KEAP1 modulator

Abstract

Disclosed in the present invention are a KEAP1 modulator represented by general formula (I), or a modulator that modulates NRF2 activity by means of modulating KEAP1 activity, a pharmaceutical composition thereof, a preparation method therefor, and the use thereof in the preparation of a drug for prevention and / or treatment of indications related to KEAP1 and NRF2, in particular the treatment of cancers.

Description

KEAP1 modulators TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to a KEAP1 modulator, a pharmaceutical composition thereof, a preparation method thereof, and use thereof in the preparation of a medicine for preventing and / or treating a KEAP1-related indication, in particular to the use of activating KEAP1 to inhibit NRF2. BACKGROUND

[0002] KEAP (Kelch-like ECH associated protein 1) is a substrate adaptor protein of a Cul3-dependent E3 ubiquitin ligase complex, which can assemble with Cul3 and Rbx1 into a functional E3 ubiquitin ligase complex (KEAP1-Cul3-E3) to regulate NRF2, and KEAP1 is a sensor of electrophilic substances in oxidative stress.

[0003] NRF2 (Nuclear factor erythroid 2-related factor 2) is an oxidative stress transcription factor that binds to the antioxidant response element (ARE) in the promoter region of a gene, thereby regulating the constitutive and induced expression of a series of antioxidant proteins (phase II metabolic enzymes, antioxidant enzymes), reducing cell damage caused by reactive oxygen species and electrophilic substances, and maintaining the body in a stable state and maintaining the redox dynamic balance of the body. The protein level of NRF2 is negatively regulated by KEAP1, and KEAP1 can bind to NRF2 to promote its ubiquitination and proteasome degradation.

[0004] The KEAP1-NRF2 pathway is the main protective response of the body to oxidative stress and electrophilic stress, resisting cytotoxicity and oxidative damage, and playing a role in detoxification, antioxidant, immune surveillance, etc.

[0005] Under normal physiological conditions, KEAP1 binds to NRF2 through the DLG and ETGE motifs of the Neh2 domain of NRF2, binds to Cul3 and E3 ubiquitin ligase, and ubiquitinated NRF2 is delivered to the 26S proteasome for degradation, so NRF2 cannot enter the nucleus to exert transcriptional activity. Human KEAP1 contains a total of 27 cysteine residues, of which multiple cysteine residues are highly reactive to ROS and electrophilic reagents. Under oxidative stress conditions, specific cysteine residues of KEAP1 are modified, resulting in a change in the conformation of KEAP1 protein. The change in the conformation of KEAP1 causes the destruction of its binding to NRF2, and NRF2 accumulates in the cell and translocates to the nucleus. NRF2 binds to the enhancer sequence of the ARE / EpRE (antioxidant response element / electrophilic response element) of the target gene through heterodimerization with the sMAF protein, and activates and induces the expression of a series of genes (phase II metabolic enzymes, antioxidant enzymes) that respond to oxidative stress.

[0006] KEAP1 / NRF2 protects normal body state and normal function from oxidative damage and cytotoxicity caused by reactive oxygen species and foreign substances, however, over-activation of NRF2 for a long time mediated by various causes can provide a strong selective advantage for the occurrence and development of tumors through metabolic remodeling, inhibition of various forms of cellular stress response, and promotion of immune escape. Expression changes of genes related to the KEAP1 / NRF2 pathway that directly or indirectly cause abnormal activation have been found in various solid tumors. Clinical data emphasize that changes in this pathway can lead to drug resistance and poor prognosis for patients in various therapies.

[0007] Diseases caused by KEAP1 and / or NRF2 abnormalities include cancer, neurodegenerative diseases, autoimmune diseases, and diseases related to reduction stress or weakening of oxidative signals. Currently, there is no drug on the market worldwide that directly targets KEAP1 to prevent and treat diseases related to KEAP1 and / or NRF2 abnormalities, and there are many unmet treatment needs for such diseases. Therefore, this innovative therapy is likely to bring new treatment options for such diseases and improve the prognosis of patients. SUMMARY

[0008] In order to solve the defects of the prior art, the purpose of the present application is to provide a KEAP1 modulator, a pharmaceutical composition thereof, a preparation method thereof, and the use thereof in the preparation of a drug for preventing and / or treating KEAP1-related indications, especially by activating KEAP1 to inhibit NRF2.

[0009] In one aspect, the present application provides a compound of formula (I):

[0010] or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof;

[0011] wherein,

[0012] R 1 is optionally substituted C1-C6 alkenyl;

[0013] X 1 is selected from O, NR 2 or C(R 2 )2;

[0014] R 2 are each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or

[0015] two R 2 and the atoms to which they are each attached form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl;

[0016] p is selected from 0, 1, 2 or 3;

[0017] m, n are selected from 0, 1 or 2;

[0018] X 2 is selected from CR 3 or N;

[0019] q is selected from 0, 1, 2 or 3;

[0020] R 3 each independently is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl;

[0021] L 1 is selected from a bond,

[0022] Ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl;

[0023] i is selected from 0, 1, 2, 3, 4 or 5;

[0024] R 4 each independently is selected from -L 2 -R 4a ;

[0025] said L 2 is selected from a bond,

[0026] said R 4a is selected from oxo, H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0027] As a preference:

[0028] R 1 is said R 1a , R 1b , R 1c is selected from H, halogen, C1-C6 alkyl optionally substituted with halogen, C1-C6 alkoxy optionally substituted with halogen;

[0029] p is selected from 0, 1, 2 or 3;

[0030] R 2each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, or

[0031] two R 2 form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with the atoms to which they are respectively attached, optionally substituted with 1-3 halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0032] m, n are selected from 0, 1 or 2;

[0033] X 2 selected from CR 3 or N;

[0034] q is selected from 0, 1, 2 or 3;

[0035] R 3 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0036] L 1 selected from a bond,

[0037] Ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl;

[0038] i is selected from 0, 1, 2, 3, 4 or 5;

[0039] R 4 each independently selected from -L 2 -R 4a ;

[0040] said L 2 selected from a bond,

[0041] said R 4a selected from oxo, H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen, or 3-6 membered heterocycloalkyl optionally substituted with halogen.

[0042] In some more preferred embodiments, the compound has the structure of Formula (II):

[0043] R 1a , R 1b , R 1cselected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0044] p is selected from 0, 1, 2, or 3;

[0045] R 2 each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, or

[0046] two R 2 form, with the atoms to which they are each attached, a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, optionally substituted with 1-3 halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0047] X 2 is selected from CR 3 or N;

[0048] R 3 each is independently selected from H, halogen, hydroxyl, amino, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0049] L 1 is selected from a bond,

[0050] Ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl;

[0051] i is selected from 0, 1, 2, 3, 4, or 5;

[0052] R 4 each is independently selected from -L 2 -R 4a ;

[0053] said L 2 is selected from a bond,

[0054] said R 4a is selected from oxo, H, halogen, hydroxyl, C1-C3 alkyl optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen.

[0055] As a preference:

[0056] Ring A is selected from

[0057] In some preferred embodiments, the compound is preferably:

[0058] L 1 selected from a bond,

[0059] Ring A is selected from an 8-15 membered bicyclic or tricyclic heterocyclyl containing 1-5 heteroatoms selected from N, O;

[0060] the L 2 selected from a bond,

[0061] the R 4a selected from oxo, H, halogen, hydroxyl, amino,

[0062] As preferred:

[0063] Ring A is selected from As preferred:

[0064] In some preferred embodiments, the compound is preferably:

[0065] L 1 selected from a bond,

[0066] Ring A is selected from a 5-8 membered monocyclic aryl, a 5-8 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O;

[0067] the L 2 selected from a bond,

[0068] the R 4a selected from oxo, H, halogen, hydroxyl, amino, optionally halogen substituted C1-C3 alkyl, optionally halogen substituted 3-6 membered cycloalkyl.

[0069] As preferred:

[0070] Ring A is selected from As preferred:

[0071] As preferred:

[0072] the R 4a selected from oxo, H, F, hydroxyl, amino, C1-C3 alkyl optionally substituted with F, cyclopropyl optionally substituted with F, cyclobutyl optionally substituted with F, cyclopentyl optionally substituted with F, more preferably oxo, H, F, hydroxyl, amino, difluoromethyl, trifluoromethyl, difluorocyclobutyl.

[0073] In some preferred embodiments:

[0074] R 1a , R 1b , R 1c is selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0075] p is selected from 0, 1, 2 or 3;

[0076] R 2 are each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0077] X 2 is selected from CR 3 or N;

[0078] R 3 are each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0079] L 1 is selected from

[0080] Ring A is selected from

[0081] i is selected from 0, 1, 2, 3;

[0082] R 4 are each independently selected from -L 2 -R 4a ;

[0083] said L 2 is selected from a bond,

[0084] said R 4a is selected from oxo, H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen.

[0085] As a preference, R 1a , R 1b , R 1cis selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy, preferably H.

[0086] As a preference, p is selected from 0, 1, 2 or 3;

[0087] R 2 are each independently selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy.

[0088] As a preference, L 1 is selected from more preferably

[0089] As a preference, ring A is preferably more preferably

[0090] As a preference, i is selected from 0, 1, 2, 3, more preferably 0, 1 or 2;

[0091] R 4 are each independently selected from -L 2 -R 4a ;

[0092] said L 2 is selected from a bond, more preferably a bond,

[0093] said R 4a is selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, amino, cyclopropyl, more preferably F, methyl, difluoromethyl, trifluoromethyl, amino, cyclopropyl.

[0094] In some preferred embodiments, the compound is as shown in formula (III):

[0095] R 2 are each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen, more preferably H, F, CI, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy, cyclopropyl;

[0096] R 1a , R 1b , R 1c is selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0097] p is selected from 0, 1, 2, or 3;

[0098] R 2 each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0099] X 2 selected from CR 3 or N;

[0100] R 3 each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen;

[0101] L 1 selected from

[0102] Ring A is selected from

[0103] i is selected from 0, 1, 2, 3;

[0104] R 4 each independently selected from -L 2 -R 4a ;

[0105] said L 2 is selected from a bond,

[0106] said R 4a is selected from oxo, H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen.

[0107] The above compounds include:

[0108] Another aspect of the present application also provides a pharmaceutical composition containing any of the above-mentioned compounds, deuterium isotope, stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0109] The present application also provides a use of any of the above-mentioned compounds, deuterated compounds, stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease associated with KEAP1 and / or NRF2 activity.

[0110] Preferably, the disease associated with KEAP1 and / or NRF2 is a disease caused by changes in KEAP1 activity and / or changes in NRF2 activity, including mutations, amplifications, overexpression, deletions of KEAP1 and / or NRF2, especially KEAP1 GOF (Gain of function) and / or NRF2 LOF (Loss of function) mutations, CUL3 mutations that can bind to KEAP1 to play a ubiquitin degradation role, and diseases with KRAS, BRAF, Myc, LKB1, PTEN, BRCA1 gene mutations or abnormal expression.

[0111] Preferably, the disease associated with KEAP1 and / or NRF2 is selected from tumors, neurodegenerative diseases, autoimmune diseases, and diseases associated with reduced reduction stress or oxidative signals.

[0112] Preferably, the disease associated with KEAP1 and / or NRF2 is selected from tumors, neurodegenerative diseases, autoimmune diseases, and diseases associated with reduced reduction stress or oxidative signals. Advantages:

[0113] The compounds provided by the present application have strong pharmacological activity, good pharmacokinetic properties, and low toxicity and side effects, and are ideal KEAP1 modulators or modulators that regulate NRF2 activity by regulating KEAP1 activity. In addition to having better NRF2 inhibitory activity and tumor cell inhibitory activity, the compounds provided by the present application have better stability in human plasma than positive compounds, and show better PK characteristics in mouse in vivo tests. The compounds provided by the present application have better KEAP1 activation activity and NRF2 inhibitory activity. The compounds of the present application are ideal high-activity KEAP1 modulators, which can be used for the treatment of tumors, metabolic diseases, autoimmune diseases, and inflammatory diseases. The tumor diseases include lung squamous cell carcinoma, lung adenocarcinoma, uterine cancer, esophageal cancer, head and neck cancer, bladder cancer, ovarian cancer, liver cancer, cervical cancer, bile duct cancer, gastric cancer, melanoma, papillary renal cell carcinoma, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, and blood cancer. DETAILED DESCRIPTION

[0114] The application will be further described in conjunction with specific examples, but the application is not limited to the following examples.

[0115] Definitions

[0116] As used herein, "optionally" or "optional" means that the item is optional and can or can not be selected. For example, "group A is optionally substituted with 1-3 groups B" includes four possibilities: group A is not substituted with group B, group A is substituted with 1 group B, group A is substituted with 2 groups B, and group A is substituted with 3 groups B.

[0117] As used herein, "substituted" or "substitution" means that any one or more hydrogen atoms on any atom in a group or moiety is / are replaced with a substituent, which can include deuterium and variations of hydrogen, as long as the valency of the particular atom is normal and the resulting compound is stable. When the substituent is "oxo" (i.e., =0), it means that two hydrogen atoms are replaced with oxygen, and when the atom replaced with oxygen is carbon, a carbonyl group (C=0) is formed. Oxygen substitution does not occur on aromatic groups.

[0118] As used herein, "optionally substituted" means that the group can or can not be substituted and, unless otherwise specified, the types and number of substituents are any that are chemically possible. For example, "optionally substituted 5-6 membered heterocyclyl" means a 5-6 membered heterocyclyl group that is substituted with any group or is unsubstituted. For another example, "optionally substituted with 1-3 R a substituted C 1-6 alkyl" means unsubstituted or substituted with 1-3 R a substituted C 1-6 alkyl.

[0119] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other instances. Thus, for example, if a group is "substituted with 0-2 R," said group can be unsubstituted, substituted with 1 R, or substituted with 2 R, and at each instance R is selected independently of the other instances. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0120] As used herein, "chemical bond" generally refers to a covalent bond between two atoms in a compound molecule, formed by sharing a pair of electrons.

[0121] When a substituent is null, it means that the substituent is absent, such as X is null in A-X, which means that the structure is actually A. When a listed substituent does not indicate through which atom it is attached to the substituted group, the substituent can be bonded through any of its atoms, for example, a pyridyl group as a substituent can be attached to the substituted group through any of the carbon atoms of the pyridyl ring.

[0122] When a listed linking group does not indicate its direction of attachment, its direction of attachment is arbitrary, for example, ring A-L 1 -R 1 linking group L 1 is -M-W-, in which case -M-W- can either attach ring A and R1to form ring A-M-W-R 1 in the same direction as the reading order from left to right, or 1 in the opposite direction as the reading order from left to right, to form ring A-W-M-R 1 . The combination of the linking group, substituent, and / or variation thereof is only allowed if such combination results in a stable compound.

[0123] Unless otherwise specified, when a group has one or more available sites for attachment, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the chemical bond is not directional and there is an H atom at the site available for attachment, the number of H atoms at the site will be reduced by one to form a corresponding valence group upon attachment of the chemical bond. The chemical bond by which the site of the group is attached to other groups can be represented by a straight solid line a dashed line , for example, the straight solid line in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line in -CH2CH2- represents attachment to other groups through both ends of the carbon atoms in the group; the dashed line in -Ph represents attachment to other groups through the 1 and 4 carbon atoms in the phenyl group; represents that any available site on the piperidinyl group can be attached to other groups by one chemical bond, including at least the four ways of attachment, even though the H atom is drawn in -N-, but still includes the group attached in this way, only that upon attachment of one chemical bond, the H at the site will be reduced by one to form a corresponding monovalent piperidinyl group.

[0124] Unless otherwise specified, in fused ring groups, the site of attachment of a group or fragment is on the ring that is connected by the dashed line. For example, Any point of attachment to the phenyl ring represented by this group can be connected to other groups by a bond, including at least These four modes of attachment.

[0125] Generally, in an aromatic or heteroaromatic ring, the double bonds and single bonds are not of limiting significance. For example, Both refer to a benzene ring or phenyl group, in which the double bonds or Specifically, a large pi bond that is delocalized over the plane of the benzene ring; In the case where ring C is defined as a 5-membered aryl or heteroaryl group, ring B and ring C form a conjugated fused aryl or fused heteroaryl group, in which case non-limiting examples include Even if The left ring contains only two double bonds, but Still includes Such a group, in which the double bonds represent a large pi bond that is delocalized over the fused aromatic ring.

[0126] As used herein, numerical ranges include the endpoints and any number in between. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0127] As used herein, "C1-C n " includes C1-C2, C1-C3,... C1-C n For example, a "C1-C6" group means that the moiety has from 1 to 6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, for example, "C1-C4 alkyl" means an alkyl group containing from 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Numerical ranges as used herein, such as "1 to 6," are intended to include each integer within the specified range.

[0128] A ring atom is a non-hydrogen atom used to form a ring in a ring group. For example In the case of In the case of In the case of In the case of

[0129] As used herein, "n-m membered" refers to the number of ring atoms in a ring group. For example, a "3-8 membered" group means that the moiety has from 3 to 8 ring atoms, i.e., the group contains 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, or 8 ring atoms. Thus, for example, a "3-8 membered cycloalkyl" refers to a saturated cyclic alkyl group having from 3 to 8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0130] The term "alkyl," as used herein alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated aliphatic hydrocarbon. Preferably, "alkyl" herein can have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l- propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, hexyl, and the like. Where a numerical range, e.g., "Ci-C6alkyl," appears within a definition of a group, as defined herein, "alkyl" of that group refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Alkyl groups as defined herein also include instances where no numerical range is specified. Alkyl groups can be optionally substituted or unsubstituted.

[0131] "Alkyl," as used herein in combination, refers to an alkyl group attached to another group, e.g., the alkyl group in an alkoxy group, which is defined the same as when used alone.

[0132] The term "alkoxy" or "-O-alkyl," as used herein alone or in combination, means "alkyl-O-." Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, s-butyloxy, t-butyloxy, and the like. Alkoxy groups can be optionally substituted or unsubstituted.

[0133] The term "cycloalkyl," as used herein alone or in combination, refers to a saturated monocyclic, bicyclic, or polycyclic carbocyclic ring. Preferably, cycloalkyl herein is 3-12 membered, more preferably 3-10 membered, and most preferably 3-8 membered. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, which can be optionally substituted or unsubstituted.

[0134] The term "aryl," used alone or in combination, refers to aromatic hydrocarbon rings. The term "aryl" includes both monocyclic aromatic hydrocarbons and polycyclic fused (annelated) aromatic hydrocarbons, wherein all of the fused ring systems (excluding any ring systems that are part of or formed by an optional substituent) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthryl, and phenanthryl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl."

[0135] The term "heterocyclyl," used alone or in combination, includes aliphatic heterocyclyl and heteroaryl groups, wherein one or more (such as one, two, three, or four) ring atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged, and spirocyclic rings. Examples of heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl groups, as discussed below. Preferred herein are 3-10 membered monocyclic, bicyclic, or tricyclic heterocyclyl groups, which can contain 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and / or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidin-2-yl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl, and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like. Heterocyclyl groups can be optionally substituted or unsubstituted.

[0136] In the definition of "heterocyclyl," "annelated" refers to a heteroatom-containing polycyclic ring group containing two or more cyclic structures that share a pair of atoms with each other. One or more of the rings can contain several unsaturated bonds, or one ring can have an aromatic system with fully conjugated π-electrons, and the ring atoms are selected from nitrogen, oxygen, or S(O) n heteroatoms, with the remaining ring atoms being carbon. Preferred herein are 6-12 membered, more preferably 8-9 membered. Depending on the number of rings comprising the ring, it can be a bicyclic, tricyclic, tetracyclic, or polycyclic annelated ring group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic annelated ring group.

[0137] The term "heterocycloalkyl" as used herein alone or in combination refers to a saturated heterocyclyl group which is a saturated monocyclic, bicyclic, or polycyclic ring wherein one or more (such as one, two, three, or four) ring atoms are heteroatoms, which can be spiro or bridged. Preferred herein is a 3-12 membered cycloalkyl, more preferred is a 3-10 membered cycloalkyl, and most preferred is a 3-8 membered cycloalkyl. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, oxetane, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0138] The term "heteroaryl" as used herein alone or in combination refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic, or tricyclic ring system, wherein at least one ring is aromatic, and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, while the heteroaryl also has one or more points of attachment to the rest of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; bicyclic, but not limited to, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazol, 1,8-naphthyridinyl, benzo[d]isoxazol, benzo[d]thiazol, pyrrolo[3,2-b]pyridine, furano[3,2-b]pyridine, pyrrolo[1,2-b]pyridazin, imidazo[1,2-b]pyridazin, pyrazolo[1,5-a]pyrimidin, thiazolo[4,5-c]pyridin, thieno[3,2-b]pyridin, pyrrolo[1,2-b]pyridazin, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazol, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, and the like. The heteroaryl group can be optionally substituted or unsubstituted.

[0139] The term "halogen" as used herein alone or in combination refers to fluorine, chlorine, bromine, or iodine.

[0140] The term "hydroxyl" as used herein alone or in combination refers to -OH.

[0141] The term "cyano" as used herein alone or in combination refers to -CN.

[0142] As used herein, the term "substituted" or "substitution" means that one or more hydrogens on a given atom are replaced with a designated group, such as, for example, halogen, alkyl, and the like, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

[0143] As used herein, the term "pharmaceutically acceptable salt" is art-recognized.

[0144] As used herein, the term "pharmaceutically acceptable" means that which is not biologically or otherwise undesirable, i.e., the material can be administered to an individual without causing any undesirable biological effects or interacting in an undesirable fashion with any of the components of the composition.

[0145] As used herein, the term "pharmaceutical composition" means a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical ingredient, including, but not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0146] As used herein, the term "carrier" means a relatively nontoxic chemical compound or substance that facilitates the introduction of a compound into a cell or tissue.

[0147] As used herein, the term "stereoisomer" includes, but is not limited to, enantiomers, diastereomers, and the like.

[0148] As used herein, the term "enantiomer" refers to the phenomenon of isomerism in which two compounds having the same molecular formula, due to the different spatial arrangement of atoms or atom groups (radicals), are mirror images of each other and cannot be superimposed. As used herein, the term "diastereomer" generally refers to the phenomenon of stereoisomerism in which the spatial arrangement of groups in a molecule is different due to the presence of a restriction factor for free rotation. Organic molecules containing such isomers, such as alkenes, azo compounds, alicyclic hydrocarbons, and the like, are considered to be diastereomeric. In the present application, diastereomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, when the cyclohexane is substituted with two substituents, diastereomerism occurs. When the two substituents are substituted on the same side of the ring, it is a "cis" isomer, and when they are substituted on different sides, it is a "trans" isomer.

[0149] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisomeric, and geometric (conformational) isomers and mixtures thereof, such as racemates, are within the scope of the present application.

[0150] Unless otherwise indicated, structures depicted throughout this specification are also meant to include all isomers (e.g., enantiomers, diastereomers, geometric (conformational) isomers, atropisomers, regioisomers, stereoisomeric forms) of the structure, for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, aliphatic ring cis and trans isomers, atropisomers of biaryls (see Basic Organic Chemistry, 2nd Ed., Hehng, et al., p. 104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers of the structures described herein. Accordingly, individual stereoisomers of the compounds of the present application, as well as mixtures of enantiomers, mixtures of diastereomers, mixtures of regioisomers and mixtures of geometric (conformational) isomers, are within the scope of the present application.

[0151] The application is further described in detail by reference to specific examples. The application is not limited to the following examples.

[0152] Some of the preparation conditions used in the examples are as follows:

[0153] Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm & 254nm; Column: Waters X-bridge (30x100mm, 10μm) or Luna C18 (30x75mm, 3μm) or Luna C18 (30x75mm, 3μm); Mobile phase: A: 10mM ammonium bicarbonate or H2O (0.1% formic acid) or H2O (0.1% trifluoroacetic acid), B: acetonitrile; Run time: 15min; Flow rate: 25mL / min.

[0154] Reverse phase column purification was performed using C18 reverse phase silica gel column (Spherical C18, 40-60μm, 40g-120g) with water / acetonitrile (95 / 5-30 / 70) as mobile phase.

[0155] The synthesis of some intermediates in the application is as follows:

[0156] Intermediate 1: (R)-3-(3-bromo-5-chlorophenyl)morpholine

[0157] (1) tert-butyl (2-(2-(3-bromo-5-chlorophenyl)-2-oxoethoxy)ethyl)carbamate

[0158] Dissolve 1,3-dibromo-5-chlorobenzene (16 g, 60 mmol) in tetrahydrofuran (160 mL), replace nitrogen, slowly drop isopropyl magnesium chloride (30 mL, 60 mmol, 2M in THF) at -30 °C, stir the reaction at room temperature for 1 hour. Then cool the reaction to -30 °C, add 3-oxomorpholine-4-carboxylic acid tert-butyl ester (10 g, 50 mmol) diluted in tetrahydrofuran (100 mL), gradually restore room temperature and stir the reaction for 3 hours. Quench the reaction at 0 °C by adding saturated ammonium chloride solution (300 mL). Then extract with ethyl acetate (150 mL x 3). Combine the organic phase, wash with saturated sodium chloride solution (300 mL), dry over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain the title compound (10 g, light yellow oil), yield: 67%. MS (ESI): m / z 414.0 [M+Na] + .

[0159] (2) (S)-tert-Butyl (2-(2-(3-bromo-5-chlorophenyl)-2-hydroxyethoxy)ethyl)carbamate

[0160] Dissolve (S)-1 -methyl-3,3-diphenyltetrahydro-1 H,3H-pyrrolo[1,2-c][1,3,2]oxazaborine (CAS: 112022-81 -8, 1.4 g, 5.1 mmol) in tetrahydrofuran (30 mL), drop borane tetrahydrofuran complex (1 M, 14.1 mL, 14.1 mmol) at 0 °C, stir at room temperature for half an hour. Drop (2-(2-(3-bromo-5-chlorophenyl)-2-oxoethoxy)ethyl)carbamate tert-butyl ester (5 g, 12.8 mmol) dissolved in tetrahydrofuran at 0 °C, keep stirring at 0 °C for 2 hours. Add methanol (20 mL) to the reaction, stir at room temperature for half an hour. Concentrate the reaction under reduced pressure, purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 ) to obtain the title compound (4.5 g, colorless oil), yield: 90%. MS (ESI): m / z 416.2 [M+Na] + .

[0161] (3) (S)-1 -(3-bromo-5-chlorophenyl)-2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate

[0162] (S)-(2-(2-(3-bromo-5-chlorophenyl)-2-hydroxyethoxy)ethyl)carbamic acid tert-butyl ester (1 g, 2.5 mmol) and triethylamine (757 mg, 7.5 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (431 mg, 3.75 mmol) was added dropwise at 0 °C, and stirred at room temperature for 2 hours. The reaction solution was added with water (20 mL), and extracted with dichloromethane (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (1 g, colorless oil) at a yield of 83%. MS (ESI): m / z 494.3 [M+Na] + .

[0163] (4) (S)-2-(2-aminoethoxy)-1-(3-bromo-5-chlorophenyl) ethyl methanesulfonate

[0164] (S)-1-(3-bromo-5-chlorophenyl)-2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (1 g, 2.1 mmol) was dissolved in hydrochloric acid / dioxane (4 M, 10 mL), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the title compound (787 mg, colorless oil). MS (ESI): m / z 372.1 [M+H] + .

[0165] (5) (R)-3-(3-bromo-5-chlorophenyl)morpholine

[0166] (S)-2-(2-aminoethoxy)-1-(3-bromo-5-chlorophenyl) ethyl methanesulfonate (780 mg, 2.1 mmol) and triethylamine (1.06 g, 10.5 mmol) were dissolved in dichloromethane (10 mL), and stirred at 40 °C for two hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (450 mg, colorless oil) at a yield of 78%. MS (ESI): m / z 276.2 [M+H] + .

[0167] Intermediate 2: (R)-1-(3-(3-bromo-5-chlorophenyl)morpholinyl)prop-2-en-1-one

[0168] (R)-3-(3-bromo-5-chlorophenyl)morpholine (450 mg, 1.6 mmol) and triethylamine (323 mg, 3.2 mmol) were dissolved in dichloromethane (10 mL), acryloyl chloride (288 mg, 3.2 mmol) was added dropwise at 0 °C, and stirred at room temperature for 2 hours. The reaction solution was added to water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (500 mg, colorless oil) at a yield of 93%. MS (ESI): m / z 330.0 [M+H] + .

[0169] Intermediate 3: (R)-1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholinyl)prop-2-en-1-one

[0170] (R)-1-(3-(3-bromo-5-chlorophenyl)morpholinyl)prop-2-en-1-one (300 mg, 0.91 mmol), pinacol diboronic acid (254 mg, 1.0 mmol), Pd(dppf)Cl2(66 mg, 0.09 mmol), and potassium acetate (176 mg, 1.8 mmol) were dissolved in dioxane (10 mL), stirred at 95 °C overnight under nitrogen protection. The reaction solution was concentrated to obtain the title compound (344 mg, crude). MS (ESI): m / z 378.4 [M+H] + .

[0171] Example 1

[0172] (R)-1-(3-(3-chloro-5-(6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one

[0173] (1) 4-(3,3-difluorocyclobutoxy)-6-iodopyrimidine

[0174] 3,3-difluorocyclobutane-1-ol (86 mg, 0.8 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium hydride (48 mg, 60%, 1.2 mmol) was added. After stirring at room temperature for 10 minutes, 4-chloro-6-iodopyrimidine (96 mg, 0.4 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (70 mg, light brown oil) at a yield of 56%. MS (ESI): m / z 313.0 [M+H]+ .

[0175] (2) (R)-1-(3-(3-chloro-5-(6-(3,3-difluorocyclobutyloxy)pyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one

[0176] Intermediate 1: 4-(3,3-difluorocyclobutyloxy)-6-iodopyrimidine 4-(3,3-difluorocyclobutyloxy)-6-iodopyrimidine (30 mg, 0.1 mmol), Intermediate 3 (36 mg, 0.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (7 mg, 0.01 mmol) and potassium carbonate (40 mg, 0.29 mmol) were dissolved in 1,4-dioxane (5 mL), then water (1 mL) was added, and the reaction was stirred at 90 °C overnight under nitrogen protection. The reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.3 mg, white solid), yield: 5.5%. MS (ESI): m / z 436.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.89 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 6.90-6.84 (m, 1H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 5.59-5.51 (m, 1H), 5.28-5.25 (m, 1H), 4.50 (d, J = 12.0 Hz, 1H), 3.89-3.79 (m, 2H), 3.54-3.49 (m, 1H), 3.30-3.17 (m, 4H), 2.88-2.77 (m, 2H).

[0177] Example 2

[0178] 1-((3R)-3-(3-chloro-5-(3-methoxyazetidin-1-yl)phenyl)morpholino)prop-2-en-1-one

[0179] Intermediate 2 (20 mg, 0.066 mmol), 3-methoxy piperidine (21 mg, 0.079 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.013 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 0.07 mmol) and cesium carbonate (54 mg, 0.165 mmol) were dissolved in ethylene glycol dimethyl ether solution (5 mL), replaced with nitrogen, and stirred under the protection of nitrogen at 90 °C for 2 hours under microwave conditions. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (11.5 mg, colorless oil) in a yield of 35%. MS (ESI): m / z 365.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.87-6.69 (m, 4H), 6.20 (dd, J = 16.4, 1.2 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 5.41-5.21 (m, 1H), 4.37 (d, J = 12.4 Hz, 1H), 3.87-3.57 (m, 5H), 3.50-3.44 (m, 3H), 3.28 (s, 3H), 2.89-2.84 (m, 1H), 2.80-2.74 (m, 1H), 1.95-1.92 (m, 1H), 1.75-1.70 (m, 1H), 1.52-1.44 (m, 1H), 1.41-1.33 (m, 1H).

[0180] Example 3

[0181] (R)-1-(3-(3-chloro-5-(6-(difluoromethoxy)pyrimidin-4-yl)phenyl)morpholino)prop-2-en-1-one

[0182] Intermediate 3 (38 mg, 0.1 mmol), 4-chloro-6-(difluoromethoxy)pyrimidine (18 mg, 0.1 mmol), Pd(dppf)Cl2(7 mg, 0.01 mmol), potassium carbonate (27.6 mg, 0.2 mmol) were dissolved in dioxane / water (10 mL / 2 mL). The reaction was stirred under the protection of nitrogen at 90 °C overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.4 mg, white solid) in a yield of 6%. MS (ESI): m / z 396.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.87 (t, J = 71.6 Hz, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 6.91 - 6.84 (m, 1H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 5.59 - 5.45 (m, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.26 - 3.97 (m, 1H), 3.90 - 3.87 (m, 1H), 3.82 - 3.79 (m, 1H), 3.55 - 3.49 (m, 1H), 3.27 - 3.17 (m, 1H).

[0183] Example 4

[0184] (R)-1-(3-(3-chloro-5-(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)phenyl)morpholino)prop-2- en-1-one

[0185] Intermediate 2 (40 mg, 0.12 mmol), 5,6,7,8-tetrahydro-1,7-naphthyridine (19.48 mg, 0.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (11.08 mg, 0.01 mmol) and cesium carbonate (98.56 mg, 0.30 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen, and stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (4.6 mg, colorless oil), yield: 10%. MS (ESI): m / z 384.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.24-7.21 (m, 1H), 6.98 (s, 1H), 6.90-6.79 (m, 2H), 6.72 (s, 1H), 6.21 (dd, J = 16.4, 2.0 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 5.44-5.18 (m, 1H), 4.42-4.39 (m, 3H), 3.89-3.86 (m, 1H), 3.76-3.74 (m, 1H), 3.58 (t, J = 5.6 Hz, 2H), 3.52-3.46 (m, 1H), 3.37-3.33 (m, 2H), 2.93 (t, J = 5.6 Hz, 2H).

[0186] Example 5

[0187] 1-(3-(6-(6-methoxy-pyrimidin-4-yl)imidazo[1,2-a]pyridin-8-yl)morpholino)prop-2-en-1-one

[0188] (1) 4-methoxy-6-(tributylstannyl)pyrimidine

[0189] 4-chloro-6-methoxypyrimidine (0.5 g, 3.46 mmol), dibutyltin (1.0 g, 1.73 mmol) and tetrakis(triphenylphosphine)palladium (799 mg, 0.69 mmol) were dissolved in 1,4-dioxane (20 mL) at 100 °C, and the reaction was stirred at 100 °C for 6 h. The reaction solution was used as it was (20 mL, brown liquid), and the yield was 100%. MS (ESI): m / z 401.5 [M+H] + .

[0190] (2) 2-(triphenylmethylamino)ethanol-1-ol

[0191] Triphenylmethyl chloride (30.0 g, 107.6 mmol) and ethanolamine (19.7 g, 322.8 mmol) were dissolved in isopropanol (200 mL), and the reaction was stirred at 26 °C for 24 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (29.0 g, white solid) at a yield of 44% and a purity of 50%. MS (ESI): m / z 243.1 [M+H-60] + .

[0192] (3) 2-((tributylstannyl)methoxy)-N-trimethylethan-1-amine

[0193] To a solution of 2-(tributylstannyl)methanol (10.0 g, 32.96 mmol) and sodium hydride (7.91 g, 329.6 mmol) in N,N-dimethylformamide (100 mL) was added 2- (tritylamino)ethan-1-ol (10.0 g, 32.96 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was diluted with water (200 mL) and ethyl acetate (200 mL). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (5.6 g, colorless oil) in 28% yield.

[0194] (4) 2-((tributylstannyl)methoxy)ethan-1-amine

[0195] To a solution of 2-((tributylstannyl)methoxy)-N-trimethylethan-1-amine (2.0 g, 3.30 mmol) in dichloromethane / 2,2,2-trifluoroethanol (14 mL / 6 mL) was added glacial acetic acid (594 mg, 9.89 mmol) at room temperature. The reaction mixture was stirred for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 90 / 10) to give the title compound (830 mg, yellow oil) in 69% yield. MS (ESI): m / z 366.3 [M+H] + .

[0196] (5) (E)-1-(6-bromoimidazo[1,2-a]pyridin-8-yl)-N-(2-((tributylstannyl)methoxy)ethyl)formimidamide

[0197] To a solution of 6-bromoimidazo[1,2-a]pyridine-8-carbaldehyde (500 mg, 2.22 mmol) and 2-((tributylstannyl)methoxy)ethan-1-amine (971 mg, 2.67 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 24 h. The reaction mixture was used as such (20 mL, yellow liquid) in 100% yield. MS (ESI): m / z 572.2 [M+H] + .

[0198] (6) 3-(6-bromoimidazo[1,2-a]pyridin-8-yl)morpholine

[0199] To a solution of 3-(6-bromoimidazo[l,2-a]pyridin-8-yl)morpholine (120 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added acryloyl chloride (46.2 mg, 0.51 mmol) and triethylamine (130 mg, 1.28 mmol) at 50 °C under nitrogen protection. The reaction was stirred for 12 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give the title compound (85 mg, yellow solid) in 59% yield. MS (ESI): m / z 335.8 [M+H] + .

[0200] (7) 1-(3-(6-bromoimidazo[l,2-a]pyridin-8-yl)morpholino)prop-2-en-1-one

[0201] To a solution of 3-(6-bromoimidazo[l,2-a]pyridin-8-yl)morpholine (120 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added acryloyl chloride (46.2 mg, 0.51 mmol) and triethylamine (130 mg, 1.28 mmol) at 50 °C under nitrogen protection. The reaction was stirred for 12 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give the title compound (85 mg, yellow solid) in 59% yield. MS (ESI): m / z 335.8 [M+H] + .

[0202] (8) 1-(3-(6-(6-methoxypyrimidin-4-yl)imidazo[l,2-a]pyridin-8-yl)morpholino)prop-2-en-1-one

[0203] To a solution of 3-(6-bromoimidazo[l,2-a]pyridin-8-yl)morpholine (120 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added acryloyl chloride (46.2 mg, 0.51 mmol) and triethylamine (130 mg, 1.28 mmol) at 50 °C under nitrogen protection. The reaction was stirred for 12 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give the title compound (85 mg, yellow solid) in 59% yield. MS (ESI): m / z 335.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (s, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 6.94 (s, 1H), 6.16 (d, J = 16.8 Hz, 1H), 5.92-5.52 (m, 2H), 4.91 (s, 1H), 4.46-4.18 (m, 1H), 4.15-3.66 (m, 7H), 3.57-3.52 (m, 1H).

[0204] Example 6

[0205] (R)-1-(3-(3-chloro-5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)phenyl)morpholino)prop-2-en-1-one

[0206] (1) 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[0207] 1,2-dihydro-3H-pyrazol-3-one (500 mg, 6.0 mmol) and 1,3-dibromopropane (1.2 g, 6.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.7 g, 12 mmol) was added, and the reaction was carried out at 130 °C overnight. Water (20 mL) was added to the reaction solution, and extraction was performed with dichloromethane (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 3), and dried over anhydrous sodium sulfate. Concentration was performed, and the title compound (738 mg, crude) was obtained. MS (ESI): m / z 125.1 [M+H] + .

[0208] (2) 3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[0209] 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (200 mg, 1.6 mmol) and N-iodosuccinimide (360 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was carried out at room temperature overnight. Water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (300 mg, yellow oil) at a yield of 74%. MS (ESI): m / z 251.1 [M+H] + .

[0210] (3) 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,l- b] [l,3]oxazine

[0211] Dissolve 3-iodo-6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazine (300 mg, 1.2 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (670 mg, 3.6 mmol) in tetrahydrofuran (10 mL), dropwise add 1.3 M isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (2.8 mL, 3.6 mmol), stir at room temperature overnight. Quench the reaction with methanol (10 mL), concentrate to give the title compound (300 mg, crude). MS (ESI): m / z 251.2 [M+H] + .

[0212] (4) (R)-l-(3-(3-chloro-5-(6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)phenyl)morpholino)prop-2-en-l-one

[0213] Dissolve 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,l- b] [l,3]oxazine (30 mg, 0.12 mmol), Intermediate 2 (20 mg, 0.06 mmol), PdCl2(dppf) (4 mg, 0.006 mmol), potassium carbonate (16 mg, 0.12 mmol) in dioxane / water (10 mL / 2 mL). Stir the reaction at 90 °C under nitrogen overnight. Concentrate the reaction, purify the residue by silica gel column chromatography (100% ethyl acetate), then purify by Prep-HPLC to give the title compound (8.6 mg, white solid) in 38% yield. MS (ESI): m / z 374.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.89 - 6.83 (m, 1H), 6.22 (dd, J = 16.8, 2.4 Hz, 1H), 5.77 (dd, J = 10.4, 1.6 Hz, 1H), 5.46 - 5.30 (m, 1H), 4.43 - 4.40 (m, 3H), 4.12 (t, J = 6.0 Hz, 2H), 3.88 - 3.75 (m, 2H), 3.52 - 3.46 (m, 1H), 3.41 - 3.39 (m, 2H), 2.25 - 2.19 (m, 2H).

[0214] Example 7

[0215] (R)-1-(3-(3-chloro-5-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)morpholino)prop-2-en-1-one

[0216] (1) (R)-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)boronic acid

[0217] Intermediate 3 (80 mg, 0.21 mmol) was dissolved in tetrahydrofuran / water (5 mL / 0.5 mL), sodium periodate (64 mg, 0.3 mmol) and 1 M dilute hydrochloric acid (0.5 mL) were added, the reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Concentration gave the title compound (62 mg, crude). MS (ESI): m / z 296.2 [M+H] + .

[0218] (2) (R)-1-(3-(3-chloro-5-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)morpholino)prop-2-en-1-one

[0219] (R)-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)boronic acid (30 mg, 0.1 mmol) and 1-methyl-1H-pyrazol-3-ol (15 mg, 0.15 mmol) were dissolved in dichloromethane (10 mL), copper acetate (18 mg, 0.1 mmol), pyridine (16 mg, 0.2 mmol) and triethylamine (20 mg, 0.2 mmol) were added, and stirred at room temperature overnight. The reaction was concentrated, and the residue was purified by Prep-HPLC to give the title compound (2.3 mg, white solid), yield: 7%. MS (ESI): m / z 348.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 3.2 Hz, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 6.89 - 6.82 (m, 1H), 6.22 (dd, J = 16.4, 1.2 Hz, 1H), 5.76 (dd, J = 10.4, 2.0 Hz, 1H), 5.56 - 5.36 (m, 2H), 4.42 (d, J = 12.0 Hz, 1H), 3.89 - 3.77 (m, 2H), 3.51 (t, J = 10.0 Hz, 1H), 3.42 - 3.40 (m, 2H), 3.14 (s, 3H).

[0220] Example 8

[0221] 1-(2-(3-chloro-5-(6-methoxy pyrimidin-4-yl)phenyl)-6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one

[0222] (1) N-[(1Z)-(3-bromo-5-chlorophenyl)methylidene]-4-methylbenzenesulfonamide

[0223] A 250 mL single-necked flask was charged with 3-bromo-5-chlorobenzaldehyde (10 g, 45.6 mmol), tetraethyl orthosilicate (10 g, 47.9 mmol) and 4-methylbenzenesulfonamide (7.81 g, 45.6 mmol) and heated at 160 °C for 5 h under nitrogen protection with a water separator to remove the ethanol produced. After the reaction was completed, the reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) and petroleum ether (70 mL) were added to the flask. After the solid was completely changed into powder, the mixture was filtered, and the filter cake was washed with petroleum ether (50 mL). The title compound (14.6 g, white solid) was obtained after vacuum drying, with a yield of 86%. MS (ESI): m / z 372.0 [M+H] + .

[0224] (2) N-(1-(3-bromo-5-chlorophenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide

[0225] A 250 mL single-necked flask was charged with 3-bromo-5-chlorobenzaldehyde (10 g, 45.6 mmol), tetraethyl orthosilicate (10 g, 47.9 mmol) and 4-methylbenzenesulfonamide (7.81 g, 45.6 mmol) and heated at 160 °C for 5 h under nitrogen protection with a water separator to remove the ethanol produced. After the reaction was completed, the reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) and petroleum ether (70 mL) were added to the flask. After the solid was completely changed into powder, the mixture was filtered, and the filter cake was washed with petroleum ether (50 mL). The title compound (14.6 g, white solid) was obtained after vacuum drying, with a yield of 86%. MS (ESI): m / z 372.0 [M+H] + .

[0226] (3) 2-(3-bromo-5-chlorophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole

[0227] A 250 mL single neck flask was charged with N-(l-(3-bromo-5-chlorophenyl)prop-2-yn-l-yl)-4-methylbenzenesulfonamide (4.5 g, 11.3 mmol), dicyclohexylamine (4.1 g, 22.6 mmol), paraformaldehyde (2.69 g, 56.5 mmol), cuprous bromide (0.65 g, 4.5 mmol) and 1,4-dioxane (60 mL). The reaction was refluxed at 120 °C overnight under nitrogen protection. The reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (1.18 g, brown oil) in 25.6% yield. MS (ESI): m / z 412.0 [M+H] + .

[0228] (4) 2-(3-bromo-5-chlorophenyl)-2,5-dihydro-lH-pyrrole

[0229] 2-(3-bromo-5-chlorophenyl)-l-[(4-methylphenyl)sulfonyl]-2,5-dihydropyrrole (4.5 g, 11.3 mmol) was dissolved in hydrobromic acid in acetic acid (4 mL, 33%) and phenol (550 mg, 5.8 mmol) was added. The reaction was refluxed at 100 °C overnight under nitrogen protection. The reaction was diluted with water (50 mL) and sodium bicarbonate was added slowly until basic. The mixture was used directly in the next step. MS (ESI): m / z 258.0 [M+H] + .

[0230] (5) 2-(3-bromo-5-chlorophenyl)-2,5-dihydropyrrole-l-carboxylic acid tert-butyl ester

[0231] To the aqueous solution from the previous step was added 1,4-dioxane (50 mL), di-tert-butyl dicarbonate (1.27 g, 5.8 mmol), 4-dimethylaminopyridine (40 mg, 0.29 mmol) and the reaction was stirred at room temperature overnight. The reaction was extracted with ethyl acetate (2 x 50 mL) and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (500 mg, brown oil) in 48% yield. MS (ESI): m / z 302.0 [M+H-56] + .

[0232] (6) 2-(3-bromo-5-chlorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0233] tert-Butyl 2-(3-bromo-5-chlorophenyl)-2,5-dihydropyrrole-1 -carboxylate (250 mg, 0.7 mmol) was dissolved in 1,2-dichloroethane (4 mL), and m-chloroperoxybenzoic acid (481 mg, 2.8 mmol) was added, and the reaction was carried out at 60 °C overnight. White crystals were precipitated after cooling to room temperature, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to obtain the title compound (80 mg, yellowish oil) in a yield of 30.6%. MS (ESI): m / z 318.2 [M+H-56] + .

[0234] (7) tert-Butyl 2-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0235] tert-Butyl 2-(3-bromo-5-chlorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.21 mmol) was dissolved in 1,4-dioxane (4 mL), and pinacol diboronic acid (81 mg, 0.32 mmol), potassium acetate (63 mg, 0.64 mmol), and [1,1 '-bis(diphenylphosphino)ferrocene] palladium dichloride (16 mg, 0.02 mmol) were added, and the reaction was carried out at 80 °C overnight under nitrogen protection. The reaction solution was directly used in the next step. MS (ESI): m / z 365.8 [M+H-56] + .

[0236] (8) tert-Butyl 2-[3-chloro-5-(6-methoxypyrimidin-4-yl)phenyl]-6-oxa-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0237] Potassium carbonate (89 mg, 0.64 mmol), 4-bromo-6-methoxypyrimidine (81 mg, 0.43 mmol), water (1 mL), and [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) were added to the reaction solution from the previous step, and the reaction was carried out at 80 °C overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 2 / 1 ) to obtain the title compound (30 mg, colorless oil) in a yield of 34.8%. MS (ESI): m / z 404.2 [M+H] + .

[0238] (9) 2-[3-Chloro-5-(6-methoxypyrimidin-4-yl)phenyl]-6-oxa-3-azabicyclo[3.1.0]hexane

[0239] Dissolve 2-[3-chloro-5-(6-methoxy-pyrimidin-4-yl)phenyl]-6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (30 mg, 0.074 mmol) in dichloromethane (2 mL), after adding trifluoroacetic acid (1 mL), react at room temperature for 3 hours. Concentrate the reaction mixture to get a light yellow oil, which is used directly in the next step. MS (ESI): m / z 304.2 [M+H] + .

[0240] (10) 1-(2-(3-chloro-5-(6-methoxy-pyrimidin-4-yl)phenyl)-6-oxa-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one

[0241] Dissolve the crude product from the previous step in dichloromethane (2 mL), after adding triethylamine (73 mg, 0.72 mmol) and acryloyl chloride (13 mg, 0.145 mmol), react at room temperature for 1 hour. Concentrate the reaction mixture, purify the residue by Prep-HPLC to get the title compound (4.4 mg, light yellow solid), yield: 17%. MS (ESI): m / z 358.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.90-8.89 (m, 1H), 8.20-8.16 (m, 1H), 8.07-8.05 (m, 1H), 7.64-7.63 (m, 1H), 7.57-7.53 (m, 1H), 6.65-6.31 (m, 1H), 6.14-6.07 (m, 1H), 5.74-5.57 (m, 1H), 5.55-5.34 (m, 1H), 4.13-4.10 (m, 1H), 4.09-4.04 (m, 1H), 3.99 (s, 3H), 3.98-3.91 (m, 1H), 3.85-3.79 (m, 1H).

[0242] Example 9

[0243] 1-(3-(3-chloro-5-(6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azepin-4-yl)phenyl) morpholino)prop-2-en-1-one

[0244] (1) 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4- carboxylic acid tert-butyl ester

[0245] tert-Butyl 3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylate (200 mg, 0.60 mmol), bis(pinacolato)diboron (230 mg, 0.91 mmol), potassium acetate (148 mg, 1.51 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (44 mg, 0.06 mmol) were stirred in 1,4-dioxane (20 mL) at 95 °C under nitrogen for 16 h. The reaction was diluted with water (20 mL) and ethyl acetate (40 mL), and the organic phase was concentrated under reduced pressure to give the title compound (100 mg, yellow oil) in 44% yield, which was used directly in the next step. MS (ESI): m / z 368.2 [M+H-56] + .

[0246] (2) tert-Butyl 3-(3-(6-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-2,2a,5,6- tetraazabenzo[cd]azepin-4-yl)-5-chlorophenyl)morpholine-4-carboxylate

[0247] tert-Butyl 3-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine- 4-carboxylate (100 mg, 0.24 mmol), tert-butyl 4-chloro-8,9-dihydro-2,2a,5,6-tetraazabenzo[cd] azepine-6(7H)-carboxylate (73 mg, 0.24 mmol), tricyclohexylphosphine (26 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (43 mg, 0.05 mmol) and potassium phosphate (125 mg, 0.59 mmol) were stirred in 1,4-dioxane / water (10 mL, 1:1) at 120 °C under nitrogen for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (54 mg, white solid) in 40% yield. MS (ESI): m / z 570.3 [M+H] + .

[0248] (3) 3-(3-chloro-5-(6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azepin-4-yl)phenyl)morpholine

[0249] tert-Butyl 3-(3-(6-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-2,2a,5,6- tetraazabenzo[cd]azepin-4-yl)-5-chlorophenyl)morpholine-4-carboxylate (27 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL) at 26 °C under nitrogen atmosphere, trifluoroacetic acid (0.5 mL) was added dropwise slowly, the reaction was stirred for 1 h. The reaction was concentrated under reduced pressure to give the title compound (30 mg, yellow oil) in 100% yield. MS (ESI): m / z 370.2 [M+H] + .

[0250] (4) 1-(3-(3-chloro-5-(6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azepin-4-yl)phenyl)morpholino)prop-2-en-1-one

[0251] 3-(3-chloro-5-(6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azepin-4-yl)phenyl)morpholine (30 mg, 0.08 mmol), acryloyl chloride (8.8 mg, 0.10 mmol) and triethylamine (21 mg, 0.20 mmol) were dissolved in dichloromethane (5 mL) at room temperature under nitrogen protection, the reaction was stirred for 1 h. The reaction was concentrated under reduced pressure, the residue was purified by Prep-HPLC to give the title compound (3.5 mg, white solid) in 10% yield. MS (ESI): m / z 424.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.26 (s, 1H), 6.87 (t, J = 14.0 Hz, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 5.63 - 5.18 (m, 1H), 4.51 (d, J = 12.4 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.54 - 3.39 (m, 5H), 2.95 - 2.86 (m, 2H), 2.03 - 1.93 (m, 2H).

[0252] Example 10

[0253] (R)-1-(3-(3-chloro-5-(2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2- e]pyridin-5-yl)phenyl)morpholino)prop-2-en-1-one

[0254] (1) 2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2-e]pyridin-5-amine

[0255] 2-Aminocyclopenta-1-en-1-carbonitrile (500 mg, 4.62 mmol), oxan-2-one (925.79 mg, 9.25 mmol) and triethylamine (935.72 mg, 9.25 mmol) were dissolved in dichloromethane (10 mL), and titanium tetrachloride (1754.01 mg, 9.25 mmol) was slowly added at 0 °C, and then the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 90 / 10) to obtain the title compound (300 mg, white solid), yield: 34%. MS (ESI): m / z 191.3 [M+H] + .

[0256] (2) 5-bromo-2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2-e]pyridine

[0257] 2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2-e]pyridin-5-amine (300 mg, 1.58 mmol), tert-butyl nitrite (1382.18 mg, 13.40 mmol) and copper bromide (880.58 mg, 3.94 mmol) were dissolved in acetonitrile (10 mL), and the reaction was stirred at 80 °C under a condensed reflux condition for 16 hours. The reaction solution was concentrated under reduced pressure, 15% ammonia water (30 mL) was added at 0 °C, and extraction was performed with ethyl acetate (20 mL x 3), and then the organic layer was washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (150 mg, yellow oil), yield: 37%. MS (ESI): m / z 254.1 [M+H] + .

[0258] (3) (R)-1-(3-(3-chloro-5-(2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2-e]pyridin-5-yl)phenyl)morpholino)prop-2-en-1-one

[0259] Intermediate 1 (25 mg, 0.10 mmol), 5-bromo-2,3,4,6,7,8-hexahydrocyclopenta[b]pyrano[3,2- e]pyridine (25 mg, 0.10 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (7.2 mg, 0.01 mmol) and potassium carbonate (40.8 mg, 0.30 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and stirred at 90 °C for 16 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (3.7 mg, white solid) in a yield of 9%. MS (ESI): m / z 425.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.43 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 6.89-6.83 (m, 1H), 6.20 (d, J = 15.2 Hz, 1H), 5.76 (dd, J = 10.4, 1.2 Hz, 1H), 5.55-5.38 (m, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.20 (t, J = 4.4 Hz, 2H), 3.89-3.76 (m, 2H), 3.52-3.47 (m, 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.55-2.54 (m, 2H), 2.43-2.39 (m, 2H), 1.97-1.94 (m, 2H), 1.81-1.79 (m, 2H).

[0260] Example 11

[0261] (R)-N-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-2-fluorobenzamide

[0262] (1) (R)-1-(3-(3-chloro-5-((diphenylmethylene)amino)phenyl)morpholino)prop-2-en-1-one

[0263] Intermediate 2 (130 mg, 0.39 mmol) was dissolved in 1,4-dioxane (10 mL), and diphenylformamide (143 mg, 0.79 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.08 mmol) and cesium carbonate (384 mg, 1.18 mmol) were added. The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (115 mg, yellow oil) in 68% yield. MS (ESI): m / z 431.2 [M+H] + .

[0264] (2) (R)-1-(3-(3-amino-5-chlorophenyl)morpholino)prop-2-en-1-one

[0265] (R)-1-(3-(3-chloro-5-((diphenylmethylene)amino)phenyl)morpholino)prop-2-en-1-one (50 mg, 0.116 mmol) was dissolved in dichloromethane (4 mL), 4M hydrochloric acid dioxane solution (1 mL) and one drop of water were added, and the reaction was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (10 mL), and the organic phase was separated. The aqueous phase was adjusted to basic with sodium bicarbonate, and then extracted with dichloromethane (2 x 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (20 mg, yellow oil) in 64.7% yield. MS (ESI): m / z 267.2 [M+H] + .

[0266] (3) (R)-N-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-2-fluorobenzamide

[0267] (R)-1-(3-(3-amino-5-chlorophenyl)morpholino)prop-2-en-1-one (20 mg, 0.075 mmol), 2-fluorobenzoic acid (11 mg, 0.075 mmol) and pyridine (30 mg, 0.38 mmol) were added to a 25 mL single-neck flask, and phosphorus oxychloride (23 mg, 0.15 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (1.7 mg, white solid) in 6% yield. MS (ESI): m / z 389.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.94 (s, 1H), 7.66 (dt, J = 7.2, 1.2 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.53 (m, 1H), 7.38 - 7.32 (m, 2H), 7.18 (s, 1H), 6.82 (br s, 1H), 6.22 (dd, J = 16.4, 2.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.54 - 5.23 (m, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.27 - 3.94 (m, 1H), 3.89 - 3.75 (m, 2H), 3.51 - 3.46 (m, 1H), 3.23 - 3.17 (m, 1H).

[0268] Example 12

[0269] (R)-N-(3-(4-acryloylpiperazin-3-yl)-5-chlorophenyl)-3-fluoropyridinamide

[0270] In a 25 mL single necked flask was added (R)-1-(3-(3-amino-5-chlorophenyl)piperazin-1- yl)prop-2-en-1-one (40 mg, 0.15 mmol), 3-fluoropyridine-2-carboxylic acid (21 mg, 0.15 mmol) and pyridine (59 mg, 0.75 mmol), to this was added phosphorous oxychloride (46 mg, 0.3 mmol) at room temperature and the reaction was allowed to proceed for 1 h at room temperature. The reaction was concentrated, the residue was diluted with methanol and filtered, the filtrate was purified by Prep-HPLC to get the title compound (6.7 mg, blue solid) in 11.5% yield. MS (ESI): m / z 390.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.97 - 7.93 (m, 1H), 7.77 - 7.73 (m, 1H), 7.69 (s, 1H), 7.18 (s, 1H), 6.83 (br s, 1H), 6.22 (dd, J = 16.4, 2.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.57 - 5.24 (m, 1H), 4.38 (d, J = 12.4 Hz, 1H), 4.29 - 3.94 (m, 1H), 3.89 - 3.76 (m, 2H), 3.52 - 3.46 (m, 1H), 3.21 - 2.92 (m, 1H).

[0271] Example 13

[0272] (R)-1-(3-(3-cyclopropyl-5-(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)phenyl) morpholino)prop-2-en-1-one

[0273] The compound of Example 4 (35 mg, 0.09 mmol), cyclopropyl potassium trifluoroborate (27.17 mg, 0.18 mmol), n-butyl bis(1-adamantyl)phosphine (9.81 mg, 0.03 mmol), palladium acetate (4.10 mg, 0.02 mmol) and cesium carbonate (89.14 mg, 0.27 mmol) were dissolved in toluene / water (5 mL / 0.5 mL) and stirred at 100 °C under nitrogen protection for 24 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (3.2 mg, white solid), yield: 9%. MS (ESI): m / z 390.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.38 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 7.6, 4.4 Hz, 1H), 6.80-6.73 (m, 2H), 6.63 (s, 1H), 6.46 (s, 1H), 6.19 (dd, J = 16.8, 2.4 Hz, 1H), 5.72 (d, J = 10.4 Hz, 1H), 5.31-5.16 (m, 1H), 4.39 (d, J = 12.4 Hz, 1H), 4.34 (s, 2H), 3.87-3.85 (m, 1H), 3.76-3.73 (m, 1H), 3.53-3.43 (m, 3H), 3.35-3.32 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 1.90-1.83 (m, 1H), 0.93-0.88 (m, 2H), 0.66-0.62 (m, 2H).

[0274] Example 14

[0275] 1-(3-(3-chloro-5-(6-methoxy-pyrimidin-4-yl)phenyl)hexahydrocyclopenta[b][1,4]oxazin- 4(4aH)-yl)prop-2-en-1-one

[0276] (1) 2-(tritylamino)cyclopentan-1-ol

[0277] To a solution of 2-aminocyclopentan-1-ol (1 g, 9.9 mmol) and triethylamine (2.0 g, 19.8 mmol) in dichloroethane (15 mL) was added triphenylmethyl chloride (3.0 g, 10.9 mmol) and stirred at room temperature overnight. Concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (2.4 g, colorless oil) in 70% yield. MS (ESI): m / z 366.4 [M+Na] + .

[0278] (2) 2-((tributylstannyl)methoxy)-N-tributylcyclopentan-1-amine

[0279] To a solution of 2-(triphenylmethylamino)cyclopentan-1-ol (2 g, 5.8 mmol) and tributyl(iodomethyl)stannane (3.7 g, 8.7 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60%, 464 mg, 11.6 mmol) and stirred at room temperature for 12 hours. The reaction solution was added to water (60 mL) and extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride solution (10 mL x 3) and dried over anhydrous sodium sulfate. Concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 30 / 1) to give the title compound (2.2 g, colorless oil) in 58% yield. 1 HNMR (400 MHz, DMSO-d6) δ 7.49-7.46 (m, 6H), 7.19-7.17 (m, 6H), 7.10-7.07 (m, 3H), 3.55 (d, J = 9.6 Hz, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.25-3.24 (m, 1H), 2.80-2.79 (m, 1H), 1.71-1.64 (m, 2H), 1.51-1.39 (m, 6H), 1.35-1.32 (m, 4H), 1.30-1.16 (m, 6H), 0.90-0.77 (m, 15H).

[0280] (3) 2-((tributylstannyl)methoxy) cyclopentan-1-amine

[0281] To a solution of 2-((tributylstannyl)methoxy)-N-tributylcyclopentan-l-amine (2.2 g, 3.4 mmol) in dichloromethane / 2,2,2-trifluoroethanol (15 mL / 5 mL) was added glacial acetic acid (5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, extracted with dichloromethane (10 mL x 3), washed with saturated aqueous sodium bicarbonate (10 mL x 3) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1) gave the title compound (900 mg, colorless oil) in 66% yield. MS (ESI): m / z 406.3 [M+H] + .

[0282] (4) 1-(3-bromo-5-chlorophenyl)-N-(2-((tributylstannyl)methoxy)cyclopentyl)methanimine

[0283] To a solution of 3-bromo-5-chlorobenzaldehyde (216 mg, 0.98 mmol) and 2-((tributylstannyl)methoxy)cyclopentan-l-amine (400 mg, 0.98 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. TLC detection showed that the reaction was completed and the title compound (593 mg) was used directly for the next step.

[0284] (5) 3-(3-bromo-5-chlorophenyl)octahydrocyclopenta[b][l,4]oxazine

[0285] To a solution of 2,6-dimethylpyridine (105 mg, 0.98 mmol) and copper trifluoromethanesulfonate (355 mg, 0.98 mmol) in hexafluoroisopropanol (3 mL) was stirred at room temperature overnight. To the above reaction mixture was added 1-(3-bromo-5-chlorophenyl)-N-(2-((tributylstannyl)methoxy)cyclopentyl)methanimine and the reaction was continued at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (15 mg, yellow oil) in 5% yield. MS (ESI): m / z 316.1 [M+H] + .

[0286] (6) 1-(3-(3-bromo-5-chlorophenyl)hexahydrocyclopenta[b][l,4]oxazin-4(4aH)-yl)prop-2-en-l-one

[0287] To a solution of 3-(3-bromo-5-chlorophenyl)octahydrocyclopenta[b][l,4]oxazine (15 mg, 0.05 mmol) and triethylamine (10 mg, 0.1 mmol) in dichloromethane (10 mL) was added acryloyl chloride (9 mg, 0.1 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added to water (10 mL) and extracted with dichloromethane (10 mL x 3), washed with saturated sodium chloride solution (10 mL x 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (10 mg, yellow oil) in 59% yield. MS (ESI): m / z 370.0 [M+H] + .

[0288] (7) 1-(3-(3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)hexahydrocyclopenta[b][l,4]oxazin-4(4aH)-yl)prop-2-en-l-one

[0289] To a solution of 1-(3-(3-bromo-5-chlorophenyl)hexahydrocyclopenta[b][l,4]oxazin-4(4aH)-yl)prop-2-en-l-one (10 mg, 0.03 mmol), bis(pinacolato)diboron (11 mg, 0.045 mmol), PdCl2(dppf) (2 mg, 0.003 mmol), potassium acetate (6 mg, 0.06 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 6 h under nitrogen. The reaction was monitored by LCMS and directly used for the next step to give the title compound (11 mg). MS (ESI): m / z 418.3 [M+H] + .

[0290] (8) 1-(3-(3-chloro-5-(6-methoxypyrimidin-4-yl)phenyl)hexahydrocyclopenta[b][l,4]oxazin-4(4aH)-yl)prop-2-en-l-one

[0291] To a reaction vial was added 1-(3-(3-chloro-5-(5H-pyrido[3,2-b]indol-5- yl)phenyl)morpholino)prop-2-en-1-one (10 mg, 0.02 mmol), 4-bromo-6- methoxy pyrimidine (7.5 mg, 0.04 mmol), PdCl2(dppf) (2 mg, 0.002 mmol), potassium carbonate (6 mg, 0.04 mmol) in 1,4-dioxane / water (5 mL / 1 mL) and heated to 95 °C with stirring overnight under nitrogen. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a crude product, which was further purified by Prep-HPLC to give the title compound (1.3 mg, white solid) in 14% yield. MS (ESI): m / z 400.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.89 (d, J = 1.2 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.57 (s, 1H), 6.54 - 6.47 (m, 1H), 6.22 (dd, J = 16.8, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.0 Hz, 1H), 5.32 (s, 1H), 4.63 (dd, J = 11.6, 1.6 Hz, 1H), 4.36 (dd, J = 11.6, 2.8 Hz, 1H), 3.99 (s, 3H), 3.93 - 3.86 (m, 1H), 3.68 - 3.61 (m, 1H), 1.72 - 1.30 (m, 6H).

[0292] Example 15

[0293] (R)-1-(3-(3-chloro-5-(5H-pyrido[3,2-b]indol-5-yl)phenyl)morpholino)prop-2-en-1-one

[0294] (1) (3R)-3-(3-chloro-5-{pyrido[3,2-b]indol-5-yl}phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0295] To a solution of (3R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol), 5H-pyrido[3,2-b]indole (89.31 mg, 0.52 mmol), trans-1,2-cyclohexanediamine (12, 13 mg, 0.11 mmol), cuprous iodide (20.23 mg, 0.11 mmol) and potassium phosphate tribasic (338.15 mg, 1.59 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C under condensing reflux condition for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 75 / 25) to give the title compound (40 mg, yellow oil) in 16% yield. MS (ESI): m / z 464.2 [M+H] + .

[0296] (2) (R)-3-(3-chloro-5-(5H pyrido[3,2-b]indol-5-yl)phenyl)morpholine

[0297] To a solution of (3R)-3-(3-chloro-5-{pyrido[3,2-b]indol-5-yl}phenyl)morpholine-4-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was added hydrochloric acid in 1,4-dioxane (2 mL) and stirred at 25 °C for 5 h. The reaction mixture was concentrated to give the title compound (30 mg, yellow solid) in 96% yield. MS (ESI): m / z 363.8 [M+H] + .

[0298] (3) (R)-1-(3-(3-chloro-5-(5H-pyrido[3,2-b]indol-5-yl)phenyl)morpholino)prop-2-en-1-one

[0299] To a solution of (R)-3-(3-chloro-5-(5H pyrido[3,2-b]indol-5-yl)phenyl)morpholine (30 mg, 0.08 mmol) and triethylamine (24.24 mg, 0.24 mmol) in dichloromethane (5 mL) was added acryloyl chloride (14.48 mg, 0.16 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (12.2 mg, white solid) in 35% yield. MS (ESI): m / z 418.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.59(dd,J=4.8,1.2Hz,1H),8.32(d,J=8.0Hz,1H),7.85(dd,J=8.0,0.8Hz,1H ),7.76(s,1H),7.61-7.51(m,4H),7.47(dd,J=8.4,4.8Hz,1H),7.43-7.39(m,1H),6.89(dd,J=16.4,1 0.4Hz,1H),6.23(d,J=16.8Hz,1H),5.78(dd,J=10.4,1.6Hz,1H),5.64-5.48(m,1H),4.51(d,J=12.4H z,1H),4.31-4.12(m,1H),3.91-3.89(m,1H),3.84-3.81(m,1H),3.56-3.51(m,1H),3.10-2.84(m,1H).

[0300] Example 16

[0301] (R)-1-(3-(3-cyclopropyl-5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)phenyl)morpholino)prop-2-en-1-one

[0302] (1)(R)-3-(3-chloro-5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0303] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (75 mg, 0.3 mmol), (R)-3-(3-bromo-5-chlorophenyl)morpholine-4-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol), PdCl2 (dppf) (7 mg, 0.01 mmol), and potassium carbonate (27.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The reaction mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (45 mg, yellow oil), yield: 88%. MS (ESI): m / z 420.2 [M+H] + .

[0304] (2)(3R)-3-(3-cyclopropyl-5-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-yl}phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0305] (R)-3-(3-chloro-5-(6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)phenyl)morpholine- 4-carboxylic acid tert-butyl ester (45 mg, 0.11 mmol), cyclopropylpotassium trifluoroborate (31.94 mg, 0.21 mmol), n-butylbis(l-adamantyl)phosphine (11.53 mg, 0.03 mmol), palladium acetate (4.81 mg, 0.02 mmol) and cesium carbonate (104.78 mg, 0.32 mmol) were dissolved in toluene / water (5 mL / 0.5 mL), replaced with nitrogen and stirred at 100 °C for 24 h under nitrogen. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (35 mg, yellow oil) in 77% yield. MS (ESI): m / z 426.3 [M+H] + .

[0306] (3) (3R)-3-(3-cyclopropyl-5-{5H,6H,7H-pyrazolo[3,2-b][l,3]oxazin-3-yl}phenyl)morpholine

[0307] (3R)-3-(3-cyclopropyl-5-{5H,6H,7H-pyrazolo[3,2-b][l,3]oxazin-3-yl}phenyl)morpholine-4- carboxylic acid tert-butyl ester (35 mg, 0.08 mmol) was dissolved in 1,4-dioxane (2 mL) and hydrochloric acid in 1,4-dioxane (2 mL) was added. The reaction was stirred at 25 °C for 5 h. The reaction was concentrated under reduced pressure to give the title compound (26 mg, white solid) in 97% yield. MS (ESI): m / z 326.3 [M+H] + .

[0308] (4) (R)-l-(3-(3-cyclopropyl-5-(6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)phenyl)morpholino)prop-2-en-l-one

[0309] (3R)-3-(3-cyclopropyl-5-{5H,6H,7H-pyrazolo[3,2-b][l,3]oxazin-3-yl}phenyl)morpholine (26 mg, 0.08 mmol) and triethylamine (24.26 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (14.46 mg, 0.16 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound (10.5 mg, white solid) in 35% yield. MS (ESI): m / z 380.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 6.83-6.77 (m, 2H), 6.20 (dd, J = 16.8, 2.0 Hz, 1H), 5.74 (d, J = 10.8 Hz, 1H), 5.46-5.23 (m, 1H), 4.41-4.37 (m, 3H), 4.12-4.09 (m, 2H), 3.86-3.84 (m, 1H), 3.77-3.74 (m, 1H), 3.50-3.44 (m, 2H), 3.08-2.91 (m, 1H), 2.22-2.20 (m, 2H), 1.91-1.87 (m, 1H), 0.96-0.92 (m, 2H), 0.66-0.62 (m, 2H).

[0310] Example 17

[0311] (R)-1-(3-(3-chloro-5-(pyrimidin-2-ylamino)phenyl)morpholino)prop-2-en-1-one

[0312] (1) Intermediate 2 (20 mg, 0.06 mmol), pyrimidin-2-amine (6.9 mg, 0.07 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (14 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.01 mmol) and cesium carbonate (49 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 95 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (15.0 mg, white solid), yield: 72%. MS (ESI): m / z 345.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.50 (d, J = 4.8 Hz, 2H), 7.97 (s, 1H), 7.63 (s, 1H), 6.97 (s, 1H), 6.91-6.73 (m, 2H), 6.21 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.76 (d, J = 10.4 Hz, 1H), 5.56-5.18 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 4.31-3.94 (m, 1H), 3.91-3.71 (m, 2H), 3.51-3.45 (m, 1H), 3.30-2.91 (m, 1H).

[0313] Example 18

[0314] (R,E)-1-(3-(3-chloro-5-(2-(pyrimidin-2-yl)vinyl)phenyl)morpholino)prop-2-en-1-one

[0315] (1) (E)-2-(2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)vinyl)pyrimidine

[0316] To a solution of 2-ethynylpyrimidine (100 mg, 0.96 mmol), cuprous iodide (37 mg, 0.19 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (56 mg, 0.10 mmol), sodium tert-butoxide (231 mg, 2.40 mmol) and pinacol diborane (293 mg, 1.15 mmol) in methanol / tetrahydrofuran (5 mL, 1:1) was stirred at 26 °C under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure, and extracted with ethyl acetate / water (10 mL, 1:1). The organic phase was concentrated to give the title compound (120 mg, yellow oil) in 100% yield. MS (ESI): m / z 233.0 [M+H] + .

[0317] (2) (R,E)-1-(3-(3-chloro-5-(2-(pyrimidin-2-yl)vinyl)phenyl)morpholino)prop-2-en-1-one

[0318] To a solution of (E)-2-(2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)vinyl)pyrimidine (120 mg, 0.52 mmol), Intermediate 2 (171 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (38 mg, 0.05 mmol) and potassium carbonate (214 mg, 1.55 mmol) in dioxane / water (10 mL, 9:1) was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (12.2 mg, white solid) in 7% yield. MS (ESI): m / z 356.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 4.8 Hz, 2H), 7.92 (d, J = 16.0 Hz, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.39 - 7.32 (m, 3H), 6.92 - 6.85 (m, 1H), 6.24 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.77 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.64 - 5.25 (m, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.32 - 3.77 (m, 3H), 3.54 - 3.48 (m, 1H), 3.29 - 2.84 (m, 1H).

[0319] Example 19

[0320] (R)-2-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4-yl)amino)acetamide

[0321] Example 20

[0322] (R)-2-(4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-2-yl)amino)acetamide

[0323] (1) 2-((2-chloropyrimidin-4-yl)amino)acetamide

[0324] 2,4-dichloropyrimidine (50 mg, 0.34 mmol), 2-aminoacetamide (24.86 mg, 0.34 mmol) and N,N-diisopropylethylamine (130.12 mg, 1.01 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 16 hours. The reaction solution was added with water (10 mL) and extracted with dichloroethane / methanol (v / v = 10 / 1) (10 mL x 3), and the organic phase was concentrated under reduced pressure to obtain the title compound (62 mg, white solid) with a yield of 100%. MS (ESI): m / z 187.2 [M+H] + .

[0325] (2) (R)-2-(2-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-4-yl)amino)acetamide and (R)-2-(4-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)pyrimidin-2-yl)amino)acetamide

[0326] Intermediate 3 (45 mg, 0.12 mmol), [1,1’-bis(diphenylphosphino)ferrocene] palladium dichloride (98.72 mg, 0.01 mmol) and potassium carbonate (41.19 mg, 0.30 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and stirred at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the compound of Example 19 (2.3 mg, white solid, yield: 5%) and the compound of Example 20 (2.9 mg, white solid, yield: 6%). The compound of Example 19: MS (ESI): m / z 402.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.21-8.16 (m, 2H), 7.76 (s, 1H), 7.49 (s, 2H), 7.08 (s, 1H), 6.91-6.84 (m, 1H), 6.58 (s, 1H), 6.24 (dd, J = 16.8, 2.4 Hz, 1H), 5.78 (dd, J = 10.0, 1.6 Hz, 1H), 5.56-5.38 (m, 1H), 4.44 (d, J = 12.4 Hz, 1H), 3.97-3.79 (m, 5H), 3.54-3.51 (m, 1H), 3.08-2.87 (m, 1H). The compound of Example 20: MS (ESI): m / z 402.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.21-8.16 (m, 2H), 7.76 (s, 1H), 7.49 (s, 2H), 7.08 (s, 1H), 6.91-6.84 (m, 1H), 6.58 (s, 1H), 6.24 (dd, J = 16.8, 2.4 Hz, 1H), 5.78 (dd, J = 10.0, 1.6 Hz, 1H), 5.56-5.38 (m, 1H), 4.44 (d, J = 12.4 Hz, 1H), 3.97-3.79 (m, 5H), 3.54-3.51 (m, 1H), 3.08-2.87 (m, 1H). The compound of Example 20: MS (ESI): m / z 402.0 [M+H]

[0327] Example 21

[0328] (R)-1-(3-(3-chloro-5-(5H-pyrido[4,3-b]indol-7-yl)phenyl)morpholino)prop-2-en-1-one

[0329] Intermediate 3 (30.55 mg, 0.08 mmol), 7-bromo-5H-pyrido[4,3-b]indole (20 mg, 0.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5.92 mg, 0.008 mmol) and potassium carbonate (27.95 mg, 0.20 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and stirred at 90 °C under nitrogen atmosphere for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound (7.3 mg, white solid) in 22% yield. MS (ESI): m / z 418.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.83 (s, 1H), 9.37 (s, 1H), 8.44 (d, J = 6.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.57 (dd, J = 8.0, 0.8 Hz, 1H), 7.50 (d, J = 5.6 Hz, 1H), 7.41 (s, 1H), 6.90 (dd, J = 16.8, 10.4 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.78 (dd, J = 10.4, 2.4 Hz, 1H), 5.62 - 5.40 (m, 1H), 4.53 (d, J = 12.4 Hz, 1H), 4.34 - 4.11 (m, 1H), 3.92 - 3.81 (m, 2H), 3.56 - 3.51 (m, 1H), 3.11 - 2.96 (m, 1H).

[0330] Example 22

[0331] (R)-1-(3-(3-chloro-5-(7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azepin-4- yl)phenyl)morpholino)prop-2-en-1-one

[0332] (1) (R)-3-(3-chloro-5-(7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azepin-4- yl)phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0333] Tert-butyl 3-(3-chloro-5-(morpholin-3-yl)phenyl)morpholine-4-carboxylate (76 mg, 0.18 mmol), 4-chloro-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azepine (37.8 mg, 0.18 mmol), tricyclohexylphosphine (2 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.036 mmol) and potassium phosphate (76 mg, 0.36 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL) and stirred at 110 °C for 4 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (15 mg, white solid) in 18% yield. MS (ESI): m / z 472.2 [M+H] + .

[0334] (2) (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)-7,8-dihydro-6H-9-oxa-2,2a,5,6- tetraazabenzo[cd]azepine

[0335] Tert-butyl (R)-3-(3-chloro-5-(7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azepin-4- yl)phenyl)morpholine-4-carboxylate (15 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give the title compound (11.8 mg, yellow oil). MS (ESI): m / z 372.0 [M+H] + .

[0336] (3) (R)-1-(3-(3-chloro-5-(7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azepin-4- yl)phenyl)morpholino)prop-2-en-1-one

[0337] (R)-4-(3-chloro-5-(morpholin-3-yl)phenyl)-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd] azepine (11.8 mg, 0.03 mmol) and triethylamine (6 mg, 0.06 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (2.7 mg, 0.03 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound (0.8 mg, white solid) in 6% yield. MS (ESI): m / z 426.0 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.98-7.93 (m, 3H), 7.72 (s, 1H), 7.26 (s, 1H), 6.92-6.84 (m, 1H), 6.23 (dd, J = 16.4, 2.0 Hz, 1H), 5.77 (d, J = 11.6 Hz, 1H), 5.59-5.33 (m, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.33 (s, 2H), 4.08-3.78 (m, 3H), 3.62 (s, 2H), 3.53-3.48 (m, 1H), 3.15-3.01 (m, 1H). Example 23

[0338] (R)-3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-5-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-4(5H)-one

[0339] (1) 3-bromo-5-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one

[0340] To a solution of 3-bromo-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (30 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (11.11 mg, 0.28 mmol, 60% w / w) and stirred at room temperature for 0.5 h. Then iodomethane (29.57 mg, 0.21 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 80) to give the title compound (23 mg, white solid) in 72% yield. MS (ESI): m / z 230.1 [M+H] + .

[0341] (2) (R)-3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-5-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-4(5H)-one

[0342] Intermediate 3 (37.77 mg, 0.10 mmol), [1,1'-Bis(diphenylphosphino)ferrocene] palladium dichloride (7.32 mg, 0.007 mmol) and potassium carbonate (34.55 mg, 0.25 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3%) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (9 mg, white solid) in a yield of 23%. MS (ESI): m / z 401.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 6.86-6.81 (m, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.74 (d, J = 10.8 Hz, 1H), 5.50-5.31 (m, 1H), 4.44-4.41 (m, 3H), 4.23-4.13 (m, 1H), 3.88-3.77 (m, 4H), 3.52-3.47 (m, 2H), 3.03 (s, 3H).

[0343] Example 24

[0344] (R)-3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one

[0345] (1) 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0346] Intermediate 3 (37.77 mg, 0.10 mmol), [1,1'-Bis(diphenylphosphino)ferrocene] palladium dichloride (7.32 mg, 0.007 mmol) and potassium carbonate (34.55 mg, 0.25 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3%) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (9 mg, white solid) in a yield of 23%. MS (ESI): m / z 401.1 [M+H] + .

[0347] (2) (R)-3-(3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-4(5H)-one

[0348] To a solution of 3-bromo-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (15 mg, 0.07 mmol), l-[(3R)-3-[3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] morpholin-4-yl]prop-2-en-l-one (26.21 mg, 0.07 mmol), [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium (5.08 mg, 0.007 mmol) and potassium carbonate (23.98 mg, 0.17 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) was stirred at 90 °C for 16 h under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 94 / 6) to give a crude product, which was further purified by Prep-HPLC to give the title compound (6.6 mg, white solid) in 25% yield. MS (ESI): m / z 387.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H), 7.90 (s, 1H), 7.79-7.75 (m, 2H), 7.28 (s, 1H), 6.82 (br s, 1H), 6.19 (dd, J = 16.4, 1.6 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 5.50-5.30 (m, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.35 (t, J = 5.6 Hz, 2H), 4.20-4.02 (m, 1H), 3.87-3.76 (m, 2H), 3.65-3.62 (m, 2H), 3.52-3.46 (m, 1H), 3.18-3.00 (m, 1H).

[0349] Example 25

[0350] (R)-1-(3-(3-chloro-5-(imidazo[l,2-c]pyrimidin-5-ylamino)phenyl)morpholino)prop-2- en- 1 -one

[0351] (R)-1-(3-(3-amino-5-chlorophenyl)morpholino)prop-2-en-1-one (30 mg, 0.11 mmol), 5-chloroimidazo[1,2-c]pyrimidine (17 mg, 0.11 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol) and potassium carbonate (46.65 mg, 0.34 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen, and stirred at 90 °C for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (14.9 mg, white solid) in a yield of 34%. MS (ESI): m / z 384.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.69-7.64 (m, 3H), 7.16 (s, 1H), 7.08 (d, J = 6.0 Hz, 1H), 6.85 (brs, 1H), 6.24 (dd, J = 16.8, 2.0 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 5.51-5.35 (m, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.25-4.10 (m, 1H), 3.90-3.76 (m, 2H), 3.54-3.49 (m, 1H), 3.06-2.89 (m, 1H).

[0352] Example 26

[0353] (R)-1-(3-(3-((5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0354] (1) 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester

[0355] 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg, 1.3 mmol), di-tert-butyl dicarbonate (567 mg, 2.6 mmol) were dissolved in dichloromethane (10 mL), and triethylamine (394 mg, 3.9 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (290 mg, white solid) in a yield of 88%. MS (ESI): m / z 198.1 [M+H-56] +.

[0356] (2) (R)-2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)-5H- pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester

[0357] (R)-2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)-5H- pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester (15 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (10 mL) was added, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined and concentrated, and the residue was purified by Prep-HPLC to give the title compound (3.8 mg, white solid) in a yield of 32%. MS (ESI): m / z 384.0 [M+H] + .

[0358] (3) (R)-1-(3-(3-((5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-5-chlorophenyl)- morpholino)prop-2-en-1-one

[0359] (R)-2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)-5H- pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester (15 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (10 mL) was added, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined and concentrated, and the residue was purified by Prep-HPLC to give the title compound (3.8 mg, white solid) in a yield of 32%. MS (ESI): m / z 384.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.43 (s, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.73 (t, J = 2.8 Hz, 1H), 6.95 - 6.77 (m, 2H), 6.36 (d, J = 2.0 Hz, 1H), 6.22 (dd, J = 16.8, 2.4 Hz, 1H), 5.76 (d, J = 9.6 Hz, 1H), 5.50 - 5.23 (m, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.27 - 4.00 (m, 1H), 3.88 - 3.75 (m, 2H), 3.49 (t, J = 9.2 Hz, 1H), 3.15 - 3.01 (m, 1H).

[0360] Example 27

[0361] (R)-1-(3-(3-chloro-5-(5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1- b][1,3]oxazin]-3'-yl)phenyl)morpholino)prop-2-en-1-one

[0362] (1) 5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]

[0363] To a stirred solution of 1,1-bis(bromomethyl)cyclopropane (2.0 g, 8.77 mmol), 1,2-dihydro-3H-pyrazol-3-one (738 mg, 8.77 mmol) and potassium carbonate (3.64 g, 26.32 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (20 mL) and ethyl acetate (40 mL) and the organic layer was separated and concentrated under reduced pressure to obtain the title compound (710 mg, yellow oil) in 54% yield. MS (ESI): m / z 151.3 [M+H] + .

[0364] (2) 3'-iodo-5'H,7'-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]

[0365] A mixture of 5'H,7'H-spiro[cyclopropane-l,6'-pyrazolo[5,l- b][l,3]oxazine] (710 mg, 4.73 mmol) and N-iodosuccinimide (1.6 g, 7.09 mmol) was stirred in N,N-dimethylformamide (20 mL) at 50 °C under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (210 mg, yellow solid) in 16% yield. MS (ESI): m / z 277.0 [M+H] + .

[0366] (3) 3'-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-5'H,7'H-spiro[cyclopropane-l,6'- pyrazolo[5,l-b][l,3]oxazine]

[0367] A mixture of 3'-iodo-5'H,7'-spiro[cyclopropane-l,6'-pyrazolo[5,l-b][l,3]oxazine] (100 mg, 0.36 mmol), 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (135 mg, 0.72 mmol) and 1 M isopropylmagnesium lithium chloride tetrahydrofuran solution (0.72 mL, 0.72 mmol) was stirred in tetrahydrofuran (10 mL) at 26 °C under nitrogen atmosphere for 4 h. The reaction mixture was added with methanol (10 mL) and concentrated under reduced pressure to give the title compound (120 mg, yellow oil) in 100% yield. MS (ESI): m / z 277.2 [M+H] + .

[0368] (4) (R)-l-(3-(3-chloro-5-(5'H,7'H-spiro[cyclopropane-l,6'-pyrazolo[5,l-b][l,3]oxazin-3'- yl)phenyl)morpholino)prop-2-en-l-one

[0369] A mixture of 3'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5'H,7'H-spiro[cyclopropane-l,6'- pyrazolo[5,l-b][l,3]oxazine] (120 mg, 0.43 mmol), Intermediate 2 (144 mg, 0.43 mmol), [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride (64 mg, 0.09 mmol) and potassium carbonate (150 mg, 1.09 mmol) was stirred in dioxane (10 mL) at 90 °C under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound (5.8 mg, white solid) in 3% yield. MS (ESI): m / z 400.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.53 (s, 1H), 7.49 (s, 1H), 7.09 (s, 1H), 6.89-6.81 (m, 1H), 6.21 (dd, J = 16.8, 2.4 Hz, 1H), 5.76 (dd, J = 10.8, 2.4 Hz, 1H), 5.55-5.22 (m, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.21 (s, 2H), 4.01-3.75 (m, 5H), 3.52-3.46 (m, 1H), 3.22-2.82 (m, 1H), 0.80-0.78 (m, 4H).

[0370] Example 28

[0371] (R)-1-(3-(3-chloro-5-(pyrazolo[1,5-a]pyrimido[2,3-e]pyrazin-5(4H)-yl)phenyl)morpholino)prop-2-en-1-one

[0372] (1) Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

[0373] Ethyl 1H-pyrazole-5-carboxylate (1 g, 7.1 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60%, 568 mg, 14.2 mmol) was added, stirred at room temperature for 5 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (1.7 g, 10.7 mmol) was added, and reacted at room temperature for 3 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (940 mg, yellow oil), yield: 49%. MS (ESI): m / z 271.3 [M+H] + .

[0374] (2) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid

[0375] Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (940 mg, 3.5 mmol) was dissolved in methanol / water (10 mL / 2 mL), lithium hydroxide (735 mg, 17.5 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was adjusted to be acidic with 1M dilute hydrochloric acid, water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL x 3), followed by drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (800 mg, yellow solid) at a rate of 95%. MS (ESI): m / z 265.2 [M+Na] + .

[0376] (3) N-(3-iodopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5- carboxamide

[0377] 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid (800 mg, 3.3 mmol) and 3-iodopyridin-2-amine (727 mg, 3.3 mmol) were dissolved in dichloromethane (10 mL), pyridine (1.3 g, 16.5 mmol) was added, and phosphorus oxychloride (1.5 g, 9.9 mmol) was added dropwise at 0°C, and the reaction was allowed to proceed overnight at room temperature. Water (20 mL) was added to the reaction solution, extraction was performed with dichloromethane (20 mL x 3), followed by drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (440 mg, yellow oil) at a rate of 30%. MS (ESI): m / z 445.0 [M+H] + .

[0378] (4) N-(3-iodopyridin-2-yl)-1H-pyrazole-5-carboxamide

[0379] N-(3-iodopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5- carboxamide (440 mg, 1 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed for 3 hours at room temperature. The reaction was complete, the reaction solution was concentrated under reduced pressure, dissolved in methanol / water (10 mL / 2 mL), sodium bicarbonate (250 mg, 3 mmol) was added, and the reaction was allowed to proceed for 4 hours at room temperature. Water (20 mL) was added to the reaction solution, extraction was performed with dichloromethane (20 mL x 3), followed by drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (210 mg, yellow solid) at a rate of 68%. MS (ESI): m / z 315.0 [M+H] + .

[0380] (5) Pyrazolo[l,5-a]pyrido[2,3-e]pyrazin-4(5H)-one

[0381] N-(3-iodopyridin-2-yl)-lH-pyrazole-5-carboxamide (150 mg, 0.48 mmol) was dissolved in dioxane (10 mL), 1,10-phenanthroline (34 mg, 0.19 mmol), cuprous iodide (18 mg, 0.09 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added, and the reaction was carried out at 110 °C overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (80 mg, yellow solid) at a yield of 90%. MS (ESI): m / z 187.1 [M+H] + .

[0382] (6) 4,5-Dihydropyrazolo[l,5-a]pyrido[2,3-e]pyrazine

[0383] Pyrazolo[l,5-a]pyrido[2,3-e]pyrazin-4(5H)-one (50 mg, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (30 mg, 0.8 mmol) was added, and the reaction was carried out at 60 °C overnight. The reaction solution was quenched by adding methanol (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 3) to obtain the title compound (20 mg, yellow solid) at a yield of 43%. MS (ESI): m / z 173.2 [M+H] + .

[0384] (7) (R)-l-(3-(3-chloro-5-(pyrazolo[l,5-a]pyrido[2,3-e]pyrazin-5(4H)-yl)phenyl)morpholino)prop-2-en-l-one

[0385] 4,5-Dihydropyrazolo[l,5-a]pyrido[2,3-e]pyrazine (10 mg, 0.06 mmol), intermediate 2 (10 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (2.7 mg, 0.003 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.9 mg, 0.006 mmol), and cesium carbonate (19 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was carried out at 95 °C overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a crude product, which was further purified by Prep-HPLC to obtain the title compound (1.6 mg, white solid) at a yield of 13%. MS (ESI): m / z 422.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.91 (dd, J = 4.8, 1.6 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 7.19 (s, 1H), 7.00 - 6.97 (m, 1H), 6.86 - 6.79 (m, 1H), 6.36 (d, J = 1.6 Hz, 1H), 6.18 (dd, J = 16.8, 2.4 Hz, 1H), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 5.58 - 5.40 (m, 1H), 5.14 (s, 2H), 4.41 (d, J = 12.0 Hz, 1H), 4.24 - 4.03 (m, 1H), 3.88 - 3.75 (m, 2H), 3.51 - 3.46 (m, 1H), 3.06 - 2.90 (m, 1H).

[0386] Example 29

[0387] (R)-1-(3-(3-chloro-5-((5-fluoropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0388] Intermediate 2 (20 mg, 0.06 mmol), 5-fluoropyrimidin-2-amine (8 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg, 0.012 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol) and cesium carbonate (39 mg, 0.12 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen and stirred at 100 °C for 16 hours under nitrogen. The reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound (4.5 mg, white solid) in a yield of 20.3%. MS (ESI): m / z 363.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.60 (s, 2H), 7.93 (s, 1H), 7.56 (s, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 6.22 (dd, J = 16.4, 2.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.47 - 5.23 (m, 1H), 4.34 (d, J = 11.6 Hz, 1H), 4.16 - 4.00 (m, 1H), 3.87 - 3.74 (m, 2H), 3.48 (dt, J = 11.6, 2.8 Hz, 1H), 3.09 - 2.87 (m, 1H).

[0389] Example 30

[0390] (R)-1-(3-(3-chloro-5-((5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0391] Intermediate 2 (20 mg, 0.06 mmol), 4-fluoropyrimidin-2-amine (7.5 mg, 0.07 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (3.5 mg, 0.006 mmol), tris(dibenzylideneacetone)dipalladium (2.8 mg, 0.003 mmol) and cesium carbonate (39 mg, 0.12 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 95 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (7.3 mg, white solid), yield: 33%. MS (ESI): m / z 363.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.60 (dd, J = 12.8, 5.6 Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.04 (s, 1H), 6.93-6.70 (m, 2H), 6.22 (dd, J = 16.4, 2.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.57-5.20 (m, 1H), 4.37-3.94 (m, 2H), 3.89-3.72 (m, 2H), 3.52-3.46 (m, 1H), 3.26-2.85 (m, 1H).

[0392] Example 31

[0393] (R)-1-(3-(3-chloro-5-((5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0394] (1)(R)-1-(3-(3-chloro-5-((5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0395] Intermediate 2 (50 mg, 0.15 mmol), 5-nitro-pyrimidin-2-amine (25 mg, 0.18 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol) and cesium carbonate (99 mg, 0.3 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen, and stirred at 100 °C for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 7) to obtain the title compound (25 mg, yellow solid) with a yield of 42.4%. MS (ESI): m / z 390.0 [M+H] + .

[0396] (2) (R)-1-(3-(3-((5-amino-pyrimidin-2-yl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0397] (R)-1-(3-(3-chloro-5-((5-nitro-pyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one (25 mg, 0.064 mmol) was dissolved in ethanol (2 mL), iron powder (11 mg, 0.19 mmol), ammonium chloride (10 mg, 0.19 mmol) and water (2 mL) were added, and the reaction was stirred at 80 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then purified by Prep-HPLC to obtain the title compound (5.5 mg, yellowish solid) with a yield of 23.9%. MS (ESI): m / z 360.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.96 (s, 2H), 7.80 (s, 1H), 7.56 (s, 1H), 6.90-6.73 (m, 2H), 6.21 (dd, J = 16.4, 2.4 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H), 5.43-5.17 (m, 1H), 4.89 (s, 2H), 4.33 (d, J = 12.0 Hz, 1H), 4.21-3.95 (m, 1H), 3.86-3.73 (m, 2H), 3.47 (dt, J = 11.6, 2.4 Hz, 1H), 3.24-3.18 (m, 1H).

[0398] Example 32

[0399] (R)-1-(3-(3-((4-amino-pyrimidin-2-yl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one (R)-1-(3-(3-((4-amino-pyrimidin-2-yl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0400] (1) tert-Butyl (2-bromopyrimidin-4-yl)(tert-butoxycarbonyl)carbamate

[0401] tert-Butyl (2-bromopyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (1.1 g, 2.97 mmol), (R)-1-(3-(3-amino-5-chlorophenyl)morpholino)prop-2-en-1-one (1.0 g, 3.24 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (0.3 g, 0.6 mmol), tris(dibenzylideneacetone)dipalladium (0.3 g, 0.3 mmol) and cesium carbonate (2.0 g, 6.1 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 100 °C under nitrogen overnight. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (1.1 g, yellow solid) in a yield of 79%. MS (ESI): m / z 560.0 [M+H] + .

[0402] (2) tert-Butyl (R)-(2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)pyrimidin-4-yl)(tert-butoxycarbonyl)carbamate

[0403] tert-Butyl (R)-(2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)pyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (5 mg, 0.008 mmol), 4-aminopyrimidine-2-carboxylic acid (2.0 mg, 0.01 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (0.3 g, 0.6 mmol), tris(dibenzylideneacetone)dipalladium (0.3 g, 0.3 mmol) and cesium carbonate (2.0 g, 6.1 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 100 °C under nitrogen overnight. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (5 mg, yellow solid) in a yield of 12%. MS (ESI): m / z 560.0 [M+H] + .

[0404] (3) (R)-1-(3-(3-((4-aminopyrimidin-2-yl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0405] tert-Butyl (R)-(2-((3-(4-acryloylmorpholin-3-yl)-5-chlorophenyl)amino)pyrimidin-4- yl)(tert-butoxycarbonyl)carbamate (5 mg, 0.009 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mg, 0.09 mmol) was added, the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, the residue was purified by Prep-HPLC to give the title compound (1.1 mg, white solid), yield: 34%. MS (ESI): m / z 360.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.93 - 7.73 (m, 2H), 6.86 - 6.79 (m, 2H), 6.64 - 6.51 (m, 2H), 6.21 (dd, J = 16.8, 2.0 Hz, 1H), 5.94 (d, J = 6.0 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 5.41 - 5.21 (m, 1H), 4.36 (d, J = 12.0 Hz, 1H), 3.86 - 3.74 (m, 3H), 3.51 - 3.44 (m, 2H).

[0406] Example 33

[0407] 1-(3-((4-Aminopyrimidin-2-yl)methyl)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0408] (1) 2-(3-Bromo-5-chlorophenyl)acetimidamide

[0409] Ammonium chloride (1.3 g, 26.1 mmol) was dissolved in toluene (20 mL), trimethylaluminum (1 M toluene solution, 26 mL, 26.1 mmol) was added dropwise at 0 °C, the reaction was stirred at room temperature for two hours, then 2-(3-bromo-5-chlorophenyl)acetonitrile (dissolved in toluene, 2 g, 8.7 mmol) was added dropwise, the reaction was stirred at 80 °C overnight. The reaction was quenched by adding methanol (20 mL), the impurities were washed away by filtering through celite (dichloromethane / methanol = 5 / 1), the product filtrate was filtered through celite (dichloromethane / methanol = 1 / 1), concentrated under reduced pressure to give the title compound (2 g, white solid), yield: 95%. MS (ESI): m / z 246.9 [M+H] + .

[0410] (2) 2-(3-Bromo-5-chlorobenzyl)pyrimidin-4-ol

[0411] Dissolve 2-(3-bromo-5-chlorophenyl)acetimidamide (1 g, 4 mmol) and ethyl propiolate (392 mg, 4 mmol) in ethanol (10 mL), then add potassium carbonate (1.1 g, 8 mmol), stir at 85 °C overnight. Concentrate under reduced pressure, purify by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (320 mg, yellow solid), yield: 27%. MS (ESI): m / z 298.9 [M+H] + .

[0412] (3) 4-(benzyloxy)-2-(3-bromo-5-chlorobenzyl)pyrimidine

[0413] Dissolve 2-(3-bromo-5-chlorobenzyl)pyrimidin-4-ol (420 mg, 1.4 mmol) and benzyl bromide (289 mg, 1.7 mmol) in N,N-dimethylformamide (10 mL), then add potassium carbonate (386 mg, 2.8 mmol), stir at 60 °C for 1 h. Add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (300 mg, yellow oil), yield: 55%. MS (ESI): m / z 389.0 [M+H] + .

[0414] (4) 3-(3-((4-(benzyloxy)pyrimidin-2-yl)methyl)-5-chlorophenyl)morpholine-4- carboxylic acid tert-butyl ester

[0415] Dissolve 4-(benzyloxy)-2-(3-bromo-5-chlorobenzyl)pyrimidine 4 (300 mg, 0.77 mmol), 4-[(tert-butoxy)carbonyl]morpholine-3-carboxylic acid 2 (356 mg, 1.54 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (171 mg, 1.0 mmol), phthalimide (113 mg, 0.77 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-KN]phenyl-KC]iridium(III) hexafluorophosphate (8.6 mg, 0.0077 mmol), and nickel chloride 4,4'-di-tert-butyl-2,2'-bipyridine (30 mg, 0.077 mmol) in dimethyl sulfoxide (5 mL), stir at 25 °C under light at 450 nm overnight. Concentrate the reaction solution under reduced pressure, purify by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (160 mg, yellow oil), yield: 42%. MS (ESI): m / z 496.3 [M+H] + .

[0416] (5) 3-(3-chloro-5-((4-hydroxypyrimidin-2-yl)methyl)phenyl)morpholine-4- carboxylic acid tert-butyl ester

[0417] Tert-butyl 3-(3-((4-(benzyloxy)pyrimidin-2-yl)methyl)-5-chlorophenyl)morpholine- 4-carboxylate (100 mg, 0.2 mmol) was dissolved in ethyl acetate (5 mL), Pd / C (20 mg) was added, and the reaction was allowed to proceed at room temperature overnight. The reaction was filtered and concentrated under reduced pressure to give the title compound (82 mg, crude). MS (ESI): m / z 428.2 [M+Na] + .

[0418] (6) 3-(3-chloro-5-((4-chloropyrimidin-2-yl)methyl)phenyl)morpholine

[0419] Tert-butyl 3-(3-chloro-5-((4-hydroxypyrimidin-2-yl)methyl)phenyl)morpholine-4- carboxylate (80 mg, 0.2 mmol) was dissolved in phosphorus oxychloride (5 mL), and the reaction was allowed to proceed at 60 °C for 1 h. The reaction was concentrated under reduced pressure, and the residue was added to aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 95 / 5) to give the title compound (30 mg, yellow oil) in 47% yield. MS (ESI): m / z 324.1 [M+H] + .

[0420] (7) 1-(3-(3-chloro-5-((4-chloropyrimidin-2-yl)methyl)phenyl)morpholino)prop-2- en-1-one

[0421] 3-(3-chloro-5-((4-chloropyrimidin-2-yl)methyl)phenyl)morpholine (30 mg, 0.09 mmol) and triethylamine (18 mg, 0.18 mmol) were dissolved in dichloromethane (5 mL), and acryloyl chloride (16 mg, 0.18 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (100% ethyl acetate) to give the title compound (30 mg, yellow oil) in 86% yield. MS (ESI): m / z 378.0 [M+H] + .

[0422] (8) tert-butyl ((2-(3-(4-acryloylmorpholin-3-yl)-5-chlorobenzyl)pyrimidin-4- yl)carbamate

[0423] To a solution of tert-butyl 1-(3-(3-chloro-5-((4-chloropyrimidin-2-yl)methyl) phenyl)morpholino)prop-2-en-1-one (30 mg, 0.08 mmol), tert-butyl carbamate (9 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.016 mmol) and cesium carbonate (52 mg, 0.16 mmol) in 1,4-dioxane (5 mL) was stirred at 95 °C under nitrogen overnight. Concentrated under reduced pressure, purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (25 mg, yellow oil) in 69% yield. MS (ESI): m / z 459.1 [M+H] + .

[0424] (9) 1-(3-((4-aminopyrimidin-2-yl)methyl)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0425] To a solution of tert-butyl ((2-(3-(4-acryloylmorpholin-3-yl)-5-chlorobenzyl)pyrimidin-4- yl)carbamate (25 mg, 1 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL) and stirred at room temperature for 3 h. Concentrated under reduced pressure, purified by Prep-HPLC to give the title compound (16 mg, white solid) in 80% yield. MS (ESI): m / z 359.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 6.0 Hz, 1H), 7.23-7.20 (m, 3H), 6.79 (s, 2H), 6.25 (d, J = 6.0 Hz, 1H), 6.19 (dd, J = 16.4, 2.0 Hz, 1H), 6.06 (s, 1H), 5.74 (d, J = 12.4 Hz, 1H), 5.51-5.35 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 3.87 (s, 2H), 3.83-3.67 (m, 4H), 3.17-3.09 (m, 1H).

[0426] Example 34

[0427] 1-(3-(3-((5-aminopyrimidin-2-yl)methyl)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0428] (1) (E)-N'-(2-(3-bromo-5-chlorobenzyl)pyrimidin-5-yl)-N,N-dimethylformamidine

[0429] In a 50 mL three-necked flask, 2-(3-bromo-5-chlorobenzyl)acetimidamide (340 mg, 1.2 mmol) and N-[2-[[(dimethylamino)methylene]amino]-3-(dimethylamino)-2-propen-1- ylidene]-N-methylmethanaminium hexafluorophosphate (468 mg, 0.96 mmol) and ethanol (5 mL) were added, followed by sodium methoxide (1.8 mL, 2 M in methanol), and the reaction was refluxed at 80 °C overnight under nitrogen protection. The reaction was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (265 mg, yellowish solid) in a yield of 62.5%. MS (ESI): m / z 353.0 [M+H] + .

[0430] (2) 2-(3-bromo-5-chlorobenzyl)pyrimidin-5-amine

[0431] (E)-N'-(2-(3-bromo-5-chlorobenzyl)pyrimidin-5-yl)-N,N-dimethylformamidine (300 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5 mL), followed by potassium carbonate (233 mg, 1.7 mmol) and water (5 mL), and the reaction was stirred at 100 °C overnight. The reaction was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (160 mg, white solid) in a yield of 63.2%. MS (ESI): m / z 298.0 [M+H] + .

[0432] (3) tert-butyl (2-(3-bromo-5-chlorobenzyl)pyrimidin-5-yl)(tert-butoxycarbonyl)carbamate

[0433] 2-(3-bromo-5-chlorobenzyl)pyrimidin-5-amine (160 mg, 0.54 mmol) was dissolved in dichloromethane (5 mL), followed by triethylamine (271 mg, 2.7 mmol), 4-dimethylaminopyridine (7 mg, 0.06 mmol), and di-tert-butyl dicarbonate (351 mg, 1.6 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (85 mg, yellowish solid) in a yield of 31.8%. MS (ESI): m / z 498.0 [M+H] + .

[0434] (4) 3-(3-((5-(bis(tert-butoxycarbonyl)amino)pyrimidin-2-yl)methyl)-5- chlorophenyl)morpholine-4-carboxylic acid tert-butyl ester

[0435] To a solution of tert-butyl (2-(3-bromo-5-chlorobenzyl)pyrimidin-5-yl)(tert- butoxycarbonyl)carbamate (85 mg, 0.17 mmol), 4-[(tert-butoxy)carbonyl]morpholine- 3-carboxylic acid 2 (78 mg, 0.34 mmol), 2-tert-butyl-l, l,3,3-tetramethylguanidine (38 mg, 0.22 mmol), phthalimide (25 mg, 0.17 mmol), (4,4'-di-tert-butyl-2,2'- bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-KN]phenyl-KC]iridium(III) hexafluorophosphate (1.9 mg, 0.0017 mmol) and nickel chloride 4,4'-di-tert-butyl-2,2'- bipyridine (6.6 mg, 0.017 mmol) in dimethyl sulfoxide (4 mL) was stirred at 25 °C under 450 nm light overnight. The reaction was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (70 mg, yellow oil) in 26% yield. MS (ESI): m / z 549.2 [M+H-tBu] + .

[0436] (5) 2-(3-chloro-5-(morpholin-3-yl)benzyl)pyrimidin-5-amine

[0437] To a solution of tert-butyl 3-(3-((4-(benzyloxy)pyrimidin-2-yl)methyl)-5- chlorophenyl)morpholine-4-carboxylate (70 mg, 0.116 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL) and stirred at room temperature for 3 hours. Concentration under reduced pressure gave the title compound as a yellow oil, which was used directly in the next step. MS (ESI): m / z 305.1 [M+H] + .

[0438] (6) 1-(3-(3-((5-aminopyrimidin-2-yl)methyl)-5-chlorophenyl)morpholino)prop-2-en- 1-one

[0439] To a solution of 2-(3-chloro-5-(morpholin-3-yl)benzyl)pyrimidin-5-amine 6 (30 mg, 0.1 mmol) in dichloromethane (4 mL) was added triethylamine (100 mg, 1 mmol) and acryloyl chloride (9 mg, 0.1 mmol) in dichloromethane (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (1.1 mg, white solid) in 3% yield. MS (ESI): m / z 359.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.18 (m, 3H), 6.81 (s, 1H), 6.18 (dd, J = 16.4, 2.0 Hz, 1H), 5.73 (d, J = 9.6 Hz, 1H), 5.54-5.26 (m, 3H), 4.35 (d, J = 12.0 Hz, 1H), 4.00 (s, 2H), 3.82-3.71 (m, 2H), 3.51-3.43 (m, 3H).

[0440] Example 35

[0441] (R)-1-(3-(3-chloro-5-(cyclopropyl(pyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0442] To a solution of (R)-1-(3-(3-chloro-5-(pyrimidin-2-ylamino)phenyl)morpholino)prop-2-en-1-one (60 mg, 0.17 mmol) and cyclopropylboronic acid (30 mg, 0.34 mmol) in N,N-dimethylformamide (5 mL) was added 2,2'-bipyridine (26 mg, 0.17 mmol), copper acetate (31 mg, 0.17 mmol) and potassium carbonate (47 mg, 0.34 mmol) and the reaction mixture was stirred at 100 °C under an oxygen balloon overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The residue was purified by silica gel column chromatography (100% EA) to give the title compound (25.2 mg, yellow oil) in 36% yield. MS (ESI): m / z 385.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 4.7 Hz, 2H), 7.33 - 7.23 (m, 3H), 6.87 - 6.81 (m, 2H), 6.19 (dd, J = 16.6, 2.2 Hz, 1H), 5.75 (dd, J = 10.4, 2.1 Hz, 1H), 5.52 - 5.31 (m, 1H), 4.41 (d, J = 12.2 Hz, 1H), 4.21 - 3.75 (m, 3H), 3.51 - 3.45 (m, 1H), 3.22 - 2.91 (m, 2H), 0.93 - 0.85 (m, 2H), 0.48 - 0.42 (m, 2H).

[0443] Example 36

[0444] (R)-1-(3-(3-((5-Aminopyrimidin-2-yl)(cyclopropyl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0445] (1) (R)-1-(3-(3-chloro-5-(cyclopropyl(5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0446] (R)-1-(3-(3-chloro-5-((5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one (100 mg, 0.26 mmol) and cyclopropylboronic acid (44 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (5 mL), 2,2'-bipyridine (40 mg, 0.26 mmol), copper acetate (47 mg, 0.26 mmol) and potassium carbonate (70 mg, 0.51 mmol) were added, and the reaction was stirred under an oxygen balloon at 100 °C overnight. LCMS detection showed that the reaction was complete, the reaction liquid was added with water (10 mL), extracted with ethyl acetate (10 mL*3), concentrated under reduced pressure, and then purified by silica gel column (PE:EA = 1:1) to obtain the title compound (100 mg, yellow solid), yield: 91%. MS (ESI): m / z 430.1 [M+H] + .

[0447] (2) (R)-1-(3-(3-((5-Aminopyrimidin-2-yl)(cyclopropyl)amino)-5-chlorophenyl)morpholino)prop-2-en-1-one

[0448] (R)-1-(3-(3-chloro-5-(cyclopropyl(5-nitropyrimidin-2-yl)amino)phenyl)morpholino)prop-2- en-1-one (100 mg, 0.23 mmol) and iron powder (52 mg, 0.93 mmol) were dissolved in ethanol / water (10 / 2 mL), ammonium chloride (49 mg, 0.93 mmol) was added, and the reaction was stirred at 90 °C overnight. LCMS detection showed that the reaction was completed. The reaction solution was filtered through celite, concentrated under reduced pressure, and then water (20 mL) was added. After extraction with dichloromethane (15 mL x 3), the title compound (25.3 mg, white solid) was obtained by Prep-HPLC purification with a yield of 27%. MS (ESI): m / z 400.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.97 (s, 2H), 7.19-7.14 (m, 2H), 7.01 (s, 1H), 6.85-6.78 (m, 1H), 6.18 (dd, J = 16.6, 2.2 Hz, 1H), 5.73 (d, J = 10.3 Hz, 1H), 5.46-5.24 (m, 1H), 5.09 (s, 2H), 4.36 (d, J = 12.2 Hz, 1H), 4.20-3.73 (m, 3H), 3.50-3.44 (m, 1H), 3.22-2.87 (m, 2H), 0.89-0.85 (m, 2H), 0.47-0.38 (m, 2H).

[0449] Example 37

[0450] (R)-1-(3-(3-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0451] 1-[(3R)-3-(3-bromo-5-chlorophenyl)morpholin-4-yl]prop-2-en-1-one (100 mg, 0.30 mmol), 1-methyl-1H-1,2,4-triazole-3-amine (30 mg, 0.30 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and cesium carbonate (197 mg, 0.61 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 90 °C under nitrogen for 16 h. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and the title compound (48.3 mg, white solid) was obtained by Prep-HPLC purification with a yield of 46%. MS (ESI): m / z 348.1 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.20 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 6.80 (s, 2H), 6.21 (dd, J = 16.6, 2.3 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 5.54 - 4.92 (m, 1H), 4.32 (d, J = 12.3 Hz, 1H), 4.26 - 3.91 (m, 1H), 3.89 - 3.82 (m, 1H), 3.77 (s, 3H), 3.76 - 3.64 (m, 1H), 3.51 - 3.42 (m, 1H), 3.28 - 2.78 (m, 1H).

[0452] Example 38

[0453] (R)-1-(3-(3-chloro-5-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl) morpholino)prop-2-en-1-one

[0454] (R)-1-(3-(3-chloro-5-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl) morpholino)prop-2-en-1-one (100 mg, 0.29 mmol) and cyclopropylboronic acid (49 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (10 mL), 2,2'-bipyridine (45 mg, 0.29 mmol), copper acetate (52 mg, 0.29 mmol) and potassium carbonate (79 mg, 0.58 mmol) were added, the reaction was stirred at 120 °C under the condition of oxygen balloon for 48 h. LCMS detected that the reaction was completed, the reaction liquid was added water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate. Concentrated under reduced pressure, purified by column chromatography (8% MeOH in DCM), Prep-HPLC to give the title compound (2.5 mg, white solid), yield: 2%. MS (ESI): m / z 388.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.30 - 7.12 (m, 2H), 6.95 (s, 1H), 6.80 (s, 1H), 6.18 (dd, J = 16.6, 2.1 Hz, 1H), 5.74 (d, J = 10.6 Hz, 1H), 5.50 - 5.19 (m, 1H), 4.35 (d, J = 12.3 Hz, 1H), 4.26 - 4.03 (m, 1H), 3.89 - 3.83 (m, 1H), 3.80 (s, 3H), 3.78 - 3.72 (m, 1H), 3.50 - 3.45 (m, 1H), 3.28 - 2.99 (m, 1H), 2.91 - 2.81 (m, 1H), 0.95 - 0.87 (m, 2H), 0.60 - 0.43 (m, 2H).

[0455] Example 39

[0456] (R)-1-(3-(3-chloro-5-((5-cyclopropylpyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0457] (R)-1-(3-(3-bromo-5-chlorophenyl)morpholino)prop-2-en-1-one (50 mg, 0.15 mmol), 5-cyclopropylpyrimidin-2-amine (20 mg, 0.15 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (17 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol) and cesium carbonate (98 mg, 0.3 mmol) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen, and stirred at 90 °C under nitrogen protection overnight. The reaction was detected by LCMS to be completed, and the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (100% EA) to obtain the title compound (21.4 mg, white solid), yield: 37%. MS (ESI): m / z 385.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 8.31 (s, 2H), 7.97 (t, J = 1.6 Hz, 1H), 7.59 (s, 1H), 6.92 - 6.83 (m, 2H), 6.21 (dd, J = 16.6, 2.3 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.45 - 5.24 (m, 1H), 4.34 (d, J = 12.1 Hz, 1H), 4.21 - 3.74 (m, 3H), 3.48 (td, J = 11.7, 2.6 Hz, 1H), 3.20 - 2.98 (m, 1H), 1.87 - 1.81 (m, 1H), 0.95 - 0.88 (m, 2H), 0.75 - 0.71 (m, 2H).

[0458] Example 40

[0459] (R)-1-(3-(3-chloro-5-(5-(difluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholino)prop-2-en-1-one

[0460] (R)-1-(3-(3-amino-5-chlorophenyl)morpholino)prop-2-en-1-one (33 mg, 0.12 mmol), 2-chloro-5-(difluoromethyl)pyrimidine (20 mg, 0.12 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (12 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) and potassium carbonate (35 mg, 0.25 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen, and stirred at 90 °C under nitrogen for 16 h. The reaction was detected to be completed by LCMS, and the reaction solution was concentrated under reduced pressure. Purification by Prep-HPLC gave the title compound (17.5 mg, white solid) in a yield of 36%. MS (ESI): m / z 395.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.71 (s, 2H), 7.94 (s, 1H), 7.65 (s, 1H), 7.21 - 6.89 (m, 2H), 6.84 (s, 1H), 6.22 (dd, J = 16.6, 2.3 Hz, 1H), 5.79 - 5.73 (m, 1H), 5.53 - 5.24 (m, J = 61.4 Hz, 1H), 4.36 (d, J = 12.2 Hz, 1H), 4.32 - 3.92 (m, 1H), 3.89 - 3.72 (m, 2H), 3.53 - 3.44 (m, 1H), 3.08 - 2.84 (m, 1H).

[0461] Test Example 1: NRF2 activity test (Luciferase reporter assay)

[0462] NRF2 binds to the promoter region of antioxidant response element (ARE) to initiate the expression of downstream genes. ARE luciferase reporter assay is to detect the effect of ligand on target gene expression by using luciferin as a reporter gene. KYSE-70 is a kind of esophageal squamous cell carcinoma cell, and the mutation of Nrf2 gene of the cell leads to the decrease of affinity of KEAP1, NRF2 and E3 ligase, so that the degradation of Nrf2 is reduced, and the NRF2 signal is in a long-time activated state.

[0463] The KYSE-70-ARE-Luc2P cells used in this experiment are inserted with luciferase gene downstream of ARE, and in the KYSE-70-ARE-Luc2P cell line with high expression of NRF2, NRF2 will bind to ARE to induce the expression of luciferase gene, so that the luciferase signal is observed. When KEAP1 agonist (NRF2 inhibitor) is added, it binds to KEAP1 and stabilizes E3 ligase, and the increase of Keap1-Cul3-E3 complex binding to NRF2 improves the degradation of Nrf2, which leads to the decrease of Nrf2 binding to ARE, and then causes the decrease of expression of luciferase gene downstream of ARE, so the signal intensity of luciferase is reduced. KEAP1 agonist as a ubiquitination promoter improves the degradation of NRF2 and thus indirectly inhibits NRF2, so as to achieve the regulation of NRF2 downstream signal.

[0464] Experimental steps:

[0465] KYSE-70-ARE-Luc2P cells 40 μL / well were placed in a 384-well plate, and the test compound was added to the cells in the 384-well plate, and cultured in a 37℃ and CO2 incubator for 24 hours. After the culture was completed, 20 μL of Bright-lite reagent was added to the well. The luciferase signal was read by BMG PHERAstar FXS. The IC 50 and Imaxvalues of the compound were fitted according to the non-linear regression equation.

[0466] Cell culture conditions: RPMI1640 medium, 10% FBS, 1% PS, 37℃ & CO2 incubator.

[0467] The test results of the compounds are shown in Table 1, in which A+ represents <1 nM, A represents 1-10 nM, B represents 10-100 nM, C represents 100-1000 nM, and D represents >1000 nM.

[0468] Positive drug VVD-130037 was prepared according to WO2024 / 073587, Example 5.

[0469] Table 1

[0470] Test Example 2: KYSE-70 cell proliferation test

[0471] KYSE-70 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS), 1% penicillin-streptomycin (PS), in a 37°C incubator containing 5% carbon dioxide. 1. 1000 KYSE-70 cells per well were inoculated into a 96-well plate in an amount of 195 μL per well. 2. On the 1st, 3rd, 5th, 7th, and 9th days, 5 μL of different concentrations of compounds were added to the cells, and incubated at 37°C, 5% CO2 for 10 days. 3. 3D CellTiter-Glo reagent was added to each well, and after shaking at room temperature for 20 minutes, it was left to stand for 60 minutes. 4. The luminescence value was read using a bioluminescence detector BMG. 5. Data analysis: The detection reliability was verified by DMSO and medium control data, and the inhibition rate % = (high concentration mean - sample value) / (high concentration mean - low concentration mean), and the IC 50 value of the compound was fitted by a nonlinear regression equation. The results of the compound detection are shown in Table 2.

[0472] Table 2

[0473] Test Example 3: Human plasma stability test

[0474] Test the in vitro stability of the test drug in human plasma. 1. To 90 μL of dimethyl sulfoxide (DMSO), add 10 μL of 10 mM dimethyl sulfoxide stock solution (for test compound or positive control compound PC, lovastatin, suitable for dog and rat plasma). To 90 μL of acetonitrile, add 10 μL of 10 mM propyl amine acetonitrile stock solution (suitable for human, mouse, monkey plasma). 2. Thaw the plasma in a 37 °C water bath, centrifuge at 3,220 g for 10 minutes at room temperature to remove blood clots. Transfer the supernatant to a new centrifuge tube and record the pH value (7-8). 3. To the preheated 497.5 μL of plasma, add 2.5 μL of 1 mM working solution, repeat twice. 4. Immediately transfer 50 μL of the spiked plasma into the sample plate containing 300 μL of methanol or acetonitrile and internal standard, vortex for 5 minutes. 5. Transfer 50 μL of the spiked plasma into the incubation plate corresponding to the 15, 30, 45, 60, 120 minute time points, respectively. 6. Centrifuge the sample plate at 3220 g for 40 minutes. 7. Place the incubation plate in a 37 °C water bath, and shake at about 60 rpm. At the designated time points, add 300 μL of methanol or acetonitrile containing internal standard to terminate the reaction, vortex for 5 minutes. 8. Centrifuge the sample plate at 3220 g for 40 minutes. 9. Transfer 100 μL of the supernatant to the analysis plate containing an appropriate amount of H2O, and perform LC-MS / MS analysis. 10. Data analysis, calculate the linear slope k (ln (compound residual percentage) VS incubation time) using Microsoft Excel, and calculate the in vitro half-life t by the formula t = 0.693 / k 1 / 2 The results are shown in Table 3.

[0475] Table 3

[0476] Test Example 4: Mouse PK Test

[0477] This test uses 3 male CD-1 (ICR) mice, and uses intravenous bolus administration. Accurately weigh an appropriate amount of test product, and mix with an appropriate amount of solvent (the administration solvent for the test product is 5% DMSO + 10% Solutol HS-15 + 85% Saline), to form a clear solution, which can be vortexed or ultrasonically treated in a water bath if necessary. Each mouse is administered a single intravenous dose of 1 mg / kg of test drug, with a drug concentration of 1 mg / mL, and a dose volume of 1 mL / kg. The blood sampling time for the animals is 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 7 h, 24 h after administration, and 20 μL of blood is sampled from each mouse at each time point through the saphenous vein or other appropriate blood sampling site. The samples are processed and detected using a validated LC / MS / MS method, and the target analyte is the test product. The test results are shown in Table 4.

[0478] Table 4

[0479] Test Example 5: Efficacy Test

[0480] This trial evaluates the efficacy of the investigational drug in human lung cancer LU6407. Antitumor effect in subcutaneous xenograft female BALB / c Nude mouse model.

[0481] A human lung cancer subcutaneous transplantation tumor model was established by subcutaneously inoculating LU6407 tumor blocks into BALB / c Nude mice. The experiment consisted of four groups: a solvent control group (Vehicle, G1), a test drug VVD-130037 group (50 mg / kg, G2), a test drug Example 17 group (50 mg / kg, G3), and a test drug Example 31 group (50 mg / kg, G4). Test drugs VVD-130037, Example 17, and Example 31 were administered orally by gavage, twice daily (BID). In the human lung cancer subcutaneous transplantation tumor PDX model, the average tumor size was 150 mm. 3 ~200mm 3 Mice were randomly assigned to four groups of five mice each using a "Matched distribution" method within the StudyDirector™ environment. After grouping, drug administration began, followed by a two-week observation period after drug withdrawal. The experiment concluded on Day 56. Efficacy was evaluated based on tumor suppression effects, and safety was evaluated based on changes in animal weight and mortality. The results showed that compounds 17 and 31 of this application were superior to the positive control drug. Table 5 shows the complete tumor regression rate in mice of different administration groups.

[0482] Table 5

Claims

1. A compound of formula (I): or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof; wherein, R 1 Ci-C6-alkenyl which is optionally substituted by one or more, identical or different R3; X 1 selected from O, NR 2 or C(R 2 )2; R 2 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or two R 2 form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl with the atom to which they are each attached; p is selected from 0, 1, 2, or 3; m, n are selected from 0, 1, or 2; X 2 selected from CR 3 or N; q is selected from 0, 1, 2, or 3; R 3 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl; L 1 selected from a chemical bond, ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl; i is selected from 0, 1, 2, 3, 4, or 5; R 4 each independently selected from -L 2 -R 4a ; The L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl.

2. The compound of claim 1, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: R 1 For said R 1a , R 1b , R 1c is selected from H, halogen, C1-C6alkyl optionally substituted with halogen, C1-C6alkoxy optionally substituted with halogen; p is selected from 0, 1, 2, or 3; R 2 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, or two R 2 form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with the atom to which they are attached, optionally substituted with 1-3 halo, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halo, C1-C3 alkoxy optionally substituted with halo; m, n are selected from 0, 1, or 2; X 2 selected from CR 3 or N; q is selected from 0, 1, 2, or 3; R 3 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; L 1 selected from a chemical bond, ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl; i is selected from 0, 1, 2, 3, 4, or 5; R 4 each independently selected from -L 2 -R 4a ; The L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C3 alkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl.

3. The compound of claim 1, or a deuterated isomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate thereof, wherein, having the structure of Formula (II): R 1a , R 1b , R 1c is selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; p is selected from 0, 1, 2, or 3; R 2 each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, or two R 2 form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with the atom to which they are attached, optionally substituted with 1-3 halo, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halo, C1-C3 alkoxy optionally substituted with halo; X 2 selected from CR 3 or N; R 3 each independently selected from H, halogen, hydroxyl, amino, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; L 1 a chemical bond, ring A is selected from 3-8 membered cycloalkyl, 3-15 membered heterocyclyl, 3-15 membered aryl, 3-15 membered heteroaryl; i is selected from 0, 1, 2, 3, 4, or 5; R 4 each independently is selected from -L 2 -R 4a ; said L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, optionally substituted C1-C3 alkyl, optionally substituted 3-6 membered cycloalkyl.

4. The compound of claim 3, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: Ring A is selected from 5. The compound of claim 3, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein, L 1 a chemical bond, ring A is selected from 8-15 membered bicyclic or tricyclic heterocyclyl, containing 1-5 heteroatoms selected from N, O; The L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, amino, C1-C3alkyl optionally substituted with halogen.

6. The compound of claim 5, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: said ring A is selected from preferably 7. The compound of claim 3, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: L 1 a chemical bond, ring A is selected from 5-8 membered monocyclic aryl, 5-8 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O; The L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, amino, optionally substituted C1-C3 alkyl, optionally substituted 3-6 membered cycloalkyl.

8. The compound of claim 7, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: said ring A is selected from preferably 9. The compound of any one of claims 3-8, or a deuterated form, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: said R 4a selected from oxo, H, F, hydroxyl, amino, optionally substituted C1-C3 alkyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, more preferably oxo, H, F, hydroxyl, amino, difluoromethyl, trifluoromethyl, difluorocyclobutyl.

10. The compound of claim 3, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: R 1a , R 1b , R 1c is selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; p is selected from 0, 1, 2 or 3; R 2 each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; X 2 selected from CR 3 or N; R 3 each independently selected from H, halogen, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen; L 1 selected from Ring A is selected from i is selected from 0, 1, 2, 3; R 4 each independently is selected from -L 2 -R 4a ; said L 2 selected from a chemical bond, said R 4a selected from oxo, H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen.

11. The compound of claim 10, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: R 1a , R 1b , R 1c is selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy, preferably H.

12. The compound of claim 10, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: p is selected from 0, 1, 2 or 3; R 2 each independently is selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy.

13. The compound of claim 10, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: L 1 selected from more preferably 14. The compound of claim 10, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: Ring A is preferably more preferably 15. The compound of claim 10, or a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate thereof, wherein: i is selected from 0, 1, 2, 3, more preferably 0, 1 or 2; R 4 each independently selected from -L 2 -R 4a ; said L 2 selected from a chemical bond, more preferably a chemical bond, said R 4a selected from H, F, CI, methyl, difluoromethyl, trifluoromethyl, amino, cyclopropyl, more preferably F, methyl, difluoromethyl, trifluoromethyl, amino, cyclopropyl.

16. A compound of Formula (III): or a deuterated isomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate thereof. R 5 each independently is selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl optionally substituted with halogen, C1-C3 alkoxy optionally substituted with halogen, 3-6 membered cycloalkyl optionally substituted with halogen, more preferably H, F, Cl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or difluoromethoxy, cyclopropyl; R 1a , R 1b , R 1c , p, R 2 , X 2 , R 3 , ring A, i, R 4 as in claim 10.

17. The following compounds:

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, a deuterated isomer, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

19. Use of a compound according to any one of claims 1-17, a deuterated isomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for the treatment and / or prevention of a disease associated with KEAP1 and / or NRF2 activity.

20. Use according to claim 19, characterized in that: The KEAP1 and / or NRF2 associated disease refers to a disease caused by changes in KEAP1 activity and / or changes in NRF2 activity; the changes in activity include mutations, amplifications, overexpression, deletions of KEAP1 and / or NRF2, especially KEAP1 GOF (Gain of function) and / or NRF2 LOF (Loss of function) mutations, also include CUL3 mutations that can bind to KEAP1 to play a ubiquitin degradation role, and diseases with KRAS, BRAF, Myc, LKB1, PTEN, BRCA1 gene mutations or abnormal expression.

21. Use according to claim 20, characterized in that: The KEAP1 and / or NRF2 associated disease is selected from a tumor, a neurodegenerative disease, an autoimmune disease, a disease associated with reduced reduction stress or oxidative signal.

22. Use according to claim 21, characterized in that: The KEAP1 and or NRF2 related disease is selected from the main tumor indications of lung squamous carcinoma, lung adenocarcinoma, uterine cancer, esophageal cancer, head and neck cancer, bladder cancer, ovarian cancer, liver cancer, cervical cancer, cholangiocarcinoma, gastric cancer, melanoma, papillary renal cell carcinoma, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, blood cancer and the like.

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