes. The mixture was cooled to 25° C. over 5 hours and stirred for 30 minutes. The precipitate was collected by filtration to give the crude product, which was triturated with water (2 L) at 25° C. for 30 minutes. The precipitate was collected by filtration, air-dried for 3 hours, and then dried in vacuo at 50° C. for 6 hours to give the title compound. 1 H NMR (400 MHz, CDCl) δ ppm 9.13 (s, 1H), 5.91 - 5.83 (m, 1H), 3.47 (s, 3H), 2.89 (s, 3H), 1.73 (d, 3H). One exchangeable proton was not 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 approximately 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 approximately 40° C. and stirred until a slightly cloudy solution was formed. The solution was cooled to ambient temperature, stirred for 30 minutes, and filtered. The filtrate was concentrated in vacuo to provide 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) at 10° C. was added 2,2,2-trifluoroacetic acid (46.4 mL) over 7 minutes. The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. Dichloromethane (100 mL) was added, and disodium hydrogen phosphate (1 M in water) was added to adjust to neutral pH. The phases were separated, and the organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo. 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 in vacuo 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 provide 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 at 50°C overnight. The reaction mixture was cooled to -78°C, lithium trisec-butylborohydride (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, which was allowed to warm 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 x 100 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to afford 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 Sodium hydride (0.475 g) was added portionwise to a solution of Example 1G (3.73 g) in tetrahydrofuran (50 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 2 hours. Iodomethane (3.26 mL) was added to the reaction mixture, which was stirred at 0° C. for 10 minutes and at ambient temperature for an additional 10 minutes. Saturated aqueous ammonium chloride (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), brine (50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel (0-60% ethyl acetate / 2-methylpentane) to provide 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-methylethanamine To a solution of Example 1H (1.90 g) in 1,4-dioxane (15 mL) and methanol (15 mL) was added 4 M HCl in 1,4-dioxane (5.10 mL), and the reaction mixture was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo, and 0.5 M aqueous HCl (80 mL) 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 dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to provide 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) was added oxalyl chloride (0.41 mL) and N,N-dimethylformamide (0.014 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo. 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 aqueous sodium bicarbonate (2 × 30 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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) was added XantPhos Pd G3 ([(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) (25.5 mg), 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 in vacuo. The crude material 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 give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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 material was purified by flash chromatography (0-100% ethyl acetate / heptane) to provide 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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) was added 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 NaCO (61.9 g, 584 mmol). The mixture was stirred at 100° C. for 12 hours, after which another batch of 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 NaCO (12.4 g, 116.8 mmol) was added, and the mixture was stirred at 100° C. for another 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 phases were washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to give 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 a solution of Example 3A (120 g, 483 mmol) in 1,4-dioxane (960 mL) and water (720 mL) was added lithium hydroxide (17.36 g, 725 mmol), and the reaction was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo 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 filter cake was washed with water (1000 mL), dissolved in tetrahydrofuran (1000 mL), dried over MgSO4, filtered, and concentrated to provide 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]pyridin-6-yl)carbamate To a mixture of Example 3B (73 g, 331 mmol, oven-dried), triethylamine (138 mL, 994 mmol, dried over molecular sieves) in toluene (1095 mL, dried over molecular sieves) was added diphenylphosphoryl azide (137 g, 497 mmol). After stirring at 20° C. for 1 hour, tert-butanol (91 mL, 994 mmol, dried over molecular sieves) was added, and the mixture was stirred at 90° C. for 2 hours. After cooling, the mixture was concentrated to a small volume. The residue was poured into water (1000 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (1:3 ethyl acetate / petroleum ether) to give 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]pyridin-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 osmate(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 filter 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), dried over MgSO4, filtered, and concentrated to provide 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]pyridin-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) was added (bromodifluoromethyl)trimethylsilane (42.4 mL, 273 mmol), and the reaction mixture was stirred at 25° C. for 3 h. 1.5 M potassium hydroxide (352 mL, 528 mmol) was added slowly, and the reaction mixture was stirred at 0° C. for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl (400 mL), and the mixture was extracted with ethyl acetate (4×800 mL). The organic layers were combined, washed with brine (700 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (3:7 ethyl acetate / petroleum ether) to give tert-butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate (50 g, 83% purity, contained POPh) and tert-butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate (265 g, 65% purity, contained POPh). POPh was removed in the next 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]pyridin-7-yl)-2,2-difluoroethan-1-ol A solution of Example 3E (50 g, 145 mmol) in 4 M HCl in 1,4-dioxane (500 mL, 2000 mmol) was stirred at 25° C. for 4 hours and then filtered. The filter cake was dissolved in ethyl acetate, basified with saturated aqueous sodium carbonate to approximately pH 8, 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 dried over NaSO and filtered. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (2:3 ethyl acetate / petroleum ether) to give 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]pyridin-6-amine

[0124] Example 3H (S)-7-(2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine To a solution of Example 3E (25 g, 102 mmol) in N,N-dimethylformamide (500 mL) at 0° C., sodium hydride (4.89 g, 122 mmol) was added, 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 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), brine (3×500 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo. The crude racemic mixture was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to give the desired product as a mixture of enantiomers (49.3 g). The enantiomers were separated by preparative chiral SFC using a CHIRAL ART Cellulose-SB, 5 x 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. Example 3G retention time: 6.93 min; Example 3H retention time: 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide To a degassed mixture of Example 3G (39 mg), Example 1J (85 mg), and cesium carbonate (147 mg) in 1,4-dioxane (2 mL) was added XantPhos Pd G3 (14.26 mg), 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 in vacuo. The crude material was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to provide 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide

[0127] Example 4A 1-(4-bromophenyl)-2,2-difluoroethan-1-one To a solution of 1-bromo-4-iodobenzene (50 g, 177 mmol) in tetrahydrofuran (500 mL) was added n-butyllithium (78 mL, 194 mmol) 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 an additional 1 hour and then at 0° C. for 1 hour. The reaction was quenched with 1 N aqueous HCl (15 mL) and extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography using ethyl acetate / petroleum ether to give 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-methylethanamine To a solution of Example 4A (30 g, 128 mmol), methanamine (39.6 g, 383 mmol) in ethyl alcohol, and titanium(IV) isopropoxide (72.6 g, 255 mmol) in dichloromethane (450 mL) was added sodium cyanoborohydride (16.04 g, 255 mmol) in portions. 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 in vacuo. 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 microns) eluting with hexane (0.1% diethylamine) / isopropanol at 20 mL / min; 10 min to give 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]pyridin-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 vessel was sealed. The reaction was stirred at 90°C for 16 hours. After cooling, the reaction mixture was filtered and concentrated. The crude material was purified by flash chromatography (40 g silica gel, 0-70% ethyl acetate / heptane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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 h. A mixture of Example 4C (207 mg, 0.527 mmol) in dichloromethane (2.7 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was concentrated and directly purified by reverse-phase HPLC (C18 Phenomenex® LUNA®, 250 × 50 mm, 10–90% acetonitrile / 0.1% trifluoroacetic acid in water). The product-containing fractions were concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1 g SiliCycle SiliaPrep carbonate cartridge to give 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-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) in 1,4-dioxane (19 mL) were sparged with N for 2 minutes. XPhos Pd G4 (methanesulfonato(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 to 95 °C for 16 hours. The reaction mixture was cooled and 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 give 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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), CHCl (50 mL), and N-methylmorpholine (0.394 mL, 3.58 mmol) were stirred at ambient temperature for 1 hour. To this solution was added Example 5A (1.00 g, 2.24 mmol), and the combined solution was stirred at ambient temperature for 15 hours. Upon completion, as determined by LCMS, the reaction mixture was concentrated. The residue was purified on silica gel (0-100% ethyl acetate / heptane) to give a residue. The residue was further purified by reverse-phase chromatography (C18 250 x 50 mm C18 Phenomenex® LUNA® HPLC column, eluting with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. Clean fractions were combined and concentrated to remove acetonitrile. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to the desired product free base. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized to provide 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]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-amine The title compound (235 mg, 86%) was prepared using the conditions described in Example 4C, substituting Example 1F for Example 3G. 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]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide The title compound (145 mg, 45%) was prepared using the conditions described in Example 4D, substituting Example 6A4C for Example 6A. 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide

[0138] Example 7A (S)-1-(4-bromophenyl)-N-ethyl-2,2,2-trifluoroethanamine To a solution of Example 1I (0.4 g, 1.575 mmol) in methanol (5.3 mL) was added acetaldehyde (0.088 mL, 1.575 mmol) 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 layers were concentrated and purified by reverse-phase HPLC (250 x 50 mm Phenomenex® LUNA® C18, 10-90% acetonitrile / 0.1% aqueous trifluoroacetic acid) to give 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) was added oxalyl chloride (0.470 mL, 0.940 mmol) and N,N-dimethylformamide (3.64 μL, 0.047 mmol) at 0° C. The mixture was stirred for 1 hour while warming to ambient temperature. The reaction was concentrated to give 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 (12 g silica gel, 0-70% acetone / heptane) to give the title compound (15 mg, 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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 combined in 1,4-dioxane (1.0 mL). The mixture was sparged with nitrogen for 5 minutes, and the vessel 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 x 50 mm C18 Phenomenex® LUNA®, 10-90% acetonitrile / 0.1% aqueous trifluoroacetic acid). The collected fractions containing the product were concentrated and repurified by flash chromatography (12 g silica gel, 0-100% ethyl acetate / heptane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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. Upon 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% by weight). 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 triturated with water. The mixture was filtered, and the filter cake was dried under vacuum at 60°C for 24 hours. After drying, the combined filter cakes provided the title compound. 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]pyridin-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. Upon completion, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel (0-40% ethyl acetate / heptane) to give the boc-protected aniline. The boc-protected aniline was dissolved in a 1:1 mixture of trifluoroacetic acid and CHCl and stirred at ambient temperature for 1 hour. Upon completion, the solution was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel (0-80% ethyl acetate / heptane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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) in 1,4-dioxane (507 mL) were sparged with N for 5 minutes. 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, ammonium 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 to 100% ethyl acetate / heptane). The residue was further purified by reverse-phase chromatography (C18 HPLC, eluting with 20-100% acetonitrile in water / 0.1% trifluoroacetic acid) to isolate the title compound. Clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized to the desired product free base with saturated aqueous sodium bicarbonate. To improve the diastereoisomeric purity to >99%, the material was subjected to chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® OJ-H column (30 × 250 mm, 5 micron) eluting with 20% methanol in CO2 at 35 °C, 150 mL / min, 120 bar to afford 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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) was added copper(II) sulfate (21.7 g, 136 mmol) at 20 °C under N. The mixture was stirred at 85 °C for 12 h. The mixture was filtered through a pad of diatomaceous earth. The filtrate was purified by column chromatography on silica gel (10:1 to ca. 5:1 petroleum ether:ethyl acetate) to provide 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) was added (trifluoromethyl)trimethylsilane (4.93 mL, 30.8 mmol) at −55° C. under N. The mixture was stirred at −20° C. for 0.5 h. The reaction was quenched with NH4Cl solution at −40° C. and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (10:1 to 3:1 petroleum ether / ethyl acetate) to give 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-trifluoroethan-1-amine To a solution of Example 9B (7.5 g, 19.0 mmol) in ethyl acetate (10 mL) was added a solution of 4 N HCl in ethyl acetate (100 mL). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was diluted with methyl tert-butyl ether. The mixture was stirred at 20° C. for 2 hours and then filtered to give (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethanamine, hydrochloride salt. The hydrochloride salt was dissolved in water (20 mL), neutralized with NaHCO solution (50 mL), and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethanamine (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-methylethan-1-amine To a mixture of Example 9C (2.5 g, 8.62 mmol) in methanol (50 mL) was added formaldehyde (0.839 g, 10.3 mmol) at 20 °C, and the resulting mixture was stirred at 20 °C for 12 h. NaBHCN (1.63 g, 25.9 mmol) was added, and the mixture was stirred at 20 °C for 2 h. The combined mixture was poured into ice water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20:1 to 5:1 petroleum ether / ethyl acetate) to provide 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) was added tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (1.75 g, 8.88 mmol) 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 layers were washed with brine (10 mL), dried over NaSO, 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 provide 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6-thiane-4-carboxamide To a solution of Example 9E (200 mg, 0.431 mmol), Example 1F (106 mg, 0.474 mmol), and CsCO (421 mg, 1.29 mmol) in 1,4-dioxane (4 mL) was added methanesulfonato(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) under N. The reaction was stirred at 90 °C for 3 h and filtered. The filtrate was concentrated under reduced pressure to give 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, 40-70% acetonitrile / 10 mM NH4HCO3 in water in 10 min) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide

[0153] Example 10A 1-(4-bromo-3-fluorophenyl)-2,2,2-trifluoroethanol To a solution of 4-bromo-3-fluorobenzaldehyde (5 g) and cesium fluoride (0.075 g) in tetrahydrofuran (50 mL) was added trimethyl(trifluoromethyl)silane (14.59 mL) 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 extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to provide 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-methylethanamine To a solution of Example 10A (1.3 g) in dichloromethane (30 mL) was added 2,6-dimethylpyridine (1.109 mL) and trifluoromethanesulfonic anhydride (1 M in dichloromethane, 7.14 mL) at -30°C. The reaction mixture was stirred for 2.5 hours and allowed to warm slowly to ambient temperature. Methanamine (33 wt% in ethanol, 15 mL) was added, and the reaction mixture was stirred at 45°C for 4 hours. The reaction mixture was allowed to stand at ambient temperature overnight. Saturated aqueous sodium bicarbonate (20 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to provide 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) was added 4-methylmorpholine (0.359 mL) and 2,4-dichloro-6-methoxy-1,3,5-triazine (588 mg). The reaction mixture was stirred for 90 minutes at ambient temperature. 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 in vacuo onto silica gel. The crude product was purified by chromatography on silica gel (0-70% ethyl acetate / 2-methylpentane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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) at ambient temperature, XPhos Pd G4 (145 mg) was added, 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 aqueous ammonium chloride solution (5 mL) were added to the filtrate, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. 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 give the product as a mixture of diastereoisomers. The mixture of diastereoisomers was separated by chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® IC column (10 × 250 mm, 5 microns) eluting with 40% methanol (0.1% ammonia) in CO at 15 mL / min, 120 bar at 40° C. to give the title compounds as individual diastereoisomers, the absolute stereochemistry of which has been 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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 under a nitrogen atmosphere for 16 hours. After cooling to ambient temperature, the 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 dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on silica gel (10% ethyl acetate / petroleum ether) to give 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. Upon complete hydrolysis, 1,4-dioxane was removed under reduced pressure. The resulting aqueous solution was adjusted to pH 2 with 1 M aqueous HCl. The mixture was filtered, and the filter cake was dried in vacuo to give 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]pyridin-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 diphenylphosphoryl azide (28.1 g, 102 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and then refluxed at 95° C. overnight. Upon cooling, the resulting solution was concentrated under reduced pressure. The residue was purified on silica gel (10% ethyl acetate / petroleum ether) to provide 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]pyridin-6-yl)carbamate Example 11C (15 g, 51.5 mmol), potassium osmate(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 dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on silica gel (20% ethyl acetate / petroleum ether) to give 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]pyridin-6-yl)carbamate A mixture of Example 11D (26 g, 89 mmol), 4 Å molecular sieves (10 g), and dimethyl sulfoxide (250 mL) was treated with (trifluoromethyl)trimethylsilane (15.1 g, 106 mmol). The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere 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 dried over 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 provide 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]pyridin-6-yl)carbamate Potassium carbonate (12.3 g, 89 mmol) and methyl iodide (5.6 mL, 89 mmol) were added to a 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 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over 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 provide 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]pyridin-6-amine; and

[0165] [Example 11H] (S)-2-Methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridin-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 complete consumption of the starting material as determined by LCMS, the reaction mixture was filtered and the filter cake was washed with ethyl acetate (80 mL). The filter cake was dispersed in water (80 mL), and the resulting suspension was adjusted to pH 9 with 15% aqueous sodium carbonate and filtered. The filter cake was washed with water (80 mL) and dried under vacuum to give a 1:1 mixture of Examples 11G and 11H. The racemic material was subjected to chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® AD-H column (5 × 25 cm, 5 microns) eluting with 15% methanol (2 mM ammonia) in CO at 150 mL / min at 35 °C to give the title compounds (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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide 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) in 1,4-dioxane (10 mL) were sparged with N for 2 minutes. XPhos Pd G4 (70 mg, 0.081 mmol) was added, and the reaction mixture was heated to 95 °C for 16 hours. The solution was cooled to ambient temperature and 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, eluting with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. Clean fractions were combined and concentrated to remove acetonitrile. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to the desired product, free base. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was lyophilized to give 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide

[0168] Example 12A N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine Example 8B (0.500 g, 2.24 mmol), Example 4B (0.588 g, 2.35 mmol), and cesium carbonate (2.19 g, 6.72 mmol) in 1,4-dioxane (25 mL) were sparged with N for 2 minutes. 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 and 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 give 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide Example 12B was prepared according to the procedure used in the preparation of Example 5B, substituting Example 5A for Example 12A to give 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]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-amine 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) in 1,4-dioxane (30 mL) were sparged with N for 2 minutes. XPhos Pd G4 (0.17 g, 0.19 mmol) was added, and the reaction mixture was heated to 95 °C for 16 hours. The reaction mixture was cooled and 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 give 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]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide Example 13B was prepared according to the procedure used in the preparation of Example 5B, substituting Example 5A for Example 13A to give 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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]pyridin-6-amine Example 14A (345.2 mg, 97%) was prepared using the conditions described in Example 4C, substituting Example 1F for Example 11G. 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ6 -thiane-4-carboxamide Example 14B (75.4 mg, 51%) was prepared using the conditions described in Example 4D, substituting Example 4C for Example 14A. 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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) was added potassium carbonate (1.096 g, 7.93 mmol) and iodomethane (0.296 mL, 4.76 mmol). 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 extracts were washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by chromatography on a Companion (24 g column, 10–50% ethyl acetate / 2-methylpentane) to give 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 for 8 hours at 93° C. After cooling, the reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate / petroleum (1:4) to give 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) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (5.21 g, 23.55 mmol) at 0° C. The reaction mixture was stirred at 50° C. overnight. After cooling, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (3×100 mL). The combined organic layers were washed with sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC using ethyl acetate / petroleum ether (1 / 1) to give 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 at ambient temperature overnight. The solvent was removed, and the residue was redissolved in ethyl acetate and 0.1 N aqueous HCl. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC on a C18 column eluting with 20 to 100% acetonitrile in 0.1% aqueous trifluoroacetic acid to give the title compound (0.082 g, 0.284 mmol, 28.7%). Also recovered was 0.10 g of Example 15C. 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 eluting with 50% ethyl acetate in heptane to give 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-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. To this reaction mixture was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (5.51 mg, 7.01 μmol). The reaction vessel was recapped, then degassed and refilled with nitrogen several times. The reaction mixture was heated at 95°C overnight. 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, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase preparative HPLC on a C18 column eluting with 20-100% acetonitrile in 0.1% aqueous trifluoroacetic acid to give 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]pyridin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide

[0184] Example 16A tert-Butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate To a suspension of Example 11D (4 g) in N,N-dimethylformamide (40 mL) was added (bromodifluoromethyl)trimethylsilane (4.24 mL) and triphenylphosphine (7.15 g), 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 added slowly. The reaction mixture was stirred at this temperature for 1 hour, and then saturated aqueous ammonium chloride (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 extracts were washed with water / brine (1:1, 3 × 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0–60% ethyl acetate / 2-methylpentane) to provide 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]pyridin-6-yl)carbamate To a solution of Example 16A (500 mg) in dichloromethane (15 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (Dess-Martin periodinane) (921 mg) and sodium bicarbonate (243 mg). 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 aqueous sodium bicarbonate (10 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to provide 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-difluoroprop-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate To a suspension of methyltriphenylphosphonium bromide (1270 mg) in tetrahydrofuran (15 mL) was slowly added potassium tert-butoxide (1 M in tetrahydrofuran, 3.23 mL) at 0° C. The reaction was stirred at this temperature for 40 minutes. To a solution of Example 16B (370 mg) in tetrahydrofuran (10 mL) was added a portion of the preformed ylide solution (6 mL) at −10° C., and the reaction mixture was stirred for 30 minutes. Additional ylide solution (6 mL) was added, and the reaction mixture was stirred overnight and allowed to warm slowly to ambient temperature. The reaction mixture was stirred at 50° C. for 1 hour, then at 70° C. for 12 hours, and then left at ambient temperature for 3 days. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate / 2-methylpentane) to give 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-difluoroprop-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate To a solution of Example 16C (130 mg) in tetrahydrofuran (3 mL) was added palladium (5 wt% on carbon, 130 mg). The reaction mixture was stirred under a hydrogen atmosphere (3 bar) at ambient temperature for 3 hours. The reaction mixture was filtered through a glass microfiber pad, washed with methanol (5 mL), and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to give 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]pyridin-6-amine To a solution of Example 16D (1.1 g) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (4.90 mL). The reaction mixture was stirred at ambient temperature for 3 hours. Toluene (10 mL) was added, and the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 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]pyridin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -thiane-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) was added XPhos Pd G4 (106 mg), 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 in vacuo, 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 the ammonium salt (APDTC) was added. The resulting suspension was stirred at 40°C for 3 hours and then filtered. The filtrate was concentrated in vacuo onto silica gel, and the residue was purified by chromatography on silica gel (0-80% ethyl acetate / 2-methylpentane) to give 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]pyridin-6-yl}amino)-3-fluorophenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide To a degassed suspension of Example 3G (116 mg), Example 10C (200 mg), and potassium phosphate (95 mg) in 1,4-dioxane (2 mL) was added XPhos Pd G4 (77 mg), and the reaction mixture was stirred at 70 °C for 16 h. After cooling to ambient temperature, the reaction mixture was filtered through diatomaceous earth and washed with dichloromethane (10 mL). The filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-100% ethyl acetate-ethanol (3:1) / 2-methylpentane) to give the product as a mixture of diastereoisomers. The mixture of diastereoisomers was separated by chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® IC column (10 × 250 mm, 5 microns) eluting with 35% methanol (0.1% ammonia) in CO at 40 °C, 15 mL / min, 120 bar, to give the title compounds as individual diastereoisomers. The absolute stereochemistry of these title compounds has been 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]pyridin-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 To a 40 mL vial containing the hydrochloride salt of Example 1I (1.0 g, 3.28 mmol), pyridine (1.328 mL, 16.42 mmol), and N,N-dimethylpyridin-4-amine (0.401 g, 3.28 mmol) in dichloromethane (3 mL) was added 1-acetylpiperidine-4-carbonyl chloride (0.747 g, 3.94 mmol). The reaction was stirred at ambient temperature for 30 minutes and diluted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous ammonium chloride (20 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated. The residue was purified by automated flash chromatography (ISCO, SiO, ethyl acetate / hexanes) to provide 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]pyridin-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 a vial. The contents were evacuated and refilled with nitrogen twice. 1,4-Dioxane was added, and the mixture was stirred under nitrogen at 90 °C overnight. The crude mixture was filtered over diatomaceous earth and concentrated in vacuo. The crude residue was purified using reverse-phase chromatography (C18 HPLC, eluting with 20-70% acetonitrile / 0.1% formic acid in water) to provide 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]pyridin-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 a vial. The contents were evacuated and refilled with nitrogen twice. 1,4-Dioxane was added, and the mixture was stirred under nitrogen at 90 °C overnight. The mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified using automated flash chromatography (ISCO, SiO2, ethyl acetate / hexanes) to provide 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0196] Example 20A (S)-tert-butyl 4-((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) was added 2.0 M oxalyl chloride (2.00 mL, 4.00 mmol) in dichloromethane at 0° C., followed by the addition of a trace amount of N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 3 hours, concentrated, and azeotroped twice with toluene. The residue was dissolved in dichloromethane (5.0 mL) and slowly added 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) at 0° C. 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, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 10-50% 3:1 ethyl acetate / ethanol in heptane) to give 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]pyridin-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, 20-60% ethyl acetate in heptane) to give 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]pyridin-6-yl)amino)phenyl)ethyl)piperidine-4-carboxamide To a mixture of Example 20B (410 mg, 0.659 mmol) in dichloromethane (7.5 mL) was added trifluoroacetic acid (2.50 mL, 32.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by reverse-phase HPLC (250 x 50 mm C18 Phenomenex® LUNA®, 10-100% acetonitrile / 0.1% aqueous trifluoroacetic acid) to give the title compound as the trifluoroacetic acid salt. 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide To a solution of Example 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) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (34 mg, 0.088 mmol) in portions. 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% aqueous trifluoroacetic acid). Product-containing fractions were combined, and the acetonitrile was removed by evaporation. The solution was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized from acetonitrile / water to give 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0201] Example 21A tert-Butyl 4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate Example 21A was prepared according to the procedure used in the preparation of Example 20B, substituting Example 1F for Example 3G to give 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]pyridin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide, trifluoroacetic acid Example 21B was prepared according to the procedure used in the preparation of Example 20C, substituting Example 20B for Example 21A to afford 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide Example 21C was prepared according to the procedure used in the preparation of Example 20D, substituting Example 20C for Example 21B to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 22 was prepared according to the procedure used in the preparation of Example 20D, substituting 2-hydroxyacetic acid for 30% 3-hydroxypropionic acid in water to afford 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 23 was prepared according to the procedure used in the preparation of Example 20D, substituting 2-hydroxyacetic acid for 2-hydroxy-2-methylpropanoic acid to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 24 was prepared according to the procedure used in the preparation of Example 20D substituting 2-hydroxyacetic acid for 20% 2,3-dihydroxypropanoic acid in water to afford 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 25 was prepared according to the procedure used in the preparation of Example 20D, substituting 2-hydroxyacetic acid for (R)-2-hydroxypropionic acid to afford 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 26 was prepared according to the procedure used in the preparation of Example 20D substituting 2-hydroxyacetic acid for (S)-2-hydroxypropionic acid to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0210] Example 27A (R)-2,2-Dimethyl-1,3-dioxolane-4-carboxylic acid To a solution of (R)-methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 6.24 mmol) in tetrahydrofuran (10 mL) was added a mixture of 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to provide 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]pyridin-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) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (100 mg, 0.264 mmol) in portions. 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 in water) to give the title compound and a protected intermediate. The protected intermediate fractions were concentrated, dissolved in a mixture of acetic acid (1.0 mL) and 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 x 50 mm C18 Phenomenex® LUNA®, 10-100% acetonitrile / 0.1% aqueous trifluoroacetic acid). The combined fractions containing the title compound were concentrated to remove acetonitrile, neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized from acetonitrile and water to give 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]pyridin-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]pyridin-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 at ambient temperature overnight. The reaction was concentrated and directly purified by flash chromatography (0-70% ethyl acetate / heptane) to give 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]pyridin-6-yl)amino)phenyl)ethyl)-N-methylpiperidine-4-carboxamide To a mixture of Example 28A (104 mg, 0.172 mmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (0.67 mL, 8.61 mmol). 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 with 3% NH4OH) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide To a solution of Example 28B (50 mg, 0.099 mmol), 2-hydroxyacetic acid (5.07 μL, 0.099 mmol), and N,N-diisopropylethylamine (34.7 μL, 0.199 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise a solution of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (41.5 mg, 0.109 mmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at ambient temperature for 2 hours and purified by reverse-phase HPLC (250×50 mm C18 The product was purified directly by Phenomenex® LUNA® (10-90% acetonitrile / 0.1% aqueous trifluoroacetic acid). Fractions containing the product were concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1 g SiliCycle SiliaPrep carbonate cartridge to give 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]pyridin-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) was added acetyl chloride (7.62 μL, 0.107 mmol) dropwise. The mixture was stirred at ambient temperature for 2 h and purified directly by reverse-phase HPLC (250 × 50 mm C18 Phenomenex® LUNA®, 10–90% acetonitrile / 0.1% aqueous trifluoroacetic acid). The desired fractions were concentrated and redissolved in acetonitrile. The sample was desalted by filtration through a 1 g SiliCycle SiliaPrep carbonate cartridge to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 30 was prepared according to the procedure used in the preparation of Example 20D, substituting 2-hydroxyacetic acid for (S)-2,3-dihydroxypropanoic acid to afford 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]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0219] Example 31A tert-Butyl 4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-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, substituting Example 4C for Example 6A. 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]pyridin-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, substituting Example 28A for Example 31A. 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]pyridin-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, substituting Example 28B for Example 31B. 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]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0223] Example 32A (S)-tert-butyl 4-((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), CHCl (50 mL), and N-methylmorpholine (1.08 mL, 9.85 mmol) were stirred at ambient temperature for 1 hour. To this solution was added Example 1I (2.50 g, 8.21 mmol), and the combined solution was stirred at ambient temperature for 15 hours. Upon completion, as determined by LCMS, 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, eluting with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. Clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to the desired product free base. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 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-Butyl 4-(((S)-1-(4-((7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate 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) in 1,4-dioxane (30 mL) were sparged with N for 2 minutes. 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 and 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 give 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]pyridin-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 complete consumption of the starting material, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 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]pyridin-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-oxide hexafluorophosphate (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. Upon complete consumption of the starting material, the crude material was directly purified by reverse-phase chromatography (C18 HPLC, eluting with 20-100% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. Clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to the desired product free base. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized to give 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]pyridin-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 a solution of Example 32C (0.30 g, 0.54 mmol) in N,N-dimethylformamide (1.0 mL). The combined mixture was stirred at ambient temperature for 20 minutes. LCMS indicated complete conversion. Upon complete consumption of the starting material, the crude material was directly purified by reverse-phase chromatography (C18 HPLC, eluting with 20-80% acetonitrile / 0.1% trifluoroacetic acid in water) to isolate the title compound. Clean fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to the desired product free base. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized to give 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]pyridin-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]pyridin-6-yl)amino)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate Example 34A was prepared according to the procedure used in the preparation of Example 32B, substituting Example 3H for Example 8B to give 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]pyridin-6-yl)amino)phenyl)ethyl)piperidine-4-carboxamide Example 34B was prepared according to the procedure used in the preparation of Example 32C, substituting Example 32B for Example 34A to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 34C was prepared according to the procedure used in the preparation of Example 32D, substituting Example 32C for Example 34B to give 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]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide Example 35 was prepared according to the procedure used in the preparation of Example 33, substituting Example 32C for Example 34B to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1-(hydroxyacetyl)-N-methylpiperidine-4-carboxamide

[0234] Example 36A tert-Butyl 4-(((S)-2,2-difluoro-1-(4-((2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridin-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, substituting Example 4C for Example 14A. 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]pyridin-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, substituting Example 28A for Example 36A. 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]pyridin-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, substituting Example 28B for Example 36B. 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]pyridin-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide The title compound was prepared using the conditions described in Example 29, substituting Example 28B for Example 36B. 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-4-carboxamide

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

[0240] Example 38B tert-Butyl (7-chloro-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate To a mixture of Example 38A (30 g, 131 mmol) and triethylamine (54.9 mL, 394 mmol) in tert-butanol (600 mL), diphenylphosphoryl azide (43.3 g, 157 mmol) was added, and the mixture was stirred at 90 °C for 12 h. The reaction mixture was then concentrated to remove tert-butanol, and the resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0–100% ethyl acetate / petroleum ether) to provide 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]pyridin-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). After this time, 1 M sodium thiosulfate solution (100 mL) was added, and the suspension was stirred for 5 minutes before being filtered and washed with water (100 mL). The filtrate was collected, triturated with ethyl acetate (500 mL), and filtered again. The residue was dried in a desiccator overnight to provide 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-trifluoroprop-1-en-2-yl)thiazolo[5,4-b]pyridin-6-yl)carbamate To a degassed suspension of Example 38C (2.4 g), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (2.043 g), and cesium carbonate (6.00 g) in 1,2-dimethoxyethane (20 mL) and water (2 mL) was added [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (0.501 g). The reaction mixture was stirred under microwave irradiation at 110° C. for 90 minutes. The reaction mixture was cooled to ambient temperature, degassed again, and [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (0.250 g) was added. The reaction mixture was stirred under microwave irradiation at 110° C. for 90 minutes. 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 aqueous HCl and extracted with ethyl acetate (50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-40% ethyl acetate / 2-methylpentane) to give 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]pyridin-6-yl)carbamate To a solution of Example 38D (200 mg) in ethanol (10 mL) was added palladium (5 wt% on carbon, 59.2 mg). 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 in vacuo to give 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]pyridin-6-amine To a solution of Example 38E (175 mg) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (1.119 mL). The reaction mixture was stirred overnight and then concentrated in vacuo. The residue was dissolved in dichloromethane (15 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was further extracted with dichloromethane (5 mL). The combined organic extracts were concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-50% ethyl acetate / 2-methylpentane) to give 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -thiane-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) was added XantPhos Pd G3 (23.59 mg), 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 in vacuo. The crude product was purified by chromatography on silica gel (0-25% acetonitrile / dichloromethane) to afford the title compound as a mixture of diastereoisomers. The mixture of diastereoisomers was separated by chiral SFC (supercritical fluid chromatography) using a CHIRALPAK® IG column (10 x 250 mm, 5 microns) eluting with 40% ethanol (0.1% ammonia) in CO2 at 15 mL / min and 120 bar at 40°C to give the title compounds as individual diastereoisomers. The absolute stereochemistry of these title compounds was arbitrarily assigned. The faster eluting diastereoisomer corresponds to Example 38G, and the slower 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide Comparative Example A was prepared according to the procedure used in the preparation of Example 1K, substituting (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-α]pyrimidin-6-amine for Example 1J to give the title compound. (S)-2-Chloro-7-(1-methoxyethyl)pyrazolo[1,5-α]pyrimidin-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)pyridin-3-yl)-3-(7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)urea Comparative Example B was prepared as described in WO2018020474, compound 142.

[0249] Biological assays MALT-1 biochemical assay Using a quenched fluorescence resonance energy transfer (quenched-FRET) enzyme assay, exemplary MALT-1 inhibitors, Examples 1 through 39, were tested for their ability to inhibit cleavage of a MALT1-specific quenched fluorescent substrate of the sequence TAMRA-PEG2-Leu-Val-Ser-Arg-Gly-Ala-Ala-Ser-PEG2-K (QSY7) by human MALT-1 protein; TAMRA is 6-carboxytetramethylrhodamine, PEG2 is a 2-(2-(2-aminoethoxy)ethoxyamide linker, and QSY7 is a non-fluorescent quencher dye (Thermo-Fisher catalog #Q10193). The assay was performed by pre-dispensing compounds into 384-well Proxiplates™ (PE 6008289). Human MALT-1 (6 nM) was incubated in assay buffer (25 mM HEPES A buffer solution (pH 7.5, 1 mM ethylenediaminetetraacetic acid, 0.8 M sodium citrate, 0.005% bovine serum albumin (BSA), 2 mM dithiothreitol (DTT)) was prepared and added to the compound plate. The plate was incubated at room temperature for 40 minutes. The reaction was carried out by adding 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 presented in Table 2 and demonstrate the ability of compounds of the present disclosure to inhibit MALT-1 protease activity. EC 50 is defined as the half-maximal effective concentration at which a 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 that detects human IL-6 present in cell culture medium in the MALT-1-dependent human ABC-DLBCL cell line, OCI-LY3. Compounds were pre-dispensed at 30 μM to 1.5 nM into a Black 384w microtiter plate (Greiner, 781090). Viable OCI-LY3 cells were then seeded on top of the compounds at a seeding density of 50,000 cells / mL. The plate was then placed in a 37°C incubator for 48 hours. After 48 hours of incubation, 2 μL of cell culture medium from each well was transferred to white ProxiPlates™ (PE 6008289). A fresh mix of AlphaLISA acceptor beads (10 μg / mL) and biotinylated IL-6 antibody (1 nM) was made in AlphaLISA immunoassay buffer and added to all wells (4 μL). The plate was incubated for 60 minutes at room temperature. Streptavidin donor beads (40 μg / mL) were prepared using assay buffer and added to all wells (5 μL). The plate was incubated for 30 minutes at room temperature and read using a PE EnVision® reader. The results are shown in Table 3.

[0252] [Table 3]

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

[0254] [Table 4]

[0255] CYP3A4 induction assay CYP induction by example compounds was assessed in vitro by determining CYP 3A4 mRNA expression levels using a qPCR (quantitative polymerase chain reaction) assay. On day 1, cryopreserved human hepatocytes were thawed in prewarmed (37°C) thawing medium (cryopreserved hepatocyte recovery medium, Gibco™ CM 7000; Thermo Fisher Scientific), centrifuged (1000g, 10 min), and resuspended in plating medium (Gibco™ CM3000, Williams medium E supplemented with serum-containing hepatocyte plating supplement pak; Thermo Fisher Scientific). Cells were counted by trypan blue exclusion using a hemocytometer to obtain a cell count of 1.2 x 10 6The cell density was adjusted to 1000 cells / µL. Then, 0.05 µL of the cell suspension was added as an aliquot per well to a 96-well plate to obtain 60,000 cells / well. The plate was shaken north-south and east-west during plating. The plated cells were incubated for 4-6 hours at 37°C / 5% CO2 in a humidified cell culture incubator. During this time, incubation medium (Gibco™ CM4000 cell maintenance supplement pack; Thermo Fisher Scientific) was mixed with Gibco™ Geltrex™ (Thermo Fisher Scientific) at the 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 next day, incubation medium was prepared by combining the hepatocyte maintenance supplement pack with Williams Medium E. The medium was warmed to 37°C. 1000x dimethyl sulfoxide compound stocks of example compounds were prepared to the desired concentrations. 10 mM compound stocks in dimethyl sulfoxide were diluted (1 μL to 1 mL CM4000; final concentration = 10 μM). The overlay medium was aspirated, and 0.1 μL of the dose solution was added to the desired labeled 96-well plate. Cells were then dosed with compound (10 μM) to induce phenotype at target concentrations of 50 μM for omeprazole (Sigma 0104 / lot BCBF-2161V) or 10 μM for rifampicin (Sigma R3501 / lot 011M1159V). The negative control, probenecid, was dosed at 10 μM (Sigma P8761 / lot 013K0148).

[0257] On day 3, RNA isolation was performed. All surfaces were cleaned using RNase RNAy. Total RNA was isolated using the MagMAX Express 96 RNA Isolation System (Life Technologies, AM1830). Briefly, hepatocytes were washed once with 1x 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 lysate was then transferred to a well of a 96-well binding plate. The sample was then mixed with 20 μL of magnetic beads from the kit. The bead-bound RNA was then captured using a magnetic tip manifold, and the beads were washed with wash solution. The sample was treated with TURBO™ DNase. After TURBO™ DNase treatment, the RNA was rebound to the beads and washed two more times with the provided wash 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) reactions were performed using Taqman™ Reverse Transcription Reagents (ThermoFisher Scientific). The RT master mix consisted of 2.5 μL 10× RT buffer, 5.5 μL 25 mM MgCl 2、 A 5 μL deoxy NTP mix, 1.25 μL 50 mM random hexamer, 0.5 μL 2× RNAse inhibitor, 0.625 μL multiscript RTase (50 U / μL), and 0.625 μL water mixture were prepared. An aliquot (16 μL) of the RT mix and an aliquot (9 μL) of the mRNA sample were added to each well of a 96-well plate. A SimpliAmp™ Thermal Cycler PCR System VIIA7 (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: 4°C hold; one cycle for each segment.

[0259] TaqMan™ qPCR was then performed using an 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 controls, 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 of gene expression primer-probe mix, and 7 μL of nuclease-free water). qPCR thermal cycling conditions: Segment 1: 50°C hold, 10 min; Segment 2: 95°C hold, 3 min; followed by 40 cycles of Segment 3: 95°C, 15 s and Segment 4: 60°C, 1 min.

[0260] The fold induction of CYP isoform mRNA caused by compound treatment was determined using comparative quantitative real-time polymerase chain reaction (qPCR). This method calculated CYP fold induction as a percentage of the response to vehicle (0.1% DMSO) and the positive control, rifampicin. Fold induction = treated / vehicle control. Percent positive control = (treated-fold induction - 1) / (rifampicin-fold induction - 1).

[0261] [Table 5]

[0262] It is understood that the foregoing detailed description and accompanying examples are illustrative only and should not be construed as limitations on the scope of the present disclosure, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope thereof. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. General formula (I) 【Chemical 1】 (In the formula: R １ａ is OCH ３ and CH ３ is selected from the group consisting of R １ｂ is CH ３ , CHF ２ and CF ３ is selected from the group consisting of R ２ is selected from the group consisting of H and F; R ３ is selected from the group consisting of H and F; R ４ is CHF ２ and CF ３ is selected from the group consisting of R ５ is C １ ~C ４ is alkyl, Ring A is 【Chemistry 2】 is a ring selected from the group consisting of R ６ is C １ ~C ４ Alkyl and C １ ~C ４ hydroxyalkyl; R ７ is H and C １ ~C ４ is selected from the group consisting of alkyl, R ８ is CHF ２ and CH ３ or a pharmaceutically acceptable salt thereof.

2. Ring A is 【Chemistry 3】 2. The compound of claim 1, wherein:

3. R ２ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

4. R ３ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

5. R １ａ OCH ３ 2. The compound of claim 1, wherein:

6. R １ｂ is CHF ２ 2. The compound of claim 1, wherein:

7. R ４ is CF ３ 2. The compound of claim 1, wherein:

8. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

9. Ring A is 【Chemistry 4】 2. The compound of claim 1, wherein:

10. R １ａ OCH ３ 10. The compound of claim 9, wherein:

11. R １ｂ is CHF ２ 10. The compound of claim 9, wherein:

12. R ６ is C １ ~C ４ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

13. R ８ is CH ３ 2. The compound of claim 1, wherein:

14. R ２ is H and R ３ is H and R ４ is CF ３ 2. The compound of claim 1, wherein:

15. R １ａ OCH ３ and R １ｂ is CHF ２ and R ２ is H and R ３ is H and R ４ is CF ３ and R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

16. R ４ is CF ３ and R ５ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

17. R ２ is H and R ３ is H and R ４ is CF ３ and R ５ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

18. 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-4-carboxamide; 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; N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-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; 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-difluoroethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-4-carboxamide; N-{(1S)-1-[3,5-difluoro-4-({7-[(1S)-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; 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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-4-carboxamide; N-{(1S)-2,2-difluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide; N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2-difluoroethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide; N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][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; N-[(1S)-1-(4-{[7-(1,1-difluoropropan-2-yl)-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; N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)-3-fluorophenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ ６ -thiane-4-carboxamide; 1-acetyl-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-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ -thiane-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]pyridin-6-yl}amino)phenyl]ethyl}-1λ ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: -thiane-4-carboxamide;

19. The compound is 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 10. The compound of claim 1, which is -thiane-4-carboxamide; or a pharmaceutically acceptable salt thereof.

20. The compound is 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 2. The compound of claim 1, which is -thiane-4-carboxamide.

21. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in combination with a pharmaceutically acceptable carrier.

22. 10. A method for treating activated B-cell-like subtype diffuse large B-cell lymphoma (ABC-DLBCL) in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1.

23. Formula (1G) 【Chemistry 5】 with a compound of formula (2G) 【Chemistry 6】 in a solvent in the presence of a base and a catalyst to obtain a compound of formula (3A): 【Chemistry 7】 (In the formula: R １ａ But OCH ３ and CH ３ is selected from the group consisting of R １ｂ But CH ３ , CHF ２ and CF ３ is selected from the group consisting of R ２ is selected from the group consisting of H and F; R ３ is selected from the group consisting of H and F; R ４ But CHF ２ and CF ３ is selected from the group consisting of R ５ But C １ ~C ４ is alkyl, Ring A is 【Chemistry 8】 is a ring selected from the group consisting of R ６ But C １ ~C ４ Alkyl and C １ ~C ４ hydroxyalkyl; R ７ However, H and C １ ~C ４ is selected from the group consisting of alkyl, R ８ But CHF ２ and CH ３ 2. A method of synthesizing a compound of formula (3A) of claim 1 by forming a compound of formula (3A)

24. The method of claim 23, wherein the solvent is 1,4-dioxane.

25. 24. The method of claim 23, wherein the reaction is carried out at a temperature above about 20°C.

26. 24. The method of claim 23, wherein the base is cesium carbonate.

27. 24. The method of claim 23, wherein the temperature is about 90°C.

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