Fibroblast growth factor receptor kinase inhibitors

Abstract

Provided herein are heteroaryl inhibitors of fibroblast growth factor receptor kinases, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat diseases.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Patent Application No. 63 / 106,812, filed October 28, 2020, and U.S. Patent Application No. 63 / 035,155, filed June 5, 2020, both of which are incorporated herein by reference in their entirety. Background Technology

[0003] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind to the fibroblast growth factor protein family. Dysregulation of the fibroblast growth factor / FGF receptor network occurs frequently in tumors. Therefore, therapies targeting aberrant FGFR kinase activity are needed to treat cancer and other conditions. Summary of the Invention

[0004] This article provides inhibitors of fibroblast growth factor receptor (FGFR) kinases, pharmaceutical compositions comprising said compounds, and methods of treating diseases using said compounds.

[0005] One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0006]

[0007] in,

[0008] Z is selected from groups having the following structures:

[0009]

[0010] t is 1 or 2;

[0011] R 1 R 2 and R 3 Each is independently selected from hydrogen, fluorine, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclic alkyl;

[0012] R 4 The nitrogen-containing 9 or 10-atom heteroaryl group is optionally substituted;

[0013] R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, optionally substituted C3-C7 heterocyclic alkyl, optionally substituted C2-C7 alkenyl, -CO2R 5 -CONHR 5 Or –CON(R) 5 )2;R5 Each is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, or optionally substituted C3-C7 heterocyclic alkyl; and

[0014] R 6 It can be an alkyl group that has been optionally substituted, a carbocycloalkyl group that has been optionally substituted, or a heterocycloalkyl group that has been optionally substituted.

[0015] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0016] One embodiment provides a method for treating a disease or condition in a patient in need, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or condition is cancer.

[0017] Incorporation

[0018] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes identified herein. Detailed Implementation

[0019] As used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include plural indicators. Thus, for example, reference to “an agent” includes multiple such agents, reference to “the cell” includes reference to one or more cells (or multiple cells) and their equivalents known to those skilled in the art, and so on. When the scope is used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments therein. When referring to a number or numerical range, the term “about” means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases, the number or numerical range will vary between 1% and 15% of that number or numerical range. The term “comprising” (and related terms such as “comprise / comprises”, “having”, or “including”) is not intended to exclude embodiments in which, for example, any embodiment of a material composition, composition, method, or process described herein is “composed of” or “substantially composed of” the described features.

[0020] definition

[0021] As used in the specification and appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0022] "Amino" refers to the –NH2 group.

[0023] "Cyano" refers to the -CN group.

[0024] "Nitro" refers to the -NO2 group.

[0025] "O-" refers to the -O- group.

[0026] "Oxo" refers to the =O group.

[0027] "Thio" refers to the =S group.

[0028] "Imine" refers to the =NH group.

[0029] "Oxime group" refers to the =N-OH group.

[0030] "Hydrazine" refers to the =N-NH2 group.

[0031] "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15Alkyl group. In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0032] "Alkoxy" refers to a group of the formula –O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0033] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In other embodiments, the alkenyl group contains 2 to 4 carbon atoms. The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, 1,4-dienyl, etc. Unless otherwise specifically stated in the specification, the alkenyl group may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R aEach of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0034] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group contains 2 to 6 carbon atoms. In still other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Unless otherwise specified in the specification, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R aEach of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0035] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain having 1 to 12 carbon atoms, with the remainder of a molecule attached to a non-unsaturated group consisting only of carbon and hydrogen, such as methylene, ethylene, propylene, butylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The connection point between the alkylene chain and the remainder of the molecule and the group is through one carbon atom or through any two carbons in the chain. In some embodiments, the alkylene comprises 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene comprises 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene comprises 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene comprises 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R)a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0036] A “olefinic” or “olefinic chain” refers to a straight-chain or branched divalent hydrocarbon chain in which the remainder of a molecule is attached to a group consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond and having 1 to 12 carbon atoms. The olefinic chain is connected to the remainder of the molecule by single bonds and to the group by single bonds. In some embodiments, the olefinic group contains 2 to 8 carbon atoms (e.g., C2-C8 olefinic). In other embodiments, the olefinic group contains 2 to 5 carbon atoms (e.g., C2-C5 olefinic). In other embodiments, the olefinic group contains 2 to 4 carbon atoms (e.g., C2-C4 olefinic). In other embodiments, the olefinic group contains 2 to 3 carbon atoms (e.g., C2-C3 olefinic). In other embodiments, the olefinic group contains 2 carbon atoms (e.g., C2 olefinic). In other embodiments, the olefinic group contains 5 to 8 carbon atoms (e.g., C5-C8 olefinic). In other embodiments, the alkenyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkenyl group). Unless otherwise specified in the specification, the alkenyl chain may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R)a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0037] A "hydrinyl" or "hydrinyl chain" refers to a straight-chain or branched divalent hydrocarbon chain in which the remainder of a molecule is attached to a group consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond and having 1 to 12 carbon atoms. The hydrinyl chain is connected to the remainder of the molecule by single bonds and to the group by single bonds. In some embodiments, the hydrinyl group contains 2 to 8 carbon atoms (e.g., C2-C8 hydrinyl). In other embodiments, the hydrinyl group contains 2 to 5 carbon atoms (e.g., C2-C5 hydrinyl). In other embodiments, the hydrinyl group contains 2 to 4 carbon atoms (e.g., C2-C4 hydrinyl). In other embodiments, the hydrinyl group contains 2 to 3 carbon atoms (e.g., C2-C3 hydrinyl). In other embodiments, the hydrinyl group contains two carbon atoms (e.g., C2 hydrinyl). In other embodiments, the hydrinyl group contains 5 to 8 carbon atoms (e.g., C5-C8 hydrinyl). In other embodiments, the ynylene group comprises 3 to 5 carbon atoms (e.g., C3-C5 ynylene). Unless otherwise specified in the specification, the ynylene chain may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R aEach of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0038] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and 5 to 18 carbon atoms, wherein at least one ring in the ring system is completely unsaturated, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2)π– electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, naphthalene, and naphthalene. Unless otherwise specified in the specification, the term "aryl" or the prefix "aromatic-" (as in "arylalkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(Ra )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), R b Each is independently a direct bond or a straight chain or a branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0039] "Aryl group" refers to the formula -R c -aryl groups, where R c The alkylene chain is as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted with the alkylene chain as described above. The aryl portion of the aralkyl group is optionally substituted with the aryl group as described above.

[0040] "Aryl" refers to the formula –R d -aryl groups, where R d It is an alkenyl chain as defined above. The aryl portion of the aryl group is optionally substituted with an aryl group as described above. The alkenyl chain portion of the aryl group is optionally substituted with an alkenyl group as described above.

[0041] "Arotyne group" refers to the formula -R e -aryl groups, where R e It is an ynyl chain as defined above. The aryl portion of the aryynyl group is optionally substituted with an aryl group as described above. The ynyl chain portion of the aryynyl group is optionally substituted with an ynyl chain as described above.

[0042] "Arylalkoxy group" refers to the group with the formula -OR bonded by an oxygen atom. c -aryl groups, where R c The alkylene chain is as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted with the alkylene chain as described above. The aryl portion of the aralkyl group is optionally substituted with the aryl group as described above.

[0043] A "carbocyclic group" is a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems, having 3 to 15 carbon atoms. In some embodiments, the carbocyclic group contains 3 to 10 carbon atoms. In other embodiments, the carbocyclic group contains 5 to 7 carbon atoms. The carbocyclic group is connected to the rest of the molecule by a single bond. The carbocyclic group is saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclic groups are also called "cycloalkyl groups". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic groups are also called "cycloalkenyl groups". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclic [2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclic [2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclic" is intended to include a carbocyclic group optionally substituted with one or more substituents, which are independently selected from alkyl, alkenyl, ynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)Ra -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), R b Each is independently a direct bond or a straight chain or a branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0044] "Carbocycloalkyl" refers to the formula –R c - A carbocyclic group, wherein R c It is an alkylene chain as defined above. The alkylene chain and carbocyclic group may optionally be substituted as defined above.

[0045] "Carbocyclic ynyl group" refers to the formula –R c - A carbocyclic group, wherein R c It is an ynylene chain as defined above. The ynylene chain and carbocyclic group are optionally substituted as defined above.

[0046] "Carbocycloalkoxy group" refers to the group bonded by an oxygen atom using the formula –OR c - A carbocyclic group, wherein R c It is an alkylene chain as defined above. The alkylene chain and carbocyclic group may optionally be substituted as defined above.

[0047] As used herein, "carboxylic acid bioisosteres" refers to functional groups or moieties that exhibit similar physical, biological, and / or chemical properties to the carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0048]

[0049] wait.

[0050] "Halogen" or "halogenated" refers to a bromine, chlorine, fluorine, or iodine substituent.

[0051] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be substituted as defined above for alkyl groups.

[0052] A "heterocyclic group" refers to a stable 3-18 membered non-aromatic cyclic group comprising 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, optionally including fused-ring or bridged-ring systems. The heteroatoms in the heterocyclic group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclic group is partially or fully saturated. The heterocyclic group is connected to the remainder of the molecule through any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclic" is intended to include heterocyclic groups as defined above, which are optionally substituted with one or more substituents selected from: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(Ra )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a Each of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), R b Each is independently a direct bond or a straight chain or a branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0053] "N-heterocyclic group" or "N-linked heterocyclic group" refers to a heterocyclic group as defined above containing at least one nitrogen atom, wherein the connection point between the heterocyclic group and the remainder of the molecule is through a nitrogen atom in the heterocyclic group. The N-heterocyclic group may optionally be substituted as described above with respect to heterocyclic groups. Examples of such N-heterocyclic groups include, but are not limited to, 1-morpholino, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolyl, imidazolinyl, and imidazolinyl.

[0054] A “C-heterocyclic group” or “C-linked heterocyclic group” refers to a heterocyclic group as defined above containing at least one heteroatom, wherein the connection point between the heterocyclic group and the remainder of the molecule is through a carbon atom in the heterocyclic group. The C-heterocyclic group may optionally be substituted as described above with respect to heterocyclic groups. Examples of such C-heterocyclic groups include, but are not limited to, 2-morpholino, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, etc.

[0055] "Heterocyclic alkyl" refers to the formula –R c - A heterocyclic group, wherein R c The alkylene chain is as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as described above regarding alkylene chains. The heterocyclic moiety of the heterocyclic alkyl group is optionally substituted as described above regarding heterocyclic groups.

[0056] "Heterocyclic alkoxy" refers to a compound with the formula –OR, bonded by an oxygen atom. c - A heterocyclic group, wherein R c The alkylene chain is as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkoxy group is optionally substituted as described above regarding alkylene chains. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as described above regarding heterocyclic groups.

[0057] "Heteroaryl" refers to a group derived from a 3-18 membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls are monocyclic, bicyclic, tricyclic, or tetracyclic systems in which at least one ring is fully unsaturated, i.e., according to Hückel's theory, it contains a cyclic, delocalized (4n+2)-electron system. Heteroaryls include fused-ring or bridged-ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl group is connected to the rest of the molecule via any atom of the ring.Examples of heteroaryl groups include, but are not limited to, azatril, benzimidazolyl, benzoindolyl, 1,3-benzo[2]dioxazolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxazolyl ethane, benzonaphthofuranyl, benzooxazolyl, benzo[2]dioxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzophenylthio), benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[ 1,2-a]pyridyl, carbazole, cyclopentadien[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadien[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cyrolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridinyl, isothiazyl Azolyl, imidazole, indazole, indole, indazole, isoindole, dihydroindole, isoindole, isoquinolinyl, indazinyl, isozolyl, 5,8-bridged methylene-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphthidone, oxadiazolyl, 2-oxoachenginyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2- [d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5Hcycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and phenylthio (i.e., thienoyl).Unless otherwise specified in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, which are optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halo, fluoroalkyl, haloalkenyl, haloynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arene, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R aEach of the following is independently hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), R b Each is independently a direct bond or a straight chain or a branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0058] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection point between the heteroaryl group and the rest of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group may optionally be substituted as described above with respect to heteroaryl groups.

[0059] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the connection point between the heteroaryl group and the rest of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group may be optionally substituted as described above regarding heteroaryl groups.

[0060] "Heteroarylalkyl" refers to the formula –R c - A heteroaryl group, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroaryl alkyl group is optionally substituted with an alkylene chain as defined above. The heteroaryl portion of the heteroaryl alkyl group is optionally substituted with a heteroaryl group as defined above.

[0061] "Heteroarylalkoxy" refers to the formula –OR, which is bonded by oxygen atoms. c - A heteroaryl group, wherein R c The alkylene chain is as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted with an alkylene chain as defined above. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted with a heteroaryl group as defined above.

[0062] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers, defined by absolute stereochemistry as (R)- or (S). Unless otherwise stated, all stereoisomers of the compounds disclosed herein are considered in this disclosure. When the compounds described herein contain an alkene double bond, and unless otherwise specified, this disclosure is intended to include E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms and all tautomers, are included. The term "geometric isomer" refers to the E or Z geometric isomer of the alkene double bond (e.g., cis or trans). The term "positional isomer" refers to a structural isomer surrounding a central ring, such as ortho, meta, and para isomers surrounding a benzene ring.

[0063] A "tautomer" is a molecule in which a proton can move from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds provided herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0064]

[0065] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, such as enriched isotopes. 2 H, 3 H, 11 C 13 C and / or 14 The content of C. In one specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0066] Unless otherwise stated, the structures described herein are intended to include compounds distinguished solely by the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this disclosure.

[0067] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may be labeled with isotopes, such as deuterium (…).2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br、 125 Isotopic substitution of I is anticipated. In some implementation schemes, it is expected that... 18 Isotopic substitution of F. All isotopic variants of the compounds of this invention, whether radioactive or not, are included within the scope of this invention.

[0068] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and the following synthetic methods are included only as non-limiting examples.

[0069] Deuterium-substituted compounds are synthesized using various methods, as described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0070] Deuterated starting materials are readily available, and the synthetic methods described herein are used to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and structural units are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0071] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer deuterated carbon atoms to the reaction substrate under nucleophilic substitution conditions. The use of CD3I is illustrated only as an example in the following reaction schemes.

[0072]

[0073] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated by way of example only in the reaction schemes below.

[0074]

[0075] The reduction of unsaturated carbon-carbon bonds and the reduction substitution of aryl carbon-halogen bonds are carried out using deuterium and palladium catalysts, as illustrated by way of example only in the following reaction schemes.

[0076]

[0077] In one embodiment, the compound disclosed herein contains one deuterium atom. In another embodiment, the compound disclosed herein contains two deuterium atoms. In another embodiment, the compound disclosed herein contains three deuterium atoms. In another embodiment, the compound disclosed herein contains four deuterium atoms. In another embodiment, the compound disclosed herein contains five deuterium atoms. In another embodiment, the compound disclosed herein contains five deuterium atoms. In another embodiment, the compound disclosed herein contains more than six deuterium atoms. In another embodiment, the compound disclosed herein is completely substituted with deuterium atoms and does not contain non-commutative atoms. 1 H hydrogen atoms. In one embodiment, the deuterium doping level is determined by a synthetic method in which deuterated synthetic structural units are used as raw materials.

[0078] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. The pharmaceutically acceptable salts of any fibroblast growth factor receptor (FGFR) inhibitor compound described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0079] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and form with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. This also includes salts formed with organic acids, such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids, such as arginine salts, gluconates, and galacturons, are also considered (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, an acid addition salt of a basic compound is prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0080] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the bioavailability and properties of the free acid, and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts form with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following substances: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, heptaamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., ibid.

[0081] A "pharmaceutically acceptable solvate" refers to a composition of substances in the form of a solvation addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during preparation using a pharmaceutically acceptable solvent such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. The compounds provided herein are present in either a non-solventized or solvated form.

[0082] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one implementation, the mammal is a human.

[0083] As used herein, the terms “treatment / treating,” “palliating,” or “ameliorating” are used interchangeably. These terms refer to methods of achieving a beneficial or desired outcome, including but not limited to therapeutic and / or preventative benefits. A “therapeutic benefit” means the eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, resulting in an observed improvement in a patient, even though the patient still has the underlying condition. In some embodiments, for the purpose of preventative benefit, the composition is administered to a patient at risk of developing a specific disease, or to a patient reporting one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0084] Fibroblast growth factor receptor (FGFR)

[0085] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) and members of the family of proteins that bind fibroblast growth factor. FGFR genes typically contain 18 exons with similar exon-intron structures and are randomly distributed throughout the genome, without obvious connections to FGF gene locations. FGFRs are differentially expressed in a tissue-specific manner throughout development and adulthood and contain an extracellular ligand-binding domain, a single transmembrane domain, and a dividing intracellular kinase domain. The extracellular region contains 2–3 immunoglobulin (Ig)-like domains involved in FGF binding. These Ig-like domains regulate ligand affinity and ligand specificity. The intracellular region contains functional domains responsible for FGFR tyrosine kinase activity, as well as additional sites that play a role in protein binding and phosphorylation or autophosphorylation of the receptor molecule. Porta et al. (Criticial Reviews in Oncology / Hematology 113(2017)256-67) and Babina and Turner (Nature Review-Cancer 2017 doi:10.1038 / nrc.2017.8).

[0086] The FGFR family comprises four members—FGFR1, FGFR2, FGFR3, and FGFR4—but these four members can generate multiple receptor isotypes through alternative splicing of the primary transcript. Recently, based on the interaction with the FGFR binding ligand (called fibroblast growth factor (FGF)), a closely associated receptor lacking the FGF signaling tyrosine kinase domain was discovered, FGFR5 (also known as FGFRL1) (Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 2011; 68(6):951–964). In summary, FGFR signaling is associated with the activation and response of multiple cellular cascades (such as cell growth, proliferation, differentiation, and survival) (Thisse B et al., Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol. 2005; 287(2):390-402; Wesche et al., Fibroblast growth factors and their receptors in cancer. Biochem J. 2011; 437(2):199–213; Haugsten EM et al., Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res. 2010; 8(11):1439-1452).

[0087] Many human pathological conditions are associated with dysregulation of FGFR signaling. Aberrant FGFR signaling is primarily attributed to several underlying mechanisms, including gene amplification, gain-of-function coding mutations, gene fusions, single nucleotide polymorphisms (SNPs), ligand availability, and impaired termination procedures in FGF-mediated signaling (Tiong KH et al., Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis. 2013; 18(12):1447-68). Furthermore, the alternative splicing of FGFRs, resulting in multiple isoforms that can promote or inhibit tumorigenesis under different conditions, adds another layer of complexity.

[0088] FGFR fusion

[0089] FGFR fusion proteins in human cancers are classified into type 1 fusion proteins caused by chromosomal translocations in hematologic malignancies and type 2 fusion proteins caused by chromosomal rearrangements in solid tumors (FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med. 2016; 38(1):3-15). Both types of FGFR fusion proteins are endowed with oncogenic potential by obtaining protein-protein interaction modules from fusion partner proteins used for ligand-independent dimerization and / or recruitment of aberrant substrates. Human FGFR fusion proteins typically consist of two main segments—the first segment is a dimerization domain derived from the partner gene, and the second segment is a tyrosine kinase domain (Garcia-Closas M et al., Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet. 2008; 4(4):e1000054). Unlike wild-type receptors, mutant FGFRs are expressed intracellularly and retained in the cytosol, thus escaping typical receptor degradation processes and further prolonging activation signals.

[0090] Dysregulation of the fibroblast growth factor (FGF) / FGF receptor (FGFR) network occurs frequently in tumors, making the development of FGF / FGFR-targeted therapies a focus of several basic, preclinical, and clinical studies.

[0091] Heteroaromatic FGFR inhibitory compounds

[0092] In one respect, this article provides a heteroaromatic FGFR inhibitory compound.

[0093] One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0094]

[0095] in,

[0096] Z is selected from groups having the following structures:

[0097]

[0098] t is 1 or 2;

[0099] R 1 R 2 and R 3 Each is independently selected from hydrogen, fluorine, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclic alkyl;

[0100] R 4 The nitrogen-containing 9 or 10-atom heteroaryl group is optionally substituted;

[0101] R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, optionally substituted C3-C7 heterocyclic alkyl, optionally substituted C2-C7 alkenyl, -CO2R 5 -CONHR 5 Or –CON(R) 5 )2;R 5 Each is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, or optionally substituted C3-C7 heterocyclic alkyl; and

[0102] R 6 It can be an alkyl group that has been optionally substituted, a carbocycloalkyl group that has been optionally substituted, or a heterocycloalkyl group that has been optionally substituted.

[0103] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. 3 It is hydrogen or fluorine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen or fluorine. 2 and R 3 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. 1 The alkyl group is optionally substituted with a C1-C4 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 1 The alkyl group is optionally substituted with a C1-C2 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R...1 The substituted C1 alkyl group is optionally substituted. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted alkyl group is substituted with an optionally substituted amino group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted amino group is dimethylamino.

[0104] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The aryl group is selected from optionally substituted nitrogen-containing 9- or 10-atom heteroaryl groups, specifically from optionally substituted benzimidazole, optionally substituted 1H-indazole, optionally substituted 2H-indazole, optionally substituted benzotriazole, optionally substituted benzoxazole, optionally substituted imidazo[4,5-c]pyridine, or optionally substituted imidazo[4,5-b]pyridine. Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof, wherein R... 4 The aryl group is selected from optionally substituted nitrogen-containing 9- or 10-atom heteroaryl groups, specifically quinoline, quinoxaline, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, imidazo[1,2-b]pyridazine, or pyrazolo[1,5-a]pyrimidine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 4 The alternative embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted benzimidazole. 4 The substituted 1H-indazole is used. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 4 The substituted 2H-indazole is used. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R... 4 The alternative is a substituted benzoxazole, a substituted imidazo[4,5-c]pyridine, or a substituted imidazo[4,5-b]pyridine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted nitrogen-containing 9 or 10-atom heteroaryl group is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted benzimidazole is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted 1H-indazole is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted 2H-indazole is optionally substituted with an alkyl, cycloalkyl, or halogen.

[0105] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C1-C6 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C3-C7 carbocyclic group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C3-C7 carbocyclic alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C3-C7 heterocyclic group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C3-C7 heterocyclic alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CO2R. 5 Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CONHR. 5 Or –CON(R) 5 2. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl group is a C1-C3 alkyl group substituted with a C1-C3 alkoxy group.

[0106] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 The alkyl group is optionally substituted. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R... 6 The alkyl group is optionally substituted with a C1-C4 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The alkyl group is optionally substituted with a C1-C3 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The alkyl group is optionally substituted with a C1-C2 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted C1 alkyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 It is CH3.

[0107] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 R is an optionally substituted carbocycloalkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 6The substituted carbocyclic methyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The methyl group is optionally substituted (C3-C6 carbocyclic) methyl. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted cyclopropylmethyl group is optionally present. Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted heterocyclic alkyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted heterocyclic ethyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The heterocyclic ethyl group is optionally substituted and the heterocyclic group is piperidinyl, pyrrolidinyl, morpholinyl or piperazine.

[0108] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The optional substituted benzimidazole is further substituted with a cycloalkyl group and at least one halogen.

[0109] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The benzimidazole is optionally substituted, further substituted with a cycloalkyl group and at least one halogen; R is a -CH2OCH3 group; and R 6 It is a methyl group.

[0110] Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The benzimidazole is optionally substituted, further substituted with a cycloalkyl group and at least one halogen; R is hydrogen; and R 6 It is a methyl group.

[0111] One embodiment provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0112]

[0113] in,

[0114] n is 0 or 1;

[0115] Z is selected from groups having the following structures:

[0116]

[0117] t is 1 or 2;

[0118] R 1 R 2 and R 3 Each is independently selected from hydrogen, fluorine, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclic alkyl;

[0119] R 4 The nitrogen-containing 9 or 10-atom heteroaryl group is optionally substituted;

[0120] R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, optionally substituted C3-C7 heterocyclic alkyl, optionally substituted C2-C7 alkenyl, -CO2R 5 -CONHR 5 Or –CON(R) 5 )2;

[0121] R 5 Each is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted C3-C7 carbocyclic alkyl, optionally substituted C3-C7 heterocyclic, or optionally substituted C3-C7 heterocyclic alkyl; and

[0122] R 6 It is hydrogen, an optionally substituted alkyl group, an optionally substituted carbocyclic group, an optionally substituted carbocyclic alkyl group, or an optionally substituted heterocyclic alkyl group.

[0123] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0124] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and the stereochemistry of the pyrrolidine ring is cis. Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and the stereochemistry of the pyrrolidine ring is trans.

[0125] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. 3 It is hydrogen or fluorine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen or fluorine. 2and R 3 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. 1 For hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. 1 The alkyl group is optionally substituted with a C1-C4 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 1 The alkyl group is optionally substituted with a C1-C2 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 1 The substituted C1 alkyl group is optionally substituted. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted alkyl group is substituted with an optionally substituted amino group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted amino group is dimethylamino.

[0126] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The aryl group is selected from optionally substituted nitrogen-containing 9- or 10-atom heteroaryl groups, specifically from optionally substituted benzimidazole, optionally substituted 1H-indazole, optionally substituted 2H-indazole, optionally substituted benzotriazole, optionally substituted benzoxazole, optionally substituted imidazo[4,5-c]pyridine, or optionally substituted imidazo[4,5-b]pyridine. Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvation thereof, wherein R... 4 The aryl group is selected from optionally substituted nitrogen-containing 9- or 10-atom heteroaryl groups, specifically quinoline, quinoxaline, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, imidazo[1,2-b]pyridazine, or pyrazolo[1,5-a]pyrimidine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 4 The alternative embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted benzimidazole. 4 The substituted 1H-indazole is used. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 4 The substituted 2H-indazole is used. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R... 4The alternative is a substituted benzoxazole, a substituted imidazo[4,5-c]pyridine, or a substituted imidazo[4,5-b]pyridine. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted nitrogen-containing 9 or 10-atom heteroaryl group is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted benzimidazole is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted 1H-indazole is optionally substituted with an alkyl, cycloalkyl, or halogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein the optionally substituted 2H-indazole is optionally substituted with an alkyl, cycloalkyl, or halogen.

[0127] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvation thereof, wherein R is hydrogen. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is an optionally substituted C1-C6 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is an optionally substituted C3-C7 carbocyclic group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is an optionally substituted C3-C7 carbocyclic alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is an optionally substituted C3-C7 heterocyclic group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is an optionally substituted C3-C7 heterocyclic alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R is -CO2R. 5 Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CONHR. 5 Or –CON(R) 5 2. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl group is a C1-C3 alkyl group substituted with a C1-C3 alkoxy group.

[0128] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is hydrogen.

[0129] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 The alkyl group is optionally substituted. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvation thereof, wherein R... 6The alkyl group is optionally substituted with a C1-C4 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The alkyl group is optionally substituted with a C1-C3 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The alkyl group is optionally substituted with a C1-C2 alkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted C1 alkyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 It is CH3.

[0130] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 R is an optionally substituted carbocycloalkyl group. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 The substituted carbocyclic methyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The methyl group is optionally substituted (C3-C6 carbocyclic) methyl. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted cyclopropylmethyl group is optionally present. Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted heterocyclic alkyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The substituted heterocyclic ethyl group is optionally present. Another embodiment provides the compound or a pharmaceutically acceptable salt or solvate thereof, wherein R... 6 The heterocyclic ethyl group is optionally substituted and the heterocyclic group is piperidinyl, pyrrolidinyl, morpholinyl or piperazine.

[0131] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The optional substituted benzimidazole is further substituted with a cycloalkyl group and at least one halogen.

[0132] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The benzimidazole is optionally substituted, further substituted with a cycloalkyl group and at least one halogen; R is a -CH2OCH3 group; and R 6 It is a methyl group.

[0133] Another embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 The benzimidazole is optionally substituted, further substituted with a cycloalkyl group and at least one halogen; R is hydrogen; and R 6 It is a methyl group.

[0134] In some embodiments, the heteroaromatic FGFR kinase inhibitory compounds disclosed herein have the structures provided in Table 1.

[0135] Table 1

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] In some embodiments, the heteroaromatic FGFR kinase inhibitory compounds disclosed herein have the structures provided in Table 2.

[0231] Table 2

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242] Preparation of compounds

[0243] The compounds used in the reactions described herein were prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman OrganicChemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0244] Suitable reference books and papers that detail the synthesis of reactants used to prepare the compounds described herein or provide reference to articles describing the preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SRSandler et al., "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd ed., WABenjamin, Inc., Menlo Park, Calif., 1972; TL Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., Wiley-Interscience, New York, 1992. Other suitable references and papers that detail the synthesis of reactants used to prepare the compounds described herein or provide reference to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G., *Organic Synthesis: Concepts, Methods, Starting Materials*, Second Revised Edition (1994), John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV., *Organic Chemistry, An Intermediate Text* (1996), Oxford University Press, ISBN 0-19-509618-5; Larock, RC., *Comprehensive Organic Transformations: A Guide to Functional Group Preparations*, 2nd Edition (1999), Wiley-VCH, ISBN: 0-471-19031-4; March, J., *Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 4th Edition (1992), John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV., *Organic Chemistry: Concepts, Methods, Starting Materials*, Second Revised Edition (1994), John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV., *Organic Chemistry: Concepts, Methods, Starting Materials* (1996), Oxford University Press, ISBN: 0-19-509618-5; Larock, RC., *Comprehensive Organic Transformations: A Guide to Functional Group Preparations*, 2nd Edition (1999), Wiley-VCH, ISBN: 0-471-19031-4; March, J., *Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 4th Edition (1992), John Wiley & Sons, ISBN: 3-527-29074-5 Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"(1999)John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942–2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups," John Wiley & Sons, over 73 volumes.

[0245] Specific and similar reactants are optionally identified by an index of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries as well as through online databases (contact the American Chemical Society, Washington, D.C. for more details). Known but not commercially available chemicals in the catalogue are optionally prepared by custom chemical synthesis facilities, many of which provide custom synthesis services to standard chemical suppliers (e.g., those listed above). A reference for the preparation and selection of pharmaceutical salts used for the compounds described herein is PHStahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0246] Pharmaceutical Composition

[0247] In some embodiments, the heteroaromatic FGFR kinase inhibitors described herein are administered as pure chemicals. In other embodiments, the heteroaromatic FGFR kinase inhibitors described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected based on, for example, the chosen route of administration and standard pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0248] This document provides pharmaceutical compositions comprising at least one heteroaromatic FGFR kinase inhibitory compound or its stereoisomer described herein, a pharmaceutically acceptable salt, hydrate or solvate, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient of the composition (i.e., the subject or patient).

[0249] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0250] One embodiment provides a method for preparing a pharmaceutical composition, the method comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0251] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound as described in formula (I) or its pharmaceutically acceptable salt or solvate is substantially pure because it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated in one or more steps of the synthetic method.

[0252] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof.

[0253] One embodiment provides a method for preparing a pharmaceutical composition, the method comprising mixing a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0254] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound as described in formula (II) or its pharmaceutically acceptable salt or solvate is substantially pure because it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated in one or more steps of the synthetic method.

[0255] Suitable oral dosage forms include tablets, pills, capsules, or pouches, such as hard or soft gelatin, methylcellulose, or other suitable materials that readily dissolve in the digestive tract. In some embodiments, a suitable non-toxic solid carrier is used, including, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)) as described in the chosen route of administration and standard pharmaceutical practice.

[0256] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some cases, the injectable formulation is an aqueous formulation. In some cases, the injectable formulation is a non-aqueous formulation. In some cases, the injectable formulation is an oil-based formulation, such as sesame oil.

[0257] The dosage of a composition comprising at least one heteroaromatic FGFR kinase inhibitory compound as described herein varies depending on the condition of the subject or patient (e.g., a person). In some embodiments, these factors include general health status, age, and other factors.

[0258] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dosage and treatment regimen provides an amount of the composition sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's body mass, weight, or blood volume.

[0259] The oral dosage is usually from about 1.0 mg to about 1000 mg, once to four times or more daily.

[0260] Treatment

[0261] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in a method of treating a human or animal body.

[0262] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in a method of treating cancer or neoplastic diseases.

[0263] One embodiment provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or neoplastic diseases.

[0264] In some embodiments, this document describes a method for treating cancer in a patient in need, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this document describes a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0265] One embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof in a method of treating a human or animal body.

[0266] One embodiment provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof in a method of treating cancer or neoplastic diseases.

[0267] One embodiment provides the use of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or neoplastic diseases.

[0268] In some embodiments, this document describes a method for treating cancer in a patient in need, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this document describes a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0269] This article provides a method for oral administration of the pharmaceutical composition. This article also provides a method for injection administration of the pharmaceutical composition.

[0270] Other embodiments and uses will be apparent to those skilled in the art from this disclosure. The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0271] Example

[0272] I. Chemical Synthesis

[0273] In some embodiments, the heteroaromatic FGFR kinase inhibitory compounds disclosed herein are synthesized according to the following examples. Unless otherwise specified, the following abbreviations, as used below and throughout the description of the invention, should be understood to have the following meanings:

[0274] ℃ Celsius

[0275] δ H Chemical shift (parts per million) of tetramethylsilane under low magnetic field

[0276] DCM (dichloromethane (CH2Cl2))

[0277] DMF (dimethylformamide)

[0278] DMSO (dimethyl sulfoxide)

[0279] EA (ethyl acetate)

[0280] ESI Electrospray Ionization

[0281] Et Ethyl

[0282] g gram

[0283] h hours

[0284] HPLC (High Performance Liquid Chromatography)

[0285] Hz Hertz

[0286] J (coupling constant in NMR spectroscopy)

[0287] LCMS (Liquid Chromatography-Mass Spectrometry)

[0288] μ micro

[0289] m (multiple peaks in a spectrum); meter; millimeter

[0290] M Moore

[0291] M + Parent molecular ions

[0292] Me methyl

[0293] MHz

[0294] min minutes

[0295] mol (mole); molecular weight (as molecular weight)

[0296] mL

[0297] MS mass spectrometry

[0298] nm nanometer

[0299] NMR (Nuclear Magnetic Resonance)

[0300] pH is the electrical potential of hydrogen; it is used to measure the acidity or alkalinity of an aqueous solution.

[0301] PE petroleum ether

[0302] RT room temperature

[0303] s Single peak (spectrum)

[0304] t triplet (spectral)

[0305] T temperature

[0306] TFA (trifluoroacetic acid)

[0307] THF Tetrahydrofuran

[0308] Intermediate 1: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide

[0309]

[0310] (2R,4R)-2-(methoxymethyl)-4-(p-toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0311] TsCl (18.79 g, 98.58 mmol) was added to a stirred solution of (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (15.20 g, 65.72 mmol), TEA (18.27 mL, 131.44 mmol), and DMAP (1.21 g, 9.86 mmol) in DCM (150.00 mL) at 0 °C. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (80 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 33% EA / PE. The fractions containing the desired product were combined and concentrated to give (2R,4R)-2-(methoxymethyl)-4-(p-toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (18.5 g, 73%) as a yellow oil. The MS ESI calculated value for C18H27NO6S[M+H]+ was 386.16, and the measured value was 386.10.

[0312] (2R,4S)-4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0313] To a mixture of 3-amino-5-bromo-2H-pyrazole-4-carboxynitrile (7.20 g, 38.50 mmol) and Cs₂CO₃ (25.09 g, 77.01 mmol) in ACN (190.00 mL), tert-butyl (2R,4R)-2-(methoxymethyl)-4-(p-toluenesulfonyloxy)pyrrolidine-1-carboxylate (17.81 g, 46.20 mmol) was added. The reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 × 70 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 46% EA / PE to give approximately 6.2 g of product, which was further purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water, 5% to 46% gradient over 30 min; detector: UV 254 nm. The fractions containing the desired product were combined and concentrated to obtain (2R,4S)-4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 32%) as a grayish-white solid. MS ESI calculated values ​​for C15H22BrN5O3[M+H]+ were 400.09 and 402.09; measured values ​​were 400.15 and 402.15.

[0314] (2R,4S)-4-(3-bromo-4-cyano-5-carbamoyl-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0315] To a mixture of (2R,4S)-4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.50 g, 8.74 mmol) and (diethoxymethoxy)ethane (70.00 mL), benzenesulfonic acid (0.23 g, 1.22 mmol) was added. The reaction mixture was stirred at 150 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dispersed in water (50 mL). The resulting mixture was extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated to give a yellow oily product, (2R,4S)-4-(3-bromo-4-cyano-5-carbamate-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.75 g, crude product), which was used directly in the next step without further purification. MS ESI calculated values ​​for C16H22BrN5O4[MH]- were 426.09 and 428.09; measured values ​​were 426.15 and 428.15.

[0316] (2R,4S)-4-(3-bromo-4-cyano-5-(methylamino)-1H-pyrazole-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0317] NaBH4 (1.56 g, 41.23 mmol) was added to a stirred solution of (2R,4S)-4-(3-bromo-4-cyano-5-carbamate-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.75 g, 8.76 mmol) in EtOH (200.00 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with brine at 0 °C. The resulting mixture was extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 62% EA / PE. The fractions containing the desired product were combined and concentrated to obtain (2R,4S)-4-(3-bromo-4-cyano-5-(methylamino)-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 91%) as a grayish-white solid. MS ESI calculated values ​​for C16H24BrN5O3[MH]- were 412.11 and 414.11; measured values ​​were 412.20 and 414.20.

[0318] (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0319] A solution of Et3N (1.75 mL, 12.61 mmol), Boc2O (2.22 g, 8.40 mmol) in DCM (2.00 mL), and DMAP (51.31 mg, 0.42 mmol) was added to a stirred solution of (2R,4S)-4-[3-bromo-4-cyano-5-(methylamino)pyrazole-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g, 4.20 mmol) in DCM (40.00 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 39% EA / PE. The fractions containing the desired product were combined and concentrated to obtain (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.12 g, 98%) as a grayish-white solid. The MS ESI calculated value of C21H32BrN5O5[M+H-56]+ was 458.16, and the measured value was 458.10.

[0320] (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0321] To a stirred solution of (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.17 g, 6.16 mmol) in EtOH (23.50 mL) and DMSO (4.70 mL), 0.5 M NaOH (8.14 mL, 7.08 mmol) and H₂O₂ (30%) (1.69 mL, 14.77 mmol) were added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 1.5 h. The resulting mixture was extracted with EA (3 × 90 mL). The combined organic layers were washed with brine (2 × 60 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 60% EA / PE. The fractions containing the desired product were combined and concentrated to obtain (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.09 g, 94%) as a grayish-white solid. The MS ESI calculated value of C21H34BrN5O6[M+H-156]+ was 376.17, and the measured value was 376.00.

[0322] 3-Bromo-1-((3S,5R)-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-1H-pyrazole-4-carboxamide dihydrochloride

[0323] A solution of 2M hydrogen chloride in EA (17 mL) was added dropwise to a stirred solution of (2R,4S)-4-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazole-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.68 g, 3.16 mmol) in EA (8.5 mL). The reaction mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with EA (3 × 30 mL). The filter cake was dried to give 1.3 g, crude product, of 3-bromo-1-((3S,5R)-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-1H-pyrazole-4-carboxamide dihydrochloride as a grayish-white solid. The MS ESI calculated value for C11H18BrN5O2[M+H]+ is 332.06, and the measured value is 332.15.

[0324] 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide

[0325] To a stirred mixture of 3-bromo-1-((3S,5R)-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-1H-pyrazole-4-carboxamide dihydrochloride (1.20 g, 2.96 mmol) in THF (24.00 mL), 14.40 mL of 2.5 M K₂CO₃ aqueous solution (36 mmol) and 6.00 mL of acryloyl chloride (0.23 g, 2.96 mmol) in THF were added. The reaction mixture was stirred at 0 °C for 10 min. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 60 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1). The fractions containing the desired product were combined and concentrated to obtain 0.89 g, 78%, of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide as a grayish-white solid. The MS ESI calculated value of C14H20BrN5O3[M+H]+ was 386.07, and the measured value was 386.05.

[0326] Example 1: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(2-methyl-3H-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide

[0327]

[0328] To a mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 0.26 mmol), 5-ethynyl-2-methyl-3H-1,3-benzodiazole (60.66 mg, 0.39 mmol), CuI (9.86 mg, 0.05 mmol) in DMF (2.50 mL), Pd(PPh3)2Cl2 (18.17 mg, 0.03 mmol) and TEA (0.11 mL, 1.07 mmol) were added. The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 16 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: SunFire Prep C18 OBD column, 19×150mm 5um 10nm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20ml / min; gradient: 20B to 50B over 4.3min. The fractions containing the desired product were combined and concentrated to give 1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-3-[2-(2-methyl-3H-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide (35.8mg, 29%) as a grayish-white solid. The MS ESI calculated value of C24H27N7O3[M+H]+ was 462.22, and the measured value was 462.15. H-NMR (400MHz, DMSO-d6+D2O): δ7.70(s,1H),7.52(d,J=8.0Hz,1H),7.34-7.32(m,1 H),6.73-6.55(m,1H),6.19-6.14(m,1H),5.71-5.67(m,1H),5.23-5.10(m,1H),4.59 -4.35(m,1H),3.90-3.85(m,1H),3.76-3.61(m,1H),3.59-3.31(m,2H),3.30(d,J=5 .2Hz,3H),2.93(d,J=4.4Hz,3H),2.56(s,3H),2.51-2.33(m,1H),2.31-2.27(m,1H).

[0329] Example 2: (S)-1-(1-Acryloylpyrrolidone-3-yl)-3-((2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0330]

[0331] Step 1: (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0332] To a stirred solution of (3S)-3-[3-bromo-4-cyano-5-(methylamino)pyrazole-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.35 mmol) in DCM (10.00 mL), TEA (0.56 mL, 4.03 mmol), Boc₂O (0.56 g, 2.70 mmol) in DCM (3.00 mL), and DMAP (16.50 mg, 0.14 mmol) were added. The reaction mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 31% EA / PE. The fraction containing the desired product was concentrated to obtain (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.6 g, 94%) as a grayish-white solid. The MS ESI calculated value of C19H28BrN5O4[M+H-112]+ was 470.13, and the measured value was 358.10.

[0333] Step 2: (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0334] At 0 °C, 0.5 M NaOH (2.44 mL, 1.22 mmol) and H₂O₂ (30%) (0.29 mL, 3.73 mmol) were added to a stirred solution of (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.06 mmol) in EtOH (4.00 mL) and DMSO (0.80 mL). The reaction mixture was stirred at ambient temperature for 1 h. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 60% EA / PE. The fractions containing the desired product were combined and concentrated to obtain (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.56 g, 97%) as a grayish-white solid. The MS ESI calculated value of C19H30BrN5O5[M+H-156]+ was 488.13, and the measured value was 332.05.

[0335] Step 3: (S)-3-bromo-5-(methylamino)-1-(pyrrolidone-3-yl)-1H-pyrazole-4-carboxamide dihydrochloride

[0336] A solution of 4M hydrogen chloride in EA (3 mL) was added dropwise to a stirred solution of (S)-3-(3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-1H-pyrazole-1-yl)pyrrolidine-1-carboxylate (0.25 g, 0.51 mmol) in DCM (1.50 mL). The reaction mixture was stirred for 1 h at room temperature and under nitrogen atmosphere. The precipitated solid was collected by filtration and washed with DCM (3 × 10 mL). The solid was dried under reduced pressure to give (S)-3-bromo-5-(methylamino)-1-(pyrrolidine-3-yl)-1H-pyrazole-4-carboxamide dihydrochloride (0.20 g, crude product) as a grayish-white solid. The MS ESI calculated value of C9H14BrN5O[M+H]+ was 288.04, and the measured value was 288.10.

[0337] Step 4: (S)-1-(1-Acryloylpyrrolidone-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide

[0338] Acryloyl chloride (36.10 mg, 0.40 mmol) and DIEA (0.32 mL, 1.84 mmol) were added dropwise to a stirred solution of (S)-3-bromo-5-(methylamino)-1-(pyrrolidone-3-yl)-1H-pyrazole-4-carboxamide dihydrochloride (0.16 g, 0.44 mmol) in DCM (5.00 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1). The fractions containing the desired product were combined and concentrated to obtain (S)-1-(1-acryloylpyrrolidine-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide (0.12 g, 75%) as a grayish-white solid. The MS ESI calculated value of C12H18BrN5O2[M+H]+ was 342.05, and the measured value was 342.00.

[0339] Step 5: (S)-1-(1-Acryloylpyrrolidone-3-yl)-3-((2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0340] TEA (0.09 mL, 0.89 mmol) was added to a stirred mixture of (S)-1-(1-acryloylpyrrolidone-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide (90.00 mg, 0.26 mmol), 5-ethynyl-2-methyl-3H-1,3-benzodiazole (61.62 mg, 0.40 mmol), CuI (10.02 mg, 0.05 mmol), and Pd(PPh3)2Cl2 (18.46 mg, 0.03 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30*150mm 5um; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 35B to 70B over 10 minutes; 210 / 254nm; RT1: 9.75. The fractions containing the desired product were combined and concentrated to obtain (S)-1-(1-acryloylpyrrolidine-3-yl)-3-((2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (22mg, 20%) as a grayish-white solid. The MS ESI calculated value of C22H23N7O2[M+H]+ was 418.19, and the measured value was 418.10. H-NMR (300MHz, CDCl3) δ7.70 (s, 1H), 7.51-7.48 (m, 1H), 7.38-7.26 (d, J = 8.3Hz, 1H), 6.97 (s, 1H), 6.66-6.31 (m, 3H), 5.77-5.66 (m,1H),5.48(s,1H),5.04-4.99(m,1H),4.16-3.94(m,3H),3.82-3.62(m,1H),2.99(t,J=6.1Hz,3H),2.65(s,4H),2.40(m,2H).

[0341] Example 3: 3-[2-(1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0342]

[0343] Step 1: 4-Bromo-N-ethyl-2-nitroaniline

[0344] A solution of 4-bromo-1-fluoro-2-nitrobenzene (5.00 g, 22.73 mmol) and ethylamine hydrochloride (9.27 g, 113.64 mmol) in Et3N (13.80 g, 136.38 mmol) was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was quenched with saturated NH4HCO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 4-bromo-N-ethyl-2-nitrobenzene (5 g, 89%) as a red solid, which was used directly in the next step without further purification. MS ESI calculated values ​​for C8H9BrN2O2[M+H]+ were 244.98 and 246.98, respectively, and found values ​​were 245.05 and 247.05.

[0345] Step 2: 4-Bromo-N1-ethylphenyl-1,2-diamine

[0346] Add AcOH (3.30 mL, 54.90 mmol) to a mixture of Fe (2.73 g, 48.96 mmol) and EtOH (66.00 mL). Stir the resulting mixture at 70 °C under a nitrogen atmosphere for 30 min. Add 4-bromo-N-ethyl-2-nitroaniline (3.00 g, 12.24 mmol) to the above mixture. Stir the reaction mixture at 70 °C for 16 h. Filter the resulting mixture and wash the filter cake with THF. Concentrate the filtrate under reduced pressure. Quench the residue with saturated NH4HCO3 (aqueous solution) (50 mL) at room temperature. Extract the resulting mixture with EtOAc (3 × 50 mL), dry to anhydrous Na2SO4, and filter. Concentrate the filtrate under reduced pressure to give 4-bromo-N1-ethylphenyl-1,2-diamine (2 g, 75%) as a brown solid, which can be used directly in the next step without further purification. The MS ESI calculated values ​​for C8H11BrN2[M+H]+ are 215.01 and 217.01, while the measured values ​​are 215.10 and 217.10.

[0347] Step 3: 5-Bromo-1-ethyl-2-methyl-1,3-benzodiazole

[0348] 1,1,1-trimethoxyethane (1.09 g, 0.01 mmol) was added to a stirred solution of 4-bromo-N1-ethylphenyl-1,2-diamine (1.30 g, 6.04 mmol) in MeOH (13.00 mL). The reaction mixture was stirred at 70 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1). The fractions containing the desired product were combined and concentrated to give 5-bromo-1-ethyl-2-methyl-1,3-benzodiazole (1.00 g, 69%) as a pale yellow solid. MS ESI calculated values ​​for C10H11BrN2[M+H]+ were 239.01 and 241.01, respectively, and found values ​​were 238.90 and 240.90.

[0349] Step 4: 1-Ethyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0350] TEA (12.70 g, 0.13 mmol) was added to a stirred mixture of 5-bromo-1-ethyl-2-methyl-1,3-benzodiazole (1.50 g, 6.27 mmol), trimethylsilylacetylene (1.85 g, 0.02 mmol), CuI (0.24 g, 1.26 mmol), and Pd(PPh3)2Cl2 (0.88 g, 1.25 mmol) in DMF (15.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1). The fractions containing the desired product were combined and concentrated to obtain 1-ethyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.5 g, 31%) as a light yellow solid. The MS ESI calculated value of C15H20N2Si[M+H]+ was 257.14, and the measured value was 257.15.

[0351] Step 5: 1-Ethyl-5-ethynyl-2-methyl-1,3-benzodiazole

[0352] TBAF (0.76 g, 2.92 mmol) was added to a THF (5.00 mL) solution of 1-ethyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.5 g, 1.95 mol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-5-ethynyl-2-methyl-1,3-benzodiazole (0.30 g, 83%) as a pale yellow solid. The MS ESI calculated value for C12H12N2[M+H]+ was 185.10, and the measured value was also 185.10.

[0353] Step 6: 3-[2-(1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0354] TEA (0.16 g, 1.55 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol), 1-ethyl-5-ethynyl-2-methyl-1,3-benzodiazole (0.14 g, 0.78 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (3 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50 B to 80 B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fraction containing the desired product was concentrated to give 3-[2-(1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (50 mg, 19%) as a white solid. The MS ESI calculated value of C26H31N7O3[M+H]+ is 490.25, and the measured value is also 490.25. H-NMR (300MHz, CDCl3) δ7.90 (s, 1H), 7.43 (d, J = 8.2Hz, 1H), 6.98 (s, 1H), 6 .98-6.77(m,2H),6.54-6.37(m,2H),5.70(dd,J=8.2,4.2Hz,1H),5.58-5.2 6(m,2H),4.56(d,J=9.0Hz,1H),4.26-3.85(m,5H),3.54-3.34(m,4H),3.05 -3.01(m,3H),2.79-2.53(m,4H),2.33-2.29(m,1H),1.43(t,J=7.2Hz,3H).

[0355] Example 4: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide

[0356] Step 1: 5-Bromo-1-methyl-1,3-benzodiazole

[0357] Trimethyl orthoformate (0.87 g, 8.21 mmol) was added to a stirred solution of 4-bromo-N1-methylphenyl-1,2-diamine (1.10 g, 5.47 mmol) in MeOH (11.00 mL). The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 4% MeOH / DCM. The fractions containing the desired product were combined and concentrated to give 5-bromo-1-methyl-1,3-benzodiazole (1.02 g, 79%) as a brown solid. The MS ESI calculated value for C8H7BrN2[M+H]+ was 210.98, and the measured value was 210.95.

[0358] Step 2: 1-Methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0359] TEA (13.17 mL, 130.16 mmol) was added to a mixture of 5-bromo-1-methyl-1,3-benzodiazole (1.00 g, 4.74 mmol), trimethylsilylacetylene (2.01 mL, 20.45 mmol), CuI (0.18 g, 0.95 mmol), and Pd(PPh3)2Cl2 (0.33 g, 0.47 mmol) in DMF (20.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The resulting mixture was diluted with water (60 mL) and extracted with EA (3 × 70 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 8% MeOH / DCM. The crude product was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 30% to 70% gradient over 30 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated to obtain 0.51 g (42%) of 1-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole as a light brown solid. The MS ESI calculated value for C13H16N2Si[M+H]+ was 229.11, and the measured value was 229.20.

[0360] Step 3: 5-ethynyl-1-methylindazole

[0361] TBAF (1 MtHF solution) (3.38 mL, 3.37 mmol) was added dropwise to a stirred THF solution of 1-methyl-5-[2-(trimethylsilyl)ethynyl]indazole (0.51 g, 2.25 mmol) in 5.00 mL of THF at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (20:1). The fractions containing the desired product were combined and concentrated to give 0.32 g, 81%, a grayish-white solid. The MS ESI calculated value of C10H8N2[M+H]+ is 157.07, and the measured value is 157.10.

[0362] Step 4: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide

[0363] TEA (0.25 mL, 2.45 mmol) was added dropwise to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.23 g, 0.59 mmol), 5-ethynyl-1-methyl-1,3-benzodiazole (0.14 g, 0.89 mmol), CuI (22.68 mg, 0.12 mmol), and Pd(PPh3)2Cl2 (41.80 mg, 0.06 mmol) in DMF (4.00 mL) at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 20% to 55% gradient over 30 min; detector: UV 254 nm. The crude product was purified by Prep-HPLC under the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35 B to 70 B over 4.3 min; 210 / 254 nm; RT1: 4.12 min. The fractions containing the desired product were combined and concentrated to obtain 1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-3-[2-(1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide (0.11 g, 37%), a grayish-white solid. The MS ESI calculated value of C24H27N7O3[M+H]+ was 462.22, and the measured value was 462.10. H-NMR (400MHz, DMSO-d6): δ12.75(brs,1H),8.33-8.30(m,1H),8.15-8.13(m,1H),7.92-7.86(m,1H),7. 66(d,J=8.4Hz,1H),7.47(d,J=8.4Hz,1H),7.38-7.34(m,1H),6.83-6.76(m,1H),6.73-6.54(m,1H),6.19 -6.14(m,1H),5.71-5.67(m,1H),5.27-5.25(m,1H),4.59-4.35(m,1H),4.03-4.02(m,1H),3.93-3.91(m ,4H),3.86-3.71(m,1H),3.45-3.30(m,3H),2.95(t,J=5.1Hz,3H),2.61-2.51(m,1H),2.33-2.24(m,1H).

[0364] Example 5: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0365]

[0366] Step 1: 5-Bromo-1,2-dimethyl-1,3-benzodiazole

[0367] 1,1,1-trimethoxyethane (3.59 g, 29.84 mmol) was added to a stirred solution of 4-bromo-N1-methylphenyl-1,2-diamine (4.00 g, 19.89 mmol) in MeOH (40.00 mL). The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 6% MeOH / DCM. The fractions containing the desired product were combined and concentrated to give 5-bromo-1,2-dimethyl-1,3-benzodiazole (3.91 g, 78%) as a pale yellow solid. MS ESI calculated values ​​for C9H9BrN2[M+H]+: 224.99, 226.99; Found values: 225.00, 227.00.

[0368] Step 2: 1,2-Dimethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0369] TEA (31.25 mL, 308.79 mmol) was added to a stirred mixture of 5-bromo-1,2-dimethyl-1,3-benzodiazole (2.53 g, 11.24 mmol), trimethylsilylacetylene (4.77 mL, 48.52 mmol), CuI (428.13 mg, 2.25 mmol), and Pd(PPh3)2Cl2 (788.94 mg, 1.12 mmol) in DMF (50.00 mL). The reaction mixture was degassed three times with nitrogen and stirred at 80 °C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 8% MeOH / DCM. Fractions containing the desired product were combined and concentrated. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 30% to 70% gradient over 35 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated to give 0.52 g (17%) of 1,2-dimethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole as a brown solid. 14 H 18 N₂Si[M+H] + The calculated MS ESI value is 243.12, and the measured value is 243.00.

[0370] Step 3: 5-ethynyl-1,2-dimethyl-1,3-benzodiazole

[0371] Under a nitrogen atmosphere, TBAF (6.56 mL, 6.56 mmol) was added dropwise to a stirred solution of 1,2-dimethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (1.06 g, 4.37 mmol) in THF (20.00 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (20:1). The fractions containing the desired product were combined and concentrated to give 0.68 g, 81%, 5-ethynyl-1,2-dimethyl-1,3-benzodiazole as a grayish-white solid. 11 H 10 N2[M+H] + The calculated MS ESI value is 171.08, and the measured value is 171.15.

[0372] Step 4: 3-[2-(1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0373] TEA (0.29 mL, 2.88 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.27 g, 0.70 mmol), 5-ethynyl-1,2-dimethyl-1,3-benzodiazole (0.18 g, 1.05 mmol), CuI (26.63 mg, 0.14 mmol), and Pd(PPh3)2Cl2 (49.06 mg, 0.07 mmol) in DMF (4.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 5 h. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 25% to 40% gradient over 25 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was then purified by Prep-HPLC under the following conditions: column: XBridgePrep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35B to 70B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain 0.16 g, 46% grayish-white solid 3-[2-(1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide. 25 H 29 N7O3[M+H] +The calculated MS ESI value is 476.23, and the measured value is 476.25. H-NMR (400MHz, DMSO-d6): δ7.76(s,1H),7.58(d,J=8.3Hz,1H),7.43-7.38(m,2H),6.76-6.59(m,3H),6.19(d,J=16.5Hz,1H),5.71(d,J=10.2Hz,1H ),5.27-5.21(m,1H),4.48-4.35(m,1H),4.11-3.82(m,1H),3.77-3.71(m, 4H),3.67-3.38(m,2H),3.34(d,J=1.1Hz,3H),2.96(t,J=4.5Hz,3H),2.66 -2.50(m,4H), 2.29-2.21(m,1H).

[0374] Example 6: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0375] Step 1: 5-Bromo-1-methyl-1,3-benzodiazole

[0376] Trimethyl orthoformate (0.80 g, 7.53 mmol) was added to a stirred solution of 4-bromo-N1-ethylphenyl-1,2-diamine (1.08 g, 5.02 mmol) in MeOH (10.00 mL). The reaction mixture was stirred at 70 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1). The fractions containing the desired product were combined and concentrated to give 5-bromo-1-ethyl-1,3-benzodiazole (1 g, 88%) as a pale yellow solid. C9H9BrN2[M+H] + The calculated MS ESI values ​​are 224.99 and 226.99; the measured values ​​are 225.00 and 227.00.

[0377] Step 2: 1-Ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0378] TEA (8.99 g, 88.85 mmol) was added to a stirred mixture of 5-bromo-1-ethyl-1,3-benzodiazole (1.00 g, 4.44 mmol), trimethylsilylacetylene (1.31 g, 13.33 mmol), CuI (0.17 g, 0.89 mmol), and Pd(PPh3)2Cl2 (0.62 g, 0.89 mmol) in DMF (10.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15:1). The fractions containing the desired product were combined and concentrated to obtain 1-ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.80 g, 74%), a light yellow solid. 14 H 18 N₂Si[M+H] + The calculated MSESI value is 243.12; the measured value is 243.20.

[0379] Step 3: 1-Ethyl-5-ethynyl-1,3-benzodiazole

[0380] TBAF (1M THF solution, 4.95 mL, 4.95 mmol) was added to a THF solution of 1-ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.80 g, 3.30 mmol) in 8.00 mL of nitrogen at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / PE (15:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-5-ethynyl-1,3-benzodiazole (0.40 g, 71%) as a yellow solid. 11 H 10 N2[M+H] + The calculated MS ESI value is 171.08; the measured value is 171.15.

[0381] Step 4: 3-[2-(1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide carboxylic acid

[0382] TEA (0.16 g, 1.55 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol), 1-ethyl-5-ethynyl-1,3-benzodiazole (0.13 g, 0.78 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (3 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: Atlantis Prep T3OBD column, 19*250mm 10μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25B to 60B over 6 min; 210 / 254nm; RT1: 5.88. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide formic acid (50.6 mg, 18%), a light yellow solid. 26 H 31 N7O5[M+H-FA] + The calculated MS ESI value is 476.23, and the measured value is 476.15. 1 H-NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.90(s,1H),7.71(d,J=8.4Hz,1H),7.49-7.31(m, 2H),6.85-6.54(m,3H),6.19-6.15(m,1H),5.71-5.67(m,1H),5.24(dd,J=16.9,7.5Hz,1H ),4.57-4.37(m,1H),4.31(q,J=7.3Hz,2H),4.07-3.70(m,2H),3.64-3.43(m,2H),3.30(s ,3H),2.95(t,J=5.2Hz,3H),2.67-2.53(m,1H),2.36-2.25(m,1H),1.42(t,J=7.2Hz,3H).

[0383] Example 7: (S)-1-(1-Acryloylpyrrolidone-3-yl)-3-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0384]

[0385] TEA (0.24 mL, 2.41 mmol) was added to a stirred mixture of 3-bromo-5-(methylamino)-1-[1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide (0.2 g, 0.58 mmol), 5-ethynyl-1,2-dimethyl-1,3-benzodiazole (0.15 g, 0.88 mmol), CuI (22.26 mg, 0.12 mmol), and Pd(PPh3)2Cl2 (41.02 mg, 0.06 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20B to 50B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(propenyl)pyrrolidine-3-yl]pyrazole-4-carboxamide (89 mg, 35%) as a grayish-white solid. 23 H 25 N7O2[M+H] + The calculated MS ESI value is 431.21, and the measured value is 431.20. H NMR (400MHz, DMSO-d6) δ7.60 (s, 2H), 7.39-7.37 (d, J = 8.3Hz, 2H), 6.81 (s, 1H),6.68-6.56(m,2H),6.19-6.13(m,1H),5.72-5.66(m,1H),5.18-5.09( m,1H),3.89-3.79(m,2H),3.78-3.70(m,4H),3.73(m,1H),3.32(s,3H),2. 97-2.90(m,2H),2.51-2.49(m,1H),2.41-2.36(m,1H),2.32-2.26(m,1H).

[0386] Example 8: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-methyl-1H-indazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0387]

[0388] TEA (0.16 g, 1.55 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol), 5-ethynyl-1-methylindazole (0.12 g, 0.78 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (2.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 3 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 60B over 4.3 min; 254 / 210 nm; RT1: 4.350. Fractions containing the desired product were combined and concentrated to give 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(1-methylindazole-5-yl)ethynyl]pyrazole-4-carboxamide (80.0 mg, 33%) as a white solid. 24 H 27 N7O3[M+H] + The calculated MS ESI value is 462.22, and the measured value is 462.05. 1 H-NMR (300MHz, d6-DMSO) δ8.10(d,J=21.4Hz,2H),7.74(d,J=8.8Hz,1H),7.55(dd,J=8.7,1.7 Hz,1H),7.36(s,1H),6.89-6.52(m,3H),6.18(d,J=16.6Hz,1H),5.71(d,J=10.3Hz,1H),5.27 (dd,J=13.6,6.9Hz,1H),4.48(d,J=39.4Hz,1H),4.14-4.00(m,4H),3.96-3.84(m,1H),3.81- 3.57(m,1H),3.50-3.48(m,1H),3.37-3.29(m,4H),2.96(t,J=4.5Hz,3H),2.33-2.30(m,1H).

[0389] Example 9: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-methyl-2H-indazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0390]

[0391] To a stirred solution of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.30 g, 0.78 mmol) in DMF (5.00 mL), 5-ethynyl-2-methylindazole (0.18 g, 1.17 mmol), palladium chloride; bis(triphenylphosphine) (54.52 mg, 0.08 mmol), copper iodide (I) (29.58 mg, 0.16 mmol), and TEA (0.24 g, 2.33 mmol) were added. The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was directly purified by reversed-phase chromatography under the following conditions: column: Spherical C18, 20-40 μm, 80 g; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 40 mL / min; gradient (B%): 0% for 5 min, 0%-23% over 20 min, 23% for 5 min, 23%-31% over 15 min, 31% for 6 min, 31%-95% over 5 min, 95% for 3 min; detector: UV 254 & 220 nm; RT: 45 min. The fractions of the desired product were combined and concentrated under reduced pressure. The residue was further purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 50% B over 4.3 min; detector: UV 210 & 254 nm; RT: 4.02 min. The fractions containing the desired product were combined and concentrated under reduced pressure to give 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(2-methylindazole-5-yl)ethynyl]pyrazole-4-carboxamide (74.0 mg, 20%) as a white solid. 24 H 27 N7O3[M+H] +The calculated MS ESI value was 462.22, and the measured value was 462.10. H-NMR (300MHz, d6-DMSO) δ 8.44 (s, 1H), 8.02 (s, 1H), 7.64 (d, J=8.9Hz, 1H), 7.33 (brs, 1H), 7.31 (dd, J=8.9, 1.6Hz, 1H), 6.80 (brs, 1H), 6.76-6.54 (m, 2H), 6.20-6.13 (m, 1H), 5.71-5.66 (m, 1H),5.31-5.17(m,1H),4.56-4.38(m,1H),4.19(s,3H),4.05-3.70(m,2H),3.63-3.43(m,2H), 3.29(s,3H),2.94-2.92(m,3H),2.66-2.56(m,0.5H),2.47-2.42(m,0.5H),2.33-2.25(m,1H).

[0392] Example 10: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0393]

[0394] TEA (0.93 mL, 9.17 mmol) was added to a mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.86 g, 2.23 mmol), 5-ethynyl-1-methyl-2-(trifluoromethyl)-1,3-benzodiazole (1.00 g, 4.45 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.22 mmol), and CuI (84.81 mg, 0.45 mmol) in DMF (9.00 mL). The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 4 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 10% to 50% gradient over 25 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 50B over 5.8 min; 210 / 254 nm; RT1: 5.58. The fractions containing the desired product were combined and concentrated to obtain 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-[1-methyl-2-(trifluoromethyl)-1,3-benzodiazol-5-yl]ethynyl]-5-(methylamino)pyrazole-4-carboxamide (0.37 g, 30%), a grayish-white solid. 25 H 26 F3N7O3[M+H] + The calculated MSESI value was 530.20; the measured value was 530.15. H-NMR (400MHz, DMSO-d6): δ 8.09 (d, J = 1.6Hz, 1H), 7.89 (d, J = 8.6Hz, 1H), 7.67 (dd, J = 8.5, 1.5Hz, 1H), 7.35 (s, 1H), 6.88-6.47 (m, 3H), 6.23-6.18 (m, 1H), 5.71-5.68 (m, 1H), 5. 27-5.24(m,1H),4.52-4.41(m,1H),4.02-4.00(m,4H),3.93-3.82(m,1H),3.63-3.42(m ,2H),3.31(d,J=5.4Hz,3H),2.94(t,J=5.1Hz,3H),2.63-260(m,1H),2.34-2.24(m,1H).

[0395] Example 11: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0396]

[0397] Step 1: 4,6-Difluoro-5-iodo-1H-1,3-benzodiazole

[0398] Trimethyl orthoformate (2.94 g, 27.70 mmol) was added to a solution of 3,5-difluoro-4-iodophenyl-1,2-diamine (5.00 g, 18.51 mmol) in MeOH (50.00 mL) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (50.00 mL). The residue was washed with water (3 × 40.00 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (0–60%). The fractions containing the desired product were combined and concentrated to give 4,6-difluoro-5-iodo-1H-1,3-benzodiazole (4.9 g, 94%) as a brown solid. C₇H₃F₂IN₂[M+H] + The calculated MS ESI value is 280.93, and the measured value is 280.95.

[0399] Step 2: 4,6-Difluoro-5-iodo-1-methyl-1,3-benzodiazole

[0400] NaH (0.13 g, 3.21 mmol, 60%) was added to a DMF (12.00 mL) solution of 4,6-difluoro-5-iodo-1H-1,3-benzodiazole (0.30 g, 1.07 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min. Iodomethane (0.23 g, 1.60 mmol) was added dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was quenched with water (1.00 mL) at 0 °C. The resulting mixture was diluted with EtOAc (20.00 mL). The residue was washed with water (3 × 10.00 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography under the following conditions: column: Spherical C18, 20-40 μm, 40 g; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient (B%): 5% for 5 min, 5%-29% over 25 min; 29% for 8 min, 29%-95% over 5 min, 95% for 5 min; detector: UV 254 & 220 nm; RT: 48 min. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain 4,6-difluoro-5-iodo-1-methyl-1,3-benzodiazole (0.18 g, 57%) as a yellow solid and 5,7-difluoro-6-iodo-1-methyl-1,3-benzodiazole (0.15 g, 47%) as a light yellow solid. C8H5F2IN2[M+H] + The calculated MS ESI value is 294.95, and the measured value is 295.00.

[0401] Step 3: 4,6-Difluoro-1-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0402] At room temperature, a solution of 4,6-difluoro-5-iodo-1-methyl-1,3-benzodiazole (1.60 g, 5.44 mmol), trimethylsilylacetylene (1.60 g, 16.32 mmol), Pd(PPh3)2Cl2 (0.38 g, 0.54 mmol), CuI (0.21 g, 1.09 mmol), and TEA (1.65 g, 16.32 mmol) in DMF (20.00 mL) was added to a 50 mL vial. The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:9). The fractions containing the desired product were combined and concentrated to obtain 4,6-difluoro-1-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (1.2 g, 83%), a yellow solid. 13 H 14 F2N2Si[M+H] + The calculated MS ESI value is 264.08, and the measured value is 265.35.

[0403] Step 4: 5-ethynyl-4,6-difluoro-1-methyl-1,3-benzodiazole

[0404] TBAF (1.93 g, 7.38 mmol) was added dropwise to a stirred solution of 4,6-difluoro-1-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (1.30 g, 4.92 mmol) in THF (10.00 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:9). The fractions containing the desired product were combined and concentrated to give 5-ethynyl-4,6-difluoro-1-methyl-1,3-benzodiazole (0.90 g, 95%) as a yellow solid. 10 H6F2N2[M+H] + The calculated MS ESI value is 192.04, and the measured value is 193.16.

[0405] Step 5: 3-[2-(4,6-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0406] Add a solution of 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.70 g, 1.62 mmol), 5-ethynyl-4,6-difluoro-1-methyl-1,3-benzodiazole (0.37 g, 1.94 mmol), Pd(PPh3)2Cl2 (0.11 g, 0.16 mmol), CuI (61.54 mg, 0.32 mmol), and TEA (0.49 g, 4.85 mmol) in DMF (10.00 mL) to a 50 mL vial at room temperature. Degas the reaction mixture three times with argon and stir at 90 °C for 2 h. Cool the mixture to room temperature. Concentrate the resulting mixture under reduced pressure. Purify the residue by silica gel column chromatography, eluting with CH2Cl2 / MeOH (0-6%). Fractions containing the desired product were combined and concentrated. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20-40 μm, 330 g; mobile phase A: water (with 3.2 g NH4HCO3); mobile phase B: ACN; flow rate: 90 mL / min; gradient: 5%-5% B for 10 min, then 25%-50% B gradient over 20 min; detector: 254 nm. The fraction containing the desired product was collected with 44% B and concentrated under reduced pressure to give 3-[2-(4,6-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.51 g, 62%) as a white solid. 24 H 25 F2N7O3[M+H] +The calculated MSESI value was 497.19; the measured value was 498.50. ¹H-NMR (400MHz, DMSO-d⁶) δ: 8.37 (s, ¹H), 7.70–7.48 (m, 2H), 6.87–6.53 (m, 3H), 6.13–6.19 (m, ¹H), 5.71–5.68 (m, 1H), 5.28–5.25 (m, 1H), 4.46 (dd, J = 56.9, 4.3Hz, ¹H), 4.07–3.71 (m, 5H), 3.65–3.42 (m, 2H), 3.31 (d, J = 5.5Hz, 3H), 2.97 (t, J = 5.4Hz, 3H), 2.65–2.62 (m, 1H), 2.32–2.29 (m, 1H).

[0407] Example 12: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0408]

[0409] Step 1: N-Cyclopropyl-4-iodo-2-nitroaniline

[0410] Aminocyclopropane (10.69 g, 187.27 mmol) was added to a stirred mixture of 1-fluoro-4-iodo-2-nitrobenzene (10.00 g, 37.453 mmol) and Et3N (29.15 mL, 288.10 mmol) at room temperature. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The mixture was then cooled to room temperature. The resulting mixture was diluted with saturated NaHCO3 (aqueous solution) (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give N-cyclopropyl-4-iodo-2-nitrobenzene (10 g, 87%) as a brown solid, which was used directly in the next step without further purification. C9H9IN2O2[M+H] + The calculated MS ESI value is 304.00, and the measured value is 305.00.

[0411] Step 2: N1-Cyclopropyl-4-iodophenyl-1,2-diamine

[0412] Zn (11.19 g, 171.00 mmol) and HCl (2.60 mL, 71.25 mmol) were added to a stirred mixture of N-cyclopropyl-4-iodo-2-nitroaniline (5.20 g, 17.10 mmol) and THF (1.00 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 h, and then at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 300 mL). The filtrate was concentrated under reduced pressure and dried to give N1-cyclopropyl-4-iodophenyl-1,2-diamine (5 g, crude product) as a brown solid, which was used directly in the next step without further purification. C9H 11 IN2[M+H] + The calculated MS ESI value is 274.95, and the measured value is also 274.95.

[0413] Step 3: 1-Cyclopropyl-5-iodo-2-methyl-1,3-benzodiazole

[0414] 1,1,1-trimethoxyethane (0.13 g, 1.09 mmol) was added to a stirred mixture of N1-cyclopropyl-4-iodophenyl-1,2-diamine (0.20 g, 0.73 mmol) and methanol (2.00 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. The resulting mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / (EtOAc / EtOH (3:1))(1:1). The fractions containing the desired product were combined and concentrated to give 1-cyclopropyl-5-iodo-2-methyl-1,3-benzodiazole (1.4 g, 51%) as a yellow solid. 11 H 11 IN2[M+H] + The calculated MS ESI value is 298.95, and the measured value is also 298.95.

[0415] Step 4: 1-Cyclopropyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0416] To a stirred mixture of 1-cyclopropyl-5-iodo-2-methyl-1,3-benzodiazole (0.70 g, 2.35 mmol) and CuI (89.44 mg, 0.47 mmol) in DMF (7.00 mL), Pd(PPh3)2Cl2 (0.16 g, 0.24 mmol), trimethylsilylacetylene (98.84 mg, 1.01 mmol), and TEA (6.53 mL, 64.51 mmol) were added. The reaction mixture was degassed three times with nitrogen and stirred at 80 °C for 16 h. The mixture was cooled to room temperature. The resulting mixture was quenched with water (50 mL) at room temperature and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / (EtOAc / EtOH (3:1))(1:1). Fractions containing the desired product were combined and concentrated to give 0.50 g, 79%, a brown solid, 1-cyclopropyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole. 16 H 20 N₂Si[M+H] + The calculated MS ESI value is 269.10, and the measured value is also 269.10.

[0417] Step 5: 1-Cyclopropyl-5-ethynyl-2-methyl-1,3-benzodiazole

[0418] TBAF (2.79 mL, 2.79 mmol) was added to a stirred THF solution of 1-cyclopropyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.50 g, 1.86 mmol) in 5.00 mL of THF. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water (50 mL) at room temperature and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4). The fractions containing the desired product were combined and concentrated to give 1-cyclopropyl-5-ethynyl-2-methyl-1,3-benzodiazole (0.28 g, 76%) as a yellow solid. 13 H 12 N2[M+H] + The calculated MS ESI value is 197.05, and the measured value is 197.05.

[0419] Step 6: 3-[2-(1-cyclopropyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0420] CuI (16.76 mg, 0.09 mmol), TEA (0.18 mL, 1.81 mmol), and Pd(PPh3)2Cl2 (30.89 mg, 0.04 mmol) were added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.17 g, 0.44 mmol) and 1-cyclopropyl-5-ethynyl-2-methyl-1,3-benzodiazole (0.13 g, 0.66 mmol) in DMF (2.00 mL) at room temperature. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (0.1% NH4HCO3), 10% to 50% gradient over 20 min; detector: UV 254 nm, yielding the crude product. The crude product was then further purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40B to 80B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(1-cyclopropyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (72.5 mg, 32%), a grayish-white solid. 27 H 31 N7O3[M+H] + The calculated MS ESI value is 501.15, and the measured value is 502.1. 1H NMR (400MHz, DMSO-d6) δ7.76 (s, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.44-7.35 (m, 2H), 6.91-6.58 (m, 2H ),6.21-6.18(m,1H),5.69(dd,J=10.3,2.7Hz,1H),5.29-5.18(m,1H),4.56-4.36(m,1H),4.10- 4.01(m,1H),3.91-3.83(m,1H),3.61-3.58(m,1H),3.51-3.43(m,2H),3.12-3.02(m,3H),2.94( s,3H),2.62(s,3H),2.48-2.43(m,1H),2.36-2.27(s,2H),1.25-1.14(m,2H),1.13-0.97(m,2H).

[0421] Example 13: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0422]

[0423] Step 1: 1-Cyclopropyl-5-iodo-1,3-benzodiazole

[0424] At room temperature to N 1 Trimethyl orthoformate (1.45 g, 13.68 mmol) was added to a stirred mixture of cyclopropyl-4-iodophenyl-1,2-diamine (2.50 g, 9.12 mmol) in methanol (30.00 mL). The reaction mixture was stirred at 70 °C for 16 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / (EtOAc / EtOH (3:1))(1:1). The fractions containing the desired product were combined and concentrated to give 1-cyclopropyl-5-iodo-1,3-benzodiazole (1.2 g, 46%) as a yellow solid. 10 H9IN2[M+H] + The calculated MS ESI value is 284.95, and the measured value is also 284.95.

[0425] Step 2: 1-Cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0426] At room temperature, Pd(PPh3)2Cl2 (0.17 g, 0.25 mmol), trimethylsilylacetylene (0.10 g, 1.06 mmol), and TEA (6.85 mL, 67.69 mmol) were added to a stirred mixture of 1-cyclopropyl-5-iodo-1,3-benzodiazole (0.70 g, 2.46 mmol) and CuI (93.85 mg, 0.49 mmol) in DMF (7.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The reaction was quenched with water (50 mL) at room temperature and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / (EtOAc / EtOH (3:1))(1:1). The fractions containing the desired product were combined and concentrated to obtain 1-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.58 g, 92%), which was a brown oil. 15 H 18 N₂Si[M+H] + The calculated MS ESI value is 255.15, and the measured value is also 255.15.

[0427] Step 3: 1-Cyclopropyl-5-ethynyl-1,3-benzodiazole

[0428] TBAF (3.54 mL, 3.54 mmol) was added to a stirred solution of 1-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.60 g, 2.36 mmol) in THF (6.00 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water (70 mL) at room temperature and extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4). The fractions containing the desired product were combined and concentrated to give 1-cyclopropyl-5-ethynyl-1,3-benzodiazole (0.26 g, 60%) as a yellow oil. 10 H 12 N2[M+H] + The calculated MS ESI value is 183.05, and the measured value is 183.05.

[0429] Step 4: 3-[2-(1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0430] CuI (16.76 mg, 0.09 mmol), TEA (0.18 mL, 1.81 mmol), and Pd(PPh3)2Cl2 (30.89 mg, 0.04 mmol) were added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.17 g, 0.44 mmol) and 1-cyclopropyl-5-ethynyl-1,3-benzodiazole (0.12 g, 0.66 mmol) in DMF (2.00 mL) at room temperature. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (0.1% NH4HCO3), 10% to 50% gradient over 20 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: XBridgePrep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40B to 80B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (74.2 mg, 34%), a grayish-white solid. 26 H 29 N7O3[M+H] +The calculated MS ESI value was 488.10, and the measured value was also 488.10. H-NMR (400MHz, DMSO-d6) δ 8.36(s, 1H), 7.90(s, 1H), 7.70(d, J=8.3Hz, 1H), 7.49(d, J=8.7Hz, 1H), 7.37(s, 1H), 6.85-6.52(m, 2H), 6.17(dd, J=16.6, 2.6Hz, 1H), 5.69(dd, J=10.2, 2.6Hz, 1H), 5.33-5.18(m, 1H),4.42-4.38(m,1H),4.07-3.98(m,1H),3.92-3.83(m,1H),3.65-3.51(m,2H),3.49-3.42-3.38(m,1 H),3.31-3.30(m,3H),2.94(t,J=5.1Hz,3H),2.53-2.48(m,2H),2.35-2.31(m,1H),1.16-1.01(m,4H).

[0431] Example 14: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-1H-indazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0432]

[0433] TEA (0.19 mL, 1.92 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.18 g, 0.47 mmol), 1-ethyl-5-ethynylindazole (0.12 g, 0.70 mmol), CuI (17.75 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (32.71 mg, 0.05 mmol) in DMF (3.00 mL). The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 16 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 25% to 40% gradient over 25 min; detector: UV 254 nm. The crude product was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40B to 60B over 4.3 min; 210 / 254 nm; RT1: 4.12. Fractions containing the desired product were combined and concentrated to obtain 3-[2-(1-ethylindazole-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (57.5 mg, 25%) as a grayish-white solid. 25 H 29 N7O3[M+H] + The calculated MS ESI value was 476.23, and the measured value was 476.25. H-NMR (400MHz, DMSO-d6): δ 8.15-8.10 (m, 2H), 7.78 (d, J = 8.6Hz, 1H), 7.59-7.50 (m, 1H), 7.36 (s, 1H), 6.90-6.49 (m, 3H), 6.18 (d, J = 16.6Hz, 1H), 5.71 (d, J = 10.4Hz, 1H). 5.26(s,1H),4.52-4.45(m,3H),4.09-3.68(m,2H),3.65-3.37(m,2H),3.33-3.31(m, 3H), 2.96 (t, J = 4.5Hz, 3H), 2.55-2.53 (m, 1H), 2.34-2.32 (m, 1H), 1.45-1.41 (m, 3H).

[0434] Example 15: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-ethyl-2H-indazole-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0435]

[0436] TEA (0.27 mL, 2.67 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.25 g, 0.65 mmol), 2-ethyl-5-ethynylindazole (0.16 g, 0.97 mmol), CuI (24.65 mg, 0.13 mmol), and Pd(PPh3)2Cl2 (45.43 mg, 0.06 mmol) in DMF (2.50 mL). The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 16 h. The resulting mixture was diluted with water (40 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 25% to 40% gradient over 25 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was then purified by Prep-HPLC under the following conditions: column: Xselect CSH OBD column 30*150 mm 5 μm, n; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 20B to 60B over 8 min; 210 / 254 nm; RT1: 7.78. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(2-ethylindazole-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (71.4 mg, 23%), a grayish-white solid. 25 H 29 N7O3[M+H] +The calculated MS ESI value is 476.23, and the measured value is 476.20. H-NMR(400MHz,DMSO-d6):8.50(s,1H),8.03(s,1H),7.70-7.62(m,1H),7.32(d d,J=8.9,1.6Hz,2H),6.88-6.47(m,3H),6.19-6.17(m,1H),5.71-5.68(m,1H),5 .27-5.23(m,1H),4.52-4.48(m,3H),4.06-3.41(m,4H),3.30(d,J=5.4Hz,3H), 2.95(t,J=5.3Hz,3H),2.64-2.61(m,1H),2.35-2.31(m,1H),1.55-1.52(m,3H).

[0437] Example 16: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4,6-difluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0438]

[0439] Step 1: 1-Ethyl-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole

[0440] Ethyl iodine (2.39 g, 15.30 mmol) was added dropwise to a stirred solution of 4,6-difluoro-5-iodo-2-methyl-1H-1,3-benzodiazole (3.00 g, 10.20 mmol) and KOH (2.86 g, 51.01 mmol) in THF (45.00 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / EtOAc (50–89%). The fractions containing the desired product were combined and concentrated to obtain 1-ethyl-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole (1.20 g, 36%) and 1-ethyl-5,7-difluoro-6-iodo-2-methyl-1,3-benzodiazole (1.00 g, 30%), both in yellow solid form. 10 H9F2IN2[M+H] + The calculated MS ESI value is 322.97, and the measured value is 323.09.

[0441] Step 2: 1-Ethyl-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0442] At room temperature, a solution of 1-ethyl-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole (1.23 g, 3.82 mmol), trimethylsilylacetylene (1.13 g, 11.46 mmol), Pd(PPh3)2Cl2 (0.27 g, 0.38 mmol), CuI (0.15 g, 0.76 mmol), and TEA (1.16 g, 11.46 mmol) in DMF (10.00 mL) was added to a 50 mL vial. The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The resulting mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0-75%). The fractions containing the desired product were combined and concentrated to give 1-ethyl-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (1.1 g, 98%) as a yellow solid. 15 H 18 F2N2Si[M+H] + The calculated MS ESI value is 293.12, and the measured value is 293.40.

[0443] Step 3: 1-Ethyl-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole

[0444] TBAF (1.61 g, 6.16 mmol) was added in portions to a stirred solution of 1-ethyl-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (1.20 g, 4.10 mmol) in THF (10.00 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20–60%). The fractions containing the desired product were combined and concentrated to obtain 0.67 g (74%) of 1-ethyl-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole, a yellow solid. 15 H 18 F2N2Si[M+H] + The calculated MS ESI value is 221.08, and the measured value is 221.22.

[0445] Step 4: 3-[2-(1-ethyl-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0446] At room temperature, a solution of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol), 1-ethyl-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole (0.14 g, 0.62 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol), and CuI (19.72 mg, 0.10 mmol) in DMF (4.00 mL) was added to a 25 mL vial, followed by TEA (0.16 g, 1.55 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The mixture was then cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (0–6%). Fractions containing the desired product were combined and concentrated. The crude product (160 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 23B to 43B over 4.3 min; 210 / 254 nm; RT₁: 4.02. The fractions containing the desired product were combined and concentrated to give 3-[2-(1-ethyl-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (85.7 mg, 31%), a white solid. 26 H 29 F2N7O3[M+H] +The calculated MS ESI value was 512.21; the measured value was 526.56. ¹H-NMR (400MHz, DMSO-d⁶) δ: 7.60 (t, J = 11.4Hz, 2H), 6.83–6.50 (m, 3H), 6.19–6.16 (m, 1H), 5.71–5.68 (m, 1H), 5.29–5.25 (m, 1H), 4.46 (d, J = 54.4Hz, 1H). 4.24(q,J=7.2Hz,2H),4.07-3.71(m,2H),3.66-3.41(m,2H),3.30(d,J=5.6Hz,3H),2.96( t,J=5.5Hz,3H),2.70-2.60(m,1H),2.57(s,3H),2.37-2.25(m,1H),1.29(t,J=7.2Hz,3H).

[0447] Example 17: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0448]

[0449] Step 1: 4,6-Difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole

[0450] TEA (4.13 g, 40.81 mmol) was added to a stirred mixture of 4,6-difluoro-5-iodo-2-methyl-1H-1,3-benzodiazole (0.60 g, 2.04 mmol), trimethylsilylacetylene (0.60 g, 6.12 mmol), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol), and CuI (77.72 mg, 0.41 mmol) in DMF (10.00 mL). The reaction mixture was degassed three times with nitrogen and stirred at 80 °C for 2 h. The resulting mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4). The fractions containing the desired product were combined and concentrated to obtain 0.40 g, 74% brown semi-solid 4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole. 13 H 14 F2N2Si[M+H] +The calculated MS ESI value is 265.09, and the measured value is 265.10.

[0451] Step 2: 5-ethynyl-4,6-difluoro-2-methyl-1H-1,3-benzodiazole

[0452] 4,6-Difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole (0.40 g, 1.51 mmol), TBAF (2.27 mL, 2.27 mmol), and THF (4.00 mL) were added to a 25 mL round-bottom flask at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 0.22 g, 75%, 5-ethynyl-4,6-difluoro-2-methyl-1H-1,3-benzodiazole as a pale yellow solid. 10 H6F2N2[M+H] + The calculated MS ESI value is 193.05, and the measured value is 193.15.

[0453] Step 3: 3-[2-(4,6-difluoro-2-methyl-1H-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0454] To a mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol) and 5-ethynyl-4,6-difluoro-2-methyl-1H-1,3-benzodiazole (0.15 g, 0.78 mmol) in DMF (4.00 mL), CuI (19.72 mg, 0.10 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol), and TEA (1.05 g, 10.34 mmol) were added. The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (10 mM NH4HCO3), 5% to 35% gradient over 30 min; detector: UV 220 nm. The crude product (150 mg) was purified by Prep-HPLC under the following conditions: column: SunFirePrep C18 OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40 B to 80 B over 4.3 min; 210 / 254 nm; RT1: 4.03. The fractions containing the desired product were combined and concentrated to give 3-[2-(4,6-difluoro-2-methyl-1H-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (43.3 mg, 16%), a white solid. 24 H 25 F2N7O3[M+H] +The calculated MS ESI value was 498.20; the measured value was also 498.20. H-NMR (400MHz, DMSO-d6): δ 7.59 (s, 1H), 7.37 (d, J=9.1Hz, 1H), 6.81–6.67 (m, 2H), 6.63–6.60 (m, 1H), 6.18–6.16 (m, 1H), 5.69–5.65 (m, 1H), 5.35–5.21 (m, 1H), 4.53–4.51 (m, 1H), 4.41–4.39 (m,1H),4.05-4.01(m,1H),3.90-3.87(m,1H),3.77-3.75(m,,1H),3.63-3.59(m,1H),3.49-3. 45(m,3H),3.30(d,J=5.6Hz,3H),2.96(t,J=5.5Hz,3H),2.69-2.65(m,1H),2.36-2.23(m,1H).

[0455] Example 18: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0456]

[0457] At room temperature, 5-ethynyl-4,6-difluoro-1,2-dimethyl-1,3-benzodiazole (0.19 g, 0.93 mmol), Pd(PPh3)2Cl2 (54.52 mg, 0.08 mmol), CuI (29.58 mg, 0.16 mmol), and TEA (0.24 g, 2.33 mmol) were added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.30 g, 0.78 mmol) in DMF (5.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The mixture was then cooled to room temperature. The resulting mixture was filtered; the filter cake was washed with DMF (3 × 3 mL). The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20-40 μm, 180 g; mobile phase A: water (NH4HCO3 0.1 mM); mobile phase B: ACN; flow rate: 90 mL / min; gradient: 5%-5% B for 10 min, then 25%-60% B gradient over 20 min; detector: 254 nm. The fraction containing the desired product was collected with 30% B and concentrated under reduced pressure to give 3-[2-(4,6-difluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (83.7 mg, 21%) as a white solid. 25 H 27 F2N7O3[M+H] + MS ESI calculated value: 512.21; measured value: 512.53. ¹H-NMR (300MHz, DMSO-d⁶): δ 7.58 (d, J = 9.3Hz, 2H), 6.88–6.51 (m, 3H), 6.23–6.11 (m, 1H), 5.73–5.69 (m, 1H), 5.29–5.26 (m, 1H), 4.48 (d, J = 41.7Hz, 1H), 4.10–3.83 (m, 2H), 3.76 (s, 3H), 3.68–3.43 (m, 2H), 3.35–3.32 (m, 3H), 3.00–2.95 (m, 3H), 2.69–2.63 (m, 1H), 2.56 (s, 3H), 2.39–2.24 (m, 1H).

[0458] Example 19: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0459]

[0460] TEA (0.12 g, 1.17 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.39 mmol), 5-ethynyl-4,6-difluoro-1-methylindazole (0.11 g, 0.58 mmol), Pd(PPh3)2Cl2 (27.26 mg, 0.04 mmol), and CuI (14.79 mg, 0.08 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN, 0.01 mmol NH4HCO3 / water, 25% to 40% gradient over 20 min; detector: UV 254 nm. The crude product was purified by Prep-HPLC under the following conditions: column: Atlantis Prep T3OBD column, 19*250 mm 10 u; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 50B over 6 min; 210 / 254 nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to give 3-[2-(4,6-difluoro-1-methylindazole-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (27.5 mg, 14%), a white solid. 24 H 25 The calculated ESI value of F2N7O3[M+H]+ is 498.2; the measured value is also 498.2. 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 7.72 (d, J = 9.5Hz, 1H), 7.57 (s, 1H), 6.9 1-6.53(m,3H),6.17-5.92(m,1H),5.69-5.45(m,1H),5.41-5.18(m,1H),4.54 -4.34(m,1H),4.06(s,3H),3.88-3.65(m,1H),3.63-3.59(m,1H),3.55-3.39( m,2H),3.31(s,3H),2.98-2.94(m,3H),2.62-2.43(m,1H),2.30-1.96(m,1H).

[0461] Example 20: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4-fluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0462]

[0463] Step 1: 3-Fluoro-4-iodo-2-nitroaniline

[0464] A solution of ICl (17.19 g, 105.88 mmol) in AcOH (50.00 mL) was added dropwise to a stirred solution of 3-fluoro-2-nitroaniline (14.50 g, 92.88 mmol) and NaOAc (8.69 g, 105.93 mmol) in AcOH (250.00 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 5 h, and then at room temperature for 1 h. Water (300.00 mL) was added to the mixture at room temperature, and the mixture was stirred for 16 h. The resulting mixture was filtered, and the filter cake was washed with water (3 × 80 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1). The fractions containing the desired product were combined and concentrated to give 3-fluoro-4-iodo-2-nitroaniline (13.1 g, 50%) as an orange solid.

[0465] Step 2: 3-Fluoro-4-iodophenyl-1,2-diamine

[0466] A mixture of Fe (10.66 g, 190.92 mmol) and CH3COOH (13.84 mL, 241.53 mmol) in EtOH (150.00 mL) and water (50.00 mL) was stirred at 70 °C for 0.5 h. 3-fluoro-4-iodo-2-nitroaniline (13.10 g, 46.45 mmol) was added in portions to the mixture at 70 °C. The resulting mixture was stirred at 70 °C for another 2 h. The mixture was cooled. The resulting mixture was filtered, and the filter cake was washed with EA (2 × 150 mL). The filtrate was concentrated under reduced pressure. Water (70 mL) was added to the residue, and the residue was extracted with EA (3 × 100 mL). The combined organic layers were washed with saturated NaCl (2 × 70 mL), dried over anhydrous Na2SO4, and filtered. The residue was concentrated to give 11.2 g (95.7%) of 3-fluoro-4-iodophenyl-1,2-diamine as a brown solid, which was used directly in the next step without further purification.

[0467] Step 3: 4-Fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole

[0468] 1,1,1-trimethoxyethane (3.58 g, 29.79 mmol) was added dropwise to a stirred solution of 3-fluoro-4-iodophenyl-1,2-diamine (5.00 g, 19.84 mmol) in MeOH (50.00 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4). Fractions containing the desired product were combined and concentrated to give 4-fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole (5.15 g, 94%) as a pale yellow solid. C8H6FIN2[M+H] + The calculated MS ESI value is 276.96, and the measured value is 276.95.

[0469] Step 4: 4-Fluoro-5-iodo-1,2-dimethyl-1H-benzo[d]imidazole

[0470] MeI (0.74 mL, 5.23 mmol) was added dropwise to a stirred solution of 4-fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole (2.35 g, 8.51 mmol) and KOH (2.87 g, 51.15 mmol) in 25.00 mL of acetone at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred for 40 min. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 1.13 g, 45%, of 4-fluoro-5-iodo-1,2-dimethyl-1H-benzo[d]imidazole as a grayish-white solid. C9H8FIN₂[M+H] + The calculated MS ESI value is 290.97, and the measured value is 290.95.

[0471] Step 5: 4-Fluoro-1,2-Dimethyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazolium

[0472] TEA (10.83 mL, 77.92 mmol) was added to a mixture of 4-fluoro-5-iodo-1,2-dimethyl-1H-benzo[d]imidazole (1.13 g, 3.89 mmol), trimethylsilylacetylene (1.15 g, 11.71 mmol), CuI (0.15 g, 0.78 mmol), and Pd(PPh3)2Cl2 (0.27 g, 0.39 mmol) in DMF (12.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with water (3 × 60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:2), and the fractions containing the desired product were combined and concentrated to give 0.94 g, 92%, a light yellow solid, 4-fluoro-1,2-dimethyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole. 14 H 17 FN2Si[M+H] + The calculated MS ESI value is 261.11, and the measured value is 261.15.

[0473] Step 6: TBAF (4.84 mL, 4.84 mmol) was added dropwise to a stirred solution of 4-fluoro-1,2-dimethyl-1H-benzo[d]imidazole (0.84 g, 3.23 mmol) in THF (10.00 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:2). Fractions containing the desired product were combined and concentrated to give 5-ethynyl-4-fluoro-1,2-dimethyl-1H-benzo[d]imidazole (0.67 g, 99%) as a grayish-white solid. 11 H9FN2[M+H] + The calculated MS ESI value is 189.07, and the measured value is 189.20.

[0474] Step 7: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4-fluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0475] TEA (0.22 mL, 1.58 mmol) was added to a mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.2 g, 0.52 mmol), 5-ethynyl-4-fluoro-1,2-dimethyl-1H-benzi[d]imidazole (0.19 g, 1.04 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 column, 19*250mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25B to 60B over 5.8min; 210 / 254nm; RT1: 5.55. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4-fluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (0.10g, 39%). 25 H 28 FN7O3[M+H] + The calculated MS ESI value was 494.22, and the measured value was 494.20. ¹H NMR (400MHz, DMSO-d⁶) δ: 7.43-7.38 (m, 3H), 6.76-6.56 (m, 3H), 6.19-6.14 (m, 1H), 5.70-5.67 (m, 1H), 5.28-5.26 (m, 1H), 4.53-4.39 (m, 1H), 3.79-3.75 (m, 5H), 3.62-3.44 (m, 2H), 3.32 (s, 3H), 2.97-2.94 (t, J = 5.2Hz, 3H), 2.58-2.52 (m, 4H), 2.32-2.27 (m, 1H).

[0476] Example 21: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0477]

[0478] Step 1: 1-Ethyl-4-fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole

[0479] Ethyl iodide (1.86 g, 11.93 mmol) was added dropwise to a stirred solution of 4-fluoro-5-iodo-2-methyl-1H-1,3-benzodiazole (2.35 g, 8.51 mmol) and KOH (2.87 g, 51.08 mmol) in acetone (25.00 mL). The resulting mixture was stirred for 2 h at room temperature and under nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / EtOAc (1:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-4-fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole (1.46 g, 56.4%) as a grayish-white solid. 10 H 10 FIN2[M+H] + The calculated MS ESI value is 304.99, and the measured value is 304.95.

[0480] Step 2: 1-Ethyl-4-fluoro-2-methyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazolium

[0481] TEA (13.35 mL, 96.04 mmol) was added to a mixture of 1-ethyl-4-fluoro-5-iodo-2-methyl-1H-benzo[d]imidazole (1.46 g, 4.80 mmol), trimethylsilylacetylene (1.41 g, 14.36 mmol), CuI (0.18 g, 0.96 mmol), and Pd(PPh3)2Cl2 (0.34 g, 0.48 mmol) in DMF (15.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 16 h. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:2), and the fractions containing the desired product were combined and concentrated to give 1-ethyl-4-fluoro-2-methyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole (1.0 g, 75%) as a light yellow solid. 15 H 19 FN2Si[M+H] + The calculated MS ESI value is 275.13, and the measured value is 275.15.

[0482] Step 3: 1-Ethyl-5-ethynyl-4-fluoro-2-methyl-1H-benzo[d]imidazole

[0483] TBAF (4.97 mL, 4.97 mmol) was added dropwise to a stirred THF solution of 1-ethyl-4-fluoro-2-methyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole (0.91 g, 3.32 mmol) in 10.00 mL of THF under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:2). Fractions containing the desired product were combined and concentrated to give 1-ethyl-5-ethynyl-4-fluoro-2-methyl-1H-benzo[d]imidazole (0.68 g, 96%) as a grayish-white solid. 12 H 11 FN2[M+H] + The calculated MS ESI value is 203.09, and the measured value is 203.20.

[0484] Step 4: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0485] TEA (0.22 mL, 2.13 mmol) was added to a mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.2 g, 0.52 mmol), 1-ethyl-5-ethynyl-4-fluoro-2-methyl-1H-benzi[d]imidazole (0.21 g, 1.04 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridgePrep OBD C18 column, 19*250mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25B to 60B over 5.8min; 210 / 254nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (0.11g, 41%). 26 H 30 FN7O3[M+H] + The calculated MS ESI value is 508.24, and the measured value is 508.25. H NMR(400MHz,DMSO-d6)δ7.48-7.38(m,3H),6.79-6.56(m,3H),6.19-6.14( m,1H),5.70-5.67(m,1H),5.30-5.24(m,1H),4.53-4.40(m,1H),4.28-4.23 (m,2H),4.08-3.72(m,2H),3.66-3.41(m,2H),3.32-3.29(m,3H),2.96(t, J=5.2Hz,3H),2.60-2.56(m,4H),2.33-2.29(m,1H),1.30(t,J=7.1Hz,3H).

[0486] Example 22: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-ethyl-2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0487]

[0488] Step 1: N-Ethyl-5-iodo-3-nitropyridine-2-amine

[0489] TEA (3.31 g, 32.69 mmol) was added to a stirred mixture of 2-chloro-5-iodo-3-nitropyridine (3.10 g, 10.90 mmol) and ethylamine (0.98 g, 21.8 mmol) in EtOH (30.00 mL) at room temperature and under air atmosphere. The reaction mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with EA (3 × 250 mL). The combined organic layers were washed with saturated NaCl (500 mL), dried over anhydrous Na₂SO₄, and filtered. The residue was concentrated to give N-ethyl-5-iodo-3-nitropyridine-2-amine (3.5 g, 99%) as an orange solid, which was used directly in the next step without further purification. C₇H₈IN₃O₂[M+H] + The calculated ESI value is 293.9; the measured value is 294.

[0490] Step 2: N2-Ethyl-5-iodopyridine-2,3-diamine

[0491] Fe (2.29 g, 40.95 mmol) was added to a stirred mixture of N-ethyl-5-iodo-3-nitropyridine-2-amine (3.00 g, 10.24 mmol) and NH4Cl (2.74 g, 51.18 mmol) in EtOH (52.00 mL) and water (8 mL) at room temperature. The reaction mixture was stirred at 75 °C under air atmosphere for 16 h. The resulting mixture was filtered, and the filter cake was washed with EA (2 × 150 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with saturated NaCl (500 mL), dried over anhydrous Na2SO4, and filtered. The resulting mixture was concentrated to give N2-ethyl-5-iodopyridine-2,3-diamine (2.6 g, 96%) as a black solid, which was used directly in the next step without further purification. C7H 10 IN3[M+H] + The calculated MS ESI value is 263.9; the measured value is 264.05.

[0492] Step 3: 3-Ethyl-6-iodo-2-methylimidazo[4,5-b]pyridine

[0493] 1,1,1-Trimethoxyethane (2.01 g, 16.73 mmol) was added to a stirred mixture of N2-ethyl-5-iodopyridine-2,3-diamine (2.20 g, 8.36 mmol) and CH3COOH (22.00 mL) at room temperature and in air. The reaction mixture was stirred at 70 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with EtOAc (100 mL). The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1). The fractions containing the desired product were combined and concentrated to give 1.7 g (70%) of 3-ethyl-6-iodo-2-methylimidazo[4,5-b]pyridine, a brown solid. (C9H) 10 IN3[M+H] + The calculated MS ESI value is 287.99; the measured value is 287.95.

[0494] Step 4: 3-Ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine

[0495] TEA (10.57 g, 104.49 mmol) was added to a stirred mixture of 3-ethyl-6-iodo-2-methylimidazo[4,5-b]pyridine (1.50 g, 5.23 mmol), trimethylsilylacetylene (1.54 g, 15.67 mmol), Pd(PPh3)2Cl2 (0.37 g, 0.52 mmol), and CuI (0.2 g, 1.05 mmol) in DMF (14.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The residue was diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1). The fractions containing the desired product were combined and concentrated to give 1.1 g, 81%, 3-ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine, a brown solid. 14 H 19 N3Si[M+H] + The calculated MS ESI value is 258.13; the measured value is 258.05.

[0496] Step 5: 3-Ethyl-6-ethynyl-2-methylimidazo[4,5-b]pyridine

[0497] TBAF (1.52 g, 5.83 mmol) was added to a stirred mixture of 3-ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine (1.00 g, 3.89 mmol) in THF (10.00 mL) at room temperature and in air. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 3-ethyl-6-ethynyl-2-methylimidazo[4,5-b]pyridine (0.28 g, 38%) as a brown solid. 11 H 11 N3[M+H] + The calculated MS ESI value is 186.1; the measured value is 186.15.

[0498] Step 6: 3-(2-[3-ethyl-2-methylimidazo[4,5-b]pyridin-6-yl]ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0499] TEA (0.16 g, 1.55 mmol) was added dropwise to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.2 g, 0.52 mmol), 3-ethyl-6-ethynyl-2-methylimidazo[4,5-b]pyridine (0.14 g, 0.78 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol), and CuI (19.72 mg, 0.1 mmol) in DMF (2.00 mL) at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN, 0.01 mmol NH4HCO3 / water, 20% to 40% gradient over 20 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was then purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25 B to 55 B over 6 min; 210 / 254 nm; RT1: 5.53. The fractions containing the desired product were combined and concentrated to obtain 3-(2-[3-ethyl-2-methylimidazo[4,5-b]pyridin-6-yl]ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (59 mg, 23%), a light yellow solid. 25 H 30 N8O3[M+H] + The calculated MS ESI value is 491.24; the measured value is 491.15. 1H NMR(400MHz,DMSO-d6)δ8.49(d,J=1.9Hz,1H),8.19-8.15(m,1H),7.31(s,1H),6.94-6.7 1(m,1H),6.69-6.47(m,2H),6.17-5.96(m,1H),5.69-5.43(m,1H),5.23-5.03(m,1H),4.4 9-4.45(m,1H),4.29(q,J=7.3Hz,2H),4.11-3.71(m,2H),3.68-3.41(m,2H),3.31(d,J=5. 4Hz,3H),3.06-2.89(m,3H),2.65-2.60(m,4H),2.38-2.25(m,1H),1.34(t,J=7.2Hz,3H).

[0500] Example 23: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0501]

[0502] Step 1: 5-Iodo-N-methyl-3-nitropyridine-2-amine

[0503] TEA (3.20 g, 31.64 mmol) was added to a stirred mixture of 2-chloro-5-iodo-3-nitropyridine (3.00 g, 10.55 mmol) and methylamine (0.65 g, 21.09 mmol) in EtOH (30.00 mL) at room temperature and under air atmosphere. The reaction mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with saturated NaCl (500 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated and dried to give 2.9 g (98%) of 5-iodo-N-methyl-3-nitropyridine-2-amine as an orange solid, which was used directly in the next step without further purification. C₆H₆IN₃O₂[M+H] + The calculated ESI value is 279.95; the measured value is 279.95.

[0504] Step 2: 5-Iodo-N2-methylpyridine-2,3-diamine

[0505] Fe (2.40 g, 43.00 mmol) was added to a stirred mixture of 5-iodo-N-methyl-3-nitropyridine-2-amine (3.00 g, 10.75 mmol) and NH4Cl (2.88 g, 53.75 mmol) in EtOH (52.00 mL) / H2O (7.00 mL) at room temperature and in an air atmosphere. The reaction mixture was stirred at 75 °C for 16 h. The resulting mixture was filtered, and the filter cake was washed with EA (2 × 150 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with saturated NaCl (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrates were combined and concentrated to give 5-iodo-N2-methylpyridine-2,3-diamine (1.7 g, 63%) as a black solid, which was used directly in the next step without further purification. C6H8IN3[M+H] + The calculated MS ESI value is 249.98; the measured value is 250.0.

[0506] Step 3: 6-Iodo-3-methylimidazo[4,5-b]pyridine

[0507] Trimethyl orthoformate (1.11 g, 0.01 mmol) was added to a stirred mixture of 5-iodo-N-2-methylpyridine-2,3-diamine (1.30 g, 5.22 mmol) and CH3COOH (13.00 mL) at room temperature and in air. The reaction mixture was stirred at 70 °C and in air for 16 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with EtOAc (100 mL). The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1). The fractions containing the desired product were combined and concentrated to obtain 0.85 g (62%) of 6-iodo-3-methylimidazo[4,5-b]pyridine, a brown solid. C7H6IN3[M+H] + The calculated MS ESI value is 258.96; the measured value is 259.85.

[0508] Step 4: 3-Methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine

[0509] TEA (6.25 g, 61.76 mmol) was added dropwise to a stirred mixture of 6-iodo-3-methylimidazo[4,5-b]pyridine (0.8 g, 3.08 mmol), trimethylsilylacetylene (0.9 g, 9.26 mmol), Pd(PPh3)2Cl2 (0.22 g, 0.31 mmol), and CuI (0.12 g, 0.62 mmol) in DMF (8.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The residue was diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). The fractions containing the desired product were combined and concentrated to obtain 0.70 g, 98%, brown solid 3-methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine. MS ESI calculated value for C12H15N3Si[M+H]+ was 230.1; measured value was 230.0.

[0510] Step 5: 6-ethynyl-3-methylimidazo[4,5-b]pyridine

[0511] TBAF (0.96 g, 3.66 mmol) was added to a stirred mixture of 3-methyl-6-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine (0.56 g, 2.44 mmol) in THF (6.00 mL) at room temperature and in an air atmosphere. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 6-ethynyl-3-methylimidazo[4,5-b]pyridine (0.30 g, 78%) as a brown solid. The MS ESI calculated value for C9H7N3[M+H]+ is 158.06; the measured value is 158.10.

[0512] Step 6: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[3-methylimidazo[4,5-b]pyridin-6-yl]ethynyl)pyrazole-4-carboxamide

[0513] TEA (0.16 g, 1.55 mmol) was added dropwise to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.2 g, 0.52 mmol), 6-ethynyl-3-methylimidazo[4,5-b]pyridine (0.12 g, 0.78 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol), and CuI (19.72 mg, 0.11 mmol) in DMF (2.00 mL) at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN, 0.01 mmol NH4HCO3 / water, 20% to 40% gradient over 20 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The residue was then purified by Prep-HPLC under the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.1% FA), mobile phase B: MeOH-HPLC; flow rate: 20 mL / min; gradient: 30B to 50B over 6 min; 210 / 254 nm; RT1: 5.68. The fractions containing the desired product were combined and concentrated to obtain 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[3-methylimidazo[4,5-b]pyridin-6-yl]ethynyl)pyrazole-4-carboxamide (22.5 mg, 9%), a light yellow solid. 23 H 26 N8O3[M+H] + The calculated MS ESI value is 463.21; the measured value is 463.15. 1 H NMR (300MHz, DMSO-d6) δ8.64-8.57 (m, 2H), 8.35 (d, J = 1.8Hz, 1H), 7.28 (s, 1H), 6. 65-6.43(m,2H),6.15-5.96(m,1H),5.68-5.43(m,1H),5.23-5.01(m,1H),4.60-4. 47(m,1H),4.44-4.34(m,1H),4.05-4.00(m,1H),3.89-3.85(m,4H),3.65-3.42(m ,2H),3.31-3.27(m,3H),2.95-2.90(m,3H),2.79-2.55(m,1H),2.39-2.19(m,1H).

[0514] Example 24: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-cyano-1-ethyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0515]

[0516] Step 1: 3-(Ethylamino)-4-nitrobenzene

[0517] TEA (25.10 mL, 248.08 mmol) was added to a stirred mixture of 3-fluoro-4-nitrobenzene (10.00 g, 60.20 mmol) and ethylamine (5.43 g, 120.40 mmol) in EtOH (90.00 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with NaHCO3 (300 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was dried to give 3-(ethylamino)-4-nitrobenzene (11.5 g, 89%), which was used directly in the next step without further purification. ¹H-NMR (400MHz, chloroform-d): δ 8.27 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 7.17 (d, J = 1.7 Hz, 1H), 6.88 (dd, J = 8.7, 1.7 Hz, 1H), 3.41–3.38 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0518] Step 2: 5-(ethylamino)-2-iodo-4-nitrobenzene

[0519] Under a nitrogen atmosphere, NIS (16.18 g, 71.92 mmol) was added in portions to a stirred solution of 3-(ethylamino)-4-nitrobenzene (12.50 g, 65.38 mmol) in AcOH (120.00 mL). The reaction mixture was stirred at 50 °C for 6 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with EtOAc (100 mL). The resulting mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by grinding with CH2Cl2 / MeOH (50:1) (500 mL). The collected precipitate was filtered and dried to give 5-(ethylamino)-2-iodo-4-nitrobenzene (13.9 g, 60%) as a reddish-brown solid. C9H8IN3O2[MH] - The calculated MS ESI value is 315.97, and the measured value is 315.90.

[0520] Step 3: 4-Amino-5-(ethylamino)-2-iodobenzylnitrile

[0521] Fe (2.11 g, 37.85 mmol) was added to a stirred mixture of 5-(ethylamino)-2-iodo-4-nitrobenzenenitrile (3.00 g, 9.46 mmol) and NH4Cl (2.53 g, 47.31 mmol) in EtOH (30.00 mL) and H2O (4.50 mL). The reaction mixture was stirred at 75 °C under a nitrogen atmosphere for 4 h. The resulting mixture was filtered, and the filter cake was washed with EtOH (6 × 300 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product, 4-amino-5-(ethylamino)-2-iodobenzyl nitrile (2.4 g, 79%), was used directly in the next step without further purification. C9H 10 IN3[MH] - The calculated MS ESI value is 285.99, and the measured value is 286.00.

[0522] Step 4: 3-Ethyl-6-iodo-2-methyl-1,3-benzodiazole-5-carboxynitrile

[0523] 1,1,1-trimethoxyethane (2.93 g, 24.38 mmol) was added to a stirred solution of 4-amino-5-(ethylamino)-2-iodobenzyl nitrile (3.50 g, 12.19 mmol) in AcOH (35.00 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 5 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with EtOAc (100 mL). The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1). The fractions containing the desired product were combined and concentrated to obtain 2.18 g (54%) of 3-ethyl-6-iodo-2-methyl-1,3-benzodiazole-5-carboxynitrile, a grayish-white solid. C 11 H 10 IN3[M+H] + The calculated MS ESI value is 311.99, and the measured value is 312.05.

[0524] Step 5: 3-Ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole-5-carboxynitrile

[0525] TEA (19.48 mL, 192.50 mmol) was added to a stirred mixture of 3-ethyl-6-iodo-2-methyl-1,3-benzodiazole-5-carboxynitrile (2.18 g, 7.01 mmol), trimethylsilylacetylene (2.97 mL, 30.25 mmol), CuI (0.27 g, 1.40 mmol), and Pd(PPh3)2Cl2 (0.49 g, 0.70 mmol) in DMF (22.00 mL). The reaction mixture was degassed three times with nitrogen and stirred at 80 °C for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (25:1). The fractions containing the desired product were combined and concentrated to obtain 2 g (94%) of 3-ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole-5-carboxynitrile, a brown solid. 16 H 19 N3Si[M+H] + The calculated MS ESI value is 282.13, and the measured value is 282.15.

[0526] Step 6: 3-Ethyl-6-ethynyl-2-methyl-1,3-benzodiazole-5-carboxynitrile

[0527] TBAF (5.33 mL, 5.33 mmol) was added dropwise to a stirred solution of 3-ethyl-2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole-5-carboxynitrile (1.00 g, 3.55 mmol) in THF (10.00 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (25:1). The fractions containing the desired product were combined and concentrated to give 3-ethyl-6-ethynyl-2-methyl-1,3-benzodiazole-5-carboxynitrile (0.70 g, 84%) as a yellow solid. 13 H 11 N3[M+H] + The calculated MS ESI value is 210.10, and the measured value is 210.20.

[0528] Step 7: 3-[2-(6-cyano-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0529] TEA (0.22 mL, 2.13 mmol) was added to a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol), 3-ethyl-6-ethynyl-2-methyl-1,3-benzodiazole-5-carboxylonitrile (0.16 g, 0.78 mmol), CuI (19.72 mg, 0.10 mmol), and Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 (10 mmol / L) / water, 10%-50% gradient over 25 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The crude product was purified by Prep-HPLC under the following conditions: column: XBridge PrepOBD C18 column, 19 × 250 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 60B over 5.8 min; 210 / 254 nm; RT1: 5.52. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(6-cyano-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (49.9 mg, 18%), a grayish-white solid. 27 H 30 N8O3[M+H] + The calculated MS ESI value was 515.24, and the measured value was 515.30. H-NMR (400MHz, DMSO-d6): δ 8.34 (d, J = 1.3Hz, 1H), 7.98 (d, J = 0.5Hz, 1H), 7.43 (s, 1H), 6.78–6.53 (m, 3H), 6.19–6.17 (m, 1H), 5.73–5.61 (m, 1H), 5.33–5.28 (m, 1H), 4.50–4.4 5(m,1H),4.35-4.30(m,2H),4.07-3.70(m,2H),3.63-3.43(m,2H),3.30(s,3H),2.96- 2.92(m,3H),2.63(s,3H),2.50-2.47(m,1H),2.36-2.27(m,1H),1.32(t,J=7.2Hz,3H).

[0530] Example 25: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-cyclopropyl-1-ethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0531]

[0532] Step 1: N-[2-(ethylamino)-5-iodophenyl]cyclopropaneformamide

[0533] N,N-diisopropylethylamine (0.74 g, 5.72 mmol) was added dropwise to a stirred mixture of cyclopropanecarboxylic acid (0.16 g, 1.91 mmol) and HATU (1.09 g, 2.86 mmol) in DMF (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 min. N1-ethyl-4-iodophenyl-1,2-diamine (0.50 g, 1.91 mmol) was added to the mixture at room temperature. The resulting mixture was stirred for another 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give N-[2-(ethylamino)-5-iodophenyl]cyclopropanecarboxamide (0.50 g, 79%) as a dark gray solid, which was used directly in the next step without further purification. 12 H 15 IN2O[M+H] + The calculated ESI value is 331.02; the measured value is 331.05.

[0534] Step 2: 2-Cyclopropyl-1-ethyl-5-iodo-1,3-benzodiazole

[0535] A mixture of N-[2-(ethylamino)-5-iodophenyl]cyclopropaneformamide (0.90 g, 2.73 mmol) and acetic acid (9.00 mL) was stirred at 80 °C for 1 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was neutralized to pH 7 with saturated NaHCO3 (aqueous solution) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1). The fractions containing the desired product were combined and concentrated to give 2-cyclopropyl-1-ethyl-5-iodo-1,3-benzodiazole (0.61 g, 71%) as a brown semi-solid. 12 H 13 IN2[M+H]+ The calculated MS ESI value is 313.01; the measured value is 312.95.

[0536] Step 3: 2-Cyclopropyl-1-ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0537] To a mixture of 2-cyclopropyl-1-ethyl-5-iodo-1,3-benzodiazole (0.61 g, 1.95 mmol) and trimethylsilylacetylene (0.58 g, 5.86 mmol) in DMF (6.00 mL), Pd(PPh3)2Cl2 (0.14 g, 0.19 mmol), CuI (74.43 mg, 0.39 mmol), and TEA (3.95 g, 39.08 mmol) were added at room temperature. The reaction mixture was degassed three times with nitrogen and stirred at 80 °C for 5 h. The mixture was then cooled to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give 0.54 g (97%) of 2-cyclopropyl-1-ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole, a light brown semi-solid. 17 H 22 N₂Si[M+H] + The calculated MS ESI value is 283.16; the measured value is 283.25.

[0538] Step 4: 2-Cyclopropyl-1-ethyl-5-ethynyl-1,3-benzodiazole

[0539] TBAF (0.75 g, 2.88 mmol) was added to a stirred solution of 2-cyclopropyl-1-ethyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.54 g, 1.91 mmol) in THF (6.00 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1). The fractions containing the desired product were combined and concentrated to give 2-cyclopropyl-1-ethyl-5-ethynyl-1,3-benzodiazole (0.35 g, 87%) as a pink semi-solid. 14H 14 N2[M+H] + The calculated MS ESI value is 211.12; the measured value is 211.05.

[0540] Step 5: 3-[2-(2-cyclopropyl-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0541] To a mixture of 2.00 mL of DMF containing 2-cyclopropyl-1-ethyl-5-ethynyl-1,3-benzodiazole (0.16 g, 0.76 mmol) and 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.35 g, 0.91 mmol), Pd(PPh3)2Cl2 (53.41 mg, 0.07 mmol), CuI (28.98 mg, 0.15 mmol), and TEA (0.23 g, 2.28 mmol) was added at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was cooled to room temperature. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The crude product (150 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15B to 60B over 4.3 min; 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(2-cyclopropyl-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (75.8 mg, 19%), a grayish-white solid. 28 H 33 N7O3[M+H] + The calculated MS ESI value is 516.26; the measured value is 516.15. 1H NMR(300MHz,DMSO-d6)δ7.69(d,J=1.4Hz,1H),7.57(d,J=8.3Hz,1H),7.38-7.31(m,2H),6.8 5-6.48(m,3H),6.16(d,J=16.6Hz,1H),5.68(d,J=10.3Hz,1H),5.31-5.13(m,1H),4.41-4.3 4(m,3H),3.87-3.84(m,1H),3.79-3.66(m,1H),3.61-3.57(m,1H),3.50-3.37(m,2H),3.30- 3.24(m,3H),2.95-2.90(m,3H),2.44-2.16(m,2H),1.34(t,J=7.1Hz,3H),1.10-1.05(m,4H).

[0542] Example 26: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-(benzo[d]isoxazol-6-ylethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0543]

[0544] Step 1: 6-[2-(trimethylsilyl)ethynyl]-1,2-benzoxazole

[0545] TEA (20.44 g, 202.00 mmol) was added to a mixture of 6-bromo-1,2-benzoxazole (2.00 g, 10.10 mmol), trimethylsilylacetylene (1.49 g, 15.15 mmol), CuI (0.38 g, 2.02 mmol), and Pd(PPh3)2Cl2 (0.71 g, 1.01 mmol) in DMF (8.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 16 h. The resulting mixture was diluted with water (100 mL). The mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The fractions containing the desired product were combined and concentrated to obtain 0.80 g (36%) of 6-[2-(trimethylsilyl)ethynyl]-1,2-benzoxazole, a yellow semi-solid. 12 H 13 NOSi[MH] - The calculated MS ESI value is 214.09, and the measured value is 214.15.

[0546] Step 2: 6-ethynyl-1,2-benzoxazole

[0547] TBAF (5.57 mL, 5.57 mmol) was added dropwise to a stirred solution of 6-[2-(trimethylsilyl)ethynyl]-1,2-benzoxazole (0.80 g, 3.72 mmol) in THF (8.00 mL) at 0 °C and in air. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The fractions containing the desired product were combined and concentrated to give 6-ethynyl-1,2-benzoxazole (0.29 g, 54%) as a light brown solid. C9H5NO[MH] - The calculated MS ESI value is 142.04, and the measured value is 142.10.

[0548] Step 3: 3-[2-(1,2-benzoxazol-6-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0549] To a stirred mixture of 3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.20 g, 0.52 mmol) and 6-ethynyl-1,2-benzoxazole (0.12 g, 0.78 mmol) in DMF (2.00 mL), CuI (19.72 mg, 0.10 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol) and TEA (0.16 g, 1.55 mmol) were added to CuI (19.72 mg, 0.10 mmol), Pd(PPh3)2Cl2 (36.34 mg, 0.05 mmol), and TEA (0.16 g, 1.55 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water (10 mM NH4HCO3), 5% to 35% gradient over 30 min; detector, UV 220 nm. The crude product (150 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 60B over 5.8 min; 210 / 254 nm; RT1: 5.65. The fractions containing the desired product were combined and concentrated to give 3-[2-(1,2-benzoxazol-6-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (37.00 mg, 16%), a white solid. 23 H 24 N6O4[M+H] + The calculated MS ESI value was 449.19, and the measured value was 449.25. H-NMR (400MHz, DMSO-d6): δ 7.67 (d, J = 7.9Hz, 1H), 7.34 (m, 1H), 7.08 (d, J = 13.3Hz, 2H), 6.71 (s, 1H), 6.58 (m, J = 16.8, 10.3Hz, 1H), 6.52 (d, J = 5.7Hz, 1H), 6.17 (d, J = 16.6Hz, 1H), 5.69 (d, J = 10.0Hz, 1H),5.30-5.14(m,1H),4.52(s,1H),4.39(s,1H),4.06-3.97(m,1H),3.89-3.79(m,1H),3.77-3.7 3(m,1H),3.61-3.58(m,1H),3.48-3.45(m,3H),2.94(s,3H),2.53-2.49(m,1H),2.36-2.32(m,1H).

[0550] Example 27: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0551]

[0552] Step 1: 1-Ethyl-5-iodo-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0553] N 1 A solution of 1-ethyl-4-iodophenyl-1,2-diamine (2.00 g, 7.63 mmol) in CF3COOH was stirred at 70 °C under a nitrogen atmosphere for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (50 mL) and quenched with saturated NH3HCO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-5-iodo-2-(trifluoromethyl)-1H-benzo[d]imidazole (2.5 g, 96%) as a grayish-white solid. 10 H8F3IN2[M+H] + The calculated ESI value is 340.97; the measured value is 340.80.

[0554] Step 2: 3-Ethyl-2-(trifluoromethyl)-6-((trimethylsilyl)ethynyl)-3H-indole

[0555] TEA (7.44 g, 73.51 mmol) was added to a stirred mixture of 1-ethyl-5-iodo-2-(trifluoromethyl)-1H-benzo[d]imidazole (1.25 g, 3.68 mmol), Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol), CuI (0.14 g, 0.74 mmol), and trimethylsilylacetylene (1.08 g, 11.03 mmol). The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1). The fractions containing the desired product were combined and concentrated to give 1.2 g (96%) of 3-ethyl-2-(trifluoromethyl)-6-((trimethylsilyl)ethynyl)-3H-indole, a white solid. 16 H 18 F3NSi[M+H] + The calculated MS ESI value is 310.12; the measured value is 310.25.

[0556] Step 3: 1-Ethyl-5-ethynyl-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0557] TBAF (1.39 g, 5.32 mmol) was added dropwise to a stirred THF solution of 3-ethyl-2-(trifluoromethyl)-6-((trimethylsilyl)ethynyl)-3H-indole (1.10 g, 3.54 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1). The fractions containing the desired product were combined and concentrated to give 0.83 g, 98%, of 1-ethyl-5-ethynyl-2-(trifluoromethyl)-1H-benzo[d]imidazole as a pale yellow solid. 12 H9F3N2[M+H] + The calculated MS ESI value is 239.07; the measured value is 239.15.

[0558] Step 4: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0559] TEA (0.14 g, 1.40 mmol) was added to a stirred mixture of 1-ethyl-5-ethynyl-2-(trifluoromethyl)-1H-benzi[d]imidazole (0.17 g, 0.70 mmol), Pd(PPh3)2Cl2 (32.71 mg, 0.05 mmol), CuI (17.75 mg, 0.09 mmol), and 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-bromo-5-(methylamino)-1H-pyrazole-4-carboxamide (0.18 g, 0.47 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: NH4HCO3 / water, 10% to 50% gradient over 10 min; detector: UV 254 nm. The crude product was purified by Prep-HPLC under the following conditions: column: Xselect CSH OBD column, 30*150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; flow rate: 30 mL / min; gradient: 20B to 60B over 6 min; 210 / 254 nm; RT: 5.59. The fractions containing the desired product were combined and concentrated to give 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (97.3 mg, 38%), a white solid. 26 H 28 F3N7O3[M+H] + The calculated MS ESI value was 544.22; the measured value was 544.25. H-NMR (300MHz, DMSO-d6) δ 8.11 (s, 1H), 7.93 (d, J = 8.6Hz, 1H), 7.75-7.55 (m, 1H), 7.35 (s, 1H), 6.98-6.51 (m, 3H), 6.18 (d, J = 16.6Hz, 1H), 5.70 (d, J = 10.4Hz, 1H), 5.26 ( s,1H),4.35-4.60(m,3H),4.14-3.66(m,2H),3.65-3.39(m,2H),3.31-3.27(m,3H), 2.95(t,J=4.4Hz,3H),2.50-2.46(m,1H),2.25-2.58(m,1H),1.41(t,J=7.1Hz,3H).

[0560] Example 28: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0561]

[0562] Step 1: 5-Fluoro-4-iodo-2-nitroaniline

[0563] NIS (22.70 g, 100.88 mmol) was added to a mixture of 5-fluoro-2-nitroaniline (15.00 g, 96.08 mmol) and AcOH (120.00 mL). The reaction mixture was stirred at 70 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The filtrate was diluted with EtOAc (50 mL). The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1). The desired product fractions were fractionated and concentrated to give 5-fluoro-4-iodo-2-nitroaniline (24 g, 79%) as a yellow solid. C6H4FIN2O2[MH] - The calculated MS ESI value is 280.93; the measured value is 281.00.

[0564] Step 2: 4-Fluoro-5-iodophenyl-1,2-diamine

[0565] Fe (8.12 g, 145.38 mmol) was added to a stirred mixture of 5-fluoro-4-iodo-2-nitroaniline (10.00 g, 35.46 mmol) and NH4Cl (9.48 g, 177.29 mmol) in EtOH (100.00 mL) and H2O (15.00 mL). The reaction mixture was stirred at 75 °C under a nitrogen atmosphere for 16 h. The resulting mixture was filtered, and the filter cake was washed with ethanol (3 × 500 mL). The filtrate was concentrated under reduced pressure. The filtrate was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and dried to give 4-fluoro-5-iodophenyl-1,2-diamine (10 g, 89%) as a black solid, which was used directly in the next step without further purification. C6H6FIN2[M+H] + The calculated MS ESI value is 252.96, and the measured value is 253.00.

[0566] Step 3: 5-Fluoro-6-iodo-2-methyl-3H-1,3-benzodiazole

[0567] 1,1,1-trimethoxyethane (2.27 g, 18.87 mmol) was added to a solution of 4-fluoro-5-iodophenyl-1,2-diamine (3.17 g, 12.58 mmol) and MeOH (30 mL). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). Fractions containing the desired product were combined and concentrated to give 5-fluoro-6-iodo-2-methyl-3H-1,3-benzodiazole (2.9 g, 83%) as a pale yellow solid. C8H6FIN2[M+H] + The calculated MS ESI value is 276.96, and the measured value is 277.00.

[0568] Step 4: 6-Fluoro-5-iodo-1,2-dimethyl-1,3-benzodiazole

[0569] Iodomethane (0.36 mL) was added dropwise to a stirred mixture of 5-fluoro-6-iodo-2-methyl-3H-1,3-benzodiazole (1 g, 3.62 mmol) and KOH (1.01 g, 18.00 mmol) in acetone under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). Fractions containing the desired product were combined and concentrated. The residue was purified by Prep-SFC under the following conditions: column: CHIRALPAK IF, 5*25cm, 5µm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MEOH); flow rate: 180mL / min; gradient: 40% B; 220nm; RT1: 5.22; RT2: 6.2. The fractions containing the desired product were combined and concentrated to obtain 0.47g, 44% (C9H8FIN2[M+H)) as a grayish-white solid. + The calculated MS ESI value is 476.23, and the measured value is 476.25.

[0570] Step 5: 3-[2-(6-fluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0571] TEA (0.19 mL, 1.86 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol), 6-fluoro-5-iodo-1,2-dimethyl-1,3-benzodiazole (0.16 g, 0.54 mmol), Pd(PPh3)2Cl2 (31.77 mg, 0.05 mmol), and CuI (17.24 mg, 0.09 mmol) in DMF (1.50 mL, 20.52 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 column, 19×250mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 50B to 80B over 4.3min; 210 / 254nm; RT1: 4.03. Fractions containing the desired product were combined and concentrated. The crude product (70mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19×150mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25B to 50B over 4.3min; 210 / 254nm. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(6-fluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (58 mg, 25%), a grayish-white solid. 25 H 28 FN7O3[M+H] +The calculated MS ESI value is 494.22, and the measured value is 494.30. H-NMR (400MHz, DMSO-d6): δ7.78 (dd, J=6.3, 1.2Hz, 1H), 7.61 (d, J=9.9Hz, 1H), 7.49(s,1H),6.79-6.52(m,3H),6.18-6.16(m,1H),5.72-5.67(m,1H),5.28-5. 25(m,1H),4.55-4.42(m,1H),4.06-3.56(m,5H),3.52-3.42(m,2H),3.35-3.28 (m,3H),2.99-2.93(m,3H),2.53(s,3H),2.49-2.43(m,1H),2.35-2.27(m,1H).

[0572] Example 29: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0573]

[0574] Step 1: 1-Ethyl-4,6-difluoro-5-iodo-1,3-benzodiazole

[0575] Sodium hydride (60% oil solution, 0.26 g) was added to a solution of 4,6-difluoro-5-iodine-1H-1,3-benzodiazole (1.00 g, 0.004 mmol) in DMF at 0 °C. The mixture was stirred for 15 min. Ethyl iodine (1.67 g, 0.01 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / EtOAc (5:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-4,6-difluoro-5-iodine-1,3-benzodiazole (0.4 g, 36%) as a grayish-white solid. C9H7F2IN2[M+H] + The calculated MS ESI value is 308.96, and the measured value is 308.90.

[0576] Step 2: 1-Ethyl-4,6-difluoro-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0577] TEA (2.63 g, 25.97 mmol) was added to a mixture of 1-ethyl-4,6-difluoro-5-iodo-1,3-benzodiazole (0.40 g, 1.29 mmol), trimethylsilylacetylene (0.38 g, 3.90 mmol), CuI (49.46 mg, 0.26 mmol), and Pd(PPh3)2Cl2 (91.14 mg, 0.13 mmol) in DMF (4.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The fractions containing the desired product were combined and concentrated to obtain 1-ethyl-4,6-difluoro-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.30 g, 83%), which was a yellow oil. 10 H6F2N2[M+H] + The calculated MS ESI value is 279.11, and the measured value is 279.25.

[0578] Step 3: 1-Ethyl-5-ethynyl-4,6-difluoro-1,3-benzodiazole

[0579] TBAF (1.62 mL, 1.62 mmol) was added dropwise to a stirred solution of 1-ethyl-4,6-difluoro-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.30 g, 1.08 mmol) in THF (3.00 mL) at 0 °C and in air. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-5-ethynyl-4,6-difluoro-1,3-benzodiazole (0.18 g, 81%) as a pale yellow solid. 11 H8F2N2[M+H] + The calculated MS ESI value is 207.07, and the measured value is 207.05.

[0580] Step 4: 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0581] TEA (0.11 g, 1.04 mmol) was added to a stirred mixture of 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.35 mmol), 1-ethyl-5-ethynyl-4,6-difluoro-1,3-benzodiazole (0.14 g, 0.692 mmol), Pd(PPh3)2Cl2 (24.30 mg, 0.04 mmol), and CuI (13.19 mg, 0.069 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (10 mM NH4HCO3), 5% to 35% gradient over 30 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The crude product (130 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 60B over 5.8 min; 210 / 254 nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to give 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (91 mg, 51%), a white solid. 25 H 27 F2N7O3[M+H] + The calculated MSESI value was 512.21; the measured value was 512.20. ¹H-NMR (400MHz, DMSO-d6): δ 8.46 (s, 1H), 7.73–7.70 (m, 1H), 7.58 (s, 1H), 6.78–6.55 (m, 3H), 6.18–6.25 (m, 1H), 5.71–5.68 (m, 1H), 5.29–5.26 (m, 1H), 4.60–4.36 (m, 1H). ),4.30(q,J=7.3Hz,2H),4.08-3.69(m,2H),3.65-3.41(m,2H),3.35-3.30(m,3H), 2.97(t,J=5.3Hz,3H),2.71-2.58(m,1H),2.33-2.30(m,1H),1.41(t,J=7.2Hz,3H).

[0582] Example 30: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-(difluoromethyl)-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0583]

[0584] Step 1: 1-(difluoromethyl)-4,6-difluoro-5-iodo-1,3-benzodiazole

[0585] Difluoro(sulfo)acetic acid (0.76 g, 4.28 mmol) and K₂CO₃ (1.48 g, 10.71 mmol) were added to a stirred solution of 4,6-difluoro-5-iodo-1H-1,3-benzodiazole (1.00 g, 3.57 mmol) in EA (8.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with saturated sodium bicarbonate aqueous solution (30 mL). The organic layer was separated and the aqueous layer was extracted with EA (3 × 45 mL). The combined organic layers were washed with brine (2 × 45 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / DCM solution (0–50%). Fractions containing the desired product were combined and concentrated. The crude product was further separated using a Prep-ahidrotic SFC under the following conditions: column: BEH 2-ethylpyridine, 30*150mm, 5μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 45mL / min; gradient: 10% B; detector: UV 254nm. The faster fractions containing the desired product (RT: 2.93min) were combined and concentrated under reduced pressure to obtain 1-(difluoromethyl)-4,6-difluoro-5-iodo-1,3-benzodiazole (0.45g, 37%) as a white solid. The slower fractions containing the desired product (RT: 3.50min) were combined and concentrated under reduced pressure to obtain 1-(difluoromethyl)-5,7-difluoro-6-iodo-1,3-benzodiazole (0.15g, 12%) as a white solid. C8H3F4IN2[M+H] + The calculated MS ESI value is 330.93, and the measured value is 330.95.

[0586] Step 2: 3-[2-[1-(difluoromethyl)-4,6-difluoro-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0587] To a stirred mixture of 1-(difluoromethyl)-4,6-difluoro-5-iodo-1,3-benzodiazole (0.18 g, 0.54 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol) in DMF (4.00 mL), Pd(PPh3)2Cl2 (44.29 mg, 0.05 mmol), CuI (20.66 mg, 0.11 mmol), and TEA (0.16 g, 1.63 mmol) were added to Pd(PPh3)2Cl2 (44.29 mg, 0.05 mmol), CuI (20.66 mg, 0.11 mmol), and TEA (0.16 g, 1.63 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (0–4.8%). Fractions containing the desired product were combined and concentrated. The crude product was further purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 60% B over 4.3 min; detector: UV 210 & 254 nm; RT; 4.02 min. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain 3-[2-[1-(difluoromethyl)-4,6-difluoro-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (44.8 mg, 15%) as a white solid. 24 H 23 F4N7O3[M+H] + The calculated MS ESI value is 534.18; the measured value is 534.25. H-NMR (400MHz, d6-DMSO) δ8.79 (s, 1H), 8.11 (t, J = 58.4Hz, 1H), 7.75 (d, J = 8 .4Hz,1H),7.56(brs,1H),6.71-6.55(m,3H),6.17(d,J=16.9Hz,1H),5.69(d ,J=10.3Hz,1H),5.28(s,1H),4.53-4.39(m,1H),4.02-3.72(m,2H),3.60-3 .45(m,2H),3.32(s,3H),2.96(s,3H),2.67-2.61(m,1H),2.33-2.30(m,1H).

[0588] Example 31: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-(difluoromethyl)-4,6-difluoro-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0589]

[0590] Step 1: 1-(difluoromethyl)-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole

[0591] Difluoro(sulfonyl)acetic acid (0.15 g, 0.82 mmol) was added dropwise to a stirred solution of 4,6-difluoro-5-iodo-2-methyl-1H-1,3-benzodiazole (0.20 g, 0.68 mmol) and K₂CO₃ (0.19 g, 1.36 mmol) in EA (3.00 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (10–35%). The fractions containing the desired product were combined and concentrated to give 1-(difluoromethyl)-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole (80 mg, 34%) as a pale yellow solid. C9H5F4IN2[M+H] + The calculated MS ESI value is 344.95, and the measured value is 345.00.

[0592] Step 2: 1-(difluoromethyl)-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole

[0593] TEA (0.36 g, 3.55 mmol) was added to a stirred mixture of 1-(difluoromethyl)-4,6-difluoro-5-iodo-2-methyl-1,3-benzodiazole (0.61 g, 1.77 mmol), trimethylsilylacetylene (0.52 g, 5.32 mmol), PdCl2(PPh3)2 (0.12 g, 0.18 mmol), and CuI (67.53 mg, 0.36 mmol) in DMF (8.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. After cooling to ambient temperature, the resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 25 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (20–50%). The fractions containing the desired product were combined and concentrated under reduced pressure to give 1-(difluoromethyl)-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.5 g, 89%) as a yellow solid. 14 H 14 F2N2Si[M+H] + The calculated MS ESI value is 315.09, and the measured value is 315.15.

[0594] Step 3: 1-(difluoromethyl)-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole

[0595] TBAF (1.0 M THF solution, 2.40 mL, 2.40 mmol) was added dropwise to a stirred solution of 1-(difluoromethyl)-4,6-difluoro-2-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (0.50 g, 1.59 mmol) in THF (5.00 mL). The reaction mixture was stirred at ambient temperature under an argon atmosphere for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (50–90%). The fractions containing the desired product were combined and concentrated under reduced pressure to obtain 0.33 g, 85%, of 1-(difluoromethyl)-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole as a yellow solid. 11 H6F4N2[M+H] + The calculated MS ESI value is 243.05, and the measured value is 242.85.

[0596] Step 4: 3-[2-[1-(difluoromethyl)-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0597] TEA (60.73 mg, 0.60 mmol) was added to a mixture of 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.13 g, 0.30 mmol), 1-(difluoromethyl)-5-ethynyl-4,6-difluoro-2-methyl-1,3-benzodiazole (87.20 mg, 0.36 mmol), PdCl2(PPh3)2 (21.06 mg, 0.03 mmol), and CuI (11.43 mg, 0.06 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. After cooling to ambient temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM solution (0-5.0%) to obtain the crude product. The crude product was further purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19×150mm 5μm; mobile phase A: water (10mM NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25%B to 50%B over 4.3min; detector: UV 210 & 254nm; RT: 4.02min. The fractions containing the desired product were combined and concentrated under reduced pressure to give 3-[2-[1-(difluoromethyl)-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (86 mg, 52%), a white solid. 25 H 25 F4N7O3[M+H] +The calculated MS ESI value is 548.20; the measured value is 548.05. H NMR(400MHz,d6-DMSO)δ8.11(t,J=57.2Hz,1H),7.67(d,J=8.8Hz,1H),7.56(br s,1H),6.75-6.56(m,3H),6.18-6.15(m,1H),5.71-5.68(m,1H),5.32-5.20(m, 1H),4.55-4.36(m,1H),4.05-3.71(m,2H),3.62-3.44(m,2H),3.30(d,J=5.7Hz ,3H),2.96(t,J=5.5Hz,3H),2.69(s,3H),2.67-2.46(m,1H),2.34-2.27(m,1H).

[0598] Example 32: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-6-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0599]

[0600] Step 1: 5-Fluoro-6-iodo-3H-1,3-benzodiazole

[0601] Trimethyl orthoformate (2.00 g, 18.85 mmol) was added to a MeOH (30 mL) solution of 4-fluoro-5-iodophenyl-1,2-diamine (3.17 g, 12.58 mmol). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 5-fluoro-6-iodo-3H-1,3-benzodiazole (2.9 g, 88%) as a light brown solid. C7H4FIN2[M+H] + The calculated MS ESI value is 262.94; the measured value is 262.95.

[0602] Step 2: 1-Ethyl-6-fluoro-5-iodo-1,3-benzodiazole

[0603] Iodoethane (0.50 mL, 3.23 mmol) was added dropwise to a stirred solution of 5-fluoro-6-iodo-3H-1,3-benzodiazole (1.10 g, 4.20 mmol) and KOH (1.18 g, 20.99 mmol) in 16.50 mL of acetone under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (15:1). The fractions containing the desired product were combined and concentrated to give 1.4 g of crude product. The crude product was purified by Prep-ahidrotic SFC under the following conditions: column: CHIRAL ART Cellulose-SB, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 100mL / min; gradient: 20% B; 220nm; RT1: 3.7; RT2: 4.3; injection volume: 2mL; number of runs: 20. The fractions containing the desired product were combined (the final peak RT2: 4.3) and concentrated to obtain 1-ethyl-6-fluoro-5-iodo-1,3-benzodiazole (0.44g, 32%) as a light brown solid.

[0604] Step 3: 3-[2-(1-ethyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0605] TEA (0.23 mL, 2.24 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.18 g, 0.54 mmol), 1-ethyl-6-fluoro-5-iodo-1,3-benzodiazole (0.19 g, 0.65 mmol), Pd(PPh3)2Cl2 (38.13 mg, 0.05 mmol), and CuI (20.69 mg, 0.11 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 6% MeOH / DCM. Fractions containing the desired product were combined and concentrated. The crude product (200 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25 B to 55 B over 4.3 min; 210 / 254 nm; RT1: 4.02. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-(1-ethyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (62.9 mg, 23%). 25 H 28 FN7O3[M+H] + The calculated MS ESI value was 494.22, and the measured value was 494.25. H-NMR (400MHz, DMSO-d6): δ 8.41 (s, 1H), 7.95 (d, J = 6.2Hz, 1H), 7.76 (d, J = 9.7Hz, 1H), 7.49 (s, 1H), 6.87–6.49 (m, 3H), 6.19–6.17 (m, 1H), 5.75–5.65 (m, 1H), 5.29–5.25 (m, 1H), 4.50 -4.45(m,1H),4.28(q,J=7.3Hz,2H),4.07-3.44(m,3H),3.35-3.29(m,3H),2.96(t,J=5.2H z,3H),2.47(t,J=7.1Hz,1H),2.45-2.44(m,1H),2.35-2.24(m,1H),1.41(t,J=7.3Hz,3H).

[0606] Example 33: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-1-ethyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0607]

[0608] Step 1: 5-Chloro-4-iodo-2-nitroaniline

[0609] NIS (6.52 g, 28.98 mmol) was added to a mixture of 5-chloro-2-nitroaniline (5.00 g, 28.97 mmol) and AcOH (50.00 mL). The reaction mixture was stirred overnight at 50 °C under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with water (2 × 150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1). The fractions containing the desired product were combined and concentrated to give 5-chloro-4-iodo-2-nitroaniline (7.6 g, 87%) as a pale yellow solid. H-NMR (400MHz, DMSO-d6) δ8.36(s,1H),7.60(s,2H),7.27(s,1H).

[0610] Step 2: 4-Chloro-5-iodophenyl-1,2-diamine

[0611] NH4Cl (6.72 g, 125.63 mmol, 5.00 equivalent) was added to a mixture of Fe (5.61 g, 100.46 mmol) and 5-chloro-4-iodo-2-nitroaniline (7.50 g, 25.13 mmol) in EtOH (100.00 mL) and H2O (25.00 mL). The reaction mixture was stirred at 75 °C under an argon atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EA (2 × 200 mL). The combined organic layers were washed with EtOAc (2 × 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 4-chloro-5-iodophenyl-1,2-diamine (6.6 g, 97.83%) as a yellow solid, which was used directly in the next step without further purification. C6H6ClIN2[M+H] + The calculated MS ESI value is 268.93, and the measured value is 268.85.

[0612] Step 3: 5-Chloro-6-iodo-2-methyl-3H-1,3-benzodiazole

[0613] To a solution of 4-chloro-5-iodophenyl-1,2-diamine (3.50 g, 13.04 mmol) in AcOH (40.00 mL), 1,1,1-trimethoxyethane (3.33 mL, 26.05 mmol) was added. The reaction mixture was stirred at 75 °C under an argon atmosphere for 3 h. The residue was neutralized to pH 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (2 × 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20 / 1). The fractions containing the desired product were combined and concentrated to give 5-chloro-6-iodo-2-methyl-3H-1,3-benzodiazole (3.2 g, 83%) as a grayish-white solid. C8H6ClIN2[M+H] + The calculated MS ESI value is 292.93, and the measured value is 292.95.

[0614] Step 4: 6-Chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole

[0615] Iodoethane (1.28 mL, 8.19 mmol) was added to a mixture of 5-chloro-6-iodo-2-methyl-3H-1,3-benzodiazole (3.20 g, 10.94 mmol) and KOH (3.68 g, 65.59 mmol) in 40.00 mL of acetone. The reaction mixture was stirred at room temperature under an argon atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give a mixture of 3.8 g. The crude product (2g) was purified by Prep-SFC under the following conditions: column: CHIRALPAK IG, 5*25cm, 10µm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MEOH); flow rate: 200mL / min; gradient: 50% B; 220nm; RT1: 5.99; RT2: 7.74; injection volume: 3mL; number of runs: 17. The fractions containing the desired product were combined and concentrated to obtain 0.80g, 22%, a light yellow solid of 6-chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole. 10 H 10 ClIN2[M+H]+ The calculated MS ESI value is 320.96, and the measured value is 320.95.

[0616] Step 5: 3-[2-(6-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0617] TEA (0.19 mL, 1.87 mmol) was added to a mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol), 6-chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole (0.17 g, 0.54 mmol), CuI (17.24 mg, 0.09 mmol), and Pd(PPh3)2Cl2 (31.77 mg, 0.05 mmol) in DMF (1.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridgePrep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 50B over 4.3 min; 210 / 254 nm; RT1: 4.23. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-(6-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (44.4 mg, 18.72%). 26 H 30 ClN7O3[M+H] +The calculated MS ESI value was 292.93, and the measured value was 292.95; ¹H-NMR (400MHz, DMSO-d6) δ 7.92–7.84 (m, 2H), 7.51 (s, 1H), 6.86 (s, 1H), 6.77–6.55 (m, 2H), 6.22–6.13 (m, 1H), 5.73–5.65 (m, 1H), 5.33–5.21 (m, 1H), 4. 58-4.36(m,1H),4.30-4.20(m,2H),4.08-3.70(m,2H),3.65-3.42(m,2H),3.33(s,1H),3 .31(d,J=5.4Hz,3H),3.00-2.93(m,3H),2.56(s,3H),2.31(m,1H),1.29(t,J=7.2Hz,3H).

[0618] Example 34: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0619]

[0620] Step 1: 4,6-Difluoro-5-iodo-1-(2,2,2-trifluoroethyl)-1,3-benzodiazole

[0621] Cs₂CO₃ (2.79 g, 8.57 mmol) was added to a stirred mixture of 4,6-difluoro-5-iodo-1H-1,3-benzodiazole (0.80 g, 2.86 mmol) and trifluoro(trifluoromethanesulfonylmethoxy)methane (0.99 g, 4.28 mmol) in DMSO (8.00 mL) at room temperature. The reaction mixture was stirred for 24 h. The reaction was quenched by adding water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by SFC to give 4,6-difluoro-5-iodo-1-(2,2,2-trifluoroethyl)-1,3-benzodiazole (0.32 g, 30%) as a pale yellow solid. C₁₆H₄F₅IN₂[M+H] + The calculated MS ESI value is 363.04, and the measured value is 363.00.

[0622] Step 2: 3-[2-[4,6-difluoro-1-(2,2,2-trifluoroethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0623] TEA (0.14 g, 1.36 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol), 4,6-difluoro-5-iodo-1-(2,2,2-trifluoroethyl)-1,3-benzodiazole (0.20 g, 0.54 mmol), Pd(PPh3)2Cl2 (31.77 mg, 0.05 mmol), and CuI (17.24 mg, 0.09 mmol) in DMF (1.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using an XBridgePrep C18 OBD column (19 × 150 mm, 5 μm); mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 55B over 4.3 min; 210 / 254 nm; RT1: 4.12. Fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-[4,6-difluoro-1-(2,2,2-trifluoroethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 39%). 25 H 24 F5N7O3[M+H] + The calculated MS ESI value is 566.19; the measured value is 566.20. 1H NMR(400MHz,d6-DMSO)δ8.51(s,1H),7.81(d,J=9.1Hz,1H),7.56(s,1H),6.75-6.56(m,3H),6.17(d,J=16.6Hz,1H),5.69(d,J=9.5Hz,1H),5.4 3-5.27(m,3H),4.57-4.37(m,1H),4.08-3.83(m,2H),3.79-3.53(m,2H) ,3.52-3.34(m,3H),2.98-2.94(m,3H),2.51(m,1H),2.33-2.29(m,1H).

[0624] Example 35: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-2-methyl-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide

[0625]

[0626] Step 1: tert-butyl 2-(1,1-difluoroethyl)morpholine-4-carboxylate

[0627] Trifluoro(trifluoromethanesulfonylmethoxy)methane (1.18 g, 5.10 mmol) and Cs₂CO₃ (3.32 g, 0.01 mmol) were added in portions to a stirred solution of 4,6-difluoro-5-iodo-2-methyl-1H-1,3-benzodiazole (1.00 g, 3.40 mmol) in DMSO (10.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by SFC column: DAICEL DCpak P4VP(02), 30*250mm, 5um; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 60mL / min; gradient: 18% B; 254nm; RT2: 6.21; injection volume: 0.8mL; number of runs: 15. The fractions containing the desired product were combined and concentrated to obtain 0.42g, 32%, a light yellow solid of 4,6-difluoro-5-iodo-2-methyl-1-(2,2,2-trifluoroethyl)-1,3-benzodiazole. 10 H6F5IN2[M+H] +The calculated MS ESI value is 376.95, and the measured value is 377.00.

[0628] Step 2: 3-[2-[4,6-difluoro-2-methyl-1-(2,2,2-trifluoroethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0629] TEA (0.14 g, 1.36 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol), 4,6-difluoro-5-iodo-2-methyl-1-(2,2,2-trifluoroethyl)-1,3-benzodiazole (0.20 g, 0.54 mmol), Pd(PPh3)2Cl2 (31.77 mg, 0.05 mmol), and CuI (17.24 mg, 0.09 mmol) in DMF (1.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using an XBridge Prep C18 OBD column (19 × 150 mm, 5 μm); mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 60B over 4.3 min; 210 / 254 nm; RT1: 4.02. Fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-[4,6-difluoro-2-methyl-1-(2,2,2-trifluoroethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 37%). 26 H 26 F5N7O3[M+H] + The calculated MS ESI value is 580.20; the measured value is 580.25. 1H NMR (400MHz, DMSO-d6) δ7.70 (d, J = 9.1Hz, 1H), 7.55 (s, 1H), 6.86-6.49 (m, 3H), 6.19-6.14 (m, 1H), 5.71-5.67 (m, 1H), 5.42-5.19 (m, 3H), 4.62-4 .35(m,1H),4.08-3.70(m,2H),3.65-3.42(m,2H),3.33-3.27(m,3H),2. 96(t,J=5.5Hz,3H),2.60(s,3H),2.52-2.48(m,1H),2.37-2.25(m,1H).

[0630] Example 36: 3-[2-(3-ethyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0631]

[0632] Step 1: 1-Ethyl-4-fluoro-5-iodine-1,3-benzodiazole and 1-Ethyl-7-fluoro-6-iodine-1,3-benzodiazole

[0633] Iodoethane (1.67 g, 10.69 mmol) was added to a stirred mixture of 4-fluoro-5-iodo-1H-1,3-benzodiazole (2.00 g, 7.63 mmol) and KOH (2.57 g, 45.80 mmol) in 20.00 mL of acetone at room temperature and in air. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 × 70 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (1 g / NH₄HCO₃), 25% to 55% gradient over 30 min; detector: UV 254 nm. The fractions containing the desired product were combined and concentrated to obtain 1-ethyl-4-fluoro-5-iodine-1,3-benzodiazole (0.80 g, 36%) and 1-ethyl-7-fluoro-6-iodine-1,3-benzodiazole (0.78 g, 35%) as yellow solids. PH-FNT-KIN-03-1434-1: C9H8FIN2[M+H] + The calculated MS ESI value is 290.97, and the measured value is 290.99. PH-FNT-KIN-03-1300-1: C9H8FIN2[M+H] +The calculated MS ESI value is 290.97, and the measured value is 290.95.

[0634] Step 2: 3-[2-(3-ethyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0635] TEA (0.23 mL, 2.24 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.18 g, 0.54 mmol), 1-ethyl-7-fluoro-6-iodo-1,3-benzodiazole (0.19 g, 0.65 mmol), CuI (20.69 mg, 0.11 mmol), and Pd(pph3)Cl2 (44.36 mg, 0.05 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridgePrep OBD C18 column, 19*250mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 25B to 60B over 5.8min; 210 / 254nm; RT1: 5.57. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-(3-ethyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (85mg, 31%). 25 H 28 FN7O3[M+H] +The calculated MS ESI value was 494.22, and the measured value was 494.25. H-NMR (400MHz, DMSO-d6) δ 8.42 (s, 1H), 7.64-7.29 (m, 3H), 6.93-6.46 (m, 3H), 6.17 (d, J=16.4Hz, 1H), 5.74-5.65 (m, 1H), 5.33-5.20 (m, 1H), 4.62-4.30 (m, 3H), 4.07-3.71 (m, 2H), 3.65-3.41 (m, 2H), 3.32-3.28 (m, 1H), 3.03-2.92 (m, 3H), 2.51 (s, 3H), 2.35-2.30 (m, 1H), 1.47-1.44 (m, 3H).

[0636] Example 37: 3-[2-(1-ethyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0637]

[0638] Step 1: 1-Ethyl-6-fluoro-5-iodo-2-methyl-1,3-benzodiazole

[0639] Iodoethane (0.48 mL, 3.07 mmol) was added dropwise to a stirred solution of 5-fluoro-6-iodo-2-methyl-3H-1,3-benzodiazole (1.1 g, 3.98 mmol) and KOH (1.12 g, 19.92 mmol) in 16.50 mL of acetone under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (15:1). The fractions containing the desired product were combined and concentrated to give 1.29 g of crude product. The crude product was purified by Prep-ahidrotic SFC under the following conditions: column: CHIRAL ART Cellulose-SB, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 100mL / min; gradient: 20% B; 220nm; RT1: 3.7; RT2: 4.3; injection volume: 2mL; number of runs: 20. The fractions containing the desired product (the slower peak RT2: 4.3) were combined and concentrated to obtain 1-ethyl-6-fluoro-5-iodo-2-methyl-1,3-benzodiazole (0.48g, 35%) as a light brown solid. 1 ¹H NMR (300MHz, chloroform-d) δ 8.02 (d, J = 5.6Hz, 1H), 7.05 (d, J = 7.8Hz, 1H), 4.11 (q, J = 7.3Hz, 2H), 2.60 (s, 3H), 1.40 (t, J = 7.3Hz, 3H)

[0640] Step 2: 3-[2-(1-ethyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0641] TEA (91.61 mg, 0.91 mmol) was added to a stirred solution of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 0.31 mmol), 1-ethyl-6-fluoro-5-iodo-2-methyl-1,3-benzodiazole (0.14 g, 0.45 mmol), Pd(PPh3)2Cl2 (21.18 mg, 0.03 mmol), and CuI (11.49 mg, 0.06 mmol) in DMF (1.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN, 0.01 mmol NH4HCO3 / water, 25% to 40% gradient over 20 min; detector: UV 254 nm. Fractions containing the desired product were combined and concentrated. The crude product was purified by Prep-HPLC under the following conditions: column: Atlantis Prep T3OBD column, 19*250 mm 10 u; mobile phase A: water (0.1% FA), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: 15B to 50B over 6 min; 210 / 254 nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to obtain 3-[2-(1-ethyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (32.8 mg, 21%), a light yellow solid. 26 H 30 FN7O3[M+H] + The calculated ESI value is 508.23; the measured value is 508.25. 1 H NMR (300MHz, DMSO-d6) δ7.78(d,J=6.3Hz,1H),7.64(d,J=9.9Hz,1H),7.48(d,J=8.0H z,1H),6.93-6.51(m,3H),6.16-5.88(m,1H),5.68-5.42(m,1H),5.25-5.01(m,1H),4. 47-4.43(m,1H),4.21(q,J=7.2Hz,2H),4.10-3.73(m,2H),3.64-3.43(m,2H),3.37-3 .26(m,3H),2.95(d,J=4.3Hz,3H),2.54(s,4H),2.33-2.28(m,1H),1.30-1.25(m,3H).

[0642] Example 38: 3-[2-(4-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0643]

[0644] Step 1: 3-Chloro-4-iodo-2-nitroaniline

[0645] NIS (6.84 g, 30.40 mmol) was added to a stirred solution of 3-chloro-2-nitroaniline (5.00 g, 28.97 mmol) in AcOH (50.00 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The mixture was extracted with EA (3 × 100 mL), and the combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4-iodo-2-nitroaniline (8.50 g, 98%) as an orange solid, which was used directly in the next step without further purification. C₆H₄ClIN₂O₂[MH] - The calculated MS ESI values ​​are 296.89 and 297.90; the measured values ​​are 297.00 and 299.00.

[0646] Step 2: 3-Chloro-4-iodophenyl-1,2-diamine

[0647] Fe (0.75 g, 13.43 mmol) and NH4Cl (0.90 g, 16.75 mmol) were added to a stirred mixture of 3-chloro-4-iodo-2-nitroaniline (1.00 g, 3.35 mmol) in EtOH (12.00 mL) and H2O (3.00 mL) at room temperature. The reaction mixture was stirred at 75 °C for 2 h. The resulting mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with EtOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 3-chloro-4-iodophenyl-1,2-diamine (0.79 g, 87%) as a brown solid, which was used directly in the next step without further purification. C6H6ClIN2[M+H] + The calculated MS ESI values ​​are 268.93 and 270.93; the measured values ​​are 268.85 and 270.85.

[0648] Step 3: 3-Chloro-4-iodophenyl-1,2-diamine

[0649] At room temperature, 1,1,1-trimethoxyethane (0.53 g, 4.41 mmol) was added to a stirred solution of 3-chloro-4-iodophenyl-1,2-diamine (0.79 g, 2.94 mmol) in MeOH (10.00 mL). The reaction mixture was stirred at 70 °C for 2 h. The resulting mixture was cooled to room temperature. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (0-70%). Fractions containing the desired product were combined and concentrated to give 0.67 g, 77% brown solid 4-chloro-5-iodo-2-methyl-1H-1,3-benzodiazole. C8H6ClIN2[M+H] + The calculated MS ESI values ​​are 292.93 and 294.93; the measured values ​​are 292.80 and 294.80.

[0650] Step 4: 4-Chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole

[0651] At room temperature, iodoethane (0.42 g, 2.66 mmol) and KOH (0.50 g, 8.88 mmol) were added to a stirred solution of 4-chloro-5-iodo-2-methyl-1H-1,3-benzodiazole (0.52 g, 1.77 mmol) in 6.00 mL of acetone. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3% MeOH / DCM. The fractions containing the desired product were combined and concentrated to give 4-chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole (0.23 g, 40%) as a grayish-white solid. Elution was also performed with 4% MeOH / DCM. The fractions containing the desired product were combined and concentrated to give 7-chloro-1-ethyl-6-iodo-2-methyl-1,3-benzodiazole (0.11 mg, 19%) as a yellow solid. 10 H 10 ClIN2[M+H] + The calculated MS ESI values ​​are 320.96 and 322.96; the measured values ​​are 320.85 and 322.85.

[0652] Step 5: 3-[2-(4-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0653] To a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.13 g, 0.39 mmol) and 4-chloro-1-ethyl-5-iodo-2-methyl-1,3-benzodiazole (0.15 g, 0.47 mmol) in DMF (3.00 mL), Pd(PPh3)2Cl2 (27.54 mg, 0.03 mmol), CuI (14.94 mg, 0.07 mmol), and TEA (0.12 g, 1.17 mmol) were added to Pd(PPh3)2Cl2 (27.54 mg, 0.03 mmol), CuI (14.94 mg, 0.07 mmol), and TEA (0.12 g, 1.17 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (0–6.0%). Fractions containing the desired product were combined and concentrated. The crude product (0.15 g) was purified by Prep-HPLC under the following conditions: column: SunFire Prep C18OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20 B to 50 B over 4.3 min; 210 / 254 nm; RT1: 4.02 min. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-(4-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (49.30 mg, 23%). 26 H 30 ClN7O3[M+H] + The calculated MS ESI values ​​are 524.22 and 526.21; the measured values ​​are 524.15 and 526.15. H-NMR(300MHz,DMSO-d6)δ7.81-7.41(m,3H),6.88(s,1H),6.65(d,J=12.3Hz,1 H),6.57(d,J=12.8Hz,1H),6.16(d,J=16.6Hz,1H),5.68(d,J=10.4Hz,1H),5.29 -5.25(m,1H),4.61-4.21(m,3H),3.98-3.94(m,4H),3.29(d,J=3.8Hz,3H),2.95 (d,J=3.1Hz,3H),2.63-2.59(m,4H),2.33-.2.30(m,1H),1.30(t,J=7.0Hz,3H).

[0654] Example 39: 3-(2-[1-ethyl-2-methylimidazo[4,5-b]pyridin-5-yl]ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0655]

[0656] Step 1: 5-Bromo-2-methyl-1H-imidazo[4,5-b]pyridine

[0657] Add 1,1,1-trimethoxyethane (3.78 mL, 31.47 mmol) to a solution of 6-bromopyridine-2,3-diamine (2.70 g, 14.36 mmol) in AcOH (30.00 mL). Stir the reaction mixture overnight at 100 °C under an argon atmosphere. Concentrate the resulting mixture under reduced pressure. Neutralize the residue to pH 7 with saturated NaHCO3 (aqueous solution). Extract the resulting mixture with EtOAc (2 × 200 mL). Wash the combined organic layers with water (2 × 100 mL), dry to anhydrous Na2SO4, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with DCM / MeOH (20 / 1). Combine and concentrate the fractions containing the desired product to give 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (2.4 g, 78%) as an orange solid. C7H6BrN3[M+H] + The calculated MS ESI value is 211.97, and the measured value is 211.90.

[0658] Step 2: 5-Bromo-1-ethyl-2-methylimidazo[4,5-b]pyridine

[0659] Iodoethane (1.27 mL, 8.13 mmol) was added to a stirred mixture of 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (2.40 g, 11.32 mmol) and KOH (3.81 g, 67.91 mmol) in 25.00 mL of acetone. The reaction mixture was stirred at room temperature under an argon atmosphere for 2 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / EtOAc (1:2). The fractions containing the desired product were combined and concentrated to give 5-bromo-1-ethyl-2-methylimidazo[4,5-b]pyridine (0.77 g, 28%) as a pale yellow solid. C9H 10 BrN3[M+H] +The calculated MS ESI value is 240.01, and the measured value is 240.05.

[0660] Step 3: 1-Ethyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine

[0661] TEA (1.30 mL, 12.81 mmol) was added to a mixture of 5-bromo-1-ethyl-2-methylimidazo[4,5-b]pyridine (0.72 g, 3.00 mmol), trimethylsilylacetylene (0.86 mL, 8.78 mmol), CuI (0.11 g, 0.60 mmol), and Pd(PPh3)2Cl2 (0.21 g, 0.30 mmol) in DMF (10.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-2-methyl-5-[2-(trimethylsilyl)acetylene]imidazo[4,5-b]pyridine (0.70 g, 90%) as a brown solid. 14 H 19 N3Si[M+H] + The calculated MS ESI value is 258.13, and the measured value is 258.20.

[0662] Step 4: 1-Ethyl-5-ethynyl-2-methylimidazo[4,5-b]pyridine

[0663] TBAF (4.06 mL, 4.06 mmol) was added dropwise to a stirred solution of 1-ethyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]imidazo[4,5-b]pyridine (0.70 g, 2.71 mmol) in THF (10.00 mL) at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1). The fractions containing the desired product were combined and concentrated to give 1-ethyl-5-ethynyl-2-methylimidazo[4,5-b]pyridine (0.34 g, 67%) as a pale yellow solid. 11 H 11 N3[M+H] + The calculated MS ESI value is 186.10, and the measured value is 186.25.

[0664] Step 5: 3-(2-[1-ethyl-2-methylimidazo[4,5-b]pyridin-5-yl]ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0665] TEA (0.14 mL, 1.01 mmol) was added to a mixture of 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.35 mmol), 1-ethyl-5-ethynyl-2-methylimidazo[4,5-b]pyridine (0.13 g, 0.69 mmol), CuI (13.19 mg, 0.07 mmol), and Pd(PPh3)2Cl2 (24.30 mg, 0.04 mmol) in DMF (1.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridgePrep OBD C18 column, 19*250mm 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20mL / min; gradient: 35B to 60B over 5.8min; 210 / 254nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to obtain 3-(2-[1-ethyl-2-methylimidazo[4,5-b]pyridin-5-yl]ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (43.7mg, 25%) as a grayish-white solid. 25 H 30 N8O3[M+H] +The calculated MS ESI value was 491.24, and the measured value was 491.25. H-NMR (400MHz, DMSO-d6) δ 8.04 (d, J = 8.0Hz, 1H), 7.54-7.48 (m, 2H), 6.90-6.52 (m, 3H), 6.17 (d, J = 16.4Hz, 1H), 5.69 (d, J = 10.4Hz, 1H), 5.29-5.25 (m, 1H), 4.60-4.32 (m, 1H). H),4.33-4.24(m,2H),4.09-3.70(m,2H),3.66-3.40(m,2H),3.32-3.27(m,1H),2.99 -2.94(m,3H),2.63(s,3H),2.55-2.52(m,3H),2.34-2.30(m,1H),1.42-1.18(m,3H).

[0666] Example 40: 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0667]

[0668] Step 1: 6-Fluoro-5-iodo-1-methyl-1,3-benzodiazole

[0669] Methyl iodine (0.04 mL) was added dropwise to a stirred mixture of 5-fluoro-6-iodo-3H-1,3-benzodiazole (0.1 g, 0.38 mmol) and KOH (0.11 g, 1.91 mmol) in acetone under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 20 min at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give the crude product. The crude product was purified by Prep-SFC under the following conditions: column: CHIRALPAK IF, 30*250mm, 5µm; mobile phase A: CO2, mobile phase B: MeOH (0.5% 2M NH3-MeOH)-HPLC; flow rate: 80mL / min; gradient: 40% B; 220nm; RT1: 3.8; RT2: 4.59; injection volume: 1mL; number of runs: 40. The fractions containing the desired product were combined and concentrated to obtain 0.44g (41%) of 6-fluoro-5-iodo-1-methyl-1,3-benzodiazole as a white solid. C8H6FIN2[M+H] + The calculated ESI value is 277; the measured value is 277.

[0670] Step 2: 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0671] TEA (0.14 g, 1.36 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol), 6-fluoro-5-iodo-1-methyl-1,3-benzodiazole (0.15 g, 0.54 mmol), Pd(PPh3)2Cl2 (31.77 mg, 0.04 mmol), and CuI (17.24 mg, 0.09 mmol) in DMF (2.00 mL) at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1). Fractions containing the desired product were combined and concentrated. The crude product was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20B to 50B over 4.3 min; 210 / 254 nm; RT1: 4.23. The fractions containing the desired product were combined and concentrated to give 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (43.6 mg, 20%) as a white solid. 24 H 26 FN7O3[M+H] + The calculated ESI value is 480.21; the measured value is 480.15. 1H NMR (300MHz, DMSO-d6) δ8.30 (s, 1H), 7.93 (d, J = 6.2Hz, 1H), 7.68 (d, J = 9.8Hz, 1H), 7.45 (s, 1H), 6.84-6.50 (m, 3H), 6.16 (d, J = 16.9Hz, 1H), 5.73-5 .63(m,1H),5.27-5.23(m,1H),4.49-4.42(m,1H),4.16-3.92(m,1H),3.8 6-3.80(m,6H),3.65-3.36(m,3H),2.95-2.73(m,4H),2.41-2.15(m,1H).

[0672] Example 41: 3-[2-(4-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0673]

[0674] Step 1: 4-Fluoro-5-iodo-1H-1,3-benzodiazole

[0675] Trimethyl orthoformate (3.16 g, 29.78 mmol) was added dropwise to a stirred solution of 3-fluoro-4-iodophenyl-1,2-diamine (5.00 g, 19.84 mmol) in MeOH (50.00 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1). The fractions containing the desired product were combined and concentrated to give 4-fluoro-5-iodo-1H-1,3-benzodiazole (4.6 g, 88%) as a pale yellow solid. C7H4FIN2[M+H] + The calculated MS ESI value is 262.94, and the measured value is 263.00.

[0676] Step 2: 4-Fluoro-5-iodo-1-methyl-1,3-benzodiazole and 7-Fluoro-6-iodo-1-methyl-1,3-benzodiazole

[0677] CH3I (1.16 mL, 8.20 mmol) was added dropwise to a stirred mixture of 4-fluoro-5-iodo-1H-1,3-benzodiazole (3.50 g, 13.36 mmol) and KOH (4.50 g, 80.21 mmol) in 35.00 mL of acetone. The reaction mixture was stirred at room temperature for 40 min. The resulting mixture was diluted with water (40 mL) and extracted with EA (3 × 70 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN / water (NH4HCO3 1 g / L), 20% to 50% gradient over 30 min; detector: UV 254 nm. The fractions containing the desired product were combined and concentrated to give 1.6 g (43%) of 4-fluoro-5-iodo-1-methyl-1,3-benzodiazole, a grayish-white solid, and 1.57 g (42%) of 7-fluoro-6-iodo-1-methyl-1,3-benzodiazole, a grayish-white solid. C8H6FIN2[M+H] + The calculated MS ESI value is 276.96, and the measured value is 277.00.

[0678] Step 3: 3-[2-(4-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0679] TEA (137.41 mg, 1.36 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.15 g, 0.45 mmol) and 4-fluoro-5-iodo-1-methyl-1,3-benzodiazole (0.16 g, 0.54 mmol), CuI (17.24 mg, 0.09 mmol), and Pd(PPh3)2Cl2 (31.77 mg, 0.045 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20:1) to obtain ~110 mg of product, which was further purified by Prep-HPLC under the following conditions: column: XBridge Prep C18OBD column, 19×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30 B to 60 B over 5.8 min; 210 / 254 nm; RT1: 5.56. The fraction containing the desired product was concentrated to obtain 3-[2-(4-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (54.7 mg, 25%), a grayish-white solid. 24 H 26 The MS ESI calculated value for FN7O3 is 479.21, and the measured value is 480.10. ¹H-NMR (400MHz, DMSO-d6) δ: 8.32 (s, 1H), 7.53–7.36 (m, 3H), 6.76–6.56 (m, 3H), 6.20–6.14 (m, 1H), 5.71–5.67 (m, 1H), 5.31–5.20 (m, 1H), 4.54–4.30 (m, 1H), 4.04–3.59 (m, 5H), 3.50–3.45 (m, 2H), 3.27 (d, J = 2.8Hz, 3H), 2.96 (t, J = 5.2Hz, 3H), 2.52–2.47 (m, 1H), 2.34–2.36 (m, 1H).

[0680] Example 42: 3-[2-(2-cyclopropyl-1H-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0681]

[0682] Step 1: 5-Bromo-2-cyclopropyl-1H-benzo[d]imidazole

[0683] Cyclopropanecarboxylic acid (3.22 g, 37.43 mmol) was added to a mixture of 4-bromophenyl-1,2-diamine (1.00 g, 5.35 mmol) in HCl (3.00 M H₂O solution, 10.00 mL). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. The resulting mixture was neutralized to pH 7 with NaOH. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (3:2). The fractions containing the desired product were combined and concentrated under reduced pressure to give 5-bromo-2-cyclopropyl-1H-1,3-benzodiazole (1.28 g, 100%) as a yellow solid. 10 H9BrN2[M+H] + The calculated MS ESI values ​​are 236.99 and 238.99, while the measured values ​​are 236.90 and 238.90.

[0684] Step 2: 2-Cyclopropyl-5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole

[0685] Trimethylsilylacetylene (1.64 g, 16.71 mmol), Pd(PPh3)2Cl2 (0.39 g, 0.56 mmol), CuI (0.21 g, 1.11 mmol), and TEA (1.69 g, 16.70 mmol) were added to a stirred solution of 5-bromo-2-cyclopropyl-1H-1,3-benzodiazole (1.32 g, 5.57 mmol) in DMF (10.00 mL) at room temperature. The reaction mixture was degassed three times with nitrogen and stirred at 85 °C for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (5:1). The fractions containing the desired product were combined and concentrated under reduced pressure to obtain 1.05 g (74%) of 2-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole, a yellow solid. 15 H 18 N₂Si[M+H] + The calculated MS ESI value is 255.12; the measured value is 255.15.

[0686] Step 3: 2-Cyclopropyl-5-ethynyl-1H-benzo[d]imidazole

[0687] TBAF (1.62 g, 6.19 mmol) was added to a mixture of 2-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole (1.05 g, 4.13 mmol) and THF (10.00 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (5:1). The fractions containing the desired product were combined and concentrated under reduced pressure to give 2-cyclopropyl-5-ethynyl-1H-1,3-benzodiazole (0.60 g, 79%) as a brown solid. 12 H 10 N2[M+H] + The calculated MS ESI value is 183.08; the measured value is 183.00.

[0688] Step 4: 3-[2-(2-cyclopropyl-1H-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0689] Pd(PPh3)2Cl2 (40.50 mg, 0.06 mmol), CuI (21.98 mg, 0.12 mmol), and TEA (0.18 g, 1.73 mmol) were added to a stirred mixture of 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.25 g, 0.58 mmol) and 2-cyclopropyl-5-ethynyl-1H-1,3-benzodiazole (0.11 g, 0.58 mmol) in DMF (2.00 mL) at room temperature. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25B to 65B over 5.8 min; 210 / 254 nm; RT1: 5.56 min. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain 3-[2-(2-cyclopropyl-1H-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (44.20 mg, 15%) as a white solid. 26 H 29 N7O3[M+H] + The calculated MS ESI value is 488.23, and the measured value is 488.15. 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),7.85-7.14(m,4H),6.94-6.43(m,3H),6.17(d,J=1 6.6Hz,1H),5.69(d,J=10.2Hz,1H),5.27-5.24(m,1H),4.49-4.45(m,1H),4.03-4.00(m, 1H),3.89-3.82(m,1H),3.69-5.65(m,1H),3.50-3.46(m,1H),3.32-3.28(m,3H),2.96-2 .90(m,3H),2.63-2.57(m,1H),2.31-2.30(m,1H),2.13-2.09(m,1H),1.12-0.90(m,4H).

[0690] Example 43: 3-[2-(2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0691]

[0692] Step 1: 2-Cyclopropyl-5-iodo-1-methyl-1,3-benzodiazole

[0693] Cyclopropane carboxylic acid (0.76 g, 8.86 mmol) was added to a stirred mixture of HATU (4.60 g, 12.09 mmol) and DIEA (3.13 g, 24.18 mmol) in DMF (10.00 mL). The reaction mixture was stirred at room temperature for 30 min. 4-Iodo-N1-methylphenyl-1,2-diamine (2.00 g, 8.06 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h. 50 mL of H2O was added to the final reaction mixture. The resulting mixture was washed with 5 × 30 mL of EtOAc. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. AcOH (20.00 mL) was added to the residue. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was alkalized to pH 8 with saturated NaHCO3, extracted with EA (4 × 150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE solution (0-50%). Fractions containing the desired product were combined and concentrated to give 2-cyclopropyl-5-iodo-1H-1,3-benzodiazole (2.1 g, 87%). 12 H 12 IN[M+H] + The calculated MS ESI value is 299.00, and the measured value is 298.90.

[0694] Step 2: 3-[2-(2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0695] CuI (11.49 mg, 0.06 mmol) and Pd(PPh3)2Cl2 (21.18 mg, 0.03 mmol) were added to a stirred mixture of 2-cyclopropyl-5-iodo-1-methyl-1,3-benzodiazole (0.11 g, 0.36 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 0.30 mmol) in DMF (2.00 mL). The reaction mixture was degassed three times with argon and stirred at 80 °C for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (0-10%) to give the crude product. The crude product was purified by reversed-phase rapid chromatography under the following conditions: column: SunFire Prep C18 OBD column, 19×150mm 5μm 10nm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20mL / min; gradient: 20B to 30B over 6 min; 210 / 254nm; RT1: 5.58. Fractions containing the desired product were combined and concentrated to give 3-[2-(2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (47.4 mg, 31%). 27 H 31 N7O3[M+H] + The calculated MS ESI value is 501.25, and the measured value is 502.15. H NMR (300MHz, DMSO-d6) δ: 7.74 (d, J = 1.4Hz, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.49–7.26 (m, 2H), 6.77 (s, 1H), 6.71–6.46 (m, 2H), 6.17 (d, J = 16.5Hz, 1H), 5.70 (d, J = 10.3Hz, 1H), 5.39–5.12 (m,1H),4.47-4.39(m,1H),4.13-3.95(m,1H),3.93-3.85(m,4H),3.77-3.72(m,1H),3.57 -3.52(m,2H),3.33-3.28(m,3H),2.97-2.92(m,3H),2.35-2.32(m,2H),1.21-1.02(m,4H).

[0696] Example 44: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(3-methyl-1,2-benzoxazol-6-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide

[0697]

[0698] TEA (0.29 mL, 2.86 mmol) was added to a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.23 g, 0.69 mmol), 6-bromo-3-methyl-1,2-benzoxazole (0.22 g, 1.04 mmol), Pd(PPh3)2Cl2 (48.72 mg, 0.07 mmol), and CuI (26.44 mg, 0.14 mmol) in DMF (2.50 mL). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 6% MeOH / DCM. Fractions containing the desired product were combined and concentrated. The crude product (150 mg) was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 60B over 5.8 min; 210 / 254 nm; RT1: 5.56. The fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-3-[2-(3-methyl-1,2-benzoxazol-6-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide (44.9 mg, 13%). 24 H 26 N6O4[M+H] +The calculated MS ESI value is 463.20, and the measured value is also 463.20. H-NMR (400MHz, DMSO-d6): δ8.04-7.90 (m, 2H), 7.56 (dd, J = 8.2, 1.2Hz, 1H), 7. 29-7.23(m,1H),6.94-6.42(m,3H),6.19-6.25(m,1H),5.71-5.67(m,1H),5.2 6-5.23(m,1H),4.56-4.33(m,1H),4.06-3.67(m,2H),3.64-3.39(m,2H),3.32 (s,3H),2.97-2.90(m,3H),2.58(s,3H),2.45-2.41(m,1H),2.35-2.26(m,1H).

[0699] Example 45: 3-[2-(2-cyclopropyl-1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0700]

[0701] Step 1: 2-Cyclopropyl-1-ethyl-4,6-difluoro-5-iodine-1,3-benzodiazole and 2-Cyclopropyl-1-ethyl-5,7-difluoro-6-iodine-1,3-benzodiazole

[0702] Cs₂CO₃ (4.58 g, 14.06 mmol) was added dropwise to a DMF (15.00 mL) solution of 2-cyclopropyl-4,6-difluoro-5-iodo-1H-1,3-benzodiazole (1.50 g, 4.69 mmol) and iodoethane (1.46 g, 9.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 45 min. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography under the following conditions: column: Spherical C18, 20–40 μm, 300 g; mobile phase A: water (10 mM NH₄HCO₃), mobile phase B: ACN; flow rate: 50 mL / min; gradient (B%): 5%–45% over 40 min; detector: UV 254 & 220 nm. The fractions containing the desired product were combined and concentrated to obtain 0.50 g (31%) of 2-cyclopropyl-1-ethyl-4,6-difluoro-5-iodine-1,3-benzodiazole, a pale yellow solid, and 0.37 g (23%) of 2-cyclopropyl-1-ethyl-5,7-difluoro-6-iodine-1,3-benzodiazole, a pale yellow solid. C9H9N3O2[M+H] +The calculated MS ESI value is 348.99, and the measured value is 348.85.

[0703] Step 2: 3-[2-(2-cyclopropyl-1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0704] TEA (0.18 g, 1.81 mmol) was added to a stirred mixture of 2.00 mL of DMF containing 2-cyclopropyl-1-ethyl-4,6-difluoro-5-iodo-1,3-benzodiazole (0.21 g, 0.60 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.14 g, 0.45 mmol), CuI (22.98 mg, 0.12 mmol), and Pd(PPh3)2Cl2 (42.34 mg, 0.06 mmol). The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography under the following conditions: column: Spherical C18, 20-40 μm, 40 g; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 40 mL / min; gradient (B%): 5%-45% over 45 min; detector: UV 254 & 220 nm. Fractions containing the desired product were combined and concentrated to obtain a grayish-white solid, 3-[2-(2-cyclopropyl-1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (84.1 mg, 25%). 28 H 31 F2N7O3[M+H] + The calculated MS ESI value is 552.25; the measured value is 552.25. 1H NMR(300MHz,d6-DMSO)δ7.66-7.52(m,2H),6.83-6.52(m,3H),6.19-6.15(m,1H),5.71-5.68(m,1H),5.30-5.27(m,1H),4.58-4.32(m,3H),3 .90(d,J=7.5Hz,2H),3.66-3.41(m,2H),3.34-3.26(m,4H),2.99-2.95(m,3H),2.30-2.25(m,2H),1.35(t,J=7.1Hz,3H),1.16-1.03(m,4H).

[0705] Example 46: 3-[2-[4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0706]

[0707] Step 1: 4,6-Difluoro-5-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole

[0708] A solution of 5.50 g (20.37 mmol) of 3,5-difluoro-4-iodophenyl-1,2-diamine in 55 mL of trifluoroacetic acid was stirred at 50 °C for 30 min. The reaction mixture was then mixed with saturated NaHCO3 at 0 °C to form an alkaline solution. The resulting mixture was poured into 550.0 mL of sodium thiosulfate and extracted with EA (3 × 500.0 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20-40 μm, 40 g; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 40 mL / min; gradient (B%): 0% for 5 min, 5%-60% over 40 min; 60% for 5 min, 60%-95% over 20 min, 95% for 5 min; detector: UV 254 & 210 nm; RT: 45 min. Fractions containing the desired product were combined and concentrated to obtain 1.3 g (18%) of 4,6-difluoro-5-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole, a pale yellow solid. C8H2F5IN2[M+H] + The calculated ESI value is 348.92; the measured value is 348.95.

[0709] Step 2: 4,6-Difluoro-2-(trifluoromethyl)-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole

[0710] To a stirred solution of 4,6-difluoro-5-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (1.00 g, 2.87 mmol) in dimethylformamide (10 mL), trimethylsilylacetylene (0.85 g, 8.62 mmol), palladium chloride; bis(triphenylphosphine) (0.20 g, 0.28 mmol), copper iodide (I) (0.11 g, 0.57 mmol), and TEA (0.87 g, 8.62 mmol) were added. The reaction mixture was degassed three times with argon and stirred at 90 °C for 2 h. After cooling to ambient temperature, the resulting mixture was poured into water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 18% EA / PE. The fractions containing the desired product were combined and concentrated to obtain 0.40 g, 44% light yellow solid 4,6-difluoro-2-(trifluoromethyl)-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole. 13 H 11 F5N2Si[M+H] + The calculated MS ESI value is 319.06; the measured value is 318.95.

[0711] Step 3: 5-ethynyl-4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazole

[0712] TBAF (1.0 M THF solution, 1.80 mL, 1.80 mmol) was added dropwise to a stirred solution of 4,6-difluoro-2-(trifluoromethyl)-5-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazole (0.38 mg, 1.19 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was poured into sodium thiosulfate (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C18 gel column chromatography, eluting with ACN / H2O (0–34%). The fractions containing the desired product were combined and concentrated to obtain 0.21 g, 71%, brown solid 5-ethynyl-4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazole. 10 H3F5N2[M+H] +The calculated MS ESI value is 247.02; the measured value is 247.14.

[0713] Step 4: 3-[2-[4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0714] To a stirred mixture of 5-ethynyl-4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazole (88.66 mg) and 3-iodo-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.13 g) in DMF (1.3 mL), Pd(PPh3)2Cl2 (21.06 mg), CuI (11.4 mg), and TEA (91 mg) were added. The reaction mixture was degassed three times with argon and stirred at 90 °C for 1.5 h. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water, 5% to 30% gradient over 30 min; detector, UV 210 nm. Fractions containing the desired product were combined and concentrated. The crude product was purified by Prep-HPLC under the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30B to 60B over 4.3 min; 210 / 254 nm; RT1: 4.23. The fractions containing the desired product were combined and concentrated to obtain 3-[2-[4,6-difluoro-2-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(propenyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide (72 mg, 43%) as a white solid. 24 H 22 F5N7O3[M+H] + The calculated MS ESI value is 552.17; the measured value is 552.48. 1H NMR(400MHz,DMSO-d6)δ14.88(s,1H),7.58(brs,2H),6.76-6.59(m,3H),6.19-6.14(m,1H),5.71-5.66(m,1H),5.30-5.25(m, 1H),4.48-4.44(m,1H),3.99-3.96(m,2H),3.59-3.44(m,2H),3.31(s,3H),2.96(s,3H),2.67-2.60(m,1H),2.32-2.28(m,1H).

[0715] Example 47: 3-[2-[1-(difluoromethyl)-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide

[0716]

[0717] Step 1: N-Cyclopropyl-4-iodo-2-nitroaniline

[0718] Aminocyclopropane (5.35 g, 93.63 mmol) was added t...

Claims

1. A compound or a pharmaceutically acceptable salt thereof having the structure of formula (I): （I） in, Z is selected from groups having the following structures: , or ; R 1 R 2 and R 3 Each is independently selected from hydrogen, fluorine, or optionally by one or more groups selected from halogen, cyano, and -OR. a C1-C4 alkyl groups substituted with substituents; R 4 It is benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, benzoxazole, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, quinolinyl, quinoxalinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl or pyrazolo[1,5-a]pyridyl, wherein R 4 Optionally, it is selected from one or more radicals selected from halogen, cyano, C1-C8 alkyl, C1-C8 fluoroalkyl, -N(R) a )2. Substituents of C1-C8 alkoxy, cyclopropyl, cyclobutyl and 4-membered heterocyclic groups containing one oxygen atom, wherein each cyclopropyl, cyclobutyl and 4-membered heterocyclic group containing one oxygen atom is independently and optionally substituted by one or more substituents selected from halogen, C1-C8 alkyl, C1-C8 fluoroalkyl, C1-C8 alkoxy and cyano. R is selected from hydrogen and optionally is selected from one or more halogens and -OR a C1-C6 alkyl groups substituted with substituents; R 6 To be optionally selected by one or more groups selected from halogen, cyano and -OR a Substituted C1-C8 alkyl, -(C1-C6 alkylene)-(C3-C 10 Carbocyclic) or -(C1-C6 alkylene)-morpholino, and Where R a Each is independently hydrogen, or optionally substituted with halogen, hydroxyl, methoxy or trifluoromethyl C1-C8 alkyl group.

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

3. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

4. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R 3 It is either hydrogen or fluorine.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 It is hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be optionally selected by one or more groups selected from halogen, cyano and -OR a The C1-C4 alkyl group is substituted with a substituent.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be optionally selected by one or more groups selected from halogen, cyano and -OR a The C1-C2 alkyl group is substituted with a substituent.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be optionally selected by one or more groups selected from halogen, cyano and -OR a The C1 alkyl group is substituted with a substituent.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is benzimidazole group, where R 4 It may optionally be substituted with C1-C8 alkyl, cyclopropyl, cyclobutyl or halogen.

11. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

12. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R is optionally composed of one or more compounds selected from halogens and -OR a The C1-C6 alkyl group is substituted with a substituent.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C1-C6 alkyl group is a C1-C3 alkyl group substituted with a C1-C3 alkoxy group.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 4 It is substituted with at least one halogen and either cyclopropyl or cyclobutyl.

15. The compound of claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein R 4 It is substituted with at least one halogen and a cyclopropyl or cyclobutyl group; R is a -CH2OCH3 group; and R 6 It is a methyl group.

16. The compound of claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein R 4 It is substituted with at least one halogen and cyclopropyl or cyclobutyl; R is hydrogen; and R 6 It is a methyl group.

17. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-16 or a pharmaceutically acceptable salt thereof.

18. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(2-methyl-3H-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide; (S)-1-(1-Acryloylpyrrolidone-3-yl)-3-((2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide; 3-[2-(1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1,2-dimethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; ( S )-1-(1-Acryloylpyrrolidone-3-yl)-3-((1,2-Dimethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-methyl-1 H -indazole-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-methyl-2 H -indazole-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-methyl-2-(trifluoromethyl)-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-1 H -indazole-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-ethyl-2 H -indazole-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4,6-difluoro-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1,2-dimethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-methyl-1 H -indazole-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4-fluoro-1,2-dimethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4-fluoro-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-ethyl-2-methyl-3H-imidazo[4,5- b ]pyridin-6-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-methyl-3 H -imidazo[4,5- b ]pyridin-6-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-cyano-1-ethyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-cyclopropyl-1-ethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-(benzo[ d Isoxazol-6-ylethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-2-(trifluoromethyl)-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-1,2-dimethyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-(difluoromethyl)-4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-(difluoromethyl)-4,6-difluoro-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-6-fluoro-1H-benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-1-ethyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1-(2,2,2-trifluoroethyl)-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-2-methyl-1-(2,2,2-trifluoroethyl)-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(3-ethyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-ethyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(4-chloro-1-ethyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[1-ethyl-2-methylimidazo[4,5- b ]pyridin-5-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(4-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-cyclopropyl-1-] H -1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(3-methyl-1,2-benzoxazol-6-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-cyclopropyl-1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[4,6-difluoro-2-(trifluoromethyl)-1 H -1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[1-(difluoromethyl)-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[3-ethyl-2-methylimidazo[4,5- c ]pyridin-6-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-amino-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-cyclopropyl-4,6-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((2-cyclopropyl-4-fluoro-1-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(quinolin-7-yl)ethynyl]pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[pyrazolo[1,5-a]pyrimidin-5-yl]ethynyl)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-(imidazo[1,2- a ]pyridin-7-ylethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-(imidazo[1,2- a ]pyridin-6-ylethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[pyrazolo[1,5- a ]pyridin-5-yl]ethynyl)pyrazole-4-carboxamide; 3-(2-[imidazo[1,2- a ]pyrimidin-6-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[imidazo[1,2- a ]pyrimidin-7-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-tert-butyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[2-(dimethylamino)-1-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(2-cyclopropyl-6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[2-cyclopropyl-3-methylimidazo[4,5- c ]pyridin-6-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(quinoxalo-6-yl)ethynyl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-3-((3-methylquinoline-7-yl)ethynyl)-1 H -Pyrazole-4-carboxamide; 3-(2-[imidazo[1,2- b ]pyridazine-7-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[pyrazolo[1,5- a ]pyridin-6-yl]ethynyl)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-3-((2-methylquinoxalo-6-yl)ethynyl)-1 H -Pyrazole-4-carboxamide; 3-[2-[1-(difluoromethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4-fluoro-1-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-3-((3-methylquinoxaloline-6-yl)ethynyl)-1 H -Pyrazole-4-carboxamide; 3-[2-[3-(difluoromethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(4-methylquinolin-7-yl)ethynyl]pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[3-methylimidazo[1,2- a ]pyridin-7-yl]ethynyl)pyrazole-4-carboxamide; 3-[2-[3-(difluoromethyl)-6-fluoro-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[1-(difluoromethyl)-6-fluoro-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-[1-(difluoromethyl)-6-fluoro-1,3-benzodiazol-5-yl]ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(2-methylquinolin-7-yl)ethynyl]pyrazole-4-carboxamide; 3-[2-(4,6-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S, 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-] H -1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-2-methyl-1-] H -1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S 5 R )-1-(prop-2-enoyl)-5-[(trifluoromethoxy)methyl]pyrrolid-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-] H -1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-2-methyl-1-] H -1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-] H -1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[6-chloro-3-(difluoromethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[6-chloro-1-(difluoromethyl)-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[6-chloro-3-(difluoromethyl)-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-[6-chloro-1-(difluoromethyl)-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(4,6-difluoro-1-methyl-1,2,3-benzotriazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-2-methyl-1-] H -1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-4-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6,7-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1,3-benzothiazo-2-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1,3-benzothiazo-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[imidazo[1,2- a ]pyridin-2-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-cyanoimidazo[1,2- a ]pyridin-2-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[[1,2,4]triazolo[1,5- a ]pyridin-6-yl]ethynyl)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-(2-[[1,2,4]triazolo[1,5- a ]pyridin-7-yl]ethynyl)pyrazole-4-carboxamide; 3-[2-(1,3-benzoxazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 5-[(cyclopropylmethyl)amino]-3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-[1-(difluoromethyl)-4,6-difluoro-2-methyl-1,3-benzodiazol-5-yl]ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-[[3-(morpholin-4-yl)propyl]amino]pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[[2-(morpholin-4-yl)ethyl]amino]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-7-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1,3-benzoxazol-2-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1,3-benzoxazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-hydroxyethyl)amino]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-methoxyethyl)amino]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-[(cyclopropylmethyl)amino]-3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-methoxyethyl)amino]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[[3-(morpholin-4-yl)propyl]amino]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((7-fluoro-1-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-[7-fluoro-[1,2,4]triazolo[1,5- a ]pyridin-6-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-hydroxyethyl)amino]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-ethyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6,7-difluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-7-fluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-1-(2-fluoroprop-2-enoyl)-5-(methoxymethyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-[6-fluoro-[1,2,4]triazolo[1,5- a ]pyridin-7-yl]ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1,3-benzothiazo-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-Fluorimidazole[1,2- a ]pyridin-7-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-chloro-4-fluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1,3-benzothiazo-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-(but-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-ethyl-4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-((methoxy-d3)methyl)pyrrolidine-3-yl)-3-((6-chloro-1-ethyl-1H-benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-7-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-ethyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6,7-difluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(fluoromethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(4,6,7-trifluoro-1,2-dimethyl-1,3-benzodiazol-5-yl)ethynyl]pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)-3-[2-(4,6,7-trifluoro-1-methyl-1,3-benzodiazol-5-yl)ethynyl]pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6,7-trifluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-5-[(difluoromethoxy)methyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-3-[2-(1-ethyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(difluoromethoxy)methyl]-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-((difluoromethoxy)methyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-ethyl-4,6,7-trifluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 S )-5-methyl-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 S )-5-methyl-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-((difluoromethoxy)methyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(difluoromethyl)-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(difluoromethyl)-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-methylpyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-methyl-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-methylpyrrolidine-3-yl)-3-((6-chloro-1-cyclopropyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 S )-1-Acryloyl-5-methylpyrrolidine-3-yl)-3-((1-Cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(difluoromethyl)-1-(prop-2-enoyl)pyrrolidone-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6,7-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-((1-Cyclopropyl-6-fluoro-1) H -benzo[ d [Imidazol-5-yl)ethynyl)-1-(1-(2-fluoroacryloyl)azacyclobutane-3-yl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-((1-Cyclopropyl-4,6-Difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-1-(1-(2-fluoroacryloyl)azacyclobutane-3-yl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(hydroxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(fluoromethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(fluoromethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(fluoromethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 S )-5-(fluoromethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[( 3S, 5S )-5-(fluoromethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-((1-Cyclopropyl-6-fluoro-1) H -benzo[ d [Imidazol-5-yl)ethynyl)-1-((3 S 5 R )-5-(methoxymethyl)-1-propynylpyrrolidine-3-yl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-(but-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-ynyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-[(3 S 5 R )-1-(but-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl]-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[1-(prop-2-ynyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S )-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-ynyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 3-((1-Cyclopropyl-6-fluoro-1) H -benzo[ d [Imidazol-5-yl)ethynyl)-1-((3 S 5 R )-1-(4-hydroxy-4-methylpentan-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-{1-[(2 E [4-(dimethylamino)but-2-enoyl]azacyclobutane-3-yl}-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(ethylamino)-1 H -Pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(hydroxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-ethyl-1,3-benzodiazol-5-yl)ethynyl]-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[1-(prop-2-enoyl)azacyclobutane-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(difluoromethoxy)methyl]-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-[(difluoromethoxy)methyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-{[1-(prop-2-enoyl)azacyclobutane-3-yl]methyl}pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(difluoromethoxy)methyl]-1-(prop-2-enoyl)pyrrolidone-3-yl]pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(2-hydroxypropyl-2-yl)-1-(propyl-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(( R )-1-hydroxyethyl)pyrrolidine-3-yl)-3-((6-chloro-1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(( S )-1-hydroxyethyl)pyrrolidine-3-yl)-3-((6-chloro-1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-1-(4-hydroxy-4-methylpentan-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-1-(4-hydroxy-4-methylpentan-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclopropyl-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-1-(4-hydroxy-4-methylpentan-2-ynyl)-5-(methoxymethyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclobutyl-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclobutyl-6-fluoro-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-chloro-1-cyclobutyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-1-cyclobutyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-{2-[6-fluoro-1-(oxetane-3-yl)-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-{2-[6-fluoro-2-methyl-1-(oxetane-3-yl)-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-3-methylquinolin-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-1-isopropyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-{2-[6-fluoro-1-(1-methylcyclopropyl)-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-(1-cyanocyclopropyl)-6-fluoro-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(( R )-1-hydroxyethyl)pyrrolidine-3-yl)-5-amino-3-((6-chloro-1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(( S )-1-hydroxyethyl)pyrrolidine-3-yl)-5-amino-3-((6-chloro-1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-1 H -Pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 R [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 5-Amino-3-[2-(1-cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-[(1 S [1-hydroxyethyl]-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-{2-[6-chloro-1-(oxetane-3-yl)-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-{2-[6-chloro-2-methyl-1-(oxetane-3-yl)-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-hydroxyethyl)amino]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-hydroxyethyl)amino]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-fluoro-2-methyl-1,3-benzodiazol-5-yl)ethynyl]-5-[(2-hydroxyethyl)amino]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-1-cyclopropyl-2-methyl-1 H -benzo[ d [Imidazol-5-yl)ethynyl)-5-((2-hydroxyethyl)amino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-Fluoro-2-] H -1,3-benzo[-1,3-benzodioxacyclopenten-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(3-chloro-6-fluoroquinoline-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-3-methylimidazo[1,2-a]pyridin-7-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-3-methylquinoline-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide; 3-[2-(1-Cyclopropyl-6-methyl-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((7-fluoro-2,3-dihydro-1 H -benzo[ d ]pyrrolo[1,2- a [Imidazol-6-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-{6-chloro-3-cyclopropylimidazo[1,2- a ]pyridin-7-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{3-cyano-6-fluoroimidazole[1,2- a ]pyridin-7-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{3-cyanopyrazolo[1,5- a ]pyridin-6-ylethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(3,6-difluoroquinolin-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(3,6-dimethylquinolin-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-4-methylcenolin-7-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(6-chloro-3-fluoroquinoline-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-chloro-4-methylcenolin-7-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-{3-cyanoimidazo[1,2- a ]pyridin-7-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-{1-[(1 S )-2,2-difluorocyclopropyl]-6-fluoro-1,3-benzodiazol-5-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-{2-[1-(( R )-(2,2-difluorocyclopropyl)-6-fluoro-1,3-benzodiazol-5-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-{2-[3-(difluoromethyl)-6-fluoroquinoline-7-yl]ethynyl}-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-fluoro-4-methylquinolin-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-methyl-1 H -indazole-4-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-[2-(1-Cyclopropylindazole-4-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{imidazo[1,5- a ]pyridin-8-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{imidazo[1,5- a ]pyridin-5-ylethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{6-chloro-1-[(1 R )-2,2-difluorocyclopropyl]-1,3-benzodiazole-5-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{6-chloro-1-[(1 S )-2,2-difluorocyclopropyl]-1,3-benzodiazole-5-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-[2-(6-chloro-4-methylquinolin-7-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((6-fluoro-3,4-dimethylquinoline-7-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-{3-cyclopropyl-6-fluoroimidazole[1,2- a ]pyridin-7-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{3-cyclopropyl-4-methoxypyrazolo[1,5- a ]pyridin-6-ylethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 1-((3 S 5 R )-1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((7-chloro-2,3-dihydro-1 H -benzo[ d ]pyrrolo[1,2- a [Imidazol-6-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 1-((3 S 5 R ) - 1-Acryloyl-5-(methoxymethyl)pyrrolidine-3-yl)-3-((1-cyclopropyl-5-fluoro-1 H -indazole-4-yl)ethynyl)-5-(methylamino)-1 H -Pyrazole-4-carboxamide; 3-(2-{6-chloro-3-[(1 R )-2,2-difluorocyclopropyl]-1,3-benzodiazole-5-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; 3-(2-{6-chloro-3-[(1 S )-2,2-difluorocyclopropyl]-1,3-benzodiazole-5-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide; and 3-(2-{3-chloro-6-fluoroimidazole[1,2- a ]pyridin-7-yl}ethynyl)-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide.

19. A pharmaceutical composition comprising the compound of claim 18 or a pharmaceutically acceptable salt thereof.

20. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is 3-[2-(1-cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3 S 5 R )-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidine-3-yl]-5-(methylamino)pyrazole-4-carboxamide.

21. A pharmaceutical composition comprising the compound of claim 20 or a pharmaceutically acceptable salt thereof.

22. Use of the compound of any one of claims 1-16, 18 or 20, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a subject with aberrant FGFR kinase activity.

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