Pyridazine derivative and pharmaceutical use thereof

Abstract

Disclosed are a pyridazine derivative and pharmaceutical use thereof. The present invention provides a compound represented by formula (I), or a stereoisomer thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, or a cocrystal thereof. The pyridazine derivative provided by the present invention has a novel structure and a good selective inhibitory effect on c-kit kinase.

Description

A pyridazine derivative and its pharmaceutical applications

[0001] This invention claims priority to Chinese Patent Application No. 2025101013774, filed January 22, 2025; Chinese Patent Application No. 2025119296231, filed December 19, 2025; and Chinese Patent Application No. 2026100762934, filed January 19, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, specifically to a pyridazine derivative and its application in medicine. Background Technology

[0003] KIT was initially identified as a homolog of the feline sarcoma virus oncogene v-kit, commonly referred to as the proto-oncogene c-kit, which encodes the mast / stem cell growth factor receptor kit protein (CD117). Kit belongs to the type III tyrosine kinase receptor family, namely the platelet-derived growth factor receptor (PDGFR family), which includes PDGFRα, PDGFRβ, CSF1R, KIT, and FLT3. The KIT protein consists of five Ig-like domains (involved in ligand binding and receptor dimerization), a transmembrane domain (anchoring KIT to the plasma membrane), a juxtamembrane domain (J), and two kinase domains (K) (responsible for SCF / KIT signaling). The SCF-KIT pathway regulates cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and melanin formation. Therefore, c-kit kinase is a promising drug target with good clinical potential. Summary of the Invention

[0004] The purpose of this invention is to provide a novel pyridazine derivative, or all its stereoisomers, that has selective inhibitory activity against c-kit kinase, and pharmaceutical compositions thereof.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound as shown in formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or eutectic thereof:

[0007] The A ring may or may not exist. When the A ring exists, the A ring is a 5-6 membered aromatic ring or a 5-6 membered heteroaromatic ring.

[0008] The B ring is a 5-6 member aromatic ring or a 5-6 member heteroaromatic ring;

[0009] The C ring is a 5-15 membered heterocyclic ring;

[0010] R1 is H, C1-C6 alkyl, 3-5 membered cycloalkyl, C1-C6 haloalkyl or 3-5 membered halocycloalkyl;

[0011] R2 is H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, alkenyl, alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 may optionally be further substituted by one or more R8s.

[0012] R3 is H, -NR5R6, -(CH2) 0-3 -OR7, C1-C6 alkyl, halogen, -CN, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, R3 optionally further substituted by one or more R8;

[0013] Ring B may be further substituted by one or more R4s, wherein R4 is a C1-C3 alkyl, a C1-C3 haloalkyl, or a halogen;

[0014] R5, R 6、 R 7、 R8 is independent for H, -CN, -OH, -S(=O)2N(CH3)2, carbonyl, C3-C5 cycloalkenyl, C 1-6 Alkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C5 cycloalkenyl or carbonyl group is optionally further surrounded by one or more -OH, halogen, -CN, alkenyl, alkynyl, Substituted with C1-C3 alkoxy, C1-C3 alkyl, 3-10 heterocyclic alkyl, 5-10 aryl or 5-10 heteroaryl;

[0015] X is N or C.

[0016] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I), or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or eutectics, are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments").

[0017] In some embodiments, the compound represented by formula (Ⅰ) contains 0, 1, or 2 R3s, each R3 being the same or different.

[0018] In some embodiments, the compound represented by formula (Ⅰ) contains 0 or 1 R3, preferably 1.

[0019] In some embodiments, R3 may also be -OH, C1-C6 alkoxy, Or C3-C 10 Cycloalkenyl; ring D is a 3-5 membered heterocycle containing a sulfone group (-SO2-).

[0020] In some implementations, R5, R6, R7 and each R8 can also be independently configured.

[0021] In some embodiments, the 3-10 membered heterocyclic alkyl, C1-C6 alkyl, C3-C5 cycloalkenyl or carbonyl groups in R5, R6, R7 and R8 may optionally be further replaced by one or more -D, C1-C3 alkylene-C1-C3 alkoxy or 3-5 membered cycloalkyl groups.

[0022] In some embodiments, each of the alkenyl groups is a C2-C6 alkenyl group.

[0023] In some embodiments, the alkynyl group is a C2-C6 alkynyl group.

[0024] In some implementations... for

[0025] In some embodiments, the heteroatoms in each of the 5-6 membered heteroaromatic rings, the 5-15 membered heterocyclic rings, the 3-10 membered heterocyclic alkyl groups and the 5-10 membered heteroaryl groups are selected from one, two or three of N, O and S; preferably, the number of heteroatoms is one, two, three or four.

[0026] In some embodiments, in each of the 5-6 membered heteroaromatic rings, the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four; for example, each of the 5-6 membered heteroaromatic rings is independently... Furthermore, for example, the heteroatom is one of N, O, and S, and the number of heteroatoms is 1; for example,

[0027] In some embodiments, each of the 5-6 member aromatic rings is independently a 6-membered aromatic ring.

[0028] In some embodiments, the heteroatom in the 5-15 membered heterocycle is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four; more preferably, the heteroatom is one or two of N, O, and S, for example, the heteroatom is selected from a combination of N, N, and O or a combination of N and S; more preferably, the 5-15 membered heterocycle is a 5-10 membered heterocycle, preferably a 5-membered heteroaromatic ring or... Wherein, ring Y is a 5-membered heteroaromatic ring, and ring Z is a 5-8 membered heterocyclic alkane. Preferably, the 5-15 membered heterocycle is...

[0029] In some embodiments, the 5-8 member heterocyclic alkanes are

[0030] In some embodiments, each of the C1-C6 alkyl groups is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl, ethyl, n-propyl, or... More preferably, it is a C1-C3 alkyl group, such as methyl, ethyl or n-propyl.

[0031] In some embodiments, in each of the 5-10 member heteroaryl groups, the heteroatom is selected from one, two, or three types of N, O, and S, and the number of heteroatoms is one, two, or three; preferably, the heteroatom is one or two types of N and S, and the number of heteroatoms is one or two; more preferably, each of the 5-10 member heteroaryl groups is a 5-6 member heteroaryl group, such as pyrazolyl, thiazolyl, pyridinyl, or pyridazinyl, and for example...

[0032] In some embodiments, each of the 3-10 membered cycloalkyl groups is independently a 3-5 membered cycloalkyl group; preferably, the ring in each of the 3-5 membered cycloalkyl groups is independently a monocyclic, spirocyclic, or bridged ring, such as cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0033] In some embodiments, in each of the 3-10 membered heterocyclic alkyl groups, the heteroatom is selected from one, two, or three types of N, O, and S, and the number of heteroatoms is one, two, or three; preferably, the heteroatom is one or two types of N and O, and the number of heteroatoms is one or two. The ring in each of the 3-10 membered heterocyclic alkyl groups can be a monocyclic or fused ring. More preferably, each of the 3-10 membered heterocyclic alkyl groups is a 3-6 membered heterocyclic alkyl group; for example, tetrahydropyranyl, morpholinyl, piperidinyl, oxetyl, tetrahydrofuranyl, oxetyl, 3-oxabicyclo[3.1.0]hexyl, preferably.

[0034] In some embodiments, each of the C3-C 10 The cycloalkenyl group is independently a C3-C5 cycloalkenyl group; the C3-C5 cycloalkenyl group is, for example...

[0035] In some embodiments, each of the C1-C6 alkoxy groups is independently a C1-C3 alkoxy group, preferably a methoxy, ethoxy, n-propoxy, or isopropoxy group.

[0036] In some embodiments, each of the 5-10 aryl groups is independently phenyl or naphthyl.

[0037] In some embodiments, each of the halogens is independently F, Cl, Br, or I.

[0038] In some implementations, R5, R6, R7, and R8 are each independently... H, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more -OH, halogen, -CN, alkenyl, alkynyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl.

[0039] In some embodiments, R1 is a C1-C6 alkyl group.

[0040] In some embodiments, R1 is H, methyl, ethyl, or cyclopropyl, preferably methyl or ethyl.

[0041] In some embodiments, R2 is H, C1-C6 alkyl, 5-10 heteroaryl, C1-C6 alkyl substituted with one or more R8s, or 5-10 heteroaryl substituted with one or more R8s.

[0042] In some implementations, R3 is H, -(CH2) 0-3 -OR7, C1-C6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C3-C 10 Cycloalkenyl, C1-C6 alkyl groups substituted with one or more R8 groups, 3-10 membered cycloalkyl groups substituted with one or more R8 groups, 3-10 membered heterocycloalkyl groups substituted with one or more R8 groups, or C3-C membered heterocycloalkyl groups substituted with one or more R8 groups. 10 Cycloalkenyl.

[0043] In some implementations, X is N.

[0044] In some implementations, ring A is a 5-6 membered heteroaryl ring.

[0045] In some embodiments, in R2, each R8 is independently a C1-C6 alkyl, 3-10 membered cycloalkyl, or 3-10 membered heterocycloalkyl, wherein the C1-C6 alkyl or 3-10 membered heterocycloalkyl is optionally further substituted by one or more -D, -OH, halogen, C1-C3 alkoxy, C1-C3 alkyl, 3-5 membered cycloalkyl, or 3-10 membered heterocycloalkyl; preferably, in R2, each R8 is independently -CH3, -CD3, -CH2OH, -CH2CH2OH -CH2CH2F, -CH2CHF2, -CH2CF3, -CF3, -CH2CH2OCH3, CH2-Cyclopropyl, Cyclopropyl, Or -OH.

[0046] In some implementations, R7 in R3 is C. 1-6 Alkyl, 3-10 membered cycloalkyl, or C substituted with one or more halogens 1-6 Alkyl group, preferably -CH2CF3, methyl or cyclopropyl.

[0047] In some embodiments, each R8 in R3 is independently -CN, -OH, -S(=O)2N(CH3)2, carbonyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, The carbonyl group is optionally further substituted with one or more C1-C3 alkoxy groups or C1-C3 alkylene-C1-C3 alkoxy groups (-CO-C1-C3 alkoxy or -COC1-C3 alkylene-C1-C3 alkoxy).

[0048] In some embodiments, each R8 in R3 is independently -F, -OCH3, -OH, -CN, -Cl, cyclopropyl, -S(=O)2N(CH3)2,

[0049] In some implementations, R2 is H, In this case, R2 is further substituted with one or more halogens, 3-6 membered cycloalkyl groups, 3-6 membered heterocycloalkyl groups, or C1-C6 alkyl groups; the 3-6 membered heterocycloalkyl groups or C1-C6 alkyl groups are optionally further substituted with one or more -OH groups, halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-10 membered cycloalkyl groups, or 3-10 membered heterocycloalkyl groups.

[0050] In some implementations, R2 is In this case, R2 is further substituted with one or more halogens, 3-6 membered cycloalkyl groups, 3-6 membered heterocycloalkyl groups, or C1-C6 alkyl groups; the C1-C6 alkyl groups are optionally further substituted with one or more -OH groups.

[0051] In some embodiments, R2 is H, methyl,

[0052] In some implementations, R3 is H, -CH2OCH2CH 3、 --CH2OH, C1-C6 alkyl group At this time, R3 is further reacted with one or more -OH, -S(=O)2N(CH3)2, =O, cyano, -O-CH3, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or C1-C6 alkyl substituents.

[0053] In some implementations, R3 is At that time, R3 was further divided by one or more =Substituents of O, cyano, -O-CH3, halogen or C1-C6 alkyl groups.

[0054] In some embodiments, R3 is -H, -F, -OH, methoxy, methyl, ethyl,

[0055] In some embodiments, ring B is a 6-membered aromatic ring, a 5-6-membered heteroaromatic ring, a 6-membered aromatic ring substituted with one or two R4 groups, or a 5-6-membered heteroaromatic ring substituted with one or two R4 groups, for example...

[0056] In some embodiments, the C ring is a 5-6 quinary heterocyclic aromatic ring, a 5-10 quinary bicyclic ring, or a 10-15 quinary tricyclic ring; wherein any two connecting rings in the tricyclic ring can be fused or screwed together.

[0057] In some implementations, ring C is

[0058] In some implementations, ring C is

[0059] In some embodiments, the present invention also provides a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal thereof, which is a compound of formula (II):

[0060] Wherein, ring B, ring C, R1, R2 and R3 are independently as described in any embodiment of the present invention;

[0061] Preferably, among them,

[0062] Ring B is a benzene ring or a pyridine ring;

[0063] C ring is

[0064] R1 is H, C1-C6 alkyl, 3-5 membered cycloalkyl, C1-C6 haloalkyl or 3-5 membered halocycloalkyl;

[0065] R2 is H, C1-C6 alkyl, halogen, 5-6 aryl, 3-6 heterocyclic alkyl or 5-6 heteroaryl;

[0066] R3 is H, -(CH2)-OR7, C1-C6 alkyl, halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OH or -O-CH3; R3 may optionally be further substituted by one or more R8s.

[0067] The present invention also provides a compound, or a stereoisomer thereof, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound is selected from any one of those in Table 1:

[0068] Table 1

[0069] The present invention also provides a compound, or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a deuterated product, a pharmaceutically acceptable salt, or a cocrystal thereof, wherein the compound is selected from any one of the following:

[0070] The present invention also provides a pharmaceutical composition comprising:

[0071] (1) Any of the above compounds or their stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals;

[0072] (2) One or more other active ingredients selected by choice; and

[0073] (3) Pharmaceutically acceptable carriers and / or excipients.

[0074] The present invention also provides the use of the above-mentioned compound or its stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition in the treatment of c-kit kinase-related diseases or in the preparation of a medicament for the treatment of c-kit kinase-related diseases.

[0075] In some embodiments, the c-kit kinase-related diseases are gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, or melanoma.

[0076] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0077] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0078] In this invention, the structural segments This means that the structural segment is connected to the rest of the molecule through this site.

[0079] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6, C1-C4, C1-C3). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or... When an alkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0080] "alkylene" is a divalent group that is connected to the rest of the molecule by two single bonds, and the rest is defined as "alkyl".

[0081] "Alkoxy" refers to the group R X -O-,R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0082] "Cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 3-10, 3-5), which can be monocyclic or bicyclic (spirocyclic or bridged). Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When substituted, it may be further substituted by 0 or more substituents.

[0083] "Cycloalkenyl" refers to a group having a specified number of carbon atoms (e.g., C3-C4). 10 A cyclic, unsaturated monovalent hydrocarbon group (C3-C5) having one or more (e.g., 1 or 2) carbon-carbon sp groups. 2 Double bonds are monocyclic, spirocyclic, or bridged rings and are not aromatic. (Monocyclic) cycloalkenyl groups include, but are not limited to: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc.

[0084] "Heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-10, 3-6), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S). The selectively substituted N and S in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be monocyclic, bicyclic (fused), bridged, or spirocyclic. Non-limiting examples of "heterocyclic alkyl" include...

[0085] "Heterocyclic alkanes" refer to cyclic, saturated carbon rings with a specified number of ring atoms (e.g., 5-8 members), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S). The selectively substituted N and S atoms in the ring of a "heterocyclic alkane" can be oxidized to various oxidation states; "heterocyclic alkanes" can be attached to heteroatoms or carbon atoms; and "heterocyclic alkanes" can be monocyclic, bicyclic (fused), bridged, or spirocyclic.

[0086] "Heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic heterocycle having a specified number of ring atoms (e.g., 5-15, 5-10). When it is an aromatic heterocycle, its definition is the same as that of "heteroaromatic ring"; when it is a non-aromatic heterocycle, its definition is the same as that of "heterocyclic alkane". One to four (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocycle" can be selectively substituted to various oxidation states; the "heterocycle" can be a bicyclic (fused ring), bridged ring, or spirocyclic ring. The "heterocycle" may optionally be further substituted by one or more substituents. Non-limiting examples of "heterocycles" include...

[0087] "Aryl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 5-10, such as 5, 6, 7, 8, 9, 10). It can be monocyclic or polycyclic (e.g., 2 or 3 rings). When polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. The aryl group is attached to the rest of the molecule via an aromatic or non-aromatic ring. Non-limiting examples of "aryl" include phenyl or naphthyl groups. The aryl group may optionally be further substituted with one or more substituents.

[0088] "Aromatic ring" refers to a cyclic, unsaturated carbon ring having a specified number of carbon atoms (e.g., 6-membered), which can be monocyclic or polycyclic (e.g., 2 or 3 rings). When polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. Non-limiting examples of "aromatic ring" include benzene rings or naphthalene rings.

[0089] "Heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond, and at least one ring is aromatic. The heteroaryl group can be attached to a heteroatom or a carbon atom, and can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrroliyl, pyrimidinyl, pyrazinyl, pyridazinyl, and imidazolyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0090] A "heteroaromatic ring" refers to a cyclic, unsaturated carbon ring having a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond, and at least one ring possessing aromaticity. Non-limiting examples include...

[0091] When the terms "alkyl", "alkoxy", "cycloalkyl", "cycloalkenyl", "heterocyclic alkane", "heterocyclic alkyl", "heterocyclic", "aryl", "aromatic ring", "heteroaromatic ring" or "heteroaryl" mentioned above are substituted, they may optionally be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3- 8 heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl and -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C6- 10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Substituents of =O and R are replaced; q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 6-10 Aryl; R q2 R q3 Selected from H and C 1-6 Alkyl; R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 and -C(=O)NR q2 R q3 The C mentioned therein 1-6 Alkyl groups may optionally be further reacted with one or more OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more N, O, or S heteroatoms.

[0092] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0093] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0094] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0095] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0096] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0097] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0098] The reagents and raw materials used in this invention are all commercially available.

[0099] The positive and progressive effects of this invention are that the compounds of this invention have very strong inhibitory activity against c-kit kinase, ensuring their effectiveness as a therapeutic drug. Detailed Implementation

[0100] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0101] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0102] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0103] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0104] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0105] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0106] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biomedical R&D.

[0107] Intermediate A

[0108] first step

[0109] Compound A-1 (2.0 g, 12.4 mmol), hydroxylamine hydrochloride (1.0 g, 14.8 mmol), and triethylamine (2.4 g, 18.5 mmol) were dissolved in ethanol (30 mL). After the addition was complete, the mixture was reacted at 80 °C for 3 h. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to remove the ethanol. Water (100 mL) was added to the residue, and a solid precipitated. The solid was filtered to give compound A-2 (yellow solid, 2.1 g, yield 88%).

[0110] LC-MS m / z(ESI) = 229.01 [M+1].

[0111] Step 2

[0112] Compound A-2 (1.0 g, 5.2 mmol), (1R, 2S)-2-fluorocyclopropanecarboxylic acid (540.8 mg, 5.2 mmol), and N,N'-carbonyldiimidazole (927.8 mg, 5.7 mmol) were dissolved in N-methylpyrrolidone (3 mL) and reacted in a microwave reactor at 120 °C for 1 h. After the reaction was complete as monitored by TLC, water (50 mL) was added and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate A (white solid, 1.1 g, yield 78%).

[0113] LC-MS m / z(ESI) = 297.01 [M+1].

[0114] Intermediate B

[0115] first step

[0116] Compound B-1 (1.0 g, 49.0 mmol) was dissolved in DMF (200 mL), and sodium hydride (2.3 g, 58.8 mmol) was added in portions at 0 °C. The mixture was stirred at room temperature for 30 min, and then 2,4-dinitrophenylhydroxylamine (11.7 g, 58.8 mmol) was added dropwise. The mixture was gradually reacted at room temperature for 10 h, and the reaction progress was monitored by TLC.

[0117] The reaction was stopped, quenched with water, extracted with ethyl acetate, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, eluted by column chromatography (EA:PE = 1:5), and evaporated to dryness to give compound B-2 (yellow solid, 9.4 g, yield 88%).

[0118] LC-MS m / z(ESI) = 218.97 [M+1].

[0119] Step 2

[0120] Compound B-1 (1.9 g, 7.2 mmol), dimethoxypropionate acetonitrile (5.0 g, 43.4 mmol), and p-toluenesulfonic acid were mixed and stirred at 80 °C for 6 h. Then DBU (6.6 g, 43.4 mmol) was added, and the reaction was continued at 80 °C for 10 h. The reaction progress was monitored by TLC.

[0121] The reaction was stopped, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, eluted by column chromatography (DCM:MeOH = 10:1), and evaporated to dryness to give compound B-3 (black liquid, 900 mg, yield 45%).

[0122] LC-MS m / z(ESI) = 237.95 [M+1].

[0123] Step 3

[0124] Compound B-3 (900 mg, 3.7 mmol) and phosphorus oxychloride (7.6 g, 49.4 mmol) were mixed and reacted at 75 °C for three hours. The reaction progress was monitored by TLC.

[0125] The reaction was stopped, phosphorus oxychloride was removed by rotary evaporation, and the solution was dissolved in DCM and cooled to 0°C. Saturated sodium bicarbonate solution was then added, and the organic phase was separated by mixing and stirring. The solution was then eluted by column chromatography (DCM:MeOH = 10:1) and dried to give compound B-4 (yellow solid, 270 mg, yield 28%).

[0126] LC-MS m / z (ESI) = 255.92 [M+1].

[0127] Step 4

[0128] Compound B-4 (270 mg, 1.0 mmol) was dissolved in DMF (10 mL), and methylhydrazine (126 mg, 1.1 mmol) and sodium carbonate (222.6 mg, 2.1 mmol) were added. The mixture was reacted at room temperature for 16 h, and the reaction progress was monitored by TLC.

[0129] The reaction was stopped, water (7.8 mL) and acetic acid (2.3 mL) were added, ethyl acetate (20 × 2 mL) was added for extraction, followed by column chromatography (DCM:MeOH = 20:1) for elution, and the solution was evaporated to dryness to give intermediate B (brown solid, 253 mg, yield 90%).

[0130] LC-MS m / z(ESI) = 266.00 [M+1].

[0131] Intermediate C

[0132] first step

[0133] Intermediate B (6 g, 22.5 mmol) was dissolved in a mixture of 1,4-dioxane / water = 4:1 (300 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (5.6 g, 27 mmol) and cesium carbonate (11 g, 67.5 mmol), then Pd(dppf)Cl2·CH2Cl2 (3 g, 3.6 mmol), and nitrogen was purged. The resulting mixture was heated to 100 °C and stirred for 12 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 70:30). The solvent was removed by rotary evaporation to give compound 1-1 (brown solid, 5 g, yield 72%).

[0134] LC-MS m / z(ESI) = 268.10 [M+1].

[0135] Step 2

[0136] Intermediate 1-1 (2.8 g, 10.5 mmol), 3-bromo-4-methylbenzonitrile (3.1 g, 15.9 mmol), cesium carbonate (17.1 g, 52.6 mmol), BrettPhos (1.8 g, 3.4 mmol), and BrettPhosPd·G3 (3.1 g, 3.4 mmol) were dissolved in DMF (60 mL) and reacted at 90 °C for 4 h under nitrogen protection. The reaction progress was monitored by TLC.

[0137] Stop the reaction, add water and EA, filter with diatomaceous earth, extract the organic phase with EA, wash twice with brine, and then perform column chromatography. First, elute impurities with EA:PE = 1:1, and then elute with DCM:MeOH = 50:1 to obtain intermediate C-1 (yellow solid, 2.2 g, yield 55%).

[0138] LC-MS m / z(ESI) = 383.17 [M+1].

[0139] Step 3

[0140] Intermediate C-1 (1.6 g, 4.2 mmol), hydroxylamine hydrochloride (1.17 g, 16.9 mmol), and DIPEA (3.3 g, 25.4 mmol) were dissolved in ethanol (100 mL) and reacted at 80 °C for 2 days. The reaction progress was monitored by TLC.

[0141] The reaction was stopped, the solvent was evaporated, water was added to precipitate the solid, the solid was filtered, and the water was evaporated to give intermediate C (reddish-brown solid, 1.3 g, yield 75%).

[0142] LC-MS m / z(ESI) = 416.19 [M+1].

[0143] Intermediate D

[0144] first step

[0145] Compound D-1 (methyl 5-bromo-6-methylpyridine-3-carboxylic acid) (5.0 g) was added to a 7M NH3 / MeOH solution (70 mL) and stirred overnight at 90 °C in a sealed tube. The reaction solution was then directly concentrated to give compound D-2 (gray solid, 4.8 g, crude product).

[0146] LC-MS m / z(ESI) = 214.98 [M+1].

[0147] Step 2

[0148] TEA (5.08 g, 50.2 mmol) and TFAA (8.44 g, 40.2 mmol) were added to a stirred solution of compound D-2 (4.8 g, 20.01 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by silica gel column chromatography, eluting with PE:EA (20:1) to give intermediate D (white solid, 3.9 g, 88% yield).

[0149] LC-MS m / z (ESI) = 196.97 [M+1].

[0150] Intermediate E

[0151] first step

[0152] Compound D-1 (methyl 5-bromo-6-methylpyridine-3-carboxylic acid ester) (5.0 g) and 100 mL THF were added to a 500 mL three-necked flask. The nitrogen gas was purged three times, and the flask was cooled to 0 °C. At this temperature, a 1 M lithium aluminum hydride / tetrahydrofuran solution was added dropwise, and the mixture was allowed to rise to room temperature to react.

[0153] After the reaction was complete, 10 mL of water and 20 mL of 15% sodium hydroxide solution were added and 10 mL of water were added to quench the reaction. Then, anhydrous magnesium sulfate was added and stirred for half an hour. The mixture was then filtered directly and washed with ethyl acetate. After concentration, the mixture was purified by silica gel column chromatography and eluted with PE:EA (10:1 to 2:1) to give compound E-1 (white solid, 2.1 g, 47%).

[0154] LC-MS m / z(ESI) = 201.98 [M+1].

[0155] Step 2

[0156] At 0 °C, a DCM solution of compound E-1 (2.1 g, 10.4 mmol) in 50 mL of DCM was added with Dysmann reagent (8.86 g, 20.9 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then sodium thiosulfate was added to quench the reaction. The mixture was then extracted with EA*3, and the organic phase was concentrated and eluted with PE:EA (8:1) to give compound E-2 (white solid, 1.82 g, 88% yield).

[0157] LC-MS m / z (ESI) = 199.99 [M+1].

[0158] Step 3

[0159] A 50% aqueous solution of hydroxylamine (7 mL) was added to a stirred solution of compound E-2 (1.82 g, 9.18 mmol) in EtOH (30 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated directly for the next step to obtain compound E-3 (white solid, 1.97 g, crude).

[0160] LC-MS m / z(ESI) = 214.97 [M+1].

[0161] Step 4

[0162] [bis(trifluoroacetyl)iodide]benzene (5.94 g, 13.8 mmol) was added to a stirred solution of compound E-3 (1.97 g, 10.4 mmol) and cyclopropylacetylene (1.22 g, 18.4 mmol) in MeOH:H₂O = 5:1 (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, washed with sodium bicarbonate solution, washed three times with ethyl acetate, concentrated, purified by silica gel column chromatography, and eluted with PE:EA (10:1) to give intermediate E (white solid, 716 mg, yield 27%).

[0163] LC-MS m / z(ESI) = 279.01 [M+1].

[0164] Example 1

[0165] first step

[0166] Intermediate B (6 g, 22.5 mmol) was dissolved in a mixture of 1,4-dioxane / water = 4:1 (300 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (5.6 g, 27 mmol) and cesium carbonate (11 g, 67.5 mmol), then Pd(dppf)Cl2·CH2Cl2 (3 g, 3.6 mmol), and nitrogen was purged. The resulting mixture was heated to 100 °C and stirred for 12 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 70:30). The solvent was removed by rotary evaporation to give compound 1-1 (brown solid, 5 g, yield 72%).

[0167] LC-MS m / z(ESI) = 268.10 [M+1].

[0168] Step 2

[0169] Intermediate A (225 mg, 0.75 mmol) was dissolved in DMF (10 mL), compound 1-1 (133 mg, 0.5 mmol) and cesium carbonate (495 mg, 1.5 mmol) were added, followed by Brettphos (53.6 mg, 0.1 mmol) and Brettphos-Pd-G3 (90 mg, 0.1 mmol), and the atmosphere was purged with nitrogen. The resulting mixture was heated to 90 °C and stirred for 8 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 90:10). The solvent was removed by rotary evaporation to give compound 1 (white solid, 111 mg, yield 46%).

[0170] 1H NMR (400MHz, DMSO) δ8.53(s,1H),8.45-8.40(m,1H),8.17(s,1H),8.08–7.99(m,2H),7.82(s,1H),7.47(s,1H),7.39-7.31(m,1H),7. 17-7.10(m,1H),5.37–5.16(m,1H),4.09(s,3H),3.87(s,3H),3.10-2.97(m,1H),2.40(s,3H),1.98–1.86(m,1H),1.61–1.50(m,1H).

[0171] LC-MS m / z(ESI) = 484.19 [M+1].

[0172] Example 2

[0173] first step

[0174] Compound 2-1 (3.0 g, 10.10 mmol), 4-pentyn-1-ol (1.0 g, 12.12 mmol), palladium dichloride (354.5 mg, 0.51 mmol), cuprous iodide (96.2 mg, 0.51 mmol), and triethylamine (5.2 g, 50.50 mmol) were dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, the mixture was reacted at room temperature for 3 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 2-2 as a yellow solid, 2.5 g, yield 98%.

[0175] LC-MS m / z(ESI) = 253.02 [M+1].

[0176] Step 2

[0177] Compound 2-2 (100.0 mg, 0.40 mmol), diphenyl azidophosphate (131.0 mg, 0.48 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (72.5 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted in a microwave oven at 150 °C for 3 h. After the reaction was complete, water was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 2-3 (yellow solid, 98 mg, yield 88%).

[0178] LC-MS m / z(ESI) = 278.02 [M+1].

[0179] Step 3

[0180] Following the synthesis of compound 1, using compounds 2-3, compound 2 (yellow solid, 65 mg, yield 76%) was obtained.

[0181] LC-MS m / z(ESI) = 465.22 [M+1].

[0182] Example 3

[0183] 3,3-Difluorocyclobutane-1-carboxylic acid (44.6 mg, 0.3 mmol) and CDI (53.1 mg, 0.3 mmol) were dissolved in NMP (2 mL) and stirred at room temperature for 20 min. Then, intermediate C (68 mg, 0.2 mmol) was added and stirred at room temperature for 30 min. The mixture was then reacted in a microwave oven at 125 °C for 30 min. The reaction progress was monitored by TLC.

[0184] The reaction was stopped, water was added, the organic phase was extracted with EA, washed twice with brine, and then eluted by column chromatography with DCM:MeOH = 100:1 to give compound 3 (white solid, 37 mg, yield 44%).

[0185] 1 H NMR (400MHz, DMSO) δ8.54(s,1H),8.52-8.48(m,1H),8.18(s,1H),8.08–8.03(m,2H),7.82(s,1H),7.55-7. 51(m,1H),7.39-7.34(m,1H),7.16-7.12(m,1H),4.09(s,3H),3.87(s,3H),3.24–2.88(m,5H),2.41(s,3H).

[0186] LC-MS m / z(ESI) = 516.20 [M+1].

[0187] Example 4

[0188] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "2-(2,2,2-trifluoroethoxy)acetic acid" to obtain compound 4 (white solid, 20 mg, yield 22%).

[0189] 1H NMR (400MHz, DMSO) δ8.54(s,1H),8.52-8.49(m,1H),8.17(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.57-7.52(m,1 H),7.40-7.35(m,1H),7.17-7.12(m,1H),5.09(s,2H),4.38-4.30(m,2H),4.10(s,3H),3.87(s,3H),2.42(s,3H).

[0190] LC-MS m / z (ESI) = 538.18 [M+1].

[0191] Example 5

[0192] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(S)-tetrahydrofuran-2-carboxylic acid" yielded compound 5 (yellow solid, 35 mg, yield 42%).

[0193] 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.50-8.44(m,1H),8.17(s,1H),8.08–8.00(m,2H),7.82(s,1H),7.54-7.48(m,1H),7.38-7.34(m,1H) ,7.16-7.12(m,1H),5.31-5.25(m,1H),4.09(s,3H),3.98–3.89(m,2H),3.87(s,3H),2.41(s,3H),2.39–2.18(m,2H),2.08–1.96(m,2H).

[0194] LC-MS m / z(ESI) = 496.21 [M+1].

[0195] Example 6

[0196] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "3-methoxycyclobutane-1-carboxylic acid" yielded compound 6 (yellow solid, 13 mg, yield 17%).

[0197] 1H NMR (400MHz, DMSO) δ8.55-8.51(m,1H),8.50-8.44(m,1H),8.17(s,1H),8.08–8.01(m,2H),7.82(s,1H),7.55-7.49(m,1H),7.43–7.33( m,2H),7.28–7.12(m,1H),4.09(s,3H),3.87(s,3H),3.47-3.40(m,1H),3.17(s,3H),2.79–2.65(m,2H),2.41(s,3H),2.29-2.17(m,2H).

[0198] LC-MS m / z(ESI) = 510.23 [M+1].

[0199] Example 7

[0200] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "2-methoxyacetic acid" yielded compound 7 (yellow solid, 21 mg, yield 31%).

[0201] 1 H NMR (400MHz, DMSO) δ8.53(s,1H),8.49-8.45(m,1H),8.17(s,1H),8.09–8.02(m,2H),7.82(s,1H),7.56-7.50( m,1H),7.39-7.35(m,1H),7.17-7.10(m,1H),4.81(s,2H),4.10(s,3H),3.87(s,3H),3.42(s,3H),2.42(s,3H).

[0202] LC-MS m / z(ESI) = 470.20 [M+1].

[0203] Example 8

[0204] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "oxetane-3-carboxylic acid" yielded compound 8 (white solid, 12 mg, yield 17%).

[0205] 1H NMR (400MHz, DMSO) δ8.53(s,1H),8.49(s,1H),8.17(s,1H),8.07-8.01(m,2H),7.82(s,1H),7.58-7.53(m,1H),7.39-7. 35(m,1H),7.14(s,1H),4.99–4.93(m,2H),4.87-4.80(m,2H),4.72-4.61(m,1H),4.09(s,3H),3.87(s,3H),2.42(s,3H).

[0206] LC-MS m / z(ESI) = 482.20 [M+1].

[0207] Example 9

[0208] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "1-hydroxycyclopropane-1-carboxylic acid" yielded compound 9 (white solid, 6 mg, yield 6%).

[0209] 1 H NMR(400MHz,DMSO)δ8.53(s,1H),8.44–8.42(m,1H),8.17(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.51-7.47(m,1H),7.37- 7.32(m,1H),7.16-7.12(m,1H),7.00(s,1H),4.09(s,3H),3.87(s,3H),2.40(s,3H),1.40–1.36(m,2H),1.25-1.23(m,2H).

[0210] LC-MS m / z(ESI) = 482.20 [M+1].

[0211] Example 10

[0212] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(S)-2,2-difluorocyclopropane-1-carboxylic acid" yielded compound 10 (white solid, 14 mg, yield 16%).

[0213] 1H NMR(400MHz,DMSO)δ8.54(s,1H),8.50-8.46(m,1H),8.18(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.53-7.49(m,1H) ,7.39-7.34(m,1H),7.17-7.12(m,1H),4.09(s,3H),3.87(s,3H),3.73-3.62(m,1H),2.41(s,3H),2.39–2.30(m,2H).

[0214] LC-MS m / z (ESI) = 502.18 [M+1].

[0215] Example 11

[0216] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(R)-oxecyclobutane-2-carboxylic acid" yielded compound 11 (yellow solid, 25 mg, yield 30%).

[0217] 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.51-8.47(m,1H),8.18(s,1H),8.07–8.03(m,2H),7.82(s,1H),7.58-7.53(m,1H),7.40-7.35(m,1H) ,7.17-7.13(m,1H),6.01-5.95(m,1H),4.78–4.71(m,2H),4.10(s,3H),3.87(s,3H),3.20-3.11(m,1H),3.05–2.96(m,1H),2.42(s,3H).

[0218] LC-MS m / z(ESI) = 482.20 [M+1].

[0219] Example 12

[0220] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(S)-oxetane-2-carboxylic acid" yielded compound 12 (yellow solid, 37 mg, yield 45%).

[0221] 1H NMR(400MHz,DMSO)δ8.54(s,1H),8.51-8.48(m,1H),8.18(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.58-7.53(m,1H),7.40-7.36(m,1H),7 .16-7.13(m,H),6.01-5.95(m,1H),4.79-4.70(m,2H),4.10(s,3H),3.87(s,3H),3.21–3.12(m,1H),3.04-2.95(m,1H),2.42(s,3H).LC-MS m / z(ESI)=482.20[M+1].

[0222] Example 13

[0223] According to the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "3-methoxybicyclo[1.1.1]pentane-1-carboxylic acid" yielded compound 13 (white solid, 45 mg, yield 51%).

[0224] 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.46-8.41(m,1H),8.17(s,1H),8.08–8.02(m,2H),7.82(s,1H),7.54-7. 49(m,1H),7.39-7.32(d,1H),7.17–7.12(m,1H),4.09(s,3H),3.87(s,3H),3.28(s,3H),2.43-2.38(m,9H).

[0225] LC-MS m / z(ESI) = 522.23 [M+1].

[0226] Example 14

[0227] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "3-fluorocyclobutane-1-carboxylic acid" yielded compound 14 (yellow solid, 45 mg, yield 54%).

[0228] 1H NMR (400MHz, DMSO) δ8.53(s,1H),8.50-8.47(m,1H),8.17(s,1H),8.07–8.03(m,2H),7.82(s,1H),7.55-7.50(m,1H),7.38-7. 34(m,1H),7.17-7.12(m,1H),5.49–5.25(m,1H),4.09(s,3H),3.97-3.90(m,1H),3.87(s,3H),2.81–2.72(m,4H),2.41(s,3H).

[0229] LC-MS m / z(ESI) = 498.21 [M+1].

[0230] Example 15

[0231] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid" yielded compound 15 (white solid, 30 mg, yield 35%).

[0232] 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.42(s,1H),8.15(s,1H),8.10–8.01(m,2H),7.82(s,1H),7.52-7.44(m,1H),7.39-7.32(m,1H),7.17-7 .10(m,1H),4.09(s,3H),3.95(d,J=8.8Hz,2H),3.87(s,3H),3.71(d,J=8.5Hz,2H),2.40(s,3H),2.17(t,J=3.2Hz,1H),1.29-1.15(m,2H).

[0233] LC-MS m / z (ESI) = 508.21 [M+1].

[0234] Example 16

[0235] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(1R,5S,6S)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid" yielded compound 16 (white solid, 40 mg, yield 47%).

[0236] 1H NMR (400MHz, DMSO) δ8.52(s,1H),8.44-8.40(m,1H),8.16(s,1H),8.06–8.03(m,2H),7.82(s,1H),7.51-7.46(m,1H),7.37-7.32(m,1H),7. 16-7.13(m,1H),4.09(s,3H),3.96(d,J=8.8Hz,2H),3.87(s,3H),3.71(d,J=8.5Hz,2H),2.40(m,3H),2.19-2.16(m,1H),1.33–1.04(m,2H).

[0237] LC-MS m / z (ESI) = 508.21 [M+1].

[0238] Example 17

[0239] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(R)-2-(tetrahydrofuran-3-yl)acetic acid" yielded compound 17 (white solid, 30 mg, yield 35%).

[0240] 1 H NMR (400MHz, DMSO) δ8.53 (s, 1H), 8.49 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 6.8Hz ,2H),7.82(s,1H),7.54-7.50(m,1H),7.38-7.33(m,1H),7.15(s,1H),4.09( s,3H),3.90-3.84(m,4H),3.81-3.62(m,2H),3.47–3.40(m,1H),3.17-3.06( m,2H),2.74-2.63(m,1H),2.41(s,3H),2.10-1.95(m,1H),1.73–1.58(m,1H).

[0241] LC-MS m / z(ESI) = 510.23 [M+1].

[0242] Example 18

[0243] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(S)-spiro[2.2]pentane-1-carboxylic acid" to obtain compound 18 (pale red solid, 22 mg, yield 26%).

[0244] 1H NMR (400MHz, DMSO) δ8.52(s,1H),8.43(s,1H),8.15(s,1H),8.06-8.01(m,2H),7.82(s,1H),7.53-7.45(m,1H),7.39-7.30( m,1H),7.17-7.11(m,1H),4.09(s,3H),3.87(s,3H),2.40(s,3H),1.67-1.61(m,1H),1.32-1.16(m,2H),1.10–0.83(m,4H).

[0245] LC-MS m / z(ESI) = 492.21 [M+1].

[0246] Example 19

[0247] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(S)-2-(tetrahydrofuran-3-yl)acetic acid" yielded compound 19 (yellow solid, 23 mg, yield 27%).

[0248] 1 H NMR (400MHz, DMSO) δ8.53(s,1H),8.49(s,1H),8.16(s,1H),8.07–8.02(m,2H),7. 82(s,1H),7.54-7.49(m,1H),7.39-7.32(m,1H),7.17–7.13(m,1H),4.09(s,3H),3 .90-3.84(m,4H),3.81-3.73(m,1H),3.70-3.62(m,1H),3.47-3.40(m,1H),3.18–3 .06(m,2H),2.74-2.64(m,1H),2.41(s,3H),2.14–2.04(m,1H),1.70-1.59(m,1H).

[0249] LC-MS m / z(ESI) = 510.23 [M+1].

[0250] Example 20

[0251] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(R)-spiro[2.2]pentane-1-carboxylic acid" to obtain compound 20 (white solid, 15 mg, yield 18%).

[0252] 1H NMR (400MHz, DMSO) δ8.52(s,1H),8.43(s,1H),8.15(s,1H),8.06-8.02(m,2H),7.82(s,1H),7.51-7.47(m,1H),7.39-7.31( m,1H),7.16-7.12(m,1H),4.09(s,3H),3.87(s,3H),2.40(s,3H),1.66-1.61(m,1H),1.23-1.19(m,2H),1.05–0.82(m,4H).

[0253] LC-MS m / z(ESI) = 492.22 [M+1].

[0254] Example 21

[0255] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "2-cyclopropyl-2,2-difluoroacetic acid" yielded compound 21 (white solid, 30 mg, yield 34%).

[0256] 1 H NMR (400MHz, DMSO) δ8.60–8.55(m,2H),8.21(s,1H),8.08–8.01(m,2H),7.82(s,1H),7.59-7.53(m,1H),7.44-7.37(m,1 H),7.17-7.12(m,1H),4.10(s,3H),3.87(s,3H),2.44(s,3H),2.04–1.94(m,1H),1.26-1.19(m,2H),0.86-0.81(m,2H).

[0257] LC-MS m / z(ESI) = 516.20 [M+1].

[0258] Example 22

[0259] first step

[0260] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethanol-1-ol” yielded compound 22-1 (brown solid, 285 mg, yield 43%).

[0261] LC-MS m / z(ESI) = 298.15 [M+1].

[0262] Step 2

[0263] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 22-1" yielded compound 22-2 (yellow solid, 185 mg, yield 42%).

[0264] LC-MS m / z(ESI) = 413.20 [M+1].

[0265] Step 3

[0266] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 22-2" yielded compound 22-3 (white solid, 110 mg, yield 63%).

[0267] LC-MS m / z(ESI) = 460.21 [M+1].

[0268] Step 4

[0269] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 22-3 to obtain compound 22 (white solid, 20 mg, yield 25%).

[0270] 1 H NMR (400MHz, DMSO) δ8.58(s,1H),8.50-8.46(m,1H),8.20(s,1H),8.11–8.01(m,2H),7.84(s,1H),7.53-7.48(m,1H),7.41-7.33( m,1H),7.17-7.12(m,1H),5.10-4.95(m,1H),4.12(s,3H),3.93–3.80(m,2H),3.63–3.20(m,4H),2.43(s,3H),1.51-1.30(m,2H).

[0271] LC-MS m / z(ESI) = 514.20 [M+1].

[0272] Example 23

[0273] first step

[0274] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "5-bromo-2-fluoro-4-methylbenzonitrile" yielded compound 23-1 (yellow solid, 165 mg, yield 45%).

[0275] LC-MS m / z(ESI) = 401.18 [M+1].

[0276] Step 2

[0277] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 23-1" yields compound 23-2 (brown solid, 155 mg, 70% yield).

[0278] LC-MS m / z(ESI) = 434.20 [M+1].

[0279] Step 3

[0280] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 23-2 to obtain compound 23 (yellow solid, 35 mg, yield 30%).

[0281] 1 H NMR (400MHz, DMSO) δ8.54(s,1H),8.50-8.46(m,1H),8.10–8.02(m,2H),7.84(s,1H),7.58-7.49(m,1H),7.41-7.32(m, 1H),7.18-7.11(m,1H),6.0-6.45(m,1H),4.09(s,3H),3.86(s,3H),3.22–3.17(m,1H),2.38(s,3H),1.48-1.32(m,2H).

[0282] LC-MS m / z(ESI) = 502.20 [M+1].

[0283] Example 24

[0284] first step

[0285] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "3-bromo-4-chlorobenzonitrile" yielded compound 24-1 (yellow solid, 150 mg, yield 43%).

[0286] LC-MS m / z(ESI) = 403.11 [M+1].

[0287] Step 2

[0288] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 24-1" yields compound 24-2 (yellow solid, 80 mg, yield 44%).

[0289] LC-MS m / z(ESI) = 436.15 [M+1].

[0290] Step 3

[0291] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 24-2 to obtain compound 24 (white solid, 20 mg, yield 15%).

[0292] 1 H NMR (400MHz, DMSO) δ8.55(s,1H),8.51-8.45(m,1H),8.19(s,1H),8.10–8.01(m,2H),7.83(s,1H),7.58-7.50(m,1H),7. 43-7.30(m,1H),7.16-7.11(m,1H),6.52-6.46(m,1H),4.10(s,3H),3.87(s,3H),3.22–3.17(m,1H),1.47-1.33(m,2H).

[0293] LC-MS m / z (ESI) = 504.15 [M+1].

[0294] Example 25

[0295] first step

[0296] Intermediate D (80 mg, 0.299 mmol) was dissolved in DMF (10 mL), and compound 1-1 (83 mg, 0.329 mmol) and cesium carbonate (68.1 mg, 0.075 mmol) were added, followed by Brettphos (292 mg, 3 mmol) and Brettphos-Pd-G3 (40 mg, 0.075 mmol). Nitrogen gas was then introduced. The resulting mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the reaction was quenched with water, extracted three times with EA, and the solvent was removed by rotary evaporation. The resulting organic phase was purified by silica gel column chromatography (dichloromethane / methanol = 100:1–50:1). The solvent was removed by rotary evaporation to give compound 25 (yellow solid, 55 mg, yield 42%).

[0297] 1H NMR(400MHz,DMSO)δ8.43(s,1H),8.31(d,1H),8.13–8.02(m,4H),7.82(s,1H),7.36(dd,1H),7.23(d,1 H),7.13(d,1H),4.05(d,3H),3.86(d,3H),2.82(tq,1H),2.34(s,3H),0.66(td,2H),0.58–0.51(m,2H).

[0298] LC-MS m / z(ESI) = 441.27 [M+1].

[0299] Example 26

[0300] first step

[0301] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "bicyclo[1.1.1]pentane-1-carboxylic acid" yielded compound 26 (pale purple solid, 30 mg, yield 36%).

[0302] 1 H NMR (400MHz, DMSO)8.52(s,1H),8.43(d,1H),8.16(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.51(d d,1H),7.35(d,1H),7.14(d,1H),4.09(s,3H),3.87(s,3H),2.61(s,1H),2.40(s,3H),2.32(s,6H).

[0303] LC-MS m / z(ESI) = 492.20 [M+1].

[0304] Example 27

[0305] According to the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid" yielded compound 27 (pale purple solid, 30 mg, yield 36%).

[0306] 1H NMR (400MHz, DMSO)8.52(s,1H),8.45(d,1H),8.17(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.51( dd,1H),7.36(d,1H),7.14(d,1H),4.09(s,3H),3.87(s,3H),2.66(d,J=2.3Hz,6H),2.40(s,3H).

[0307] LC-MS m / z(ESI) = 510.32 [M+1].

[0308] Example 28

[0309] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "1-(methanesulfonyl)azacyclobutane-3-carboxylic acid" yielded compound 28 (white solid, 26 mg, yield 28%).

[0310] 1 H NMR (400MHz, DMSO)8.55–8.52(m,2H),8.17(s,1H),8.07–8.03(m,2H),7.82(s,1H),7.55(dd,1H),7.38(d ,1H),7.15(d,1H),4.34–4.28(m,3H),4.21(dd,2H),4.09(d,3H),3.87(s,3H),3.10(s,3H),2.42(s,3H).

[0311] LC-MS m / z (ESI) = 559.25 [M+1].

[0312] Example 29

[0313] According to the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid" yielded compound 29 (grayish-white solid, 50 mg, yield 57%).

[0314] 1 H NMR(400MHz,DMSO)8.52(s,1H),8.45(s,1H),8.16(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.5 3–7.48(m,1H),7.35(d,1H),7.14(d,1H),4.09(s,3H),3.87(s,3H),2.81(s,6H),2.40(s,3H).

[0315] LC-MS m / z (ESI) = 517.25 [M+1].

[0316] Example 30

[0317] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(R)-tetrahydrofuran-3-carboxylic acid" yielded compound 30 (a grayish-white solid, 40 mg, yield 48%).

[0318] 1 H NMR (400MHz, DMSO)8.52(s,1H),8.45(s,1H),8.16(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.53–7.48(m ,1H),7.35(d,1H),7.14(d,1H),4.09(s,3H),3.87(s,3H),3.33–3.26(m,1H),2.81(s,6H),2.40(s,3H).

[0319] LC-MS m / z(ESI) = 496.20 [M+1].

[0320] Example 31

[0321] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "thiophene-3-carboxylic acid 1,1-dioxide" yielded compound 31 (a grayish-white solid, 26 mg, yield 29%).

[0322] 1 H NMR (400MHz, DMSO)8.57–8.51(m,2H),8.18(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.55(dd,1H),7.3 7(d,1H),7.14(d,1H),6.26(s,1H),5.85(s,1H),4.09(s,3H),3.87(s,3H),2.41(s,3H),2.21(s,3H).

[0323] LC-MS m / z(ESI) = 530.1 [M+1].

[0324] Example 32

[0325] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "3-chlorobicyclo[1.1.1]pentane-1-carboxylic acid" to obtain compound 32 (white solid, 55 mg, yield 62%).

[0326] 1 H NMR (400MHz, DMSO)8.52(s,1H),8.45(d,1H),8.16(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.50(d d,1H),7.35(d,1H),7.14(d,1H),4.09(d,3H),3.87(s,3H),2.73(s,6H),2.46(d,2H),2.39(d,3H).

[0327] LC-MS m / z (ESI) = 526.1 [M+1].

[0328] Example 33

[0329] first step

[0330] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" yielded compound 33a (yellow solid, 370 mg, yield 69%).

[0331] LC-MS m / z(ESI) = 294.14 [M+1].

[0332] Step 2

[0333] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 33a" yielded compound 33b (yellow solid, 142 mg, yield 27%).

[0334] LC-MS m / z (ESI) = 409.18 [M+1].

[0335] Step 3

[0336] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 33b" yielded compound 33c (brown solid, 99 mg, yield 64%).

[0337] LC-MS m / z(ESI) = 442.20 [M+1].

[0338] Step 4

[0339] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 33c to obtain compound 33 (white solid, 18 mg, yield 15%).

[0340] 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.44-8.41(m,1H),8.17-8.14(m,2H),8.08-8. 05(m,1H),7.82(s,1H),7.49-7.45(m,1H),7.37-7.33(m,1H),7.17-7.13(m,1H) ,5.37–5.18(m,1H),4.09(s,3H),3.76-3.70(m,1H),3.08–2.97(m,1H),2.40(s, 3H),1.97–1.85(m,1H),1.62-1.51(m,1H),1.08-1.05(m,2H),1.01–0.97(m,2H).

[0341] LC-MS m / z(ESI) = 510.21 [M+1].

[0342] Example 34

[0343] first step

[0344] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 34a (yellow solid, 322 mg, yield 71%).

[0345] LC-MS m / z(ESI) = 338.17 [M+1].

[0346] Step 2

[0347] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 34a" yielded compound 34b (yellow solid, 205 mg, yield 47%).

[0348] LC-MS m / z(ESI) = 453.21 [M+1].

[0349] Step 3

[0350] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 34b" yielded compound 34c (brown solid, 170 mg, yield 77%).

[0351] LC-MS m / z(ESI) = 486.23 [M+1].

[0352] Step 4

[0353] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 34c to obtain compound 34 (white solid, 36 mg, yield 31%).

[0354] 1 H NMR(400MHz,DMSO)δ8.53(s,1H),8.45-8.40(m,1H),8.20-8.14(m,2H),8.09-8. 04(m,1H),7.86(s,1H),7.51–7.46(m,1H),7.38-7.32(m,1H),7.19-7.14(m,1H) ,5.38–5.17(m,1H),4.45–4.36(m,1H),4.10(s,3H),4.02–3.93(m,2H),3.54-3. 42(m,2H),3.08-2.97(m,1H),2.40(s,3H),2.05-1.88(m,5H),1.61-1.51(m,1H).

[0355] LC-MS m / z(ESI) = 554.23 [M+1].

[0356] Example 35

[0357] first step

[0358] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 35-a (yellow solid, 180 mg, yield 62%).

[0359] LC-MS m / z(ESI) = 296.15 [M+1].

[0360] Step 2

[0361] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 35a" yielded compound 35-b (yellow solid, 157 mg, yield 62%).

[0362] LC-MS m / z(ESI) = 411.20 [M+1].

[0363] Step 3

[0364] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 35b" yielded compound 35-c (yellow solid, 102 mg, yield 57%).

[0365] LC-MS m / z(ESI) = 444.22 [M+1].

[0366] Step 4

[0367] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 35c to obtain compound 35 (yellow solid, 30 mg, yield 33%).

[0368] 1 H NMR (400MHz, DMSO) δ

[0369] LC-MS m / z(ESI) = 512.22 [M+1].

[0370] Example 36

[0371] first step

[0372] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "pinacol methylborate" yielded compound 36a (yellow solid, 146 mg, yield 48%).

[0373] LC-MS m / z(ESI) = 202.10[M+1].

[0374] Step 2

[0375] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 36a" yielded compound 36b (yellow solid, 132 mg, yield 57%).

[0376] LC-MS m / z(ESI) = 317.14 [M+1].

[0377] Step 3

[0378] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 36b" yielded compound 36c (gray solid, 100 mg, yield 75%).

[0379] LC-MS m / z (ESI) = 350.17 [M+1].

[0380] Step 4

[0381] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 36c to obtain compound 36 (yellow solid, 6 mg, yield 5%).

[0382] 1 H NMR (400MHz, DMSO) δ8.48(s,1H),8.42-8.38(m,1H),8.13(s,1H),7.63(s,1H),7.49-7.44(m,1H),7.36-7.31(m,1H),6.76( s,1H),5.38–5.16(m,1H),4.04(s,3H),3.07–2.96(m,1H),2.39(s,3H),2.29(s,3H),1.98–1.86(m,1H),1.58–1.53(m,1H).

[0383] LC-MS m / z(ESI) = 418.17 [M+1].

[0384] Example 37

[0385] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "(R)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole" to obtain compound 37 (yellow solid, 52 mg, yield 30%).

[0386] 1H NMR(400MHz,DMSO)δ8.54(s,1H),8.27(s,1H),8.09–8.02(m,3H),7.84(s, 1H),7.32–7.22(m,2H),7.17-7.14(m,1H),4.99-4.92(m,1H),4.54-4.45( m,1H),4.20-4.14(m,2H),4.11(s,3H),3.97-3.88(m,1H),3.81-3.73(m,2 H),3.32-3.25(m,2H),2.76-2.67(m,1H),2.36(s,3H),1.27-1.24(m,3H).

[0387] LC-MS m / z(ESI) = 509.24 [M+1].

[0388] Example 38

[0389] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "(S)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole". The reaction yielded compound 22-1 and compound 38 (yellow solid, 60 mg, yield 34%).

[0390] 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.29–8.25(m,1H),8.08–8.03(m,3H),7.8 4(s,1H),7.32–7.22(m,2H),7.17-7.14(m,1H),4.98-4.93(m,1H),4.54-4. 47(m,1H),4.19-4.13(m,2H),4.11(s,3H),3.95-3.89(m,1H),3.80-3.74(m ,2H),3.32-3.25(m,2H),2.77–2.66(m,1H),2.36(s,3H),1.27-1.24(m,3H).

[0391] LC-MS m / z(ESI) = 509.24 [M+1].

[0392] Example 39

[0393] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "compound 2-3", and the reaction yielded compound 39 (yellow solid, 3 mg, yield 2%).

[0394] 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.25(s,1H),8.07–8.01(m,3H),7.83(s,1H),7.30–7.22(m,2H),7.15-7.12(m,1H),4.98-4.90( m,1H),4.34-4.29(m,2H),4.18-4.12(m,2H),4.09(s,3H),3.78-3.73(m,2H),3.11-3.06(m,2H),2.82–2.75(m,2H),2.35(s,3H).

[0395] LC-MS m / z(ESI) = 495.23 [M+1].

[0396] Example 40

[0397] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methanesulfonyl)azacyclobutane-3-carboxylic acid" and reacted with compounds 22-3 to give compound 40 (red solid, 29 mg, yield 41%).

[0398] 1 H NMR (400MHz, DMSO) δ8.55-8.50(m,2H),8.17(s,1H),8.07(s,2H),7.84(s,1H),7.58-7.52(m,1H),7.40-7.35(m,1H),7.17( s,1H),4.97-4.91(m,1H),4.34-4.29(m,2H),4.23-4.12(m,5H),4.10(s,3H),3.79-3.74(m,2H),3.10(s,3H),2.42(s,3H).

[0399] LC-MS m / z (ESI) = 589.20 [M+1].

[0400] Example 41

[0401] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(1r,3r)-3-methoxycyclobutane-1-carboxylic acid" yielded compound 41 (white solid, 38 mg, yield 44%).

[0402] 1 H NMR (400MHz, DMSO) δ8.54(s,1H),8.51–8.48(m,1H),8.17(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.56-7.52(m,1H),7.38-7.34(m,1H),7.16– 7.12(m,1H),4.23–4.14(m,1H),4.10(s,3H),3.87(s,3H),3.82-3.74( m,1H),3.40(s,3H),2.65–2.57(m,2H),2.48-2.43(m,2H),2.41(s,3H).

[0403] LC-MS m / z(ESI) = 510.23 [M+1].

[0404] Example 42

[0405] first step

[0406] Compound 2-1 (5.0 g, 16.89 mmol), ethoxypropynyl ether (2.0 g, 20.00 mmol), palladium dichloride (701.0 mg, 1.00 mmol), cuprous iodide (190.0 mg, 1.00 mmol), and triethylamine (10.1 g, 100.00 mmol) were dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, the mixture was reacted at room temperature for 4 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 42-1 as a yellow solid, 2.1 g, yield 40%.

[0407] LC-MS m / z(ESI) = 269.01 [M+1].

[0408] Step 2

[0409] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 42-1" yielded compound 42-2 (yellow solid, 1.1 g, yield 81%). LC-MS m / z (ESI) = 294.02 [M+1].

[0410] Step 3

[0411] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "compound 42-2" to obtain compound 42 (yellow solid, 70 mg, yield 67%).

[0412] 1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.14(s,1H),8.05(dd,3H),7.82(s,1H),7.29–7.19(m,2 H),7.14(d,1H),5.18(s,2H),4.49–4.41(m,2H),4.16–4.07(m,5H),3.87(s,3H),2.37(s,3H).

[0413] LC-MS m / z(ESI) = 481.21 [M+1].

[0414] Example 43

[0415] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "1-methoxycyclopropane-1-carboxylic acid" yielded compound 43 (pale pink solid, 30 mg, yield 39%).

[0416] 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.49(d,1H),8.18(s,1H),8.07–8.03(m,2H),7.82(s,1H),7.51(dd, 1H),7.36(d,1H),7.14(d,1H),4.09(s,3H),3.87(s,3H),3.47(s,3H),2.41(s,3H),1.54–1.41(m,4H).

[0417] LC-MS m / z(ESI) = 496.23 [M+1].

[0418] Example 44

[0419] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "2-cyclopropoxyacetic acid" yielded compound 44 (pale yellow solid, 35 mg, yield 42%).

[0420] 1 H NMR (400MHz, DMSO) δ8.53(s,1H),8.48(s,1H),8.17(s,1H),8.08–8.02(m,2H),7.82(s,1H),7.54(t,1H),7.38(d,1 H),7.15(d,1H),4.87(s,2H),4.10(s,3H),3.87(s,3H),3.59–3.54(m,1H),2.42(s,3H),1.22(s,2H),0.58(dt,2H).

[0421] LC-MS m / z(ESI) = 496.23 [M+1].

[0422] Example 45

[0423] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(1s,3s)-3-fluorocyclobutane-1-carboxylic acid" yielded compound 45 (white solid, 25 mg, 30% yield).

[0424] 1 H NMR(400MHz,DMSO)δ8.53(d,1H),8.48(d,1H),8.17(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.53(dd,1H),7.36(d,1H) ,7.14(d,1H),5.14(dp,1H),4.09(s,3H),3.87(s,3H),3.43(ddd,1H),2.88(ttd,2H),2.63–2.53(m,2H),2.41(s,3H).

[0425] LC-MS m / z(ESI) = 498.3 [M+1].

[0426] Example 46

[0427] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(S)-tetrahydrofuran-3-carboxylic acid" yielded compound 46 (yellow solid, 45 mg, yield 54%).

[0428] 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.49(d,1H),8.17(s,1H),8.08–8.02(m,2H),7.83(s,1H),7.53(dd,1H) ,7.37(d,1H),7.15(d,1H),5.29(dd,1H),4.10(s,3H),3.98–3.87(m,5H),2.41(d,3H),2.29–1.94(m,4H).

[0429] LC-MS m / z(ESI) = 496.24 [M+1].

[0430] Example 47

[0431] first step

[0432] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethyl)morpholine” yielded compound 47a (yellow solid, 271 mg, yield 77%).

[0433] LC-MS m / z(ESI) = 367.19 [M+1].

[0434] Step 2

[0435] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 47a" yielded compound 47b (yellow solid, 241 mg, yield 66%).

[0436] LC-MS m / z(ESI) = 482.23 [M+1].

[0437] Step 3

[0438] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 47b" yielded compound 47c (yellow solid, 191 mg, yield 76%).

[0439] LC-MS m / z(ESI) = 514.26 [M+1].

[0440] Step 4

[0441] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "2-cyclopropyl-2,2-difluoroacetic acid" and reacted with compound 47c to obtain compound 47 (white solid, 12 mg, yield 51%).

[0442] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.43(s,1H),8.16(s,1H),8.10–8.05(m,2H),7.83(s,1H),7.48(dd,1H),7.37(dd,1H),7.14(d,1H),5.37-5. 18(m,1H),4.25(t,2H),4.10(s,3H),3.56(t,4H),3.08-2.99(m,1H),2.7 5(t,2H),2.43(d,4H),2.40(s,3H),1.98-1.87(m,1H),1.61-1.53(m,1H).

[0443] LC-MS m / z(ESI) = 583.26 [M+1].

[0444] Example 48

[0445] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "(1s,3s)-3-methoxycyclobutane-1-carboxylic acid" yielded compound 48 (white solid, 30 mg, yield 35%).

[0446] 1 H NMR (400MHz, DMSO) δ8.53(s,1H),8.47(d,1H),8.17(s,1H),8.07–8.02(m,2H),7.83(s,1H),7.54(dd,1H),7.39–7.34(m,1H),7.15( d,1H),4.10(s,3H),3.93(dd,1H),3.88(s,3H),3.50–3.40(m,1H),3.18(s,3H),2.80–2.69(m,2H),2.41(s,3H),2.29–2.19(m,2H).

[0447] LC-MS m / z(ESI) = 510.24 [M+1].

[0448] Example 49

[0449] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "2-(oxecyclobutane-3-yl)acetic acid" yielded compound 49 (a grayish-white solid, 30 mg, yield 36%).

[0450] 1 H NMR (400MHz, DMSO) δ8.53(s,1H),8.48(d,1H),8.15(s,1H),8.07–8.02(m,2H),7.82(s,1H),7.50(dd,1H),7.35(d ,1H),7.15(d,1H),4.75(dd,2H),4.44(t,2H),4.10(s,3H),3.87(s,3H),3.49(dt,1H),3.39(d,2H),2.41(s,3H).

[0451] LC-MS m / z(ESI) = 496.23 [M+1].

[0452] Example 50

[0453] first step

[0454] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)prop-2-ol" yielded compound 50a (yellow solid, 311 mg, yield 73%).

[0455] LC-MS m / z(ESI) = 326.17 [M+1].

[0456] Step 2

[0457] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 50a" yielded compound 50b (yellow solid, 298 mg, yield 69%).

[0458] LC-MS m / z(ESI) = 441.20 [M+1].

[0459] Step 3

[0460] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 50b" yielded compound 50c (yellow solid, 243 mg, yield 78%).

[0461] LC-MS m / z(ESI) = 474.23 [M+1].

[0462] Step 4

[0463] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 50c to obtain compound 50 (white solid, 47 mg, yield 68%).

[0464] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.43(d,1H),8.20(s,1H),8.08(dd,1H),8.03(s,1H),7.83(s,1H),7.48(dd,1H),7.35(t,1H),7.17(d,1H) ,5.37-5.18(m,1H),4.78(s,1H),4.09(s,3H),4.03(s,2H),3.09–2.99( m,1H),2.40(s,3H),1.98-1.87(m,1H),1.61-1.53(m,1H),1.10(s,6H). ＝

[0465] LC-MS m / z(ESI) = 542.24 [M+1].

[0466] Example 51

[0467] first step

[0468] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole" with "1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole" yielded compound 51a (yellow solid, 244 mg, yield 76%).

[0469] LC-MS m / z(ESI) = 282.14 [M+1].

[0470] Step 2

[0471] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 51a" yielded compound 51b (yellow solid, 267 mg, yield 77%).

[0472] LC-MS m / z(ESI) = 397.18 [M+1].

[0473] Step 3

[0474] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 51b" yielded compound 51c (yellow solid, 201 mg, yield 75%).

[0475] LC-MS m / z(ESI) = 430.20 [M+1].

[0476] Step 4

[0477] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 51c to obtain compound 51 (white solid, 57 mg, yield 73%).

[0478] 1H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.45(d,1H),8.16(s,1H),7.97–7.90(m,2H),7.48(dd,1H),7.35(d,1H),7.05(d,1H),5. 39–5.14(m,1H),4.10(s,3H),3.79(s,3H),3.10–2.97(m,1H),2.40(s,3H),2.36(s,3H),2.00–1.93(m,1H),1.59-1.53(m,1H).

[0479] LC-MS m / z(ESI) = 498.21 [M+1].

[0480] Example 52

[0481] first step

[0482] Following the synthesis of compound 2-2, replacing "4-pentyn-1-ol" with "(S)-2-methylpent-4-yn-1-ol" yielded compound 52a (yellow solid, 2.5 g, 96% yield).

[0483] LC-MS m / z(ESI) = 267.03 [M+1].

[0484] Step 2

[0485] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 52a" yielded compound 52b (yellow solid, 2.1 g, 95% yield).

[0486] LC-MS m / z(ESI) = 292.04 [M+1].

[0487] Step 3

[0488] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "compound 52b" to obtain compound 52 (yellow solid, 66 mg, yield 72%).

[0489] 1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.28(d,1H),8.08–8.01(m,3H),7.82(s,1H),7.29(dd,1H),7.23(d,1H),7.14(d,1H), 4.50(dd,1H),4.10(s,3H),3.96–3.89(m,1H),3.87(s,3H),3.33–3.27(m,2H),2.75-2.66(m,1H),2.36(s,3H),1.26(d,3H).

[0490] LC-MS m / z(ESI) = 479.23 [M+1].

[0491] Example 53

[0492] first step

[0493] Following the synthesis of compound 2-2, replacing "4-pentyn-1-ol" with "(R)-2-methylpent-4-yn-1-ol" yielded compound 53a (yellow solid, 1.8 g, yield 89%).

[0494] LC-MS m / z(ESI) = 267.03 [M+1].

[0495] Step 2

[0496] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 53a" yielded compound 53b (yellow solid, 1.3 g, yield 88%).

[0497] LC-MS m / z(ESI) = 292.04 [M+1].

[0498] Step 3

[0499] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "compound 53b" to obtain compound 53 (yellow solid, 76 mg, yield 77%).

[0500] 1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.27(d,1H),8.09–8.04(m,3H),7.82(s,1H),7.29(dd,1H),7.23(d,1H),7.13(d,1H), 4.52(dd,1H),4.11(s,3H),3.97–3.88(m,1H),3.90(s,3H),3.36–3.25(m,2H),2.79-2.68(m,1H),2.35(s,3H),1.24(d,3H).

[0501] LC-MS m / z(ESI) = 479.23 [M+1].

[0502] Example 54

[0503] Following the synthesis of compound 3, replacing "3,3-difluorocyclobutane-1-carboxylic acid" with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" yielded compound 54 (white solid, 47 mg, yield 78%).

[0504] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.51(d,1H),8.17(s,1H),8.05(d,1H),8.04(s,1H),7.82(s,1H),7.55 (dd,1H),7.37(d,1H),7.15(d,1H),4.42–4.16(m,5H),4.10(s,3H),3.87(s,3H),3.60(s,3H),2.42(s,3H).

[0505] LC-MS m / z(ESI) = 539.22 [M+1].

[0506] Example 55

[0507] first step

[0508] Following the synthesis of compound 2-2, replacing "4-pentyn-1-ol" with "(S)-2-ethylpent-4-yn-1-ol" yielded compound 55a (yellow solid, 1.3 g, yield 84%).

[0509] LC-MS m / z(ESI) = 281.05 [M+1].

[0510] Step 2

[0511] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 55a" yielded compound 55b (yellow solid, 1.1 g, yield 89%).

[0512] LC-MS m / z (ESI) = 306.05 [M+1].

[0513] Step 3

[0514] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "compound 55b" to obtain compound 55 (yellow solid, 54 mg, yield 81%).

[0515] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.28(d,1H),8.04(dd,3H),7.81(s,1H),7.32(dd,1H),7.24(d,1H),7.14(d,1H),4.51(dd,1H ),4.11(s,3H),4.03–3.92(m,1H),3.87(s,3H),3.28–3.12(m,2H),2.79-2.73(m,1H),2.36(s,3H),1.69-1.61(m,2H),0.96(t,3H).

[0516] LC-MS m / z(ESI) = 493.25 [M+1].

[0517] Example 56

[0518] first step

[0519] Following the synthesis of compound 2-2, replacing "4-pentyn-1-ol" with "5-hexyn-1-ol" yielded compound 56a (yellow solid, 1.1 g, yield 88%).

[0520] LC-MS m / z(ESI) = 267.03 [M+1].

[0521] Step 2

[0522] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 56a" yielded compound 55b (yellow solid, 0.9 g, yield 86%).

[0523] LC-MS m / z(ESI) = 292.04 [M+1].

[0524] Step 3

[0525] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 56b" yielded compound 56 (yellow solid, 65 mg, yield 84%).

[0526] 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.28(d,1H),8.07–8.02(m,3H),7.82(s,1H),7.32(dd,1H),7.25(d,1H),7.1 3(d,1H),4.36(t,2H),4.08(s,3H),3.87(s,3H),3.04(t,2H),2.37(s,3H),2.05-1.99(m,2H),1.94-1.88(m,2H).

[0527] LC-MS m / z(ESI) = 479.23 [M+1].

[0528] Example 57

[0529] first step

[0530] Following the synthesis of compound 2-2, replacing "4-pentyn-1-ol" with "(R)-2-ethylpent-4-yn-1-ol" yielded compound 57a (yellow solid, 1.7 g, yield 56%).

[0531] LC-MS m / z(ESI) = 281.05 [M+1].

[0532] Step 2

[0533] Following the synthesis of compounds 2-3, replacing "compound 2-2" with "compound 57a" yielded compound 57b (yellow solid, 900 mg, yield 46%).

[0534] LC-MS m / z (ESI) = 306.05 [M+1].

[0535] Step 3

[0536] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 57b" yielded compound 57 (white solid, 40 mg, 50% yield).

[0537] 1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.28(s,1H),8.06–8.01(m,3H),7.81 (s,1H),7.35–7.28(m,2H),7.27–7.20(m,1H),7.15–7.13(m,1H),4.55–4. 49(m,1H),4.11(s,3H),4.01–3.95(m,1H),3.87(s,3H),3.21–3.14(m,1H) ,2.80–2.72(m,1H),2.36(s,3H),1.70–1.58(m,3H),0.96(t,J=7.4Hz,3H).

[0538] LC-MS m / z(ESI) = 493.25 [M+1].

[0539] Example 58

[0540] first step

[0541] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole” with “1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole” yielded compound 58a (yellow solid, 289 mg, yield 89%).

[0542] LC-MS m / z(ESI) = 271.14 [M+1].

[0543] Step 2

[0544] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 58a" yielded compound 58b (yellow solid, 281 mg, yield 73%).

[0545] LC-MS m / z (ESI) = 386.18 [M+1].

[0546] Step 3

[0547] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 58b" yielded compound 58c (yellow solid, 211 mg, yield 77%).

[0548] LC-MS m / z(ESI) = 419.20 [M+1].

[0549] Step 4

[0550] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 58c to give compound 58 (white solid, 101 mg, yield 71%).

[0551] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.44(d,1H),8.16(s,1H),8.09–8.02(m,2H),7.83(s,1H),7.49(dd,1H),7.35(d,1 H),7.15(d,1H),5.42–5.17(m,1H),4.10(s,3H),3.09–2.95(m,1H),2.41(s,3H),1.98-1.87(m,1H),1.61-1.53(m,1H).

[0552] LC-MS m / z(ESI) = 487.21 [M+1].

[0553] Example 59

[0554] first step

[0555] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole" with "1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole" yielded compound 59a (yellow solid, 331 mg, yield 87%).

[0556] LC-MS m / z(ESI) = 268.12 [M+1].

[0557] Step 2

[0558] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 59a" yielded compound 59b (yellow solid, 303 mg, yield 78%).

[0559] LC-MS m / z(ESI) = 383.18 [M+1].

[0560] Step 3

[0561] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 59b" yielded compound 59c (yellow solid, 277 mg, yield 79%).

[0562] LC-MS m / z(ESI) = 416.19 [M+1].

[0563] Step 4

[0564] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 59c to obtain compound 59 (white solid, 71 mg, yield 69%).

[0565] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.43(d,1H),8.18(s,1H),8.12(d,1H),7.71(d,1H),7.49(dd,1H),7.35(d,1H),7.20(d,1H) ,6.63(d,1H),5.37-5.19(m,1H),4.11(s,3H),3.88(s,3H),3.07-2.99(m,1H),2.41(s,3H),1.97-1.88(m,1H),1.60-1.54(m,1H).

[0566] LC-MS m / z(ESI) = 484.20 [M+1].

[0567] Example 60

[0568] first step

[0569] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole" with "5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isothiazole" yielded compound 60a (yellow solid, 308 mg, yield 87%).

[0570] LC-MS m / z(ESI) = 271.07 [M+1].

[0571] Step 2

[0572] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 60a to obtain compound 60b (yellow solid, 299 mg, yield 77%)".

[0573] LC-MS m / z(ESI) = 386.11 [M+1].

[0574] Step 3

[0575] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 60b" yielded compound 60c (yellow solid, 241 mg, yield 72%).

[0576] LC-MS m / z(ESI) = 419.13 [M+1].

[0577] Step 4

[0578] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 60c to give compound 60 (white solid, 55 mg, yield 71%).

[0579] 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.59–8.55(m,1H),8.50–8.40(m,2H),8.24(s,1H),7.75(d,1H),7.50(dd,1H),7. 41–7.32(m,2H),5.37-5.19(m,1H),4.12(s,3H),3.11–2.96(m,1H),2.41(s,3H),1.97-1.88(m,1H),1.61-1.53(m,1H).

[0580] LC-MS m / z(ESI) = 487.14 [M+1].

[0581] Example 61

[0582] first step

[0583] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "1-isopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" yielded compound 61a (yellow solid, 381 mg, yield 89%).

[0584] LC-MS m / z(ESI) = 324.19 [M+1].

[0585] Step 2

[0586] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 61a" to obtain compound 61b (yellow solid, 377 mg, yield 76%).

[0587] LC-MS m / z(ESI) = 439.23 [M+1].

[0588] Step 3

[0589] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 61b" yielded compound 61c (yellow solid, 359 mg, yield 74%).

[0590] LC-MS m / z(ESI) = 472.25 [M+1].

[0591] Step 4

[0592] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 61c to obtain compound 61 (white solid, 68 mg, yield 74%).

[0593] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.43(d,1H),8.16(s,1H),8.10(s,1H), 8.06(d,1H),7.83(s,1H),7.49(dd,1H),7.35(d,1H),7.16(d,1H),5.28(dt,J 1H),4.14(t,2H),4.10(s,3H),3.12–2.97(m,1H),2.41(s,3H),1.97-1.87(m,1H),1.71(q,2H),1.59-1.50(m,2H),0.93(d,6H).

[0594] LC-MS m / z (ESI) = 540.26 [M+1].

[0595] Example 62

[0596] first step

[0597] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(trifluoromethyl)-1H-pyrazole" yielded compound 62a (yellow solid, 1.19 g, 98% yield).

[0598] LC-MS m / z(ESI) = 322.19 [M+1].

[0599] Step 2

[0600] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 62a" yielded compound 62b (yellowish-brown solid, 600 mg, yield 38%).

[0601] LC-MS m / z(ESI) = 437.16 [M+1].

[0602] Step 3

[0603] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 62b" yielded compound 62c (pale yellow solid, 250 mg, 95% yield).

[0604] LC-MS m / z(ESI) = 470.15 [M+1].

[0605] Step 4

[0606] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 62c to obtain compound 62 (pale green solid, 100 mg, yield 58%).

[0607] 1 H NMR(400MHz,DMSO-d6)δ8.88(d,1H),8.59(s,1H),8.48–8.41(m,2H),8.27(d,1H),8.19(s,1H),7.49(dd,1H),7 .39–7.32(m,2H),5.40–5.15(m,1H),4.08(d,3H),3.10–2.97(m,1H),2.40(s,3H),1.92(dd,1H),1.57(dq,1H).

[0608] LC-MS m / z(ESI) = 538.20 [M+1].

[0609] Example 63

[0610] first step

[0611] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "5-bromo-6-methylnicotinamide" and reacted with compound 1-1 to give compound 63a (white solid, 130 mg, yield 52%).

[0612] LC-MS m / z(ESI) = 384.21 [M+1].

[0613] Step 2

[0614] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 63a" yielded compound 63b (white solid, 90 mg, yield 63%).

[0615] LC-MS m / z(ESI) = 417.16 [M+1].

[0616] Step 3

[0617] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 63b to obtain compound 63 (pale yellow solid, 20 mg, yield 19%).

[0618] 1 H NMR(400MHz,DMSO-d6)δ8.84(d,1H),8.64(s,1H),8.58(d,1H),8.38(d,1H),8.10–8.02(m,2H),7.83(s,1H),7.17(d ,1H),5.42–5.20(m,1H),4.14(d,3H),3.87(s,3H),3.14–3.02(m,1H),2.66(s,3H),1.95(dd,1H),1.66–1.55(m,1H).

[0619] LC-MS m / z(ESI) = 485.20 [M+1].

[0620] Example 64

[0621] first step

[0622] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine" yielded compound 64a (brown solid, 470 mg, yield 98%).

[0623] LC-MS m / z(ESI) = 265.19 [M+1].

[0624] Step 2

[0625] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 64a" yielded compound 64b (yellowish-brown solid, 295 mg, yield 41%).

[0626] LC-MS m / z (ESI) = 380.16 [M+1].

[0627] Step 3

[0628] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 64b" yielded compound 64c (gray solid, 206 mg, 70% yield).

[0629] LC-MS m / z(ESI) = 413.18 [M+1].

[0630] Step 4

[0631] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 64c to obtain compound 64 (yellow solid, 35 mg, yield 30%).

[0632] 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.60–8.54(m,3H),8.46(d,1H),8.20(s,1H),7.84(d,2H),7.58(d,1H),7.49(dd ,1H),7.35(d,1H),5.28(dd,1H),4.15(d,3H),3.09–2.97(m,1H),2.40(s,3H),2.01–1.85(m,1H),1.64–1.51(m,1H).

[0633] LC-MS m / z(ESI) = 482.11 [M+1].

[0634] Example 65

[0635] first step

[0636] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole” with “4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridazine” yielded compound 65a (brown solid, 120 mg, yield 25%).

[0637] LC-MS m / z(ESI) = 266.19 [M+1].

[0638] Step 2

[0639] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 65a" yields compound 65b (yellowish-brown solid, 65 mg, yield 32%).

[0640] LC-MS m / z(ESI) = 381.16 [M+1].

[0641] Step 3

[0642] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 65b" yielded compound 65c (yellow solid, 72 mg, 95% yield).

[0643] LC-MS m / z(ESI) = 414.17 [M+1].

[0644] Step 4

[0645] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 65c to obtain compound 65 (brown solid, 15 mg, yield 18%).

[0646] 1 H NMR(400MHz,DMSO-d6)δ9.77(d,1H),9.18(d,1H),8.79–8.70(m,2H),8.46(d,1H),8.30(s,1H),8.08(dd,1H),7.74(t,1H) ,7.49(dd,1H),7.36(t,1H),5.40–5.15(m,1H),4.16(d,3H),3.10–2.97(m,1H),2.43(d,3H),1.93(dd,1H),1.57(dq,1H).

[0647] LC-MS m / z(ESI) = 482.18 [M+1].

[0648] Example 66

[0649] first step

[0650] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-(trifluoromethyl)-1H-pyrazole" yielded compound 66a (yellow solid, 440 mg, yield 72%).

[0651] LC-MS m / z(ESI) = 336.12 [M+1].

[0652] Step 2

[0653] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 66a" yielded compound 66b (yellow solid, 200 mg, yield 34%).

[0654] LC-MS m / z(ESI) = 451.16 [M+1].

[0655] Step 3

[0656] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 66b" yielded compound 66c (gray solid, 206 mg, 95% yield).

[0657] LC-MS m / z(ESI) = 484.17 [M+1].

[0658] Step 4

[0659] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 66c to obtain compound 66 (white solid, 80 mg, yield 34%).

[0660] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.45(d,1H),8.29(s,1H),8.20(s,1H),7.89(s,1H),7.49(dd,1H),7.35(d,1H),7 .06(d,1H),5.27(dd,1H),4.08(s,3H),3.97(s,3H),3.11–2.96(m,1H),2.40(s,3H),1.92(dd,1H),1.64–1.50(m,1H).

[0661] LC-MS m / z (ESI) = 552.19 [M+1].

[0662] Example 67

[0663] first step

[0664] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiazole" yielded compound 67a (yellowish-brown solid, 170 mg, yield 34%).

[0665] LC-MS m / z(ESI) = 271.07 [M+1].

[0666] Step 2

[0667] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 67a" yielded compound 67b (yellow solid, 36 mg, yield 14%).

[0668] LC-MS m / z(ESI) = 386.11 [M+1].

[0669] Step 3

[0670] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 67b" yielded compound 67c (yellow solid, 30 mg, yield 77%).

[0671] LC-MS m / z(ESI) = 419.13 [M+1].

[0672] Step 4

[0673] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 67c to obtain compound 67 (white solid, 80 mg, yield 34%).

[0674] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.63(s,1H),8.45(s,1H),8.27(dd,3H),7.50(d,1H),7.36(dd,1H),7. 32(s,1H),5.39–5.15(m,1H),4.14(d,3H),3.11–2.96(m,1H),2.41(s,3H),1.99–1.87(m,1H),1.57(td,1H).

[0675] LC-MS m / z(ESI) = 487.14 [M+1].

[0676] Example 68

[0677] first step

[0678] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 68a (brown oily liquid, 581 mg, yield 98%).

[0679] LC-MS m / z(ESI) = 326.17 [M+1].

[0680] Step 2

[0681] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 68a" yielded compound 68b (yellowish-brown solid, 330 mg, yield 42%).

[0682] LC-MS m / z(ESI) = 441.21 [M+1].

[0683] Step 3

[0684] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 68b" yielded compound 68c (grayish-brown solid, 340 mg, yield 95%).

[0685] LC-MS m / z(ESI) = 474.23 [M+1].

[0686] Step 4

[0687] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 68b to give compound 68 (white solid, 80 mg, yield 34%).

[0688] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.44(d,1H),8.31(s,1H),8.18(s,1H) ,8.12(d,1H),7.92(s,1H),7.49(dd,1H),7.35(d,1H),7.23(d,1H),5.56(q, 1H),5.28(dd,1H),4.11(s,3H),3.46(dq,1H),3.31–3.21(m,1H),3.11–2.97 (m,1H),2.41(s,3H),1.93(dd,1H),1.64(d,3H),1.56(dt,1H),1.07(t,3H).

[0689] LC-MS m / z(ESI) = 542.23 [M+1].

[0690] Example 69

[0691] first step

[0692] 5-tert-Butoxycarbonylamino-3-oxavallic acid (437 mg, 1.99 mmol) was dissolved in tetrahydrofuran (20 mL), and propylphosphonic anhydride (2.5 g, 7.96 mmol) was added. The mixture was reacted at room temperature for 30 minutes. Then, 69a (500 mg, 2.19 mmol) and N,N-diisopropylethylamine (1.5 g, 11.94 mmol) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated brine (40 mL), extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 69b (yellow solid, 560 mg, yield 69%).

[0693] LC-MS m / z(ESI) = 430.09 [M+1].

[0694] Step 2

[0695] Compound 69b (560 mg, 1.36 mmol), p-toluenesulfonyl chloride (310 mg, 1.63 mmol), and triethylamine (412 mg, 4.08 mmol) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 4 h. After the reaction was complete, the crude product was obtained by vacuum distillation. The crude product was then subjected to column chromatography (dichloromethane:methanol = 50:1) to give compound 69c (yellow solid, 520 mg, yield 93%).

[0696] LC-MS m / z(ESI) = 412.08 [M+1].

[0697] Step 3

[0698] Compound 69c (390 mg, 1.25 mmol) and triethylamine (380 mg, 3.76 mmol) were dissolved in toluene (20 mL) and reacted at 110 °C for 4 h. After the reaction was complete, the crude product was obtained by vacuum distillation. The crude product was then subjected to column chromatography (dichloromethane:methanol = 60:1) to give compound 69d (yellow solid, 120 mg, yield 33%).

[0699] LC-MS m / z(ESI) = 294.01 [M+1].

[0700] Step 4

[0701] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 69d" yielded compound 69 (yellow solid, 35 mg, yield 77%).

[0702] 1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.31(d,1H),8.15(s,1H),8.08–8.02(m,2H),7.82(s,1H),7.38–7 .30(m,2H),7.14(d,1H),4.96(s,2H),4.24(t,2H),4.08(s,3H),4.04(t,2H),3.87(s,3H),2.42(s,3H).

[0703] LC-MS m / z(ESI) = 481.21 [M+1].

[0704] Example 70

[0705] first step

[0706] Referring to the synthesis of compound 69b, replacing "5-tert-butoxycarbonylamino-3-oxavaranic acid" with "4-(tert-butoxycarbonyl)amino)butyric acid" yielded compound 70a (yellow solid, 420 mg, yield 89%).

[0707] LC-MS m / z(ESI) = 413.10 [M+1].

[0708] Step 2

[0709] Following the synthesis of compound 69c, "compound 69b" was replaced with "compound 70a" to obtain compound 70b (yellow solid, 410 mg, yield 78%).

[0710] LC-MS m / z (ESI) = 395.09 [M+1].

[0711] Step 3

[0712] Following the synthesis of compound 69d, "compound 69c" was replaced with "compound 70b" to obtain compound 70c (yellow solid, 210 mg, yield 43%).

[0713] LC-MS m / z(ESI) = 278.02 [M+1].

[0714] Step 4

[0715] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 70c" yielded compound 70 (yellow solid, 38 mg, 75% yield).

[0716] 1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.43(s,1H),8.13(s,1H),8.10–8.02(m,2H),7.82(s,1H),7.38 (d,2H),7.15(d,1H),4.28(t,2H),4.10(s,3H),3.87(s,3H),2.87(d,2H),2.74(t,2H),2.41(s,3H).

[0717] LC-MS m / z(ESI) = 465.22 [M+1].

[0718] Example 71

[0719] first step

[0720] 71a (500 mg, 2.55 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tri-n-butyltin azide (2.54 g, 2.65 mmol) was added. The reaction was carried out at 100 °C for 4 h. After the reaction was completed, the reaction was quenched with saturated brine (40 mL), and the solid was filtered to give compound 71b (white solid, 420 mg, yield 69%).

[0721] LC-MS m / z(ESI) = 238.99 [M+1].

[0722] Step 2

[0723] Compound 71b (420 mg, 1.76 mmol), 3-bromo-1,1-difluorocyclobutane (451 mg, 2.64 mmol), and potassium carbonate (486 mg, 3.52 mmol) were dissolved in N,N-dimethylformamide (20 mL) and reacted at room temperature for 5 h. After the reaction was complete, the reaction was quenched with saturated brine (40 mL), extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 69b (yellow solid, 444 mg, yield 77%).

[0724] LC-MS m / z(ESI) = 329.01 [M+1].

[0725] Step 3

[0726] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 71c" yielded compound 71 (yellow solid, 42 mg, yield 71%).

[0727] 1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.54(s,1H),8.17(s,1H),8.08–8.02(m,2H),7.82(s,1H),7.60(d,1H ),7.37(d,1H),7.15(d,1H),5.60-5.55(m,1H),4.10(s,3H),3.87(s,3H),3.50–3.35(m,4H),2.41(s,3H).

[0728] LC-MS m / z(ESI) = 516.21 [M+1].

[0729] Example 72

[0730] first step

[0731] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 72a (yellowish-brown solid, 480 mg, yield 95%).

[0732] LC-MS m / z(ESI) = 308.17 [M+1].

[0733] Step 2

[0734] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 72a" yielded compound 72b (yellow solid, 300 mg, yield 45%).

[0735] LC-MS m / z(ESI) = 423.30 [M+1].

[0736] Step 3

[0737] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 72b" yielded compound 72c (white solid, 290 mg, 95% yield).

[0738] LC-MS m / z(ESI) = 456.22 [M+1].

[0739] Step 4

[0740] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 72c to obtain compound 72 (yellow solid, 50 mg, yield 24%).

[0741] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.44(d,1H),8.31(s,1H),8.18(s,1H),8.12(d,1H),7.92(s,1H),7.49(dd,1H),7.35(d,1H),7.23 (d,1H),4.28-4.18(m,4H),4.07(s,3H),3.68(dq,2H),3.51(dq,1H),2.97(s,3H),2.20(s,3H),1.13(dd,1H),0.92(dt,2H),0.8(t,2H).

[0742] LC-MS m / z(ESI) = 599.23 [M+1].

[0743] Example 73

[0744] first step

[0745] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 73a (yellow solid, 500 mg, yield 92%).

[0746] LC-MS m / z(ESI) = 300.13 [M+1].

[0747] Step 2

[0748] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 73a" yielded compound 73b (white solid, 280 mg, yield 40%).

[0749] LC-MS m / z(ESI) = 415.17 [M+1].

[0750] Step 3

[0751] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 73b" yielded compound 73c (a grayish-white solid, 275 mg, yield 91%).

[0752] LC-MS m / z(ESI) = 448.19 [M+1].

[0753] Step 4

[0754] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 73c to obtain compound 73 (pale yellow solid, 180 mg, yield 57%).

[0755] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.44(d,1H),8.17(s,1H),8.13(s,1H),8.09(t,1H),7.91(s,1H),7.49(dd,1H),7.36(t,1H),7. 18(d,1H),5.39–5.17(m,1H),4.81(dt,2H),4.46(dt,2H),4.10(s,3H),3.10–2.97(m,1H),2.41(s,3H),1.93(dd,1H),1.57(td,1H).

[0756] LC-MS m / z(ESI) = 516.20 [M+1].

[0757] Example 74

[0758] first step

[0759] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 74a (yellow solid, 371 mg, yield 80%).

[0760] LC-MS m / z(ESI) = 312.15 [M+1].

[0761] Step 2

[0762] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 74a" yielded compound 74b (yellow solid, 142 mg, yield 38%).

[0763] LC-MS m / z(ESI) = 427.19 [M+1].

[0764] Step 3

[0765] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 74b" yielded compound 74c (brown solid, 131 mg, yield 92%).

[0766] LC-MS m / z(ESI) = 460.21 [M+1].

[0767] Step 4

[0768] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 74c to give compound 74 (yellow solid, 28 mg, yield 39%).

[0769] 1 H NMR(400MHz,DMSO)δ8.63–8.42(m,2H),8.32–8.05(m,3H),7.85(s,1H),7 .52–7.46(m,1H),7.40–7.28(m,1H),7.22–7.15(m,1H),5.39–5.18(m,1H) ,4.31–4.24(m,2H),4.15–4.06(m,3H),3.74–3.70(m,2H),3.26(s,3H),3. 09–2.99(m,1H),2.45–2.38(m,3H),2.00–1.84(m,1H),1.64–1.53(m,1H).

[0770] LC-MS m / z(ESI) = 528.22 [M+1].

[0771] Example 75

[0772] first step

[0773] Compound 75b (577.8 mg, 2.53 mmol) and T3P (2.9 g, 9.21 mmol) were dissolved in THF (30 mL) at 0 °C and stirred at 0 °C for 30 min. Then, compound 75a (500 mg, 2.30 mmol) and DIPEA (1.80 g, 13.80 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. The reaction progress was monitored by TLC.

[0774] The reaction was stopped, quenched with water, extracted with EA, and the organic phase was collected. The organic phase was then eluted by column chromatography with DCM:MeOH = 50:1 to give compound 75c (yellow solid, 481 mg, yield 48%).

[0775] LC-MS m / z(ESI) = 428.11 [M+1].

[0776] Step 2

[0777] Compound 75c (481 mg, 1.12 mmol) was dissolved in DCM (20 mL), and then TsCl (257.7 mg, 1.25 mmol) and TEA (341.9 mg, 3.37 mmol) were added. The reaction was carried out at room temperature for 8 h, and the reaction progress was monitored by TLC.

[0778] The reaction was stopped, and direct column chromatography (DCM:MeOH = 50:1) was performed to elute compound 75d (red solid, 430 mg, yield 93%).

[0779] LC-MS m / z(ESI) = 410.10[M+1].

[0780] Step 3

[0781] Compound 75d (430 mg, 1.05 mmol) was dissolved in EA (8 mL), and then 1,4-Dioxane solution of 4 mol / L HCl (24 mL) was added. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC.

[0782] The reaction was stopped, a small amount of DCM was added, and the mixture was filtered to give compound 75e (white solid, 330 mg, yield 98%).

[0783] LC-MS m / z(ESI) = 310.05 [M+1].

[0784] Step 4

[0785] Compound 75e (318 mg, 0.77 mmol) and TEA (314.9 mg, 2.3 mmol) were dissolved in toluene (50 mL) and reacted at 110 °C for 2 days. The reaction progress was monitored by TLC.

[0786] The reaction was stopped, the solvent was evaporated, and column chromatography was performed to elute with DCM:MeOH = 50:1, giving compound 75f (white solid, 150 mg, yield 50%).

[0787] LC-MS m / z(ESI) = 292.04 [M+1].

[0788] Step 5

[0789] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "compound 75f" to obtain compound 75 (white solid, 70 mg, yield 43%).

[0790] 1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.38(s,1H),8.11(s,1H),8.08–8.04(m,2H),7.83(s,1H),7.41–7.30(m,2H),7.17 –7.13(m,1H),4.97–4.89(m,1H),4.10(s,3H),3.87(s,3H),3.03–2.80(m,3H),2.43–2.30(m,4H),1.32(d,J=6.4Hz,3H).

[0791] LC-MS m / z(ESI) = 479.23 [M+1].

[0792] Example 76

[0793] first step

[0794] Following the synthesis of intermediate B, replacing "methylhydrazine" with "ethylhydrazine" yielded compound 76a (yellow solid, 1.8 g, yield 81%).

[0795] LC-MS m / z(ESI) = 280.01 [M+1].

[0796] Step 2

[0797] Following the synthesis of compound 1-1, replacing "compound B" with "76a" yielded compound 76b (yellow solid, 388 mg, 96% yield).

[0798] LC-MS m / z(ESI) = 282.14 [M+1].

[0799] Step 3

[0800] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 76b" yielded compound 76c (white solid, 229 mg, yield 40%).

[0801] LC-MS m / z(ESI) = 397.18 [M+1].

[0802] Step 4

[0803] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 76c" yielded compound 76d (gray solid, 180 mg, yield 72%).

[0804] LC-MS m / z(ESI) = 430.20 [M+1].

[0805] Step 5

[0806] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 76d to obtain compound 76 (yellow solid, 40 mg, yield 43%).

[0807] 1 H NMR (400MHz, DMSO) δ8.57(s,1H),8.54(s,1H),8.18(s,1H),8.06(s,2H),7.83(s,1H),7.51–7.45(m,1H),7.38–7.32(m,1H),7.16–7.12(m, 1H),5.37–5.16(m,1H),4.49–4.41(m,2H),3.87(s,3H),3.10–2.98(m ,1H),2.41(s,3H),2.01–1.90(m,1H),1.60–1.53(m,1H),1.49(t,3H).

[0808] LC-MS m / z(ESI) = 498.21 [M+1].

[0809] Example 77

[0810] first step

[0811] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine" yielded compound 77a (yellow solid, 313 mg, yield 66%).

[0812] LC-MS m / z(ESI) = 265.11 [M+1].

[0813] Step 2

[0814] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 77a" yielded compound 77b (yellow solid, 180 mg, yield 47%).

[0815] LC-MS m / z (ESI) = 380.15 [M+1].

[0816] Step 3

[0817] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 77b" yielded compound 77c (brown solid, 148 mg, yield 75%).

[0818] LC-MS m / z(ESI) = 413.18 [M+1].

[0819] Step 4

[0820] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 77c to give compound 77 (white solid, 22 mg, yield 23%).

[0821] 1 H NMR (400MHz, DMSO) δ9.15–9.11(m,1H),8.65–8.62(m,1H),8.51–8.45(m,3H),8.28–8.19(m,2H),7.57–7.54(m,1H),7.53–7.44( m,2H),7.39–7.34(m,1H),5.39–5.18(m,1H),4.14(s,3H),3.10–2.98(m,1H),2.41(s,3H),2.00–1.88(m,1H),1.63–1.53(m,1H).

[0822] LC-MS m / z(ESI) = 481.18 [M+1].

[0823] Example 78

[0824] first step

[0825] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole” yielded compound 78a (yellow solid, 263 mg, yield 52%).

[0826] LC-MS m / z(ESI) = 336.11 [M+1].

[0827] Step 2

[0828] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 78a" yielded compound 78b (yellow solid, 86 mg, yield 46%).

[0829] LC-MS m / z(ESI) = 451.15 [M+1].

[0830] Step 3

[0831] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 78b" yielded compound 78c (brown solid, 83 mg, yield 89%).

[0832] LC-MS m / z(ESI) = 484.17 [M+1].

[0833] Step 4

[0834] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 78c to obtain compound 78 (white solid, 30 mg, yield 31%).

[0835] 1 H NMR (400MHz, DMSO) δ8.55(s,1H),8.46–8.42(m,1H),8.21–8.13(m,3H),8.01(s,1H),7.51–7.47(m,1H),7.38–7.33(m,1H),7.24–7. 21(m,1H),5.38–5.21(m,1H),5.19–5.14(m,2H),4.10(s,3H),3.08–2.98(m,1H),2.40(s,3H),2.00–1.86(m,1H),1.63–1.52(m,1H).

[0836] LC-MS m / z (ESI) = 552.18 [M+1].

[0837] Example 79

[0838] first step

[0839] Compound 79a (3.0 g, 10.1 mmol) was dissolved in triethylamine (100 mL), and then Pd(PPh3)2Cl2 (212.7 mg, 0.3 mmol), cuprous iodide (57.7 mg, 0.3 mmol), and trimethylsilylacetylene (1.48 g, 15.1 mmol) were added. Under nitrogen protection, the reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0840] The reaction was stopped, the mixture was filtered, the filtrate was dried by rotary evaporation, and then eluted with petroleum ether by column chromatography to give compound 79b (yellow liquid, 2.6 g, yield 81%).

[0841] LC-MS m / z(ESI) = 267.01 [M+1].

[0842] Step 2

[0843] Compound 79b (2.4 g, 9.0 mmol) was dissolved in THF (30 mL) and methanol (10 mL), and then anhydrous potassium carbonate (7.5 g, 54.0 mmol) was added. The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored by TLC.

[0844] The reaction was stopped, the mixture was filtered, and the filtrate was then subjected to column chromatography with petroleum ether elution to give compound 79c (yellow liquid, 1.5 g, yield 86%).

[0845] LC-MS m / z (ESI) = 194.97 [M+1].

[0846] Step 3

[0847] Compound 79c (1.3 g, 6.7 mmol) and trimethylsilazine (1.2 g, 10.1 mmol) were dissolved in DMF (24 mL) and methanol (6 mL), and then cuprous iodide (64.4 mg, 0.3 mmol) was added. The mixture was then reacted at 100 °C for 8 h under nitrogen protection, and the reaction progress was monitored by TLC.

[0848] The reaction was stopped, the mixture was filtered, and the filtrate was added. Water was added, and the mixture was extracted with EA. The filtrate was washed twice with brine, and the organic phase was collected and evaporated to dryness. A small amount of water was added to adjust the pH to alkaline, and the mixture was extracted twice with PE. The aqueous phase was collected, and the pH was adjusted to acidic with dilute hydrochloric acid. The mixture was then extracted with EA, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give compound 79d (white solid, 1.8 g, 99% yield).

[0849] LC-MS m / z(ESI) = 237.99 [M+1].

[0850] Step 4

[0851] Compound 79d (270 mg, 1.1 mmol) and anhydrous potassium carbonate (315 mg, 2.2 mmol) were dissolved in DMF (8 mL), and then 3-bromo-1,1-difluorocyclobutane (233.8 mg, 1.3 mmol) was added. The mixture was then reacted at 100 °C for 8 h under nitrogen protection, and the reaction progress was monitored by TLC.

[0852] The reaction was stopped, water was added, and the mixture was extracted with EA. The mixture was washed twice with brine, and the organic phase was collected. The organic phase was then eluted by column chromatography with a PE:EA ratio of 10:1 to give compound 79e (white solid, 86 mg, yield 37%).

[0853] LC-MS m / z(ESI) = 308.01 [M+1].

[0854] Step 5

[0855] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 79e" yielded compound 79 (white solid, 60 mg, yield 65%).

[0856] 1 H NMR(400MHz,DMSO)δ8.88(s,1H),8.49(s,1H),8.27–8.24(m,1H),8.09(s,1H),8.05–8.02(m,2H),7.82(s,1H),7.75–7.69(m,1H) ,7.42–7.38(m,1H),7.32–7.28(m,1H),7.18–7.06(m,2H),5.05(s,1H),5.02–4.90(m,1H),4.11(s,3H),3.87(s,3H),2.37(s,3H).

[0857] LC-MS m / z(ESI) = 495.21 [M+1].

[0858] Example 80

[0859] first step

[0860] Compound 79d (350 mg, 1.47 mmol) and anhydrous potassium carbonate (408 mg, 2.95 mmol) were dissolved in DMF (8 mL), and then compound 80a (501.9 mg, 1.77 mmol) was added. The mixture was then reacted at 100 °C for 4 h under nitrogen protection, and the reaction progress was monitored by TLC.

[0861] The reaction was stopped, water was added, and the mixture was extracted with EA. The mixture was washed twice with brine, and the organic phase was collected. The organic phase was then eluted by column chromatography with EA:PE = 1:5 to give compound 80b (yellow liquid, 444.0 mg, yield 75%).

[0862] LC-MS m / z(ESI) = 393.08 [M+1].

[0863] Step 2

[0864] Compound 80b (444.0 mg, 1.13 mmol) was dissolved in DCM (6 mL), and then TFA (1.5 mL) was added. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0865] The reaction was stopped, the solvent was evaporated, water was added, sodium hydroxide was added to adjust the pH to alkaline, and the mixture was extracted twice with EA. The solution was evaporated, a small amount of DCM was added, and then 1,4-Dioxane·HCl (4 mol / L) was added. The solid precipitated, and the solid was filtered and evaporated to give compound 80c (white solid, 265 mg, yield 80%).

[0866] LC-MS m / z(ESI) = 293.03 [M+1].

[0867] Step 3

[0868] Compound 80c (82 mg, 0.28 mmol) and triethylamine (85.9 mg, 0.84 mmol) were dissolved in DCM (8 mL), and then methanesulfonic anhydride (63.5 mg, 0.36 mmol) was added. The mixture was reacted at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0869] The reaction was stopped, water was added, and the mixture was extracted twice with DCM. The organic phase was collected and then eluted by column chromatography with PE:EA = 1:1 to give compound 80d (white solid, 86 mg, yield 83%).

[0870] LC-MS m / z(ESI) = 371.01 [M+1].

[0871] Step 4

[0872] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 80d" yielded compound 80 (white solid, 47 mg, yield 46%).

[0873] 1 H NMR(400MHz,DMSO)δ8.50(s,1H),8.33–8.29(m,2H),8.09(s,1H),8.06–8.02(m,2H),7.82(s,1H),7.43–7.39(m,1H),7.31– 7.26(m,1H),7.16–7.13(m,1H),5.65–5.53(m,1H),4.44–4.36(m,4H),4.10(s,3H),3.87(s,3H),3.13(s,3H),2.37(s,3H).

[0874] LC-MS m / z(ESI) = 558.21 [M+1].

[0875] Example 81

[0876] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "3,3-difluorocyclobutane-1-carboxylic acid" and reacted with compound 33c to compound 81 (yellow solid, 50 mg, yield 40%).

[0877] 1H NMR (400MHz, DMSO) δ8.55–8.53(m,1H),8.51–8.48(m,1H),8.19–8.14(m,2H),8.10–8.05(m,2H),7.57–7.51(m,1H),7.40–7.35(m,1 H),7.19–7.15(m,1H),3.90–3.80(m,1H),3.26–2.97(m,4H),2.41(s,3H),2.35–2.16(m,4H),1.35–1.13(m,2H),1.09–0.94(m,2H).

[0878] LC-MS m / z(ESI) = 542.22 [M+1].

[0879] Example 82

[0880] first step

[0881] Compound 80c (164 mg, 0.56 mmol) and triethylamine (114 mg, 1.12 mmol) were dissolved in DCM (8 mL) under nitrogen protection. Dimethyl dicarbonate (75 mg, 0.56 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 h. The reaction progress was monitored by TLC.

[0882] The reaction was stopped, water was added, and the mixture was extracted with DCM. The organic phase was collected and then eluted by column chromatography with EA:PE = 1:1 to give compound 82a (yellow liquid, 135.0 mg, yield 93%).

[0883] LC-MS m / z(ESI) = 351.04 [M+1].

[0884] Step 2

[0885] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 82a" yielded compound 82 (white solid, 47 mg, yield 43%).

[0886] 1H NMR(400MHz,DMSO)δ8.50(s,1H),8.31–8.26(m,2H),8.10(s,1H),8.05–8.02(m,2H),7.82(s,1H),7.43–7.38(m,1H),7.31–7.26(m,1 H),7.16–7.10(m,1H),5.62–5.52(m,1H),4.54–4.43(m,2H),4.36–4.25(m,2H),4.09(s,3H),3.87(s,3H),3.61(s,3H),2.36(s,3H).

[0887] LC-MS m / z(ESI) = 538.23 [M+1].

[0888] Example 83

[0889] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methanesulfonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 33c to give compound 83 (yellow solid, 18 mg, yield 23%).

[0890] 1 H NMR (400MHz, DMSO) δ8.56–8.51(m,2H),8.19–8.14(m,1H),8.10–8.04(m,2H),7.88–7.81(m,1H),7.58–7.53(m,1H),7.40–7.35(m,1H), 7.21–7.14(m,1H),4.35–4.19(m,5H),4.10(s,3H),3.10(s,3H),2.70–2.51(m,1H),2.42(s,3H),1.28–1.20(m,2H),1.14–0.80(m,2H).

[0891] LC-MS m / z(ESI) = 585.21 [M+1].

[0892] Example 84

[0893] first step

[0894] Compound 80c (150 mg, 0.51 mmol) and triethylamine (157 mg, 1.53 mmol) were dissolved in DCM (10 mL), and methoxyacetyl chloride (83 mg, 0.77 mmol) was added at 0 °C. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[0895] The reaction was stopped, water was added, and the mixture was extracted with DCM. The organic phase was collected and then eluted by column chromatography with DCM:MeOH = 50:1 to give compound 84a (yellow liquid, 150.0 mg, yield 90%).

[0896] LC-MS m / z (ESI) = 365.05 [M+1].

[0897] Step 2

[0898] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 84a" yielded compound 84 (yellow solid, 70 mg, yield 48%).

[0899] 1 H NMR(400MHz,DMSO)δ8.50(s,1H),8.31–8.27(m,2H),8.11(s,1H),8.06–8.0 2(m,2H),7.82(s,1H),7.42–7.39(m,1H),7.31–7.25(m,1H),7.16–7.12(m,1 H),5.64–5.56(m,1H),4.78–4.70(m,1H),4.57–4.44(m,2H),4.31–4.25(m, 1H),4.08(s,3H),4.01–3.93(m,2H),3.87(s,3H),3.29(s,3H),2.36(s,3H).

[0900] LC-MS m / z (ESI) = 552.25 [M+1].

[0901] Example 85

[0902] first step

[0903] Following the synthesis of compound 84a, replacing "methoxyacetyl chloride" with "N,N-dimethylmethanesulfonamide" yielded compound 85a (yellow liquid, 180.0 mg, yield 99%).

[0904] LC-MS m / z(ESI) = 400.04 [M+1].

[0905] Step 2

[0906] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 85a" yielded compound 85 (yellow solid, 90 mg, yield 46%).

[0907] 1H NMR (400MHz, DMSO) δ8.51(s,1H),8.34–8.32(m,1H),8.30(s,1H),8.10(s,1H),8.06–8.03(m,2H),7.83–7.81(m,1H),7.42–7.38(m,1 H),7.30–7.27(m,1H),7.16–7.14(m,1H),5.64–5.57(m,1H),4.39–4.30(m,4H),4.10(s,3H),3.87(s,3H),2.78(s,6H),2.37(s,3H).

[0908] LC-MS m / z (ESI) = 587.23 [M+1].

[0909] Example 86

[0910] first step

[0911] Compound 86a (4.0 g, 20.6 mmol) and BuSnN3 (20.6 g, 62. mmol) were dissolved in DMF (20 mL), and the mixture was reacted at 100 °C for 8 h under nitrogen protection. The reaction progress was monitored by TLC.

[0912] Stop the reaction, add water (150 mL), add sodium hydroxide to adjust the pH to alkaline, extract three times with PE, retain the aqueous phase, adjust the pH to acidic to precipitate the solid, filter to obtain compound 86b (white solid, 1.0 g, yield 26%).

[0913] LC-MS m / z(ESI) = 238.99 [M+1].

[0914] Step 2

[0915] Compound 86b (195 mg, 0.81 mmol) was dissolved in DMF (8 mL), and then anhydrous potassium carbonate (453 mg, 3.27 mmol), 3-bromo-1,1-difluorocyclobutane (420 mg, 2.40 mmol), and sodium iodide (245 mg, 1.60 mmol) were added. The reaction was carried out under nitrogen protection at 100 °C for 8 h, and the reaction progress was monitored by TLC.

[0916] The reaction was stopped, water was added, EA was added for extraction, the mixture was washed twice with water, and then column chromatography was performed to elute with PE:EA = 5:1 to give compound 86c (yellow liquid, 152 mg, yield 75%).

[0917] LC-MS m / z(ESI) = 329.01 [M+1].

[0918] Step 3

[0919] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "compound 86c". The reaction yielded compound 86 (yellow solid, 28 mg, yield 40%).

[0920] 1 H NMR (400MHz, DMSO) δ8.59–8.56(m,1H),8.54(s,1H),8.17(s,1H),8.08–8.05(m,2H),7.84(s,1H),7.62–7.58(m,1H),7.39–7.35(m,1H),7. 18–7.15(m,1H),5.63–5.53(m,1H),5.00–4.94(m,1H),4.19–4.14(m, 2H),4.10(s,3H),3.81–3.73(m,2H),3.51–3.35(m,4H),2.41(s,3H).

[0921] LC-MS m / z(ESI) = 546.22 [M+1].

[0922] Example 87

[0923] first step

[0924] Following the synthesis of compound 80b, replacing "compound 79d" with "compound 87a" yielded compound 87a (white solid, 1.0 g, yield 63%).

[0925] LC-MS m / z(ESI) = 394.08 [M+1].

[0926] Step 2

[0927] Following the synthesis of compound 80c, replacing "compound 80b" with "compound 87b" yielded compound 87b (white solid, 785 mg, yield 78%).

[0928] LC-MS m / z(ESI) = 294.03 [M+1].

[0929] Step 3

[0930] Following the synthesis of compound 80d, replacing "compound 80c" with "compound 87c" yielded compound 87c (white solid, 830 mg, 90% yield).

[0931] LC-MS m / z(ESI) = 372.01 [M+1].

[0932] Step 4

[0933] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 33a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 87c" to obtain compound 87 (yellow solid, 12 mg, yield 18%).

[0934] 1 H NMR(400MHz,DMSO)δ8.61–8.58(m,1H),8.54(s,1H),8.18(s,1H),8.15(s,1H ),8.07–8.05(m,1H),7.84–7.81(m,1H),7.64–7.60(m,1H),7.40–7.35(m,1H) ,7.19–7.15(m,1H),5.96–5.88(m,1H),4.53–4.43(m,4H),4.10(s,3H),3.76– 3.70(m,1H),3.16(s,3H),2.42(s,3H),1.26–1.21(m,2H),1.04–0.97(m,2H).

[0935] LC-MS m / z(ESI) = 585.22 [M+1].

[0936] Example 88

[0937] first step

[0938] Compound 1-1,5-bromo-6-methylnicotinonitrile, XantPhos, Pd2(dba)3, and Cs2CO3 were added to a 100 mL flask, along with dioxane solvent. The mixture was reacted at 90 °C for 8 h under nitrogen protection. After the reaction was complete, the sample was directly stirred by rotary evaporation and eluted with DCM:MeOH = 100:1 to 40:1 to obtain compound 88a (brown solid, 260 mg, yield 36%).

[0939] LC-MS m / z(ESI) = 384.16 [M+1].

[0940] Step 2

[0941] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 88a" yielded compound 88b (reddish-brown solid, 160 mg, yield 55%).

[0942] LC-MS m / z(ESI) = 417.20 [M+1].

[0943] Step 3

[0944] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methanesulfonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 88b to give compound 88 (pale yellow solid, 42 mg, yield 39%).

[0945] 1H NMR(400MHz,DMSO)δ8.93(d,1H),8.65(d,2H),8.42(s,1H),8.08(d,1H),8.04(s,1H),7.83( s,1H),7.18(d,1H),4.36–4.22(m,5H),4.13(s,3H),3.87(s,3H),3.12(s,3H),2.68(s,3H).

[0946] LC-MS m / z (ESI) = 560.20 [M+1].

[0947] Example 89

[0948] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 88b to give compound 89 (yellow solid, 70 mg, yield 67%).

[0949] 1H NMR(400MHz,DMSO)δ8.91(d,1H),8.67–8.62(m,2H),8.41(s,1H),8.07(d,1H),8.04(s,1H),7.85– 7.80(m,1H),7.17(d,1H),4.42–4.17(m,5H),4.13(s,3H),3.88(s,3H),3.60(s,3H),2.67(s,3H).

[0950] LC-MS m / z(ESI) = 540.23 [M+1].

[0951] Example 90

[0952] first step

[0953] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine" yielded compound 90a (yellowish-brown solid, 300 mg, yield 52%).

[0954] LC-MS m / z(ESI) = 265.11 [M+1].

[0955] Step 2

[0956] Following the synthesis of compound 88a, replacing "compound 1-1" with "compound 90a" yielded compound 90b (yellow solid, 85 mg, yield 19%).

[0957] LC-MS m / z(ESI) = 381.15 [M+1].

[0958] Step 3

[0959] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 90b" yielded compound 90c (brown solid, 55 mg, yield 57%).

[0960] LC-MS m / z(ESI) = 414.19 [M+1].

[0961] Step 4

[0962] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 90c to obtain compound 90 (pale yellow solid, 16 mg, yield 21%).

[0963] 1 H NMR(400MHz,DMSO)δ8.96(d,1H),8.77(s,1H),8.66(d,1H),8.62(d,1H),8.58(d,2H),8.47(s,1H),7.90–7.85(m,2H ),7.64(d,1H),5.43–5.28(m,1H),4.18(s,3H),3.74–3.67(m,1H),2.68(d,3H)2.05–1.91(m,1H),1.66–1.57(m,1H)

[0964] LC-MS m / z(ESI) = 482.18 [M+1].

[0965] Example 91

[0966] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 90c to give compound 91 (yellow solid, 48 mg, yield 77%).

[0967] 1H NMR(400MHz,DMSO)δ8.93(d,1H),8.74(s,1H),8.63(d,1H),8.57(dd,3H),8.43(s,1H) ,7.83(d,2H),7.59(d,1H),4.41–4.19(m,5H),4.16(s,3H),3.60(s,3H),2.67(s,3H).

[0968] LC-MS m / z(ESI) = 537.20 [M+1].

[0969] Example 92

[0970] first step

[0971] Following the synthesis of compound 86b, replacing "3-bromo-4-methylbenzonitrile" with "5-bromo-6-methylnicotinonitrile" yielded compound 92b (white solid, 1.0 g, yield 26%).

[0972] LC-MS m / z(ESI) = 239.99 [M+1].

[0973] Step 2

[0974] Following the synthesis of compound 87a, replacing "compound 86b" with "compound 92b" yielded compound 92c (white solid, 700 mg, yield 56%).

[0975] LC-MS m / z(ESI) = 394.09 [M+1].

[0976] Step 3

[0977] Following the synthesis of compound 87b, replacing "compound 87a" with "compound 92c" yielded compound 92d (white solid, 300 mg, yield 38%).

[0978] LC-MS m / z(ESI) = 294.09 [M+1].

[0979] Step 4

[0980] Following the synthesis of compound 87c, replacing "compound 87b" with "compound 92d" yielded compound 92e (white solid, 152 mg, yield 75%).

[0981] LC-MS m / z(ESI) = 373.01 [M+1].

[0982] Step 5

[0983] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 90a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 92e" to obtain compound 92 (yellow solid, 18 mg, yield 14%).

[0984] 1 H NMR (400MHz, DMSO) δ9.02(d,1H),8.76(s,1H),8.73(d,1H),8.60(d,1H),8.57(d,2H),8.44(s,1H),7. 86(d,2H),7.62(d,1H),6.02–5.91(m,1H),4.56–4.46(m,4H),4.18(s,3H),3.19(s,3H),2.68(s,3H).

[0985] LC-MS m / z (ESI) = 557.20 [M+1].

[0986] Example 93

[0987] first step

[0988] Following the synthesis of compound 80d, "methanesulfonic anhydride" was replaced with "dimethyl dicarbonate" and reacted with compound 92d to obtain compound 93a (white solid, 300 mg, yield 31%).

[0989] LC-MS m / z(ESI) = 353.04 [M+1].

[0990] Step 2

[0991] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 90a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 93a" to obtain compound 93 (yellow solid, 30 mg, yield 24%).

[0992] 1 H NMR(400MHz,DMSO)δ9.00(d,1H),8.76(s,1H),8.71(s,1H),8.63–8.54(m,3H),8.44(s,1H),7.87(d ,2H),7.62(s,1H),5.92(dd,1H),4.57(s,2H),4.41(s,2H),4.17(s,3H),3.63(s,3H),2.67(s,3H).

[0993] LC-MS m / z(ESI) = 537.21 [M+1].

[0994] Example 94

[0995] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 90a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 87e" to obtain compound 94 (white solid, 35 mg, yield 27%).

[0996] 1 H NMR (400MHz, DMSO) δ8.66–8.55(m,5H),8.22(s,1H),7.85(d,2H),7.66–7.59(m,2H),7. 39(d,1H),5.99–5.87(m,1H),4.53–4.43(m,4H),4.15(s,3H),3.17(s,3H),2.42(s,3H).

[0997] LC-MS m / z (ESI) = 557.19 [M+1].

[0998] Example 95

[0999] first step

[1000] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" yielded compound 95a (yellowish-brown solid, 280 mg, yield 96%).

[1001] LC-MS m / z(ESI) = 308.10 [M+1].

[1002] Step 2

[1003] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 95a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 92e" to obtain compound 95 (yellow solid, 40 mg, yield 34%).

[1004] 1H NMR(400MHz,DMSO)δ8.60(d,1H),8.54(s,1H),8.17(s,1H),8.13(s,1H),8.07(d,1H),7.83(s,1H),7.62(dd,1H),7.38(d,1H),6.00–5.86 (m,1H),4.54–4.43(m,4H),4.12(d,3H),3.99(d,2H),3.16(s,3H),2.42(s,3H),1.30–1.24(m,1H),0.60–0.54(m,2H),0.43–0.36(m,2H).

[1005] LC-MS m / z(ESI) = 600.32 [M+1].

[1006] Example 96

[1007] first step

[1008] Following the synthesis of compound 86b, replacing "3-bromo-4-methylbenzonitrile" with "5-bromo-6-chloronicotinonitrile" yielded compound 96b (white solid, 400 mg, yield 33%).

[1009] Step 2

[1010] Following the synthesis of compound 87a, "compound 86b" was replaced with "compound 96b". Compound 96c (white solid, 470 mg, yield 63%).

[1011] LC-MS m / z(ESI) = 414.05 [M+1].

[1012] Step 3

[1013] Following the synthesis of compound 87b, replacing "compound 87a" with "compound 96c" yielded compound 96d (white solid, 300 mg, yield 84%).

[1014] LC-MS m / z(ESI) = 314.10 [M+1].

[1015] Step 4

[1016] Following the synthesis of compound 87c, replacing "compound 87b" with "compound 96d" yielded compound 96e (white solid, 300 mg, yield 54%).

[1017] LC-MS m / z (ESI) = 391.95 [M+1].

[1018] Step 5

[1019] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 96e" yielded compound 96 (yellow solid, 50 mg, yield 23%).

[1020] 1 H NMR (400MHz, DMSO) δ8.86(s,1H),8.64(s,1H),8.59(s,1H),8.10–8.03(m,2H),7.83(s,1H),7.66( s,2H),7.19(d,1H),6.00–5.90(m,1H),4.54–4.44(m,4H),4.15(s,3H),3.88(s,3H),3.17(s,3H).

[1021] LC-MS m / z (ESI) = 579.15 [M+1].

[1022] Example 97

[1023] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "2-(2-oxooxazolidine-3-yl)acetic acid" and reacted with compound 63b to give compound 97 (white solid, 30 mg, yield 47%).

[1024] 1 H NMR (400MHz, DMSO) δ8.92(d,1H),8.65(s,1H),8.62(d,1H),8.42(s,1H),8.07(d,1H),8.04(s,1H),7.82(s, 1H),7.17(d,1H),4.85(s,2H),4.43–4.34(m,2H),4.12(s,3H),3.87(s,3H),3.77–3.71(m,2H),2.67(s,3H).

[1025] LC-MS m / z(ESI) = 526.20 [M+1].

[1026] Example 98

[1027] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 33a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 92e" to obtain compound 98 (white solid, 11 mg, yield 16%).

[1028] 1H NMR (400MHz, DMSO) δ9.01–8.98(m,1H),8.75–8.71(m,1H),8.65(s,1H),8.41(s,1H),8.15(s,1H),8.10–8.07(m,1H),7.82(s,1H),7.22–7.17( m,1H),6.01–5.92(m,1H),4.56–4.44(m,4H),4.13(s,3H),3.77–3.70( m,1H),3.18(s,3H),2.67(s,3H),1.09–1.04(m,2H),1.03–0.96(m,2H).

[1029] LC-MS m / z(ESI) = 586.21 [M+1].

[1030] Example 99

[1031] first step

[1032] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "5-bromo-6-methylnicotinonitrile" yielded compound 99a (yellow solid, 220 mg, yield 60%).

[1033] LC-MS m / z(ESI) = 382.03 [M+1].

[1034] Step 2

[1035] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole", and "compound B" was replaced with "compound 99a". The reaction yielded compound 99b (yellow solid, 157 mg, yield 45%).

[1036] LC-MS m / z(ESI) = 410.18 [M+1].

[1037] Step 3

[1038] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 99b" yielded compound 99c (yellow solid, 130 mg, yield 80%).

[1039] LC-MS m / z(ESI) = 443.20 [M+1].

[1040] Step 4

[1041] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 99c to obtain compound 99 (yellow solid, 7 mg, yield 6%).

[1042] 1 H NMR(400MHz,DMSO)δ8.85–8.82(m,1H),8.64(s,1H),8.59–8.57(m,1H),8.4 0(s,1H),8.15(s,1H),8.10–8.07(m,1H),7.82(s,1H),7.20–7.17(m,1H),5. 41–5.19(m,1H),4.12(s,3H),3.78–3.69(m,1H),3.13–3.03(m,1H),2.66(s ,3H),1.98(s,1H),1.65–1.55(m,1H),1.11–1.04(m,2H),1.02–0.94(m,2H).

[1043] LC-MS m / z(ESI) = 511.20 [M+1].

[1044] Example 100

[1045] first step

[1046] Following the synthesis of compound 79b, replacing "compound 79a" with "compound 100a" yielded compound 100b (yellow solid, 3.8 g, yield 70%).

[1047] LC-MS m / z(ESI) = 205.11 [M+1].

[1048] Step 2

[1049] Compound 100b (3.7 g, 18.1 mmol) was added to ACN (120 mL), CuBr2 (6.0 g, 27.1 mmol) was added at 0 °C, and t-butyl nitrite solution in acetonitrile (30 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 h, and then gradually reacted at room temperature. The reaction progress was monitored by TLC.

[1050] The reaction was stopped, water was added, the mixture was filtered with EA, and then extracted with EA. The organic phase was collected and eluted by column chromatography with EA:PE = 1:8 to give compound 100c (yellow solid, 1.1 g, yield 33%).

[1051] LC-MS m / z(ESI) = 268.01 [M+1].

[1052] Step 3

[1053] Following the synthesis of compound 79c, replacing "compound 79b" with "compound 100c" yielded compound 100d (yellow liquid, 450 mg, yield 40%).

[1054] LC-MS m / z (ESI) = 195.97 [M+1].

[1055] Step 4

[1056] Following the synthesis of compound 79d, replacing "compound 79c" with "compound 100d" yielded compound 100e (white solid, 414 mg, yield 83%).

[1057] LC-MS m / z(ESI) = 238.99 [M+1].

[1058] Step 5

[1059] Following the synthesis of compound 80b, replacing "compound 80a" with "compound 100e" yielded compound 100f (yellow liquid, 640 mg, yield 89%).

[1060] LC-MS m / z(ESI) = 394.08 [M+1].

[1061] Step 6

[1062] Following the synthesis of compound 80c, replacing "compound 80b" with "compound 100f" yielded 100g of compound (white solid, 420mg, yield 66%).

[1063] LC-MS m / z(ESI) = 294.03 [M+1].

[1064] Step 7

[1065] Following the synthesis of compound 80d, replacing "compound 80c" with "compound 100g" yielded compound 100h (white solid, 320mg, yield 7%).

[1066] LC-MS m / z(ESI) = 372.01 [M+1].

[1067] Step 8

[1068] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 100h" yielded compound 100 (white solid, 60 mg, yield 51%).

[1069] 1H NMR (400MHz, DMSO) δ8.75–8.70(m,1H),8.61(s,1H),8.58–8.53(m,1H),8.44(s,1H),8.31(s,1H),8.09–8.02(m,2H),7. 82(s,1H),7.20–7.13(m,1H),5.67–5.60(m,1H),4.44–4.38(m,4H),4.13(s,3H),3.87(s,3H),3.15(s,3H),2.61(s,3H).

[1070] LC-MS m / z (ESI) = 559.20 [M+1].

[1071] Example 101

[1072] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 78a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 87c" to obtain compound 101 (yellow solid, 14 mg, yield 20%).

[1073] 1 H NMR (400MHz, DMSO) δ8.62–8.59(m,1H),8.57(s,1H),8.22–8.18(m,2H),8.16–8.13(m,1H),8.01(s,1H),7.65–7.61(m,1H),7.40– 7.36(m,1H),7.25–7.21(m,1H),5.98–5.87(m,1H),5.22–5.14(m,2H),4.54–4.42(m,4H),4.11(s,3H),3.16(s,3H),2.42(s,3H).

[1074] LC-MS m / z(ESI) = 627.19 [M+1].

[1075] Example 102

[1076] first step

[1077] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole", and "compound B" was replaced with "compound 99a". The reaction yielded compound 102a (yellow solid, 157 mg, yield 51%).

[1078] LC-MS m / z(ESI) = 452.15 [M+1].

[1079] Step 2

[1080] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 102a" yields compound 102b (brown solid, 150 mg, 90% yield).

[1081] LC-MS m / z(ESI) = 485.17 [M+1].

[1082] Step 3

[1083] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 102b to obtain compound 102 (yellow solid, 17 mg, yield 25%).

[1084] 1 H NMR (400MHz, DMSO) δ8.93–8.90(m,1H),8.67(s,1H),8.65–8.61(m,1H),8.43(s,1H),8.20(s,1H),8.19–8.14(m,1 H),8.02(s,1H),7.28–7.22(m,1H),5.23–5.14(m,2H),4.42–4.19(m,5H),4.14(s,3H),3.60(s,3H),2.68(s,3H).

[1085] LC-MS m / z(ESI) = 608.20 [M+1].

[1086] Example 103

[1087] first step

[1088] Following the synthesis of compound 1-1, replacing "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" with "3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" yielded compound 103a (white solid, 132 mg, yield 52%).

[1089] LC-MS m / z(ESI) = 308.15 [M+1].

[1090] Step 2

[1091] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 103a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 87c" to obtain compound 103 (white solid, 50 mg, yield 49%).

[1092] 1 H NMR(400MHz,DMSO)δ8.64–8.60(m,1H),8.57(s,1H),8.17(s,1H),8.04–8.0 0(m,1H),7.92(s,1H),7.65–7.61(m,1H),7.41–7.37(m,1H),7.15–7.11(m,1 H),5.98–5.90(m,1H),4.53–4.43(m,4H),4.11(s,3H),3.77(s,3H),3.16(s ,3H),2.43(s,3H),2.12–2.05(m,1H),0.95–0.89(m,2H),0.80–0.76(m,2H).

[1093] LC-MS m / z(ESI) = 599.23 [M+1].

[1094] Example 104

[1095] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 102b to obtain compound 104 (yellow solid, 6 mg, yield 9%).

[1096] 1 H NMR (400MHz, DMSO) δ8.87–8.83(m,1H),8.67(s,1H),8.61–8.56(m,1H),8.41(s,1H),8.21(s,1H),8.19–8.15(m,1H),8.02( s,1H),7.25(s,1H),5.42–5.14(m,3H),4.14(s,3H),3.13–3.01(m,1H),2.66(s,3H),2.03–1.90(m,1H),1.68–1.55(m,1H).

[1097] LC-MS m / z (ESI) = 553.18 [M+1].

[1098] Example 105

[1099] first step

[1100] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)prop-2-ol” yielded compound 103a (yellow solid, 142 mg, yield 35%).

[1101] LC-MS m / z(ESI) = 326.17 [M+1].

[1102] Step 2

[1103] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 105a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 87c" to obtain compound 105 (yellow solid, 50 mg, yield 40%).

[1104] 1 H NMR (400MHz, DMSO) δ8.62–8.58(m,1H),8.54(s,1H),8.17(s,1H),8.10–8.06(m,1H),8.03(s,1H),7.84(s,1H),7.65–7.61(m,1H),7.40–7.35( m,1H),7.20–7.17(m,1H),5.97–5.89(m,1H),4.77(s,1H),4.52–4.43(m ,4H),4.11(s,3H),4.03(s,2H),3.16(s,3H),2.42(s,3H),1.10(s,6H).

[1105] LC-MS m / z(ESI) = 617.24 [M+1].

[1106] Example 106

[1107] first step

[1108] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)prop-2-ol", and "compound B" was replaced with "compound 99a". The reaction yielded compound 106a (yellow solid, 142 mg, yield 35%).

[1109] LC-MS m / z(ESI) = 442.20 [M+1].

[1110] Step 2

[1111] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 106a" yielded compound 106b (brown solid, 60 mg, yield 40%).

[1112] LC-MS m / z(ESI) = 475.22 [M+1].

[1113] Step 3

[1114] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 106b to give compound 106 (black solid, 8 mg, yield 8%).

[1115] 1 H NMR (400MHz, DMSO) δ8.92–8.90(m,1H),8.67–8.62(m,2H),8.42(s,1H),8.12–8.09(m,1H),8.04(s,1H),7.84(s,1H),7.24–7.1 7(m,1H),5.76(s,1H),4.34–4.27(m,1H),4.21(s,2H),4.13(s,3H),4.07–4.00(m,4H),3.60(s,3H),2.68(s,3H),1.10(s,6H).

[1116] LC-MS m / z(ESI) = 598.26 [M+1].

[1117] Example 107

[1118] first step

[1119] Compound 107a (1.0 g, 4.27 mmol), (S)-(-)-epoxypropyl methyl ether (451 mg, 5.12 mmol), and cesium carbonate (1.39 g, 4.27 mmol) were placed in DMF (10 mL) under nitrogen protection and heated to 100 °C for 1 day. The reaction progress was monitored by TLC.

[1120] The reaction was stopped, water was added, and the mixture was extracted with EA. After washing twice with water, column chromatography was performed to elute the compound 107b (yellow liquid, 180 mg, yield 18%).

[1121] LC-MS m / z(ESI) = 323.21 [M+1].

[1122] Step 2

[1123] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "compound 107b", and "compound B" was replaced with "compound 99a". The reaction yielded compound 107c (yellow solid, 118 mg, yield 66%).

[1124] LC-MS m / z(ESI) = 498.23 [M+1].

[1125] Step 3

[1126] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 107c" yielded compound 107d (yellow solid, 130 mg, 90% yield).

[1127] LC-MS m / z (ESI) = 531.25 [M+1].

[1128] Step 4

[1129] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 107d to obtain compound 107 (yellow solid, 10 mg, yield 10%).

[1130] 1 H NMR (400MHz, DMSO) δ8.95–8.91(m,1H),8.69–8.63(m,2H),8.43(s,1H),8.09–8.02( m,1H),7.93(s,1H),7.20–7.13(m,1H),5.15(s,1H),4.43–4.34(m,2H),4.33–4.26( m,1H),4.21(s,2H),4.13(s,3H),4.09–3.88(m,4H),3.60(s,3H),3.28(s,3H),3.27 –3.26(m,1H),2.68(s,3H),2.21–2.12(m,1H),0.99–0.91(m,2H),0.83–0.78(m,2H).

[1131] LC-MS m / z (ESI) = 654.28 [M+1].

[1132] Example 108

[1133] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "3-(2-oxooxazolidine-3-yl)propionic acid" and reacted with compound 63b to give compound 108 (white solid, 30 mg, yield 47%).

[1134] 1 H NMR(400MHz,DMSO)δ8.86(d,1H),8.64(s,1H),8.61(d,1H),8.39(s,1H),8.07(d,1H),8.04(s,1H),7.82(s, 1H),7.16(d,1H),4.28–4.22(m,2H),4.13(s,3H),3.87(s,3H),3.68–3.58(m,4H),3.30(t,2H),2.66(s,3H).

[1135] LC-MS m / z(ESI) = 540.22 [M+1].

[1136] Example 109

[1137] first step

[1138] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 109a" yielded compound 109b (brown solid, 50 mg, yield 36%).

[1139] LC-MS m / z(ESI) = 491.22 [M+1].

[1140] Step 2

[1141] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 109b to obtain compound 109 (brown solid, 10 mg, yield 30%).

[1142] 1 H NMR (400MHz, DMSO) δ8.83(d,1H),8.64(s,1H),8.57(d,1H),8.39(s,1H),8.09(d,1H),8.04(s,1H),7.85(s,1H),7.19(d,1H),5.41–5.18( m,2H),4.22–4.16(m,1H),4.12(s,3H),4.08–3.96(m,2H),3.29(d,5H),3.13–3.01(m,1H),2.66(s,3H),1.95(dd,1H),1.66–1.55(m,1H).

[1143] LC-MS m / z(ESI)=559.24.20[M+1].

[1144] Example 110

[1145] first step

[1146] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "6-bromo-5-methylnicotinonitrile", and "compound 1-1" was replaced with "compound 66a". The reaction yielded compound 110a (yellow solid, 80 mg, yield 28%).

[1147] LC-MS m / z(ESI) = 452.16 [M+1].

[1148] Step 2

[1149] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 110a" yielded compound 110b (pale yellow solid, 80 mg, yield 46%).

[1150] LC-MS m / z(ESI) = 485.19 [M+1].

[1151] Step 3

[1152] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 110b to give compound 110 (white solid, 35 mg, yield 34%).

[1153] 1 H NMR(400MHz,DMSO)δ8.92(t,1H),8.72(s,1H),8.64(d,2H),8.43(d,1H),8.29(s,1H) ,7.91(d,1H),7.08(d,1H),4.41–4.19(m,5H),4.11(s,3H),3.97(s,3H),3.60(s,3H).

[1154] LC-MS m / z (ESI) = 594.19 [M+1].

[1155] Example 111

[1156] first step

[1157] Following the synthesis of compound C-1, "3-bromo-4-methylbenzonitrile" was replaced with "6-bromo-5-methylnicotinonitrile", and "compound 1-1" was replaced with "compound 72a". The reaction yielded compound 111a (yellow solid, 150 mg, yield 46%).

[1158] LC-MS m / z(ESI) = 424.19 [M+1].

[1159] Step 2

[1160] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 111a" yielded compound 111b (white solid, 92 mg, 70% yield).

[1161] LC-MS m / z(ESI) = 457.21 [M+1].

[1162] Step 3

[1163] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 111b to give compound 111 (white solid, 100 mg, yield 85%).

[1164] 1 H NMR(400MHz,DMSO)δ8.90(d,1H),8.66–8.62(m,2H),8.41(s,1H),8.13(s,1H),8.08(d,1H),7.83(s,1H),7.18(d,1H) ,4.41–4.18(m,5H),4.13(s,3H),3.99(d,2H),3.60(s,3H),2.67(s,3H),1.22(s,1H),0.61–0.52(m,2H),0.40(d,2H).

[1165] LC-MS m / z(ESI) = 580.26 [M+1].

[1166] Example 112

[1167] first step

[1168] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole", and "compound B" was replaced with "compound 99a". The reaction yielded compound 112a (yellow solid, 112 mg, yield 40%).

[1169] LC-MS m / z(ESI) = 428.19 [M+1].

[1170] Step 2

[1171] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 112a" yields compound 112b (yellow solid, 60 mg, 50% yield).

[1172] LC-MS m / z(ESI) = 460.21 [M+1].

[1173] Step 3

[1174] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 112b to give compound 112 (yellow solid, 25 mg, yield 33%).

[1175] 1 H NMR(400MHz,DMSO)δ8.90(d,1H),8.66–8.61(m,2H),8.40(s,1H),8.08(d,1H),8.06(s,1H),7.85(s,1 H),7.18(d,1H),4.41–4.19(m,7H),4.12(s,3H),3.72(t,2H),3.60(s,3H),3.26(s,3H),2.67(s,3H).

[1176] LC-MS m / z(ESI) = 584.21 [M+1].

[1177] Example 113

[1178] first step

[1179] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "(R)-2-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethane-1-ol", and "compound B" was replaced with "compound 99a". The reaction yielded compound 113a (brown solid, 230 mg, yield 64%).

[1180] LC-MS m / z(ESI) = 458.10 [M+1].

[1181] Step 2

[1182] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 113a" yielded compound 113b (gray solid, 76 mg, yield 30%).

[1183] LC-MS m / z(ESI) = 490.12 [M+1].

[1184] Step 3

[1185] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 113b to obtain compound 113 (yellow solid, 40 mg, yield 43%).

[1186] 1 H NMR(400MHz,DMSO)δ8.89(s,1H),8.63(s,2H),8.39(s,1H),8.08(s,1H),8.03(s,1H),7.84(s,1H),7.18(s, 1H),5.20(d,1H),4.42–4.16(m,7H),4.13(d,3H),4.07–3.97(m,2H),3.60(s,3H),3.29(d,4H),2.66(s,3H).

[1187] LC-MS m / z (ESI) = 614.25 [M+1].

[1188] Example 114

[1189] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 72a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 92e" to obtain compound 114 (yellow solid, 18 mg, yield 40%).

[1190] 1 H NMR(400MHz,DMSO)δ8.99(d,1H),8.73(d,1H),8.65(s,1H),8.40(s,1H),8.13(s,1H),8.09(d,1H),7.84(s,1H),7.19(d, 1H),4.58–4.43(m,5H),4.14(s,3H),4.00(d,2H),3.18(s,3H),2.68(s,3H),0.86(t,1H),0.61–0.53(m,2H),0.40(q,2H).

[1191] LC-MS m / z(ESI) = 600.10[M+1].

[1192] Example 115

[1193] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 66a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 93a" to obtain compound 115 (yellow solid, 25 mg, yield 27%).

[1194] 1 H NMR (400MHz, DMSO) δ8.99(d,1H),8.75–8.68(m,2H),8.43(s,1H),8.29(s,1H),7.91(s,1H),7.09( d,1H),5.98–5.87(m,1H),4.63–4.34(m,4H),4.10(d,3H),3.97(s,3H),3.62(d,3H),2.67(s,3H).

[1195] LC-MS m / z(ESI) = 608.21 [M+1].

[1196] Example 116

[1197] first step

[1198] Following the synthesis of compound 80d, "methanesulfonic anhydride" was replaced with "compound 116a" and reacted with compound 92d to obtain compound 116b (white solid, 1.3 g, yield 65%).

[1199] LC-MS m / z(ESI) = 239.98 [M+1].

[1200] Step 2

[1201] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 66a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 116b" to obtain compound 116 (yellow solid, 25 mg, yield 27%).

[1202] 1 H NMR(400MHz,DMSO)δ8.99(d,1H),8.71(dd,2H),8.43(s,1H),8.29(s,1H),7.91(d,1H),7 .08(d,1H),5.68–5.55(m,1H),4.13(d,3H),3.97(s,3H),3.53–3.39(m,4H),2.67(s,3H).

[1203] LC-MS m / z (ESI) = 585.19 [M+1].

[1204] Example 117

[1205] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 72a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 116b" to obtain compound 117 (yellow solid, 70 mg, yield 53%).

[1206] 1 H NMR(400MHz,DMSO)δ8.97(d,1H),8.71(d,1H),8.65(s,1H),8.40(s,1H),8.13(s,1H),8.09(d,1H),7.84(s,1H),7.19(d,1H) ,5.67–5.55(m,1H),4.14(s,3H),3.98(t,2H),3.52–3.40(m,4H),2.67(s,3H),1.35(d,1H),0.62–0.53(m,2H),0.40(q,2H).

[1207] LC-MS m / z (ESI) = 557.24 [M+1].

[1208] Example 118

[1209] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 66a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 92e" to obtain compound 118 (yellow solid, 30 mg, yield 32%).

[1210] 1H NMR(400MHz,DMSO)δ9.01(d,1H),8.74(s,1H),8.44(s,1H),8.30(s,1H),7.92(s,1H),7.10(d, 1H),6.02–5.90(m,1H),4.54–4.46(m,4H),4.13(s,3H),3.97(s,3H),3.18(s,4H),2.68(s,3H).

[1211] LC-MS m / z (ESI) = 628.19 [M+1].

[1212] Example 119

[1213] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid". Compound 99c was reacted to give compound 119 (white solid, 17 mg, yield 15%).

[1214] 1 H NMR (400MHz, DMSO) δ8.92–8.87(m,1H),8.65–8.61(m,2H),8.40(s,1H),8. 15(s,1H),8.09–8.04(m,1H),7.84–7.79(m,1H),7.20–7.14(m,1H),4.44– 4.34(m,2H),4.33–4.26(m,1H),4.25–4.17(m,2H),4.12(s,3H),3.77–3.6 9(m,1H),3.60(s,3H),2.67(s,3H),1.10–1.04(m,2H),1.03–0.97(m,2H).

[1215] LC-MS m / z (ESI) = 566.23 [M+1].

[1216] Example 120

[1217] first step

[1218] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole", and "compound B" was replaced with "compound 99a". The reaction yielded compound 120b (yellow solid, 113 mg, yield 33%).

[1219] LC-MS m / z(ESI) = 424.19 [M+1].

[1220] Step 2

[1221] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 120b" yielded compound 120c (yellow solid, 110 mg, yield 88%).

[1222] LC-MS m / z(ESI) = 457.21 [M+1].

[1223] Step 3

[1224] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 120c to obtain compound 120 (yellow solid, 15 mg, yield 9%).

[1225] 1 H NMR(400MHz,DMSO)δ8.95–8.90(m,1H),8.67(s,1H),8.66–8.62(m,1H),8.4 2(s,1H),8.07–8.03(m,1H),7.92(s,1H),7.16–7.12(m,1H),4.41–4.35(m,2 H),4.32–4.26(m,1H),4.25–4.18(m,2H),4.13(s,3H),3.77(s,3H),3.60(s ,3H),2.68(s,3H),2.11–2.03(m,1H),0.94–0.89(m,2H),0.80–0.76(m,2H).

[1226] LC-MS m / z (ESI) = 580.25 [M+1].

[1227] Example 121

[1228] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "compound 116b" to obtain compound 121 (yellow solid, 50 mg, yield 43%).

[1229] 1H NMR (400MHz, DMSO) δ8.99–8.96(m,1H),8.72–8.69(m,1H),8.65(s,1H),8.40(s,1H),8.09–8.06(m,2H),7.84(s,1H),7.22–7. 17(m,1H),5.66–5.57(m,1H),4.95(s,1H),4.18–4.15(m,2H),4.13(s,3H),3.80–3.76(m,2H),3.48–3.38(m,4H),2.67(s,3H).

[1230] LC-MS m / z(ESI) = 547.22 [M+1].

[1231] Example 122

[1232] first step

[1233] According to the synthesis of compound 1-1,

[1234] The reaction was carried out by replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethyl)morpholine” and replacing “compound B” with “compound 99a” to obtain compound 122a (yellow solid, 237 mg, yield 47%).

[1235] LC-MS m / z(ESI) = 483.23 [M+1].

[1236] Step 2

[1237] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 122a" yielded compound 122b (brown solid, 200 mg, yield 81%).

[1238] LC-MS m / z(ESI) = 516.25 [M+1].

[1239] Step 3

[1240] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 122b to obtain compound 122 (brown solid, 22 mg, yield 15%).

[1241] 1H NMR (400MHz, DMSO) δ8.93–8.89(m,1H),8.67–8.63(m,2H),8.41(s,1H),8.10(s,1H),8.08–8.07(m,1H),7.84(s,1H),7.18–7.15(m,1H) ,4.42–4.34(m,2H),4.32–4.20(m,5H),4.12(s,3H),3.60(s,3H),3.59–3.55(m,4H),2.79–2.74(m,2H),2.67(s,3H),2.46–2.42(m,4H).

[1242] LC-MS m / z (ESI) = 639.28 [M+1].

[1243] Example 123

[1244] first step

[1245] Following the synthesis of compound 1-1, "1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole" was replaced with "2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethanol", and "compound B" was replaced with "compound 99a". The reaction yielded compound 123a (yellow solid, 164 mg, yield 36%).

[1246] LC-MS m / z(ESI) = 414.17 [M+1].

[1247] Step 2

[1248] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 123a" yielded compound 123b (brown solid, 130 mg, yield 83%).

[1249] LC-MS m / z(ESI) = 447.19 [M+1].

[1250] Step 3

[1251] According to the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "1-(methoxycarbonyl)azacyclobutane-3-carboxylic acid" and reacted with compound 123b to obtain compound 123 (white solid, 17 mg, yield 9%).

[1252] 1H NMR (400MHz, DMSO) δ8.92–8.89(m,1H),8.66–8.62(m,2H),8.41(s,1H),8.10–8.06(m,2H),7.86–7.83(m,1H),7.21–7.17(m,1H),5.02–4.92( m,1H),4.43–4.34(m,2H),4.33–4.26(m,1H),4.25–4.19(m,2H),4.18– 4.14(m,2H),4.12(s,3H),3.80–3.75(m,2H),3.60(s,3H),2.67(s,3H).

[1253] LC-MS m / z(ESI) = 570.22 [M+1].

[1254] Example 124

[1255] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 105a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 116b" to obtain compound 124 (yellow solid, 30 mg, yield 47%).

[1256] 1 H NMR (400MHz, DMSO) δ8.99–8.96(m,1H),8.72–8.69(m,1H),8.65(s,1H),8.40(s,1H),8.12–8.09(m,1H),8.04(s,1H),7.84( s,1H),7.20(s,1H),5.67–5.56(m,1H),4.77(s,1H),4.14(s,3H),4.04(s,2H),3.52–3.38(m,4H),2.67(s,3H),1.11(s,6H).

[1257] LC-MS m / z (ESI) = 575.25 [M+1].

[1258] Example 125

[1259] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 78a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 125 (white solid, 34 mg, yield 43%).

[1260] 1H NMR (400MHz, DMSO) δ8.66–8.63(m,2H),8.46–8.44(m,1H),8.34(s,1H),8.20(s,1H),8.17–8.14(m,1H),8.02(s,1H),7.26–7. 23(m,1H),6.77(s,1H),5.23–5.14(m,2H),4.13(s,3H),2.63(s,3H),2.24–2.15(m,1H),1.13–1.09(m,2H),0.98–0.92(m,2H).

[1261] LC-MS m / z(ESI) = 534.19 [M+1].

[1262] Example 126

[1263] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 22-1", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 126 (white solid, 27 mg, yield 31%).

[1264] 1 H NMR (400MHz, DMSO) δ8.65–8.63(m,1H),8.61(s,1H),8.46–8.43(m,1H),8.33(s,1H),8.09–8.06(m,2H),7.85(s,1H),7.20–7.17(m,1H),6.77(s, 1H),5.00–4.93(m,1H),4.19–4.15(m,2H),4.12(s,3H),3.81–3.74(m,2H ),2.63(s,3H),2.24–2.16(m,1H),1.14–1.08(m,2H),0.98–0.92(m,2H).

[1265] LC-MS m / z(ESI) = 496.21 [M+1].

[1266] Example 127

[1267] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 105a", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 127 (white solid, 28 mg, yield 40%).

[1268] 1H NMR (400MHz, DMSO) δ8.65–8.63(m,1H),8.61(s,1H),8.46–8.43(m,1H),8.32(s,1H),8.10–8.08(m,1H),8.03(s,1H),7.84(s,1H),7.20– 7.18(m,1H),6.76(s,1H),4.76(s,1H),4.12(s,3H),4.03(s,2H),2.62(s,3H),2.23–2.15(m,1H),1.12–1.08(m,8H),0.97–0.93(m,2H).

[1269] LC-MS m / z(ESI) = 524.24 [M+1].

[1270] Example 128

[1271] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 33a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 128 (yellow solid, 30 mg, yield 36%).

[1272] 1 H NMR (400MHz, DMSO) δ8.65–8.63(m,1H),8.62(s,1H),8.47–8.43(m,1H),8.34(s,1H),8.15(s,1H),8.10–8.04(m,1H),7.82(s,1H),7. 19–7.16(m,1H),6.76(s,1H),4.11(s,3H),3.77–3.71(m,1H),2.62(s,3H),2.23–2.15(m,1H),1.12–1.05(m,4H),1.03–0.94(m,4H).

[1273] LC-MS m / z(ESI) = 492.22 [M+1].

[1274] Example 129

[1275] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 78a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 129 (white solid, 60 mg, yield 71%).

[1276] 1H NMR (400MHz, DMSO) δ9.02–9.00(m,1H),8.75–8.72(m,1H),8.68(s,1H),8.42(s,1H),8.20(s,1H),8.18–8.15(m,1H),8.02( s,1H),7.28–7.25(m,1H),6.02–5.94(m,1H),5.24–5.14(m,2H),4.54–4.47(m,4H),4.15(s,3H),3.19(s,3H),2.68(s,3H).

[1277] LC-MS m / z (ESI) = 628.18 [M+1].

[1278] Example 130

[1279] first step

[1280] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)ethyl)morpholine” yielded compound 130a (yellow solid, 210 mg, yield 57%).

[1281] LC-MS m / z(ESI) = 367.19 [M+1].

[1282] Step 2

[1283] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 130a", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E". The reaction used compounds 103a and E to give compound 130 (yellow solid, 46 mg, yield 54%).

[1284] 1 H NMR (400MHz, DMSO) δ8.68–8.64(m,1H),8.61(s,1H),8.47–8.43(m,1H),8. 32(s,1H),8.10–8.05(m,2H),7.84(s,1H),7.14(s,1H),6.75(s,1H),4.27 –4.22(m,2H),4.11(s,3H),3.58–3.54(m,4H),2.79–2.72(m,2H),2.62(s, 3H),2.43(s,4H),2.22–2.13(m,1H),1.12–1.07(m,2H),0.96–0.91(m,2H).

[1285] LC-MS m / z (ESI) = 565.27 [M+1].

[1286] Example 131

[1287] first step

[1288] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 131a (yellow solid, 126 mg, yield 27%).

[1289] LC-MS m / z(ESI) = 318.12 [M+1].

[1290] Step 2

[1291] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 131a", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 131 (yellow solid, 27 mg, yield 32%).

[1292] 1 H NMR (400MHz, DMSO) δ8.70–8.62(m,2H),8.48–8.44(m,1H),8.16–8.11(m,2H),7.96(s,1H),7.24–7.20(m,1H),6.77(s,1H),6.57– 6.24(m,1H),5.78(t,1H),4.71–4.61(m,2H),4.13(s,3H),2.63(s,3H),2.24–2.16(m,1H),1.13–1.09(m,2H),0.98–0.93(m,2H).

[1293] LC-MS m / z(ESI) = 516.20 [M+1].

[1294] Example 132

[1295] first step

[1296] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” yielded compound 132a (yellow solid, 190 mg, yield 45%).

[1297] LC-MS m / z(ESI) = 300.13 [M+1].

[1298] Step 2

[1299] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 132a", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 132 (yellow solid, 30 mg, yield 40%).

[1300] 1 H NMR (400MHz, DMSO) δ8.66–8.61(m,2H),8.46–8.44(m,1H),8.33(s,1H),8.13(s,1H),8.11–8.09(m,1H),7.91(s,1H),7.23–7.18(m,1H) ,6.77(s,1H),4.89–4.73(m,2H),4.52–4.41(m,2H),4.12(s,3H),2.63(s,3H),2.23–2.16(m,1H),1.14–1.09(m,2H),0.98–0.92(m,2H).

[1301] LC-MS m / z(ESI) = 498.21 [M+1].

[1302] Example 133

[1303] first step

[1304] Compound 133a (5.0 g, 22.0 mmol) was dissolved in THF (150 mL) under nitrogen protection. LAH (2.48 g, 65.0 mmol) was added in portions at 0 °C, and the reaction was allowed to proceed gradually overnight at room temperature. The reaction progress was monitored by TLC.

[1305] The reaction was stopped, and water (10 mL) was slowly added dropwise to quench it. Then, 15% sodium hydroxide solution (20 mL) was added, followed by water (10 mL) to quench it. Anhydrous magnesium sulfate was then added for adsorption. The mixture was filtered to obtain the filtrate. The filter cake was washed three times with EA and then eluted by column chromatography with EA:PE = 1:3 to obtain compound 133b (yellow solid, 2.4 g, yield 40%).

[1306] LC-MS m / z(ESI) = 201.98 [M+1].

[1307] Step 2

[1308] Compound 133b (2.4 g, 12.1 mmol) was dissolved in DCM (40 mL) under nitrogen protection. Dess matin (10.3 g, 24.2 mmol) was added in portions at 0 °C and gradually incubated at room temperature for 1 h. The reaction progress was monitored by TLC.

[1309] The reaction was stopped, and the Dess matin was neutralized with sodium thiosulfate. The mixture was filtered, and the filtrate was adjusted to alkaline pH with saturated sodium bicarbonate solution. The mixture was extracted twice with DCM, followed by column chromatography with EA:PE = 1:10 elution to give compound 133c (yellow liquid, 2.0 g, yield 78%).

[1310] LC-MS m / z (ESI) = 199.96 [M+1].

[1311] Step 3

[1312] Cyclopropylacetylene (415.4 mg, 6.28 mmol) was dissolved in THF (30 mL) under nitrogen protection. 2.58 mL of n-butyllithium (6.47 mmol) was added dropwise at -78 °C and stirred at -78 °C for 2 h. Then, a THF mixture of compound 133c (500 mg, 2.5 mmol) was added dropwise, and the mixture was gradually reacted at room temperature for 2 h. The reaction progress was monitored by TLC.

[1313] The reaction was stopped, quenched with saturated ammonium chloride solution (10 mL), concentrated, extracted with EA, washed with brine, and then eluted by column chromatography with EA:PE = 1:4 to give compound 133d (yellow liquid, 240 mg, yield 45%).

[1314] LC-MS m / z(ESI) = 266.01 [M+1].

[1315] Step 4

[1316] Compound 133d (210.0 mg, 0.79 mmol) was dissolved in chloroform (30 mL), and manganese dioxide (1.03 g, 11.8 mmol) was added. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC.

[1317] The reaction was stopped, the mixture was filtered, and the filtrate was evaporated to dryness to give compound 133e (yellow liquid, 220 mg, yield 99%).

[1318] LC-MS m / z (ESI) = 263.99 [M+1]

[1319] Step 5

[1320] Compound 133d (200.0 mg, 0.76 mmol) was dissolved in 1,4-dioxane solution (12 mL) and water (6 mL). Hydroxylamine sulfonic acid (103.2 mg, 0.91 mmol) was added at 0 °C and stirred at room temperature for 8 h. Then sodium bicarbonate (67.1 mg, 0.79 mmol) and NaHS (44.7 mg, 0.79 mmol) were added, and the reaction was carried out at room temperature for 1 day. The reaction progress was monitored by TLC.

[1321] The reaction was stopped, concentrated, water was added, EA was extracted, brine was washed, and column chromatography was performed with EA:PE = 1:5 to elute, giving compound 133f (yellow solid, 93 mg, yield 44%).

[1322] LC-MS m / z(ESI) = 294.98 [M+1].

[1323] Step 6

[1324] Following the synthesis of compound C-1, replacing "3-bromo-4-methylbenzonitrile" with "compound 133f" yielded compound 133 (yellow solid, 17 mg, yield 21%).

[1325] 1 H NMR (400MHz, DMSO) δ8.76–8.74(m,1H),8.64–8.62(m,1H),8.60–8.58(m,1H),8.31(s,1H),8.08–8.06(m,1H),8.04(s,1H),7.83–7.81( m,1H),7.66(s,1H),7.17–7.15(m,1H),4.11(s,3H),3.87(s,3H),2.61(s,3H),2.40–2.33(m,1H),1.21–1.18(m,2H),0.92–0.88(m,2H).

[1326] LC-MS m / z(ESI) = 482.18 [M+1].

[1327] Example 134

[1328] Following the synthesis of compound 3, replacing "compound C" with "compound 102b" yielded compound 134 (light brown solid, 25 mg, yield 21%).

[1329] 1H NMR (400MHz, DMSO) δ8.93–8.90(m,1H),8.69–8.67(m,1H),8.65–8.63(m,1H),8.43(s,1H),8.20(s,1H),8.18–8.15(m,1 H),8.02(s,1H),7.28–7.23(m,1H),5.23–5.14(m,2H),4.14(s,3H),3.93–3.85(m,1H),3.25–3.04(m,4H),2.68(s,3H).

[1330] LC-MS m / z (ESI) = 585.18 [M+1].

[1331] Example 135

[1332] Following the synthesis of compound 3, replacing "compound C" with "compound 99c" yields compound 134 (resulting in compound 135 (white solid, 20 mg, yield 9%)).

[1333] 1 H NMR(400MHz,DMSO)δ8.90(s,1H),8.69–8.61(m,2H),8.41(s,1H),8.15(s,1H),8.08(s,1H),7.82(s,1H),7.19(s,1H),4 .12(s,3H),3.78–3.70(m,1H),3.19–3.08(m,4H),2.67(s,3H),2.04–1.92(m,1H),1.10–1.05(m,2H),1.02–0.96(m,2H).

[1334] LC-MS m / z(ESI) = 543.21 [M+1].

[1335] Example 136

[1336] first step

[1337] Compound 136c (300 mg, 1.5 mmol) and hydroxylamine aqueous solution (1 mL) were added to ethanol (15 mL) and refluxed at 80 °C for 3 h. The reaction progress was monitored by TLC.

[1338] The reaction was stopped, and the solution was directly evaporated to dryness to give compound 136a (yellow solid, 309 mg, yield 99%).

[1339] LC-MS m / z(ESI) = 214.97 [M+1].

[1340] Step 2

[1341] Compound 136a (222.0 mg, 1.04 mmol) and 3-ethynyl-1,1-difluorocyclobutane (243.0 mg, 2.08 mmol) were dissolved in methanol (10 mL) and water (2 mL). Bis[trifluoroacetoxy]iodobenzene (671.9 mg, 1.56 mmol) was added at 0 °C, and the reaction was gradually carried out at room temperature for 1 day. The reaction progress was monitored by TLC.

[1342] The reaction was stopped, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with EA. Then, column chromatography was performed to elute the extract with EA:PE = 1:10, yielding compound 136b (yellow solid, 230 mg, yield 85%).

[1343] LC-MS m / z(ESI) = 329.00 [M+1].

[1344] Step 3

[1345] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 78a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 136b" to obtain compound 136 (white solid, 14 mg, yield 19%).

[1346] 1 H NMR (400MHz, DMSO) δ8.71–8.63(m,2H),8.52–8.48(m,1H),8.36(s,1H),8.20(s,1H),8.18–8.14(m,1H),8.02(s,1H),7.26–7. 24(m,1H),7.09(s,1H),5.22–5.14(m,2H),4.13(s,3H),3.74–3.64(m,1H),3.19–3.08(m,2H),2.97–2.85(m,2H),2.64(s,3H)

[1347] LC-MS m / z (ESI) = 584.19 [M+1].

[1348] Example 137

[1349] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 123b to obtain compound 137 (brown solid, 4 mg, yield 5%).

[1350] 1H NMR (400MHz, DMSO) δ8.86–8.82(m,1H),8.67–8.62(m,2H),8.59–8.56(m,1H),8.44–8.37(m,1H),8.09–8.07(m,2H),7.85(s,1H),7.20–7.18( m,1H),4.97(s,1H),4.16–4.15(m,2H),4.13(s,3H),3.79–3.76(m,2H) ,3.12–3.03(m,1H),2.66(s,3H),2.01–1.93(m,1H),1.64–1.56(m,1H).

[1351] LC-MS m / z (ESI) = 515.20 [M+1].

[1352] Example 138

[1353] Following the synthesis of compound 3, replacing "compound C" with "compound 123b" yielded compound 138 (yellow solid, 12 mg, yield 8%).

[1354] 1 H NMR (400MHz, DMSO) δ8.91(s,1H),8.67–8.62(m,2H),8.42(s,1H),8.10–8.06(m,2H),7.85(s,1H),7.19(s,1H),5.04–4.92(m, 1H),4.19–4.15(m,2H),4.13(s,3H),3.92–3.86(m,1H),3.79–3.75(m,2H),3.23–3.16(m,2H),3.13–3.06(m,2H),2.67(s,3H).

[1355] LC-MS m / z(ESI) = 547.21 [M+1].

[1356] Example 139

[1357] first step

[1358] Following the method for compound 136a, "compound 133c" was replaced with "compound 139a" to obtain compound 139b (yellow solid, 208 mg, yield 99%).

[1359] LC-MS m / z(ESI) = 214.97 [M+1].

[1360] Step 2

[1361] Following the method for compound 136b, "compound 1336a" was replaced with "compound 139b" to obtain compound 139c (yellow solid, 210 mg, yield 82%).

[1362] LC-MS m / z(ESI) = 329.00 [M+1].

[1363] Step 3

[1364] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 78a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound 139c" to obtain compound 139 (white solid, 50 mg, yield 55%).

[1365] 1 H NMR (400MHz, DMSO) δ8.65–8.57(m,2H),8.49–8.46(m,1H),8.33(s,1H),8.21(s,1H),8.19–8.17(m,1H),8.02(s,1H),7.30–7. 27(m,1H),6.95(s,1H),5.22–5.15(m,2H),4.20(s,3H),3.73–3.64(m,1H),3.16–3.06(m,2H),2.96–2.85(m,2H),2.40(s,3H).

[1366] LC-MS m / z (ESI) = 584.19 [M+1].

[1367] Example 140

[1368] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 95a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 140 (white solid, 15 mg, yield 30%).

[1369] 1 H NMR (400MHz, DMSO) δ8.64–8.59(m,2H),8.44(d,1H),8.32(s,1H),8.12(s,1H),8.07(d,1H),7.83(s,1H),7.17(d,1H),6.76(s,1H),4.10(d,3H ),3.99(d,2H),2.62(s,3H),2.25–2.14(m,1H),1.30–1.26(m,1H),1.13 –1.06(m,2H),0.99–0.90(m,2H),0.60–0.53(m,2H),0.44–0.35(m,2H).

[1370] LC-MS m / z (ESI) = 506.23 [M+1].

[1371] Example 141

[1372] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 62a" and "3-bromo-4-methylbenzonitrile" was replaced with "compound E" to obtain compound 141 (white solid, 20 mg, yield 27%).

[1373] 1 H NMR(400MHz,DMSO)δ8.87(s,1H),8.68–8.63(m,2H),8.46–8.41(m,2H),8.35(s,1H),8.28(d,1H),7.3 7(d,1H),6.75(d,1H),4.13(d,3H),2.62(s,3H),2.19(dq,1H),1.14–1.06(m,2H),0.98–0.92(m,2H).

[1374] LC-MS m / z (ESI) = 520.17 [M+1].

[1375] Example 142

[1376] first step

[1377] Following the synthesis of compound 1-1, replacing “1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole” with “1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole-1-yl)piperidine” yielded compound 142a (yellow solid, 130 mg, yield 50%).

[1378] LC-MS m / z(ESI) = 350.20 [M+1].

[1379] Step 2

[1380] Following the synthesis of compound C-1, "compound 1-1" was replaced with "compound 142a", and "3-bromo-4-methylbenzonitrile" was replaced with "compound E". The reaction yielded compound 142 (white solid, 20 mg, yield 28%).

[1381] 1H NMR (400MHz, DMSO) δ8.66–8.62(m,2H),8.45(d,1H),8.37(s,1H),8.17(s,1H),8.10(d,1H),7.92(s,1H),7.20(d,1H),6.78(d,1H),4. 47(t,1H),4.12(d,3H),3.58(d,2H),3.20(s,2H),2.82(s,3H),2.63(d,3H),2.37–2.14(m,5H),1.14–1.06(m,2H),0.98–0.91(m,2H).

[1382] LC-MS m / z (ESI) = 549.29 [M+1].

[1383] Example 143

[1384] first step

[1385] Following the synthesis of compound 1-1, "3-bromo-4-methylbenzonitrile" was replaced with "6-bromo-5-methylnicotinonitrile" and reacted with compound 99a to give compound 143a (gray solid, 200 mg, yield 54%).

[1386] LC-MS m / z(ESI) = 467.24 [M+1].

[1387] Step 2

[1388] Following the synthesis of intermediate C, replacing "compound C-1" with "compound 143a" yielded compound 143b (grayish-brown solid, 110 mg, yield 49%).

[1389] LC-MS m / z(ESI) = 500.27 [M+1].

[1390] Step 3

[1391] Following the synthesis of compound 3, "3,3-difluorocyclobutane-1-carboxylic acid" was replaced with "(1R,2S)-2-fluorocyclopropane-1-carboxylic acid" and reacted with compound 143b to obtain compound 143 (yellow solid, 20 mg, yield 16%).

[1392] 1H NMR (400MHz, DMSO) δ8.82(d,1H),8.66(s,1H),8.56(s,1H),8.47(s,1H),8.16(s,1H),8.07(s,1H),7.84(s,1H),7. 18(s,1H),5.42–5.17(m,1H),4.11(s,3H),3.13–2.98(m,2H),2.87(d,2H),2.65(s,3H),2.20(d,3H),2.00(dq,8H).

[1393] LC-MS m / z (ESI) = 568.26 [M+1].

[1394] Example 144

[1395] Following the synthesis of compound C-1, replacing "compound 1-1" with "compound 142a" and "3-bromo-4-methylbenzonitrile" with "compound 136b" yielded compound 144 (yellow solid, 30 mg, yield 49%).

[1396] 1 H NMR (400MHz, DMSO) δ8.68(dd,1H),8.64(d,1H),8.48(d,1H),8.38(s,1H),8.19(s,1H),8.10(d,1H),7.91(s,1H),7.19(d,1H),7.08( d,1H),4.50–4.36(m,1H),4.11(s,3H),3.67(dd,2H),3.13(ddd,3H),2.97–2.82(m,4H),2.71(s,3H),2.63(s,3H),2.28–2.16(m,4H).

[1397] LC-MS m / z (ESI) = 599.29 [M+1].

[1398] Biological testing evaluation

[1399] I. Cell Proliferation Experiment

[1400] Experimental objective: The purpose of this test item is to measure the inhibitory effect of the compound on the proliferation of M07e-cKIT and SW579-PDGFRα cells.

[1401] 1. Experimental instruments and reagents:

[1402] 2.1 Instruments:

[1403] Table 2

[1404] 2.2 Reagents:

[1405] Table 3

[1406] 2. Experimental Methods:

[1407] 3.1 Cell Culture:

[1408] Human giant cell leukemia cells M07e (Nanjing Kebai Biotechnology Co., Ltd., CBP60791) were cultured in RPMI-1640 medium containing 20% ​​FBS, 1% penicillin antibiotics, and 10 ng / mL GM-CSF factor (Beyotime, P5286) at 37°C and 5% CO2. Human thyroid squamous cell carcinoma cells SW579 (BNCC, BNCC100182) were cultured in L-15 medium containing 10% FBS and 1% penicillin antibiotics at 37°C and 5% CO2.

[1409] 3.2 Cell proliferation experiment:

[1410] a) Seed cells in the logarithmic growth phase at a density of 3000 cells / well in 96-well plates and incubate overnight in a cell culture incubator.

[1411] b) The following day, the cells were treated with the appropriate drugs, starting with 3 μM of the compound and diluting it 3-fold, for a total of 9 concentration gradients. A blank control group and a negative control group were also set up. After adding the compound to the M07e cell treatment group, the cells were incubated in an incubator for 2 hours, followed by stimulation with rh-SCF (proteintech, HZ-1024) at a final concentration of 100 ng / mL.

[1412] c) Place the drug-treated well plate in an incubator (37°C, 5% CO2) and incubate for 4 days.

[1413] d) Add CellCounting-Lite 2.0 Luminescent solution (Vazyme, DD1101-03), place on a constant temperature shaker and shake for 2 min, then incubate at room temperature in the dark for 10 min.

[1414] e) Place the sample in an ELISA reader, shake for 5 seconds, and then perform a chemiluminescence reading.

[1415] f) Statistically analyze the data using Excel and Graphpad Prism, derive the dose-response curve using nonlinear S-curve regression, and calculate the IC50 from it. 50 value.

[1416] 3. Experimental Results and Discussion:

[1417] Table 4 KIT IC50 result

[1418] Note: KIT IC 50 If (nM)≤10, it is grade A; 10 <KIT IC 50 If (nM) ≤ 100, it is grade B; 100 <KIT IC 50 If (nM) ≤ 1000, it is grade C; 1000 <KIT IC 50 (nM) is grade D.

[1419] Table 5. Results of Selective Multiples

[1420] Note: Selectivity factor = PDGFRαIC 50 (nM) / KIT IC 50 (nM); if the selectivity multiple is ≥100, it is Grade A; if the selectivity multiple is ≤20 and <100, it is Grade B; if the selectivity multiple is ≤10 and <20, it is Grade C; if the selectivity multiple is <10, it is Grade D.

[1421] Experimental conclusions: The compounds of this invention exhibit varying degrees of activity against KIT at the cellular level and varying degrees of selectivity against PDGFRα.

[1422] The existing c-kit kinase inhibitors do not have selectivity for PDGFRα / β, CSF1R, and FLT3 kinases. The c-kit kinase inhibitor provided in this invention can achieve selective inhibition, which theoretically can reduce the toxic side effects caused by the inhibition of PDGFRα / β, CSF1R, FLT3, and other kinases, and is worthy of further research.

[1423] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or eutectic thereof: The A ring may or may not exist. When the A ring exists, the A ring is a 5-6 membered aromatic ring or a 5-6 membered heteroaromatic ring. The B ring is a 5-6 member aromatic ring or a 5-6 member heteroaromatic ring; The C ring is a 5-15 membered heterocyclic ring; R1 is H, C1-C6 alkyl, 3-5 membered cycloalkyl, C1-C6 haloalkyl or 3-5 membered halocycloalkyl; R2 is H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, alkenyl, alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 may optionally be further substituted by one or more R8s. R3 represents H, -NR5R6, and -(CH2). 0-3 -OR7, C1-C6 alkyl, halogen, -CN, -OH, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl or C3-C 10 Cycloalkenyl group, R3 optionally further substituted with one or more R8 groups; ring D is a 3- to 5-membered heterocycle containing a sulfone group (-SO2-); Ring B may be further substituted by one or more R4s, wherein R4 is a C1-C3 alkyl, a C1-C3 haloalkyl, or a halogen; R5, R6, R7, and each R8 are independently... H, -CN, -OH, -S(=O)2N(CH3)2, carbonyl, C3-C5 cycloalkenyl, C1-C6 alkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl or The 3-10 membered heterocyclic alkyl, C1-C6 alkyl, C3-C5 cycloalkenyl or carbonyl group may optionally be further surrounded by one or more -OH, halogen, -CN, alkenyl, alkynyl, or other radicals. Substituted with C1-C3 alkoxy, C1-C3 alkyl, 3-10 heterocyclic alkyl, 5-10 aryl, 5-10 heteroaryl, -D, C1-C3 alkylene-C1-C3 alkoxy or 3-5 cycloalkyl; X is N or C; The compound represented by formula (Ⅰ) contains 0, 1, or 2 R3s, each of which may be the same or different.

2. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, R3 is H, -NR5R6, -(CH2) 0-3 -OR7, C1-C6 alkyl, halogen, -CN, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, R3 optionally further substituted by one or more R8s; R5, R6, R7 and each R8 are independently... H, -CN, -OH, -S(=O)2N(CH3)2, carbonyl, C3-C5 cycloalkenyl, C1-C6 alkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C5 cycloalkenyl or carbonyl may optionally be further surrounded by one or more -OH, halogen, -CN, alkenyl, alkynyl, It is substituted by C1-C3 alkoxy, C1-C3 alkyl, 3-10 heterocyclic alkyl, 5-10 aryl or 5-10 heteroaryl.

3. The compound of formula (I) as described in claim 2, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, In the compound represented by formula (Ⅰ), R5, R6, R7 and each R8 are each independently... H, -CN, -OH, C1-C6 alkyl, -O-C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more -OH, halogen, -CN, alkenyl, ynyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl.

4. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, In each of the 5-6 membered heteroaryl rings, the 5-15 membered heteroaryl rings, the 3-10 membered heterocyclic alkyl groups and the 5-10 membered heteroaryl groups, the heteroatom is selected from one, two or three of N, O and S; preferably, the number of heteroatoms is one, two, three or four.

5. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound shown in formula (I) satisfies one or more of the following conditions: (1) In each of the 5-6 membered heteroaromatic rings, the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four; for example, each of the 5-6 membered heteroaromatic rings is independently... Furthermore, for example, the heteroatom is one of N, O, and S, and the number of heteroatoms is 1; for example, (2) Each of the 5-6 member aromatic rings is independently... (3) In the 5-15 membered heterocycle, the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four; more preferably, the heteroatom is one or two of N, O, and S, for example, the heteroatom is selected from a combination of N, N, and O or a combination of N and S; more preferably, the 5-15 membered heterocycle is a 5-10 membered heterocycle, preferably a 5-membered heteroaromatic ring or Wherein, ring Y is a 5-membered heteroaromatic ring, and ring Z is a 5-8 membered heterocyclic alkane; more preferably, the 5-8 membered heterocyclic alkane is Ideally, the 5-15 member heterocycle is (4) Each of the C1-C6 alkyl groups is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl, ethyl, n-propyl, or... More preferably, it is a C1-C3 alkyl group, such as methyl, ethyl, or n-propyl; (5) In each of the 5-10 member heteroaryl groups, the heteroatom is selected from one, two, or three types of N, O, and S, and the number of heteroatoms is one, two, or three; preferably, the heteroatom is one or two types of N and S, and the number of heteroatoms is one or two; more preferably, each of the 5-10 member heteroaryl groups is a 5-6 member heteroaryl group, such as pyrazolyl, thiazolyl, pyridinyl, or pyridazinyl, or for example... (6) Each of the 3-10 membered cycloalkyl groups is independently a 3-5 membered cycloalkyl group; preferably, the ring in each of the 3-5 membered cycloalkyl groups is independently a monocyclic, spirocyclic, or bridged ring, such as cyclopropyl, cyclobutyl, cyclopentyl, etc. (7) In each of the 3-10 membered heterocyclic alkyl groups, the heteroatom is selected from one, two, or three types of N, O, and S, and the number of heteroatoms is one, two, or three; preferably, the heteroatom is one or two types of N and O, and the number of heteroatoms is one or two; the ring in each of the 3-10 membered heterocyclic alkyl groups can be monocyclic or fused; more preferably, each of the 3-10 membered heterocyclic alkyl groups is a 3-6 membered heterocyclic alkyl group; the 3-6 membered heterocyclic alkyl group is preferably a monocyclic or bicyclic 3-6 membered heterocyclic alkyl group, such as tetrahydropyranyl, morpholinyl, piperidinyl, oxadiazonyl, tetrahydrofuranyl, oxadiazonyl, 3-oxadiazonyl[3.1.0]hexyl, preferably (8) Each of the C3-C 10 The cycloalkenyl group is independently a C3-C5 cycloalkenyl group; the C3-C5 cycloalkenyl group is, for example... (9) Each of the C1-C6 alkoxy groups is independently a C1-C3 alkoxy group, preferably a methoxy, ethoxy, n-propoxy or isopropoxy group; (10) Each of the 5-10 aryl groups is independently phenyl or naphthyl; (11) Each of the halogens is independently F, Cl, Br or I; (12) Each of the alkenyl groups is a C2-C6 alkenyl group; (13) Each of the alkyne groups is a C2-C6 alkyne group; (14) for 6. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound shown in formula (I) satisfies one or more of the following conditions: (1) R1 is a C1-C6 alkyl group; (2) R2 is H, C1-C6 alkyl, 5-10 heteroaryl, C1-C6 alkyl substituted with one or more R8 or 5-10 heteroaryl substituted with one or more R8; (3) R3 is H, -(CH2) 0-3 -OR7, C1-C6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C3-C 10 Cycloalkenyl, C1-C6 alkyl groups substituted with one or more R8 groups, 3-10 membered cycloalkyl groups substituted with one or more R8 groups, 3-10 membered heterocycloalkyl groups substituted with one or more R8 groups, or C3-C membered heterocycloalkyl groups substituted with one or more R8 groups. 10 Cycloalkenyl; (4) X is N; (5) Ring A is a 5-6 membered heteroaryl ring; (6) In R2, each R8 is independently a C1-C6 alkyl, 3-10 membered cycloalkyl, or 3-10 membered heterocycloalkyl, wherein the C1-C6 alkyl or 3-10 membered heterocycloalkyl is optionally further substituted by one or more -D, -OH, halogen, C1-C3 alkoxy, C1-C3 alkyl, 3-5 membered cycloalkyl, or 3-10 membered heterocycloalkyl; preferably, in R2, each R8 is independently -CH3, -CD3, -CH2OH, -CH2CH2OH, -CH2CH2F、-CH2CHF2、-CH2CF3、-CF3、-CH2CH2OCH3、 CH2-Cyclopropyl, Cyclopropyl, or -OH; (7) In R3, R7 is C 1-6 Alkyl, 3-10 membered cycloalkyl, or C substituted with one or more halogens 1-6 Alkyl group; preferably, in R3, R7 is -CH2CF3, methyl or cyclopropyl; (8) In R3, each R8 is independently -CN, -OH, -S(=O)2N(CH3)2, carbonyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, The carbonyl group is optionally further substituted with one or more C1-C3 alkoxy or C1-C3 alkylene-C1-C3 alkoxy groups; preferably, in R3, each R8 is independently -F, -OCH3, -OH, -CN, -Cl, cyclopropyl, -S(=O)2N(CH3)2, (9) The compound represented by formula (Ⅰ) contains 0 or 1 R3, preferably 1.

7. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound shown in formula (I) satisfies one or more of the following conditions: (1) R1 is H, methyl, ethyl or cyclopropyl; (2) R2 is H, In this case, R2 is further substituted with one or more halogens, 3-6 membered cycloalkyl groups, 3-6 membered heterocycloalkyl groups, or C1-C6 alkyl groups; the 3-6 membered heterocycloalkyl groups or C1-C6 alkyl groups are optionally further substituted with one or more -OH groups, halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-10 membered cycloalkyl groups, or 3-10 membered heterocycloalkyl groups. Preferably, R2 is In this case, R2 is further substituted with one or more halogens, 3-6 membered cycloalkyl groups, 3-6 membered heterocycloalkyl groups, or C1-C6 alkyl groups; the C1-C6 alkyl groups are optionally further substituted with one or more -OH groups; (3) R3 is H, -CH2OCH2CH3, -CH2OH, C1-C6 alkyl, At this time, R3 is further reacted with one or more -OH, -S(=O)2N(CH3)2, =Substituents of O, cyano, -O-CH3, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or C1-C6 alkyl; Preferably, R3 is At that time, R3 was further divided by one or more =Substituents of O, cyano, -O-CH3, halogen, or C1-C6 alkyl groups; (4) The B ring is a 6-membered aromatic ring, a 5-6-membered heteroaromatic ring, a 6-membered aromatic ring substituted by one or two R4s, or a 5-6-membered heteroaromatic ring substituted by one or two R4s. (5) The C ring is a 5-6 quinary heterocyclic aromatic ring, a 5-10 quinary bicyclic ring, or a 10-15 quinary tricyclic ring; wherein, any two connecting rings in the tricyclic ring can be fused or screwed together.

8. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound shown in formula (I) satisfies one or more of the following conditions: (1) R1 is methyl or ethyl; (2) R2 is H, methyl, (3) R3 is -H, -F, -OH, methoxy, methyl, ethyl, (4) Ring B is (5) C ring is Preferably, ring C is 9. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound shown in formula (I) is the same as the compound shown in formula (II): Wherein, ring B, ring C, R1, R2 and R3 are independently as described in any one of claims 1-8.

10. The compound of formula (I) as claimed in claim 9, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, in, Ring B is a benzene ring or a pyridine ring; C ring is R1 is H, C1-C6 alkyl, 3-5 membered cycloalkyl, C1-C6 haloalkyl or 3-5 membered halocycloalkyl; R2 is H, C1-C6 alkyl, halogen, 5-6 aryl, 3-6 heterocyclic alkyl or 5-6 heteroaryl; R3 is H, -(CH2)-OR7, C1-C6 alkyl, halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -OH or -O-CH3; R3 may optionally be further substituted by one or more R8s.

11. The compound of formula (I) as claimed in claim 1, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, characterized in that, The compound represented by formula (I) is selected from any one of the following:

12. A pharmaceutical composition comprising: (1) The compound of formula (I) as described in any one of claims 1-11, or its stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals; (2) Pharmaceutically acceptable carriers and / or excipients; and, (3) One or more other active ingredients may be selected.

13. The use of a compound, stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or cocrystal, or pharmaceutical composition as described in any one of claims 1-11, in the preparation of a medicament for treating c-kit kinase-related diseases.

14. The application as described in claim 13, characterized in that, The c-kit kinase-related diseases are gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, or melanoma.

15. The use of a compound, stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or cocrystal, or pharmaceutical composition as described in any one of claims 1-11, in the treatment of c-kit kinase-related diseases; preferably, the c-kit kinase-related diseases are gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, or melanoma.

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