N-Acryloylmorpholine Derivatives as KEAP1 Modulators and Uses Thereof

Abstract

Compounds and methods for inhibiting Nif2 by activating KEAP1.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of the earlier filing dates of U.S. Provisional Patent Application No. 63 / 377,589, filed September 29, 2022, and U.S. Provisional Patent Application No. 63 / 519,541, filed August 14, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Sequence Listing Statement The Sequence Listing, having the title "BHC234005_WO_SeqListing_ST26.xml," was created on August 23, 2023, has a file size of 3 kilobytes, and is incorporated herein by reference in its entirety. The Sequence Listing is hereby submitted.

[0003] Field of Disclosure The present disclosure relates to compounds and methods for modulating Nrf2 by modulating KEAP1 or mediating the activation of KEAP1. [Background technology]

[0004] Disclosure process Diseases such as neurodegenerative diseases and cancer are widespread, and improved therapies are needed to treat these diseases. Summary of the Invention [Means for solving the problem]

[0005] overview In some embodiments, the present specification discloses modulators of Kelch-like ECH-associated protein 1 (KEAP1). Some such embodiments relate to KEAP1 agonists. KEAP1 agonists can include compounds described herein. KEAP1 agonists can be useful in the methods described herein.

[0006] Disclosed herein in some embodiments are compounds that inhibit nuclear factor erythroid 2-related factor 2 (Nrf2). Inhibition of Nrf2 can be indirect. For example, some embodiments relate to KEAP1 agonists that indirectly inhibit Nrf2. Some such embodiments can include an Nrf2 inhibitor. The Nrf2 inhibitor can include a compound described herein. The Nrf2 inhibitor can be useful in the methods described herein. Inhibition of Nrf2 can include Nrf2 degradation. For example, the Nrf2 inhibitor can mediate its degradation. DETAILED DESCRIPTION OF THE INVENTION

[0007] In one embodiment, a compound of formula (I): [ka] [during the ceremony; R A teeth, [ka] where: R 6a is H, D, halogen, or C1-C6 haloalkyl, and R 6b and R 6c are each independently H or D; Ring A is aryl, heteroaryl, or heterocyclyl; Z is O, S(=O)2, C(R 1 )2, or NR 7 and; R 7 is -C(=O)R 7a , S(=O)R 7a , or S(=O)2R 7a where R 7a is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; Each R 1are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2 or or two R's 1 together with the atom(s) to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl; X 1 is N or CR 2 and; Each R 2 are independently H, halogen, CN, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 4 is H or optionally substituted C1-C6 alkyl; or R 2 and R 4 together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; Each R 3 are independently H, D, halogen, oxo (=O), thio (=S), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; Each R a is independently C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C-C alkyl(aryl), —C-C alkyl(heteroaryl), —C-C alkyl(cycloalkyl), or —C-C alkyl(heterocycloalkyl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl; and Each R b are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with 1, 2, or 3 -OH, C1-C6 alkyl, or C1-C6 haloalkyl; or two R on the nitrogen atom b groups, together with the nitrogen atom to which they are attached, form a heterocycloalkyl optionally substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is an integer from 1 to 12; and q is an integer from 1 to 10. Described herein are compounds having the structure: or a pharmaceutically acceptable salt or solvate thereof.

[0008] In some embodiments, the compound of formula (I) has formula (II): [ka] [During the ceremony, Z is O, S(=O)2, CR 1d R 1e , or NR 7 and; R 1a , R 1b , R 1c , R 1d , and R 1e are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2; or R 1a and R 1b together with the atom to which they are attached form an optionally substituted C3-C8 cycloalkyl; or R 1b and R 1c together with the carbon atoms to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R 1d and R 1e together with the carbon atoms to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; R 2a is H, halogen, CN, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and R 4is H or optionally substituted C1-C6 alkyl; or R 2a and R 4 together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0009] In some embodiments, ring A is: [ka] [During the ceremony, X 2 , X 3 , X 4 , and X 5 are each independently N, NR 3a , or CR 3 and; Each R 3a are independently H or optionally substituted C1-C6 alkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 Or two R's 3a Or R 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; is.

[0010] In some embodiments, the compound of formula (I) has formula (III): [ka] [During the ceremony, X 2 , X 3 , and X 4 are each independently N, NR 3a , or CR 3 and; Each R 3a are independently H or optionally substituted C1-C6 alkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR bC(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 Or two R's 3a Or R 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, the compound of Formula (I) has the formula (IIIa): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the compound of formula (I) has formula (IV): [ka] [During the ceremony, X 2 is N or CR 3 and; X 4 is N or C; and Ring B is an optionally substituted 5-6 membered heteroaryl; or Ring C is an optionally substituted 5- to 6-membered heteroaryl. or a pharmaceutically acceptable salt or solvate thereof.

[0013] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0014] In another aspect, provided herein is a method for inhibiting Nrf2 by mediating activation of KEAP1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0015] In another aspect, provided herein is a method for treating a disease mediated by activation of KEAP1 and inhibition of Nrf2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, the disease is associated with oxidative stress. In some embodiments, the disease is cancer.

[0017] In another aspect, the present disclosure provides a compound disclosed herein for use as a pharmaceutical.

[0018] In another aspect, the present disclosure provides a compound disclosed herein for use in treating a disease mediated by activation of KEAP1 and inhibition of Nrf2.

[0019] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament useful for treating diseases mediated by the activation of KEAP1 and the inhibition of Nrf2. Further aspects and advantages of the present disclosure will be readily apparent to those skilled in the art from the following detailed description, in which only exemplary embodiments of the present disclosure are shown and described. As will be understood, the present disclosure is capable of other and different embodiments, and its several details can be modified in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not restrictive.

[0020] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material.

[0021] Detailed Description Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that may play a central role in cytoprotection against electrophilic and oxidative stress. Nrf2 can upregulate the expression of a series of cytoprotective enzymes that have antioxidant response elements in their promoter regions, thus protecting cells from oxidative damage or influencing oxidative cell signaling.

[0022] In some cases, Nrf2 is continuously synthesized under normal conditions but is degraded due to its interaction with Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 may be involved as a substrate adaptor protein in an E3 ubiquitin ligase complex with RBX1 and Cul3. In some cases, the E3 ubiquitin ligase continuously degrades Nrf2. KEAP1 acts as a fast-acting thiol sensor for electrophiles and oxidants.

[0023] Under certain conditions, such as oxidative stress or oxidative signaling, cysteine ​​151 of KEAP1 (and possibly other KEAP1 cysteines) can be oxidized, destabilizing the E3 ubiquitin ligase complex. Nrf2 accumulates and translocates to the nucleus, where it binds to ARE elements and initiates the transcription of genes responsive to oxidative stress. Some compounds that bind to cysteine ​​151 may be useful in modulating this pathway.

[0024] Reducing Nrf2 activity (e.g., when Nrf2 is upregulated or activated without being degraded) may be useful as a therapeutic intervention in the chemoprevention of a range of chronic neurodegenerative conditions and cancer. One mechanism by which Nrf2 may be negatively regulated involves its interaction with Kelch-like ECH-associated protein 1 (KEAP1), a ubiquitination-promoting protein that promotes Nrf2 degradation. Inhibition of this process may underlie the mechanism of action of a wide range of compounds that increase Nrf2 activity. Many natural products, including the isothiocyanate sulforaphane, upregulate Nrf2 by covalently interacting with KEAP1 and stalling its activity.

[0025] The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) upregulates the expression of a series of cytoprotective enzymes that have antioxidant response elements in their promoter regions, thereby protecting cells from oxidative damage. Increasing Nrf2 activity may be useful as a therapeutic intervention in the chemoprevention of various chronic neurodegenerative conditions and cancer. One mechanism by which Nrf2 is negatively regulated involves its interaction with Kelch-like ECH-associated protein 1 (KEAP1), a ubiquitination-promoting protein that promotes Nrf2 degradation. Inhibition of this process underlies the mechanism of action of a wide range of compounds that increase Nrf2 activity. Many natural products, including the isothiocyanate sulforaphane, upregulate Nrf2 by covalently interacting with KEAP1 and stalling its activity. Agents that reduce Nrf2 levels in cells may render them more susceptible to oxidative stress. In some embodiments, the compounds described herein enhance oxidative stress, such as in cancer cells or damaged cells, such as those affected by neurodegenerative diseases. This can lead to cell destruction.

[0026] Disclosed herein are compounds and methods for inhibiting Nrf2 by mediating the activation of KEAP1. Some embodiments relate to compounds or methods for inhibiting Nrf2. The inhibition of Nrf2 can be in vitro or in vivo. The inhibition of Nrf2 can include contacting KEAP1 protein with a compound disclosed herein. The inhibition of Nrf2 can increase antioxidants or improve antioxidant capacity in a subject or cell. The compound for inhibiting Nrf2 can be formulated for administration to a subject. The inhibition of Nrf2 can be performed in a subject.

[0027] Details and examples of several Nrf2 proteins can be found at www.uniprot.org under accession number Q16236 (at the priority date of this application). The Nrf2 protein may comprise a peptide of about 705 amino acids in length, or may comprise a mass of about 68 kD.

[0028] Some embodiments relate to compounds or methods for activating KEAP1. Activation of KEAP1 can be in vitro or in vivo. Activation of KEAP1 can include contacting KEAP1 with a compound disclosed herein. Activation of KEAP1 can increase antioxidants or improve antioxidant capacity in a subject or cell. Compounds for activating KEAP1 can be formulated for administration to a subject. Activation of AP1 can be performed in a subject. Details and examples of several KEAP1 proteins can be found at www.uniprot.org under accession number Q14145 (as of the priority date of this application). KEAP1 can comprise a peptide of approximately 624 amino acids in length or a mass of approximately 70 kD.

[0029] The compounds disclosed herein can be useful for treating diseases in which Nrf2 activity is a concern, such as neurodegenerative diseases or cancer.In some cases, the compounds are useful in diseases where reductive stress exists or when oxidative signaling is reduced.In some embodiments, the compounds are used to treat neurodegenerative diseases.In some embodiments, the compounds are used to treat cancer.The compounds can be useful for treating disorders related to oxidative stress or for reducing oxidative stress or damage.

[0030] Compounds of the Disclosure Disclosed herein, in some embodiments, are modulators of Kelch-like ECH-associated protein 1 (KEAP1). Some such aspects relate to KEAP1 agonists. In some embodiments, the KEAP1 agonist inhibits nuclear factor erythroid 2-related factor 2 (Nrf2). Some embodiments relate to Nrf2 modulators, such as inhibitors of Nrf2. Inhibition of Nrf2 may be indirect, such as by activation of KEAP1. Inhibition of Nrf2 may include degradation of Nrf2. Compounds, including KEAP1 agonists, may stabilize E3 ubiquitin ligases, including KEAP1, and increase or result in degradation of Nrf2.

[0031] In one embodiment, a compound of formula (I): [ka] [during the ceremony; R A teeth, [ka] where: R 6a is H, D, halogen, or C1-C6 haloalkyl, and R 6b and R 6c are each independently H or D; Ring A is aryl, heteroaryl, or heterocyclyl; Z is O, S(=O)2, C(R 1 )2, or NR 7 and; R 7 is -C(=O)R 7a , S(=O)R 7a , or S(=O)2R 7a where R 7a is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; Each R 1 are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2, or two R's 1 together with the atom(s) to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl; X 1 is N or CR 2 and; Each R 2are independently H, halogen, CN, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 4 is H or optionally substituted C1-C6 alkyl; or R 2 and R 4 together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; Each R 3 are independently H, D, halogen, oxo (=O), thio (=S), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; Each R ais independently C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C-C alkyl(aryl), —C-C alkyl(heteroaryl), —C-C alkyl(cycloalkyl), or —C-C alkyl(heterocycloalkyl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl; and Each R b are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with 1, 2, or 3 -OH, C1-C6 alkyl, or C1-C6; or two R on the nitrogen atom b groups, together with the nitrogen atom to which they are attached, form a heterocycloalkyl optionally substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is an integer from 1 to 12, and q is an integer from 1 to 10. Provided herein are compounds having the structure: or a pharmaceutically acceptable salt or solvate thereof.

[0032] In one embodiment, a compound of formula (I): [ka] [During the ceremony, R A teeth, [ka] where: R 6a is H, D, or chloro, and R 6b and R 6c are independently H or D; Ring A is imidazolyl, isoxazolyl, oxazolyl, phenyl, pyridinyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, triazinyl, purinyl, or pyrrolo[3,2-c]pyridinyl; Z is O, S(=O)2, C(R 1 )2, or NR 7 where: R 7 is -C(=O)R 7a where R 7a is C1-C3-alkyl or C3-C7 cycloalkyl; Each R 1 are independently H, —OH, fluoro, C1-C3-alkyl, or C1-C3-haloalkyl; or two R's 1 together with the atom(s) to which they are attached form a C3-C8 cycloalkyl; X 1 is N or CH; R 2 is chloro; R 4 is H or methyl; Each R 3 are independently H, halogen, C1-C3-alkyl, C1-C3-alkoxy, thio(=S), amino, C1-C3-alkylamino, di-C1-C3-alkylamino, -C(=O)NH2 or N,N-di-C1-C2-alkylamino-C2-C3-alkyl; m is 1; n is 1 or 2; p is 6 or 8; and q is 2, 3, 4, or 5. Provided herein are compounds having the structure: or a pharmaceutically acceptable salt or solvate thereof.

[0033] In some embodiments, the compound of formula (I) has formula (II): [ka] [During the ceremony, Z is O, S(=O)2, CR 1d R 1e , or NR 7 and; R 1a , R 1b , R 1c , R 1d , and R 1e are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2; or R 1a and R 1b together with the atom to which they are attached form an optionally substituted C3-C8 cycloalkyl; or R 1b and R 1c together with the carbon atoms to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R 1d and R 1e together with the carbon atoms to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; R 2a is H, halogen, CN, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; and R 4 is H or optionally substituted C1-C6 alkyl; or R 2a and R 4together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0034] In some embodiments, R 1a and R 1b taken together with the atom to which they are attached form an optionally substituted C-C cycloalkyl. In some embodiments, R 1a and R 1b together with the atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1a and R 1b together with the atom to which they are attached form a cyclopropyl. 1a and R 1b together with the atom to which they are attached form a cyclobutyl. 1a and R 1b together with the atom to which they are attached form cyclopentyl.

[0035] In some embodiments, R 1b and R 1c taken together with the carbon atom to which they are attached form an optionally substituted C-C cycloalkyl. In some embodiments, R 1b and R 1c together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl. 1b and R 1c together with the carbon atom to which they are attached form a cyclopropyl. 1b and R 1c together with the carbon atom to which they are attached form a cyclobutyl.1b and R 1c together with the carbon atom to which they are attached to form cyclopentyl.

[0036] In some embodiments, R 1d and R 1e taken together with the carbon atom to which they are attached form an optionally substituted C-C cycloalkyl. In some embodiments, R 1d and R 1e together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl. 1d and R 1e together with the carbon atom to which they are attached form a cyclopropyl. 1d and R 1e together with the carbon atom to which they are attached form a cyclobutyl. 1d and R 1e together with the carbon atom to which they are attached to form cyclopentyl.

[0037] In some embodiments, R 1d and R 1e taken together with the carbon atom to which they are attached form an optionally substituted 3-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, R 1d and R 1e together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O. In some embodiments, R 1d and R 1e taken together with the carbon atom to which they are attached form an optionally substituted 4-membered heterocycloalkyl. In some embodiments, R 1d and R 1etaken together with the carbon atom to which they are attached form an optionally substituted 5-membered heterocycloalkyl. In some embodiments, R 1d and R 1e taken together with the carbon atom to which they are attached form an optionally substituted 6-membered heterocycloalkyl.

[0038] In some embodiments, R 1a is H;R 1b and R 1c are each independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2. In some embodiments, R 1b and R 1c are each independently H or optionally substituted C1-C6. In some embodiments, R 1b and R 1c are each independently methyl or ethyl. In some embodiments, R 1b and R 1c Each is methyl. In some embodiments, R 1b and R 1c are H respectively.

[0039] In some embodiments, R 1a is halogen, —OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or —C(═O)N(R b )2; and R 1b and R 1c are each H. In some embodiments, R 1a is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl. 1ais an optionally substituted C1-C6. In some embodiments, R 1a is isopropyl, ethyl, or methyl. In some embodiments, R 1a is methyl. In some embodiments, R 1a is an optionally substituted C1-C6 haloalkyl. In some embodiments, R 1a is CHF2 or CF3. In some embodiments, R 1a is -C(=O)N(R b )2. In some embodiments, R 1a is -C(=O)N(CH3)2, -C(=O)NHCH3, or -C(=O)NH2.

[0040] In some embodiments, Z is CR 1d R 1e and;R 1d and R 1e are each independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2. In some embodiments, R 1d and R 1e are each independently H, halogen, —OH, or optionally substituted C1-C6. 1d and R 1e are each independently a halogen. 1d and R 1e are each independently Cl or F. In some embodiments, R 1d and R 1e are H, respectively.

[0041] In some embodiments, R 2a and R 4taken together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl, where the heteroatom is selected from N or O. In some embodiments, the heteroatom is O. In some embodiments, R 2a and R 4 taken together with the atoms to which they are attached form a 5-membered heteroalkyl. In some embodiments, R 2a and R 4 together with the atom to which they are attached form a 6-membered heterocycloalkyl. In some embodiments, R 2a and R 4 together with the atom to which they are attached form a 7-membered heterocycloalkyl.

[0042] In some embodiments, R 2a is H, halogen, CN, or OH. In some embodiments, R 2a is halogen. In some embodiments, R 2a is H.

[0043] In some embodiments, rings A and R 2 In some embodiments, rings A and R 2 In some embodiments, rings A and R 2 is in the 1,4,5 configuration.

[0044] In some embodiments, ring A is C 6-10 It is aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycloalkyl.

[0045] In some embodiments, ring A is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N. In some embodiments, ring A is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyridinyl or pyrazinyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl.

[0046] In some embodiments, ring A is: [ka] [During the ceremony, X 2 , X 3 , X 4 , and X 5 are independently N, NR 3a , or CR 3 and; Each R 3a are independently H or optionally substituted C1-C6 alkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 Or two R's 3a Or R 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; is.

[0047] All other substituents are as defined above.

[0048] In some embodiments, the compound has the formula (III): [ka] [During the ceremony, X 2 , X 3 , X 4 , and X 5 are independently N, NR 3a , or CR 3 and; Each R 3a are independently H or optionally substituted C1-C6 alkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(Rb )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms 3 Or two R's 3a Or R 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0049] All other substituents are as defined above.

[0050] In some embodiments, the compound has the formula (III): [ka] [During the ceremony, R A teeth, [ka] and where: R 6a is H, D, halogen, R 6b and R 6c are each independently H or D; Z is O, S(=O)2, C(R 1 )2, or NR 7 where: R 7 is -C(=O)R7a where R 7a is an optionally substituted C3-C5 cycloalkyl; Each R 1 are independently H, —OH, fluorine, C1-C3-alkyl or C1-C3-fluoroalkyl, or two R's 1 together with the carbon atom(s) to which they are attached form a C3-C4-cycloalkyl, X 1 is N or CH; R 2 is chloro; Each R 3 are independently H, D, chloro, fluoro, -O-C1-C4 alkyl, -NH2, -NHC1-C4 alkyl, -NH-C 2-3 -alkyl-N(CH3)2, -C(=O)N(H)2, or optionally substituted C1-C4 alkyl; or two R on adjacent atoms 3 together with the atom(s) to which they are attached form an optionally substituted pyrrolyl or imidazolyl ring; R 4 is H or methyl; X 2 , X 3 , X 4 and X 5 are each independently N or CR 3 and; m is 1; n is 1 or 2; p is 6 or 8; q is an integer of 2 to 5. or a pharmaceutically acceptable salt or solvate thereof.

[0051] In some embodiments, the compound has the formula (IIIx): [ka] [During the ceremony, R Ateeth, [ka] and where: R 6a , R 6b and R 6c are each independently H; Z is O; Each R 1 are independently H or methyl, provided that no more than two R 1 is methyl; X 1 is CH; R 2 is chlorine; Each R 3 are independently H, D, -O-CH3, -NH2, -NH-CH3, or methyl; R 4 is H; X 2 , X 3 , X 4 and X 5 are each independently N or CR 3 and; where X 2 , X 3 , X 4 and X 5 At least one, but not more than three, of is N; m is 1; n is 1; p is 6; q is an integer of 2 to 4. or a pharmaceutically acceptable salt or solvate thereof.

[0052] In some embodiments, the compound has the formula (IIIa): [ka] [During the ceremony, R A teeth, [ka] where: R 6a is H, D, or chloro, and R 6b and R 6c are independently H or D; Z is O, S(=O)2, CR 1d R 1e , or NR 7 where: R 7 is -C(=O)R 7a where R 7a is C3-C5 cycloalkyl; Each R 1a are independently H, C1-C4 alkyl, or C1-C4 haloalkyl; Each R 1b are independently H or C1-C4 alkyl; Each R 1c are independently H or C1-C4 alkyl; Or, R 1b and R 1c together with the atoms to which they are attached form a C3-C5 cycloalkyl; Each R 1d and R 1e is independently H, fluoro, hydroxy, or methyl; X 1 is N or CH; R 2 is a halogen; R 4 is H or C1-C4 alkyl; X 2 , X 3 , X 4 , and X 5 are each independently N or CR 3 and; Each R 3 are independently H, D, halogen, -OR a , -N(R b )2, —C(═O)NH2, or C1-C4 alkyl; Or, two R on adjacent atoms 3 together with the atom(s) to which they are attached form an optionally substituted heteroaryl ring; Each R a are independently C1-C4 alkyl; Each R b are independently H, C1-C4 alkyl, where alkyl is optionally substituted independently with 1, 2, or 3 -OH, C1-C4 alkyl, C1-C4 haloalkyl, or -C1-C4 alkyl-N(methyl)2; m is 1 or 2; n is 1 or 2; p is 6 or 8; and q is an integer from 1 to 10. or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, X 2 is N. In some embodiments, X 2 is NR 3a In some embodiments, X 2 is CR 3 In some embodiments, X 3 is N. In some embodiments, X 3 is NR 3a In some embodiments, X 3 is CR 3 In some embodiments, X 4 is N. In some embodiments, X 4 is NR 3a In some embodiments, X 4 is CR 3 In some embodiments, X 5 is N. In some embodiments, X 5 is NR 3a In some embodiments, X 5 is CR 3 is.

[0054] In some embodiments, X 2 is N and X 3 , X 4 and X 5 are CR 3 In some embodiments, X 3 is N and X 2 , X 4 and X 5 are CR 3 In some embodiments, X 4 is N and X 2 , X 3 and X 5 are CR 3 In some embodiments, X 5 is N and X 2 , X 3 and X 5 are CR 3 is.

[0055] In some embodiments, X 2 and X 3 are N and X respectively. 4 and X 5 are CR 3 In some embodiments, X 2 and X 5 is N and X 3 and X 4 are CR 3 In some embodiments, X 4 and X 5 is N and X 2 and X 3 are CR 3 In some embodiments, X 3 and X 4 is N and X 2 and X 5 are CR 3 In some embodiments, X 2 , X 3 and X 4 are N and X respectively.5 is CR 3 is.

[0056] All other substituents are as defined above.

[0057] In some embodiments, the compound of Formula (III) has the formula (IIIb): [ka] [During the ceremony, X 2 , X 3 , and X 4 are independently N, NR 3a , or CR 3 and; Each R 3a are independently H or optionally substituted C1-C6 alkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2NH2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0058] In some embodiments, X 2 and X 3 are each independently N, and X 4 is CR 3 In some embodiments, X 2 and X 4 are each independently N, and X 3 is CR 3 In some embodiments, X 4 is N and X 2 and X 3 are CR 3 In some embodiments, X 2 , X 3 , and X 4 are N, respectively.

[0059] In some embodiments, ring A is a bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is a bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N.

[0060] In some embodiments, ring A is quinoxaline, naphthyridine, imidazopyridine, imidazopyrimidine, pyrrolopyridine, triazolopyridine, or purine. In some embodiments, ring A is quinoxaline or naphthyridine. In some embodiments, ring A is imidazopyridine, imidazopyrimidine, pyrrolopyridine, triazolopyridine, or purine.

[0061] All other substituents are as defined above.

[0062] In some embodiments, the compound has formula (IV): [ka] [During the ceremony, X 2 is N or CR 3 and; X 4 is N or C; and Ring B is an optionally substituted 5-6 membered heteroaryl; or Ring C is an optionally substituted 5- to 6-membered heteroaryl. or a pharmaceutically acceptable salt or solvate thereof.

[0063] All other substituents are as defined above.

[0064] In some embodiments, the compound has the formula (IVa): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0065] In some embodiments, ring B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, ring B is pyridinyl, pyrazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, or thiophenyl. In some embodiments, ring B is pyridinyl or pyrazinyl. In some embodiments, ring B is pyrrolyl, imidazolyl, or pyrazolyl.

[0066] In some embodiments, ring C is an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, ring C is pyridinyl, pyrazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, or thiophenyl. In some embodiments, ring C is pyridinyl or pyrazinyl. In some embodiments, ring C is pyrrolyl, imidazolyl, or pyrazolyl.

[0067] In some embodiments, ring A is a 5-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N or O.

[0068] In some embodiments, ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring A is triazinyl, pyrrolyl, imidazolyl, pyrazolyl, or tetrazolyl. In some embodiments, ring A is toridinyl. In some embodiments, ring A is pyrrolyl. In some embodiments, ring A is imidazolyl. In some embodiments, ring A is pyrazolyl.

[0069] In some embodiments, ring A is: [ka] is.

[0070] In some embodiments, ring A is: [ka] is.

[0071] In some embodiments, ring A is: [ka] is.

[0072] In some embodiments, ring A is: [ka] is.

[0073] In some embodiments, ring A is: [ka] is.

[0074] In some embodiments, ring A is: [ka] is.

[0075] In some embodiments, ring A is: [ka] is.

[0076] In some embodiments, ring A is: [ka] is.

[0077] In some embodiments, ring A is heterocycloalkyl. In some embodiments, heterocycloalkyl is monocyclic, bicyclic, or polycyclic and can be fully or partially saturated. In some embodiments, heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S.

[0078] In some embodiments, heterocycloalkyl is optionally substituted piperazine, piperidine, morpholine, tertolahydropyran, pyrrolidine, or tetrahydrofuran.

[0079] In some embodiments, ring A is: [ka] is.

[0080] In some embodiments, [ka] teeth, [ka] is.

[0081] In some embodiments, Z is -O- or -SO2-. In some embodiments, Z is -O-. In some embodiments, Z is -SO2-.

[0082] In some embodiments, Z is C(R 1 )2. In some embodiments, Z is CF2. In some embodiments, Z is CH2.

[0083] In some embodiments, Z is NR 7 where R 7 is -C(=O)R 7a , S(=O)R 7a , or S(=O)2R 7a In some embodiments, Z is NC(=O)R 7a In some embodiments, Z is NC(=O)CH. In some embodiments, Z is NC(=O)(cyclopropyl). In some embodiments, Z is NS(=O)R 7a In some embodiments, Z is NS(=O)2CH3. In some embodiments, Z is NS(=O)R 7a is.

[0084] In some embodiments, R 7a is H. In some embodiments, R 7a is an optionally substituted C1-C6 alkyl. In some embodiments, R 7a is an optionally substituted C-C cycloalkyl. In some embodiments, R 7ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 7a is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 7a is cyclopropyl.

[0085] In some embodiments, each R 1 are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2.

[0086] In some embodiments, each R 1 is independently H, halogen, or —OH, and in some embodiments, each R 1 is independently an optionally substituted C1-C6 alkyl or an optionally substituted C1-C6 haloalkyl. In some embodiments, each R 1 is independently H, F, Cl, OH, CH, CF, or CHF. In some embodiments, each R 1 is independently H, F, or CH. In some embodiments, each R 1 is independently H or CH. In some embodiments, each R 1 are independently -C(=O)N(R b )2. In some embodiments, each R 1 are independently —C(═O)N(CH3)2, —C(═O)NHCH3, or —C(═O)NH2.

[0087] In some embodiments, two R 1together with the atom(s) to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, two R on the same carbon atom or on adjacent carbon atoms 1 together with the atom(s) to which they are attached form an optionally substituted C-C cycloalkyl. In some embodiments, two R 1 together with the atom(s) to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R 1 together with the atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl. 1 together with the atom to which they are attached form a cyclopropyl. 1 together with the atom to which they are attached form a cyclobutyl. 1 together with the atom to which they are attached form cyclopentyl.

[0088] In some embodiments, two R on the same carbon atom or on adjacent carbon atoms 1 together with the atom(s) to which they are attached form an optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, two R 1 together with the atom(s) to which they are attached form a 4-6 membered heterocyclic ring. 1 together with the atom(s) to which they are attached form oxetenyl.

[0089] In some embodiments, X 1 is N. In some embodiments, X 1 is CR 2 is.

[0090] In some embodiments, R 2 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C1-C6 hydroxyalkyl. 2 is halogen or CN. In some embodiments, R 2 is halogen. In some embodiments, R 2 is Cl or F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is CN.

[0091] In some embodiments, each R 3 are independently H, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, each R 3 are independently H, halogen, oxo (=O), -CN, -OH, -ORa , -N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or optionally substituted 4-8 membered heterocycloalkyl.

[0092] In some embodiments, each R 3 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl. In some embodiments, each R 3 are independently CH3, CF3, CHF2, or -OCH3.

[0093] In some embodiments, each R 3 are independently an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, each R 3 are independently an optionally substituted 4- to 8-membered heterocycloalkyl.

[0094] In some embodiments, each R 3 are independently H, halogen, -N(R b )2, -C(=O)R a , -C(=O)OR b or —C(═O)NH. In some embodiments, each R 3 is independently H, Cl, F, —NH, or —C(═O)NH. In some embodiments, each R 3are independently H, —NH2, or —C(═O)NH2.

[0095] In some embodiments, each R 3 are independently H.

[0096] In some embodiments, each R 3 are independently oxo (=O).

[0097] In some embodiments, two R on adjacent atoms 3 Or two R's 3a or R 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl.

[0098] In some embodiments, two R on adjacent atoms 3 are taken together with the atom(s) to which they are attached to form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl. In some embodiments, two R on adjacent atoms 3 together with the atom(s) to which they are attached form an optionally substituted aryl. In some embodiments, two R on adjacent atoms 3 together with the atom(s) to which they are attached form an optionally substituted heteroaryl. In some embodiments, two R on adjacent atoms 3 taken together with the atom(s) to which they are attached form an optionally substituted heterocycloalkyl.

[0099] In some embodiments, two R on adjacent atoms 3ataken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl.

[0100] In some embodiments, R on adjacent atoms 3 and R 3a taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl.

[0101] In some embodiments, each R 3a are independently H or optionally substituted C1-C6. In some embodiments, each R 3a is independently an optionally substituted C1-C6 alkyl. In some embodiments, each R 3a is independently methyl or ethyl. In some embodiments, each R 3a are independently H.

[0102] In some embodiments, R 4 is an optionally substituted C1-C6. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is H.

[0103] In some embodiments, R A is a reactive group that contains a Michael acceptor. In some embodiments, R A is a reactive group capable of forming a bond with a sulfur group.

[0104] In some embodiments, R A teeth: [ka] [during the ceremony; R 6a is H, D, halogen, or C1-C6 haloalkyl, and R 6b and R 6c are each independently H or D; Or, R 6b and R 6d together with the carbon atoms to which they are attached form a cyclopropyl ring. is.

[0105] In some embodiments, R 6a is H or D. In some embodiments, R 6a is H. In some embodiments, R 6a is D. In some embodiments, R 6a is halogen. In some embodiments, R 6a is Br, Cl, or F. In some embodiments, R 6a is Br. In some embodiments, R 6a is Cl. In some embodiments, R 6a is F. In some embodiments, R 6a is C1-C6 haloalkyl. In some embodiments, R 6a is CF3 or CHF2.

[0106] In some embodiments, R 6b and R 6c are each independently H. In some embodiments, R 6b and R 6c are each independently D. In some embodiments, R 6b is H and R 6c is D. In some embodiments, R 6b is D and R 6c is H.

[0107] In some embodiments, R 6b and R 6d taken together with the carbon atoms to which they are attached form a cyclopropyl ring.

[0108] In some embodiments, R A teeth, [ka] is.

[0109] In some embodiments, R A teeth, [ka] is.

[0110] In some embodiments, R A teeth, [ka] is.

[0111] In some embodiments, R A teeth, [ka] is.

[0112] In some embodiments, R A teeth, [ka] is.

[0113] In some embodiments, R A teeth, [ka] is.

[0114] In some embodiments, R A teeth, [ka] is.

[0115] In some embodiments, R A teeth, [ka] is.

[0116] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, m is 1.

[0117] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 1.

[0118] In some embodiments, p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is an integer of 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1 or 2. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0119] In some embodiments, q is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, q is 1, 2, 3, 4, or 5. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1.

[0120] In some embodiments, each R a is independently C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C-C alkyl(aryl), —C-C alkyl(heteroaryl), —C-C alkyl(cycloalkyl), or —C-C alkyl(heterocycloalkyl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl. In some embodiments, each R a are independently C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl. In some embodiments, each R a is independently C1-C6 alkyl or C1-C6 heteroalkyl; wherein the alkyl or heteroalkyl is optionally substituted independently with 1, 2, or 3 -OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0121] In some embodiments, each R bare independently hydrogen, C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C heteroalkyl. In some embodiments, each R b are independently hydrogen, C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl. In some embodiments, each R b is independently hydrogen, C-C alkyl, or C-C heteroalkyl; wherein the alkyl or heteroalkyl is optionally substituted independently with 1, 2, or 3 -OH, C-C alkyl, or C-C haloalkyl. In some embodiments, R b is hydrogen.

[0122] In some embodiments, two R on the nitrogen atom b The groups, together with the nitrogen atom to which they are attached, form a heterocycloalkyl optionally substituted with 1, 2, or 3 C-C alkyl or C-C haloalkyl. In some embodiments, two R on the nitrogen atom b The groups, together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocycloalkyl optionally substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, two R on the nitrogen atom bThe groups, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl optionally substituted with 1, 2, or 3 C-C alkyl or C-C haloalkyl. In some embodiments, two R on the nitrogen atom b The groups, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, or morpholine optionally substituted with 1, 2, or 3 C-C alkyl or C-C haloalkyl. In some embodiments, two R on the nitrogen atom b The groups, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, or morpholine.

[0123] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0124] The compounds of formula (I), (II), (III), (IIIa), (IIIb), (IV), or (IVa) can exist in chiral or achiral forms, which can be either racemic or in the R or S configuration.

[0125] Compounds of the present disclosure include, but are not limited to: Table 1. Compounds of the present disclosure. [Table 1] TIFF2025534334000045.tif247170TIFF2025534334000046.tif222170TIFF2025534334000047.tif244170TIFF2025534334000048.tif238170TIFF2025534334000049.tif237170TIFF2025534334000050.tif241170TIFF2025534334000051.tif228170TIFF2025534334000052.tif246170TIFF2025534334000053.tif244170TIFF2025534334000054.tif248170TIFF2025534334000055.tif224170TIFF2025534334000056.tif240170TIFF2025534334000057.tif236170TIFF2025534334000058.tif246170TIFF2025534334000059.tif245170TIFF2025534334000060.tif236170TIFF2025534334000061.tif231170TIFF2025534334000062.tif234170TIFF2025534334000063.tif233170TIFF2025534334000064.tif242170TIFF2025534334000065.tif248170TIFF2025534334000066.tif235170TIFF2025534334000067.tif221170TIFF2025534334000068.tif242170TIFF2025534334000069.tif246170TIFF2025534334000070.tif236170TIFF2025534334000071.tif243170TIFF2025534334000072.tif248170TIFF2025534334000073.tif245170TIFF2025534334000074.tif244170TIFF2025534334000075.tif249170TIFF2025534334000076.tif248170TIFF2025534334000077.tif230170TIFF2025534334000078.tif218170TIFF2025534334000079.tif228170TIF F2025534334000080.tif228170TIFF2025534334000081.tif234170TIFF202553433400 0082.tif248170TIFF2025534334000083.tif245170TIFF2025534334000084.tif2301 70TIFF2025534334000085.tif239170TIFF2025534334000086.tif232170TIFF2025534 334000087.tif229170TIFF2025534334000088.tif242170TIFF2025534334000089.ti f237170TIFF2025534334000090.tif238170TIFF2025534334000091.tif246170TIFF20 25534334000092.tif230170TIFF2025534334000093.tif245170TIFF20255343340000 94.tif225170TIFF2025534334000095.tif242170TIFF2025534334000096.tif187170.

[0126] According to further embodiments, the compound of the present disclosure is selected from: 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-3'-(4-acryloylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-(3-(3-chloro-5-(2-methoxypyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)picolinamide; 3'-(7-Acryloyl-4-oxa-7-azaspiro[2.5]octan-6-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(6-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-dimethylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methylpyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; 6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-4-carboxamide; 1-((3R,5R)-3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; compound 1-((3R,5R)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; 6-(4-(4-acryloylmorpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(9H-purin-6-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 5-(4-((3R,5R)-4-acryloyl-5-methylmorpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; 4-((3R,5R)-4-acryloyl-5-methylmorpholin-3-yl)-6-chloro-[2,4'-bipyridine]-2'-carboxamide; (R)-1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(6-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 3'-((3R,6R)-4-acryloyl-6-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 5-(4-((3R,5S)-4-acryloyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; (R)-1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-diamino1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; 191 (R)-1-(3-(3-(2-amino-1H-imidazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 193 (R)-3'-(1-acryloyl-4-(cyclopropanecarbonyl)piperazin-2-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(2-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,6R)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-6-fluoro-1,4-oxazepan-4-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-chloro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,5S)-3-(2-chloro-6-(6-methylpyrimidin-4-yl)pyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-(methylamino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (R)-1-(3-(3-(4-amino-6-(methylamino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 6-(4-((3R,5S)-4-acryloyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxamide; 1-((3R)-3-(3-chloro-5-(1-methyl-2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethyl-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-fluoropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2R,4S)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-hydroxy-4-methylpiperidin-1-yl)prop-2-en-1-one; 1-(4-acetyl-6-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,7-diazaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-chloropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-3-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-fluoropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-chloroprop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)morpholino)prop-2-en-1-one; or (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isonicotinamide; or a pharmaceutically acceptable salt thereof.

[0127] According to further embodiments, the compound of the present disclosure is selected from: (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-dimethylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methylpyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-diamino1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-(methylamino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-(methylamino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; or (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isonicotinamide; or a pharmaceutically acceptable salt thereof.

[0128] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0129] Further forms of the compound In some embodiments, the compounds disclosed herein possess one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form diastereomeric compound / salt pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation and recrystallization of diastereomeric salts, or by chromatography, or any combination thereof. Jacques, J. et al., "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In one embodiment, stereoisomers are obtained by stereoselective synthesis.

[0130] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of a prodrug increases effective water solubility. An example of a prodrug includes, but is not limited to, a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental, but once inside cells where water solubility is beneficial, is metabolically hydrolyzed to the active carboxylic acid. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0131] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other properties or characteristics of a drug. Knowledge of in vivo pharmacokinetic and pharmacodynamic processes and drug metabolism allows the design of prodrugs of a compound once a pharmaceutically active compound is known. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401; Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery," Annual Reports in Medicinal Chemistry, Vol. 41, pp. 395-407, 2006; T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14).

[0132] In some embodiments, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0133] In some embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions, and the incorporation of appropriate substituents on the aromatic ring structure reduces, minimizes, or eliminates this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0134] In another embodiment, the compounds described herein are isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0135] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14 Incorporation of radioactive isotopes such as C is useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium offers certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0136] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce a metabolic product that is used to produce a desired effect, including a desired therapeutic effect.

[0137] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., does not cause undesired biological effects or interacts in a deleterious manner with any of the components of the composition in which it is contained, and that allows the substance to be administered to an individual.

[0138] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound disclosed herein with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound disclosed herein with a base to form a salt.

[0139] The compounds described herein can be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) acid addition salts formed by reacting the free base form of the compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or the like; or acid addition salts formed by reacting the free base form of the compound with an inorganic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]octadecanoic acid, or the like. (2) Acid addition salts formed by reacting an acid proton present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, calcium), or an aluminum ion. In some cases, the compounds described herein may be coordinated with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine, lysine, and the like.Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0140] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc.Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated form and solvated form.In general, solvated form is considered equivalent to unsolvated form for the purposes of the compounds and methods provided herein.

[0141] Treatment method In another aspect, provided herein is a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof, for use in a method for inhibiting Nrf2 by mediating activation of KEAP 1. In some embodiments, provided herein is a method for inhibiting Nrf2 by mediating activation of KEAP 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, the present disclosure provides a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof, disclosed herein, for use as a pharmaceutical.

[0143] In another aspect, the present disclosure provides a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof, as disclosed herein, for use in treating a disease mediated by activation of KEAP1 and inhibition of Nrf2.

[0144] In another aspect, the present disclosure discloses the use of a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa) disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of a disease mediated by activation of KEAP1 and inhibition of Nrf2.

[0145] In another aspect, provided herein is a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease. In some embodiments, provided herein is a method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is mediated by activation of KEAP1 and inhibition of Nrf2.

[0146] In another embodiment, provided herein is a method for treating a disease mediated by activation of KEAP1 and inhibition of Nrf2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof.

[0147] In some embodiments, the disease is associated with oxidative stress. In some embodiments, the compounds described herein (e.g., compounds of Formula (I), or pharmaceutically acceptable salts thereof) enhance oxidative stress, such as in cancer cells or damaged cells, such as those in neurodegenerative diseases.

[0148] In some embodiments, the disease is diabetes, fibrosis, neurotoxicity, or cancer.

[0149] In some embodiments, the disease is abdominal aortic aneurysm, acute kidney injury, adult glioblastoma, advanced solid tumor, aging, alcohol sensitivity, allergies, Alport syndrome, Alzheimer's disease, asthma, atopic asthma, autism spectrum disorder, autosomal dominant polycystic kidney disease, Barrett's esophagus, low-grade dysplasia, cerebral ischemia, breast cancer or breast tumor, cardiovascular risk, cataracts, cholelithiasis, cholestasis, chronic hepatitis C, chronic kidney disease, Chronic lymphocytic leukemia, chronic renal failure, chronic schizophrenia, chronic subclinical inflammation, CKD associated with type 1 diabetes, dementia, colorectal cancer, COPD, corneal endothelial cell loss, Crohn's disease, cutaneous T-cell lymphoma, diabetes, diabetic nephropathy, diarrhea, endometriosis, environmental carcinogenesis, focal segmental glomerulosclerosis, Friedreich's ataxia, Helicobacter pylori infection, liver dysfunction, Huntington's disease, IgA nephropathy, inflammation and pain after ophthalmic surgery, insulin resistance, liver disease, lung cancer, non-small cell lung cancer, squamous non-small cell lung cancer, lung adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, head and neck cancer, squamous cell head and neck cancer, bladder cancer, squamous cell bladder cancer, uterine endometrial cancer, cervical cancer, cervical squamous cell carcinoma, major depression, melanoma, metabolic syndrome X, mild cognitive impairment, mitochondrial myopathy, multiple sclerosis, tumor, non-alcoholic fatty liver disease or non-alcoholic fatty liver disease In some embodiments, the disease is selected from the group consisting of: diabetes mellitus, non-insulin dependent, non-ischemic cardiomyopathy, obstructive sleep apnea, eye inflammation, eye pain, polymorphisms, prediabetes, primary biliary cirrhosis, primary focal segmental glomerulosclerosis (FSGS), prostate cancer, psoriasis, psychosis, pulmonary arterial hypertension (PAH), pulmonary hypertension, redox status, rheumatoid arthritis, rhinitis, schistosomiasis, schizophrenia, small lymphocytic lymphoma, subarachnoid hemorrhage, and type 2 (type 2 diabetes).

[0150] In some embodiments, the disease is selected from the group consisting of adult glioblastoma, solid tumors, lymphoid malignancies, breast cancer or breast tumors, chronic lymphocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, environmental carcinogenesis, lung cancer, non-small cell lung cancer, squamous non-small cell lung cancer, lung adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, head and neck cancer, squamous cell head and neck cancer, bladder cancer, squamous cell bladder cancer, uterine endometrial cancer, cervical cancer, cervical squamous cell carcinoma, major depression, melanoma, metabolic syndrome X, mild cognitive impairment, mitochondrial myopathy, multiple sclerosis, tumors, non-alcoholic fatty liver or non-alcoholic steatohepatitis, non-insulin dependent, non-ischemic cardiomyopathy, obstructive sleep apnea, ocular inflammation, eye pain, polymorphism, pre-diabetes, prostate cancer, small lymphocytic lymphoma.

[0151] In some embodiments, the disease is selected from the group consisting of major depression, metabolic syndrome X, mild cognitive impairment, mitochondrial myopathy, multiple sclerosis, tumors, non-alcoholic fatty liver or non-alcoholic steatohepatitis, non-insulin-dependent, non-ischemic cardiomyopathy, obstructive sleep apnea, ocular inflammation, eye pain, polymorphisms, and pre-diabetes.

[0152] In some embodiments, the disease is cancer.

[0153] In some embodiments, the disease is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, bile duct cancer, stomach cancer, kidney cancer, and pancreatic cancer.

[0154] In another aspect, provided herein is a method for degrading Nrf2 in a cell or a subject, the method comprising administering to the cell or subject an effective amount of a compound of any of Formulas (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound activates KEAP1, thereby resulting in Nrf2 degradation.

[0155] Medication and Treatment Regimen In one aspect, the compounds disclosed herein are used in the preparation of medicaments for treating the diseases or conditions described herein.In addition, the method for treating any of the diseases or conditions described herein in a subject who needs such treatment comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound disclosed herein or its pharmaceutically acceptable salt, active metabolite, prodrug or solvate.

[0156] In certain embodiments, compositions containing the compounds disclosed herein are administered for preventive and / or therapeutic treatment.In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially stop at least one of the symptoms of the disease or condition.The amount effective for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health, weight, and response to the drug, and the judgment of the treating physician.The therapeutically effective amount can be optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0157] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0158] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended for a particular period of time (ie, a "drug holiday").

[0159] Doses used in adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in single or divided doses.

[0160] Pharmaceutical Composition In another aspect, provided herein is a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament.

[0161] In one embodiment, a compound described herein (e.g., a compound of Formula (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof) is formulated into a pharmaceutical composition. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compound into a preparation that can be used as a medicament. Appropriate formulations depend upon the route of administration selected. Summary summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0162] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. A pharmaceutical composition facilitates administration of a compound to an organism.

[0163] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate- and controlled-release formulations.

[0164] In some embodiments, the compounds disclosed herein are administered orally.

[0165] In some embodiments, the compound disclosed herein is administered topically.In such embodiments, the compound disclosed herein is formulated into various topically administrable compositions, such as solution, suspension, lotion, gel, paste, shampoo, scrub, rub, paint, medicated stick, medicated bandage, balm, cream or ointment.In one aspect, the compound disclosed herein is administered topically to skin.

[0166] In another embodiment, the compounds disclosed herein are administered by inhalation.

[0167] In another embodiment, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0168] In another embodiment, the compounds disclosed herein are formulated as eye drops.

[0169] In any of the above aspects, there are further embodiments in which an effective amount of a compound disclosed herein is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by inhalation to a mammal; and / or (e) administered intranasally to a mammal; and / or (f) administered by injection to a mammal; and / or (g) administered topically to a mammal; and / or (h) administered ophthalmically; and / or (i) administered rectally to a mammal; and / or (j) administered non-systemically or topically to a mammal.

[0170] In any of the foregoing aspects, there are further embodiments comprising a single administration of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered multiple times to the mammal over the course of a day; (iii) the compound is administered continuously; or (iv) the compound is administered continuously.

[0171] In any of the above-mentioned aspects, there are further embodiments that comprise multiple administrations of an effective amount of the compound disclosed herein, including: (i) the compound is administered continuously or intermittently, such as a single dose; (ii) the interval between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound administered is temporarily reduced; and at the end of the drug holiday, the administration of the compound is resumed.In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0172] In certain embodiments, the compounds disclosed herein are administered in a local rather than systemic manner.

[0173] In some embodiments, the compounds disclosed herein are administered locally. In some embodiments, the compounds disclosed herein are administered systemically.

[0174] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0175] In one embodiment, the liquid dosage form for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0176] For administration by inhalation, the compounds disclosed herein are formulated for use as an aerosol, mist, or powder.

[0177] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

[0178] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0179] In one aspect, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0180] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0181] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0182] Combination therapy In certain instances, it will be appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.

[0183] In one specific embodiment, a compound disclosed herein is administered in combination with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0184] For the combination therapies described herein, the dose of the co-administered compound will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0185] When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms, by way of example only.

[0186] Modified proteins In another embodiment, provided herein is a modified KEAP1 protein comprising a naturally occurring small molecule fragment having a covalent bond to cysteine ​​151 of the KEAP1 protein, comprising SEQ ID NO: 1 or a variant thereof; [ka] [During the ceremony: S is the sulfur atom of cysteine ​​151 of SEQ ID NO: 1 or a variant thereof; 1-150 and 152-624 represent the amino acids at positions 1-150 and 152-624, respectively, of SEQ ID NO: 1 or a variant thereof; and Q is the formula (X*): [ka] (In the formula, TIFF2025534334000099.tif16137 shows the join points; Ring A is aryl, heteroaryl, or heterocyclyl; Z is O, S(=O)2, C(R 1 )2, or NR 7 and; R 7 is -C(=O)R 7a , S(=O)R 7a , or S(=O)2R 7a where R 7a is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; Each R 1 are independently H, halogen, —OH, optionally substituted C-C alkyl, optionally substituted C-C haloalkyl, optionally substituted C-C hydroxyalkyl, or —C(═O)N(R b )2, or two R's1 together with the atom(s) to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl; X 1 is N or CR 2 and; Each R 2 are independently H, halogen, CN, OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 hydroxyalkyl; R 4 is H or optionally substituted C1-C6 alkyl; or R 2 and R 4 together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; Each R 3 are independently H, D, halogen, oxo (=O), -CN, -OH, -OR a , -SH, -SR a , -S(=O)R a , -NO2, -N(R b )2, -S(=O)2R a , -NHS(=O)2R a , -S(=O)2N(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NH2, -OC(=O)N(R b )2, -NR b C(=O)N(R b )2, -NR b C(=O)R a , -NR b C(=O)OR b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms3 taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; Each R a is independently C-C alkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C-C alkyl(aryl), —C-C alkyl(heteroaryl), —C-C alkyl(cycloalkyl), or —C-C alkyl(heterocycloalkyl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with 1, 2, or 3 —OH, C-C alkyl, or C-C haloalkyl; and Each R b are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with 1, 2, or 3 -OH, C1-C6 alkyl, or C1-C6 haloalkyl; or two R on the nitrogen atom b groups, together with the nitrogen atom to which they are attached, form a heterocycloalkyl optionally substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is an integer from 1 to 12; and q is an integer from 1 to 10. is a small molecule fragment of A modified KEAP1 protein having the structure:

[0187] SEQ ID NO: 1 relates to the sequence of human KEAP1, also referenced by the Uniprot identifier Q14145 (see Uniprot version downloaded on 23 Aug. 2023), namely: , wherein the sequence is modified with any of the compounds set forth in Table 1. According to a highly preferred embodiment, cysteine ​​151 of SEQ ID NO: 1 bears a modification as set forth in Table 1, i.e., the respective compound according to Table 1 is covalently attached to the protein encoded by SEQ ID NO: 1 via the side chain of C151.

[0188] In some embodiments, the KEAP1 protein comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, or at least 90% identical to the sequence of SEQ ID NO: 1. In some embodiments, the KEAP1 protein comprises an amino acid sequence that is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO: 1. In some embodiments, the KEAP1 protein comprises an amino acid sequence that is at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% identical to the sequence of SEQ ID NO: 1. "Sequence identity" or "percent identity" is a numerical value that represents how similar a query sequence is to a target sequence, or more precisely, how many characters are identical in each sequence after alignment. The most common tool for calculating sequence identity is BLAST (basic local alignment search tool, https: / / blast.ncbi.nlm.nih.gov / ), which performs a comparison between pairs of sequences and searches for regions of local similarity. Suitable alignment methods are known in the art, such as the Needleman-Wunsch algorithm for global-global alignment using the BLOSUM62 matrix, with a gap opening penalty of 11 and a gap extension penalty of 1. The number of aligned identical residue pairs is then counted and then divided by the total length of the alignment (including gaps, internal and external) to obtain a percent identity value. KEAP proteins can include functional fragments of any of these sequences, such as functional fragments at least 300 amino acids long, at least 350 amino acids long, at least 400 amino acids long, at least 450 amino acids long, at least 500 amino acids long, at least 550 amino acids long, or at least 600 amino acids long.According to the present invention, a protein fragment is considered to be functional if the fragment is capable of at least partially exerting the biological function of its parent protein, i.e., in the case of KEAP1, a fragment of a parent protein is considered to be functional if it has activity in the Nrf2 antagonism assay according to Example 108, for example.

[0189] In some embodiments, the compounds described herein form an adduct with the KEAP1 protein at cysteine ​​151. Cysteine ​​151 may be the cysteine ​​at amino acid residue 151 of the polypeptide chain of the KEAP1 protein, numbered N to C. Cysteine ​​151 may be relative to SEQ ID NO: 1. In embodiments where the KEAP1 amino acid sequence is not 100% identical to SEQ ID NO: 1, cysteine ​​151 may be the equivalent cysteine ​​to cysteine ​​151 relative to SEQ ID NO: 1.

[0190] In some embodiments, the adduct is a compound fragment resulting from the reaction of a compound described herein with a thiol group of a protein. In some embodiments, the compound prior to reaction with the protein is a compound of any of Formulas (I), (II), (III), (IIIx), (IIIa), (IIIb), (IV), or (IVa), or a pharmaceutically acceptable salt thereof.

[0191] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Also, the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0192] The following terms, as used herein, have the following meanings unless otherwise indicated: "Oxo" refers to the =O substituent.

[0193] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 For example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include C1-C 10 Examples of alkyl include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, alkyl is methyl or ethyl. Unless otherwise specifically stated herein, alkyl groups may be optionally substituted as described below.

[0194] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0195] "Alkoxy" refers to a radical of the formula OR, where R is an alkyl radical as defined herein. Unless otherwise specifically stated herein, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0196] "Heteroalkyl" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N (i.e., NH, N-alkyl), or S atom. "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOMe, or -OCHCHOCHCHNH. Representative heteroalkylene groups include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO-, or -OCHCHOCHCHOCHCHO-.

[0197] "Alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0198] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0199] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated in this specification, the term "aryl" or the prefix "ar" (e.g., "aralkyl") is meant to include aryl radicals that may be optionally substituted.

[0200] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties to the carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to the carboxylic acid group. A compound having a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and can have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, the carboxylic acid bioisostere ionizes at physiological pH to approximately the same extent as the carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to, the following:

[0201] [ka] etc.

[0202] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. The cycloalkyl may be saturated or partially unsaturated. The cycloalkyl may be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decanyl, and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, a cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.In some embodiments, the cycloalkyl group is selected from spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalen-1(2H)-one, and decalinyl. In some embodiments, the cycloalkyl group is polycyclic. Polycyclic radicals include, for example, adamantyl. In some embodiments, the polycyclic cycloalkyl group is adamantyl. Unless otherwise specifically stated in the specification, the cycloalkyl group may be optionally substituted.

[0203] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring can be replaced with a nitrogen atom.

[0204] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0205] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2 trifluoroethyl, 1,2 difluoroethyl, 3 bromo 2 fluoropropyl, 1,2 dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0206] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2 trifluoroethoxy, 1,2 difluoroethoxy, 3 bromo 2 fluoropropoxy, 1,2 dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0207] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 14-membered non-aromatic ring radical containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical can be monocyclic, bicyclic (which can include fused bicyclic heterocycloalkyls (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), bridged heterocycloalkyls, or spiroheterocycloalkyls), or polycyclic. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is bicyclic. The nitrogen, carbon, or sulfur atoms in a heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. A heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 8 carbons and 1 or 2 N atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 10 carbons, 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, a heterocycloalkyl has 2 to 10 carbons, 1 to 2 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0208] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl.In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0209] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halogen, acyl, acyloxy, -COH, -COalkyl, nitro, and amino (including mono- and di-substituted amino groups (e.g., -NH, -NHR, -NR)), and protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, and -COalkyl. In some embodiments, optional substituents are independently selected from fluorine, chlorine, bromine, iodine, -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0210] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, with a switch of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Examples of tautomeric interconversions include:

[0211] [ka]

[0212] The term "co-administration" and the like, as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0213] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered drug or compound to relieve to some extent one or more symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein necessary to provide a clinically significant reduction in a disease symptom. The appropriate "effective" amount in any individual case can be determined using techniques such as a dose escalation study. An "effective amount" is an amount sufficient for a compound to achieve its stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." "Alleviation" of a symptom or symptoms (and grammatical synonyms of this phrase) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, achieves the intended prophylactic effect, e.g., prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or its symptoms. A complete prophylactic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0214] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as a compound of formula (I) and a co-agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as a compound of formula (I) and a co-agent, are administered to a patient simultaneously, in parallel, or consecutively without a specific time interval, as separate entities, where such administration provides an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[0215] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0216] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition. [Example]

[0217] Example The following examples are presented to illustrate the invention, but do not limit the claimed invention. The following examples further illustrate the invention, but, of course, should not be construed as in any way limiting its scope.

[0218] The following synthetic schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods for preparing the compounds described herein. Those skilled in the art will understand that these compounds can be prepared by similar methods or by combining other methods known to those skilled in the art. Those skilled in the art will also understand that by using appropriate starting materials and modifying the synthetic route as necessary, they can be prepared in a similar manner to those described below. In general, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described herein.

[0219] In further embodiments, the compounds described herein and other related compounds having different structures can be synthesized using, for example, the techniques and materials described herein and those known in the art, for example, Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of the compounds disclosed herein may be derived from reactions, which may be modified by using appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein. The following synthetic methods may be used as a guide.

[0220] Abbreviation DCM: dichloromethane DIEA: Diisopropylethylamine DMAP: 4-(dimethylamino)pyridine DMF: dimethylformamide DMSO: dimethyl sulfoxide EA or EtOAc: Ethyl acetate ESI: electrospray ionization HPLC: High-performance liquid chromatography HRMS: High resolution mass spectrometry h or hr(s): hour MeOH: Methanol Ms: mesyl or methanesulfonyl min(s): minutes m / z: mass-to-charge ratio 1 H NMR: proton nuclear magnetic resonance 13 C NMR: Carbon-13 nuclear magnetic resonance PE: Petroleum ether rt: room temperature TLC: Thin Layer Chromatography TFA: Trifluoroacetic acid

[0221] Example 1. Procedure A and synthesis of 1-(3-(5-chloro-[1,1'-biphenyl]-3-yl)morpholino)prop-2-en-1-one (Compound 1) Step A [ka]

[0222] To a mixture of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (200 mg, 0.86 mmol) and 1-bromo-3-chloro-5-iodobenzene (315 mg, 0.99 mmol) in DMF (6 mL, 0.14 M) was added [IR(DF(CF)PPY)(DTBPY)]PF (9.7 mg, 0.0086 mmol), nickel(II) chloride (19 mg, 0.086 mmol), dtbbpy (34 mg, 0.12 mmol), and CsCO (845 mg, 2.59 mmol) under a N atmosphere in a glove box at 20 °C. The mixture was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 12 h. The mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL, 2 equiv.), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE / EtOAc 100:1 to 0:1) to afford tert-butyl 3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (300 mg, 92% yield) as a white solid.

[0223] To a mixture of tert-butyl 3-(3-bromo-5-chloro-phenyl)morpholine-4-carboxylate (100 mg, 0.26 mmol) and phenylboronic acid (37 mg, 0.31 mmol) in 1,4-dioxane (2 mL), MeCN (2 mL), and water (1 mL) was added K2CO3 (2 equivalents, 75 mg) and Pd(PPh3)4 (30 mg) under a N2 atmosphere at 20 °C. The mixture was stirred at 90 °C for 3 h. The reaction mixture was poured into ice water (30 mL), extracted with EtOAc (20 mL × 2), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , PE:EtOAc=5:1) to give tert-butyl 3-(5-chloro-[1,1′-biphenyl]-3-yl)morpholine-4-carboxylate (170 mg) as a yellow oil.

[0224] To tert-butyl 3-(3-chloro-5-phenyl-phenyl)morpholine-4-carboxylate (170 mg, 0.45 mmol) in ethyl acetate (5 mL, 0.09 M) was added hydrochloric acid (10 mL) in EtOAc at 20° C. and stirred for 3 h. The mixture was concentrated in vacuo to give 3-(5-chloro-[1,1′-biphenyl]-3-yl)morpholine HCl (170 mg) as a white solid.

[0225] To a mixture of 3-(5-chloro-[1,1'-biphenyl]-3-yl)morpholine HCl (170 mg, 0.62 mmol) in DCM (5 mL, 0.12 M) was added triethylamine (94 mg, 0.93 mmol) and acryloyl chloride (56 mg, 0.62 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 20 min. The mixture was poured into ice water (3 mL), extracted with DCM (2 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC and concentrated in vacuo to give 1-(3-(5-chloro-[1,1'-biphenyl]-3-yl)morpholino)prop-2-en-1-one (48 mg, 22% yield) as a colorless oil. LC-MS m / z: 328.1 [M+1]. Stereochemistry: Racemic.

[0226] Example 2. Synthesis of 1-(3-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)morpholino)prop-2-en-1-one (Compound 5) [ka]

[0227] tert-Butyl 3-(3-bromo-5-chloro-phenyl)morpholine-4-carboxylate was obtained from procedure A.

[0228] To a mixture of tert-butyl 3-(3-bromo-5-chloro-phenyl)morpholine-4-carboxylate (660 mg, 1.75 mmol) and bis(pinacolato)diboron (1334 mg, 5.25 mmol) in 1,4-dioxane (10 mL, 0.17 M) was added AcOK (2 equivalents, 345 mg) and Pd(dppf)Cl.CHCl (0.1 equivalents, 100 mg) at 25 °C. The reaction was stirred at 120 °C under a N atmosphere for 3 hours. The mixture was poured into ice water (30 mL), extracted with EtOAc (20 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography (PE / EtOAc 1:0→0:1) to afford tert-butyl 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (700 mg, 94% yield) as a white solid.

[0229] To a mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (263 mg, 1.13 mmol) and tert-butyl 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (400 mg, 0.94 mmol) in ethanol (2 mL, 0.14 M), toluene (4 mL, 0.14 M), and water (0.5 mL, 0.14 M) was added NaHCO (3 equivalents, 290 mg) and Pd(PPh)Cl (40 mg) at 25 °C. The reaction was stirred at 130 °C under a N atmosphere for 3 h. The mixture was poured into ice water (20 mL), extracted with EtOAc (20 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, PE: EtOAc = 2:1) and concentrated under reduced pressure to give tert-butyl 3-(3-chloro-5-(3,6-dihydro-2H-pyran-4-yl) phenyl) morpholine-4-carboxylate (130 mg, 36% yield) as a colorless oil.

[0230] To a mixture of tert-butyl 3-(3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)phenyl)morpholine-4-carboxylate (20 mg, 0.052 mmol) in ethyl acetate (5 mL, 0.01 M) was added PtO (20 mg) at 25 °C and stirred under H (15 psi) at 25 °C for 3 h. The mixture was concentrated in vacuo to give crude tert-butyl 3-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine-4-carboxylate (20 mg) as a colorless oil. The crude material was used in the next step.

[0231] Using tert-butyl 3-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)morpholine-4-carboxylate in step 3 of Procedure A gave the title compound. LC-MS m / z: 336.1 [M+1]. Enantiomer separation conditions: Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm, 10 μm); Mobile phase: CO2 and MeOH. Retention time: 2.03. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0232] Example 3. Procedure B and synthesis of (R)-1-(3-(3-(2-aminopyridin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 136) Step B [ka]

[0233] n-Butyllithium (2.5 M, 29.59 mL, 73.97 mmol, 1 equiv.) was added dropwise to a solution of 1,3-dibromo-5-chlorobenzene (20 g, 73.97 mmol, 1 equiv.) in isopropyl ether (200 mL) under N2 atmosphere at -65°C, followed by stirring for 1 hour. tert-Butyl 3-oxomorpholine-4-carboxylate (14.88 g, 73.97 mmol, 1 equiv.) in isopropyl ether (100 mL) was added dropwise and stirred at -65°C for 1 hour.

[0234] The mixture was quenched with saturated aqueous NH4Cl (100 mL). The solution was extracted with ethyl acetate (100 mL), and the combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 4:1) to obtain tert-butyl N-[2-[2-(3-bromo-5-chloro-phenyl)-2-oxo-ethoxy]ethyl]carbamate (6.0 g, 15.28 mmol, 21% yield) as a yellow oil.

[0235] BH3-THF (5.88 mL, 5.88 mmol, 1.1 equiv) was added to (S)-2-methyl-CBS-oxazaborolidine (1.02 g, 1.06 mmol) in THF (10 mL) at 0 °C under a N2 atmosphere. It was warmed to 25 °C and stirred for 1 h. A solution of tert-butyl N-[2-[2-(3-bromo-5-chloro-phenyl)-2-oxo-ethoxy]ethyl]carbamate (2.1 g, 5.34 mmol, 1 equiv) in THF (15 mL) was added at 0 °C. The mixture was warmed to 25 °C and stirred for 1 h. The reaction was quenched with MeOH (15 mL) at 0 °C, stirred at 25 °C for 2 h, and then concentrated in vacuo. The crude residue was purified by column chromatography (SiO, 6–15% EtOAc in pet ether) to give (S)-(2-(2-(3-bromo-5-chlorophenyl)-2-hydroxyethoxy)ethyl)carbamate (1.80 g, 4.56 mmol, 85% yield) as a white oil. Stereochemistry was assigned according to Angew. Chem. Int. Ed. 1998, 37, 1986–2012.

[0236] To a solution of tert-butyl (S)-(2-(2-(3-bromo-5-chlorophenyl)-2-hydroxyethoxy)ethyl)carbamate (1.80 g, 4.56 mmol, 1 equiv) in DCM (15 mL) was added 4-(dimethylamino)pyridine (27 mg, 0.23 mmol, 0.05 equiv) and triethylamine (1.38 g, 13 mmol) at 0 °C. A solution of methylsulfonylmethanesulfonate (1.191 g, 6.84 mmol, 1.5 equiv) in DCM (5 mL) was added slowly at 0 °C, then warmed to room temperature and stirred for 16 h. The reaction mixture was poured into water (15 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with brine (15 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1 to 0:1) to give (S)-1-(3-bromo-5-chlorophenyl)-2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (2.00 g, 4.23 mmol, 93% yield) as a white solid.

[0237] [ka]

[0238] To a solution of (S)-1-(3-bromo-5-chlorophenyl)-2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (100 g, 211 mmol, 1 equiv) in 1,4-dioxane (200 mL, 1.06 M) was added HCl in dioxane (4 M, 1000 mL) at 0° C. The mixture was warmed to 25° C. and stirred for 3 h. The mixture was concentrated in vacuo to give (S)-2-(2-aminoethoxy)-1-(3-bromo-5-chlorophenyl)ethyl methanesulfonate HCl as a colorless oil, which was used in the next step without purification.

[0239] To an aqueous solution of (S)-2-(2-aminoethoxy)-1-(3-bromo-5-chlorophenyl)ethyl methanesulfonate HCl (16.5 g, 44 mmol) in DCM (200 mL, 0.22 M) was added N,N-diethylethanamine (26.8 g, 265 mmol) under a N atmosphere at 0 °C. The reaction was stirred at 25 °C for 16 h. The solution was diluted with HO (40 mL), extracted with EtOAc (40 mL*3), washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 to 88:12) to give (R)-3-(3-bromo-5-chlorophenyl)morpholine (3.90 g, 14.1 mmol, 32% yield) as a yellow solid.

[0240] To a solution of (R)-3-(3-bromo-5-chlorophenyl)morpholine (5 g, 18.07 mmol) in DCE (60 mL, 0.30 M) was added triethylamine (3658 mg, 36 mmol), 4-(dimethylamino)pyridine (2208 mg, 18 mmol), and di-tert-butyl dicarbonate (7891 mg, 36 mmol) at 0 °C. The mixture was stirred at 70 °C under N atmosphere for 16 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (80 mL * 3). The combined organic layer was washed with brine (50 mL * 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SEPAFLASH® silica flash column, eluting with a 0 to 30% ethyl acetate / petroleum ether gradient (75 mL / min)) to afford tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (4.90 g, 13.0 mmol, 72% yield) as a yellow solid.

[0241] Pd(dppf)Cl (578 mg, 0.1 equiv.) was added to a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (3 g, 7.96 mmol, 1 equiv.), bis(pinacolato)diboron (2427 mg, 9.55 mmol, 1.2 equiv.), and potassium acetate (1954 mg, 19.91 mmol, 2.5 equiv.) in 1,4-dioxane (30 mL, 0.26 M) at 25 °C under a N atmosphere. The reaction was stirred at 80 °C for 3 h. The mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL*2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (petroleum ether / ethyl acetate) to give tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (2700 mg, 6.37 mmol, 80% yield) as a yellow oil. [ka]

[0242] Pd(dppf)Cl (20 mg, 0.028 mmol, 0.1 equiv) was added to a solution of tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (120 mg, 0.28 mmol, 1 equiv), 2-amino-4-bromopyridine (58 mg, 0.33 mmol, 1.2 equiv), and potassium carbonate (97 mg, 0.70 mmol, 2.5 equiv) in 1,4-dioxane (2 mL) and water (0.4 mL) at 25 °C under a N atmosphere. The reaction was stirred at 25 °C under a N atmosphere for 3 h. The mixture was poured into water (4 mL), extracted with ethyl acetate (4 mL*2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO, PE: EtOAc = 1:5) to give tert-butyl (R)-3-(3-(2-aminopyridin-4-yl) -5-chlorophenyl) morpholine-4-carboxylate (90 mg, 0.23 mmol, 82% yield) as a yellow oil.

[0243] 4 M HCl in EtOAc (1 mL) was added to a solution of tert-butyl (R)-3-(3-(2-aminopyridin-4-yl)-5-chlorophenyl)morpholine-4-carboxylate (100 mg, 0.25 mmol, 1 equiv) in EtOAc (1 mL) at 0° C., and the mixture was stirred at 25° C. for 3 h, then concentrated to give crude (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)pyridin-2-amine HCl (100 mg, 0.24 mmol, 94% yield).

[0244] Triethylamine (55 mg, 0.55 mmol, 2 equiv.) was added to a solution of (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)pyridin-2-amine HCl (80 mg, 0.27 mmol, 1 equiv.) in DCM (1 mL) at 0° C. Acryloyl chloride (14 mg, 0.16 mmol, 0.6 equiv.) in DCM (1 mL) was added at 0° C. The mixture was stirred for 25 oThe mixture was stirred at RT for 1 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL*3), washed with brine (3 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, MeOH:EtOAc=1:10) to give (R)-1-(3-(3-(2-aminopyridin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (24 mg, 0.066 mmol, 24% yield) as a pale yellow solid. LC-MS m / z: 344.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0245] [ka] [Table 2]

[0246] Example 4. Procedure C and synthesis of (R)-3'-(4-acryloylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide (compound 44) Step C [ka]

[0247] (R)-3-(3-bromo-5-chlorophenyl)morpholine was obtained from Procedure B, Step 5.

[0248] To a solution of (R)-3-(3-bromo-5-chlorophenyl)morpholine (5 g, 18.07 mmol, 1 equiv.) in DCM (60 mL, 0.30 M) under a N atmosphere was added triethylamine (2.74 g, 27 mmol, 1.5 equiv.) and acryloyl chloride (1.8 g, 19.88 mmol, 1.1 equiv.) dropwise at 0 °C. After stirring at 25 °C for 2 h, it was poured into HO (40 mL). The aqueous layer was extracted with DCM (30 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE / EA = 77 / 23 to 3 / 1) to give (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one (5.17 g, 15.6 mmol, 86% yield) as a yellow oil.

[0249] To a solution of (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one (310 mg, 0.93 mmol) in 1,4-dioxane (8 mL, 0.09 M) and water (1.6 mL, 0.097 M) was added 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (298 mg, 1.12 mmol, 1.2 equiv.) and potassium carbonate (324 mg, 2.34 mmol, 2.5 equiv.). Pd(dppf)Cl (68 mg, 0.093 mmol) was added, and the resulting mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was quenched with saturated aqueous NH Cl (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with 20 mL of saturated brine. The organic layer was then separated, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0.5 / 1 to 0 / 1) to afford the title compound (96.8 mg, 0.36 mmol, 38% yield) as a white solid. LC-MS m / z: 389.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0250] [ka]

[0251] The title compounds can be obtained using appropriate coupling partners in Procedure C. All compounds are single enantiomers of known absolute configuration.

[0252] [Table 3]

[0253] Example 5. Procedure D and synthesis of (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 96) Step D [ka]

[0254] Procedure C gave (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one.

[0255] To a solution of (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one (5.8 g, 17 mmol, 1 equiv.) and bis(pinacolato)diboron (6.68 g, 26.31 mmol, 1.5 equiv.) in 1,4-dioxane (60 mL, 0.29 M) was added potassium acetate (4.30 g, 43 mmol, 2.5 equiv.) and Pd(dppf)Cl (0.89 g, 1.22 mmol, 0.07 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The solution was filtered and concentrated. The residue was dissolved in EtOAc (10 ml), washed with water (8 mL × 2), brine (8 mL × 2), dried over NaSO, filtered, and concentrated to give 5.9 g of crude (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one as a brown oil. The crude material was used in the next step.

[0256] To a solution of (R)-1-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (30 mg, 0.0794 mmol, 1 equiv.) and 2-chloropyrimidin-4-amine (10.29 mg, 0.079 mmol, 1 equiv.) in 1,4-dioxane (2 mL, 0.03 M) was added Pd(dppf)Cl (5.7 mg, 0.0079 mmol, 0.1 equiv.) and potassium carbonate (21.9 mg, 0.15 mmol, 2 equiv.) at 0° C. The mixture was stirred at 80° C. for 6 hours. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc, Rf=0.45) to give the title compound (5 mg, 0.014 mmol, 18% yield) as a white solid. LC-MS m / z: 345.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration. [ka]

[0257] The title compounds can be obtained using an appropriate coupling partner in Procedure D. All compounds are single enantiomers of known absolute configuration.

[0258] [Table 4] TIFF2025534334000115.tif255167TIFF2025534334000116.tif138166

[0259] Example 6. Synthesis of (R)-1-(3-(3-chloro-5-(4-methyl-1H-pyrazol-1-yl)phenyl)morpholino)prop-2-en-1-one (Compound 118) [ka]

[0260] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 6.

[0261] To a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (350 mg, 0.92 mmol, 1 equiv.) in DMA (15 mL, 0.062 M) was added 4-methylpyrazole (152 mg, 1.85 mmol, 2 equiv.), trans-N-N'-dimethylcyclohexane-1,2-diamine (97%) (26 mg, 0.18 mmol, 0.2 equiv.), potassium tert-butoxide (312 mg, 2.78 mmol), and CuI (35 mg, 0.18 mmol). The mixture was stirred at 130 °C for 16 h. The crude product was purified by preparative HPLC (column: Waters XBridge BEH C18 100*30mm*10um; liquid phase: [A - 10mM NH4HCO3 / HO; B - ACN] B%: 50%~80%, 10min]) to give tert-butyl (R)-3-(3-chloro-5-(4-methyl-1H-pyrazol-1-yl)phenyl)morpholine-4-carboxylate (40mg, 0.084mmol, 9% yield) as a white solid.

[0262] To a solution of tert-butyl (R)-3-(3-chloro-5-(4-methyl-1H-pyrazol-1-yl)phenyl)morpholine-4-carboxylate (20 mg, 0.053 mmol, 1 equiv) in ethyl acetate (3 mL, 0.017 M) was added HCl in ethyl acetate (4 M, 3 mL). The mixture was stirred at 20° C. for 4 hours. The solution was concentrated under reduced pressure, and the crude product was used directly without further purification.

[0263] To a solution of (R)-3-(3-chloro-5-(4-methyl-1H-pyrazol-1-yl)phenyl)morpholine (16 mg, 0.057 mmol, 1 equiv) in DCM (3 mL, 0.019 M) was added triethylamine (8.74 mg, 0.086 mmol) and acryloyl chloride (6.25 mg, 0.069 mmol). The mixture was stirred at 20 °C under N atmosphere for 3 h. The reaction was poured into HO (10 mL), and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 1 / 1) to give the title compound (11 mg, 0.032 mmol, 56% yield) as a yellow solid. LC-MS m / z: 332.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0264] Example 7. Synthesis of (R)-1-(3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (Compound 147) [ka]

[0265] tert-Butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 7.

[0266] Pd(dppf)Cl (20 mg, 0.1 equiv.) was added to a solution of tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.18 mmol, 1 equiv.), 4-chloro-1,3,5-triazin-2-amine (231 mg, 1.77 mmol, 1.5 equiv.), and potassium carbonate (407 mg, 2.94 mmol, 2.5 equiv.) in 1,4-dioxane (2 mL, 0.49 M) and water (0.40 mL, 0.49 M) at 25° C. The reaction was stirred at 80° C. under a N atmosphere for 3 h. The mixture was poured into water (4 mL), extracted with ethyl acetate (4 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO, PE:ETOAC = 1:5) to give tert-butyl (R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (130 mg, 0.33 mmol, 28% yield) as a yellow solid.

[0267] To a solution of tert-butyl (R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (110 mg, 0.28 mmol, 1 equiv) in DMF (1.5 mL, 0.18 M) under N atmosphere was added tert-butyl nitrite (86 mg, 0.84 mmol, 3 equiv) at 0° C. and stirred at 80° C. for 3 h. The mixture was poured into water (2 mL), extracted with ethyl acetate (1 mL × 3), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO, PE:ETOAC=1:1) to give tert-butyl (R)-3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (18 mg, 0.052 mmol, 19% yield) as a yellow solid.

[0268] Hydrochloric acid in EtOAc (1 mL, 4 M) was added to a solution of (R)-3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (20 mg, 0.053 mmol, 1 equiv) in EtOAc (1 mL) at 0° C. The mixture was stirred at 25° C. for 3 h. The solution was concentrated in vacuo to give (R)-3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholine HCl (10 mg, 0.036 mmol, 68% yield).

[0269] Triethylamine (10 mg, 0.11 mmol, 1.5 equiv) was added to a solution of (R)-3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholine (20 mg, 0.072 mmol, 1 equiv) in DCM (1 mL) at 0 °C. A solution of acryloyl chloride (7.8 mg, 0.086 mmol, 1.2 equiv) in DCM (1 mL) was added slowly at 0 °C, followed by stirring at 25 °C for 1 h. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL × 3), washed with brine (3 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO , EtOAc:PE = 1:1) to give the title compound (5.2 mg, 0.015 mmol, 22% yield) as a pale yellow solid. LC-MS m / z: 331.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0270] Example 8. Synthesis of (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-6-amino-1,3,5-triazin-2(1H)-one (Compound 177) [ka]

[0271] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from procedure B.

[0272] To a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (6.5 g, 17.25 mmol, 1 equiv.) in methanol (180 mL, 0.095 M) was added triethylamine (17.46 g, 172 mmol, 10 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.25 g, 1.72 mmol, 0.1 equiv.). The suspension was degassed several times, purged with CO, and then stirred at 65°C under CO (50 psi) for 48 hours. The reaction mixture was filtered and concentrated. The material was taken up in water (30 mL), extracted with ethyl acetate (30 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA=1:0 to 5:1) to give tert-butyl (R)-3-(3-chloro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (120 mg, 0.34 mmol, 64% yield) as a yellow oil.

[0273] To a solution of tert-butyl (R)-3-(3-chloro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (520 mg, 1.46 mmol, 1 equiv.) in methanol (10 mL, 0.14 M) was added sodium borohydride (0.346 g, 9.15 mmol, 3 equiv.), carbamimidoyl urea (596 mg, 5.84 mmol, 4 equiv.), and sodium methoxide (631 mg, 11.69 mmol, 8 equiv.). The mixture was stirred at 80° C. under a N atmosphere for 7 h. The crude was then purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; liquid phase: [A-10mM NH4HCO3 / HO; B-ACN] B%: 20%~60%, 8min]) to give tert-butyl (R)-3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (35mg, 0.085mmol, 6% yield) as a white solid.

[0274] Sodium nitrite (38.15 g, 553 mmol, 50 equiv.) in water (40 mL, 0.092 M) was added to tert-butyl (R)-3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (4.5 g, 11.06 mmol, 1 equiv.) in acetic acid (80 mL, 0.092 M) at 20 °C. The mixture was stirred for 2 days. The reaction mixture was filtered and washed with water (10 mL) to give tert-butyl (R)-3-(3-(6-amino-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (3.50 g, 8.58 mmol, 78% yield) as a yellow solid. The crude product was used in the next step without further purification.

[0275] [ka]

[0276] HCl in dioxane (50 mL) was added to a solution of tert-butyl (R)-3-(3-(6-amino-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (12 g, 23.53 mmol, 1 equiv.) in 1,4-dioxane (100 mL, 0.23 M). The mixture was stirred at 15° C. for 6 h and then concentrated to give crude (R)-6-amino-4-(3-chloro-5-(morpholin-3-yl)phenyl)-1,3,5-triazin-2(1H)-one HCl (8.0 g, 23.2 mmol, 99% yield) as a yellow solid. The crude product was used in the next step without further purification.

[0277] Acryloyl chloride (352 mg, 3.89 mmol, 0.5 equiv) was added to a mixture of (R)-6-amino-4-(3-chloro-5-(morpholin-3-yl)phenyl)-1,3,5-triazin-2(1H)-one HCl (2.4 g, 7.79 mmol, 1 equiv) and N,N-diisopropylethylamine (2.01 g, 15.59 mmol, 2 equiv) in DCM (50 mL, 0.15 M) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into water (100 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%~40%, 20min) to give the title compound (600mg, 1.66mmol, 21% yield) as a yellow solid. LC-MS m / z: 362.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0278] Example 9. Synthesis of (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1,3-dihydro-2H-imidazol-2-one (Compound 184) [ka]

[0279] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from procedure B.

[0280] A solution of 1,3-dihydroimidazol-2-one (15 mg, 0.17 mmol, 1 equiv.), tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (100.8 mg, 0.26 mmol, 1.5 equiv.), palladium acetate (4.01 mg, 0.017 mmol, 0.1 equiv.), and sodium acetate (43.9 mg, 0.53 mmol, 3 equiv.) in DMSO (2 mL, 0.089 M) was stirred at 80° C. for 12 h. The mixture was poured into water (3 mL), extracted with ethyl acetate (2 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO, EtOAc = 1) to give tert-butyl (R)-3-(3-chloro-5-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)phenyl)morpholine-4-carboxylate (17 mg, 0.045 mmol, 25% yield) as a yellow oil.

[0281] Using tert-butyl (R)-3-(3-chloro-5-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)phenyl)morpholine-4-carboxylate in step 9 of procedure B gave the title compound. LC-MS m / z: 334.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0282] Example 10. Synthesis of (R)-1-(3-(3-(2-amino-1H-imidazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 193) [ka]

[0283] To a solution of 2-nitro-1H-imidazole (1 g, 8.84 mmol, 1 equiv) in THF (20 mL, 0.44 M) was added sodium hydride (459 mg, 11.49 mmol, 1.3 equiv) (60% purity) at 0 °C under a N atmosphere. The reaction was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (1.91 g, 11.49 mmol, 1.3 equiv) was added and the reaction was stirred at 25 °C for 2 h. The reaction was poured into HO (100 mL) and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 5:1) to obtain trimethyl-[2-[(2-nitroimidazol-1-yl)methoxy]ethyl]silane (1.90 g, 7.81 mmol, 88% yield) as a yellow oil.

[0284] To a solution of trimethyl-[2-[(2-nitroimidazol-1-yl)methoxy]ethyl]silane (2.1 g, 8.62 mmol, 1 equiv) in DMF (10 mL, 0.86 M) and CHCl3 (10 mL) was added N-bromosuccinimide (1.68 g, 9.49 mmol, 1.1 equiv). The reaction was stirred at 20 °C for 16 h. The reaction was poured into HO (100 mL) and the aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 3:1) to give 2-[(4-bromo-2-nitro-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (1.50 g, 4.66 mmol, 54% yield) as a yellow oil.

[0285] tert-Butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 7.

[0286] To a solution of tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (580 mg, 1.36 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.11 M) and water (2.5 mL, 0.11 M), 2-[(4-bromo-2-nitro-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (661 mg, 2.05 mmol, 1.5 equiv.), potassium phosphate tribasic (581 mg, 2.73 mmol, 2 equiv.), and cataCXiumA Pd G2 (91.5 mg, 0.13 mmol, 0.1 equiv.) were added under a N2 atmosphere. The reaction was stirred at 80 °C for 16 h. The reaction mixture was poured into HO (20 mL), and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to afford tert-butyl (R)-3-(3-chloro-5-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxylate (470 mg, 0.87 mmol, 64% yield) as a brown oil.

[0287] [ka]

[0288] To a solution of tert-butyl (R)-3-(3-chloro-5-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)morpholine-4-carboxylate (300 mg, 0.55 mmol, 1 equiv) in DCM (10 mL, 0.055 M) was added ZnBr (250 mg, 1.11 mmol, 2 equiv). The reaction was stirred at 25 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give 342 mg as a crude brown oil. The product was used in the next step without further purification.

[0289] To a solution of (R)-3-(3-chloro-5-(2-nitro-1-(2-(trimethylsilyl)ethoxy)-1H-imidazol-4-yl)phenyl)morpholine (342 mg, 0.78 mmol, 1 equiv.) in DCM (10 mL, 0.078 M) was added acrylic acid (84 mg, 1.17 mmol, 1.5 equiv.), N,N-diisopropylethylamine (201 mg, 1.55 mmol, 2 equiv.), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (991 mg, 1.55 mmol, 2 equiv.). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into HO (50 mL) and the aqueous layer was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to give (R)-1-(3-(3-chloro-5-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)morpholino)prop-2-en-1-one (177 mg, 0.36 mmol, 46% yield) as a yellow oil.

[0290] To a solution of (R)-1-(3-(3-chloro-5-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)morpholino)prop-2-en-1-one (177 mg, 0.35 mmol, 1 equiv) in ethanol (2 mL, 0.14 M) and water (0.6 mL) was added iron powder (60 mg, 1.07 mmol, 3 equiv) and ammonium chloride (19 mg, 0.35 mmol, 1 equiv). The reaction was stirred at 80° C. for 1 h. The organic layer was filtered and evaporated to dryness to give 166 mg of crude product. The crude material was used in the next step without further purification.

[0291] To a solution of (R)-1-(3-(3-(2-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (154 mg, 0.33 mmol, 1 equiv.) in DCM (2 mL, 0.11 M) was added trifluoroacetic acid (1 mL, 0.11 M). The reaction was stirred at 25° C. for 1 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (55 mg, 0.165 mmol, 49% yield) as a white solid. LC-MS m / z: 333.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0292] Example 11. Synthesis of (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 208) [ka]

[0293] (R)-1-(3-(3-(4-amino-6-chloro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one was obtained using procedure D.

[0294] To a solution of (R)-1-(3-(3-(4-amine-6-chloro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (100 mg, 0.26 mmol, 1 equiv.) in DO (2 mL) and THF (1 mL, 0.26 M) were added zinc (granular, 200 mg, 3.06 mmol, 11.63 equiv.) and acetic acid-D3 (47 mg, 0.78 mmol, 3 equiv.) at 25 °C. The mixture was stirred under N2 atmosphere at 40 °C for 12 h. The reaction mixture was filtered, poured into water (15 mL), and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge Prep OBD C18 150*40mm*10um; liquid phase: [A - 10mM NH4HCO3 / H2O; B - ACN] B%: 15%~45%, 8min) to give (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one (10mg, 0.028mmol, 11% yield) as a white solid. LC-MS m / z: 347.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0295] Example 12. Synthesis of (R)-1-(3-(3-chloro-5-(3-hydroxy-1H-1,2,4-triazol-5-yl)phenyl)morpholino)prop-2-en-1-one (Compound 210) [ka]

[0296] (R)-3-(3-bromo-5-chlorophenyl)morpholine was obtained from Procedure B, Step 5.

[0297] To a solution of (R)-3-(3-bromo-5-chlorophenyl)morpholine (200 mg, 0.72 mmol, 1 equiv) in MeCN (10 mL, 0.072 M) was added potassium carbonate (199.9 mg, 1.44 mmol, 2 equiv) and 4-methoxybenzyl chloride (226.51 mg, 1.44 mmol, 2 equiv). The mixture was stirred at 80° C. for 16 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (petroleum ether: EtOAc = 3:1) to give (R)-3-(3-bromo-5-chlorophenyl)-4-(4-methoxybenzyl)morpholine (260 mg, 0.65 mmol, 91% yield) as a yellow oil.

[0298] Tetrakis(triphenylphosphine) (2.91 g, 2.52 mmol, 0.2 equiv) and zinc cyanide (1.18 g, 10.08 mmol, 0.8 equiv) were added to a solution of (R)-3-(3-bromo-5-chlorophenyl)-4-(4-methoxybenzyl)morpholine (5 g, 12.6 mmol, 1 equiv) in DMF (50 mL, 0.25 M). The mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with water (50 mL*2), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC (40 g SEPAFLASH® silica flash column, eluting with a 0-15% ethyl acetate / petroleum ether gradient) to give (R)-3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)benzonitrile (2.50 g, 7.29 mmol, 58% yield) as a colorless oil.

[0299] Sodium methoxide (210.1 mg, 1.16 mmol, 0.2 equiv) was added to a solution of (R)-3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)benzonitrile (2 g, 5.83 mmol, 1 equiv) in methanol (20 mL, 0.29 M). The resulting mixture was stirred at 50 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by MPLC (12 g SEPAFLASH® silica flash column, 0–20% ethyl acetate / petroleum ether eluent, gradient @ 36 mL / min) to afford (R)-3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)benzimidate (500 mg, 1.33 mmol, 23% yield) as a white solid.

[0300] [ka]

[0301] N-Methylmorpholine (674 mg, 6.66 mmol, 5 equiv.) and aminourea hydrochloride (148 mg, 1.33 mmol, 1 equiv.) were added to a solution of methyl (R)-3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)benzimidate (500 mg, 1.33 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.13 M). The resulting mixture was heated to 120° C. and stirred for 16 hours. The reaction mixture was concentrated to a residue. The residue was purified by MPLC (12 g SEPAFLASH® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient @ 36 mL / min) to give (R)-5-(3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)phenyl)-1H-1,2,4-triazol-3-ol (300 mg, 0.75 mmol, 56% yield).

[0302] A mixture of (R)-5-(3-chloro-5-(4-(4-methoxybenzyl)morpholin-3-yl)phenyl)-1H-1,2,4-triazol-3-ol (280 mg, 0.69 mmol, 1 equiv.) and TfOH (3 mL) in trifluoroacetic acid (3 mL, 0.23 M) was stirred at 90 °C for 2 days. The reaction mixture was poured into saturated aqueous NaHCO (50 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 1% to 30%, 10 min).

[0303] Acrylic acid (14.11 mg, 0.19 mmol, 1.1 equiv.), N,N-diisopropylethylamine (446 mg, 3.45 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (283 mg, 0.44 mmol, 2.5 equiv.) were added to a solution of (R)-5-(3-chloro-5-(morpholin-3-yl)phenyl)-1H-1,2,4-triazol-3-ol (50 mg, 0.17 mmol, 1 equiv.) in DCM (1 mL, 0.17 M) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by preparative TLC (EtOAc:MeOH = 10:1) and preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to give (R)-1-(3-(3-chloro-5-(3-hydroxy-1H-1,2,4-triazol-5-yl)phenyl)morpholino)prop-2-en-1-one (1.9 mg, 0.0055 mmol, 3 equiv.) as a white solid. LC-MS m / z: 335.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0304] Example 13. Synthesis of (R)-1-(3-(3-(4-amino-1H-pyrazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 211) [ka]

[0305] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0306] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (300 mg, 0.79 mmol, 1 equiv) in MeCN (8 mL, 0.099 M) was added 4-nitro-1H-pyrazole (233 mg, 2.06 mmol, 2.6 equiv), boric acid (294 mg, 4.76 mmol, 6 equiv), 4A molecular sieves (300 mg), and copper(II) acetate (72 mg, 0.39 mmol, 0.5 equiv) at 25° C. The mixture was stirred at 90° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; liquid phase: [A-10mM NH4HCO3 / HO; B-ACN] B%: 35%-55%, 8min]) to give (R)-1-(3-(3-chloro-5-(4-nitro-1H-pyrazol-1-yl)phenyl)morpholino)prop-2-en-1-one (50mg, 0.138mmol, 17% yield) as a yellow solid.

[0307] To a solution of (R)-1-(3-(3-chloro-5-(4-nitro-1H-pyrazol-1-yl)phenyl)morpholino)prop-2-en-1-one (50 mg, 0.13 mmol, 1 equiv.) in ethanol (3 mL, 0.028 M), water (1.5 mL, 0.028 M), and acetic acid (0.30 mL, 0.028 M), zinc (granular, 31.53 mg, 0.48 mmol, 3.5 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 30 minutes. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; liquid phase: [A - 10mM NH4HCO3 / H2O; B - ACN] B%: 20%-40%, 8min) to give (R)-1-(3-(3-(4-amino-1H-pyrazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (6.6mg, 0.019mmol, 14% yield) as a brown solid. LC-MS m / z: 333.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0308] Example 14. Synthesis of (R)-1-(3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 212) [ka]

[0309] tert-Butyl (R)-3-(3-chloro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate was obtained from step 1 of the synthesis of compound 177.

[0310] NaH (40 mg, 1.68 mmol, 3 equiv) was added to a solution of acetonitrile (46 mg, 1.12 mmol, 2 equiv) in THF (3 mL, 0.18 M) and stirred for 15 min, after which tert-butyl (R)-3-(3-chloro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (200 mg, 0.56 mmol, 1 equiv) was added at 25 °C. The mixture was stirred at 60 °C under a N atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NH Cl (6 mL) and extracted with EtOAc (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , PE:EtOAc=1:1) to give tert-butyl (R)-3-(3-chloro-5-(2-cyanoacetyl)phenyl)morpholine-4-carboxylate (100 mg, 0.274 mmol, 49% yield).

[0311] To a solution of tert-butyl (R)-3-(3-chloro-5-(2-cyanoacetyl)phenyl)morpholine-4-carboxylate (100 mg, 0.27 mmol, 1 equiv.) in methanol (3 mL, 0.091 M) was added hydroxylamine hydrochloride (57 mg, 0.82 mmol, 3 equiv.) at 25 °C. The mixture was stirred at 25 °C under a N atmosphere for 16 h. The reaction mixture was poured into saturated aqueous NH Cl (6 mL) and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO , EtOAc) to give tert-butyl (R)-3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholine-4-carboxylate (70 mg, 0.184 mmol, 67% yield).

[0312] To a solution of tert-butyl (R)-3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholine-4-carboxylate (70 mg, 0.18 mmol, 1 equiv) in DCM (3 mL, 0.061 M) was added THF (1 mL) at 0 °C. The mixture was stirred at 25 °C under N atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NH Cl (6 mL) and extracted with DCM (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give crude (R)-3-(3-chloro-5-(morpholin-3-yl)phenyl)isoxazol-5-amine (51 mg, 0.182 mmol, 99% yield).

[0313] To a solution of (R)-3-(3-chloro-5-(morpholin-3-yl)phenyl)isoxazol-5-amine (104 mg, 0.37 mmol, 1 equiv.) in DCM (5 mL, 0.078 M) was added DIEA (120 mg, 3 equiv.) and acryloyl chloride (16 mg, 0.18 mmol, 0.5 equiv.) at 0° C. The mixture was stirred at 25° C. under a N atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (6 mL) and extracted with DCM (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give (R)-1-(3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (30 mg, 0.089 mmol, 24% yield) as a pale yellow solid. LC-MS m / z: 334.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0314] Example 15. Synthesis of (R)-1-(3-(3-(3-amino-1H-1,2,4-triazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 215) [ka]

[0315] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0316] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino-2-en-1-one (400 mg, 1.05 mmol, 1 equiv) in MeCN (8 mL, 0.13 M) was added 3-nitro-1H-1,2,4-triazole (314 mg, 2.75 mmol, 2.6 equiv), boric acid (392 mg, 6.35 mmol, 6 equiv), 4A molecular sieves (400 mg), and copper diacetate (96 mg, 0.52 mmol, 0.5 equiv) at 25 °C. The mixture was stirred at 80 °C under O for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Purification by SEPAFLASH® silica flash column, eluting with a 20-60% ethyl acetate / petroleum ether gradient at 60 mL / min, gave (R)-1-(3-(3-chloro-5-(3-nitro-1H-1,2,4-triazol-1-yl)phenyl)morpholino)prop-2-en-1-one (80 mg, 0.22 mmol, 21% yield) as a yellow oil.

[0317] To a solution of (R)-1-(3-(3-chloro-5-(3-nitro-1H-1,2,4-triazol-1-yl)phenyl)morpholino)prop-2-en-1-one (80 mg, 0.22 mmol, 1 equiv.) in ethanol (2 mL), water (1 mL), and acetic acid (0.2 mL), zinc granules (50 mg, 0.76 mmol, 3.5 equiv.) were added at 0° C. and stirred for 30 minutes. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA:MeOH=5:1) to give (R)-1-(3-(3-(3-amino-1H-1,2,4-triazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (38 mg, 0.11 mmol, 51% yield) as a white solid. LC-MS m / z: 334.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0318] Example 16. Synthesis of (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-5-carboxamide (Compound 220) [ka]

[0319] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0320] A solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (1200 mg, 2.83 mmol), ethyl 2-bromooxazole-5-carboxylate (560 mg, 2.54 mmol, 0.9 equiv.), potassium carbonate (782.8 mg, 5.66 mmol), and Pd(dppf)Cl (204 mg, 0.28 mmol, 0.1 equiv.) in 1,4-dioxane (12 mL, 0.18 M) and water (3 mL, 0.18 M) was stirred at 80 °C under N atmosphere for 12 h. The reaction mixture was poured into HO (10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (PE=EA=3:1) to afford tert-butyl (R)-3-(3-chloro-5-(5-(ethoxycarbonyl)oxazol-2-yl)phenyl)morpholine-4-carboxylate (740 mg, 1.69 mmol, 60% yield) as a yellow oil.

[0321] A solution of tert-butyl (R)-3-(3-chloro-5-(5-(ethoxycarbonyl)oxazol-2-yl)phenyl)morpholine-4-carboxylate (740 mg, 1.69 mmol, 1 equiv.) and lithium hydroxide monohydrate (284 mg, 6.77 mmol, 4 equiv.) in THF (6 mL, 0.23 M) and water (1.2 mL, 0.23 M) was stirred at 25 °C for 3 h. The reaction mixture was diluted with HO (10 mL) and extracted with MTBA (10 mL*2). The pH was adjusted to 4-5 by adding 1 M aqueous HCl. The aqueous layer was extracted with ethyl acetate (10 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give (R)-2-(3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-chlorophenyl)oxazole-5-carboxylic acid (560 mg, 1.37 mmol, 81% yield) as a yellow oil.

[0322] To a solution of (R)-2-(3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-chlorophenyl)oxazole-5-carboxylic acid (150 mg, 0.36 mmol, 1 equiv.) in THF (2 mL, 0.18 M) was added ammonium bicarbonate (58 mg, 0.73 mmol, 2 equiv.), pyridine (58 mg, 0.73 mmol, 2 equiv.), and di-tert-butyl dicarbonate (160 mg, 0.73 mmol, 2 equiv.) under N2 atmosphere at 25 °C and stirred for 12 h. The reaction mixture was diluted with HO (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give tert-butyl (R)-3-(3-(5-carbamoyloxazol-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (130 mg, 0.319 mmol, 87% yield) as a yellow solid.

[0323] tert-Butyl (R)-3-(3-(5-carbamoyloxazol-2-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of Procedure B to give the title compound. LC-MS m / z: 334.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0324] Example 17. Synthesis of (R)-1-(3-(3-chloro-5-(4-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (Compound 221) [ka]

[0325] To a solution of 3-amino-1-propanol (601 mg, 8.0 mmol, 1.2 equiv) in 1,4-dioxane (10 mL, 0.66 M), DIEA (1.3 equiv) and 2,4-dichloro-1,3,5-triazine (1 g, 6.66 mmol) were added and stirred at 35 °C under N atmosphere for 2 h. The reaction mixture was poured into water (15 mL). The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give 3-[(4-chloro-1,3,5-triazin-2-yl)amino]propan-1-ol (820 mg, 4.35 mmol, 65% yield) as a yellow solid.

[0326] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0327] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (1505.3 mg, 3.55 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.22 M), HO (1.8 mL), 3-[(4-chloro-1,3,5-triazin-2-yl)amino]propan-1-ol (670 mg, 3.55 mmol, 1 equiv.), KCO (2 equiv., 981 mg), and Pd(PPh) (0.1 equiv., 411 mg) were added under a N atmosphere and stirred at 80 °C for 3 h. The reaction mixture was poured into water (15 mL). The aqueous layer was extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl (R)-3-(3-chloro-5-(4-((3-hydroxypropyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.11 mmol, 31% yield) as a yellow solid.

[0328] To a solution of tert-butyl (R)-3-(3-chloro-5-(4-((3-hydroxypropyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (200 mg, 0.44 mmol, 1 equiv) in DCM (5 mL, 0.08 M) was added Dess-Martin periodinane (245.1 mg, 0.57 mmol) and stirred at 20 °C under N atmosphere for 2 h. The reaction was poured into water (8 mL). The aqueous layer was extracted with DCM (5 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give tert-butyl (R)-3-(3-chloro-5-(4-((3-oxopropyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (40 mg, 0.089 mmol, 20% yield) as a yellow solid.

[0329] To a solution of tert-butyl (R)-3-(3-chloro-5-(4-((3-oxopropyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (40 mg, 0.089 mmol, 1 equiv) in DCM (5 mL, 0.018 M), dimethylamine hydrochloride (11 mg, 0.13 mmol) was added and stirred at 20 °C under N atmosphere for 12 h. The reaction was poured into water (8 mL). The aqueous layer was extracted with EtOAc (5 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give tert-butyl (R)-3-(3-chloro-5-(4-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (100 mg, 0.084 mmol, 94% yield).

[0330] tert-Butyl (R)-3-(3-chloro-5-(4-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate was used in step 9 of Procedure B to give the title compound. LC-MS m / z: 431.3 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0331] Example 18. Synthesis of (R)-5-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)tetrahydropyrimidin-2(1H)-one (Compound 222) [ka]

[0332] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 6.

[0333] To a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (3 g, 7.96 mmol, 1 equiv.) in DMF (30 mL, 0.26 M) was added sodium carbonate (2.53 g, 23.8 mmol, 3 equiv.), triethylsilane (2.31 g, 19.91 mmol, 2.5 equiv.), and Pd(dppf)Cl (404.57 mg, 0.55 mmol, 0.07 equiv.). The suspension was degassed several times, purged with CO, and then stirred at 80 °C under CO (50 psi) for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 5 / 1) to give tert-butyl (R)-3-(3-chloro-5-formylphenyl)morpholine-4-carboxylate (2.00 g, 6.14 mmol, 77% yield) as a yellow oil.

[0334] Nitromethane (937 mg, 15.31 mmol, 50 equiv.) was added to tert-butyl (R)-3-(3-chloro-5-formylphenyl)morpholine-4-carboxylate (100 mg, 0.31 mmol, 1 equiv.) and Al2O3 (100 mg). The mixture was stirred at 95 °C for 4 h. The mixture was filtered and washed with EtOAc (10 mL). 10% aqueous citric acid (10 mL) was added, the mixture was extracted three times with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (R)-3-(3-chloro-5-(1,3-dinitropropan-2-yl)phenyl)morpholine-4-carboxylate (100 mg, 0.23 mmol, 76% yield) as a yellow oil.

[0335] To a solution of tert-butyl (R)-3-(3-chloro-5-(1,3-dinitropan-2-yl)phenyl)morpholine-4-carboxylate (600 mg, 1.39 mmol, 1 equiv.) and 1,3,5-trichlorobenzene (253 mg, 1.39 mmol, 1 equiv.) in THF (1 mL, 1.39 M) was added PtO (10 mg) under an Ar atmosphere at 25 °C. The reaction was stirred under H (50 PSI) at 25 °C for 12 h. The organic layer was filtered and evaporated to dryness. The crude residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um; liquid phase: [A-TFA / HO=0.075%v / v; B-ACN] B%: 1%-30%, 8min]) to give tert-butyl (R)-3-(3-chloro-5-(1,3-diaminopropan-2-yl)phenyl)morpholine-4-carboxylate (100mg, 0.270mmol, 20% yield) as a white solid.

[0336] To a solution of tert-butyl (R)-3-(3-chloro-5-(1,3-diaminopropan-2-yl)phenyl)morpholine-4-carboxylate (40 mg, 0.11 mmol, 1 equiv.) in THF (1 mL, 0.11 M), a solution of 1,1'-carbonyl-diimidazole (17 mg, 0.11 mmol, 1 equiv.) in THF (0.5 mL) was slowly added under N atmosphere at 25 °C and stirred for 16 hours. The solution was concentrated in vacuo, and the residue was purified by preparative TLC (SiO, EA:MeOH = 5:1) to give tert-butyl (R)-3-(3-chloro-5-(2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (40 mg, 0.101 mmol, 93% yield) as a yellow oil.

[0337] tert-Butyl (R)-3-(3-chloro-5-(2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate was used in step 9 of Procedure B to give the title compound. LC-MS m / z: 350.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0338] Example 19. Synthesis of (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxamide (Compound 224) [ka]

[0339] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0340] A solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (2.4 g, 5.66 mmol), ethyl 2-bromooxazole-4-carboxylate (1.24 g, 5.66 mmol, 1 equiv.), potassium carbonate (1.56 g, 11.32 mmol), and Pd(dppf)Cl (0.41 g, 0.56 mmol, 0.1 equiv.) in 1,4-dioxane (25 mL, 0.18 M) and water (5 mL, 0.18 M) was stirred at 80 °C under N atmosphere for 16 h. The reaction mixture was poured into HO (30 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (PE:EA = 0:1 to 1:1) to give tert-butyl (R)-3-(3-chloro-5-(4-(ethoxycarbonyl)oxazol-2-yl)phenyl)morpholine-4-carboxylate (2.10 g, 4.81 mmol, 85% yield).

[0341] A solution of tert-butyl (R)-3-(3-chloro-5-(4-(ethoxycarbonyl)oxazol-2-yl)phenyl)morpholine-4-carboxylate (0.50 g, 1.14 mmol) and LiOH (0.18 g, 4.43 mmol, 4 equiv.) in THF (5 mL, 0.18 M) and water (1.2 mL, 0.18 M) was stirred at 25 °C under N atmosphere for 3 h. The reaction mixture was diluted with HO (10 mL) and extracted with MTBA (10 mL*2). Aqueous HCl (1 M) was added to the aqueous layer to adjust the pH to 4-5. The aqueous layer was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-2-(3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxylic acid (0.43 g).

[0342] To a solution of (R)-2-(3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxylic acid (200 mg, 0.48 mmol, 1 equiv.) in THF (2 mL, 0.24 M), ammonium bicarbonate (77 mg, 0.97 mmol, 2 equiv.), pyridine (77.39 mg, 0.97 mmol, 2 equiv.), and di-tert-butyl dicarbonate (213.53 mg, 0.97 mmol, 2 equiv.) were added under N2 atmosphere at 25 °C and stirred for 12 h. The reaction mixture was diluted with HO (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (R)-3-(3-(4-carbamoyloxazol-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (220 mg).

[0343] tert-Butyl (R)-3-(3-(4-carbamoyloxazol-2-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of procedure B to give the title compound. LC-MS m / z: 362.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0344] Example 20. Synthesis of (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)piperazin-2-one (Compound 228) [ka]

[0345] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 6.

[0346] Palladium(II) acetate (40.53 mg, 0.18 mmol, 0.10 equiv.) and Vinap (racemic) (224 mg, 0.36 mmol, 0.20 equiv.) in 1,4-dioxane (40 mL, 0.045 M) were stirred at 40 °C for 30 min under a N atmosphere. tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (680 mg, 1.81 mmol, 1 equiv.), 1-boc-2-oxopiperazine (361.47 mg, 1.81 mmol, 1 equiv.), and cesium carbonate (882.3 mg, 2.70 mmol, 1.5 equiv.) were added, and the solution was stirred at 80 °C for 12 h. The reaction mixture was poured into HO (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SEPAFLASH® silica flash column, eluting with a 0-70% ethyl acetate / petroleum ether gradient at 80 mL / min) to give tert-butyl (R)-3-(3-(4-(tert-butoxycarbonyl)-3-oxopiperazin-1-yl)-5-chlorophenyl)morpholine-4-carboxylate (650 mg, 1.31 mmol, 73% yield).

[0347] tert-Butyl (R)-3-(3-(4-(tert-butoxycarbonyl)-3-oxopiperazin-1-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of procedure B to give the title compound. LC-MS m / z: 349.8 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0348] Example 21. Synthesis of (R)-1-(3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 229) [ka]

[0349] A solution of 4,6-dichloro-1,3,5-triazin-2-amine (1 g, 6.06 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.61 M), DIEA (1.3 equiv., 1.01 g), and 3-amino-1-propanol (546.32 mg, 7.27 mmol) was stirred at 35° C. under a N atmosphere for 2 hours. The reaction was poured into water (15 mL). The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate=2 / 1 to 0 / 1) to give 3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]propan-1-ol (1.00 g, 4.91 mmol, 81% yield) as a yellow solid.

[0350] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0351] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (228.9 mg, 0.54 mmol, 1.1 equiv.) in 1,4-dioxane (2 mL, 0.15 M) and HO (1.8 mL), 3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]propan-1-ol (100 mg, 0.49 mmol, 1 equiv.), KCO (2 equiv., 65 mg), and Pd(PPh) (0.1 equiv., 30 mg) were added and stirred at 80 °C for 12 h under a N atmosphere. The reaction was poured into water (8 mL). The aqueous layer was extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give tert-butyl (R)-3-(3-(4-amino-6-((3-hydroxypropyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate.

[0352] [ka]

[0353] To a solution of tert-butyl (R)-3-(3-(4-amino-6-((3-hydroxypropyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (500 mg, 1.04 mmol, 1 equiv) in DCM (5 mL, 0.21 M) was added Dess-Martin periodinane (592.95 mg, 1.39 mmol) and stirred at 20 °C under N atmosphere for 2 h. The reaction was poured into water (8 mL). The aqueous layer was extracted with DCM (5 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl (R)-3-(3-(4-amino-6-((3-oxopropyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (450 mg, 0.680 mmol, 63% yield).

[0354] To a solution of tert-butyl (R)-3-(3-(4-amino-6-(3-oxopropyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (450 mg, 0.91 mmol, 1 equiv.) in DCM (5 ml, 0.19 M), dimethylamine hydrochloride (119 mg, 1.46 mmol) and sodium triacetoxyborohydride (515 mg, 2.43 mmol) were added and stirred at 20 °C under N atmosphere for 12 h. The reaction mixture was poured into water (8 mL). The aqueous layer was extracted with DCM (5 mL * 3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous NaSO, filtered and concentrated in vacuo to give tert-butyl (R)-3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate (280 mg, 0.39 mmol, 41% yield).

[0355] tert-Butyl (R)-3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of procedure B to give the title compound. LC-MS m / z: 446.3 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0356] Example 22. Synthesis of (R)-1-(3-(3-chloro-5-(2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one (Compound 233) [ka]

[0357] tert-Butyl (R)-3-(3-chloro-5-(1,3-diaminopropan-2-yl)phenyl)morpholine-4-carboxylate was obtained from step 3 of the synthesis of compound 222.

[0358] To a solution of tert-butyl (R)-3-(3-chloro-5-(1,3-diaminopropan-2-yl)phenyl)morpholine-4-carboxylate (320 mg, 0.86 mmol, 1 equiv.) in THF (1 mL, 0.86 M), di(imidazol-1-yl)methanethione (154 mg, 0.86 mmol, 1 equiv.) in THF (0.5 mL) was slowly added, followed by stirring for 16 h. The residue was purified by preparative TLC (SiO, EA:MeOH=10:1) to give tert-butyl (R)-3-(3-chloro-5-(2-thioxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (100 mg, 0.24 mmol, 28% yield).

[0359] tert-Butyl (R)-3-(3-chloro-5-(2-thioxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate was used in step 9 of Procedure B to give the title compound. LC-MS m / z: 366.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0360] Example 23. Synthesis of (R)-1-(3-(3-(2-aminooxazol-5-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 234) [ka]

[0361] tert-Butyl (R)-3-(3-chloro-5-formylphenyl)morpholine-4-carboxylate was obtained from step 2 of the synthesis of compound 222.

[0362] To a solution of (methoxymethyl)triphenylphosphonium chloride (136.79 mg, 0.39 mmol, 1.3 equiv) in THF (3 mL, 0.10 M) was added sodium bis(trimethylsilyl)amide (1.3 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h, then tert-butyl (R)-3-(3-chloro-5-formylphenyl)morpholine-4-carboxylate (100 mg, 0.31 mmol) was added at 0° C., and the mixture was stirred for 2 h. The reaction mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (PE: EtOAc = 3:1) to give tert-butyl (R, Z)-3-(3-chloro-5-(2-methoxyvinyl) phenyl) morpholine-4-carboxylate (130 mg) as a colorless oil.

[0363] To a solution of tert-butyl (R,Z)-3-(3-chloro-5-(2-methoxyvinyl)phenyl)morpholine-4-carboxylate (130 mg, 0.36 mmol) in 1,4-dioxane (2 mL, 0.09 M) and water (2 mL), N-bromosuccinimide (71 mg, 0.40 mmol, 1.1 equiv) was added at 0° C. and stirred for 1 h. Urea (22 mg, 0.36 mmol, 1 equiv) was added and stirred at 70° C. for 16 h. The mixture was evaporated to dryness and the crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; liquid phase: [Preparative HPLC (column: Phenomenex C18 75*30mm*3um; liquid phase: [A-10mM NH4HCO3 / HO; B-ACN] B%: 25%-70%, 8min]) to give tert-butyl (R)-3-(3-(2-aminooxazol-5-yl)-5-chlorophenyl)morpholine-4-carboxylate (15mg, 0.039mmol, 11% yield).

[0364] tert-Butyl (R)-3-(3-(2-aminooxazol-5-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of procedure B to give the title compound. LC-MS m / z: 334.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0365] Example 24. Synthesis of 1-((R)-3-(3-chloro-5-((S)-5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one and 1-((R)-3-(3-chloro-5-((R)-5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one (Compounds 240 and 241) [ka]

[0366] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from Procedure B, Step 6.

[0367] To a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (20 g, 53 mmol, 1 equiv.) and potassium vinyltrifluoroborate (8.53 g, 63.71 mmol, 1.2 equiv.) in ethanol (200 mL, 0.26 M), triethylamine (16.11 g, 159.29 mmol, 3 equiv.) and Pd(dppf)Cl DCM complex (430.4 mg, 0.53 mmol, 0.01 equiv.) were added under a N atmosphere and then stirred at 85 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (12 g silica flash column, eluent of 30–70% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl (R)-3-(3-chloro-5-vinylphenyl)morpholine-4-carboxylate (20.80 g) as a pale yellow oil.

[0368] To a solution of tert-butyl (R)-3-(3-chloro-5-vinylphenyl)morpholine-4-carboxylate (5 g, 15.44 mmol, 1 equiv.) in DCM (50 mL, 0.31 M) was added 3-chloroperbenzoic acid (6.66 g, 30.88 mmol, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 5 h. Aqueous NaSO (50 mL) was added to the reaction mixture and stirred for 30 min. The mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO (50 mL * 2), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SEPAFLASH® silica flash column, elution with a 0-50% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl (3R)-3-(3-chloro-5-(oxiran-2-yl)phenyl)morpholine-4-carboxylate (2.50 g, 7.36 mmol, 48% yield).

[0369] tert-Butyl (3R)-3-(3-chloro-5-(oxiran-2-yl)phenyl)morpholine-4-carboxylate (2.5 g, 7.35 mmol, 1 equiv.) in a large excess of ammonia in methanol (26.27 mL, 183 mmol, 25 equiv.) was stirred at 70° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give tert-butyl (3R)-3-(3-(2-amino-1-hydroxyethyl)-5-chlorophenyl)morpholine-4-carboxylate (2.30 g, 6.45 mmol, 88% yield) as a yellow solid. The purity was 55%. 1 The assignment was made by H-NMR.

[0370] [ka]

[0371] To a solution of tert-butyl (3R)-3-(3-(2-amino-1-hydroxyethyl)-5-chlorophenyl)morpholine-4-carboxylate (2.25 g, 6.30 mmol, 1 equiv) in DCM (20 mL, 0.32 M) was added triethylamine (1091 mg, 10.78 mmol, 1.71 equiv) at 0° C. Chloroacetyl chloride (783 mg, 6.93 mmol, 1.1 equiv) was added slowly at 0° C., followed by stirring at 25° C. for 2 h. The mixture was concentrated to give tert-butyl (3R)-3-(3-chloro-5-(2-(2-chloroacetamido)-1-hydroxyethyl)phenyl)morpholine-4-carboxylate in approximately 40% purity. The crude residue was not purified.

[0372] A solution of tert-butyl (3R)-3-(3-chloro-5-(2-(2-chloroacetamido)-1-hydroxyethyl)phenyl)morpholine-4-carboxylate (2.6 g, 6 mmol, 1 equiv) in THF (30 mL, 0.20 M) was cooled to 0 °C, followed by the addition of sodium hydride (480 mg, 12 mmol, 2 equiv). The reaction was stirred at 50 °C for 2 h. The mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give tert-butyl (3R)-3-(3-chloro-5-(5-oxomorpholin-2-yl)phenyl)morpholine-4-carboxylate (210 mg, 0.52 mmol, 9% yield).

[0373] To a solution of phosphorus pentasulfide (179.22 mg, 0.40 mmol, 1 equiv.) in m-xylene (2 mL, 0.20 M) was added tert-butyl (3R)-3-(3-chloro-5-(5-oxomorpholin-2-yl)phenyl)morpholine-4-carboxylate (160 mg, 0.40 mmol, 1 equiv.) at 25 °C. The mixture was heated to 135 °C for 16 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (instrument: ACSTJ-GX-AP; column: water Xbridge BEH C18 100 × 30 mm × 10 μm; conditions: water (NH4HCO3-ACN)) to give 6-(3-chloro-5-((R)-morpholin-3-yl)phenyl)morpholine-3-thione (30 mg, 0.096 mmol, 24% yield).

[0374] [ka]

[0375] Triethylamine (19.40 mg, 0.19 mmol, 2 equiv) was added to a solution of 6-(3-chloro-5-((R)-morpholin-3-yl)phenyl)morpholine-3-thione (30 mg, 0.095 mmol, 1 equiv) in DCM (1 mL, 0.095 M) under a N atmosphere at 0° C. Acryloyl chloride (7.81 mg, 0.086 mmol, 0.9 equiv) was added and the mixture was stirred at 0° C. for 1 h. The mixture was concentrated, and the diastereomers were separated using preparative HPLC (ACSTJ-GX-AK, column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm, condition: water (NH4HCO3)-ACN) to give 1-((3R)-3-(3-chloro-5-(5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one (20 mg, 0.054 mmol, yield 56%).

[0376] Stereochemistry: Single enantiomer of known absolute configuration at the morpholine stereocenter. Stereocenter on morpholine-3-thione arbitrarily assigned.

[0377] 1-((R)-3-(3-chloro-5-((S)-5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one, LC-MS m / z: 367.2 [M+1]. 1-((R)-3-(3-chloro-5-((R)-5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one, LC-MS m / z: 367.2 [M+1].

[0378] Example 25. Synthesis of (S)-6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one and (R)-6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one (Compounds 231 and 232) tert-Butyl (3R)-3-(3-chloro-5-(5-oxomorpholin-2-yl)phenyl)morpholine-4-carboxylate from step 5 of the synthesis of compounds 240 and 241 was used in step 9 of procedure B.

[0379] The diastereomeric mixture of 6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one (78 mg, 0.22 mmol, 1 equiv.) was separated by chiral SFC.

[0380] Chiralpak IH-3, 100 × 4.6 mm i.d., 3 μm, mobile phase: A:CO2B:EtOH (0.1% IPAm, v / v), flow rate: 3.4 mL / min; column temperature: 35 °C.

[0381] Stereochemistry: Single enantiomer of known absolute configuration at the morpholine stereocenter. Stereocenter on the morpholin-3-one arbitrarily assigned.

[0382] The first eluting compound was arbitrarily assigned as (S)-6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one (18.5 mg).

[0383] The second eluting compound was arbitrarily assigned as (R)-6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one (18.7 mg).

[0384] Example 26. Synthesis of (R)-1-(3-(3-(5-amino-3,6-dihydropyrazin-1(2H)-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 244) tert-Butyl (R)-3-(3-(4-(tert-butoxycarbonyl)-3-oxopiperazin-1-yl)-5-chlorophenyl)morpholine-4-carboxylate was obtained from the synthesis of compound 228. [ka]

[0385] To a solution of tert-butyl (R)-3-(3-(4-(tert-butoxycarbonyl)-3-oxopiperazin-1-yl)-5-chlorophenyl)morpholine-4-carboxylate (840 mg, 1.69 mmol, 1 equiv) in DCM (6 mL, 0.28 M) was added TFA (2 mL) at 25° C. and stirred for 2 h. The reaction was concentrated under reduced pressure to give a residue (500 mg) that was used in the next step without further purification.

[0386] To a solution of crude (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)piperazin-2-one (500 mg, 1.69 mmol, 1 equiv) in DCM (10 mL, 0.17 M) was added triethylamine (342.14 mg, 3.38 mmol, 2 equiv) and di-tert-butyl dicarbonate (368.96 mg, 1.69 mmol, 1 equiv) under N atmosphere at 0° C. The solution was stirred at 25° C. for 12 hours. The reaction mixture was poured into HO (15 mL) and extracted with DCM (15 mL×3). The combined organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 50-100% ethyl acetate / petroleum ether gradient at 60 mL / min) to give tert-butyl (R)-3-(3-chloro-5-(3-oxopiperazin-1-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.26 mmol, 75% yield) as a yellow oil.

[0387] To a solution of tert-butyl (R)-3-(3-chloro-5-(3-oxopiperazin-1-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.26 mmol, 1 equiv) in DCM (6 mL, 0.21 M) was added trimethyloxonium tetrafluoroborate (242 mg, 1.64 mmol, 1.3 equiv) under a N atmosphere at 0° C. The solution was stirred at 25° C. for 12 hours. The mixture was used in the next step.

[0388] To a solution of crude tert-butyl (R)-3-(3-chloro-5-(5-methoxy-3,6-dihydropyrazin-1(2H)-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.22 mmol, 1 equiv) in DCM (6 mL) was added aqueous NH (6 mL) under N atmosphere at −40° C. The solution was stirred at −40° C. for 2 h and then allowed to warm to 25° C. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Phenomenex C18 80*30mm*3um; liquid phase: [A-TFA / HO=0.075%v / v; B-ACN] B%: 20%~50%, 8min]) to give tert-butyl (R)-3-(3-(5-amino-3,6-dihydropyrazin-1(2H)-yl)-5-chlorophenyl)morpholine-4-carboxylate (125mg, 0.32mmol, 26% yield).

[0389] tert-Butyl (R)-3-(3-(5-amino-3,6-dihydropyrazin-1(2H)-yl)-5-chlorophenyl)morpholine-4-carboxylate was used in step 9 of procedure B to give the title compound. LC-MS m / z: 349.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0390] Example 27. Synthesis of (R)-N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-5-yl)acetamide (Compound 248) [ka]

[0391] (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from procedure D.

[0392] To a solution of (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one (250 mg, 0.73 mmol, 1 equiv) in DCM (3 mL, 0.24 M) was added triethylamine (110 mg, 1.08 mmol, 1.5 equiv), acetyl chloride (68.3 mg, 0.87 mmol, 1.2 equiv), and 4-(dimethylamino)pyridine (8.85 mg, 0.072 mmol, 0.1 equiv) at 0 °C. The mixture was stirred under a N atmosphere at 20 °C for 20 h. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; liquid phase: [A-TFA / HO=0.075%v / v; B-ACN] B%: 20%-45%, 8min) to give (R)-N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-5-yl)acetamide (121mg, 0.31mmol, 43% yield) as a white solid. LC-MS m / z: 387.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0393] Example 28. Synthesis of (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one (Compound 253) [ka]

[0394] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0395] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (300 mg, 0.79 mmol, 1 equiv.) in 1,4-dioxane (5 mL, 0.13 M) and water (1 mL, 0.13 M), 2-chloro-5-nitro-pyrimidin-4-amine (221.83 mg, 1.27 mmol, 1.6 equiv.), potassium carbonate (219.56 mg, 1.58 mmol, 2 equiv.), and Pd(dppf)Cl (57 mg, 0.079 mmol, 0.1 equiv.) were added at 20° C. The mixture was stirred at 80° C. under a N atmosphere for 20 h. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 30–60% ethyl acetate / petroleum ether gradient at 50 mL / min) to give (R)-1-(3-(3-(4-amino-5-nitropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (220 mg, 0.56 mmol, 71% yield).

[0396] To a solution of (R)-1-(3-(3-(4-amino-5-nitropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (200 mg, 0.51 mmol, 1 equiv.) in ethanol (2 mL, 0.12 M), water (1 mL, 0.12 M), and acetic acid (1 mL, 0.12 M), zinc granules (130 mg, 1.98 mmol) were added at 25 °C. The mixture was stirred at 25 °C under a N atmosphere for 20 h. The mixture was filtered, and the solution was quenched with 1 N HCl. The solution pH was adjusted to pH = 8–9 with saturated aqueous NaHCO and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one (40.7 mg, 0.11 mmol, 22% yield). LC-MS m / z: 360.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0397] Example 29. Synthesis of (R)-N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4-yl)acetamide (Compound 256) [ka]

[0398] (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one was obtained from procedure D.

[0399] To a solution of (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (200 mg, 0.58 mmol, 1 equiv) in acetic anhydride (4 mL, 0.14 M) was added 4-(dimethylamino)pyridine (2.12 mg, 0.017 mmol, 0.03 equiv) at 20° C. The mixture was stirred at 80° C. under a N atmosphere for 4 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; liquid phase: [A-10mM NH4HCO3 / H2O; B-ACN] B%: 30%-50%, 8min) to give (R)-N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4-yl)acetamide (85mg, 0.21mmol, 37% yield) as a white solid. LC-MS m / z: 387.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0400] Example 30. Synthesis of Compound 263 [ka]

[0401] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (1 g, 5.98 mmol, 1 equiv.) was added aqueous NH (40 mL) at 25° C. The mixture was stirred under N atmosphere at 35° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give crude 2-chloro-5-fluoro-pyrimidin-4-amine.

[0402] 2-Chloro-5-fluoro-pyrimidin-4-amine was used in step 2 of procedure D to give the title compound. LC-MS m / z: 363.1 [M+1].

[0403] Example 31 Synthesis of (R)-1-(3-(3-chloro-5-(1H-1,2,3-triazol-4-yl)phenyl)morpholino)prop-2-en-1-one (Compound 269) [ka]

[0404] To a solution of 4-bromo-1H-triazole (100 mg, 0.67 mmol, 1 equiv) in DMF (2 mL, 0.33 M) at 0 °C, cesium carbonate (440.42 mg, 1.37 mmol, 2 equiv) and 2-(trimethylsilyl)ethoxymethyl chloride (169.02 mg, 1.013 mmol, 1.5 equiv) were added. The mixture was stirred at 20 °C for 12 h. The reaction was poured into HO (5 mL), and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 5 / 1) to give 2-[(4-bromotriazol-1-yl)methoxy]ethyl-trimethyl-silane (30 mg, 0.108 mmol, 16% yield) as a yellow solid.

[0405] (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one was obtained from Procedure D, Step 1.

[0406] To a solution of (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (50 mg, 0.13 mmol, 1 equiv.) in 1,4-dioxane (2 mL, 0.02 M) and water (0.40 mL, 0.055 M), 2-[(4-bromotriazol-1-yl)methoxy]ethyl-trimethyl-silane (36 mg, 0.13 mmol, 1 equiv.), potassium carbonate (45 mg, 0.33 mmol, 2.5 equiv.), and Pd(dppf)Cl (9.5 mg, 0.013 mmol, 0.1 equiv.) were added under a N atmosphere at 25 °C. The mixture was stirred at 80 °C for 7 h. The reaction mixture was poured into HO (10 mL), and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 1 / 1) to give (R)-1-(3-(3-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholino)prop-2-en-1-one (10 mg, 0.022 mmol, 17% yield).

[0407] To a solution of (R)-1-(3-(3-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholino)prop-2-en-1-one (110 mg, 0.24 mmol, 1 equiv) in DCM (2 mL, 0.08 M) was added trifluoroacetic acid (1 mL, 0.08 M) at 20° C. The mixture was stirred under N atmosphere at 35° C. for 16 h and then concentrated in vacuo. The crude material was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; liquid phase: [A - 10mM NH4HCO3 / H2O; B - ACN] B%: 10%~40%, 8min) to give (R)-1-(3-(3-chloro-5-(1H-1,2,3-triazol-4-yl)phenyl)morpholino)prop-2-en-1-one (47mg, 0.14mmol, 59% yield) as a yellow solid. LC-MS m / z: 319.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0408] Example 32. Synthesis of (R)-1-(3-(3-(5-amino-4-fluoropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 278) [ka]

[0409] To a solution of 2,4-dichloropyrimidin-5-amine (400 mg, 2.43 mmol, 1 equiv) in DMF (3 mL, 0.81 M) was added potassium fluoride (283 mg, 4.87 mmol). The mixture was stirred in a microwave at 130 °C for 13 hours. The reaction was poured into HO (10 mL) and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude 2-chloro-4-fluoropyrimidin-5-amine (400 mg) as a brown oil. The product was used in the next step without further purification.

[0410] The crude 2-chloro-4-fluoropyrimidin-5-amine was used in procedure D to give the title compound. LC-MS m / z: 363.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0411] Example 33 Synthesis of (R)-1-(3-(3-(6-amino-5-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 279) [ka]

[0412] A solution of 6-chloropyrazin-2-amine (500 mg, 3.85 mmol, 1 equiv.), SELECTFLUOR® (1.025 g, 2.89 mmol, 0.75 equiv.), and silver carbonate (106.42 mg, 0.38 mmol, 0.1 equiv.) in MeCN (8 mL, 0.48 M) was stirred at 85° C. for 24 h in a microwave. The reaction mixture was poured into HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (30 mL) and concentrated. The crude residue was purified by flash column chromatography (pet ether:ethyl acetate = 1:0 to 1:1) to give 6-chloro-3-fluoro-pyrazin-2-amine (200 mg, 1.36 mmol, 35% yield) and 6-chloro-5-fluoro-pyrazin-2-amine (170 mg, 1.15 mmol, 30% yield).

[0413] 6-Chloro-3-fluoro-pyrazin-2-amine was used in procedure D to give the title compound. LC-MS m / z: 363.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0414] Example 34. Synthesis of (R)-1-(3-(3-(6-amino-3-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 280) 6-Chloro-5-fluoro-pyrazin-2-amine from the synthesis of compound 279 was used in procedure D to give the title compound. LC-MS m / z: 363.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0415] Example 35. Synthesis of (R)-1-(3-(3-(6-amino-2-fluoropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 283) [ka]

[0416] To a solution of 2,6-dichloropyrimidin-4-amine (1 g, 6.09 mmol, 1 equiv.) in DMF (10 mL, 0.61 M) was added potassium fluoride (1.77 g, 30.49 mmol) at 20 °C. The mixture was stirred at 130 °C for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Phenomenex luna C18 75 × 30 mm × 3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-30%, 8 min] to give 6-chloro-2-fluoropyrimidin-4-amine (50 mg, 0.34 mmol, 6% yield) as a white solid.

[0417] 6-Chloro-2-fluoropyrimidin-4-amine was used in step 2 of procedure D to give the title compound. LC-MS m / z: 363.2 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0418] Example 36. Synthesis of (R)-1-(3-(3-(5-amino-6-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 289) [ka]

[0419] A solution of 5-chloropyrazin-2-amine (500 mg, 3.85 mmol, 1 equiv.), SELECTFLUOR® (1.025 g, 2.89 mmol, 0.75 equiv.), and silver carbonate (106.42 mg, 0.38 mmol, 0.10 equiv.) in MeCN (8 mL, 0.48 M) was stirred at 85° C. in a microwave for 12 hours. The reaction was poured into HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (30 mL) and concentrated. The crude material was purified by flash column chromatography (PE:EA = 1:0 to 1:1) to afford 5-chloro-3-fluoro-pyrazin-2-amine (100 mg, 0.67 mmol, 18% yield) as a yellow solid.

[0420] 5-Chloro-3-fluoro-pyrazin-2-amine was used in procedure D to give the title compound. LC-MS m / z: 363.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0421] Example 37. Procedure E and synthesis of 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyridin-2(1H)-one (Compound 11) Step E [ka]

[0422] To a solution of morpholin-3-one (10.098 g, 99.88 mmol) in THF (100 mL, 0.99 M) was added triethylamine (15 g) and DMAP (300 mg) at 10 °C. Di-tert-butyl dicarbonate (23.97 g, 109.87 mmol) was added portionwise, followed by stirring at 10 °C for 1 h. The reaction was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL) and concentrated to give tert-butyl 3-oxomorpholine-4-carboxylate (20 g, 99.39 mmol, 99% yield) as a yellow solid.

[0423] To a solution of tert-butyl 3-oxomorpholine-4-carboxylate (5000 mg, 24.84 mmol) in THF (100 mL, 0.24 M) was added LiHMDS (28.4 mL, 1 M) dropwise at −30° C. The reaction was stirred at −30° C. for 30 minutes. Diphenyl phosphorochloridate (7342.5 mg, 27.33 mmol) was added dropwise at −30° C., followed by stirring at 10° C. for 1 hour. The reaction was poured into water (100 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine (50 mL) and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 10:1) to give tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (4500 mg, 10.38 mmol, 42% yield) as a brown oil.

[0424] [ka]

[0425] To a solution of 1,3-dibromo-5-chloro-benzene (20 g, 73.97 mmol) in 1,4-dioxane (200 mL, 0.36 M) was added bis(pinacolato)diboron (56 g, 221.9 mmol, 3 equiv.), KOAc (36 g, 5 equiv.), and Pd(dppf)Cl (2 g). The resulting mixture was stirred at 90 °C under a N atmosphere for 16 h. The reaction mixture was quenched with HO (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with 50 mL of saturated aqueous sodium chloride solution. The organic layer was then separated, dried over NaSO, filtered, and concentrated. The crude residue was purified by flash column chromatography (PE: EtOAc) to give 2,2'-(5-chloro-1,3-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (16 g, 43.6 mmol, 59% yield) as a white solid.

[0426] To a solution of 2,2'-(5-chloro-1,3-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (18 g, 49.38 mmol) in 1,4-dioxane (72 mL, 0.34 M), MeCN (72 mL), and HO (36 mL) was added tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (16.49 g, 39.51 mmol), KCO (2 equivalents, 13.8 g), and Pd(dppf)Cl (1.8 g). The resulting mixture was stirred at 80 °C under a N atmosphere for 4 h. The reaction mixture was quenched with HO (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with 50 mL of saturated brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (PE:EtOAc = 10:1 to 1:1) to give tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (10.0 g, 23.7 mmol, 48% yield) as a yellow oil.

[0427] [ka]

[0428] To a solution of tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (200 mg, 0.47 mmol, 1 equiv.) in 1,4-dioxane (1 mL, 0.47 M), MeCN (1 mL), and water (0.5 mL) was added 4-bromo-1-methylpyridin-2-one (89.2 mg, 0.47 mmol, 1 equiv.), KCO (131.26 mg), and Pd(dppf)Cl (20 mg). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction was quenched with HO (3 mL) and extracted with EtOAc (3 mL × 3). The organic layer was washed with 3 mL of saturated brine. The organic layer was separated, dried (NaSO), and concentrated to dryness. The crude material was purified by column chromatography (PE: EtOAc = 0:1) to give tert-butyl 5-(3-chloro-5-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (100 mg, 0.25 mmol, 52% yield) as a yellow oil.

[0429] To a solution of tert-butyl 5-(3-chloro-5-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (400 mg, 1.03 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0° C. The reaction was warmed to 25° C. and stirred for 30 minutes. The reaction was concentrated to give crude 4-(3-chloro-5-(5,6-dihydro-2H-1,4-oxazin-3-yl)phenyl)pyridin-2(1H)-one (290 mg) as a yellow oil.

[0430] To a solution of 4-(3-chloro-5-(5,6-dihydro-2H-1,4-oxazin-3-yl)phenyl)pyridin-2(1H)-one (550 mg, 1.90 mmol, 1 equiv.) in methanol (5 mL, 0.38 M) was added NaBH4 (144 mg, 3.80 mmol, 2 equiv.) under N2 atmosphere at 0 °C. The reaction mixture was stirred at 25 °C for 30 min. The solution was quenched with aqueous HCl to adjust the pH to 5-6 and then concentrated under reduced pressure. The aqueous layer was adjusted to pH = 9-10 with saturated aqueous NaHCO3 and then extracted with EtOAc (5 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Al2O3, dichloromethane / methanol = 100 / 1 to 10 / 1) to give 4-(3-chloro-5-morpholin-3-yl-phenyl)-1H-pyridin-2-one (300 mg, 1.03 mmol, 54% yield) as a yellow oil.

[0431] To a solution of 4-(3-chloro-5-morpholin-3-yl-phenyl)-1H-pyridin-2-one (300 mg, 1.03 mmol, 1 equiv) in DCM (4 mL, 0.25 M) was added triethylamine (156 mg, 1.54 mmol, 1.5 equiv) and acryloyl chloride (112 mg, 1.23 mmol, 1.2 equiv) at 0° C. The mixture was stirred under a N atmosphere at 25° C. for 1 hour. The reaction mixture was poured into water (12 mL) and extracted with DCM (9 mL×3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure.

[0432] The residue was purified by preparative TLC (PE: EtOAc = 0:1). The enantiomers were separated by SFC (column: (S,S)-WHELK-O1, 50x4.6 mm ID, 3.5 μm) with the mobile phase CO2 and EtOH (0.05% IPAm, v / v).

[0433] The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 345.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0434] [ka]

[0435] The title compound can be obtained using an appropriate coupling partner in Procedure E. The enantiomers were separated and the absolute stereochemistry was not assigned.

[0436] [Table 5] TIFF2025534334000157.tif190164

[0437] Example 38. Synthesis of 1-(3-(3-chloro-5-(1H-1,2,4-triazol-3-yl)phenyl)morpholino)prop-2-en-1-one (Compound 41) [ka]

[0438] tert-Butyl 5-(3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate was obtained in procedure E by coupling 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole.

[0439] To a solution of tert-butyl 5-(3-chloro-5-(1-(tetrahydra-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (400 mg, 0.89 mmol, 1 equiv.) in THF (4 ml, 0.22 M) was added borane dimethyl sulfide (430.13 mg, 5.37 mmol, 6 equiv.) dropwise at 0° C. under a N atmosphere. The mixture was stirred at 70° C. for 2 hours. Methanol was added dropwise to the reaction mixture at 0° C. until gas bubbles disappeared, and then the mixture was stirred at 60° C. for 1 hour. The solution was concentrated under reduced pressure to give 3-(3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine (180 mg, 0.52 mmol, 58% yield) as a white solid.

[0440] To a solution of crude 3-(3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine (180 mg, 0.52 mmol, 1 equiv.) and triethylamine (104.43 mg, 1.03 mmol, 2 equiv.) in DCM (2 mL, 0.26 M) was added acryloyl chloride (56 mg, 0.62 mmol, 1.2 equiv.) dropwise at 0° C., and the mixture was stirred for 2 h. The mixture was poured into HO (5 mL), extracted with DCM (5 mL × 3), washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (ethyl acetate) to afford 3-(3-chloro-5-(1H-1,2,4-triazol-3-yl)phenyl)morpholine (20 mg, 0.063 mmol, 12% yield) as a yellow oil.

[0441] 3-(3-chloro-5-(1H-1,2,4-triazol-3-yl)phenyl)morpholine was used in procedure E to give the title compound. The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 319.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0442] Example 39. Synthesis of (R)-1-(3-(3-chloro-5-(9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one (Compound 58) [ka]

[0443] (R)-3-(3-bromo-5-chlorophenyl)morpholine was obtained from Procedure B, Step 5.

[0444] To a solution of bis(pinacolato)diboron (1079.8 mg, 4.25 mmol, 1.2 equiv.) (R)-3-(3-bromo-5-chlorophenyl)morpholine (980 mg, 3.54 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.35 M), potassium acetate (1043.3 mg, 10.63 mmol, 3 equiv.) and Pd(dppf)Cl (257.14 mg, 0.35 mmol, 0.1 equiv.) were added under a N atmosphere. The resulting mixture was stirred at 90 °C for 12 h. The mixture was concentrated and then used directly in the next step.

[0445] [ka]

[0446] To a solution of 6-chloro-9H-purine (1.64 g, 10.61 mmol, 1 equiv.) in ethyl acetate (5 mL, 2.12 M) was added TsOH (0.02 equiv., 20 mg) and 3,4-dihydro-2H-pyran (1338.9 mg, 15.92 mmol, 1.5 equiv.). The reaction was stirred at 90 °C for 1 h. The solution was concentrated and then purified by column chromatography (PE:EA = 10:1 to 0:1) to afford 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2.2 g, 9.22 mmol, 87% yield) as a yellow solid.

[0447] To a solution of (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)morpholine (1100 mg, 3.40 mmol) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (892.38 mg, 3.74 mmol) in 1,4-dioxane (10 ml), MeCN (10 ml) and water (5 ml) was added potassium carbonate (939.5 Pd(dppf)Cl (6 mg, 6.80 mmol) and Pd(dppf)Cl (246.66 mg, 0.34 mmol) were added under a N atmosphere. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (9 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10 um; liquid phase: [A - 10 mM NH HCO / HO; B - ACN] B%: 35%~65%, 20 min) to give (3R)-3-(3-chloro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-pyrin-6-yl)phenyl)morpholine (500 mg, 1.25 mmol, 37% yield).

[0448] To a solution of (3R)-3-(3-chloro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)phenyl)morpholine (400 mg, 1.0 mmol, 1 equiv) in DCM (6 mL, 0.17 M) was added acrylic acid (86.5 mg, 1.20 mmol), N,N-diisopropylethylamine (193.92 mg, 1.50 mmol, 1.5 equiv), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (954.85 mg, 1.50 mmol, 1.5 equiv) at 0° C. The resulting mixture was stirred at 25° C. under a N atmosphere for 2 h. The crude product was concentrated to give 1-((3R)-3-(3-chloro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one (420 mg, 0.93 mmol, 92% yield) as a brown solid.

[0449] A solution of 1-((3R)-3-(3-chloro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one (420 mg, 0.93 mmol, 1 equiv) in trifluoroacetic acid (3 mL, 0.15 M) and DCM (3 mL, 0.15 M) was stirred at 25° C. under a N atmosphere for 1 h and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; liquid phase: [A - TFA / HO = 0.075% v / v; B - ACN] B%: 20%~40%, 8 min) to give (R)-1-(3-(3-chloro-5-(9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one (253 mg, 0.68 mmol, 73% yield). LC-MS m / z: 370.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0450] Example 40. Synthesis of 1-(3-(3-chloro-5-(imidazo[1,2-a]pyrimidin-7-yl)phenyl)morpholino)prop-2-en-1-one (Compound 63) [ka]

[0451] To a solution of 4-bromopyrimidin-2-amine (500 mg, 2.87 mmol, 1 equiv.) in water (5 mL, 0.48 M), acetic acid (1 mL, 0.48 M) and bromoacetaldehyde diethyl acetal (1506.3 mg, 7.64 mmol, 2.66 equiv.) were added. The solution was stirred at 70° C. for 12 hours. The reaction mixture was concentrated to give 7-bromoimidazo[1,2-a]pyrimidine (100 mg, 0.051 mmol, 18% yield) as a yellow oil.

[0452] 7-Bromoimidazo[1,2-a]pyrimidine was used in procedure E to give 1-(3-(3-chloro-5-(imidazo[1,2-a]pyrimidin-7-yl)phenyl)morpholino)prop-2-en-1-one. The enantiomers were separated by SFC. The absolute stereochemistry was not assigned. LC-MS m / z: 369.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0453] Example 41. Synthesis of 1-(3-(3-chloro-5-(imidazo[1,5-a]pyrimidin-3-yl)phenyl)morpholino)prop-2-en-1-one (Compound 68) [ka]

[0454] To a solution of (5-chloropyrimidin-2-yl)methanamine (1 g, 6.96 mmol, 1 equiv.) in triethyl orthoformate (10 mL) was added acetic acid (1 mL) at room temperature. The reaction was stirred at 80 °C for 2 h and then concentrated. The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 um; liquid phase: [A - 10 mM NH4HCO3 / HO; B - ACN] B%: 10%~50%, 10 min) to give N-((5-chloropyrimidin-2-yl)methyl)formamide (0.50 g, 2.91 mmol, 42% yield) as a white solid.

[0455] A solution of N-((5-chloropyrimidin-2-yl)methyl)formamide (140 mg, 0.82 mmol, 1 equiv) in POCl (3 mL) was stirred at 130 °C for 1 h. The mixture was concentrated, poured into ice water (15 mL), basified with NaCO (s) to pH ∼9, and extracted with DCM (20 mL × 2). The combined organic layers were washed with water (10 mL × 2) and brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC to give 3-chloroimidazo[1,5-a]pyrimidine (67 mg, 0.44 mmol, 53% yield).

[0456] 3-Chloroimidazo[1,5-a]pyrimidine was used in procedure E to give 1-(3-(3-chloro-5-(imidazo[1,5-a]pyrimidin-3-yl)phenyl)morpholino)prop-2-en-1-one. The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 369.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0457] Example 42. Synthesis of 7-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)imidazo[1,2-a]pyridine-5-carboxamide (Compound 85) [ka]

[0458] To a solution of methyl 6-amino-4-bromopicolinate (500 mg, 2.16 mmol, 1 equiv.) in methanol (10 mL, 0.22 M) was added chloroacetaldehyde (424.69 mg, 2.16 mmol, 1 equiv.). The reaction mixture was stirred at 75 °C for 16 h and then concentrated. The residue was diluted with saturated aqueous NaHCO (8 mL), stirred for 30 min, and then filtered. The filter cake was dried to give methyl 7-bromoimidazo[1,2-a]pyridine-5-carboxylate (500 mg, 1.96 mmol, 91% yield) as a yellow solid.

[0459] To a solution of methyl 7-bromoimidazo[1,2-a]pyridine-5-carboxylate (500 mg, 1.96 mmol, 1 equiv) in methanol (5 mL, 0.39 M) was added 7M NH3 in MeOH (5 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction was concentrated, and the crude residue was dissolved in MTBE, filtered, and dried under vacuum to give 7-bromoimidazo[1,2-a]pyridine-5-carboxamide (470 mg, 1.96 mmol, 99% yield) as a yellow solid.

[0460] 7-Bromoimidazo[1,2-a]pyridine-5-carboxamide was used in procedure E to give 7-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)imidazo[1,2-a]pyridine-5-carboxamide. The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 411.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0461] Example 43. Synthesis of 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-2-carboxamide (Compound 89) [ka]

[0462] tert-Butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate was obtained using procedure E.

[0463] To a solution of tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (100 mg, 0.24 mmol, 1 equiv.) in ethanol (4 mL, 0.059 M) was added PtO (10 mg) at 20 °C. The mixture was stirred under an H atmosphere at 20 °C for 3 h. The solution was filtered and concentrated to give 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (90 mg, 0.21 mmol, 90% yield) as a brown oil.

[0464] To a solution of 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (1 g, 3.09 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added 2,4-dichloropyrimidine (0.55 g, 3.70 mmol), K2CO3 (1.3 g, 9.27 mmol), and Pd(dppf)Cl2 (0.1 equiv., 0.22 g) at 25 °C. The mixture was stirred at 80 °C under a N2 atmosphere for 12 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (35 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SEPAFLASH® silica flash column, eluting with a 0-20% MeOH / ethyl acetate gradient at 60 mL / min) to give 3-(3-chloro-5-(2-chloropyrimidin-4-yl)phenyl)morpholine (560 mg, 1.80 mmol, 58% yield).

[0465] [ka]

[0466] To a solution of 3-[3-chloro-5-(2-chloropyrimidin-4-yl)phenyl]morpholine (560 mg, 1.80 mmol) in DMF (5 mL, 0.36 M) was added zinc cyanide (380 mg, 3.23 mmol) and Pd(PPh) (0.1 equiv., 207 mg) at 25 °C. The mixture was stirred at 110 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 0–20% MeOH / ethyl acetate gradient at 60 mL / min) to give 4-(3-chloro-5-morpholin-3-yl-phenyl)pyrimidine-2-carbonitrile (390 mg).

[0467] To a solution of 4-(3-chloro-5-morpholin-3-yl-phenyl)pyrimidine-2-carbonitrile (390 mg, 1.29 mmol) in methanol (5 mL, 0.25 M) was added aqueous HO (30%, 410 mg, 3 equiv.) and NaOH (155.6 mg, 3 equiv., 1 M, 3.89 mL) at 0 °C. The mixture was stirred at 25 °C under a N atmosphere for 12 h. The reaction mixture was quenched with aqueous NaSO (40 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give 270 mg of a gray solid.

[0468] To a solution of 4-(3-chloro-5-morpholin-3-yl-phenyl)pyrimidine-2-carboxamide (120 mg, 0.37 mmol) in DCM (3 mL, 0.12 M) was added triethylamine (76 mg, 0.75 mmol) and acryloyl chloride (40 mg, 0.45 mmol) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; liquid phase: [A-10mM NH4HCO3 / HO; B-ACN] B%: 10%-40%, 8min]) to give 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-2-carboxamide (30mg, 0.08mmol, yield 21%).

[0469] The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 373.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0470] Example 44. Synthesis of 6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4(3H)-one (Compound 94) [ka]

[0471] tert-Butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate was obtained from procedure E.

[0472] To a solution of tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (100 mg, 0.24 mmol, 1 equiv.) in ethanol (4 mL, 0.059 M) was added PtO (10 mg) at 20 °C. The mixture was stirred under an H atmosphere at 20 °C for 3 h. The solution was filtered and concentrated to give 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (90 mg, 0.21 mmol, 90% yield) as a brown oil.

[0473] To a solution of crude 4-bromo-1H-pyrimidin-6-one (216.28 mg, 1.236 mmol, 1 equiv.) and 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (500 mg, 1.24 mmol, 1 equiv.) in 1,4-dioxane (10 mL, 0.08 M) and water (5 mL, 0.08 M) was added Na2CO3 (393 mg, 3 equiv.) and Pd(dppf)Cl2 (18 mg, 0.1 equiv.). The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH=1 / 0 to 5 / 1) to give 6-(3-chloro-5-(morpholin-3-yl)phenyl)pyrimidin-4(3H)-one (800 mg) as a yellow solid.

[0474] Using 6-(3-chloro-5-(morpholin-3-yl)phenyl)pyrimidin-4(3H)-one in procedure E gave the title compound. LC-MS m / z: 346.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0475] Example 45. Synthesis of 1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one (Compound 111) [ka]

[0476] 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine was obtained from the synthesis of compound 94.

[0477] To 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (1.0 g, 3.09 mmol, 1 equiv) in DCM (10 mL, 0.31 M) was added acryloyl chloride (279.68 mg, 3.09 mmol, 1 equiv) and triethylamine (625.36 mg, 6.18 mmol, 2 equiv) at 25 °C under a N atmosphere. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with water (20 ml) and extracted with DCM (20 × 2 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by flash column chromatography (EA:PE=0-20%) to give 1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (1.2 g, 2.54 mmol, 82% yield) as a white solid, which was used in the next step without further purification.

[0478] [ka]

[0479] To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.02 mmol) in THF (10 mL, 0.10 M) was added sodium hydride (48 mg, 1.22 mmol) at 0 °C, followed by stirring for 30 min under a N atmosphere. 2-(Trimethylsilyl)ethoxymethyl chloride (203 mg, 1.22 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give 2-[(4-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (230 mg, 0.70 mmol, 69% yield).

[0480] To a solution of 2-[(4-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethylsilane (207.98 mg, 0.63 mmol, 1.2 equiv.) in 1,4-dioxane (1 mL, 0.44 M), 1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholino)prop-2-en-1-one (200 mg, 0.53 mmol, 1 equiv.), Pd(dppf)Cl (38.42 mg, 0.053 mmol, 0.1 equiv.), and potassium carbonate (146.38 mg, 1.059 mmol, 2 equiv.) were added at room temperature under a N atmosphere. The reaction was stirred at 80 °C for 16 h. The reaction solution was filtered and then evaporated under reduced pressure. The crude residue was purified by preparative TLC and preparative HPLC to give 1-(3-(3-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one (90 mg, 0.181 mmol, 34% yield).

[0481] To a solution of 1-(3-(3-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one (90 mg, 0.18 mmol, 1 equiv) in DCM (5 mL) was added TFA (1.5 mL) slowly at 0° C. The reaction was stirred at 35° C. for 16 h. The solution was concentrated to give crude 1-(3-(3-chloro-5-(1-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one (95 mg), which was used in the next step without further purification.

[0482] To a solution of crude 1-(3-(3-chloro-5-(1-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one (75 mg, 0.19 mmol, 1 equiv) in MeCN (3 mL, 0.06 M) and water (1 mL, 0.06 M) was added K2CO3 (18 equiv, 561 mg). The mixture was stirred at 90 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic solution was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC.

[0483] The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 368.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0484] Example 46. Synthesis of (R)-1-(3-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 178) [ka]

[0485] To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (200 mg, 1.22 mmol, 1 equiv) in toluene (2 mL, 0.61 M) was added NH in methanol (4 M, 1.2 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to give the crude product, 4-chloro-6-methyl-1,3,5-triazin-2-amine (150 mg, 1.04 mmol, 85% yield) as a yellow solid.

[0486] 4-Chloro-6-methyl-1,3,5-triazin-2-amine was used in procedure D to give the title compound. LC-MS m / z: 360.1 [M+1]. Stereochemistry: Scalemic mixture of unknown absolute configuration, ee=84%.

[0487] Example 47. Synthesis of (R)-1-(3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (Compound 191) [ka]

[0488] tert-Butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate was obtained from procedure B.

[0489] Pd(PPh3)4 (2.08 g, 1.81 mmol) and zinc cyanide (847.84 mg, 7.22 mmol, 0.80 equiv.) were added to a solution of tert-butyl (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (3.4 g, 9.03 mmol, 1 equiv.) in DMF (50 mL, 0.18 M) at 20 °C. The mixture was stirred at 120 °C under a N2 atmosphere for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL*2). The combined organic layer was washed with water (20 mL*3), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude residue was purified by MPLC (ISCO®; 40 g SEPAFLASH® silica flash column, eluting with a 0-15% ethyl acetate / petroleum ether gradient at 100 mL / min) to give tert-butyl (R)-3-(3-chloro-5-cyanophenyl)morpholine-4-carboxylate (1.30 g, 4.03 mmol, 45% yield) as a white solid.

[0490] 2-Cyanoguanidine (338.62 mg, 4.03 mmol, 1 equiv.) and potassium hydroxide (225.98 mg, 4.03 mmol, 1 equiv.) were added to a solution of tert-butyl (R)-3-(3-chloro-5-cyanophenyl)morpholine-4-carboxylate (1.3 g, 4.03 mmol, 1 equiv.) in DME (20 mL, 0.20 M). The mixture was heated to 125 °C and stirred for 20 min. The reaction mixture was concentrated, and the residue was crystallized from MeOH (20 mL) to give tert-butyl (R)-3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate (1.30 g, 3.20 mmol, 79% yield) as a pale yellow solid.

[0491] tert-Butyl (R)-3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholine-4-carboxylate was used in procedure B to give the title compound. LC-MS m / z: 361.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0492] Example 48. Synthesis of both diastereomers of 5-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methyltetrahydropyrimidin-2(1H)-one (compounds 216 and 217) [ka]

[0493] tert-Butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate was obtained from procedure B.

[0494] To a solution of tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (500 mg, 1.18 mmol) in 1,4-dioxane (1 mL, 0.98 M) and water (0.20 mL, 0.98 M), 5-bromo-1-methyl-pyrimidin-2-one (267.63 mg, 1.41 mmol, 1.2 equiv), Pd(dppf)Cl (85.62 mg, 0.12 mmol, 0.10 equiv), and potassium carbonate (407.71 mg, 2.95 mmol, 2.5 equiv) were added. The mixture was stirred at 80 °C under a N atmosphere for 4 h. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, ethyl acetate) to give tert-butyl (R)-3-(3-chloro-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (300 mg, 0.74 mmol, 63% yield).

[0495] To a solution of tert-butyl (R)-3-(3-chloro-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (2.8 g, 6.89 mmol, 1 equiv.) in THF (10 mL, 0.69 M) was added platinum dioxide (548.29 mg, 2.41 mmol, 0.35 equiv.) and 1,3,5-trichlorobenzene (1.25 g, 6.89 mmol, 1 equiv.). The reaction was stirred under an atmosphere of H (15 psi) at 20 °C for 72 h. The mixture was filtered and concentrated in vacuo. The crude product was subjected to silica gel chromatography (PE / EA 20:1→1:1→0:1) to give tert-butyl (3R)-3-(3-chloro-5-(1-methyl-2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate.

[0496] To a solution of tert-butyl (3R)-3-(3-chloro-5-(1-methyl-2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (130 mg, 0.32 mmol, 1 equiv) in 1,4-dioxane (1 mL, 0.25 M) was added HCl in dioxane (4 M, 2 mL) at 25° C. The mixture was stirred for 2 h, filtered, and concentrated in vacuo to give crude 5-(3-chloro-5-((R)-morpholin-3-yl)phenyl)-1-methyltetrahydropyrimidin-2(1H)-one (100 mg, 0.32 mmol, 83% yield) as a yellow oil.

[0497] [ka]

[0498] N,N-Diisopropylethylamine (83.43 mg, 0.65 mmol) was added to a solution of 5-(3-chloro-5-((R)-morpholin-3-yl)phenyl)-1-methyltetrahydropyrimidin-2(1H)-one (100 mg, 0.33 mmol) in DCM (5 mL, 0.065 M) at 0 °C. Acrylic acid (25.58 mg, 0.35 mmol) was added dropwise at 0 °C, followed by the addition of a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (308 mg, 0.48 mmol) in DCM (2 mL, 0.024 M). The mixture was stirred at 25 °C for 30 min. The mixture was diluted with water (20 mL), extracted with DCM (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO; PE: EtOAc = 1:5) to give 5-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methyltetrahydropyrimidin-2(1H)-one (50 mg, 0.14 mmol, 43% yield).

[0499] The diastereomers were separated by SFC [column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm) CO₂ and EtOH], and the stereochemistry of 1-methyltetrahydropyrimidin-2(1H)-one was arbitrarily assigned. LC-MS m / z: 364.2 [M+1]. Stereochemistry: Single diastereomer of known absolute configuration on the morpholine and unknown absolute configuration on the pyrimidine.

[0500] Example 49. Synthesis of 1-((R)-3-(3-chloro-5-((R)-1-methyl-2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one diastereomers 1 and 2 (compounds 226 and 227) [ka]

[0501] tert-Butyl (3R)-3-(3-chloro-5-(1-methyl-2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate was obtained from the synthesis of compounds 216 and 217.

[0502] To a solution of tert-butyl (3R)-3-(3-chloro-5-(1-methyl-2-oxohexahydropyrimidin-5-yl)phenyl)morpholine-4-carboxylate (2 g, 4.88 mmol, 1 equiv.) in m-xylene (40 mL, 0.12 M) was added (dithioxo-λ5-phosphanyl)sulfanyl-dithioxo-λ5-phosphane (2.17 g, 4.87 mmol, 1 equiv.) at 25° C. The mixture was heated to 130° C. under a N2 atmosphere for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA) to give 5-(3-chloro-5-((R)-morpholin-3-yl)phenyl)-1-methyltetrahydropyrimidine-2(1H)-thione (530 mg, 1.63 mmol, 33% yield) as a yellow solid.

[0503] 5-(3-chloro-5-((R)-morpholin-3-yl)phenyl)-1-methyltetrahydropyrimidine-2(1H)-thione was used in the final step of the route to compounds 216 and 217 to give the title compound.

[0504] The diastereomers were separated by SFC and the stereochemistry of 1-methyltetrahydropyrimidine-2(1H)-thione was arbitrarily assigned. LC-MS m / z: 380.0 [M+1]. LC-MS m / z: 380.2 [M+1]. Stereochemistry: Single stereoisomer of unknown absolute configuration. The morpholine stereocenter is known and the stereochemistry of 1-methyltetrahydropyrimidine-2(1H)-thione was arbitrarily assigned.

[0505] Example 50. Synthesis of 1-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-3-aminopyrrolidin-2-one (Compound 230) [ka]

[0506] (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one was obtained from procedure C.

[0507] To a solution of (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one (50 mg, 0.15 mmol, 1 equiv.) and tert-butyl N-(2-oxopyrrolidin-3-yl)carbamate (60.56 mg, 0.30 mmol, 2 equiv.) in 1,4-dioxane (5 mL, 0.03 M) was added tris(dibenzylideneacetone)dipalladium(0) (13.84 mg, 0.015 mmol, 0.10 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.75 mg, 0.015 mmol, 0.10 equiv.), cesium carbonate (88.69 mg, 0.27 mmol, 1.8 equiv.). The mixture was stirred at 90° C. for 12 hours under a N atmosphere. The reaction mixture was diluted with water, extracted with EtOAc (20 mL×3), and concentrated in vacuo. The residue was purified by preparative TLC (SiO, EA:MeOH=10:1) to give tert-butyl (1-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-2-oxopyrrolidin-3-yl)carbamate (90 mg) as a yellow oil. The diastereomers were separated by SFC.

[0508] To a solution of tert-butyl (1-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-2-oxopyrrolidin-3-yl)carbamate (35 mg, 0.077 mmol, 1 equiv) in DCM (1.5 mL, 0.04 M) was added trifluoroacetic acid (0.50 mL, 0.038 M) at 0° C. The mixture was stirred under N atmosphere at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; liquid phase: [A-TFA / HO=0.075% v / v; B-ACN] B%: 1%-30%, 8min) to give 1-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-3-aminopyrrolidin-2-one as a white solid. LC-MS m / z: 349.8. [M+1]. Stereochemistry: Single enantiomer of known absolute configuration. The stereocenter of the morpholine is known, the stereochemistry of the 3-aminopyrrolidin-2-one is unknown.

[0509] Example 51. Synthesis of 4-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)tetrahydropyrimidin-2(1H)-one (Compound 242) [ka]

[0510] tert-Butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate was obtained from procedure B.

[0511] To a solution of tert-butyl (R)-3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (1 g, 2.35 mmol, 1 equiv.) and 2,4-dichloropyrimidine (703.17 mg, 4.71 mmol, 2 equiv.) in 1,4-dioxane (20 mL, 0.098 M) and water (4 mL, 0.098 M), potassium carbonate (652.33 mg, 4.71 mmol, 2 equiv.) and Pd(dppf)Cl (85.62 mg, 0.12 mmol, 0.05 equiv.) were added. The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was poured into saturated aqueous NH Cl (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=3:1) to give tert-butyl (R)-3-(3-chloro-5-(2-chloropyrimidin-4-yl)phenyl)morpholine-4-carboxylate (192 mg, 0.47 mmol, 20% yield) as a white solid.

[0512] tert-Butyl (R)-3-(3-chloro-5-(2-chloropyrimidin-4-yl)phenyl)morpholine-4-carboxylate (850 mg, 2.07 mmol, 1 equiv.) in 38% aqueous HCl (20 mL) was stirred at 100° C. for 16 hours. The mixture was cooled, and the pH was adjusted to 8 with 1 M aqueous sodium hydroxide. Most of the water was removed under reduced pressure, and the remaining solution was extracted with DCM:iPrOH=3:1 (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)pyrimidin-2-ol (830 mg) as a yellow solid.

[0513] [ka]

[0514] To a solution of crude (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)pyrimidin-2-ol (630 mg, 2.15 mmol, 1 equiv.) in THF (5 mL) and EtOH (10 mL) under an Ar atmosphere was added PtO (0.2 equiv., 98 mg). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 25 °C under an atmosphere of 15 Psi hydrogen pressure for 16 h. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOH (10 mL × 3). The combined filtrate was concentrated to dryness to give 4-(3-chloro-5-((R)-morpholin-3-yl)phenyl)tetrahydropyrimidin-2(1H)-one (550 mg, 1.49 mmol, 69% yield) as a yellow solid.

[0515] To a solution of 4-(3-chloro-5-((R)-morpholin-3-yl)phenyl)tetrahydropyrimidin-2(1H)-one (50 mg, 0.16 mmol), acrylic acid (12.18 mg, 0.16 mmol), and N,N-diisopropylethylamine (43.69 mg, 0.33 mmol) in DCM (2 mL, 0.05 M) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (161.37 mg, 0.25 mmol) under a N atmosphere at 0 °C. The reaction was stirred for 30 min. The reaction mixture was poured into saturated aqueous NH4Cl (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions) to give the desired compound (60 mg) as a white solid. The diastereomers were separated by SFC. LC-MS m / z: 350.2 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration. The stereocenter of the morpholine is known, the stereochemistry of the tetrahydropyrimidin-2(1H)-one is unknown.

[0516] Example 52. Synthesis of 1-(3-(3-(2-aminooxazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one (Compound 282) [ka]

[0517] To a solution of 1,3-dibromo-5-chlorobenzene (10 g, 36.98 mmol) in i-PrO (150 mL) was added n-butyllithium solution (10.56 g, 38.83 mmol) at −60 °C under a N atmosphere and stirred for 30 min. 2-Chloro-N-methoxy-N-methyl-acetamide (5.59 g, 40.68 mmol) in i-PrO (20 mL) was added dropwise, and the reaction was warmed to 0 °C and stirred for 1 h. The solution was diluted with saturated aqueous NHCl (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic solution was washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate=1:0 to 99:1) to give 1-(3-bromo-5-chlorophenyl)-2-chloroethan-1-one (3.70 g, 13.8 mmol, 37% yield).

[0518] To a solution of 1-(3-bromo-5-chlorophenyl)-2-chloroethan-1-one (1.3 g, 4.85 mmol) in acetone (10 mL, 0.48 M) was added sodium bromide (1.99 g, 19.40 mmol) under a N atmosphere at 20° C. The reaction was stirred at 60° C. for 16 hours. The solution was diluted with HO (20 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), dried over NaSO, filtered, and concentrated in vacuo to give 2-bromo-1-(3-bromo-5-chlorophenyl)ethan-1-one (2.0 g) as a yellow solid.

[0519] To a solution of 2-bromo-1-(3-bromo-5-chlorophenyl)ethan-1-one (500 mg, 1.60 mmol, 1 equiv) in MeCN (5 mL, 0.32 M) was added urea (961.3 mg, 16.01 mmol, 10 equiv) at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (8 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give 4-(3-bromo-5-chlorophenyl)oxazol-2-amine (241 mg, 0.88 mmol, 55% yield).

[0520] [ka]

[0521] To a solution of 4-(3-bromo-5-chlorophenyl)oxazol-2-amine (570 mg, 2.08 mmol, 1 equiv.) in 1,4-dioxane (5 mL, 0.42 M), bis(pinacolato)diboron (582.14 mg, 2.29 mmol, 1.1 equiv.), potassium acetate (409.05 mg, 4.16 mmol, 2 equiv.), and Pd(dppf)Cl (150.81 mg, 0.21 mmol, 0.10 equiv.) were added under a N atmosphere at 25 °C. The mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into water (6 mL) and extracted with EtOAc (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol-2-amine (780 mg) as a yellow oil.

[0522] To a solution of 4-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol-2-amine (785 mg, 2.44 mmol, 1 equiv.) in 1,4-dioxane (5 mL, 0.41 M) and water (1 mL, 0.41 M) was added tert-butyl 5-diphenoxyphosphoryloxy-2,3-dihydro-1,4-oxazine-4-carboxylate (1061.2 mg, 2.44 mmol, 1 equiv.), potassium carbonate (676.87 mg, 4.89 mmol, 2 equiv.), and Pd(dppf)Cl (88.59 mg, 0.12 mmol, 0.05 equiv.) at 25° C. The mixture was stirred at 80° C. under a N atmosphere for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (6 mL) and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give tert-butyl 5-(3-(2-aminooxazol-4-yl)-5-chlorophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (300 mg, 0.79 mmol, 32% yield).

[0523] [ka]

[0524] To a solution of tert-butyl 5-(3-(2-aminooxazol-4-yl)-5-chlorophenyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (305 mg, 0.81 mmol, 1 equiv) in DCM (3 mL, 0.20 M) was added trifluoroacetic acid (1 mL, 0.20 M) under a N atmosphere at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure. The mixture was neutralized with 2 N NaOH solution at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give crude 4-(3-chloro-5-(5,6-dihydro-2H-1,4-oxazin-3-yl)phenyl)oxazol-2-amine (224 mg, 0.81 mmol, 100% yield). The crude product was used in the next step without further purification.

[0525] To a solution of 4-(3-chloro-5-(5,6-dihydro-2H-1,4-oxazin-3-yl)phenyl)oxazol-2-amine (147 mg, 0.53 mmol, 1 equiv.) in DCM (2 mL, 0.26 M) was added sodium cyanoborohydride (33.26 mg, 0.59 mmol, 1 equiv.) at 0 °C. The mixture was stirred under N atmosphere at 25 °C for 1 h. The reaction mixture was poured into saturated aqueous NH Cl (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA condition) to give 4-(3-chloro-5-(morpholin-3-yl)phenyl)oxazol-2-amine (50 mg, 0.18 mmol, 34% yield) as a white solid.

[0526] 4-(3-chloro-5-(morpholin-3-yl)phenyl)oxazol-2-amine was used in step 8 of Procedure E to give the title compound.

[0527] The enantiomers were separated by SFC and the absolute stereochemistry was not assigned. LC-MS m / z: 344.2 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0528] Example 53. Procedure F and synthesis of 1-(5-chloro-7-phenyl-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (Compound 7) Step F [ka]

[0529] To a solution of 1-(5-chloro-2-hydroxy-phenyl)ethanone (50 g, 293.1 mmol, 1 equivalent) in DMF (500 mL, 0.58 M) was added N-bromosuccinimide (54.77 g, 307.76 mmol, 1.05 equivalent) at 25° C. The mixture was stirred under a N atmosphere at 25° C. for 16 hours. The solution was poured into water (600 mL), washed with aqueous NaSO (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 1-(3-bromo-5-chloro-2-hydroxy-phenyl)ethanone (65.0 g, 261 mmol, 89% yield) as a brown solid.

[0530] To a solution of 1-(3-bromo-5-chloro-2-hydroxy-phenyl)ethanone (5000 mg, 20.04 mmol, 1 equiv.) in DCM (50 mL, 0.40 M) was added triethylamine (6083 mg, 60.12 mmol, 3 equiv.) and tert-butyldimethylsilyl trifluoromethanesulfonate (10595 mg, 40.08 mmol, 2 equiv.) at 0° C. The mixture was stirred at 25° C. under a N atmosphere for 12 hours. The reaction mixture was poured into water (60 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (ISCO®; 80 g SEPAFLASH® silica flash column, eluting with a 0-10% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give ((1-(3-bromo-2-((tert-butyldimethylsilyl)oxy)-5-chlorophenyl)vinyl)oxy)(tert-butyl)dimethylsilane (7.25 g, 14.7 mmol, 73% yield) as a colorless oil.

[0531] To a solution of ((1-(3-bromo-2-((tert-butyldimethylsilyl)oxy)-5-chlorophenyl)vinyl)oxy)(tert-butyl)dimethylsilane (7.25 g, 15.17 mmol) in DCM (80 mL, 0.19 M) was added sodium bicarbonate (3185 mg, 37.91 mmol, 2.5 equiv) and 3-chloroperbenzoic acid (4926 mg, 24.26 mmol) at 0 °C. The mixture was stirred at 25 °C under a N atmosphere for 4 h. The reaction mixture was quenched with aqueous NaSO (100 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SEPAFLASH® silica flash column, eluting with a 0-10% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give ((2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)-5-chlorophenyl)oxiran-2-yl)oxy)(tert-butyl)dimethylsilane (5.00 g, 10.1 mmol, 67% yield) as a yellow oil.

[0532] [ka]

[0533] To a solution of ((2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)-5-chlorophenyl)oxiran-2-yl)oxy)(tert-butyl)dimethylsilane (20 g, 40.48 mmol) in THF (200 mL, 0.18 M) and water (20 mL, 0.18 M) was added p-toluenesulfonic acid monohydrate (1.54 g, 8.09 mmol) at 25 °C. The mixture was stirred at 70 °C under N atmosphere for 12 h. The reaction mixture was poured into water (650 mL) and extracted with EtOAc (750 mL*3). The combined organic layers were washed with brine (300 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(3-bromo-5-chloro-2-hydroxyphenyl)-2-hydroxyethan-1-one (10.00 g, 37.7 mmol, 93% yield) as a yellow solid.

[0534] To a solution of 1-(3-bromo-5-chloro-2-hydroxyphenyl)-2-hydroxyethan-1-one (6.72 g, 25 mmol, 1 equiv.) in ethanol (50 mL, 0.25 M) and water (50 mL, 0.25 M), diammonium carbonate (12647 mg, 131 mmol, 5.2 equiv.) and trimethylsilyl cyanide (98%) (3264 mg, 32 mmol, 1.3 equiv.) were added at 0 °C. The mixture was stirred at 55 °C under a N atmosphere for 12 h. The reaction mixture was filtered, and the filter cake was dried under vacuum to give 3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-carboxamide (5.14 g, 17.6 mmol, 70% yield) as a yellow solid.

[0535] To a solution of 3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-carboxamide (5.14 g, 17.63 mmol, 1 equiv.) in ethanol (30 mL, 0.58 M) was added potassium hydroxide (2967 mg, 52 mmol, 3 equiv.) (dissolved in 30 mL of water) at 0° C. The mixture was stirred at 55° C. under a N atmosphere for 12 hours. The muddy mixture became clear. The pH of the reaction mixture was adjusted to 4 with HCl in EtOAc. The filter cake was collected by filtration and dried under reduced pressure to give 3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-carboxylic acid (4.26 g, 14.6 mmol, 82% yield) as a white solid.

[0536] [ka]

[0537] To a solution of 3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-carboxylic acid (4.26 g, 14.56 mmol, 1 equiv) in THF (40 mL, 0.36 M) was added borane THF (72.8 mL, 72.8 mmol, 5 equiv) at 0 °C. The mixture was stirred at 70 °C under a N atmosphere for 2 h and then quenched with MeOH (100 mL). The solution was stirred at 70 °C for 1 h and then concentrated under reduced pressure to give (3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-yl)methanol (4.60 g, 13.2 mmol, 90% yield) as a white solid.

[0538] To a solution of (3-amino-7-bromo-5-chloro-2,3-dihydrobenzofuran-3-yl)methanol (1000 mg, 3.59 mmol, 1 equiv) in THF (10 mL, 0.3 M) was added NaH (287 mg, 7.18 mmol, 2 equiv) at 0 °C. The mixture was stirred under N atmosphere at 0 °C for 30 minutes. Then, ethyl chloroacetate (659 mg, 5.38 mmol, 1.5 equiv) was added slowly at 0 °C. The mixture was stirred under N atmosphere at 25 °C for 12 hours, poured into water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 10–30% ethyl acetate / petroleum ether gradient (60 mL / min)) to give 7-bromo-5-chloro-2H-spiro[benzofuran-3,3′-morpholin]-5′-one (413 mg, 1.30 mmol, 36% yield) as a yellow solid.

[0539] To a solution of 7-bromo-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-5'-one (413 mg, 1.29 mmol, 1 equiv) in THF (10 mL, 0.13 M) was added borane THF (6.5 mL, 6.48 mmol, 5 equiv) at 0 °C. The mixture was stirred at 70 °C under a N atmosphere for 2 h. The mixture was quenched with methanol (30 mL) at 0 °C and then stirred at 70 °C under a N atmosphere for 12 h. The mixture was concentrated under reduced pressure to give 7-bromo-5-chloro-2H-spiro[benzofuran-3,3'-morpholin] (470 mg, 1.23 mmol, 95% yield) as a yellow oil.

[0540] [ka]

[0541] To a solution of 7-bromo-5-chloro-2H-spiro[benzofuran-3,3'-morpholine] (470 mg, 1.54 mmol, 1 equiv.) in DCM (5 mL, 0.31 M) was added triethylamine (0.43 mL, 3.08 mmol, 2 equiv.) and acryloyl chloride (139.67 mg, 1.54 mmol, 1 equiv.) at 0 °C. The mixture was stirred under a N atmosphere at 0 °C for 1 h. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® silica flash column, eluent of 20–40% ethyl acetate / petroleum ether, 36 mL / min) to give 1-(7-bromo-5-chloro-2H-spiro[benzofuran-3,3′-morpholin]-4′-yl)prop-2-en-1-one (346 mg, 0.97 mmol, 62% yield) as a yellow solid.

[0542] To a solution of phenylboronic acid (3.43 mg, 0.028 mmol) and 1-(7-bromo-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (15 mg, 0.042 mmol) in MeCN (3 mL), 1,4-dioxane (3 mL), and water (1 mL) was added K2CO3 (23 mg) and Pd(dppf)Cl2 (20 mg). The resulting mixture was stirred at 80 °C for 1 h. The reaction was quenched with brine (20 mL) and then extracted with EtOAc (20 mL × 2). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC to give racemic 1-(5-chloro-7-phenyl-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (8.7 mg, 83% yield) as a yellow solid. LC-MS m / z: 356.1 [M+1]. Stereochemistry: Racemic.

[0543] Example 54. Synthesis of 1-(7-(4-amino-1,3,5-triazin-2-yl)-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (Compound 151) [ka]

[0544] 7-Bromo-5-chloro-spiro[2H-benzofuran-3,3′-morpholine] was obtained from procedure F.

[0545] To a solution of 7-bromo-5-chloro-spiro[2H-benzofuran-3,3'-morpholine] (300 mg, 0.98 mmol, 1 equiv.) in CPME (3 mL) was added potassium acetate (290 mg, 2.95 mmol, 3 equiv.), bis(pinacolato)diboron (250.13 mg, 0.985 mmol, 1 equiv.), and CPyPdG (0.1 equiv., 58.16 mg) in a glove box at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The solution was used directly in the next step.

[0546] [ka]

[0547] To a solution of 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[2H-benzofuran-3,3'-morpholine] (300 mg, 0.85 mmol, 1 equiv.) in CPME (3 mL) and water (0.6 mL) was added potassium carbonate (353 mg, 2.55 mmol), 4-chloro-1,3,5-triazin-2-amine (111 mg, 0.85 mmol), and Pd(dppf)Cl (0.1 equiv., 62.41 mg) at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® silica flash column, eluent of 0–20% MeOH / EtOAc @ 36 mL / min) to afford 4-(5-chloro-2H-spiro[benzofuran-3,3′-morpholin]-7-yl)-1,3,5-triazin-2-amine (110 mg, 0.344 mmol, 40% yield) as a yellow oil.

[0548] 4-(5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-7-yl)-1,3,5-triazin-2-amine was used in procedure F to give the title compound. LC-MS m / z: 374.1 [M+1]. The enantiomers were separated by chiral SFC (column: Chiralpak AS-3, 50 x 4.6 mm ID, 3 μm) using a mobile phase of CO₂ and 0.1% IPAm / MeOH. The absolute stereochemistry of the title compound was not assigned. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0549] Example 55. Synthesis of 5-(4'-acryloyl-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-7-yl)-2-fluorobenzamide (Compound 143) [ka]

[0550] 1-(7-Bromo-5-chloro-spiro[2H-benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one was obtained from procedure F.

[0551] To a solution of 1-(7-bromo-5-chloro-spiro[2H-benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (100 mg, 0.27 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (96 mg, 0.36 mmol, 1.3 equiv), potassium carbonate (115 mg, 0.83 mmol, 3 equiv), and Pd(dppf)Cl (0.1 equiv, 20 mg) were added at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to give 100 mg of crude product as a yellow oil. The product was further purified by preparative HPLC to give 5-(4'-acryloyl-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-7-yl)-2-fluorobenzamide.

[0552] The enantiomers were separated by chiral SFC (column: Chiralpak AD-3, 50x4.6mm ID, 3um) using CO2 and 0.1% IPAm / MeOH as the mobile phase. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 417.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0553] Example 56. Synthesis of 1-(7-(2-aminopyrimidin-4-yl)-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one (Compound 158) [ka]

[0554] 5-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[2H-benzofuran-3,3′-morpholine] was obtained from the synthesis of compound 151.

[0555] To a solution of 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[2H-benzofuran-3,3'-morpholine] (400 mg, 1.13 mmol, 1 equiv.) in 1,4-dioxane (5 mL, 0.19 M) and water (1 mL, 0.19 M), potassium carbonate (471 mg, 3.41 mmol, 3 equiv.), 4-chloropyrimidin-2-amine (147 mg, 1.13 mmol, 1 equiv.), and Pd(dppf)Cl (0.1 equiv., 83.19 mg) were added at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® silica flash column, eluent of 0–20% MeOH / EtOAc at 60 mL / min) to afford 4-(5-chlorospiro[2H-benzofuran-3,3′-morpholin]-7-yl)pyrimidin-2-amine (115 mg, 0.361 mmol, 32% yield) as a yellow oil.

[0556] 4-(5-chlorospiro[2H-benzofuran-3,3'-morpholin]-7-yl)pyrimidin-2-amine was used in procedure F to give the title compound.

[0557] The enantiomers were separated by chiral SFC (column: Chiralpak AD-3, 50 x 4.6 mm ID, 3 um) using CO2 and 0.1% I-PAm / EtOH as the mobile phase. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 373.0 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0558] Example 57. Synthesis of 7-(2-aminopyrimidin-4-yl)-5-chloro-2H-dispiro[benzofuran-3,5'-morpholine-2',1''-cyclopropane]-3'-one (Compound 192) [ka]

[0559] Introduction of the cyclopropane was achieved with 7-bromo-5-chloro-2H-spiro[benzofuran-3,3′-morpholin]-5′-one from Procedure F. The product was elaborated to give 7-(2-aminopyrimidin-4-yl)-5-chloro-2H-dispiro[benzofuran-3,5′-morpholin-2′,1″-cyclopropan]-3′-one.

[0560] The enantiomers were separated by SFC. The absolute stereochemistry of the title compound was not assigned. LC-MS m / z: 399.1 [M+1]. Stereochemistry: Single enantiomer of unknown absolute configuration.

[0561] Example 58. Procedure G and synthesis of 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one (Compound 112) Step G [ka]

[0562] 1,3-Dibromo-5-chloro-benzene (30 g, 110.97 mmol) was dissolved in anhydrous i-PrO (300 mL) in a dry flask under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C. A 2.5 M solution of n-BuLi in hexane (44.40 mL, 110.97 mmol) was added dropwise to the above solution, and the reaction mixture was stirred at -78 °C for 30 minutes. N-Methoxy-N-methylacetamide (13.73 g, 133.16 mmol, 1.2 equiv.) was added slowly at -78 °C. The reaction mixture was slowly warmed to room temperature and stirred for 30 minutes. The reaction mixture was poured into 120 mL of saturated aqueous NHCl, and the mixture was stirred for 15 minutes. The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1) to give 1-(3-bromo-5-chlorophenyl)ethan-1-one (21 g, 89.9 mmol, 81% yield) as a yellow oil.

[0563] A solution of 1-(3-bromo-5-chlorophenyl)ethanone (21 g, 89.94 mmol, 1 equiv.), (NH)CO (45 g, 5.2 equiv.), and TMSCN (12 g, 1.31 equiv.) in ethanol (250 mL, 0.18 M) and water (250 mL, 0.18 M) was stirred at 55 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The solid was collected, washed with water, and dried under vacuum to give 5-(3-bromo-5-chlorophenyl)-5-methylimidazolidine-2,4-dione (24.5 g, 80.7 mmol, 90% yield) as a white solid.

[0564] To a solution of 5-(3-bromo-5-chlorophenyl)-5-methylimidazolidine-2,4-dione (24.5 g, 80.71 mmol, 1 equiv.) in water (250 mL, 0.32 M) was added NaOH (12.9 g, 322.8 mmol, 4 equiv.) at 25°C. The resulting mixture was stirred at 135°C under a N2 atmosphere for 10 h. The reaction mixture was cooled to 0°C, and 2N aqueous HCl was added until the pH reached 6. The solid was collected by filtration, washed with water, and dried under vacuum to give 2-amino-2-(3-bromo-5-chlorophenyl)propanoic acid (20 g, 71.8 mmol, 89% yield) as a white solid.

[0565] [ka]

[0566] To a solution of 2-amino-2-(3-bromo-5-chlorophenyl)propanoic acid (15 g, 53.85 mmol, 1 equiv.) in THF (150 mL, 0.36 M) was added borane tetrahydrofuran complex solution (235.88 g, 269.27 mmol, 5 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h under a N atmosphere. The reaction mixture was quenched with MeOH (200 mL) and aqueous HCl (5 mL), stirred for 1 h, and then concentrated under reduced pressure. The mixture was neutralized with 2 N aqueous sodium hydroxide solution at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give 2-amino-2-(3-bromo-5-chlorophenyl)propan-1-ol (13.8 g, 52.1 mmol, 97% yield).

[0567] To a solution of 2-amino-2-(3-bromo-5-chloro-phenyl)propan-1-ol (2 g, 7.56 mmol, 1 equiv.) in toluene (30 mL, 0.25 M) was added NaH (10.65 g, 2 equiv.) at 0 °C. The reaction was stirred for 30 minutes, after which ethyl chloroacetate (1.11 g, 9.07 mmol, 1.2 equiv.) was added dropwise. The reaction was warmed to 25 °C and stirred for 30 minutes. The mixture was then heated to 130 °C for 16 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (30 mL*3). The organic layer was washed with 100 mL of saturated brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (PE:EA=1:0 to 1:1) to give 5-(3-bromo-5-chlorophenyl)-5-methylmorpholin-3-one (1.4 g, 4.59 mmol, 61% yield) as a white solid.

[0568] [ka]

[0569] To a solution of 5-(3-bromo-5-chlorophenyl)-5-methylmorpholin-3-one (0.50 g, 1.64 mmol, 1 equiv.) in THF (5 mL, 0.32 M) was added borane tetrahydrofuran complex solution (8.628 g, 9.85 mmol, 6 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h under a N atmosphere. The reaction mixture was quenched with MeOH (15 mL) and HCl (1 mL) and then stirred for 1 h before being concentrated under reduced pressure. The mixture was neutralized with 2 N aqueous sodium hydroxide solution at 0 °C, extracted with ethyl acetate, washed with water and brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash silica gel column (EA:PE=0-60%) to give 3-(3-bromo-5-chlorophenyl)-3-methylmorpholine (240 mg, 0.83 mmol, 50% yield) as a yellow oil.

[0570] To a solution of 3-(3-bromo-5-chlorophenyl)-3-methylmorpholine (240 mg, 0.82 mmol, 1 equiv.) and bis(pinacolato)diboron (251.69 mg, 0.99 mmol, 1.2 equiv.) in 1,4-dioxane (2 mL, 0.41 M), potassium acetate (243.17 mg, 2.47 mmol, 3 equiv.) and Pd(dppf)Cl (59.9 mg, 0.082 mmol, 0.1 equiv.) were added under a N atmosphere. The resulting mixture was stirred at 90 °C for 12 h under a N atmosphere. The mixture was concentrated and used directly in the next step without purification. [ka]

[0571] To a solution of crude 3-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-morpholine (500 mg, 1.48 mmol, 1 equiv.) and triethylamine (449 mg, 4.44 mmol, 3 equiv.) in DCM (6 mL, 0.25 M) was added acryloyl chloride (160 mg, 1.77 mmol, 1.2 equiv.) dropwise under N2 atmosphere at 0 °C. The reaction mixture was quenched with water (1 mL) and extracted with DCM (2 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated.

[0572] The crude product was purified by flash column chromatography (PE:EA=1:0-1:1) to give 1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholino)prop-2-en-1-one (110 mg 0.281 mmol, 19% yield) as a yellow oil.

[0573] To a solution of 1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholino)prop-2-en-1-one (300 mg, 0.76 mmol, 1 equiv.) and 4-chloro-1,3,5-triazin-2-amine (109.98 mg, 0.84 mmol, 1.1 equiv.) in 1,4-dioxane (5 mL, 0.14 M) and water (0.5 mL, 0.14 M) was added Pd(dppf)Cl (55.42 mg, 0.076 mmol) and potassium carbonate (211.71 mg, 1.53 mmol) under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was quenched with water (2 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (3 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:0 to 0:1) to afford 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one (150 mg, 0.42 mmol, 54% yield) as a yellow solid. LC-MS m / z: 360.1 [M+1]. The enantiomers of 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one were separated by SFC. The absolute stereochemistry was not assigned.

[0574] Stereochemistry: Single enantiomer of unknown absolute configuration.

[0575] [ka]

[0576] An appropriate coupling partner can be used in step G to give the title compound. [Table 6]

[0577] Example 59. Procedure H and synthesis of 1-((3R,5R)-3-(2-(2-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (Compound 144) Step H [ka]

[0578] To a solution of D-alaninol (25 g, 332 mmol) in toluene (500 mL, 0.66 M), NaH (19.17 g, 2 equiv.) was added at 0° C. and stirred for 30 minutes. Ethyl chloroacetate (48.94 g, 399.41 mmol, 1.2 equiv.) was added dropwise, then warmed to 25° C. and stirred for 30 minutes. The reaction mixture was heated to 130° C. for 16 hours. The solution was quenched with saturated aqueous NH4Cl (1000 mL) and extracted with ethyl acetate (1000 mL*3). The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated to give (R)-5-methylmorpholin-3-one.

[0579] To a solution of (R)-5-methylmorpholin-3-one (25 g, 217.15 mmol, 1 equiv.) in DCM (300 mL, 0.72 M), di-tert-butyl dicarbonate (56.87 g, 260.58 mmol, 1.2 equiv.), triethylamine (43.94 g, 434.29 mmol, 2 equiv.), and 4-(dimethylamino)pyridine (5.30 g, 43.49 mmol, 0.2 equiv.) were added at 25 °C and then stirred for 16 h. The reaction mixture was quenched with water (300 ml) and extracted with DCM (300 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by flash column chromatography (petroleum ether and ethyl acetate) to give tert-butyl (R)-3-methyl-5-oxomorpholine-4-carboxylate.

[0580] To a solution of tert-butyl (R)-3-methyl-5-oxomorpholine-4-carboxylate (5 g, 23.23 mmol) in THF (50 mL, 0.46 M) was added lithium bis(trimethylsilyl)amide (4275 mg, 25.55 mmol) dropwise at −30° C. The reaction was stirred for 30 minutes, and then diphenyl phosphorochloridate (6863 mg, 25.55 mmol) was added dropwise at −30° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL) and concentrated. The crude product was purified by column chromatography (PE:EA=5:1 to 2:1) to give tert-butyl (R)-5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (9300 mg, 20.8 mmol, 89% yield) as a yellow oil.

[0581] [ka]

[0582] A solution of tert-butyl (R)-5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (6.3 g, 14.08 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.24 g, 15.49 mmol, 1.1 equiv), KCO (5.86 g, 111.75 mmol, 2.0 equiv), and Pd(dppf)Cl (1.55 g, 0.1 equiv) in MeCN (20 mL, 0.28 M), 1,4-dioxane (20 mL, 0.28 M), and water (10 mL, 0.28 M) was stirred at 80 °C for 12 h under a N atmosphere. The reaction mixture was quenched with HO (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic layer was concentrated and then purified by column chromatography (PE / EA = 10 / 1 to PE / EA = 5 / 1) to give tert-butyl (R)-5-(2,6-dichloropyridin-4-yl)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (3.6 g, 10.42 mmol, 74% yield) as a white solid.

[0583] A solution of tert-butyl (R)-5-(2,6-dichloropyridin-4-yl)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (26 g, 75.31 mmol) in 4 M HCl in EtOAC (60 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give (R)-5-(2,6-dichloropyridin-4-yl)-3-methyl-3,6-dihydro-2H-1,4-oxazine HCl (21 g, 70.6 mmol, 94% yield) as a yellow solid.

[0584] Zn (2.32 g, 2 equivalents, 24.4 mmol) was added to a solution of (R)-5-(2,6-dichloropyridin-4-yl)-3-methyl-3,6-dihydro-2H-1,4-oxazine HCl (4000 mg, 14.21 mmol) in acetic acid (40 mL), then stirred for 20 minutes at 25° C. The reaction was quenched with 1N HCl (50 mL), extracted with DCM (50 ml*3), washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 0-30% ethyl acetate / petroleum ether gradient at 80 mL / min) to afford (3R,5R)-3-(2,6-dichloropyridin-4-yl)-5-methylmorpholine (3000 mg, 12.1 mmol, 86% yield) as a yellow oil.

[0585] [ka]

[0586] A solution of (3R,5R)-3-(2,6-dichloropyridin-4-yl)-5-methylmorpholine (200 mg, 0.81 mmol), 4-trimethylstannylpyrimidin-2-amine (187.86 mg, 0.73 mmol, 0.9 equiv), LiCl (3.43 mg, 0.081 mmol, 0.10 equiv), and Pd(PPh) (93.52 mg, 0.081 mmol, 0.1 equiv) in 1,4-dioxane (5 mL, 0.16 M) was stirred at 90 °C under a N atmosphere for 12 h. The reaction was quenched with HO (5 mL) and extracted with EtOAc (2 mL × 3). The organic layer was concentrated and purified by preparative TLC (PE / EtOAc=0 / 1) to give 4-(6-chloro-4-((3R,5R)-5-methylmorpholin-3-yl)pyridin-2-yl)pyrimidin-2-amine (80 mg, 0.26 mmol, 32% yield) as a yellow oil.

[0587] A solution of 4-(6-chloro-4-((3R,5R)-5-methylmorpholin-3-yl)pyridin-2-yl)pyrimidin-2-amine (80 mg, 0.26 mmol, 1 equiv.), acryloyl chloride (23.68 mg, 0.26 mmol, 1 equiv.), and triethylamine (0.5 mL) in DCM (2 mL, 0.13 M) was stirred at 25° C. for 2 h. The reaction was quenched with HO (5 mL) and extracted with DCM (5 mL × 3). The organic layer was concentrated and purified by preparative TLC (EtOAc / MeOH=10 / 1) to give 1-((3R,5R)-3-(2-(2-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (7.2 mg, 0.02 mmol, 8% yield) as a white solid. LC-MS m / z: 360.1 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0588] [ka]

[0589] An appropriate coupling partner can be used in step H to give the title compound. [Table 7]

[0590] Example 60. Procedure I and synthesis of 1-((3R,5R)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (Compound 138) [ka]

[0591] (3R,5R)-3-(2,6-Dichloropyridin-4-yl)-5-methylmorpholine was obtained from procedure H.

[0592] To a solution of (3R,5R)-3-(2,6-dichloropyridin-4-yl)-5-methylmorpholine (470 mg, 1.90 mmol) and acryloyl chloride (189.36 mg, 2.09 mmol) in DCM (5 mL, 0.38 M) was added DIEA (0.8 mL) at 25 °C, then stirred for 2 h. The mixture was diluted with HO (15 mL) and extracted with DCM (15 mL * 3). The combined organic solution was washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluting with a 0-30% ethyl acetate / petroleum ether gradient at 80 mL / min) to give 1-((3R,5R)-3-(2,6-dichloropyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (440 mg, 1.46 mmol, 77% yield).

[0593] To a solution of 1-((3R,5R)-3-(2,6-dichloropyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (100 mg, 0.33 mmol, 1 equiv.) and imidazo[1,2-a]pyridin-7-ylboronic acid pinacol ester (64.84 mg, 0.26 mmol, 0.8 equiv.) in 1,4-dioxane (3 mL, 0.09 M) and water (0.60 mL, 0.09 M), AcOK (65.17 mg, 0.66 mmol, 2 equiv.) and Pd(dppf)Cl (24.29 mg, 0.033 mmol, 0.1 equiv.) were added. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Waters Xbridge BECH C18 100 × 25 mm * 5 μm; liquid phase: [A - 10 mM NHHCO / HO; B - ACN] B%: 30% - 60%, 10 min) to give 1-((3R,5R)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one (10 mg, 0.027 mmol, 8% yield) as a yellow solid. LC-MS m / z: 383.0 [M+1]. Stereochemistry: Single enantiomer of known absolute configuration.

[0594] [ka]

[0595] Using the appropriate coupling partner in Procedure I, the title compound can be obtained. [Table 8]

[0596] Example 61. Synthesis of 1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one (Compound 152) [ka]

[0597] To a solution of 1,4-oxazepan-5-one (3000 mg, 26.05 mmol) and di-tert-butyl dicarbonate (7393.2 mg, 33.87 mmol) in DCM (60 mL, 0.43 M) was added DMAP (3.42 g, 1 equiv.) and triethylamine (3.94 g, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction was diluted with HO (150 mL) and extracted with EtOAc (150 mL*3). The combined organic solution was washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluent of 0–30% ethyl acetate / petroleum ether, 80 mL / min) to give tert-butyl 5-oxo-1,4-oxazepane-4-carboxylate (3000 mg, 13.9 mmol, 53% yield).

[0598] To a solution of tert-butyl 5-oxo-1,4-oxazepane-4-carboxylate (2500 mg, 11.61 mmol) in THF (30 mL, 0.38 M) was added LiHMDS (13.7 mL, 1.1 equiv.) dropwise at −30° C. The reaction was stirred at −30° C. for 30 minutes, after which diphenyl phosphorochloridate (3432 mg, 12.77 mmol, 1.1 equiv.) was added dropwise. The reaction was warmed to 25° C. and then stirred under a N atmosphere for 1 hour. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (10 mL) and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=5:1 to 2:1) to give tert-butyl 5-diphenoxyphosphoryloxy-3,7-dihydro-2H-1,4-oxazepine-4-carboxylate (2100 mg, 4.69 mmol, 40% yield).

[0599] 2,2'-(5-chloro-1,3-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) was obtained from procedure A.

[0600] To a solution of tert-butyl 5-diphenoxyphosphoryloxy-3,7-dihydro-2H-1,4-oxazepine-4-carboxylate (4.3 g, 9.61 mmol) and 2,2'-(5-chloro-1,3-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (4203 mg, 11.53 mmol) in 1,4-dioxane (40 mL, 0.2 M) and water (8 mL, 0.2 M), KCO (3 equiv., 3.978 g) and Pd(dppf)Cl (0.1 equiv., 600 mg) were added at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL*3). The combined organic solution was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluent: 0–30% ethyl acetate / petroleum ether, 80 mL / min) to give tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (1500 mg, 3.44 mmol, 36%). [ka]

[0601] To a solution of tert-butyl 5-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (200 mg, 0.45 mmol, 1 equiv.) and 4-chloro-1,3,5-triazin-2-amine (71 mg, 0.55 mmol, 1.2 equiv.) in 1,4-dioxane (2.5 mL, 0.15 M) and water (0.5 mL, 0.15 M) was added KCO (3 equiv., 182 mg) and Pd(dppf)Cl (0.1 equiv., 32 mg) at 25 °C. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The mixture was diluted with HO (15 mL) and extracted with EtOAc (15 mL*3). The combined extracts were washed with brine (15 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (PE: EtOAc = 1:1) to give tert-butyl 5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (50 mg, 0.123 mmol, 27% yield) as a white solid.

[0602] A solution of tert-butyl 5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (80 mg, 0.19 mmol, 1 equiv.) in 4 M HCl / ethyl acetate (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-(3-chloro-5-(2,3,6,7-tetrahydro-1,4-oxazepin-5-yl)phenyl)-1,3,5-triazin-2-amine (60 mg).

[0603] [ka]

[0604] To a solution of 4-(3-chloro-5-(2,3,6,7-tetrahydro-1,4-oxazepin-5-yl)phenyl)-1,3,5-triazin-2-amine (60 mg, 0.19 mmol, 1 equiv.) in methanol (1 mL, 0.19 M) was added NaBH4 (24.6 mg, 2 equiv., 0.39 mmol) at 0 °C. The mixture was stirred at room temperature under N2 atmosphere for 2 h. The mixture was diluted with NH4Cl (3 mL) and extracted with EtOAc (5 mL*3). The extract was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give 4-(3-chloro-5-(1,4-oxazepan-5-yl)phenyl)-1,3,5-triazin-2-amine (20 mg, 0.065 mmol, 33% yield).

[0605] To a solution of 4-(3-chloro-5-(1,4-oxazepan-5-yl)phenyl)-1,3,5-triazin-2-amine (20 mg, 0.065 mmol, 1 equiv.) in DCM (1 mL, 0.065 M) and EtN (0.1 mL) was added acryloyl chloride (5.92 mg, 0.06 mmol, 1 equiv.) at 0° C. The mixture was stirred under N atmosphere at 25° C. for 2 h. The mixture was diluted with HO (13 mL) and extracted with EtOAc (15 mL*3). The combined organic solution was washed with brine (15 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc:PE=1:0) to give 1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one (13 mg, 0.036 mmol, 55% yield) as a white solid. LC-MS m / z: 360.1 [M+1]. Stereochemistry: Racemic.

[0606] Example 62. Synthesis of 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one (Compound 162) [ka]

[0607] To a solution of 1,4-oxazepan-3-one (9 g, 78.17 mmol, 1 equiv.) in DCM (100 mL, 0.78 M) was added di-tert-butyl dicarbonate (22.17 g, 101.62 mmol, 1.3 equiv.), DMAP (2.33 g, 0.2 equiv.), and triethylamine (15.82 g, 156.35 mmol, 2 equiv.). The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether: EtOAc = 3:1) to give the product, tert-butyl 3-oxo-1,4-oxazepan-4-carboxylate (2500 mg, 11.6 mmol, 15% yield), as a yellow oil.

[0608] To a solution of 1,3-dibromo-5-chloro-benzene (1.256 g, 4.64 mmol, 1 equiv.) in i-PrO (10 mL) was added n-BuLi (1.86 ml, 1 equiv.) at −78° C. The mixture was stirred at −78° C. for 1 h under a N atmosphere. A solution of tert-butyl 3-oxo-1,4-oxazepane-4-carboxylate (1000 mg, 4.64 mmol, 1 equiv.) in i-PrO (10 mL) was added slowly at −78° C. The mixture was stirred at −78° C. for 1 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL*3). The extract was washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give tert-butyl N-[2-[3-(3-bromo-5-chloro-phenyl)-3-oxo-propoxy]ethyl]carbamate (600 mg, 1.48 mmol, 32% yield).

[0609] [ka]

[0610] To a solution of tert-butyl N-[2-[3-(3-bromo-5-chloro-phenyl)-3-oxo-propoxy]ethyl]carbamate (600 mg, 1.47 mmol, 1 equiv) in methanol (6 mL, 0.25 M) was added NaBH4 (279 mg, 7.35 mmol, 5 equiv) under N2 atmosphere at 0 °C. The reaction was stirred at room temperature for 1.5 h. The mixture was diluted with HO (15 mL) and extracted with DCM (15 mL * 3). The extract was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give tert-butyl N-[2-[3-(3-bromo-5-chloro-phenyl)-3-hydroxy-propoxy]ethyl]carbamate (540 mg, 1.32 mmol, 90% yield) as a yellow oil.

[0611] To a solution of tert-butyl N-[3-[2-(3-bromo-5-chloro-phenyl)-2-hydroxy-ethoxy]propyl]carbamate (540 mg, 1.32 mmol) in DCM (6 mL, 0.22 M) was added MsO (343 mg, 1.97 mmol, 1.5 equiv), DMAP (80 mg, 0.5 equiv), and triethylamine (399 mg, 3.95 mmol, 3 equiv). The mixture was stirred at 25 °C for 12 h. The solution was concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether: EtOAc = 3:1) to give [1-(3-bromo-5-chloro-phenyl)-2-[3-(tert-butoxycarbonylamino)propoxy]ethyl]methanesulfonate (400 mg, 0.82 mmol, 62% yield).

[0612] 4M HCl / EtOAc (5 mL) was added to [1-(3-bromo-5-chloro-phenyl)-2-[3-(tert-butoxycarbonylamino)propoxy]ethyl]methanesulfonate (400 mg, 0.82 mmol, 1 equiv.) and then stirred at 25° C. for 1 h. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure to give [2-(3-aminopropoxy)-1-(3-bromo-5-chloro-phenyl)ethyl]methanesulfonate (400 mg) as a yellow solid.

[0613] [ka]

[0614] CsCO (450 mg, 3 equiv.) was added to a solution of [2-(3-aminopropoxy)-1-(3-bromo-5-chloro-phenyl)ethyl]methanesulfonate (400 mg, 1.03 mmol, 1 equiv.) in MeCN (5 mL, 0.21 M) at room temperature. The mixture was heated to 80 °C for 16 h under a N atmosphere. The reaction mixture was poured into water (15 mL), extracted with DCM (15 mL × 3), washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (petroleum ether:ethyl acetate) to give 3-(3-bromo-5-chloro-phenyl)-1,4-oxazepane (40 mg, 0.14 mmol, 13% yield) as a white oil.

[0615] To a solution of 3-(3-bromo-5-chloro-phenyl)-1,4-oxazepane (40 mg, 0.14 mmol, 1 equiv.) in DCM (3 mL, 0.045 M) was added acryloyl chloride (12 mg, 0.13 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 25 °C under N atmosphere for 2 h. The mixture was diluted with HO (13 mL) and extracted with DCM (15 mL*3). The extract was washed with brine (15 mL), dried over NaSO, and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc:PE=1:5) to give 1-[3-(3-bromo-5-chloro-phenyl)-1,4-oxazepan-4-yl]prop-2-en-1-one (40 mg, 0.12 mmol, 84% yield) as a white solid.

[0616] [ka]

[0617] To a solution of 1-[3-(3-bromo-5-chloro-phenyl)-1,4-oxazepan-4-yl]prop-2-en-1-one (40 mg, 0.12 mmol, 1 equiv.) and Pin2B2 (44 mg, 2 equiv.) in 1,4-dioxane (3 mL, 0.04 M), KOAc (24.5 mg) and Pd(dppf)Cl2 (10.4 mg, 0.1 equiv.) were added. The reaction mixture was stirred at 90 °C under a N2 atmosphere for 16 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 1-[3-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-oxazepan-4-yl]prop-2-en-1-one (45 mg, 0.12 mmol, 99% yield) as a dark oil.

[0618] To a solution of 1-[3-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-oxazepan-4-yl]prop-2-en-1-one (45 mg, 0.11 mmol) and 4-chloro-1,3,5-triazin-2-amine (17 mg, 0.13 mmol, 1.2 equiv.) in 1,4-dioxane (3 mL, 0.03 M) and water (0.60 mL, 0.032 M) was added KCO (47.5 mg, 3 equiv.) and Pd(dppf)Cl (10.4 mg, 0.1 equiv.). The reaction mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was diluted with HO (15 mL) and extracted with EtOAc (15 mL*3). The extract was washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one (19 mg, 0.051 mmol, 44% yield) as a pale yellow solid. LC-MS m / z: 360.0 [M+1]. Stereochemistry: Racemic.

[0619] Example 63. Procedure J and synthesis of 1-((3R,5R)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-(hydroxymethyl)morpholino)prop-2-en-1-one (Compound 157) Procedure J [ka]

[0620] LiAlH4 (17.11 g, 1.5 equiv.) was added to a solution of O-benzyl-D-serine (60 g, 307.35 mmol, 1 equiv.) in THF (1 L, 0.3 M) under a N2 atmosphere. The mixture was stirred at 70 °C for 16 h. The reaction mixture was carefully diluted with water (18 mL), 15% aqueous NaOH (18 mL), and then water (36 mL). The mixture was stirred for 3 h and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100 / 1 to 5 / 1) to give (S)-2-amino-3-(benzyloxy)propan-1-ol (20.0 g, 110 mmol, 36% yield) as a yellow oil.

[0621] NaH (60 wt%) (8.828 g, 2 equiv.) was added to a solution of (S)-2-amino-3-(benzyloxy)propan-1-ol (20 g, 110.36 mmol) in toluene (300 mL, 0.37 M) under a N atmosphere at 0° C. and stirred for 30 min. Ethyl chloroacetate (20.286 g, 165.54 mmol, 1.5 equiv.) was added dropwise and stirred at 0° C. for 30 min. The mixture was heated to 130° C. for 16 h. The reaction mixture was poured into water (80 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude (R)-5-((benzyloxy)methyl)morpholin-3-one (23.00 g, 104 mmol, 94% yield) as a brown oil.

[0622] To a solution of (R)-5-((benzyloxy)methyl)morpholin-3-one (23 g, 103.95 mmol, 1 equiv) in DCM (250 mL, 0.42 M) was added di-tert-butyl dicarbonate (27.226 g, 124.75 mmol, 1.2 equiv), triethylamine (28.89 mL, 2 equiv), and DMAP (2.54 g, 0.2 equiv). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl (R)-3-((benzyloxy)methyl)-5-oxomorpholine-4-carboxylate (8.10 g, 25.2 mmol, 24% yield) as a yellow oil.

[0623] [ka]

[0624] To a solution of tert-butyl (R)-3-((benzyloxy)methyl)-5-oxomorpholine-4-carboxylate (8.1 g, 25.20 mmol, 1 equiv) in THF (100 mL, 0.2520 M) was added lithium bis(trimethylsilyl)amide (4.639 g, 27.72 mL, 1 M, 1.1 equiv) dropwise at −30° C. under a N atmosphere. The reaction was stirred at −30° C. for 1 h. Diphenyl phosphorochloridate (7.447 g, 27.75 mmol, 1.1 equiv) in THF (50 mL) was added dropwise at −30° C., followed by stirring at 25° C. for 1 h. The reaction was poured into water (80 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (100 mL) and concentrated. The crude product was purified by column chromatography (PE:EA = 5:1 to 2:1) to give tert-butyl (R)-3-((benzyloxy)methyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (13.00 g, 23.5 mmol, 93% yield) as a yellow oil.

[0625] A solution of tert-butyl (R)-3-((benzyloxy)methyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (13 g, 23.48 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.077 g, 25.83 mmol, 1.1 equiv), potassium carbonate (6491 mg, 46.97 mmol), and Pd(dppf)Cl (852.11 mg, 1.17 mmol, 0.05 equiv) in MeCN (50 mL, 0.18 M), 1,4-dioxane (50 mL, 0.18 M), and water (25 mL, 0.18 M) was stirred at 80 °C for 16 h under a N atmosphere. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (20 mL × 3). The organic layer was concentrated and purified by column chromatography (PE / EA = 10 / 1 to PE / EA = 1 / 1) to give tert-butyl (R)-3-((benzyloxy)methyl)-5-(2,6-dichloropyridin-4-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (7.5 g, 16.6 mmol, 71% yield).

[0626] [ka]

[0627] To a solution of tert-butyl (R)-3-((benzyloxy)methyl)-5-(2,6-dichloropyridin-4-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (7.5 g, 16.62 mmol, 1 equiv) in ethyl acetate (30 mL, 0.55 M) was added HCl in EtOAc (40 mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give (R)-3-((benzyloxy)methyl)-5-(2,6-dichloropyridin-4-yl)-3,6-dihydro-2H-1,4-oxazine (6.00 g) as a yellow oil.

[0628] To a solution of (R)-3-((benzyloxy)methyl)-5-(2,6-dichloropyridin-4-yl)-3,6-dihydro-2H-1,4-oxazine (6 g, 17.08 mmol, 1 equiv.) in acetic acid (30 mL) was added Zn (2.23 g, 2 equiv., 34.16 mmol). The mixture was stirred at 25 °C for 30 min. The reaction was quenched with 1N HCl (25 mL) and adjusted to pH = 8-9 with saturated aqueous N...

Claims

1. Formula (I): 【Chemical 1】 [In the ceremony; R Ａ teeth, 【Chemistry 2】 where: R ６ａ is H, D, halogen, or C １ -C ６ is haloalkyl, and R ６ｂ and R ６ｃ are each independently H or D; Ring A is aryl, heteroaryl, or heterocyclyl; Z is O, S(=O) ２ , C(R １ ) ２ , or NR ７ and R ７ is -C(=O)R ７ａ , S(=O)R ７ａ , or S(=O) ２ R ７ａ where R ７ａ is H, optionally substituted C １ -C ６ Alkyl or optionally substituted C ３ -C ７ is cycloalkyl; Each R １ are independently H, halogen, —OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ and or two R's １ together with the atom(s) to which they are attached, may be optionally substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; X １ is N or CR ２ and Each R ２ are independently H, halogen, CN, OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ haloalkyl, or optionally substituted C １ -C ６ is hydroxyalkyl; R ４ is H or optionally substituted C １ -C ６ is alkyl; or R ２ and R ４ together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; Each R ３ are independently H, D, halogen, oxo (=O), thio (=S), -CN, -OH, -OR ａ , -SH, -SR ａ , -S(=O)R ａ , -NO ２ , -N(R ｂ ) ２ , -S(=O) ２ R ａ , -NHS(=O) ２ R ａ , -S(=O) ２ N (R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms ３ taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; Each R ａ is independent, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl), or -C １ -C ６ alkyl(heterocycloalkyl); wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains 1, 2, or 3 —OH, C １ -C ６ Alkyl, or C １ -C ６ optionally substituted with haloalkyl; and Each R ｂ are independently H, C １ -C ６ Alkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contain one, two, or three —OH, C １ -C ６ Alkyl, or C １ -C ６ optionally substituted with haloalkyl; or two R on a nitrogen atom ｂ The groups, together with the nitrogen atom to which they are attached, may contain one, two or three C １ -C ６ Alkyl or C １ -C ６ forming a heterocycloalkyl optionally substituted with haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is an integer from 1 to 12; and and q is an integer of 1 to 10. or a pharmaceutically acceptable salt thereof.

2. Rings A and R ２ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is in the 1,3,5-configuration.

3. Formula (II): 【Chemistry 3】 [During the ceremony, Z is O, S(=O) ２ , C.R. １ｄ R １ｅ , or NR ７ and R １ａ , R １ｂ , R １ｃ , R １ｄ , and R １ｅ are each independently H, halogen, —OH, or optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ and or R １ａ and R １ｂ together with the atoms to which they are attached, may be optionally substituted C ３ -C ８ Forming a cycloalkyl; or R １ｂ and R １ｃ together with the carbon atom to which they are attached, may be substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R １ｄ and R １ｅ together with the carbon atom to which they are attached, may be substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; R ２ａ is H, halogen, CN, OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ haloalkyl, or optionally substituted C １ -C ６ is hydroxyalkyl; and R ４ is H or optionally substituted C １ -C ６ is alkyl; or R ２ａ and R ４ together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

4. R ２ａ and R ４ and R 1 and R 2 together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

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

6. R ４ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein

7. R １ａ and R １ｂ together with the atoms to which they are attached, optionally substituted C ３ -C ８ 7. The compound according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

8. R １ｂ and R １ｃ together with the carbon atom to which they are attached, optionally substituted C ３ -C ８ 7. The compound according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

9. R １ｂ and R １ｃ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl.

10. R １ａ is H; R １ｂ and R １ｃ are each independently H, halogen, —OH, or optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ 7. The compound according to any one of claims 3 to 6, wherein:

11. R １ｂ and R １ｃ are each independently H or optionally substituted C １ -C ６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein:

12. R １ｂ and R １ｃ and R are each methyl, or a pharmaceutically acceptable salt thereof.

13. R １ｂ and R １ｃ and R are each H, or a pharmaceutically acceptable salt thereof.

14. R １ａ is halogen, —OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ and R １ｂ and R １ｃ The compound according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, wherein each is H.

15. R １ａ is optionally substituted C １ -C ６ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:

16. Ring A is C ６－１０ 16. The compound of any one of claims 1 to 15, which is aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

17. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N.

18. 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl.

19. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

20. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl or pyrazinyl.

21. Ring A is: 【Chemistry 4】 [During the ceremony, X ２ , X ３ , X ４ , and X ５ are each independently N, NR ３ａ , or CR ３ and Each R ３ａ are independently H or optionally substituted C １ -C ６ is alkyl; Each R ３ are independently H, D, halogen, oxo (=O), -CN, -OH, or -OR ａ , -SH, -SR ａ , -S(=O)R ａ , -NO ２ , -N(R ｂ ) ２ , -S(=O) ２ R ａ , -NHS(=O) ２ R ａ , -S(=O) ２ N (R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms ３ Or two R's ３ａ Or R ３ and R ３ａ together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; 17. The compound according to any one of claims 1 to 16, wherein:

22. Formula (III): 【Chemistry 5】 [During the ceremony, X ２ , X ３ , X ４ , and X ５ are each independently N, NR ３ａ , or CR ３ and Each R ３ａ are independently H or optionally substituted C １ -C ６ is alkyl; Each R ３ are independently H, D, halogen, oxo (=O), -CN, -OH, or -OR ａ , -SH, -SR ａ , -S(=O)R ａ , -NO ２ , -N(R ｂ ) ２ , -S(=O) ２ R ａ , -NHS(=O) ２ R ａ , -S(=O) ２ N (R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms ３ taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; 2. The compound of claim 1, wherein:

23. Formula (IIIa): 【Chemistry 6】 [During the ceremony, Z is O, S(=O) ２ , C.R. １ｄ R １ｅ , or NR ７ and R １ａ , R １ｂ , R １ｃ , R １ｄ , and R １ｅ are each independently H, halogen, —OH, or optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ and or R １ａ and R １ｂ together with the atoms to which they are attached, may be optionally substituted C ３ -C ８ Forming a cycloalkyl; or R １ｂ and R １ｃ together with the carbon atom to which they are attached, may be substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R １ｄ and R １ｅ together with the carbon atom to which they are attached, may be substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; R ２ is halogen or CN; X ２ , X ３ , X ４ , and X ５ are each independently N, NR ３ａ , or CR ３ and Each R ３ａ are independently H or optionally substituted C １ -C ６ is alkyl; and Each R ３ are independently H, D, halogen, oxo (=O), -CN, -OH, or -OR ａ , -SH, -SR ａ , -S(=O)R ａ , -NO ２ , -N(R ｂ ) ２ , -S(=O) ２ R ａ , -NHS(=O) ２ R ａ , -S(=O) ２ N (R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms ３ taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; 2. The compound of claim 1, wherein:

24. X ２ and X ３ are each independently N; and X ４ and X ５ are CR respectively ３ 24. The compound of claim 22 or 23, wherein:

25. X ２ and X ４ are each independently N; and X ３ and X ５ are CR respectively ３ 24. The compound of claim 22 or 23, wherein:

26. X ４ is N; and X ２ , X ３ , and X ５ are CR respectively ３ 24. The compound of claim 22 or 23, wherein:

27. X ２ , X ３ and X ４ are each N; and X ５ is CR ３ 24. The compound of claim 22 or 23, wherein:

28. Two R on adjacent atoms ３ or a pharmaceutically acceptable salt thereof.

29. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

30. Formula (IV): 【Chemistry 7】 [During the ceremony, X ２ is N or CR ３ and X ４ is N or C; and Ring B is an optionally substituted 5-6 membered heteroaryl; or Ring C is an optionally substituted 5- or 6-membered heteroaryl.

2. The compound of claim 1, wherein:

31. 31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 5- to 6-membered heteroaryl.

32. 31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein Ring C is an optionally substituted 5- to 6-membered heteroaryl.

33. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

34. 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

35. Ring A is: 【Chemistry 8】 34. The compound of claim 33, wherein:

36. Each R ３ are independently hydrogen, halogen, —CN, —OH, —OR ａ , -N(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ haloalkyl, or optionally substituted C １ -C ６ 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, which is hydroxyalkyl.

37. Each R ３ are independently hydrogen, halogen, -N(R ｂ ) ２ or -C(=O)NH ２ 37. The compound of claim 36, wherein:

38. Ring A is 【Chemistry 9】 16. The compound according to any one of claims 1 to 15, wherein:

39. 【Catalog 10】 but, 【Chemistry 11】 16. The compound according to any one of claims 1 to 15, wherein:

40. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein q is 1.

41. 40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein q is 2.

42. R ２ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein is halogen or CN.

43. R ２ 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein is Cl.

44. X １ The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein

45. X １ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein is CH.

46. Z is NR ７ 46. ​​The compound according to any one of claims 1 to 45, wherein:

47. Z is —O— or —SO ２ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

48. 48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

49. 49. The compound of any one of claims 1 to 48, wherein m is 1 and n is 1, or a pharmaceutically acceptable salt thereof.

50. 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 2.

51. R Ａ but, 【Chemistry 12】 51. The compound according to any one of claims 1 to 50, wherein:

52. R Ａ but, 【Chemistry 13】 52. The compound of claim 51, wherein:

53. 1-(3-(5-chloro-[1,1′-biphenyl]-3-yl)morpholino)prop-2-en-1-one; (R)—N-(3′-(4-acryloylmorpholin-3-yl)-5′-chloro-[1,1′-biphenyl]-3-yl)acetamide; 1-(3-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)morpholino)prop-2-en-1-one; N-(4-(3-(1-acrylolyl-4-(methylsulfonyl)piperazin-2-yl)-5-chlorophenyl)pyridin-2-yl)acetamide; 1-(5-chloro-7-phenyl-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one; 3-(4-acryloylmorpholin-3-yl)-5-(pyrimidin-2-yl)benzonitrile; (R)-1-(3-(3-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(pyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyridin-2(1H)-one; (R)-1-(4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyridin-2-yl)pyrrolidin-2-one; (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methylpyridin-2(1H)-one; 1-(3-(3-chloro-5-(pyridazin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-4-(3-(1-acrylolyl-4-(methylsulfonyl)piperazin-2-yl)-5-chlorophenyl)pyridin-2(1H)-one; (R)-1-(4-(3-(1-acrylolyl-4-(methylsulfonyl)piperazin-2-yl)-5-chlorophenyl)pyridin-2-yl)pyrrolidin-2-one; (R)-1-(4-acetyl-2-(3-chloro-5-(pyrimidin-2-yl)phenyl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-5-chlorophenyl)pyridin-2-yl)pyrrolidin-2-one; (R)-1-(3-(3-chloro-5-(5-fluoropyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(pyrimidin-2-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(2-(3-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-4-(methylsulfonyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(4-acetyl-2-(3-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)piperazin-1-yl)prop-2-en-1-one; 1-(3-(2-chloro-6-(2-methyl-2H-tetrazol-5-yl)pyridin-4-yl)morpholino)prop-2-en-1-one; 4-(3-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-5-chlorophenyl)-1-methylpyridin-2(1H)-one; 4-(4-acryloylmorpholin-3-yl)-6-chloro-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one; (R)-1-(4-acetyl-2-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one; 1-(3-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 4-(3-(4-acrylolyl-1,1-dioxidethiomorpholin-3-yl)-5-chlorophenyl)-1-methylpyridin-2(1H)-one; 1-(3-(2-chloro-6-(pyridazin-4-yl)pyridin-4-yl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(pyrimidin-2-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 4-(4-acryloylmorpholin-3-yl)-6-chloro-[2,4′-bipyridin]-2′(1′H)-one; 1-(3-(3-chloro-5-(quinoxalin-6-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; 3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methylpyridin-2(1H)-one; 1-(3-(3-chloro-5-(1,5-naphthyridin-3-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(6-methylpyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; 4-(3-(4-acrylolyl-1,1-dioxidethiomorpholin-3-yl)-5-chlorophenyl)pyridin-2(1H)-one; 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(1H-1,2,4-triazol-3-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(pyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(imidazo[1,2-a]pyridin-7-yl)phenyl)morpholino)prop-2-en-1-one; (R)-3'-(4-acryloylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(5-(3-chloro-5-(5-fluoropyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(6-methylpyrimidin-4-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(quinoxalin-6-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(2-methoxypyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(6-methylpyridin-2-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(6-methylpyridin-2-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 5-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-2-methylpyridazin-3(2H)-one; 1-(3-(3-chloro-5-(pyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(6-methoxypyridazin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(2-methylimidazo[1,2-a]pyridin-7-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(6-methylpyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; 3'-(4-acryloylmorpholin-3-yl)-5'-chloro-6-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-3'-(4-acrylolyl-6,6-dimethylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-2-(3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1H-1,2,4-triazol-1-yl)acetamide; 1-(3-(3-chloro-5-(imidazo[1,2-a]pyrimidin-7-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)morpholino)prop-2-en-1-one; 5-(4-(4-acryloylmorpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; (R)-1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 3'-(4-acryloylmorpholin-3-yl)-5'-cyano-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-(3-(3-chloro-5-(imidazo[1,5-a]pyrimidin-3-yl)phenyl)morpholino)prop-2-en-1-one; 5-(4-(4-acrylolyl-6,6-dimethylmorpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; 3'-(4-acryloylmorpholin-3-yl)-5'-chloro-[1,1'-biphenyl]-4-carboxamide; 3'-(4-acryloylmorpholin-3-yl)-5'-chloro-[1,1'-biphenyl]-3-carboxamide; 3'-(4-acryloylmorpholin-3-yl)-5'-chloro-5-fluoro-[1,1'-biphenyl]-3-carboxamide; 3'-(4-acryloylmorpholin-3-yl)-5'-chloro-2-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(4-acetyl-2-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)piperazin-1-yl)prop-2-en-1-one; 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)picolinamide; 3'-(7-acrylolyl-4-oxa-7-azaspiro[2.5]octan-6-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-4-carboxamide; 1-(5-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-3'-(4-acetyl-1-acrylolylpiperazin-2-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(4-acetyl-2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)piperazin-1-yl)prop-2-en-1-one; (R)-6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isoindolin-1-one; 1-(6-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(6-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 7-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)imidazo[1,2-a]pyridine-5-carboxamide; (R)-1-(3-(3-chloro-5-(6-methoxypyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-2-carboxamide; (R)-1-(3-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(2-methoxypyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-dimethylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; 6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4(3H)-one; (R)-1-(3-(3-(4-amino-6-methylpyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(6-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; 1-(5-(2-(2-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(6-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methoxypyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-2-carbonitrile; 6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-4-carboxamide; 3'-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-((3R,5R)-3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 3'-(4-acrylolyl-3-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(3-(3-chloro-5-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-pyrazol-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methyl-1H-pyrazol-1-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; 1-(5-(2-chloro-6-(2-methylpyrimidin-4-yl)pyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(3-(2-chloro-6-(2-methylpyrimidin-4-yl)pyridin-4-yl)morpholino)prop-2-en-1-one; 4-(3-(7-acrylolyl-4-oxa-7-azaspiro[2.5]octan-6-yl)-5-chlorophenyl)picolinamide; (R)-1-(2-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-4-(methylsulfonyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-(methylsulfonyl)piperazin-1-yl)prop-2-en-1-one; 6-(4-(4-acryloylmorpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; (R)-1-(3-(3-chloro-5-(pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyridazin-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 6-(4-(4-acryloylmorpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carbonitrile; 1-((3R,5R)-3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyridazin-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-4-(3-(4-acrylolyl-6,6-dimethylmorpholin-3-yl)-5-chlorophenyl)picolinamide; 4-(3-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-5-chlorophenyl)picolinamide; (R)-1-(3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(2-aminopyridin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(9H-purin-6-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one; 5-(4-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; 1-(6-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyridazin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(2-chloro-6-(2-methylpyrimidin-4-yl)pyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one; 5-(4'-acrylolyl-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-7-yl)-2-fluorobenzamide; 1-((3R,5R)-3-(2-(2-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-methylmorpholino)prop-2-en-1-one; 4-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-6-chloro-[2,4'-bipyridine]-2'-carboxamide; 1-(3-(2-(4-amino-1,3,5-triazin-2-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(7-(4-amino-1,3,5-triazin-2-yl)-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one; 1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-(hydroxymethyl)morpholino)prop-2-en-1-one; 1-(7-(2-aminopyrimidin-4-yl)-5-chloro-2H-spiro[benzofuran-3,3'-morpholin]-4'-yl)prop-2-en-1-one; 1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2-oxa-6-azaspiro[3.3]heptan-6-yl)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(6-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,4-oxazepan-4-yl)prop-2-en-1-one; 1-(8-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-8-methyl-6-oxa-9-azaspiro[4.5]decan-9-yl)prop-2-en-1-one; 1-(8-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-8-methyl-6-oxa-9-azaspiro[4.5]decan-9-yl)prop-2-en-1-one; 1-(6-(3-chloro-5-(5-fluoropyrimidin-2-yl)phenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(8-(3-chloro-5-(5-fluoropyrimidin-2-yl)phenyl)-8-methyl-6-oxa-9-azaspiro[4.5]decan-9-yl)prop-2-en-1-one; 1-(6-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2-oxa-6-azaspiro[3.3]heptan-6-yl)prop-2-en-1-one; (3S,5R)-4-acrylolyl-5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-N,N-dimethylmorpholine-3-carboxamide; 1-(8-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-8-methyl-6-oxa-9-azaspiro[4.5]decan-9-yl)prop-2-en-1-one; 1-(8-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-8-methyl-6-oxa-9-azaspiro[4.5]decan-9-yl)prop-2-en-1-one; (3S,5R)-4-acrylolyl-5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholine-3-carboxamide; (3S,5R)-4-acrylolyl-5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-N-methylmorpholine-3-carboxamide; 1-(6-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-6-amino-1,3,5-triazin-2(1H)-one; (R)-1-(3-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 3'-((3R,6R)-4-acrylolyl-6-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 5-(4-((3R,5S)-4-acrylolyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; (3S,5R)-4-acrylolyl-5-(2-(3-carbamoyl-4-fluorophenyl)-6-chloropyridin-4-yl)morpholine-3-carboxamide; 3'-((3S,6R)-4-acrylolyl-6-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(4-acetyl-2-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)piperazin-1-yl)prop-2-en-1-one; (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1,3-dihydro-2H-imidazol-2-one; (R)-1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; (R)-3-(4-acrylolyl-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)piperazin-1-yl)-3-oxopropanenitrile; (R)-1-(4-acetyl-2-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(4-acetyl-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)piperazin-1-yl)prop-2-en-1-one; (R)—N-(4-(3-(1-acrylolyl-4-(2-cyanoacetyl)piperazin-2-yl)-5-chlorophenyl)pyrimidin-2-yl)-2-cyanoacetamide; 1-(6-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; 7-(2-aminopyrimidin-4-yl)-5-chloro-2H-dispiro[benzofuran-3,5′-morpholine-2′,1″-cyclopropan]-3′-one; (R)-1-(3-(3-(2-amino-1H-imidazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(2-chloro-6-(imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; (R)-3'-(1-acrylolyl-4-(cyclopropanecarbonyl)piperazin-2-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(2-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,6R)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-6-fluoro-1,4-oxazepan-4-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-chloro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,5S)-3-(2-chloro-6-(6-methylpyrimidin-4-yl)pyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(2-chloro-6-(2-methylpyrimidin-4-yl)pyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 2-((3R,5R)-4-acrylolyl-5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholin-3-yl)acetonitrile; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(3-hydroxy-1H-1,2,4-triazol-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1H-pyrazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-5-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methylpyrimidin-2(1H)-one; (R)-1-(3-(3-chloro-5-(4-(methylamino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (R)-1-(3-(3-(3-amino-1H-1,2,4-triazol-1-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 5-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-1-methyltetrahydropyrimidin-2(1H)-one; (R)-1-(3-(3-(4-amino-6-(methylamino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-((2-hydroxyethyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-5-carboxamide; (R)-1-(3-(3-chloro-5-(4-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-5-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)tetrahydropyrimidin-2(1H)-one; 6-(4-((3R,5S)-4-acrylolyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxamide; 1-((3R)-3-(3-chloro-5-(1-methyl-2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)piperazin-2-one; (R)-1-(3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)-3-aminopyrrolidin-2-one; 6-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)morpholin-3-one; (R)-1-(3-(3-chloro-5-(2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(2-aminooxazol-5-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-1H-pyrazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2S,5R)-4-acetyl-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-methylpiperazin-1-yl)prop-2-en-1-one; 1-((2S,5S)-4-acetyl-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-methylpiperazin-1-yl)prop-2-en-1-one; 1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5,5-difluoropiperidin-1-yl)prop-2-en-1-one; 1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)piperidin-1-yl)prop-2-en-1-one; 1-((R)-3-(3-chloro-5-((S)-5-thioxomorpholin-2-yl)phenyl)morpholino)prop-2-en-1-one; 4-(3-((R)-4-acryloylmorpholin-3-yl)-5-chlorophenyl)tetrahydropyrimidin-2(1H)-one; 1-((2S,5R)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)-5-methylpiperazin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-3,6-dihydropyrazin-1(2H)-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2R,5R)-4-acetyl-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-methylpiperazin-1-yl)prop-2-en-1-one; 1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethyl-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)—N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-5-yl)acetamide; (R)-1-(6-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,4-dioxide-4-thia-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)—N-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4-yl)acetamide; 1-((2R,5R)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-hydroxy-5-methylpiperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(6-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)-4,7-diazaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-fluoropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2R,4R)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-hydroxy-4-methylpiperidin-1-yl)prop-2-en-1-one; 1-((2S,4S)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-hydroxy-4-methylpiperidin-1-yl)prop-2-en-1-one; 1-((2R,4S)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-hydroxy-4-methylpiperidin-1-yl)prop-2-en-1-one; 1-(4-acetyl-6-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,7-diazaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-2-chloropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-1,2,3-triazol-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-chloropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2R,5S)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-hydroxy-5-methylpiperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-fluoropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-3-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(2-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; 1-(3-(3-(2-aminooxazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-fluoropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; 1-(2-(3-chloro-5-(6-methylpyrimidin-4-yl)phenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-cyclopropylideneethan-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-chloroprop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-(trifluoromethyl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-fluoroprop-2-en-1-one; or (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isonicotinamide or a pharmaceutically acceptable salt thereof.

54. 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-3'-(4-acryloylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-(3-(3-chloro-5-(2-methoxypyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(9H-purin-6-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)picolinamide; 3'-(7-acrylolyl-4-oxa-7-azaspiro[2.5]octan-6-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(6-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-dimethylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methylpyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; 6-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidine-4-carboxamide; 1-((3R,5R)-3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 1-(3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-3-methylmorpholino)prop-2-en-1-one; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; 6-(4-(4-acryloylmorpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; 1-(3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(9H-purin-6-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 5-(4-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; 4-((3R,5R)-4-acrylolyl-5-methylmorpholin-3-yl)-6-chloro-[2,4'-bipyridine]-2'-carboxamide; (R)-1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(5-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; 1-(6-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-6-methyl-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; 1-(6-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 3'-((3R,6R)-4-acrylolyl-6-methylmorpholin-3-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; 5-(4-((3R,5S)-4-acrylolyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)-2-fluorobenzamide; (R)-1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; １９１ (R)-1-(3-(3-(2-amino-1H-imidazol-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 193 (R)-3'-(1-acrylolyl-4-(cyclopropanecarbonyl)piperazin-2-yl)-5'-chloro-4-fluoro-[1,1'-biphenyl]-3-carboxamide; (R)-1-(2-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,6R)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-6-fluoro-1,4-oxazepan-4-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-chloro-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-(cyclopropanecarbonyl)piperazin-1-yl)prop-2-en-1-one; 1-((3R,5S)-3-(2-chloro-6-(6-methylpyrimidin-4-yl)pyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(2-(6-aminopyrimidin-4-yl)-6-chloropyridin-4-yl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-1,1-dioxidethiomorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminoisoxazol-3-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-(methylamino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one (R)-1-(3-(3-(4-amino-6-(methylamino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 6-(4-((3R,5S)-4-acrylolyl-5-(difluoromethyl)morpholin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carboxamide; (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)oxazole-4-carboxamide; 1-((3R)-3-(3-chloro-5-(1-methyl-2-thioxohexahydropyrimidin-5-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-((3-(dimethylamino)propyl)amino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethyl-1,1-dioxidethiomorpholino)prop-2-en-1-one; 1-(2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-fluoropyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((2R,4S)-2-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4-hydroxy-4-methylpiperidin-1-yl)prop-2-en-1-one; 1-(4-acetyl-6-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-4,7-diazaspiro[2.5]octan-7-yl)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-chloropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-3-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-2-fluoropyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-(2-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-fluoropyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; 1-((3R,5S)-3-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-5-(difluoromethyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)-2-chloroprop-2-en-1-one; (R)-1-(3-(3-chloro-5-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)morpholino)prop-2-en-1-one; or (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isonicotinamide or a pharmaceutically acceptable salt thereof.

55. (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5-methylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-dimethylpyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-methylpyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methylpyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-methoxypyridin-2-yl)phenyl)morpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-chloro-5-(2-methylpyrimidin-4-yl)phenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; 1-((3R,5R)-3-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-5-methylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(2-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(6-aminopyrimidin-4-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(4-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-(5-aminopyrimidin-2-yl)-5-chlorophenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,6-diamino-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-1,3,5-triazin-2-yl-6-d)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4-(methylamino)-1,3,5-triazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-6-(methylamino)-1,3,5-triazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-aminopyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-4-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(5-amino-6-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(6-amino-5-methoxypyrazin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(3-(3-(4-amino-5-methoxypyrimidin-2-yl)-5-chlorophenyl)morpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(5,6-diaminopyrazin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; (R)-1-(5-(3-chloro-5-(4,5-diaminopyrimidin-2-yl)phenyl)-2,2-dimethylmorpholino)prop-2-en-1-one; or (R)-2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)isonicotinamide or a pharmaceutically acceptable salt thereof.

56. 56. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

57. 1. A modified KEAP1 protein comprising a non-naturally occurring small molecule fragment covalently bonded to cysteine ​​151 of the KEAP1 protein, The modified KEAP1 protein comprises SEQ ID NO: 1 or a variant thereof and has the formula (X): 【Chemistry 14】 [In the ceremony: S is the sulfur atom of cysteine ​​151 of SEQ ID NO: 1 or a variant thereof; 1-150 and 152-624 represent amino acids 1-150 and 152-624, respectively, of SEQ ID NO: 1 or a variant thereof; and Q is a group represented by the formula (X*): 【Chemistry 15】 [During the ceremony, 【change】 indicates the point of attachment; Ring A is aryl, heteroaryl, or heterocyclyl; Z is O, S(=O) ２ , C(R １ ) ２ , or NR ７ and R ７ is -C(=O)R ７ａ , S(=O)R ７ａ , or S(=O) ２ R ７ａ where R ７ａ is H, optionally substituted C １ -C ６ Alkyl or optionally substituted C ３ -C ７ is cycloalkyl; Each R １ are independently H, halogen, —OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, or —C(═O)N(R ｂ ) ２ and or two R's １ together with the atom(s) to which they are attached, may be optionally substituted C ３ -C ８ forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; X １ is N or CR ２ and Each R ２ are independently H, halogen, CN, OH, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ haloalkyl, or optionally substituted C １ -C ６ is hydroxyalkyl; R ４ is H or optionally substituted C １ -C ６ is alkyl; or R ２ and R ４ together with the atom to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl; Each R ３ are independently H, D, halogen, oxo (=O), -CN, -OH, or -OR ａ , -SH, -SR ａ , -S(=O)R ａ , -NO ２ , -N(R ｂ ) ２ , -S(=O) ２ R ａ , -NHS(=O) ２ R ａ , -S(=O) ２ N (R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NH ２ , -OC(=O)N(R ｂ ) ２ , -NR ｂ C(=O)N(R ｂ ) ２ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 4-8 membered heterocycloalkyl; or two R on adjacent atoms ３ taken together with the atom(s) to which they are attached form an optionally substituted aryl, an optionally substituted heteroaryl ring, or an optionally substituted heterocycloalkyl; Each R ａ is independent, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl), or -C １ -C ６ alkyl(heterocycloalkyl), and each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains 1, 2, or 3 —OH, C １ -C ６ Alkyl, or C １ -C ６ optionally substituted with haloalkyl; and Each R ｂ are independently H, C １ -C ６ Alkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contain one, two, or three —OH, C １ -C ６ Alkyl, or C １ -C ６ optionally substituted with haloalkyl; or two R on the nitrogen atom ｂ The groups, together with the nitrogen atom to which they are attached, may contain one, two or three C １ -C ６ Alkyl or C １ -C ６ forming a heterocycloalkyl optionally substituted with haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is an integer from 1 to 12; and and q is an integer from 1 to 10. The modified KEAP1 protein has the following structure:

58. A method for inhibiting Nrf2 by mediating activation of KEAP1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof.

59. A method for degrading Nrf2 in a cell or a subject, comprising administering to the cell or subject an effective amount of a compound described in any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof.

60. 60. The method of claim 59, wherein the compound activates KEAP1, thereby resulting in the degradation of Nrf2.

61. 60. A method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof.

62. 62. The method of claim 61, wherein the disease is mediated by activation of KEAP1 and inhibition of Nrf2.

63. 63. The method of claim 62, wherein the disease is associated with oxidative stress.

64. 64. The method of any one of claims 61 to 63, wherein the disease is selected from the group consisting of adult brain glioblastoma, solid tumors, lymphoid malignancies, breast cancer or breast tumors, chronic lymphocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, environmental carcinogenesis, lung cancer, non-small cell lung cancer, squamous non-small cell lung carcinoma, lung adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, head and neck cancer, squamous cell head and neck carcinoma, bladder cancer, squamous cell bladder carcinoma, uterine endometrial cancer, cervical cancer, cervical squamous cell carcinoma, major depression, melanoma, metabolic syndrome X, mild cognitive impairment, mitochondrial myopathy, multiple sclerosis, tumors, non-alcoholic fatty liver or non-alcoholic steatohepatitis, non-insulin dependent, non-ischemic cardiomyopathy, obstructive sleep apnea, ocular inflammation, eye pain, polymorphism, pre-diabetes, prostate cancer, and small lymphocytic lymphoma.

65. 65. The method of claim 64, wherein the disease is selected from the group consisting of major depression, metabolic syndrome X, mild cognitive impairment, mitochondrial myopathy, multiple sclerosis, tumor, non-alcoholic fatty liver or non-alcoholic steatohepatitis, non-insulin dependent, non-ischemic cardiomyopathy, obstructive sleep apnea, ocular inflammation, ocular pain, polymorphism, and pre-diabetes.

66. 64. The method of any one of claims 61 to 63, wherein the disease is cancer.

67. 67. The method of claim 66, wherein the cancer is selected from the group consisting of lung cancer, bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, bile duct cancer, stomach cancer, kidney cancer, and pancreatic cancer.

68. 67. The method of claim 66, wherein the cancer is selected from the group consisting of non-small cell lung cancer, squamous non-small cell lung cancer, lung adenocarcinoma, esophageal cancer, squamous cell esophageal cancer, esophageal adenocarcinoma, head and neck cancer, squamous cell head and neck cancer, bladder cancer, squamous cell bladder cancer, uterine endometrial cancer, cervical cancer, and cervical squamous cell carcinoma.

69. 69. The method of claim 68, wherein the cancer is squamous non-small cell lung cancer or lung adenocarcinoma.

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