Thiazolo [5, 4-b] pyridine MALT-1 inhibitors

Abstract

The present disclosure provides compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein R1a, R1b, R2, R3, R4, R5, R6, R7, R8 and ring A have any of the values defined in the specification. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application is a non-provisional application, which claims the benefit and priority of U.S. Provisional Application No. 63 / 362,302 filed on March 31, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to compounds that inhibit the activity of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) and compositions containing these compounds. Background Art

[0004] B cells and T cells of the adaptive immune system utilize the pleiotropic NF-κB signaling pathway to transduce extracellular signals from cognate antigen receptors to increase survival and proliferation. This signaling leads to rapid nuclear localization of NF-κB and activation of target genes, including proinflammatory 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 important regulatory role. Following B-cell receptor and T-cell receptor stimulation, the CBM complex forms and recruits multiple signaling proteins, initiating canonical NF-κB activation.

[0005] The caspase-like protein MALT1 is an important regulator within the CBM complex. MALT1 not only serves as a scaffold for the assembly of protein complexes for NF-κB activation, but also acts as a protease that cleaves negative regulators of the NF-κB pathway for enhanced signaling.

[0006] Aberrant activation of NF-κB signaling occurs in activated B-cell-like subtype diffuse large B-cell lymphoma (ABC-DLBCL). ABC-DLBCL tumors have a gene expression signature characteristic of B cells activated through their B-cell receptors. In the case of DLBCL, gain-of-function alterations in the BCR pathway are frequently detected, and these mutations trigger constitutive NF-κB activation that is required for tumor cell survival.

[0007] Considering that MALT-1 is a regulator of the NF-κB pathway, which plays an important role in diseases including ABC-DLBCL, there is a need for compounds that inhibit MALT-1 protease activity for use in anti-ABC-DLBCL treatment. In particular, there is a need for MALT-1 compounds that inhibit MALT-1 protease activity and have improved pharmaceutical properties. Summary of the invention

[0008] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in:

[0011] R 1a Selected from OCH3 and CH3;

[0012] R 1b Selected from CH3, CHF2 and CF3;

[0013] R 2 Selected from H and F;

[0014] R 3 Selected from H and F;

[0015] R 4 Selected from CHF2 and CF3;

[0016] R 5 is a C1-C4 alkyl group;

[0017] Ring A is a ring selected from the following:

[0018] R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl;

[0019] R 7 is selected from H and C1-C4 alkyl; and

[0020] R 8 Selected from CHF2 and CH3.

[0021] On the other hand, ring A is On the other hand, R 2 is H. On the other hand, R 3 is H. On the other hand, R 1a is OCH3. On the other hand, R 1b is CHF2. On the other hand, R 5 It is methyl.

[0022] On the other hand, ring A is On the other hand, R 1a is OCH3. On the other hand, R 1b is CHF2. On the other hand, R 6 is a C1-C4 alkyl group. 5 It is a C1-C4 alkyl group.

[0023] In another aspect, the compound is selected from:

[0024] 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 -thiazane-4-carboxamide;

[0025] 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 -thiazane-4-carboxamide;

[0026] 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 -thiazane-4-carboxamide;

[0027] 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 -thiazane-4-carboxamide;

[0028] 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 -thiazane-4-carboxamide;

[0029] 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 -thiazane-4-carboxamide;

[0030] 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 -thiazane-4-carboxamide;

[0031] 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 -thiazane-4-carboxamide;

[0032] 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 -thiazane-4-carboxamide;

[0033] 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 -thiazane-4-carboxamide;

[0034] 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 -thiazane-4-carboxamide;

[0035] 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 -thiazane-4-carboxamide;

[0036] 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 -thiazane-4-carboxamide;

[0037] 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-thiazane-4-carboxamide;

[0038] 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 -thiazane-4-carboxamide;

[0039] 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 -thiazane-4-carboxamide;

[0040] 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 -thiazane-4-carboxamide;

[0041] 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;

[0042] 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;

[0043] 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;

[0044] 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;

[0045] 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;

[0046] 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;

[0047] 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;

[0048] 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;

[0049] 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;

[0050] 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;

[0051] 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;

[0052] 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;

[0053] 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;

[0054] 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;

[0055] 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;

[0056] 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;

[0057] 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;

[0058] 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;

[0059] 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;

[0060] 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;

[0061] 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 -thiazane-4-carboxamide; and

[0062] 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 -thiazane-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0063] On the other hand, 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 -thiazane-4-carboxamide or a pharmaceutically acceptable salt thereof.

[0064] On the other hand, 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 -thiazane-4-carboxamide.

[0065] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any of the preceding aspects or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

[0066] In another aspect, the present disclosure provides a method for treating activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0067] In another aspect, the present disclosure provides a method for synthesizing a compound of formula (3A) according to claim 1, comprising reacting a compound of formula (1G) in a solvent in the presence of a base and a catalyst. and a compound of formula (2G) Reaction to form a compound of formula (3A)

[0068] in:

[0069] R 1a Selected from OCH3 and CH3;

[0070] R 1b Selected from CH3, CHF2 and CF3;

[0071] R 2 Selected from H and F;

[0072] R 3 Selected from H and F;

[0073] R 4 Selected from CHF2 and CF3;

[0074] R 5 is a C1-C4 alkyl group;

[0075] Ring A is a ring selected from the following:

[0076] R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl;

[0077] R 7 is selected from H and C1-C4 alkyl; and

[0078] R 8 Selected from CHF2 and CH3. DETAILED DESCRIPTION

[0079] The present disclosure describes compounds that inhibit the activity of MALT-1.

[0080] Disclosed herein are compounds of formula (I)

[0081]

[0082] in:

[0083] R1a Selected from OCH3 and CH3;

[0084] R 1b Selected from CH3, CHF2 and CF3;

[0085] R 2 Selected from H and F;

[0086] R 3 Selected from H and F;

[0087] R 4 Selected from CHF2 and CF3;

[0088] R 5 is a C1-C4 alkyl group;

[0089] Ring A is a ring selected from the following:

[0090] R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl;

[0091] R 7 is selected from H and C1-C4 alkyl; and

[0092] R 8 Selected from CHF2 and CH3.

[0093] definition

[0094] Certain terms used in this specification are intended to refer to the following definitions as described in detail below.

[0095] Note that, as used in this specification and the intended 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 identical or different compounds.

[0096] As used in the specification and the appended claims, unless indicated to the contrary, the following terms have the indicated meanings:

[0097] As used herein, the term "alkyl" 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, etc.

[0098] As used herein, the term "hydroxyalkyl" refers to one or more hydroxyl groups (OH) attached to the parent molecular moiety via an alkyl group as defined herein. Unless otherwise indicated, a hydroxyalkyl group may have one, two, three or four carbons. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

[0099] In some cases, the number of carbon atoms in a moiety is indicated by the prefix "C x -C y ” means, where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. 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.

[0100] With respect to the use of the words "comprise", "comprises" and "comprising" in this disclosure, including the claims, unless the context requires otherwise, those words are used with the following in mind and with the clear understanding that those words are to be construed as inclusive rather than exclusive.

[0101] The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical use.

[0102] The phrase "pharmaceutically acceptable carrier" means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers and the like.

[0103] The phrase "pharmaceutically acceptable salts" refers to those salts which 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, and are commensurate with a reasonable benefit / risk ratio.

[0104] The term "stable" refers to compounds that possess stability sufficient to allow for manufacture and maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein.

[0105] As used herein, the term "subject" refers to a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0106] The phrase "therapeutically effective amount" refers to the amount of a compound or a pharmaceutically acceptable salt thereof, which, when administered for treatment in a particular subject or population of subjects, is sufficient to treat one or more symptoms of the condition or disorder being treated.

[0107] As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or eliminating a disease and / or its associated symptoms.

[0108] Compound

[0109] The compounds of the present disclosure have the general formula (I) as described herein.

[0110] In an embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0111]

[0112] in:

[0113] R 1a Selected from OCH3 and CH3;

[0114] R 1b Selected from CH3, CHF2 and CF3;

[0115] R 2 Selected from H and F;

[0116] R 3 Selected from H and F;

[0117] R 4 Selected from CHF2 and CF3;

[0118] R 5 is a C1-C4 alkyl group;

[0119] Ring A is a ring selected from the following:

[0120] R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl;

[0121] R 7 is selected from H and C1-C4 alkyl; and

[0122] R 8 Selected from CHF2 and CH3.

[0123] Specific values ​​for the variable groups in the compounds of formula (I) are as follows. Such values ​​may be used, where appropriate, with any other values, definitions, claims or embodiments defined herein.

[0124] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a is selected from OCH3 and CH3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For CH3.

[0125] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R1b is selected from CH3, CHF2 and CF3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1b is selected from CH3 and CHF2. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1b is selected from CH3 and CF3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1b is selected from CHF2 and CF3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1b 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 It is CF3.

[0126] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a is OCH3 and R 1b is CHF2.

[0127] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 2 is selected from 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 For F.

[0128] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b is CHF2, and R 2 For H.

[0129] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 3 is selected from 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 For F.

[0130] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 is H, and R 3 For H.

[0131] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R4 is selected from CHF2 and CF3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 4 is CHF2. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 4 It is CF3.

[0132] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 is H, and R 4 It is CF3.

[0133] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 5 is a C1-C4 alkyl group. In certain embodiments of formula (I) or a pharmaceutically acceptable salt thereof, R 5 In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 5 It is ethyl.

[0134] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 is CF3, and R 5 It is methyl.

[0135] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 is CF3, and R 5 For H.

[0136] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, Ring A is selected from In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, Ring A is In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, Ring A is

[0137] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 6 is selected from C1-C4 alkyl and C1-C4 hydroxyalkyl. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 6is a C1-C4 alkyl group. In certain embodiments of formula (I) or a pharmaceutically acceptable salt thereof, R 6 It is a C1-C4 hydroxyalkyl group.

[0138] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 For CF3, R 5 is H, and ring A is

[0139] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 7 is selected from 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 a C1-C4 alkyl group. In certain embodiments of formula (I) or a pharmaceutically acceptable salt thereof, R 7 It is methyl.

[0140] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 For CF3, R 5 is H, ring A is And R 7 For H.

[0141] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 8 is selected from CHF2 and CH3. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 8 is CHF2. In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 8 For CH3.

[0142] In certain embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 For CF3, R 5 is H, ring A is R 7 is H, and R8 For CH3.

[0143] The compounds disclosed herein may contain one or more variables that appear more than once in any substituent or formula herein. The definition of a variable at each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents are permissible only if such combinations result in stable compounds.

[0144] The compounds and intermediates disclosed herein are prepared by using the ACD / Name 2021.1.3 (file version N15E41, Build 123232, July 7, 2021) software program and / or by using a It is named according to the Struct=Name naming algorithm which is part of Professionalv.15.0.0.106.

[0145] Exemplary compounds of formula (I) include, but are not limited to, the compounds shown in Table 1 below and pharmaceutically acceptable salts thereof. It should be understood that when there is a discrepancy between the name of a compound found herein and the structure found in Table 1, the structure in Table 1 shall prevail.

[0146] Table 1. Exemplary compounds

[0147]

[0148]

[0149]

[0150]

[0151] The compounds of formula (I) may be used in the form of pharmaceutically acceptable salts.

[0152] The compounds of formula (I) may contain basic or acidic functionalities, or both, and, if desired, may be converted into pharmaceutically acceptable salts by use of appropriate acids or bases.

[0153] Methods of Preparing Exemplary Compounds

[0154] The compounds of the present disclosure may be better understood in conjunction with the following synthetic schemes and methods that illustrate the manner in which the compounds may be prepared. The compounds of the present disclosure may be prepared by various synthetic methods. Representative synthetic methods are shown, but not limited to, in Schemes 1-8. Variable R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 8 and A are as defined in detail herein.

[0155] The abbreviations used in the schemes and descriptions thereof have the following meanings: BOC represents the tert-butoxycarbonyl protecting group.

[0156] Representative schemes for the synthesis of exemplary intermediates and compounds of formula (I):

[0157] Solution 1

[0158]

[0159] Scheme 1 describes the synthesis of the intermediate of formula (1G). 1A , R 1B and R 8 The compound of formula (1A) as described herein is reacted with (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one to convert the compound of formula (1A) to a compound of formula (1B). The reaction is typically carried out at ambient temperature in a solvent such as, but not limited to, dichloromethane. The separation of the compound of formula (1B) from the compounds of formula (1C) and formula (1D) can be carried out by precipitation techniques as 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 obtain a compound of formula (1E). The reaction is typically carried out in an aqueous environment and can be carried out at an elevated temperature, wherein the elevated temperature is a temperature greater than ambient temperature, for example greater than 20°C. The compound of formula (1F) can be prepared by reacting the compound of formula (1E) with diphenylphosphoryl azide in tert-butyl alcohol in the presence of a base such as triethylamine. The reaction is typically carried out at an elevated temperature. 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.

[0160] Solution 2

[0161]

[0162] As shown in Scheme 2, R 2 , R 3 and R 4 The compound of formula (2A) as described herein can be reacted with (R)-2-methylpropane-2-sulfenamide and tetraisopropoxytitanium at elevated temperature, followed by treatment with lithium tri-sec-butylborohydride at low temperature to give a compound of formula (2B). The reaction is typically carried out in a solvent such as tetrahydrofuran. The compound of formula (2B) can be prepared by treating the compound with sodium hydride at low temperature in a solvent such as, but not limited to, tetrahydrofuran, followed by addition of R 5 and X1 Compounds of formula (2C) as described herein are used to prepare compounds of formula (2D). Compounds of formula (2D) may be treated with hydrochloric acid in a solvent such as 1,4-dioxolane, methanol, or mixtures thereof to obtain compounds of formula (2E). Compounds of formula (2F) wherein A is as described herein may be treated with oxalyl chloride at ambient temperature to obtain an intermediate acyl chloride, which is then reacted with a compound of formula (2E) and a base such as, but not limited to, N,N-diisopropylethylamine to obtain a compound of formula (2G). The reaction is typically carried out in a solvent such as dichloromethane, N,N-dimethylformamide, or mixtures thereof.

[0163] Solution 3

[0164]

[0165] Scheme 3 describes the synthesis of a compound of formula (3A) as a representative compound of formula (I). 1A , R 1B and R 8 Compounds of formula (1G) as described herein can be coupled to a compound wherein R 2 , R 3 , R 4 , R 5 and A as described herein, the compound of formula (2G), these coupling reaction conditions 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 give a compound of formula (3A). The reaction is typically carried out at elevated temperature in a solvent such as but not limited to 1,4-dioxolane.

[0166] Solution 4

[0167]

[0168] As shown in Scheme 4, a compound wherein R 1a and R 1bCompounds of formula (4A) as described herein, give compounds of formula (4B). The reaction is typically carried out at ambient temperature in a solvent such as, but not limited to, N,N-dimethylformamide. Compounds of formula (4B) may be treated with selenium dioxide to give compounds of formula (4C). The reaction is typically carried out at elevated temperatures in solvents such as, but not limited to, 1,4-dioxolane. Compounds of formula (4D) may be prepared by treating compounds of formula (4C) with [bis(2-methoxyethyl)amino]sulfur trifluoride at low temperatures, followed by heating. The reaction is typically carried out in solvents such as, but not limited to, toluene. Compounds of formula (4D) are treated with a base such as sodium carbonate in a solvent such as methanol at ambient temperature to give compounds of formula (4E). Compounds of formula (4F) may be prepared by reacting compounds of formula (4E) with diphenylphosphoryl azide in tert-butyl alcohol in the presence of a base such as triethylamine. The reaction is typically carried out at elevated temperatures. Compounds of formula (4F) can be used as described in Scheme 3 to provide compounds of formula (I).

[0169] Solution 5

[0170]

[0171] Scheme 5 describes the synthesis of a compound of formula (5C) as a representative compound of formula (I). 8 , R 1a and R 1b Compounds of formula (5A) as described herein can be coupled to (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methyleth-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 give compounds of formula (5B). The reaction is typically carried out at elevated temperature in a solvent such as, but not limited to, 1,4-dioxolane. A compound of formula (2F) as described herein, followed by the addition of a compound of formula (5B), can be treated with 2,4-dichloro-6-methoxy-1,3,5-triazine and N-methylmorpholine in dichloromethane at ambient temperature to give a compound of formula (5C) as a representative compound of formula (I).

[0172] Solution 6

[0173]

[0174] As shown in Scheme 6, a compound wherein R 8A compound of formula (6A) as described herein, to obtain a compound of formula (6B). The reaction is typically carried out at ambient temperature in an aqueous solvent system (such as, but not limited to, a mixture of water and 1,4-dioxolane). A compound of formula (6C) can be prepared by reacting a compound of formula (6B) with diphenylphosphoryl azide in tert-butyl alcohol 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 obtain a compound of formula (6D). The reaction is typically carried out at low temperatures in a solvent such as, but not limited to, acetonitrile. The compound of formula (6E) can be prepared by reacting the compound of formula (6D) with 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-ene-2-yl)-1,3,2-dioxaborane 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 by microwave radiation and in a solvent such as 1,2-dimethoxyethane, water, or a mixture thereof. The compound of formula (6E) can be treated with hydrogen and palladium (5% by weight on carbon) to obtain a compound of formula (6F). The reaction is typically carried out at elevated temperatures in a solvent such as, but not limited to, ethanol. The compound of formula (6G) can be prepared by treating the compound of formula (6F) with 2,2,2-trifluoroacetic acid in dichloromethane at ambient temperature. Compounds of formula (6G) can be used as described in Scheme 3 to provide compounds of formula (I).

[0175] Solution 7

[0176]

[0177] Scheme 7 describes the synthesis of a compound of formula (7B), which can be used as an intermediate in the synthesis of a compound of formula (I). 4 Compounds of formula (7A) as described herein are reacted with 1-acetylpiperidine-4-carbonyl chloride to provide compounds of formula (7B).

[0178] Solution 8

[0179]

[0180] 1-(tert-Butyloxycarbonyl)piperidine-4-carboxylic acid can be treated with oxalyl chloride at ambient temperature to give the intermediate acid chloride, which can then be reacted with 4The compound of formula (7A) as described herein and a base (such as but not limited to N, N-diisopropylethylamine) react to obtain a compound of formula (8A). The reaction is usually carried out at low temperature in a solvent such as dichloromethane, N, N-dimethylformamide or a mixture thereof. The compound of formula (8A) and the compound of formula (5A) can be reacted under Buchwald coupling conditions, which include 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 obtain a compound of formula (8B). The reaction is usually carried out at high temperature in a solvent such as but not limited to dioxolane. The compound of formula (8C) can be prepared by treating the compound of formula (8B) with an acid (such as 2,2,2-trifluoroacetic acid) in a solvent (such as dichloromethane). The compound of formula (8D) as a representative compound of formula (I) can be prepared by reacting the 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 at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide.

[0181] It should be understood that the synthetic schemes and specific examples shown 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 of the synthetic methods and specific examples are included within the scope of the claims.

[0182] The optimum reaction conditions and reaction times for the various steps may vary depending on the specific reactants used and the substituents present in the reactants used. Specific methods are provided in the Synthesis Examples section. Unless otherwise stated, 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.

[0183] Pharmaceutical composition

[0184] When used as a drug, the compounds of the present disclosure may be administered in the form of a pharmaceutical composition. Such a composition may be a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0185] How to use

[0186] The compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition 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 a method of contacting a compound with a subject in need thereof.

[0187] In another embodiment, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure can be used in medicine. In a specific embodiment, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure can be used to treat diseases or conditions as described above, including ABC-DLBCL.

[0188] The present disclosure also relates 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.

[0189] Example

[0190] The following examples may be used for illustrative purposes and should not be considered to narrow the scope of the present disclosure.

[0191] Unless otherwise stated, all reagents were of commercial grade and were used as received without further purification. Reactions were performed under an inert atmosphere using commercially available anhydrous solvents. Reagent grade solvents were used in all other cases unless otherwise stated. 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 to the appropriate residual solvent peak, i.e., CHCl 3 (δ 7.27).

[0192] Unless otherwise indicated, the following abbreviations have the designated meanings: NMR means nuclear magnetic resonance; s means singlet; brs means broad singlet; d means doublet or doublet; m means multiplet; t means triplet; q means quartet; LC / MS or LCMS means liquid chromatography-mass spectrometry; min means minutes; mL means milliliters; μL means microliters; L means liters; g means grams; mg means milligrams; mmol means millimoles; HPLC means high pressure liquid chromatography; ppm means parts per million; DCI means desorption chemical ionization; DSI means droplet spray ionization; ESI means electrospray ionization; M means molarity (moles per liter); N means equivalents (equivalents per liter); and APCI means atmospheric pressure chemical ionization.

[0193] Example 1

[0194] 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 -Thiazane-4-carboxamide

[0195] Example 1A

[0196] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl-7-(1-methoxyethyl)-2-methylthiazolo[5,4- b]pyridine-6-carboxylate

[0197] N, N'-dicyclohexylcarbodiimide (175g) and 4-dimethylaminopyridine (9.44g) were added to a solution of 7-(1-methoxyethyl)-2-methylthiazole [5,4-b] pyridine-6-carboxylic acid (195g, WO2018020474A1) in dichloromethane (2L), and the reaction mixture was stirred at 20°C for 10 minutes. (R)-3-hydroxy-4,4-dimethyldihydrofuran-2 (3H) -one (101g) was added, and the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated in vacuo to obtain a residue, which was ground with tetrahydrofuran (2.5L) at 50°C for 30 minutes. The reaction mixture was concentrated in vacuo to reduce the volume to about 400mL and stirred at 20°C for 30 minutes. The precipitate was collected by filtration to obtain the title compound. 1 HNMR(400MHz,CDCl3)δppm 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,2 H),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).

[0198] Example 1B

[0199] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl-7-((S)-1-methoxyethyl)-2-methylthiazol- [5,4-b]pyridine-6-carboxylate; and

[0200] Example 1C

[0201] (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl-7-((R)-1-methoxyethyl)-2-methylthiazol- [5,4-b]pyridine-6-carboxylate

[0202] A solution of 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 about 1 L and then stirred at 25 °C for 30 minutes. The resulting precipitate was collected by filtration to give a crude product. This process was repeated 3 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: 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (s, 1H), 5.68 (s, 1H), 5.37 (q, 1H), 4.12 (s, 2H), 3.30 (s, 3H), 2.90 (s, 3H), 1.75 (d, 3H), 1.36 (s, 3H), 1.25 (s, 3H). The chiral purity of the combined Example 1B: 97.66% de. The chiral purity of Example 1C: 92% de.

[0203] Example 1D

[0204] (S)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid

[0205] A mixture of Example 1B (230 g) and lithium hydroxide hydrate (79 g) in water (1.2 L) was stirred at 80 ° C for 1.5 hours. The reaction mixture was filtered and the filtrate was diluted with water (2 L). A 6M HCl aqueous solution was added to adjust the pH to 1.57. The mixture was heated to 100 ° C in a time period of 50 minutes and then stirred at 100 ° C for 30 minutes. The mixture was cooled to 25 ° C in a time period of 5 hours and stirred for 30 minutes. The precipitate was collected by filtration to obtain a crude product, which was ground with water (2 L) at 25 ° C for 30 minutes. The precipitate was collected by filtration, air-dried in a time period of 3 hours, and then vacuum-dried at 50 ° C for 6 hours to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 9.13 (s, 1H), 5.91–5.83 (m, 1H), 3.47 (s, 3H), 2.89 (s, 3H), 1.73 (d, 3H). No exchangeable protons were observed.

[0206] Example 1E

[0207] (S)-tert-Butyl (7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0208] Triethylamine (14.36 mL) was added to a solution of tert-butyl alcohol (305 mL) of Example 1D (20 g) at 40 ° C and under a nitrogen atmosphere. The mixture was heated to 60 ° C and diphenylphosphoryl azide (18.79 mL) was added dropwise over about 6 minutes. The reaction mixture was stirred at 60 ° C for 5 hours. After cooling to ambient temperature, sodium hydroxide (5 wt % in water, 60 mL) was added to the reaction mixture and then concentrated in vacuo. Water (200 mL) was added and the suspension was stirred for 15 minutes. The precipitate was collected by filtration, washed with water (2×200 mL), and air-dried for 1 hour. Ethyl acetate (600 mL) was added to the precipitate, and the resulting suspension was warmed to about 40 ° C and stirred until a slightly turbid solution was formed. The solution was cooled to ambient temperature, stirred for 30 minutes and filtered. The filtrate was concentrated in vacuo to obtain the title compound. 1 H NMR (600MHz, CDCl3) δppm 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) + .

[0209] Example 1F

[0210] (S)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine

[0211] 2,2,2-trifluoroacetic acid (46.4 mL) was added to a solution of Example 1E (22.9 g) in anhydrous dichloromethane (201 mL) at 10 ° C over a period of 7 minutes. The reaction mixture was stirred overnight at ambient temperature and then concentrated in vacuo. Dichloromethane (100 mL) was added and sodium hydrogen phosphate (1M in water) was added to adjust to neutral pH. The two 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 about 80 mL. Heptane (150 mL) was added and the mixture was stirred at 70 ° C for 5 minutes. The mixture was cooled to ambient temperature and the precipitate was collected by filtration to obtain the title compound. 1 H NMR (600MHz, CDCl3) δppm 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) + .

[0212] Example 1G

[0213] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide

[0214] 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 tri-sec-butylborohydride (1M in tetrahydrofuran, 59.3 mL) was added, and the reaction mixture was stirred at -78 ° C for 3 hours. Brine (50 mL) was added to the reaction mixture and 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 (2×100 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-100% ethyl acetate / 2-methylpentane) to give the title compound. 1 HNMR (400MHz, CDCl3) δppm7.58–7.52(m,2H),7.33–7.30(m,2H),4.80(p,1H),3.59(d,1H),1.25(s,9H). MS(ESI)m / z358 / 360(M+H) + .

[0215] Example 1H

[0216] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-2-dimethylpropane-2-sulfenamide

[0217] At 0°C, sodium hydride (0.475 g) was added in batches to a solution of Example 1G (3.73 g) in tetrahydrofuran (50 mL), and the reaction mixture was stirred at 0°C for 2 hours. Iodomethane (3.26 mL) was added to the reaction mixture, which was stirred at 0°C for 10 minutes, and stirred for another 10 minutes at ambient temperature. Saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-60% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm7.56–7.49(m,2H),7.39–7.30(m,2H),5.05(q,1H),2.45(s,3H),1.25(s,9H). MS(ESI)m / z372.1 / 374.2(M+H)+ .

[0218] Example II

[0219] (S)-1-(4-Bromophenyl)-2,2,2-trifluoro-N-methylethylamine

[0220] To a solution of 1,4-dioxolane (15 mL) and methanol (15 mL) of Example 1H (1.90 g) was added a 4M HCl solution in 1,4-dioxolane (5.10 mL), and the reaction mixture was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo, and 0.5M HCl aqueous solution (80 mL) was added. The aqueous layer was extracted with ethyl acetate (3×30 mL). Sodium hydroxide (2M in water) was added to the aqueous layer, adjusted to pH 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 give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm7.64–7.58(m,2H),7.47–7.38(m,2H),4.30(p,1H),2.87(dq,1H),2.20(d,3H). MS(ESI)m / z268.1 / 270.1(M+H) + .

[0221] Example 1J

[0222] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dicarboxamide Oxide

[0223] 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 II (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 solution (2×30 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-10% methanol / dichloromethane) to provide the title compound. 1H NMR(400MHz, DMSO-d6)δppm 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 / z428 / 430(M+H) + .

[0224] Example 1K

[0225] 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 -Thiazane-4-carboxamide

[0226] To a degassed mixture of Example 1F (60 mg), Example 1J (127 mg) and cesium carbonate (263 mg) in 1,4-dioxolane (6 mL) was added XantPhosPdG3 ([(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]methanesulfonatepalladium(II)) (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 celite, washed with ethyl acetate (20 mL) and concentrated in vacuo. The crude material was purified by silica gel chromatography (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(400MHz,DMSO-d6,90℃)δppm 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) + .

[0227] Example 2

[0228] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1R)-2,2,2-trifluoro- [1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0229] Example 11G (50 mg, 0.180 mmol), Example 1J (85 mg, 0.198 mmol), XPhosPdG2 (14.19 mg, 0.018 mmol) and cesium carbonate (176 mg, 0.541 mmol) were mixed in 1,4-dioxolane (0.9 mL). The mixture was bubbled 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 directly loaded onto a 40 g silica gel column. The crude material was purified by flash chromatography (0%-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.59(s,1H),7.60(s,1H),7.24(d,J=8.4Hz,2H),7.14(d,J=8.6Hz,2H),6.46(q,J=9.3Hz,1H),5. 93(q,J=7.6Hz,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) + .

[0230] Example 3

[0231] 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 -Thiazane-4-carboxamide

[0232] Example 3A

[0233] 2-Methyl-7-vinylthiazo[5,4-b]pyridine-6-carboxylic acid ethyl ester

[0234] 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-dioxolane (600 mL) and water (100 mL) were 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 Na2CO3 (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 Na2CO3 (12.4 g, 116.8 mmol) were 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 Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 1.33(t,J=7.1Hz,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.

[0235] Example 3B

[0236] 2-Methyl-7-vinylthiazo[5,4-b]pyridine-6-carboxylic acid

[0237] To a solution of Example 3A (120 g, 483 mmol) in 1,4-dioxolane (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-dioxolane. The pH was adjusted to about 3 with 2M 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 give the title compound. 1HNMR(300MHz,DMSO-d6)δppm2.87(s,3H),5.95(dd,J=11.7,2.1Hz,1H),6.74(dd ,J=17.6,2.1Hz,1H),7.45(dd,J=17.6,11.7Hz,1H),8.87(s,1H),13.62(s,1H). LCMS(ES)m / z 221(M+H) + .

[0238] Example 3C

[0239] tert-Butyl (2-methyl-7-vinylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0240] To a mixture of Example 3B (73 g, 331 mmol, dried by oven), 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-butyl alcohol (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 Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (1:3 ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 1.46 (s, 9H), 2.86 (s, 3H), 5.89 (d, J = 11.5Hz, 1H), 6.86 (d, J = 15.2Hz, 1H), 6.93-7.06 (m, 1H), 8.43 (s, 1H), 9.09 (s, 1H). LCMS(ES)m / z 292.25(M+H) + .

[0241] Example 3D

[0242] tert-Butyl (7-formyl-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0243] 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) at 0°C, followed by sodium periodate (110 g, 515 mmol). 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 give the title compound. 1 H NMR (300MHz, DMSO-d6) δppm 1.53 (s, 9H), 2.93 (s, 3H), 9.41 (s, 1H), 10.17 (s, 1H), 10.81 (s, 1H). LCMS(ES)m / z294.05(M+H) + .

[0244] Example 3E

[0245] tert-Butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0246] 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 hours. 1.5 M potassium hydroxide (352 mL, 528 mmol) was slowly added, and the reaction mixture was stirred at 0 °C for another hour. The reaction was quenched with saturated aqueous NH4Cl solution (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, containing POPh3) and tert-butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate (265 g, 65% purity, containing POPh3). POPh3 was removed in the next step. 1H NMR (400MHz, DMSO-d6) δppm 1.46 (s, 9H), 2.82 (s, 3H), 5.75 (s, 1H), 6.39 (t, J = 55.2Hz, 1H), 7.28-7.43 (m, 1H), 8.87 (s, 1H), 8.98 (s, 1H). LCMS(ES)m / z 346.25(M+H) + .

[0247] Example 3F

[0248] 1-(6-amino-2-methylthiazolo[5,4-b]pyridin-7-yl)-2,2-difluoroethan-1-ol

[0249] A solution of 4M HCl and 1,4-dioxolane (500 mL, 2000 mmol) of Example 3E (50 g, 145 mmol) was stirred at 25 °C for 4 hours and then filtered. The filter cake was dissolved in ethyl acetate and basified to about pH 8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (4×600 mL). The combined organic extracts were washed with water (800 mL), saturated sodium bicarbonate solution (800 mL) and brine (800 mL). The organic layer was dried over Na2SO4 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 (400MHz, DMSO-d6) δppm2.74 (s, 3H), 5.58 (d, J = 26.5Hz, 3H), 6.12-6.49 (m, 1H), 6.74 (s, 1H), 8.05 (s, 1H). LCMS(ES)m / z 346.01(M+H) + .

[0250] Example 3G

[0251] (R)-7-(2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine

[0252] Example 3H

[0253] (S)-7-(2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine

[0254] At 0°C, sodium hydride (4.89 g, 122 mmol) was added to a solution of Example 3E (25 g, 102 mmol) in N,N-dimethylformamide (500 mL), and the reaction mixture was stirred at 0°C for 20 minutes. Iodomethane (15.92 g, 112 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with a half-saturated saline solution (1000 mL), and the mixture was extracted with ethyl acetate (4×600 mL). The organic layers were combined, washed with water (3×600 mL) and brine (3×500 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude racemic mixture was purified by column chromatography (1:4 ethyl acetate / petroleum ether) to obtain the desired product (49.3 g) in the form of a mixture of enantiomers. The enantiomers were separated by preparative chiral SFC using a CHIRALART Cellulose-SB (5*25 cm, 10 μm) column. The conditions used were as follows: mobile phase A: CO2, mobile phase B: isopropanol (0.5% 2M ammonia 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 minutes; Example 3H retention time: 8.25 minutes. 1 HNMR (400MHz, DMSO-d6) δppm2.76(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) + .

[0255] Example 3I

[0256] 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 -Thiazane-4-carboxamide

[0257] To a degassed mixture of Example 3G (39 mg), Example 1J (85 mg) and cesium carbonate (147 mg) in 1,4-dioxolane (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 celite, washed with ethyl acetate (20 mL) and concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-100% ethyl acetate / 2-methylpentane) to give the title compound. 1H NMR(500MHz,DMSO-d6)δppm 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) + .

[0258] Example 4

[0259] 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 -Thiazane-4-carboxamide

[0260] Example 4A

[0261] 1-(4-Bromophenyl)-2,2-difluoroethan-1-one

[0262] To a solution of 1-bromo-4-iodobenzene (50g, 177mmol) in tetrahydrofuran (500mL) was added n-butyllithium (78mL, 194mmol). The reaction mixture was stirred at -78°C for 30 minutes. Ethyl 2,2-difluoroacetate (24.12g, 194mmol) was added dropwise at -78°C within 1 hour. The reaction mixture was stirred at -78°C for another hour and then stirred at 0°C for 1 hour. The reaction was quenched with 1N HCl aqueous solution (15mL) and extracted with dichloromethane (3×200mL). 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 with ethyl acetate / petroleum ether to give the title compound. 1 H NMR (400MHz, DMSO) δppm 7.16 (t, 1H), 7.80-7.89 (m, 2H), 7.94-8.01 (m, 2H).

[0263] Example 4B

[0264] (S)-1-(4-Bromophenyl)-2,2-difluoro-N-methylethylamine

[0265] To a solution of Example 4A (30 g, 128 mmol), methylamine (39.6 g, 383 mmol) in ethanol 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 OD-H column (20 mm×250 mm, 5 μm), eluted with hexane (0.1% diethylamine) / isopropanol, 20 mL / min; 10 minutes to obtain the title compound. 1 HNMR (400MHz, DMSO-d6) δppm2.16 (s, 3H), 2.54 (d, J = 3.2Hz, 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 / z250(M+H) + . [α] 22.7 D = +50.67 (C 0.01 CH3OH).

[0266] Example 4C

[0267] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((S)-1-methoxyethyl)-2-methyl Thiazolo[5,4-b]pyridin-6-amine

[0268] 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-dioxolane (8.9 mL). The mixture was bubbled with nitrogen for 5 minutes and the container was sealed. The reaction was stirred at 90 °C for 16 hours. After cooling, the reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography (40 g silica gel, 0%-70% ethyl acetate / heptane) to give the title compound. MS (ESI) m / z 393.0 (M+H) + .

[0269] Example 4D

[0270] 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 -Thiazane-4-carboxamide

[0271] Tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (113mg, 0.633mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (142mg, 0.791mmol) and N-methylmorpholine (87μL, 0.791mmol) were mixed in dichloromethane (2.7mL) and stirred at ambient temperature for 1 hour. A mixture of Example 4C (207mg, 0.527mmol) in dichloromethane (2.7mL) was added, and the mixture was stirred overnight at ambient temperature. The mixture was concentrated and directly purified by reverse phase HPLC (C18 250 mm x 50 mm, 10%-90% acetonitrile / 0.1% trifluoroacetic acid in water) was purified. The 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(400MHz,DMSO-d6)δppm 8.46(s,1H),7.49(s,1H),7.26(d,J=8.2Hz,2H),7.04(d,J=8.6Hz,2H),6.66(t,J=54.9Hz,1H),5.70(s,1H),5.40(q,J= 6.7Hz,1H),3.28(s,3H),3.25–3.06(m,5H),2.93(s,3H),2.83(s,3H),2.09(q,J=7.1,5.4Hz,4H),1.54(d,J=6.6Hz,3H). MS(APCI)m / z 553.2(M+H) + .

[0272] Example 5

[0273] 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 -Thiazane-4-carboxamide

[0274] Example 5A

[0275] 7-((S)-2,2-difluoro-1-methoxyethyl)-2-methyl-N-(4-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)- 1-(4-(2-(4-(2-(4-nitrophenyl)ethyl)phenyl)thiazolo[5,4-b]pyridin-6-amine

[0276] A solution of Example 3H (1.00 g, 3.86 mmol), Example II (1.29 g, 4.24 mmol) and cesium carbonate (3.77 g, 11.6 mmol) in 1,4-dioxolane (19 mL) was bubbled with N2 for 2 minutes. XPhos Pd G4 (methanesulfonyl (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1, 1'-biphenyl) (2'-methylamino-1, 1'-biphenyl-2-yl) palladium (ii), 0.33 g, 0.39 mmol) was added, and the reaction mixture was heated at 95 ° C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The filtrate was concentrated. The material was purified by silica gel (0%-70% ethyl acetate / heptane) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.84(s,1H),7.29(d,J=8.3Hz,3H),6.95(d,J=8.6Hz,2H),6.75(ddd,J=57.6,54.5,5.9Hz,1 H), 5.34 (dt, J = 13.9, 5.7Hz, 1H), 4.10 (q, J = 8.1Hz, 1H), 3.29 (s, 3H), 2.86 (s, 3H), 2.22 (d, J = 5.8Hz, 3H). MS(ESI)m / z 447.7(M+H) + .

[0277] Example 5B

[0278] 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 -Thiazane-4-carboxamide

[0279] Tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.60 g, 3.36 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (0.65 g, 3.58 mmol), CH2Cl2 (50 mL) and N-methylmorpholine (0.394 mL, 3.58 mmol) were stirred at ambient temperature for 1 hour. Example 5A (1.00 g, 2.24 mmol) was added to the solution, and the combined solution was stirred at ambient temperature for 15 hours. After completion of the determination by LCMS, the reaction mixture was concentrated. The residue was purified by silica gel (0%-100% ethyl acetate / heptane) to give a residue. The residue was purified by reverse phase chromatography (C18 250 mm×50 mm C18 The title compound was further purified by HPLC column, eluting with 20%-100% acetonitrile in water / 0.1% trifluoroacetic acid. The pure fractions were combined and concentrated to remove acetonitrile. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to give the free base of the desired product. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated. The residue was lyophilized to give the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.53(s,1H),7.99(s,1H),7.21(d,J=8.3Hz,2H),7.016.92(m,2H),6.75(ddd,J=57.7,54.3,5.9Hz,1H),6.44(q,J=9 .3Hz,1H),5.31(dt,J=14.1,5.5Hz,1H),3.28(s,3H),3.263.06(m,4H),2.91(s,3H),2.86(s,3H),2.171.91(m,4H). MS(ESI+)m / z 607.3(M+H) + .

[0280] Example 6

[0281] 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 -Thiazane-4-carboxamide

[0282] Example 6A

[0283] 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

[0284] Using the conditions described in Example 4C, substituting Example 3G for Example 1F, the title compound (235 mg, 86%) was prepared. MS (APCI) m / z 429.3 (M+H) + .

[0285] Example 6B

[0286] 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 -Thiazane-4-carboxamide

[0287] Using the conditions described in Example 4D, substituting Example 6A for Example 4C, the title compound (145 mg, 45%) was prepared. 1H NMR(400MHz,DMSO-d6)δppm 8.48(s,1H),7.61(s,1H),7.24(d,J=8.2Hz,2H),7.07–6.89(m,2H),6.66(ddd,J=56.8,54.8,5.5Hz,2H),5.70(s,1H ),5.40(ddd,J=13.0,7.3,5.5Hz,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 / z589.3(M+H) + .

[0288] Example 7

[0289] 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 -Thiazane-4-carboxamide

[0290] Example 7A

[0291] (S)-1-(4-Bromophenyl)-N-ethyl-2,2,2-trifluoroethylamine

[0292] To a solution of Example II (0.4 g, 1.575 mmol) in methanol (5.3 mL) was added acetaldehyde (0.088 mL, 1.575 mmol). 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 mm×50 mm C18, 10%-90% acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to give the title compound (100 mg, 16.03%). MS (APCI) m / z 282.2 (M+H) + .

[0293] Example 7B

[0294] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-ethyltetrahydro-2H-thiopyran-4-carboxamide-1,1- Dioxide

[0295] 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 reactants were 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) + .

[0296] Example 7C

[0297] 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 -Thiazane-4-carboxamide

[0298] Example 1F (19.69 mg, 0.088 mmol), Example 7B (30 mg, 0.068 mmol), XPhos Pd G2 (5.34 mg, 6.78 μmol) and cesium carbonate (66.3 mg, 0.203 mmol) were mixed in 1,4-dioxolane (1.0 mL). The mixture was bubbled with nitrogen for 5 minutes and the container was sealed. The reaction was stirred at 90 ° C for 16 hours. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by reverse phase HPLC (250 mm×50 mm C18 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. 1H NMR(400MHz,DMSO-d6)δppm 8.46(s,1H),7.57(s,1H),7.29(d,J=8.2Hz,2H),7.05(d,J=8.7Hz,2H),6.33(s,1H),5.38(q,J=6. 7Hz, 1H), 3.51–3.04 (m, 10H), 2.83 (s, 3H), 2.27–1.95 (m, 4H), 1.53 (d, J = 6.6Hz, 3H), 0.88 (m, 3H). MS(APCI)m / z 585.2(M+H) + .

[0299] Example 8

[0300] 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 -Thiazane-4-carboxamide

[0301] Example 8A

[0302] (R)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid

[0303] Example 1C (20 g, 54.9 mmol), lithium hydroxide-H2O (11.52 g, 274 mmol), tetrahydrofuran (80 mL) and water (40 mL) were stirred at ambient temperature for 24 hours. After completion, tetrahydrofuran was removed under reduced pressure, the mixture was filtered and the filter cake was washed with water. The aqueous filtrate was acidified to pH 1 with concentrated HCl (37 wt %). The mixture was filtered, the filter cake was washed with water and vacuum dried at 60°C for 24 hours. The aqueous filtrate was concentrated under reduced pressure and ground with water. The mixture was filtered and the filter cake was vacuum dried at 60°C for 24 hours. After drying, the filter cakes were combined to obtain the title compound. 1 H NMR (500MHz, DMSO-d6) δppm 13.36 (s, 1H), 8.62 (s, 1H), 5.31 (q, J = 6.7Hz, 1H), 3.13 (s, 3H), 2.88 (s, 3H), 1.62 (d, J = 6.6Hz, 3H). MS(ESI)m / z253.4(M+H) + .

[0304] Example 8B

[0305] (R)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine

[0306] Example 8A (11.6 g, 46.2 mmol), tert-butyl alcohol (300 mL), N,N-diisopropylethylamine (40 mL, 231 mmol) and diphenylphosphoryl azide (11.9 mL, 55.4 mmol) were heated at 90 ° C for 90 minutes. After completion, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel (0%-40% ethyl acetate / heptane) to obtain boc-protected aniline. The boc-protected aniline was dissolved in a 1:1 mixture of trifluoroacetic acid and CH2Cl2 and stirred at ambient temperature for 1 hour. After completion, the solution was concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel (0%-80% ethyl acetate / heptane) to obtain the title compound. 1 HNMR (600MHz, DMSO-d6) δppm 8.04 (s, 1H), 5.40 (s, 2H), 5.37 (q, J = 6.7Hz, 1H), 3.22 (s, 3H), 2.75 (s, 3H), 1.46 (d, J = 6.7Hz, 3H). MS(ESI)m / z 224.4(M+H) + .

[0307] Example 8C

[0308] 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 -Thiazane-4-carboxamide

[0309] A solution of 1,4-dioxolane (507 mL) of Example 8B (5.65 g, 3.86 mmol), Example II (12.5 g, 29.1 mmol) and cesium carbonate (24.8 g, 11.6 mmol) was bubbled with N2 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-dithiocarboxylic 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 by silica gel (0%-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. The pure fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to give the free base of the desired product. To increase the purity of the diastereoisomers to >99%, the material was separated using Chiral SFC (supercritical fluid chromatography) was performed on an OJ-H column (30 mm×250 mm, 5 microns) at 35° C., 150 mL / min, 120 bar, eluting with 20% methanol in CO 2 to give the title compound. 1 HNMR(500MHz,DMSO-d6)δppm 8.51(s,1H),7.73(d,J=15.3Hz,1H),7.22(d,J=8.3Hz,2H),7.107.02(m,2H),6.45(q,J=9.3Hz,1H),5.33(q,J=6.7Hz,1H),3.24(dd,J =13.3,3.5Hz,1H),3.21(s,3H),3.213.15(m,1H),3.173.07(m,2H),2.92(s,3H),2.84(s,3H),2.141.95(m,5H),1.52(d,J=6.7Hz,3H). MS(ESI+)m / z571.7(M+H) + .

[0310] Example 9

[0311] 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 -Thiazane-4-carboxamide

[0312] Example 9A

[0313] (R,E)-N-(4-Bromo-3,5-difluorobenzylidene)-2-methylpropane-2-sulfenamide

[0314] 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 N2. The mixture was stirred at 85 ° C for 12 hours. The mixture was filtered through a celite pad. The filtrate was purified by silica gel column chromatography (10: 1-about 5: 1 petroleum ether: ethyl acetate) to give the title compound. 1 HNMR (400MHz, CDCl3) δppm8.49 (s, 1H), 7.45 (d, J = 6.5Hz, 2H), 1.28 (s, 9H). LCMS m / z 324.0(M+H) + .

[0315] Example 9B

[0316] (R)-N-((S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenyl amine

[0317] 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 and N2. The mixture was stirred at -20 °C for 0.5 hours. The reaction was quenched with NH4Cl solution at -40 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (10: 1-3: 1 petroleum ether: ethyl acetate) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm 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) + .

[0318] Example 9C

[0319] (S)-1-(4-Bromo-3,5-difluorophenyl)-2,2,2-trifluoroethane-1-amine

[0320] To a solution of Example 9B (7.5 g, 19.0 mmol) in ethyl acetate (10 mL) was added a solution of 4N HCl in ethyl acetate (100 mL). The mixture was stirred at 25 ° C for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was diluted with methyl tert-butyl ether. The mixture was stirred at 20 ° C for 2 hours and then filtered to obtain (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethylamine hydrochloride. The hydrochloride was dissolved in water (20 mL), neutralized with NaHCO3 solution (50 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethylamine (5.2 g, 92%), which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δppm 7.16-7.05 (m, 2H), 4.41 (q, J = 7.0Hz, 1H), 1.78 (br d, J = 2.2Hz, 2H). LCMS m / z290.0(M+H) + .

[0321] Example 9D

[0322] (S)-1-(4-Bromo-3,5-difluorophenyl)-2,2,2-trifluoro-N-methylethan-1-amine

[0323] At 20 ° C, formaldehyde (0.839 g, 10.3 mmol) was added to a mixture of Example 9C (2.5 g, 8.62 mmol) in methanol (50 mL), and the resulting mixture was stirred at 20 ° C for 12 hours. NaBH4CN (1.63 g, 25.9 mmol) was added, and the mixture was stirred at 20 ° C for 2 hours. The combined mixture was poured into ice water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20: 1 to 5: 1 petroleum ether / ethyl acetate) to obtain the title compound. 1 HNMR (400MHz, CDCl3) δppm 7.08 (d, J = 7.1Hz, 2H), 4.03 (q, J = 6.9Hz, 1H), 2.40 (s, 3H), 1.69 (br s, 1H). LCMS m / z 304.0(M+H) + .

[0324] Example 9E

[0325] (S)-N-(1-(4-bromo-3,5-difluorophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxylic Amide-1,1-dioxide

[0326] 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 Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3:1-about 1:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 6.99 (br d, J=7.1Hz, 2H), 6.61 (q, J=8.6Hz, 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 / z464.0(M+H) + .

[0327] Example 9F

[0328] 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 -Thiazane-4-carboxamide

[0329] To a solution of Example 9E (200 mg, 0.431 mmol), Example 1F (106 mg, 0.474 mmol) and Cs2CO3 (421 mg, 1.29 mmol) in 1,4-dioxolane (4 mL) was added methanesulfonyloxy(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (111 mg, 0.129 mmol) under N2. The reaction was stirred at 90°C for 3 hours 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 mm×40 mm×10 μm, Waters TM Xbridge Prep OBD C18, 10 min, 40%-70% acetonitrile / 10 mM NH4HCO3 aqueous solution) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.96(t,J=2.6Hz,1H),7.58(s,1H),7.02(brd,J=8.6Hz,2H),6.63(q,J=8.6Hz,1H),5.62(q,J=6.7Hz,1H),3.56-3.48(m,1H) ,3.45(s,3H),3.33(ddd,J=3.5,7.4,10.8Hz,1H),3.10-2.90(m,6H),2.84(s,3H),2.54-2.25(m,4H),1.66(d,J=6.8Hz,3H). LCMS m / z607.1(M+H) + .

[0330] Example 10

[0331] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[3-fluoro-4-({7-[(1S)-1-methoxyethyl 1-(2-Methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -Thiazane-4-carboxamide

[0332] Example 10A

[0333] 1-(4-Bromo-3-fluorophenyl)-2,2,2-trifluoroethanol

[0334] Trimethyl(trifluoromethyl)silane (14.59 mL) was added to a solution of 4-bromo-3-fluorobenzaldehyde (5 g) and cesium fluoride (0.075 g) in tetrahydrofuran (50 mL) at 0 ° C. The reaction mixture was slowly warmed to ambient temperature and stirred during the weekend. 1M HCl aqueous solution (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 silica gel chromatography (0%-40% ethyl acetate / 2-methylpentane) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 7.77(dd,1H),7.47(dd,1H),7.31(dt,1H),7.08(d,1H),5.32–5.19(m,1H).

[0335] Example 10B

[0336] 1-(4-Bromo-3-fluorophenyl)-2,2,2-trifluoro-N-methylethylamine

[0337] To a solution of Example 10A (1.3 g) in dichloromethane (30 mL) was added 2,6-lutidine (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 slowly warmed to ambient temperature. Methylamine (33% by weight in ethanol, 15 mL) was added and the reaction mixture was stirred at 45 ° C for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature. Saturated aqueous sodium bicarbonate solution (20 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0%-50% ethyl acetate / 2-methylpentane) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm7.77(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) + .

[0338] Example 10C

[0339] N-(1-(4-bromo-3-fluorophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide-1,1- Dioxide

[0340] 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 at ambient temperature for 90 minutes. A solution of Example 10B (850 mg) in dichloromethane (1.5 mL) was added, and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was concentrated in vacuo on silica gel. The crude product was purified by silica gel chromatography (0%-70% ethyl acetate / 2-methylpentane) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 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) + .

[0341] Example 10D

[0342] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[3-fluoro-4-({7-[(1S)-1-methoxyethyl 1-(2-Methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-1λ 6 -Thiazane-4-carboxamide

[0343] XPhos Pd G4 (145 mg) was added to a degassed suspension of Example 1F (125 mg), Example 10C (250 mg) and cesium carbonate (548 mg) in 1,4-dioxolane (5 mL) at ambient temperature, and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was filtered through celite 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 (3×10 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 silica gel chromatography (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. Use IC column (10mm x 250mm, 5 microns), eluted with 40% methanol (0.1% ammonia) in CO2, at 40°C, 15mL / min, 120 bar, the diastereomeric mixture was separated by chiral SFC (supercritical fluid chromatography) to give the title compounds in the form of single diastereoisomers. The absolute stereochemical structures of these title compounds are arbitrarily assigned. 1H NMR(400MHz,DMSO-d6)δppm8.50(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) + .

[0344] Embodiment 11

[0345] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1S)-2,2,2-trifluoro- [1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0346] Example 11A

[0347] 2-Methyl-7-vinylthiazo[5,4-b]pyridine-6-carboxylic acid ethyl ester

[0348] 7-Chloro-2-methylthiazole [5,4-b] pyridine-6-carboxylic acid ethyl ester (30g, 117mmol, WO2018020474A1, Example 16), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (27g, 175mmol) and Na2CO3 (24.8g, 234mmol) were dissolved in a mixture of 1,4-dioxolane (300mL) and water (30mL). The solution was purged with nitrogen and tetrakis(triphenylphosphine)palladium (6.75g, 5.84mmol) was added. The resulting solution was heated at 110°C under a nitrogen atmosphere for 16 hours. After cooling to ambient temperature, 1,4-dioxolane was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate (300mL) and washed with water (2×300mL). 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 HNMR(300MHz,CD3OD)δppm 1.44(t,J=7.1Hz,3H),2.89(s,3H),4.44(q,J=7.1Hz,2H),5.94(dd,J=11.7,1.8H z, 1H), 6.70 (dd, J=17.6, 1.8Hz, 1H), 7.47 (dd, J=17.6, 11.7Hz, 1H), 8.87 (s, 1H). MS(ESI+)m / z249(M+H) + .

[0349] Example 11B

[0350] 2-Methyl-7-vinylthiazo[5,4-b]pyridine-6-carboxylic acid

[0351] Example 11A (18.5 g, 74.5 mmol) and lithium hydroxide (3.57 g, 149 mmol) were dissolved in a mixture of 1,4-dioxolane (180 mL) and water (100 mL). The reaction mixture was stirred at ambient temperature for 2 hours. After complete hydrolysis, 1,4-dioxolane was removed under reduced pressure. The resulting aqueous solution was adjusted to pH 2 with 1M HCl aqueous solution. The mixture was filtered and the filter cake was dried under vacuum to give the title compound (15 g, 91%). 1 HNMR(300MHz,DMSO-d6)δppm 2.89(s,3H),5.96(dd,J=11.7,2.1Hz,1H),6.75(dd,J=17.6,2.1Hz,1H),7.46(dd,J=17.6,11.7Hz,1H),8.88(s,1H),13.61(s,1H).

[0352] Example 11C

[0353] tert-Butyl (2-methyl-7-vinylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0354] Example 11B (15 g, 68 mmol) and triethylamine (19 mL, 136 mmol) were dissolved in tert-butyl alcohol (300 mL) and The reaction mixture was stirred at ambient temperature for 10 minutes and then The mixture was then refluxed at 95°C overnight. After cooling, the resulting solution was concentrated under reduced pressure. The residue was passed through silica gel (10% ethyl acetate / silicon) The title compound was obtained by purification with ether. 1 HNMR (300MHz, CDCl3) δppm2.85 (s, 3H), 5.95 (dd, J = 11.7, 1.6Hz, 1H), 6.37-6.49 (m, 1H), 6.62 (s, 1H), 7.03 (dd, J = 17.9, 11.7Hz, 1H), 8.92 (s, 1H). MS (ESI+)m / z292(M+H) + Example 11D

[0355] tert-Butyl (7-formyl-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0356] 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 by silica gel (20% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300MHz, CDCl3) δppm 1.59 (s, 9H), 2.92 (s, 3H), 9.82 (s, 1H), 10.34 (s, 1H), 11.10 (d, J = 0.8Hz, 1H). MS(ESI+)m / z294(M+H) + .

[0357] Example 11E

[0358] tert-Butyl (2-methyl-7-(2,2,2-trifluoro-1-hydroxyethyl)thiazolo[5,4-b]pyridin-6-yl)carbamate ester

[0359] Example 11D (26 g, 89 mmol), A mixture of 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 and 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 by silica gel (20% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR (300MHz, DMSO-d6) δppm 1.47 (s, 9H), 2.85 (s, 3H), 6.08-6.25 (m, 1H), 8.29 (d, J = 6.2Hz, 1H), 8.62 (s, 1H), 9.07 (s, 1H).

[0360] Example 11F

[0361] tert-(2-methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridin-6-yl)carbamic acid Butyl Ester

[0362] 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 (3×300 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 by silica gel (0%-100% ethyl acetate / petroleum ether) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm 1.47 (s, 9H), 2.87 (s, 3H), 3.54 (s, 3H), 5.98 (q, J = 7.6Hz, 1H), 8.28 (s, 1H), 8.97 (s, 1H). MS(ESI+)m / z 378(M+H) + .

[0363] Example 11G

[0364] (R)-2-methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridin-6-amine; and

[0365] Example 11H

[0366] (S)-2-Methyl-7-(2,2,2-trifluoro-1-methoxyethyl)thiazolo[5,4-b]pyridin-6-amine

[0367] Example 11F (35.2 g, 93.3 mmol) was dissolved in 4M 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 solution and filtered. The filter cake was washed with water (80 mL) and dried under vacuum to give a 1:1 mixture of Example 11G and Example 11H. Use Chiral SFC (supercritical fluid chromatography) was performed on the racemic material using an AD-H column (5 cm×25 cm, 5 microns) at 35° C. and 150 mL / min, eluting with 15% methanol (2 mM ammonia) in CO2 to give the title compound (Example 11G: retention time 5.14 minutes, Example 11H: retention time 5.95 minutes). Example 11G: 1 H NMR (300MHz, DMSO-d6) δppm 2.77 (s, 3H), 3.44 (s, 3H), 5.64 (s, 2H), 5.83 (q, J = 7.8Hz, 1H), 8.12 (s, 1H). MS(ESI+)m / z 278(M+H) + Example 11H: 1 H NMR (300MHz, DMSO-d6) δppm 2.77 (s, 3H), 3.44 (s, 3H), 5.64 (s, 2H), 5.83 (q, J = 7.8Hz, 1H), 8.12 (s, 1H). MS(ESI+)m / z 278(M+H) + .

[0368] Example 11I

[0369] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(1S)-2,2,2-trifluoro- [1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0370] A solution of 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-dioxolane (10 mL) was bubbled with N2 for 2 minutes. XPhosPdG4 (70 mg, 0.081 mmol) was added, and the reaction mixture was heated at 95 ° C for 16 hours. The solution was cooled to ambient temperature, filtered through diatomaceous earth, and the diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by reverse phase chromatography (C18 HPLC, eluted with 20%-100% acetonitrile aqueous solution / 0.1% trifluoroacetic acid) to isolate the title compound. The pure fractions were combined and concentrated to remove acetonitrile. The aqueous solution was distributed with ethyl acetate and neutralized with saturated sodium bicarbonate aqueous solution to obtain the free base of the desired product. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was freeze-dried to obtain the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.60(s,1H),7.62(d,J=18.2Hz,1H),7.25(d,J=8.4Hz,2H),7.15(d,J=8.6Hz,2H),6.46(q,J=9.2Hz,1H ), 5.93 (q, J = 7.6Hz, 1H), 3.52 (s, 3H), 3.30-3.07 (m, 5H), 2.92 (s, 3H), 2.86 (s, 3H), 2.19-1.94 (m, 4H). MS(ESI+)m / z 626.0(M+H) + .

[0371] Example 12

[0372] 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 -Thiazane-4-carboxamide

[0373] Example 12A

[0374] N-(4-((S)-2,2-difluoro-1-(methylamino)ethyl)phenyl)-7-((R)-1-methoxyethyl)-2-methyl Thiazolo[5,4-b]pyridin-6-amine

[0375] A solution of 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-dioxolane (25 mL) was bubbled with N2 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, filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel (0%-100% ethyl acetate / heptane) to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δppm 8.48(s,1H),7.55(s,1H),7.29-7.22(m,2H),7.07-6.99(m,2H),6.00(d,J=4.3Hz,1H),5.37(q,J=6.6Hz,1H) ,3.70(d,J=13.9Hz,1H),3.24(s,3H),2.83(s,3H),2.34(s,1H),2.19(d,J=3.2Hz,3H),1.52(d,J=6.7Hz,3H). MS(ESI)m / z 393.2(M+H) + .

[0376] Example 12B

[0377] 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 -Thiazane-4-carboxamide

[0378] Example 12B was prepared according to the method used to prepare Example 5B, substituting Example 12A for Example 5A, to provide the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.49(d,J=2.6Hz,1H),7.62(s,1H),7.29(d,J=8.5Hz,1H),7.24-7.20(m,2H),7.0 8-7.01(m,2H),6.73(dd,J=12.3,5.3Hz,0H),5.80-5.72(m,1H),5.34(q,J=6.7Hz ,1H),3.22(d,J=2.9Hz,4H),3.13-3.06(m,3H),2.93(s,3H),2.83(d,J=1.5Hz,3H ), 2.67 (s, 1H), 2.09-2.00 (m, 3H), 2.02-1.95 (m, 1H), 1.52 (dd, J = 6.6, 1.7Hz, 3H). MS(ESI)m / z 553.6(M+H) + .

[0379] Example 13

[0380] 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 -Thiazane-4-carboxamide

[0381] Example 13A

[0382] 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

[0383] A solution of 1,4-dioxolane (30 mL) of 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) was bubbled with N2 for 2 minutes. XPhos Pd G4 (0.17 g, 0.19 mmol) was added, and the reaction mixture was heated at 95 ° C for 16 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel (0%-100% ethyl acetate / heptane) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.77(s,1H),7.39-7.11(m,2H),7.10-6.93(m,2H),6.74(ddd,J=57.5,54.5,5.8Hz,1H),5.99(td,J=56.3 ,4.3Hz,1H),5.36(dt,J=13.8,5.9Hz,1H),3.71(t,J=12.8Hz,1H),3.31(s,3H),2.85(s,3H),2.32(s,1H),2.19(s,3H). MS(ESI)m / z429.8(M+H) + .

[0384] Example 13B

[0385] 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 -Thiazane-4-carboxamide

[0386] Example 13B was prepared according to the method used to prepare Example 5B, substituting Example 13A for Example 5A, to provide the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.51(d,J=3.3Hz,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=13.3,5.3Hz,1H),5 .33(dt,J=14.0,5.5Hz,1H),3.29(d,J=2.3Hz,3H),3.27-3.04(m,5H),2.93(s,3H),2.86(d,J=1.9Hz,3H),2.16-1.87(m,4H). MS(ESI)m / z 589.5(M+H) + .

[0387] Embodiment 14

[0388] 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 -Thiazane-4-carboxamide

[0389] Example 14A

[0390] 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

[0391] Using the conditions described in Example 4C, substituting Example 11G for Example 1F, Example 14A (345.2 mg, 97%) was prepared. MS (APCI) m / z 447.3 (M+H) + .

[0392] Example 14B

[0393] 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 -Thiazane-4-carboxamide

[0394] Example 14B (75.4 mg, 51%) was prepared using the conditions described in Example 4D, substituting Example 14A for Example 4C. 1 HNMR(400MHz,DMSO-d6)δppm8.53(s,1H),7.37(s,1H),7.29(d,J=8.3Hz,2H),7.12(d,J=8.7Hz,2H),6.88–6.46(m,1 H),5.94(q,J=7.7Hz,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 / z607.3(M+H) + .

[0395] Embodiment 15

[0396] N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][1,3]thiazolo[5,4-b]pyrrolidone [6-pyridin-1-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Thiazane-4-carboxamide

[0397] Example 15A

[0398] (S)-7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester

[0399] Potassium carbonate (1.096 g, 7.93 mmol) and iodomethane (0.296 mL, 4.76 mmol) were added to a solution of Example 1D (1 g, 3.96 mmol) in N,N-dimethylformamide (12 mL). The resulting suspension was stirred at ambient temperature for 2 hours. The reaction mixture was distributed 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 Companion (24 g column, 10%-50% ethyl acetate / 2-methylpentane) to give the title compound (980 mg, 3.68 mmol, 93%). 1 H NMR (400MHz, DMSO-d6) δppm 8.61 (s, 1H), 5.25 (q, J = 6.7Hz, 1H), 3.86 (s, 3H), 3.14 (s, 3H), 2.89 (s, 3H), 1.59 (d, J = 6.6Hz, 3H). MS(ESI)m / z 267.1(M+H) + .

[0400] Example 15B

[0401] (S)-2-Formyl-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester

[0402] A mixture of Example 15A (15 g, 56.3 mmol) and selenium dioxide (25.00 g, 225 mmol) in 1,4-dioxolane (210 mL) was stirred at 93° C. for 8 hours. After cooling, the reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum (1:4) to give the title compound (2.808 g, 9.66 mmol, 17.15%). 1 HNMR (300MHz, DMSO-d6) δppm 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 = 6.7Hz, 3H). LCMS(ESI)m / z281(M+H) + .

[0403] Example 15C

[0404] (S)-2-(Difluoromethyl)-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester

[0405] 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 with ethyl acetate / petroleum ether (1 / 1) to give the title compound (812.4 mg, 2.63 mmol, 61.5%). 1 HNMR (400MHz, DMSO-d6) δppm 8.83 (d, J = 1.4Hz, 1H), 5.27 (q, J = 6.6Hz, 1H), 3.86 (s, 3H), 3.13 (s, 3H), 1.58 (d, J = 6.7Hz, 3H). MS(ESI)m / z 303(M+H) + .

[0406] Example 15D

[0407] (S)-2-(Difluoromethyl)-7-(1-methoxyethyl)thiazolo[5,4-b]pyridine-6-carboxylic acid

[0408] A mixture of Example 15C (0.3 g, 0.992 mmol) and sodium carbonate (0.526 g, 4.96 mmol) in methanol (10 mL) was stirred overnight at ambient temperature. The solvent was removed and the residue was redissolved in ethyl acetate and 0.1 N aqueous HCl. The aqueous layer was extracted twice more with 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%-100% acetonitrile in 0.1% aqueous trifluoroacetic acid to give the title compound (0.082 g, 0.284 mmol, 28.7%). 0.10 g of Example 15C was also recovered. 1 HNMR (600MHz, DMSO-d6) δppm 13.60 (s, 1H), 8.86 (s, 1H), 7.63-7.45 (m, 1H), 5.35 (q, J = 6.6Hz, 1H), 3.15 (s, 3H), 1.64 (d, J = 6.7Hz, 3H). MS(ESI)m / z 289.0(M+H) + .

[0409] Example 15E

[0410] A mixture of Example 15D (0.07 g, 0.243 mmol), diphenylphosphoryl azide (0.080 g, 0.291 mmol) and triethylamine (0.203 mL, 1.457 mmol) in tert-butanol (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 HNMR (500MHz, DMSO-d6) δppm8.26 (s, 1H), 7.42 (t, J = 53.9Hz, 1H), 5.67 (s, 2H), 5.37 (q, J = 6.7Hz, 1H), 3.24 (s, 3H), 1.49 (d, J = 6.7Hz, 3H). MS(ESI)m / z261.0(M+H) + .

[0411] Example 15F

[0412] N-{(1S)-1-[4-({2-(difluoromethyl)-7-[(1S)-1-methoxyethyl][1,3]thiazolo[5,4-b]pyrrolidone [6-pyridin-1-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Thiazane-4-carboxamide

[0413] 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-dioxolane (1.5 mL) was degassed and backfilled with nitrogen several times. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (5.51 mg, 7.01 μmol) was added to the reaction mixture. The reaction vessel was recapped, then degassed and backfilled 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 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% trifluoroacetic acid in water to afford the title compound (0.031 g, 0.051 mmol, 73.0%). 1H NMR(600MHz,DMSO-d6)δppm 8.70(s,1H),7.88(s,1H),7.50(t,J=53.8Hz,1H).,7.24(d,J=8.4Hz,2H),7.14–7.07(m,2H),6.45(q,J=9.3Hz,1H),5.32(q,J=6.7Hz,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=8.7,3.3Hz,2H),2.05–1.96(m,1H),1.56(d,J=6.7Hz,3H). MS (ESI) m / z 608.0 (M+H) + .

[0414] Example 16

[0415] 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 -Thiazane-4-carboxamide

[0416] Example 16A

[0417] tert-Butyl (7-(2,2-difluoro-1-hydroxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0418] To a suspension of N,N-dimethylformamide (40 mL) of Example 11D (4 g) 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 (2M in water, 13.64 mL) was slowly added. The reaction mixture was stirred at this temperature for 1 hour, and then a saturated aqueous ammonium chloride solution (50 mL) was added. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×70 mL), and the combined organic 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 silica gel chromatography (0%-60% ethyl acetate / 2-methylpentane) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm9.00(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 / z345.8(M+H) + .

[0419] Example 16B

[0420] tert-Butyl (7-(2,2-difluoroacetyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0421] To a solution of Example 16A (500 mg) in dichloromethane (15 mL) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzodioxole-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 solution (10 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0%-40% ethyl acetate / 2-methylpentane) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm 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) + .

[0422] Example 16C

[0423] tert-Butyl (7-(3,3-difluoroprop-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0424] 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. A portion of the preformed ylide solution (6 mL) was added to a solution of Example 16B (370 mg) in tetrahydrofuran (10 mL) at -10°C, and the reaction mixture was stirred for 30 minutes. Another portion of the ylide solution (6 mL) was added, and the reaction mixture was stirred overnight, slowly warming to ambient temperature. The reaction mixture was stirred at 50°C for 1 hour, then at 70°C for 12 hours, and allowed to stand at ambient temperature for 3 days. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted twice 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 silica gel chromatography (0%-100% ethyl acetate / 2-methylpentane) to provide the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 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) + .

[0425] Example 16D

[0426] tert-Butyl (7-(3,3-difluoroprop-1-en-2-yl)-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0427] 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 for 3 hours under a hydrogen atmosphere (3 bar) at ambient temperature. 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 silica gel chromatography (0%-50% ethyl acetate / 2-methylpentane) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 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 / z344.2(M+H) + .

[0428] Example 16E

[0429] 7-(1,1-difluoropropan-2-yl)-2-methylthiazolo[5,4-b]pyridin-6-amine

[0430] 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 solution (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound. 1 HNMR(400MHz,DMSO-d6)δppm 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) + .

[0431] Example 16F

[0432] 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 -Thiazane-4-carboxamide

[0433] To a degassed suspension of Example 16E (150 mg), Example 1J (396 mg) and potassium phosphate (262 mg) in 1,4-dioxolane (5 mL) was added XPhosPdG4 (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 celite and washed with dichloromethane (15 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (0%-80% ethyl acetate / 2-methylpentane). The product was dissolved in tetrahydrofuran (5 mL) and pyrrolidine-1-dithiocarboxylic acid, 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 silica gel chromatography (0%-80% ethyl acetate / 2-methylpentane) to give the title compound. 1 HNMR(400MHz,DMSO-d6)δppm 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) + .

[0434] Embodiment 17

[0435] 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 -Thiazane-4-carboxylic acid amine

[0436] To a degassed suspension of Example 3G (116 mg), Example 10C (200 mg) and potassium phosphate (95 mg) in 1,4-dioxolane (2 mL) was added XPhos Pd G4 (77 mg) and the reaction mixture was stirred at 70 °C for 16 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite and washed with dichloromethane (10 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (0%-100% ethyl acetate-ethanol (3:1) / 2-methylpentane) to give the product as a mixture of diastereoisomers. Use IC column (10mm x 250mm, 5 microns), eluted with 35% methanol (0.1% ammonia) in CO2, at 40°C, 15mL / min, 120 bar, the diastereomeric mixture was separated by chiral SFC (supercritical fluid chromatography) to give the title compounds in the form of single diastereoisomers. The absolute stereochemical structures of these title compounds are arbitrarily assigned.1 H NMR(400MHz,DMSO-d6)δppm 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) + .

[0437] Embodiment 18

[0438] 1-Acetyl-N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolidine oxazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide

[0439] Example 18A

[0440] (S)-1-Acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide

[0441] 1-acetyl piperidine-4-carbonyl chloride (0.747g, 3.94mmol) is added in the 40mL bottle of the hydrochloride (1.0g, 3.28mmol) of embodiment II contained in dichloromethane (3mL), pyridine (1.328mL, 16.42mmol) and N, N-dimethylpyridine-4-amine (0.401g, 3.28mmol).The reaction is stirred at ambient temperature for 30 minutes, and diluted with dichloromethane (20mL).The organic layer is washed with saturated aqueous ammonium chloride solution (20mL), dried over anhydrous magnesium sulfate and filtered.The filtrate is concentrated.Residue is passed through automatic flash chromatography (ISCO, SiO2, ethyl acetate / hexane) purification to obtain title compound.

[0442] Example 18B

[0443] 1-Acetyl-N-{(1S)-1-[4-({7-[(1R)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiazolidine oxazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide

[0444] 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 backfilled twice with nitrogen. 1,4-dioxolane was added, and the mixture was stirred overnight at 90 ° C under nitrogen. The crude mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude residue was purified using reverse phase chromatography (C18 HPLC, eluted with 20%-70% acetonitrile in water / 0.1% formic acid) to give the title compound. 1 H NMR (500MHz, CDCl3)8.61(s,1H),7.26(t,J=8.5Hz,2H),7.08-7.02(m,2H),6.59(q,J=9.0Hz,1H),6.12(td,J=55Hz,1H),5.57(m,1H),4.61(t,J=12 .1Hz,1H),3.91(d,J=13.2Hz,1H),3.57(s,3H),3.14(m,1H),2.93(d,J=2. 4Hz,3H),2.83(s,3H),2.82-2.67(m,3H),2.11(s,3H),1.92-1.70(m,4H). MS(ESI)m / z600.4(M+H) + .

[0445] Embodiment 19

[0446] 1-Acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl 4-thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0447] 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 backfilled twice with nitrogen. 1,4-dioxolane was added and the mixture was stirred overnight at 90 °C under nitrogen. The mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was purified using automatic flash chromatography (ISCO, SiO2, ethyl acetate / hexane) to give the title compound. 1HNMR(500MHz, CDCl3)8.60(s,1H),7.46(s,1H),7.26(t,J=7.4Hz,2H),7.16-7.05(m,2H) ,6.59(q,J=9.0Hz,1H),5.57(q,J=6.7Hz,1H),4.61(t,J=12.1Hz,1H),3.91(d,J=13.2Hz ,1H),3.41(s,3H),3.14(ddd,J=17.2,9.8,4.4Hz,1H),2.94(d,J=2.4Hz,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 = 6.7Hz, 3H). MS(ESI)m / z 564.0(M+H) + .

[0448] Embodiment 20

[0449] 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

[0450] Example 20A

[0451] (S)-tert-Butyl 4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidin-1-carboxylic Acid esters

[0452] At 0°C, 2.0M oxalyl chloride in dichloromethane (2.00mL, 4.00mmol) was added to a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (459mg, 2.00mmol) in dichloromethane (10mL) followed by a trace 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 (5.0mL) and slowly added to a mixture of the hydrochloride of Example II (305mg, 1.00mmol) and N,N-diisopropylethylamine (0.875mL, 5.01mmol) in dichloromethane (5.0mL) 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 solution and saturated aqueous sodium chloride solution, 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) + .

[0453] Example 20B

[0454] 4-(Methyl((S)-2,2,2-trifluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4- b] tert-butyl)pyridin-6-yl)amino)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate

[0455] 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 dioxolane (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 celite, 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) + .

[0456] Example 20C

[0457] 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

[0458] 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 mm×50 mm C18 10%-100% acetonitrile / 0.1% trifluoroacetic acid in water) to give the title compound as a trifluoroacetate salt. MS (ESI+) m / z 522.3 (M+H) + .

[0459] Example 20D

[0460] 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

[0461] 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) portionwise. The reaction mixture was stirred at ambient temperature for 2 hours and the HPLC was performed on a reverse phase HPLC (250 mm×50 mm C18 The product was purified by 10% to 100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The fractions containing the product were combined and the acetonitrile was removed by evaporation. The solution was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was lyophilized with acetonitrile / water to give the title compound. 1 HNMR (500MHz, DMSO-d6) δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.7Hz,2H),6.46( q,J=9.4Hz,1H),5.33(q,J=6.6Hz,1H),4.50(s,1H),4.35(d,J=13.1Hz,1H),4. 16–4.01(m,2H),3.71(d,J=13.4Hz,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) + .

[0462] Embodiment 21

[0463] 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

[0464] Example 21A

[0465] 4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- tert-butyl (6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate

[0466] Example 21A was prepared according to the method used to prepare Example 20B, substituting Example 3G for Example 1F to provide the title compound. MS (ESI+) m / z 658.6 (M+H) + .

[0467] Example 21B

[0468] N-((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- 6-amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide, trifluoroacetic acid

[0469] Example 21B was prepared according to the method used to prepare Example 20C, substituting Example 21A for Example 20B to provide the title compound. MS (ESI+) m / z 558.4 (M+H) + .

[0470] Example 21C

[0471] 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

[0472] Example 21C was prepared according to the method used to prepare Example 20D, substituting Example 21B for Example 20C to provide the title compound. 1 H NMR(500MHz,DMSO-d6)δppm 8.53(s,1H),7.99(s,1H),7.20(d,J=8.3Hz,2H),6.97(d,J=8.7Hz,2H),6.75(ddd,J=57. 6,54.4,5.9Hz,1H),6.45(q,J=9.4Hz,1H),5.31(dt,J=14.0,5.6Hz,1H),4.49(s,1H),4.3 5(d,J=13.1Hz,1H),4.15–4.01(m,2H),3.70(d,J=13.2Hz,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) + .

[0473] Embodiment 22

[0474] 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

[0475] Example 22 was prepared according to the procedure used to prepare Example 20D, substituting 30% aqueous 3-hydroxypropionic acid for 2-hydroxyacetic acid to provide the title compound. 1H NMR(600MHz,DMSO-d6)δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.7Hz,2H),6.46(q,J=9.4Hz,1H ),5.33(q,J=6.7Hz,1H),4.48(t,J=5.4Hz,1H),4.40(d,J=13.1Hz,1H),3.92(d,J=13.5Hz,1H ),3.63(td,J=6.5,5.3Hz,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 / z594.3(M+H) + .

[0476] Embodiment 23

[0477] 1-(2-Hydroxy-2-methylpropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methyl [1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]piperidine-4-carboxamide

[0478] Example 23 was prepared according to the method used to prepare Example 20D, substituting 2-hydroxy-2-methylpropionic acid for 2-hydroxyacetic acid to provide the title compound. 1 H NMR (600MHz, DMSO-d6) δppm8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.7Hz,2H),6.46(q,J=9.4Hz,1H),5.38(s,1H),5.33(q,J=6 .7Hz,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) + .

[0479] Embodiment 24

[0480] 1-(2,3-dihydroxypropanoyl)-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxy 2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0481] Example 24 was prepared according to the procedure used to prepare Example 20D, substituting 20% ​​aqueous 2.3-dihydroxypropionic acid for 2-hydroxyacetic acid to provide the title compound. 1 H NMR(500MHz,DMSO-d6)δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.7Hz,2H),6.46(q,J=9.3 Hz,1H),5.33(q,J=6.7Hz,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,3H),3.15–3.00(m,2 H),2.92(s,3H),2.84(s,3H),2.75–2.65(m,1H),1.80–1.66(m,2H),1.59–1.37(m,5H). MS(ESI+)m / z 610.2(M+H) + .

[0482] Embodiment 25

[0483] 1-[(2R)-2-Hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxy 2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0484] Example 25 was prepared according to the method used to prepare Example 20D, substituting (R)-2-hydroxypropionic acid for 2-hydroxyacetic acid to provide the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.6Hz,2H),6.46( q,J=9.4Hz,1H),5.33(q,J=6.7Hz,1H),4.87–4.80(m,1H),4.47–4.31(m,2H),4 .01(d,J=12.9Hz,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) + .

[0485] Embodiment 26

[0486] 1-[(2S)-2-Hydroxypropanoyl]-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1S)-1-methoxy 2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0487] Example 26 was prepared according to the method used to prepare Example 20D, substituting (S)-2-hydroxypropionic acid for 2-hydroxyacetic acid to provide the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.4Hz,2H),7.05(d,J=8.7Hz,2H),6.46(q ,J=9.4Hz,1H),5.33(q,J=6.7Hz,1H),4.84(d,J=6.9Hz,1H),4.46–4.34(m,2H), 4.02(d,J=13.2Hz,1H),3.21(s,3H),3.14–2.99(m,2H),2.92(s,3H),2.84(s,3 H),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) + .

[0488] Embodiment 27

[0489] 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

[0490] Example 27A

[0491] (R)-2,2-Dimethyl-1,3-dioxolane-4-carboxylic acid

[0492] 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 a 2M HCl aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to obtain the title compound.

[0493] Example 27B

[0494] 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

[0495] 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 the product was analyzed by reverse phase HPLC (250 mm×50 mm C18 The title compound and the protected intermediate were obtained by purification with 1% LUNA, 10%-100% acetonitrile / 0.1% trifluoroacetic acid in water. The protected intermediate fractions were concentrated, dissolved in a mixture of acetic acid (1.0 mL) / water (0.50 mL), stirred at 70°C for 15 minutes, cooled to ambient temperature and concentrated. The residue was purified by reverse phase HPLC (250 mm×50 mm C18 The title compound was purified by 10%-100% acetonitrile / 0.1% trifluoroacetic acid aqueous solution). The combined fractions of the title compound were concentrated to remove acetonitrile, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was lyophilized with acetonitrile / water to give the title compound. 1 H NMR(500MHz,DMSO-d6)δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.4Hz,2H),7.05(d,J=8.7Hz,2H),6.46(q,J=9.4Hz,1H),5. 33(q,J=6.7Hz,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=6.7Hz,3H),1.48–1.37(m,1H). MS(ESI+)m / z610.3(M+H) + .

[0496] Embodiment 28

[0497] 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

[0498] Example 28A

[0499] 4-(((S)-2,2-difluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- tert-butyl (6-yl)amino)phenyl)ethyl)(methyl)carbamoyl)piperidine-1-carboxylate

[0500] 1-(tert-Butyloxycarbonyl)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 purified directly by flash chromatography (0% to 70% ethyl acetate / heptane) to give the title compound. MS (ESI) m / z 604.4 (M+H) + .

[0501] Example 28B

[0502] N-((S)-2,2-difluoro-1-(4-((7-((S)-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- 6-amino)phenyl)ethyl)-N-methylpiperidine-4-carboxamide

[0503] 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) + .

[0504] Example 28C

[0505] 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

[0506] 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 mm×50 mm C18 The product was purified directly from 10% to 90% acetonitrile / 0.1% trifluoroacetic acid in water. The 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(400MHz,DMSO-d6)δppm 8.46(s,1H),7.48(s,1H),7.25(d,J=8.3Hz,2H),7.04(d,J=8.6Hz,2H),6.64(td,J=55.0,5.1Hz,1H),5.70(s,1H),5.40 (q,J=6.6Hz,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=10.4Hz,2H),1.54(m,5H). MS(APCI)m / z 562.3(M+H) + .

[0507] Embodiment 29

[0508] 1-Acetyl-N-{(1S)-2,2-difluoro-1-[4-({7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiophene oxazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}-N-methylpiperidine-4-carboxamide

[0509] 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 hours and purified by reverse phase HPLC (250 mm×50 mm C18 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. 1H NMR (400MHz, DMSO-d6) δppm8.46(s,1H),7.48(s,1H),7.25(d,J=8.3Hz,2H),7.04(d,J=8.6Hz,2H),6.64(td,J=55.2,5.1Hz,1H),5.70(s,1H),5 .40(q,J=6.6Hz,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 = 11.4Hz, 2H), 1.63–1.41 (m, 5H). MS(APCI)m / z 546.4(M+H) + .

[0510] Embodiment 30

[0511] 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

[0512] Example 30 was prepared according to the method used to prepare Example 20D, substituting (S)-2,3-dihydroxypropionic acid for 2-hydroxyacetic acid to provide the title compound (26 mg, 18%). 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.05(d,J=8.6Hz,2H),6.46(q,J=9.4 Hz,1H),5.33(q,J=6.7Hz,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,3H),3.13–2.99(m,2 H),2.92(s,3H),2.84(s,3H),2.75–2.65(m,1H),1.82–1.67(m,2H),1.63–1.36(m,5H). MS(ESI+)m / z610.3(M+H) + .

[0513] Embodiment 31

[0514] 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

[0515] Example 31A

[0516] 4-(((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- tert-butyl (6-yl)amino)phenyl)-2,2-difluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate

[0517] Using the conditions described in Example 28A, substituting Example 6A for Example 4C, the title compound (100 mg, 45%) was prepared. MS (APCI) m / z 640.4 (M+H) + .

[0518] Example 31B

[0519] N-((S)-1-(4-((7-((R)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- 6-amino)phenyl)-2,2-difluoroethyl)-N-methylpiperidine-4-carboxamide

[0520] Using the conditions described in Example 28B, substituting Example 31A for Example 28A, the title compound (70 mg, 83%) was prepared. MS (APCI) m / z 540.4 (M+H) + .

[0521] Example 31C

[0522] 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

[0523] Using the conditions described in Example 28C, substituting Example 31B for Example 28B, the title compound (33.4 mg, 43%) was prepared. 1 H NMR(400MHz,DMSO-d6)δppm 8.48(s,1H),7.60(s,1H),7.24(d,J=8.4Hz,2H),6.97(d,J=8.6Hz,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=8.3Hz,2H),1.54(d,J=12.9Hz,2H). MS(APCI)m / z 598.4(M+H) + .

[0524] Embodiment 32

[0525] 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

[0526] Example 32A

[0527] (S)-tert-Butyl 4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidin-1-carboxylic Acid esters

[0528] 1-(tert-Butyloxycarbonyl)piperidine-4-carboxylic acid (2.45 g, 10.7 mmol), 2,4-dichloro-6-methoxy-1,3,5-triazine (1.77 g, 9.85 mmol), CH2Cl2 (50 mL) and N-methylmorpholine (1.08 mL, 9.85 mmol) were stirred at ambient temperature for 1 hour. Example II (2.50 g, 8.21 mmol) was added to the solution, and the combined solution was stirred at ambient temperature for 15 hours. After completion of the determination by LCMS, the reaction mixture was concentrated. The residue was purified by silica gel (0%-100% ethyl acetate / heptane). The residue was further purified by reverse phase chromatography (C18 HPLC, eluted with 20%-100% acetonitrile aqueous solution / 0.1% trifluoroacetic acid) to isolate the title compound. The pure fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated sodium bicarbonate aqueous solution to obtain the free base of the desired product. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to give the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 7.80-7.61(m,2H),7.30(d,J=8.3Hz,2H),6.55(q,J=9.2Hz,1H),3.96(d, J=13.3Hz,2H),3.08-2.67(m,6H),1.70(t,J=16.9Hz,2H),1.40(s,11H). MS(ESI+)m / z 479.6and481.7(M+H) + .

[0529] Example 32B

[0530] 4-(((S)-1-(4-((7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- tert-butyl (6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate

[0531] A solution of 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-dioxolane (30 mL) was bubbled with N2 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, filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The filtrate was concentrated. The material was purified by silica gel (0%-70% ethyl acetate / heptane) to obtain the title compound. 1H NMR(500MHz,DMSO-d6)δppm 8.53(s,1H),7.99(s,1H),7.20(d,J=8.3Hz,2H),7.01-6.91(m,2H),6.76(ddd,J=57.7,54.3,6.0Hz,1H),6.46(q,J=9.3Hz,1H),5.32(d t,J=14.2,5.5Hz,1H),3.99(dd,J=39.7,10.1Hz,2H),3.28(s,3H),2.88(d,J=20.3Hz,9H),1.68(dd,J=34.8,12.9Hz,2H),1.40(s,11H). MS(ESI)m / z 658.7(M+H) + .

[0532] Example 32C

[0533] N-((S)-1-(4-((7-((S)-2,2-difluoro-1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridine- 6-amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide

[0534] 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 stirred at ambient temperature for 30 minutes. After the raw material was completely consumed, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The water layer was extracted with dichloromethane (20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to obtain the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.53(s,1H),8.00(s,1H),7.20(d,J=8.4Hz,2H),7.03-6.94(m,2H),6.75(ddd,J=57.8,54.3,5.9Hz,1H), 6.44(q,J=9.3Hz,1H),5.31(dt,J=14.1,5.5Hz,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) + .

[0535] Example 32D

[0536] 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

[0537] 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) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.15 g, 0.40 mmol) in three portions over 10 minutes. The combined solution was stirred at ambient temperature for 1 hour. After complete consumption of the starting material, the crude material was directly purified by reverse phase chromatography (C18 HPLC, eluting with 20%-100% acetonitrile in water / 0.1% trifluoroacetic acid) to isolate the title compound. The pure fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to give the free base of the desired product. 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(600MHz,DMSO-d6)δppm 8.53(s,1H),7.99(s,1H),7.20(d,J=8.4Hz,2H),7.02-6.94(m,2H),6.75(ddd,J=57.8,54. 3,5.9Hz,1H),6.45(q,J=9.3Hz,1H),5.32(dt,J=14.1,5.5Hz,1H),4.49(t,J=5.4Hz,1H),4. 35(d,J=12.9Hz,1H),4.23-4.01(m,2H),3.70(d,J=13.8Hz,1H),3.28(s,3H),3.03(tq,J=11 .1,3.6Hz,1H),2.92(s,3H),2.86(s,3H),2.71(dt,J=24.0,13.0Hz,1H),1.84-1.32(m,5H). MS(ESI)m / z 616.0(M+H) + .

[0538] Embodiment 33

[0539] 1-Acetyl-N-{(1S)-1-[4-({7-[(1S)-2,2-difluoro-1-methoxyethyl]-2-methyl[1,3]thiophene oxazolo[5,4-b]pyridin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylpiperidine-4-carboxamide

[0540] 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 showed complete conversion. After complete consumption of the starting material, the crude material was directly purified by reverse phase chromatography (C18 HPLC, eluted with 20%-80% acetonitrile in water / 0.1% trifluoroacetic acid) to isolate the title compound. The pure fractions were combined and concentrated. The aqueous solution was partitioned with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate to give the free base of the desired product. 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(400MHz,DMSO-d6)δppm 8.53(s,1H),8.00(s,1H),7.20(d,J=8.3Hz,2H),7.07-6.94(m,2H),6.92-6.58(m, 1H),6.44(t,J=9.4Hz,1H),5.31(dt,J=13.8,5.6Hz,1H),4.37(d,J=13.1Hz,1H),3 .83(d,J=13.4Hz,1H),3.28(s,3H),3.05(dt,J=41.6,11.7Hz,1H),2.91(s,3H),2. 86(s,3H),2.61(q,J=19.1,16.6Hz,2H),1.99(d,J=1.8Hz,3H),1.87-1.22(m,4H). MS(ESI)m / z 600.5(M+H) + .

[0541] Embodiment 34

[0542] 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

[0543] Example 34A

[0544] 4-(Methyl((S)-2,2,2-trifluoro-1-(4-((7-((R)-1-methoxyethyl)-2-methylthiazolo[5,4- b] tert-butyl)pyridin-6-yl)amino)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate

[0545] Example 34A was prepared according to the method used to prepare Example 32B, substituting Example 8B for Example 3H to provide the title compound. 1HNMR(600MHz,DMSO-d6)δppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.09-6.99(m,2H),6.45(t,J=9.4Hz,1H),5.33(q,J=6.7Hz,1H),3. 95(s,2H),3.21(s,3H),2.87(d,J=43.2Hz,7H),1.68(dd,J=42.3,13.3Hz,2H),1.52(d,J=6.7Hz,3H),1.40(m,13H). MS(ESI)m / z622.4(M+H) + .

[0546] Example 34B

[0547] N-methyl-N-((S)-2,2,2-trifluoro-1-(4-((7-((R)-1-methoxyethyl)-2-methylthiazol[5, 4-b]pyridin-6-yl)amino)phenyl)ethyl)piperidine-4-carboxamide

[0548] Example 34B was prepared according to the method used to prepare Example 32C, substituting Example 34A for Example 32B to provide the title compound. 1 H NMR(600MHz,DMSO-d6)δppm 8.50(s,1H),7.72(s,1H),7.22(d,J=8.4Hz,2H),7.06-6.97(m,2H),6.45(q,J=9.3Hz,1H),5.33(q,J =6.7Hz,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=6.6Hz,3H). MS(ESI)m / z 522.4(M+H) + .

[0549] Example 34C

[0550] 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

[0551] Example 34C was prepared according to the method used to prepare Example 32D, substituting Example 34B for Example 32C to provide the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.50(s,1H),7.70(s,1H),7.21(d,J=8.3Hz,2H),7.09-7.03(m,2H),6.46(q,J =9.4Hz,1H),5.32(q,J=6.7Hz,1H),4.49(t,J=5.4Hz,1H),4.35(d,J=12.9Hz, 1H),4.17-3.99(m,2H),3.70(d,J=13.6Hz,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, 12.5Hz, 1H), 1.82-1.33 (m, 8H). MS (ESI) m / z 580.4 (M+H) + .

[0552] Embodiment 35

[0553] 1-acetyl-N-methyl-N-{(1S)-2,2,2-trifluoro-1-[4-({7-[(1R)-1-methoxyethyl]-2-methyl 4-thiazolo[5,4-b]pyridin-6-yl}amino)phenyl]ethyl}piperidine-4-carboxamide

[0554] Example 35 was prepared according to the method used to prepare Example 33, substituting Example 34B for Example 32C, to provide the title compound. 1 HNMR(500MHz,DMSO-d6)δppm8.51(s,1H),7.70(s,1H),7.21(d,J=8.2Hz,2H),7.10-7.02(m,2 H),6.46(q,J=9.4Hz,1H),5.33(q,J=6.7Hz,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=7.1Hz,1H),2.00(d,J=2.3Hz, 3H), 1.75 (t, J = 15.7Hz, 1H), 1.66 (d, J = 16.2Hz, 1H), 1.52 (d, J = 6.6Hz, 4H), 1.44-1.31 (m, 1H). MS(ESI)m / z 564.7(M+H) + .

[0555] Embodiment 36

[0556] 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

[0557] Example 36A

[0558] 4-(((S)-2,2-difluoro-1-(4-((2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolidine tert-Butyl (5,4-b)pyridin-6-yl)amino)phenyl)ethyl)(methyl)carbamoyl)piperidine-1-carboxylate

[0559] Using the conditions described in Example 28A, substituting Example 14A for Example 4C, the title compound (175.7 mg, 51%) was prepared. MS (APCI) m / z 640.4 (M+H) + .

[0560] Example 36B

[0561] N-((S)-2,2-difluoro-1-(4-((2-methyl-7-((R)-2,2,2-trifluoro-1-methoxyethyl)thiazolidine [5,4-b]pyridin-6-yl)amino)phenyl)ethyl)-N-methylpiperidine-4-carboxamide

[0562] Using the conditions described in Example 28B, substituting Example 36A for Example 28A, the title compound (149.9 mg, 100%) was prepared. MS (APCI) m / z 558.4 (M+H) + .

[0563] Example 36C

[0564] 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

[0565] Using the conditions described in Example 28C, substituting Example 36B for Example 28B, the title compound (58.6 mg, 71%) was prepared. 1 H NMR(400MHz,DMSO-d6)δppm 8.53(s,1H),7.37(s,1H),7.28(d,J=8.3Hz,2H),7.12(d,J=8.6Hz,2H),6.66(td,J=5 5.2,5.1Hz,1H),5.94(q,J=7.7Hz,1H),5.72(s,1H),4.36–3.70(m,5H),3.56(s,3H),k 2.85(s,3H),1.72(dd,J=13.0,6.8Hz,2H),1.55(d,J=12.9Hz,2H). MS(APCI)m / z 616.0(M+H) + .

[0566] Embodiment 37

[0567] 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

[0568] Using the conditions described in Example 29, substituting Example 36B for Example 28B, the title compound was prepared. 1HNMR(400MHz,DMSO-d6)δppm 8.53(s,1H),7.37(s,1H),7.28(d,J=8.4Hz,2H),7.12(d,J=8.6Hz,2H),6.66(td,J=55.1,5.1Hz,1H),5.94(q,J=7.7Hz,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) + .

[0569] Embodiment 38

[0570] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2R)-1,1,1-trifluoro [2-propan-1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0571] Example 38A

[0572] To a solution of ethyl 7-chloro-2-methylthiazolo[5,4-b]pyridine-6-carboxylate (50 g, 195 mmol) in 1,4-dioxolane (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 as is in the next step. LCMS (ESI) m / z 375 (M+H) + .

[0573] Example 38B

[0574] tert-Butyl (7-chloro-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0575] To a mixture of Example 38A (30 g, 131 mmol), triethylamine (54.9 mL, 394 mmol) in tert-butyl alcohol (600 mL) was added diphenylphosphoryl azide (43.3 g, 157 mmol) and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was then concentrated to remove the tert-butyl alcohol 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 Na2SO4, filtered and the filtrate concentrated. The residue was purified by flash column chromatography on silica gel (0%-100% ethyl acetate / petroleum ether) to give the title compound. 1H NMR (300MHz, DMSO-d6) δppm 1.48 (s, 9H), 2.87 (s, 3H), 8.62 (s, 1H), 9.21 (s, 1H). LCMS(ESI)m / z300(M+H) + .

[0576] Example 38C

[0577] tert-Butyl (7-iodo-2-methylthiazolo[5,4-b]pyridin-6-yl)carbamate

[0578] 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 reactant was stirred at 0 ° C for 3 hours. The reaction mixture was poured into a stirred, cooled (10 ° C) saturated sodium bicarbonate solution (500 mL). Then, 1 M sodium thiosulfate solution (100 mL) was added, the suspension was stirred for 5 minutes, then filtered, and washed with water (100 mL). The filtrate was collected, ground with ethyl acetate (500 mL) and filtered again. The residue was dried in a desiccator overnight to obtain the title compound. 1 H NMR (300MHz, DMSO-d6) δppm 1.48 (s, 9H), 2.86 (s, 3H), 8.32 (s, 1H), 9.00 (s, 1H). LCMS(ES)m / z 392(M+H) + .

[0579] Example 38D

[0580] tert-Butyl (2-methyl-7-(3,3,3-trifluoroprop-1-en-2-yl)thiazolo[5,4-b]pyridin-6-yl)carbamate ester

[0581] 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-dioxaborolane (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 at 110° C. for 90 minutes under microwave irradiation. The reaction mixture was cooled to ambient temperature and degassed again, and [bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (0.250 g) was added. The reaction mixture was stirred at 110° C. for 90 minutes under microwave irradiation. The reaction mixture was cooled to ambient temperature and partitioned between water (30 mL) and ethyl acetate (80 mL). The aqueous layer was adjusted to pH 7 by the addition of 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 silica gel chromatography (0%-40% ethyl acetate / 2-methylpentane) to give the title compound. MS (ESI) m / z 360.2 (M+H) + .

[0582] Example 38E

[0583] tert-Butyl (2-methyl-7-(1,1,1-trifluoropropan-2-yl)thiazolo[5,4-b]pyridin-6-yl)carbamate

[0584] 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 celite. The filtrate was concentrated in vacuo to give the title compound. MS (ESI) m / z 362.1 (M+H) + .

[0585] Example 38F

[0586] 2-Methyl-7-(1,1,1-trifluoropropan-2-yl)thiazolo[5,4-b]pyridin-6-amine

[0587] 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 solution (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 silica gel chromatography (0%-50% ethyl acetate / 2-methylpentane) to give the title compound. MS (ESI) m / z 262.1 (M+H)+ .

[0588] Example 38G

[0589] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2R)-1,1,1-trifluoro [2-propan-1,3]thiazolo[5,4-b]pyridin-6-yl]amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0590] and

[0591] Embodiment 39

[0592] N-methyl-1,1-dioxo-N-{(1S)-2,2,2-trifluoro-1-[4-({2-methyl-7-[(2S)-1,1,1-trifluoro [2-propan-2-yl] [1,3]thiazolo [5,4-b]pyridin-6-yl] amino)phenyl]ethyl]-1λ 6 -Thiazane-4-carboxamide

[0593] To a degassed mixture of Example 38F (65 mg), Example 1J (107 mg) and cesium carbonate (243 mg) in 1,4 dioxolane (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 celite, washed with dichloromethane (12 mL), and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0%-25% acetonitrile / dichloromethane) to give the title compound as a mixture of diastereoisomers. Use IG column (10mm x 250mm, 5 microns), eluted with 40% ethanol (0.1% ammonia) in CO2, at 40°C, 15mL / min, 120 bar, the diastereomeric mixture was separated by chiral SFC (supercritical fluid chromatography) to give the title compound as a single diastereoisomer. The absolute stereochemical structures of these title compounds are arbitrarily assigned. The fast eluting diastereomer corresponds to Example 38G, and the slow eluting diastereomer corresponds to Example 39. Example 38G: 1 H NMR(400MHz,DMSO-d6,90℃)δppm 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 / z609.4(M+H) + Example 39: 1HNMR(400MHz,DMSO-d6,90℃)δppm 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) + .

[0594] Comparative Example A

[0595] N-{(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]pyrazolo[1,5-a]pyrimidin-6-yl}amino) phenyl]-2,2,2-trifluoroethyl}-N-methyl-1,1-dioxo-1λ 6 -Thiazane-4-carboxamide

[0596] Comparative Example A was prepared according to the method used to prepare Example 1K, substituting (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-amine for Example 1J to obtain the title compound. (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-amine was obtained as described in WO2018226150, Intermediate I-2b, page 87. 1 H NMR(500MHz,DMSO-d6)δppm 8.55(s,1H),7.81(s,1H),7.20(d,J=8.4Hz,2H),6.98–6.90(m,3H),6.44(q,J=9.3Hz,1H),5. 29(q,J=6.7Hz,1H),3.30–3.07(m,7H),2.91(s,3H),2.15–1.96(m,5H),1.60(d,J=6.7Hz,3H). MS(ESI)m / z 574.1(M+H) + .

[0597] Comparative Example B

[0598] (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

[0599] Comparative Example B was prepared as described in WO2018020474, compound 142.

[0600] Biological assays

[0601] MALT-1 biochemical assay

[0602] The quenched fluorescence resonance energy transfer (Quench-FRET) enzyme assay was used to test the ability of the exemplary MALT-1 inhibitors Examples 1 to 39 to inhibit the MALT1-specific quenching of a fluorescent substrate of the human MALT-1 protein cleavage sequence [TAMRA-PEG2-Leu-Val-Ser-Arg-Gly-Ala-Ala-Ser-PEG2-K(QSY7)]; wherein TAMRA is 6-carboxytetramethylrhodamine, PEG2 is a 2-(2-(2-aminoethoxy)ethoxyamide linker, and QSY7 is a non-fluorescent quenching dye (Thermo-Fisher Catalog No. Q10193). Compounds were pre-dispensed into 384-well Proxiplates. TM (PE 6008289) was used to perform the assay. Human MALT-1 (6 nM) was prepared using assay buffer (25 mM HEPES pH 7.5, 1 mM EDTA, 0.8 M sodium citrate, 0.005% bovine serum albumin (BSA), 2 mM dithiothreitol (DTT)) and added to the compound plate. The plate was incubated at room temperature for 40 minutes. The reaction was performed by adding substrate (2 μM) to the plate and incubating at room temperature for 60 minutes. PE was then used to perform the assay. The reader (excitation 535 / emission 590) measures the fluorescence reading. The results of the enzyme assay are then provided in Table 2 and demonstrate the ability of the compounds of the present disclosure to inhibit MALT-1 protease activity. EC 50 It is defined as the half maximal effective concentration of the compound that inhibits MALT-1 protease activity.

[0603] Table 2.

[0604]

[0605]

[0606] IL-6 AlphaLISA assay for MALT-1 cells

[0607] The following MALT-1 cell interleukin-6 (IL-6) AlphaLISA assay was performed using Perkin IL-6 The IL-6 detection kit (PE AL223) was used. The IL-6 detection assay is a homogeneous immunoassay that detects human IL-6 present in the cell culture medium of the MALT-1-dependent human ABC-DLBCL cell line OCI-LY3. The compounds were pre-dispensed into Black384w microtiter plates (Greiner, 781090) at 30 μM to 1.5 nM. The surviving OCI-LY3 cells were then seeded on the compounds at a seeding density of 50,000 cells / mL. The plates were then placed in a 37°C incubator for 48 hours. After 48 hours of incubation, 2 μL of cell culture medium per well was transferred to white ProxiPlates TM (PE 6008289). Prepare a fresh mixture of AlphaLISA acceptor beads (10 μg / mL) and biotinylated IL-6 antibody (1 nM) in AlphaLISA immunoassay buffer and add to all wells (4 μL). Incubate the plate at room temperature for 60 minutes. Prepare streptavidin donor beads (40 μg / mL) using assay buffer and add to all wells (5 μL). Incubate the plate at room temperature for 30 minutes and use PE The results are shown in Table 3.

[0608] Table 3.

[0609]

[0610]

[0611] Cardiovascular testing

[0612] The following cardiovascular measurements were performed using male Sprague-Dawley rats, which were anesthetized with Inactin (thiobutyral barbital), instrumented (femoral artery and vein were catheterized; left ventricle was catheterized) and stabilized. After a 30-minute baseline period, each compound was infused at low, medium and high doses / 30 minutes. Plasma samples were collected at the end of each dose infusion. At any time, if the mean arterial pressure (MAP) of the animal dropped below 70 mmHg, the infusion was immediately stopped, a final blood sample was collected, and the hemodynamic data of the animal was removed from the group mean of all subsequent time points. A 15% change in MAP or heart rate (HR) relative to the vehicle was considered biologically relevant. A 20% change in dP / dt@50 relative to the vehicle was considered biologically relevant. The results are shown in Table 4.

[0613] Table 4.

[0614]

[0615] CYP3A4 induction assay

[0616] The CYP induction of the example compounds was evaluated in vitro by measuring the expression level of CYP 3A4 mRNA using a qPCR (quantitative polymerase chain reaction) assay. On day 1, cryopreserved human hepatocytes were thawed in pre-warmed (37°C) thawing medium (Cryopreserved Hepatocyte Recovery Medium, Gibco TM CM 7000; Thermo Fisher Scientific), centrifuged (1000 g, 10 min) and resuspended in plating medium (Gibco TM CM3000 (Williams Medium E supplemented with hepatocyte plate supplement pak-serum; Thermo Fisher Scientific). Cells were counted by trypan blue exclusion using a hemacytometer and adjusted to 1.2 × 10 6 The cell density was 100 cells / μL. Thereafter, 0.05 μL of the cell suspension was aliquoted into each well of a 96-well plate, resulting in 60,000 cells / well. During plating, the plate was shaken in the north-south and east-west directions. The plated cells were incubated at 37°C / 5% CO2 in a humidified cell culture incubator for 4 to 6 hours. During this time, the incubation medium (Gibco TM CM4000, Cell Maintenance Supplement Pack; Thermo Fisher Scientific) and Gibco TM Geltrex TM (Thermo Fischer Scientific) with appropriate Geltrex TM Protein concentrations were mixed. After recovery, 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).

[0617] On the second day, incubation medium was prepared by combining the hepatocyte maintenance supplement package with Williams Medium E. The medium was warmed to 37°C. 1000x dimethyl sulfoxide compound stock solutions of the example compounds were prepared to the desired concentration. 10mM compound stock solutions were diluted in dimethyl sulfoxide (1 μL to 1mL CM4000; final concentration = 10 μM). The covering medium was aspirated and a 0.1 μL dose of the solution was added to the desired labeled 96-well plate. The cells were then dosed with the compound (10 μM), and the prototype induced target concentration was 50 μM omeprazole (Sigma 0104 / lotBCBF-2161V) or 10 μM rifampicin (Sigma R3501 / lot 011M1159V). Negative control probenecid was administered at 10 μM (Sigma P8761 / lot 013K0148).

[0618] On day 3, RNA isolation was performed. All surfaces were cleaned using RNase RNAy. Total RNA was isolated using the MagMAX Express96 RNA Isolation System (Life Technologies, AM1830). Briefly, the 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 by pipetting several times. The lysate was then transferred to the wells of a 96-well binding plate. The sample was then mixed with 20 μL of magnetic beads from the kit. The RNA bound to the beads was then captured by a magnetic tip manifold, and the beads were washed with a wash solution. The sample was washed with TURBO TM DNase treatment. TM After DNase treatment, RNA was rebound onto the beads and washed twice more 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 into an RNase-free sealable microtiter plate and stored at -80°C until use.

[0619] After mRNA isolation, Taqman TMReverse transcription (RT) reactions were performed using the Reverse Transcription Reagent (ThermoFisher Scientific). RT master mix was prepared by mixing 2.5 μL 10X RT buffer, 5.5 μL 25 mM MgCl2, 5 μL deoxyNTP mix, 1.25 μL 50 mM random hexamers, 0.5 μL 2X RNase inhibitor, 0.625 μL multi-instruction RTase (50 U / μL), and 0.625 μL water. Aliquots of RT mix (16 μL) and aliquots of mRNA sample (9 μL) were added to each well of a 96-well plate. The mRNA was expressed in 4% paraformaldehyde (60% paraformaldehyde) and 1% paraformaldehyde (60% paraformaldehyde). The mRNA was expressed in 2% paraformaldehyde (60% paraformaldehyde) and 1% paraformaldehyde (60% paraformaldehyde). The mRNA was expressed in 2% paraformaldehyde (60% paraformaldehyde) and 1% paraformaldehyde (60% paraformaldehyde). The mRNA was expressed in 2% paraformaldehyde (60% paraformaldehyde) and 1% paraformaldehyde (60% paraformaldehyde). TM Reverse transcription was performed using the Thermal Cycler PCR System VIIA7 under the following conditions: fragment 1: 25°C for 10 minutes; fragment 2: 45°C for 45 minutes; fragment 3: 95°C for 5 minutes; fragment 4: maintained at 4°C; wherein each fragment had 1 cycle.

[0620] Thereafter, TaqMan TM qPCR. TaqMan TM Rapid Advanced Master Mix and gene expression assay primers (HS00604506_m1 (ThermoFisher) for CYP3A4 and HS02758991_g1 (ThermoFisher) for hGAPDH as a control, glyceraldehyde-3-phosphate dehydrogenase) were purchased from Applied Biosystems. The PCR reaction mixture included diluted cDNA (2 μL) and 18 μL of TaqMan TM qPCR master mix (10 μL TaqMan TM Rapid Advanced Master Mix, 1 μL of Gene Expression Primer Probe Mix, 7 μL of nuclease-free water). qPCR thermal cycling conditions: Segment 1: 50 °C for 10 min; Segment 2: 95 °C for 3 min; followed by 40 cycles of the following: Segment 3: 95 °C for 15 s, Segment 4: 60 °C for 1 min.

[0621] Comparative quantitative real-time polymerase chain reaction (qPCR) was used to determine the induction fold in CYP isoform mRNA caused by compound treatment. The method calculated the CYP fold induction relative to vehicle (0.1% DMSO) and used as the percentage of the response of the positive control rifampicin. Induction fold = fold of treatment / fold of vehicle control. Percentage of positive control = (fold of treatment - 1) / (fold of rifampicin - 1).

[0622] Table 5.

[0623]

[0624]

[0625] It should be understood that the foregoing specific embodiments and the accompanying examples are merely illustrative and should not be regarded as limiting the scope of the present disclosure, which is limited only 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 may be made without departing from the spirit and scope of the present invention. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: R 1a Selected from OCH3 and CH3; R 1b Selected from CH3, CHF2 and CF3; R 2 Selected from H and F; R 3 Selected from H and F; R 4 Selected from CHF2 and CF3; R 5 is a C1-C4 alkyl group; Ring A is a ring selected from the following: R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from H and C1-C4 alkyl; and R 8 Selected from CHF2 and CH3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 For H.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a It is OCH3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1b is CHF2.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is CF3.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is methyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1a It is OCH3.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1b is CHF2.

12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 6 It is a C1-C4 alkyl group.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 For CH3.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For H, R 3 is H, and R 4 It is CF3.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a For OCH3, R 1b For CHF2, R 2 For H, R 3 For H, R 4 is CF3, and R 5 It is methyl.

16. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is CF3, and R 5 It is methyl.

17. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 For H, R 3 For H, R 4 is CF3, and R 5 It is methyl.

18. The compound according to claim 1, wherein the compound is selected from: 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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-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 -thiazane-4-carboxamide; or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein 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 -thiazane-4-carboxamide; or or pharmaceutically acceptable salts thereof.

20. The compound according to claim 1, wherein 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 -thiazane-4-carboxamide.

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

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

23. A method for synthesizing a compound of formula (3A) according to claim 1, said method comprising reacting a compound of formula (1G) in a solvent in the presence of a base and a catalyst. and a compound of formula (2G) Reaction to form a compound of formula (3A) in: R 1a Selected from OCH3 and CH3; R 1b Selected from CH3, CHF2 and CF3; R 2 Selected from H and F; R 3 Selected from H and F; R 4 Selected from CHF2 and CF3; R 5 is a C1-C4 alkyl group; Ring A is a ring selected from the following: R 6 Selected from C1-C4 alkyl and C1-C4 hydroxyalkyl; R 7 is selected from H and C1-C4 alkyl; and R 8 Selected from CHF2 and CH3.

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

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

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

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

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