Pyrazole compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The application discloses a pyrazole compound with the structure of formula (I), which also comprises stereoisomers, deuterium compounds, pharmaceutically acceptable salts or mixtures thereof. The compound and a pharmaceutical composition thereof can effectively inhibit wild-type and mutant TRK kinase and have excellent inhibitory activity, and the inhibitory activity on the mutant is significantly better than that of an existing TRK kinase small molecule inhibitor. The compound has wide application and can be prepared into a medicine for treating and / or preventing diseases related to wild-type and mutant TRK kinase, and especially for treating the mutant, thereby providing a promising candidate medicine for solving the drug resistance problem of the existing medicine.

Description

Technical Field

[0001] This invention relates to a pyrazole compound, pharmaceutical compositions thereof, and applications, and more particularly to a pyrazole compound that can be prepared as a tropomyosin kinase TRK inhibitor, pharmaceutical compositions thereof, and applications. Background Technology

[0002] Tropomyosin-associated kinase (TRK) is a target for broad-spectrum antitumor drugs. As a class of tyrosine kinases activated by nerve growth factor, it belongs to the transmembrane receptor protein family, which includes three subtypes: TRKA, B, and C, encoded by the NTRK1, 2, and 3 genes, respectively. Studies have shown that mutations, splicing variations, overexpression, and gene fusions of TRK can drive tumorigenesis and development, and various NTRK fusion proteins act as oncogenic drivers in different types of tumors.

[0003] Currently, larotrectinib (LOXO-101) and entrectinib are first-generation TRK inhibitors used to treat solid tumors with NTRK fusions and no known acquired resistance mutations. Both drugs are ATP-competitive type I kinase inhibitors that recognize the DFG-in structure-activity relationship of TRK proteins, exhibiting strong inhibitory activity against wild-type TRKA, TRKB, and TRKC. Although these small-molecule inhibitors have achieved good clinical efficacy in the treatment of various tumors, drug resistance is an unavoidable problem in TRK drug therapy with continued use. Clinical studies have found that mutations can occur in the solvent front region of TRK proteins, primarily manifested as TRKA mutations. G595R and TRKC G623R These amino acid residue mutations interfere with inhibitor binding through steric hindrance, altering the conformation of the kinase domain or changing ATP binding affinity, thus rendering first-generation TRK inhibitors ineffective.

[0004] To address the aforementioned resistance mutations, second-generation TRK inhibitors are primarily rigid macrocyclic compounds, with representative molecules including selitrectinib (LOXO-195) and repotrectinib (TPX-0005). In application, although mutations in the solvent front region of the TRK protein disappear with second-generation TRK inhibitors, new mutations occur in the xDFG region, mainly manifesting as TRKA. G667C / A and TRKC G696A This results in second-generation inhibitors being unable to effectively inhibit TRK kinases mutated in the xDFG region, and they have failed to control tumor progression in clinical practice. Currently, there are no specific treatments for xDFG region mutation resistance, which greatly limits the clinical application of TRK inhibitors. Summary of the Invention

[0005] Purpose of the invention: To address the problem that existing small molecule drugs are not effective against TRK kinase mutant drug-resistant diseases, this invention aims to provide a pyrazole compound that can significantly inhibit drug-resistant mutants, as well as its pharmaceutical composition and applications.

[0006] Technical solution: As a first aspect of the present invention, the pyrazole compounds of the present invention have the structure of formula (I), and further comprise stereoisomers thereof, deuterated compounds, pharmaceutically acceptable salts, or mixtures thereof:

[0007]

[0008] in:

[0009] L1 is selected from amide group or carbonyl group;

[0010] A 1 A 3 A 4 Independently selected from N and CR 6 And not all of them are N;

[0011] A 2 Selected from N, CR 7 ;

[0012] R 1 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 2-8 Alkyl ethers, -C(O)R A C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups containing 0 to 5 N, S, and O ring heteroatoms, and C-ring groups containing 0 to 5 N, S, and O ring heteroatoms. 3-10 C substituted with carbocyclic group 1-8 Alkyl groups, C-shaped groups substituted with 3 to 10-membered heterocyclic groups containing 0 to 5 N, S, and O ring heteroatoms 1-8 Alkyl group, and containing 0 to 5 substituents of the following: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -OR A -NR A R B -CN, =O, -OC(O)R A -C(O)R A -C(O)OR A -NR A C(O)R B -C(O)NR A R B -NR AS(O)2R B -S(O)2NR A R B Benzyl, 5- to 6-membered heterocyclic aryl groups containing 0 to 3 N, S, and O ring heteroatoms, 3- to 6-membered heterocyclic alkyl rings containing 0 to 3 N, S, and O ring heteroatoms, OR A Replacement C 1-4 Alkoxy, -OR A Replacement C 1-4 alkoxy, or R 1 A single atom in the atom and two substituents thereon form a 3- to 6-membered heterocyclic alkyl or 3- to 6-membered cycloalkyl containing 0 to 3 N, S, O ring heteroatoms;

[0013] R 2 Indicates -NR C R D ;

[0014] R 3 Represents -C(O)NR E R F ;

[0015] R 4 Is it H or C? 1-4 alkyl;

[0016] L2 indicates a group selected from the following: -CH=CH-, -C≡C-, carbonyl, C 3-10 Carbocyclic groups, 3- to 6-membered heterocyclic alkyl groups containing 0 to 3 N, S, and O ring heteroatoms, -NR G 、-(CR H R I ) m -or-CR H R I -C(O)NH;

[0017] R 5 Selected from saturated, partially unsaturated or completely unsaturated 3 to 7 member monocyclic carbon rings, 3 to 7 member monocyclic heterocyclic rings or 8 to 14 member bicyclic rings;

[0018] Among them, 3 to 7-membered monocyclic heterocycles have 0 to 5 cyclic heteroatoms selected from N, S, and O;

[0019] The 8- to 14-membered bicyclic rings are selected from carbon rings or heterocycles connected by single bonds or chemical bonds, and contain 0 to 3 substituents of the following: halogen, CN, OH, =O, NO2, NR. J R K SO2R L SR L 0 to 3 OH groups and / or C 1-3 alkoxy-substituted C 1-4Alkyl group, 0 to 3 OH groups and / or C groups 1-3 alkoxy-substituted C 3-6 Cycloalkyl, 0 to 3 halogen-substituted C 1-3 Alkyl, -O(C) 1-3 alkoxy group), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 3-6 cycloalkyl), -O (0 to 3 halogen-substituted C) 1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 1-3 Alkyl), NR J SO2R L R M C(O)R M NR J C(O)R L OR M S(O)R L or CH2R M ;

[0020] m is 1 or 2;

[0021] R 6 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OR N Replacement C 1-6 alkyl;

[0022] R 7 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OR N Replacement C 1-6 alkyl;

[0023] R A R B Independently selected from H and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, phenyl, benzyl, -OR N Replacement C 1-4 alkyl;

[0024] R C R D R E R F Independently selected from H and C 1-4 Alkyl, C1-4 Haloalkyl, C 3-10 carbonyl group, C 3-10 C substituted with carbocyclic group 1-4 Alkyl, 1 to 2 R N or -OR N Replace C 3-10 C substituted with carbocyclic group 1-4 Alkyl groups, and 3- to 10-membered heterocyclic groups containing 0 to 5 N, S, and O ring heteroatoms;

[0025] R G Selected from H, C 1-4 alkyl;

[0026] R H R I Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OR N Replacement C 1-6 alkyl;

[0027] R J R K C independently selected from H, 0 to 3 of the following substituents 1-5 Alkyl groups: OH, C(O)NR L R L SO2R L OR L CH2OH, CO2R L SONR L R L NR L SO2R L CN, NO2, R O C 3-5 Cycloalkyl, propeller alkyl, 4- to 6-membered saturated heterocycles containing 0 to 3 N, S, or O ring heteroatoms, or R J R K It forms a 4- to 7-membered ring with the attached N, and contains 0 to 2 N, O, S heteroatoms and C. 1-3 Alkoxy, C 1-3 Alkyl substitution;

[0028] Where C 3-5 Cycloalkyl, propeller alkyl, and 4- to 6-membered saturated heterocycles containing 0 to 3 substituents such as OH, C(O)NR L R L SO2R L CO2R L SONR L R L NRL SO2R L CN, NO2, halogens, NR L R L SR L 0 to 3 OH groups and / or C 1-3 alkoxy-substituted C 1-4 Alkyl group, 0 to 3 OH groups and / or C groups 1-3 alkoxy-substituted C 3-6 cycloalkyl, 1 to 3 halogenated C 1-3 Alkyl groups, -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 3-6 cycloalkyl), -O (0 to 3 halogen-substituted C) 1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 1-3 Alkyl), =O, NR L CO2R L S(O)R L ;

[0029] R L Selected from H, C 1-5 Alkyl, C 1-5 Alkoxy, where C 1-5 Alkyl, C 1-5 Alkoxy groups contain 0 to 3 halogen substituents;

[0030] R M Selected from saturated, partially unsaturated, and fully unsaturated 3- to 7-membered monocyclic carbon rings, 3- to 7-membered heterocyclic rings, and 8- to 14-membered bicyclic rings;

[0031] Among them, the 3 to 7 membered heterocycles contain 0 to 5 N, S, and O ring heteroatoms;

[0032] The 8- to 14-membered bicyclic rings are selected from carbon rings or heterocycles connected by single bonds or chemical bonds, and contain 0 to 3 substituents of the following: halogen, CN, NR. J R K SO2R L SR L 0 to 3 OH groups and / or C 1-3 alkoxy-substituted C 1-4 Alkyl group, 0 to 3 OH groups and / or C groups 1-3 alkoxy-substituted C 3-6 cycloalkyl, 1 to 3 halogenated C 1-3 Alkyl, OH, -O(C) 1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 3-6 cycloalkyl), -O (0 to 3 halogen-substituted C)1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 1-3 Alkyl), NR J SO2R L =O, NO2, NR L COR L NR J CO2R L and S(O)R L ;

[0033] R N Selected from H, C 1-4 Alkyl, C 1-6 Halogenated alkyl groups;

[0034] R O Selected from saturated, partially unsaturated, or fully unsaturated 3- to 7-membered monocyclic carbon rings, 3- to 7-membered heterocyclic rings, or 8- to 14-membered bicyclic rings;

[0035] Among them, the 3 to 7 membered heterocycles contain 0 to 5 N, S, and O ring heteroatoms;

[0036] The 8- to 14-membered bicyclic rings are selected from two carbon rings or heterocycles connected by single bonds or chemical bonds, and contain 0 to 3 substituents of the following: halogen, CN, NR. L R L SO2R L SR L 0 to 3 OH groups and / or C 1-3 alkoxy-substituted C 1-4 Alkyl group, 0 to 3 OH groups and / or C groups 1-3 alkoxy-substituted C 3-6 cycloalkyl, 1 to 3 halogenated C 1-3 Alkyl, OH, -O(C) 1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 3-6 cycloalkyl), -O (0 to 3 halogen-substituted C) 1-3 Alkyl groups), -O (0 to 3 OH groups and / or C groups) 1-3 alkoxy-substituted C 1-3 Alkyl), NR L SO2R L =O, NO2, NR L CO2R L NR L COR L S(O)R L .

[0037] Preferably, A in the above structure 1 For N, A 3A 4 For CR 6 A 2 For CR 7 ;

[0038] Where R 6 Selected from H, halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-5 cycloalkyl, R 7 Selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl groups, specifically fluorine, chlorine, methyl, and cyclopropyl.

[0039] Further optimization, in the above structure, A 3 A 4 For CH.

[0040] Preferably, in the above structure, L1 is C(O)NH; L2 is selected from C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic alkyl groups, CH2, CH(CH3), C(CH3)2, CHF, CF2, specifically CH2, NH, CH2C(O)NH, CH2=CH2,

[0041] CH2CH2、 C=O、 NH(CH3),

[0042] Preferably, in the above structure, R 2 For NH2, R 3 For -C(O)NH2, R 4 For H.

[0043] R 1 Selected from substituted or unsubstituted methyl, ethyl, isopropyl, isobutyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, butynyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, piperidinyl, substituted piperidinyl, oxetane substituted C 1-8 Alkyl, morpholine substituted C 1-8 Alkyl, morpholine substituted C 1-8 Acyl, tetrazolium-substituted C 1-8 alkyl and piperidine substituted C 1-8 alkyl- or piperazine-substituted C 1-8 alkyl and cyclohexyl substituted C 1-8Alkyl group; wherein the substituent is selected from 1 to 5 of the following substituents: -OH, =O, -OMe, methyl, CF3, Cl, F, -OBn, -CO2Et; specifically as follows:

[0044]

[0045] (CH3)2CH, (CH3)3C, CH3CH2, (CH3)2CHCH2, CH2CF3, CH3CH(CF3)CH2, (CH3)2C(CF3)CH2, CH3C(O), (CH3)2CCF3, CH3CHCF3,.

[0046] R 5 Selected from substituted or unsubstituted benzene rings, wherein the substituents are selected from 1 to 3 of the following substituents: halogen, CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 halogen-substituted C 1-3 Alkyl, OH, -O(C) 1-3 Alkyl), -O (0 to 3 halogen-substituted C) 1-3 Alkyl groups, specifically as follows:

[0047]

[0048] Most preferably, the mixture of the above general formula is selected from any of the following compounds:

[0049]

[0050]

[0051]

[0052] Pharmaceutically acceptable salts of the above-mentioned pyrazole compounds are salts formed by the compounds with acids selected from the following:

[0053] Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and acidic amino acids.

[0054] As a second aspect of this invention, the aforementioned pyrazole compounds and pharmaceutically acceptable carriers constitute the pharmaceutical composition of this invention. Common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, or injections, are prepared by adding pharmaceutically acceptable carriers. Common pharmaceutical excipients such as flavorings, sweeteners, liquid / solid fillers, and diluents may be added to the preparations.

[0055] As a third aspect of this invention, the aforementioned pyrazole compounds and their pharmaceutical compositions are used in the preparation of medicaments for the prevention and / or treatment of tropomyosin kinase-mediated diseases, specifically medicaments for the prevention and / or treatment of pain or cancer. The tropomyosin kinase-mediated diseases are those that have developed at least partial resistance to at least one existing therapeutic agent, specifically diseases related to tropomyosin-related kinase dysfunction caused by gene amplification, overexpression, mutation, or fusion, including lung cancer, hematologic malignancies, prostate cancer, breast cancer, ovarian cancer, glioma, pancreatic cancer, hepatobiliary hepatocellular carcinoma, papillary thyroid carcinoma, colon cancer, head and neck squamous cell carcinoma, melanoma, etc.

[0056] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0057] 1. These compounds and their drug compositions exhibit excellent inhibitory activity against both wild-type and mutant TRK kinases, with an IC50 value of [missing value]. 50 Values ​​reached nanomolar concentration levels, with particularly superior inhibitory activity against mutants, IC50. 50 The optimal value is below 10 nM, which is significantly better than existing small molecule TRK kinase inhibitors.

[0058] 2. It has a wide range of applications and can be formulated into drugs for the treatment and / or prevention of diseases mediated by wild-type and mutant TRK kinases, especially for mutants, providing promising candidate drugs for solving the problem of drug resistance to existing drugs. Detailed Implementation

[0059] The technical solution of the present invention will be further described below with reference to the embodiments.

[0060] Unless otherwise specified, the experimental methods described in the following embodiments of the present invention are generally performed under conventional conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the embodiments are commercially available products.

[0061] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0062] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0063] The term "halogenated" refers to one of the halogens in Group 17 of the periodic table. Specifically, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0064] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that includes both branched and straight chains with a specific number of carbon atoms. For example, the definition of "C1-C8" in "C1-C8 alkyl" includes groups with 1, 2, 3, 4, 5, 7, or 8 carbon atoms arranged in a straight or branched chain.

[0065] The term "alkoxy" refers to a group in which an alkyl group is directly attached to an oxygen group, i.e., a group with an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0066] The term "alkyl ether" refers to a straight-chain or branched alkyl chain that is interrupted by a single oxygen atom to provide an ether. For example: "C 2-6 "Alkyl ether" refers to a straight or branched hydrocarbon chain containing 2, 3, 4, 5 or 6 carbon atoms and a single oxygen atom in the chain, such as -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3 or -(CH2)2O(CH2)2CH3.

[0067] The term "carbocyclic" refers to a saturated or unsaturated carbon-containing ring system. A "carbocyclic" system can be a monocyclic or fused polycyclic system, such as a bicyclic or tricyclic system. The "carbocyclic" moiety can contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" systems include cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems, and fused ring systems that include aromatic moieties.

[0068] The term "heterocycle" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O, or S. A "heterocycle" system can contain 1, 2, 3, or 4 heteroatoms. A "heterocycle" system can be a monocyclic or fused polycyclic system, such as a bicyclic or tricyclic system. The "heterocycle" moiety can contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocycle" encompasses heterocyclic alkyl moieties, heterocyclic alkenyl moieties, and heteroaromatic moieties. For example, a heterocyclic group can be ethylene oxide, aziridine, aziridine butane, oxaziridine butane, tetrahydrofuran, pyrrolidine, imidazoline, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0069] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain in which at least one heteroatom selected from N, O, and S is located between any carbons in the chain or at the end of the chain. For example, the term "C 1-6 "Heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, and at least one heteroatom selected from N, O and S is located between any carbons in the chain or at the end of the chain.

[0070] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. A "cycloalkyl" group can be represented as a "C" group containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 3-10 "Cycloalkyl". The cyclic system can be monocyclic, bicyclic, or tricyclic. For example, "cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclohexyl, cycloheptyl, and cyclooctyl.

[0071] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. "Cycloalkenyl" can be represented as "C 3-10 "Cycloalkenyl". 3-10 "Cycloalkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The ring can contain more than one double bond, provided the ring system is not aromatic. The ring system can be monocyclic, bicyclic, or tricyclic. For example, "cycloalkenyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl.

[0072] The term "heterocyclic alkyl" refers to a saturated hydrocarbon ring system having at least one heteroatom selected from N, O, and S within the ring. "Heterocyclic alkyl" can be represented as "C 3-10 Heterocyclic alkyl groups. "C" 3-10 A "heterocyclic alkyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. The ring system can be monocyclic, bicyclic, or tricyclic. When the ring system is bicyclic, one of the rings can be an aromatic ring, such as in indane. A "heterocyclic alkyl" can be bonded to the rest of the molecule by any carbon atom or heteroatom. A "heterocyclic alkyl" can have one or more, for example, one or two bonds to the rest of the molecule: these bonds can be made by any atom in the ring. For example, a "heterocyclic alkyl" can be ethylene oxide, aziridine, aziridine butane, oxaziridine butane, tetrahydrofuran, pyrrolidine, imidazoline, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and indane.

[0073] The term "heterocyclic alkenyl" refers to a non-aromatic unsaturated hydrocarbon ring system having at least one heteroatom selected from N, O, and S within the ring. "Heterocyclic alkenyl" can be represented as "C 3-10Heterocyclic alkenyl groups. "C" 3-10 A "heterocyclic alkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. The ring system can be monocyclic, bicyclic, or tricyclic. When the ring system is bicyclic, one ring can be an aromatic ring, such as in dihydroindole and dihydrobenzofuran. A "heterocyclic alkenyl" can be bonded to the rest of the molecule by any carbon atom or heteroatom. A "heterocyclic alkenyl" can have one or more, for example, one or two bonds to the rest of the molecule: these bonds can be made by any atom in the ring. For example, "C 3-8 "Heterocyclic alkenyl" can be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene, and dihydroindole.

[0074] The term "aryl" refers to an aromatic hydrocarbon ring system. This ring system has 4n+2 electrons in a conjugated π-system within the ring, where all atoms contributing to the conjugated π-system lie in the same plane. The ring system can be monocyclic, bicyclic, or tricyclic. For example, "aryl" can be phenyl or naphthyl. The aryl system itself can be substituted with other groups.

[0075] Example 1: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0076]

[0077] Step 1: tert-butyl(3-((5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate

[0078] 5-((tert-butoxycarbonyl)amino)-4-cyano-1-isopropyl-1H-pyrazole-3-carboxylic acid (200.0 mg, 0.68 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (310.1 mg, 0.82 mmol) and N,N-diisopropylethylamine (280.8 μL, 1.70 mmol) were dissolved in 20 mL of N,N'-dimethylformamide. After stirring at room temperature for 10 min, N-(5-amino-6-fluoropyridin-3-yl)-2-(4-chlorophenyl)acetamide (195.6 mg, 0.75 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (DCM / MeOH = 80:1) to give tert-butyl(3-((5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate, in 53.6% yield, as a white solid. ESI-MS m / z: 556.2 [M+H] + .

[0079] Step 2: 5-Amino-N-(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-4-cyano-1-isopropyl-1H-pyrazole-3-carboxamide

[0080] 100.0 mg (0.20 mmol) of tert-butyl(3-((5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate was dissolved in 5 mL of 5.5 N hydrochloric acid-ethanol solution and stirred at room temperature for 0.5 h. After the reaction was complete, the mixture was slowly poured into 50 mL of 2 N sodium hydroxide aqueous solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (DCM / MeOH = 80:1) to give 5-amino-N-(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-4-cyano-1-isopropyl-1H-pyrazole-3-carboxamide, yield 81.1%, white solid. ESI-MS m / z: 456.1 [M+H] + .

[0081] Step 3: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0082] 5-Amino-N-(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-4-cyano-1-isopropyl-1H-pyrazole-3-carboxamide (50 mg, 0.12 mmol) was dissolved in 10 mL of a mixture of ethanol and water (v / v = 4:1), followed by the addition of acetaldehyde oxime (27.0 mg, 0.46 mmol), palladium acetate (2.6 mg, 0.01 mmol), and triphenylphosphine (3.0 mg, 0.01 mmol). The reaction was carried out overnight under nitrogen protection and reflux. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (DCM / MeOH = 50:1) to give the product 5-amino-N- 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide, 78.5% yield, white solid. 1 H NMR (300MHz, DMSO-d6) δ10.60(s,1H),9.85(s,1H),9.18(s,1H),8.71(dd,J=8.8,2.5Hz,1H),8.30(t,J=2.1Hz,1H),7.49–7. 32(m,4H),7.22(s,1H),6.86(s,2H),4.61(p,J=6.5Hz,1H),3.72(s,2H),1.43(s,4H),1.41(s,3H); HR-MS(ESI)m / z:calcdfor C 21 H 22 ClFN7O3[M+H] + 474.1451 found 474.1451.

[0083] Example 2: 5-Amino-N 3 -(5-(3-(4-chlorophenyl)ureo)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0084]

[0085] The synthesis method was the same as in Example 1, with a yield of 74.8% and a white solid. 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.15(d,J=7.9Hz,2H),9.01(s,1H),8.59(dd,J=8.5,2.6Hz,1H),8.07(d,J=2.5Hz,1H),7.54–7.46(m,2 H),7.34(dd,J=8.7,1.2Hz,2H),7.16(s,1H),6.81(d,J=5.0Hz,2H),4.58(h,J=6.5Hz,1H),1.42(s,2H),1.40(s,3H); HR-MS(ESI)m / z:calcd forC 20 H 21 ClFN8O3[M+H] + 475.1404 found 475.1407.

[0086] Example 3: 5-Amino-N 3 -(5-(1-(4-chlorophenyl)cyclopropane-1-carboxylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0087]

[0088] The synthesis method was the same as in Example 1, with a yield of 77.1% and a white solid. 1 H NMR(300MHz,DMSO-d6)δ9.83(s,1H),9.47(s,1H),9.29–9.05(m,1H),8.62(dd ,J=8.9,2.5Hz,1H),8.26(t,J=2.1Hz,1H),7.45(s,4H),7.22(d,J=15.1Hz,1H ),6.97–6.65(m,2H),4.66–4.54(p,1H),1.53(p,J=3.9,3.5Hz,2H),1.42(s,J =2.8Hz,3H),1.40(s,J=2.2Hz,3H),1.21–1.14(m,2H); HR-MS(ESI)m / z:calcd for C 23 H 24 ClFN7O3[M+H] + 500.1608 found 500.1611.

[0089] Example 4: 5-Amino-N 3 -(5-(1-((4-chlorophenyl)carbamoyl)cyclopropane-1-carboxylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0090]

[0091] The synthesis method was the same as in Example 1, with a yield of 68.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.21(s,1H),9.84(s,1H),9.14(s,1H),8.69(dd,J=8.8,2.5Hz,1H),8.30(t,J=2.1Hz,1H),7.71–7.62(m,2 H),7.43–7.31(m,2H),7.18(s,1H),6.82(s,2H),4.59(p,J=6.5Hz,1H),1.46(t,J=2.7Hz,4H),1.41(s,3H),1.39(s,3H); HR-MS(ESI)m / z:calcdfor C 24 H 25 ClFN8O4[M+H] + 543.1666 found 543.1666.

[0092] Example 5: (E)-5-amino-N 3 -(5-(3-(4-chlorophenyl)acryloylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0093]

[0094] The synthesis method was the same as in Example 1, with a yield of 74.6% and a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.64(s,1H),9.87(s,1H),9.19(s,1H),8.81(dd,J =8.8,2.5Hz,1H),8.41(t,J=2.2Hz,1H),7.70(d,J=3.5Hz,1H),7.66(d,J=10 .8Hz,2H),7.56–7.46(m,2H),7.23(s,1H),6.86(s,2H),6.83(d,J=10.5Hz, 1H), 4.63 (p, J = 6.5Hz, 1H), 1.45 (s, 3H), 1.43 (s, 3H); HR-MS (ESI) m / z: calcd for C 24 H 25 ClFN8O4[M+H] + 486.1451 found 486.1455.

[0095] Example 6: 5-amino-N3-(5-(2-(4-chlorophenyl)cyclopropane-1-carboxylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0096]

[0097] The synthesis method was the same as in Example 1, with a yield of 77.1% and a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),9.82(s,1H),9.13(s,1H),8.71(dd,J=8.8,2.5Hz,1H),8 .25(t,J=2.2Hz,1H),7.39–7.33(m,2H),7.28–7.22(m,2H),7.20(s,1H),6.83(s,2H),4.59(p, J=6.5Hz,1H),2.45(ddd,J=9.1,6.3,4.0Hz,1H),2.07(ddd,J=8.2,5.4,4.0Hz,1H),1.55(ddd, J=9.4,5.4,4.2Hz,1H),1.41(s,3H),1.39(s,3H),1.23–1.12(m,1H).HR-MS(ESI)m / z:calcdfor C 23 H 24 ClFN7O3[M+H] + 500.1608 found 500.1611.

[0098] Example 7: 5-Amino-N 3 -(5-(3-(4-chlorophenyl)propionylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0099]

[0100] The synthesis method was the same as in Example 1, with a yield of 70.9% and a white solid. 1H NMR(300MHz,DMSO-d6)δ10.33(s,1H),9.85(s,1H),9.17(s,1H),8.68(dd,J =8.8,2.5Hz,1H),8.27(t,J=2.1Hz,1H),7.37(d,J=8.5Hz,2H),7.31(d,J=8. 5Hz,2H),7.21(s,1H),6.85(s,2H),4.62(p,J=6.5Hz,1H),2.95(t,J=7.5Hz, 2H),2.69(t,J=7.5Hz,2H),1.44(s,3H),1.42(s,3H).HR-MS(ESI)m / z:calcd for C 22 H 24 ClFN7O3[M+H] + 488.1608 found 488.1608.

[0101] Example 8: 5-Amino-N 3 -(2-Fluoro-5-(2-(pyridin-4-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0102]

[0103] The synthesis method was the same as in Example 1, with a yield of 81.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),9.85(s,1H),9.12(s,1H),8.67(dd,J=8.9,2.5Hz,1H),8.55–8.46(m,2H),8.27(t,J=2.1Hz,1H ),7.41–7.33(m,2H),7.18(s,1H),6.82(s,2H),4.58(p,J=6.5Hz,1H),3.76(s,2H),1.40(s,3H),1.39(s,3H).HR-MS(ESI)m / z:calcd for C 20 H 22 FN8O3[M+H] + 441.1793 found 441.1793.

[0104] Example 9: 5-Amino-N 3 -(5-(2-(6-chloropyridin-3-yl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0105]

[0106] The synthesis method was the same as in Example 1, with a yield of 74.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),9.83(s,1H),9.12(s,1H),8.68(td,J= 9.0,2.5Hz,1H),8.37(d,J=2.4Hz,1H),8.28–8.22(m,1H),7.83(dd,J=8.2,2 .5Hz,1H),7.51(d,J=8.2Hz,1H),7.17(s,1H),6.81(d,J=9.4Hz,2H),4.58(p ,J=6.5Hz,1H),3.79(s,3H),1.41(s,4H),1.39(s,4H).HR-MS(ESI)m / z:calcd for C 20 H 21 ClFN8O3[M+H] + 475.1404 found 475.1404.

[0107] Example 10: 5-Amino-N 3 -(5-(2-(4-chloro-2-fluorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0108]

[0109] The synthesis method was the same as in Example 1, with a yield of 77.0% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.63(s,1H),9.83(s,1H),9.13(s,1H),8.69(d,J=8.6Hz,1H),8.38–8.13(m,1H),7.52–7.38(m,2H),7.32 –7.25(m,1H),7.17(s,1H),6.82(d,J=7.4Hz,2H),4.70–4.52(m,1H),3.80(s,2H),1.42(s,3H),1.40(s,3H).HR-MS(ESI)m / z:calcd for C 21 H 21 ClF2N7O3[M+H] + 492.1357 found 492.1357.

[0110] Example 11: 5-Amino-N 3-(2-Fluoro-5-(2-(4-methoxyphenyl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0111]

[0112] The synthesis method was the same as in Example 1, with a yield of 78.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.82(s,1H),9.12(s,1H),8.68(td,J=8.8,2.5Hz,1H),8.31–8.21(m,1H),7.30–7.23(m,2H),7.16(s,1H) ),6.95–6.86(m,2H),6.80(d,J=9.3Hz,2H),4.58(p,J=6.5Hz,1H),3.73(s,3H),3.60(s,2H),1.41(s,3H),1.39(s,3H).HR-MS(ESI)m / z:calcd forC 22 H 25 FN7O4[M+H] + 470.1947 found 470.1947.

[0113] Example 12: 5-Amino-N 3 -(5-(2-(2,3-dihydrobenzofuran-5-yl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0114]

[0115] The synthesis method was the same as in Example 1, with a yield of 68.1% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.45(s,1H),9.79(s,1H),9.09(s,1H),8.63(dt,J=8.9,4 .6Hz,1H),8.23(t,J=2.1Hz,1H),7.15(s,2H),6.99(dd,J=8.1,1.9Hz,1H),6.83–6 .74(m,2H),6.66(d,J=8.1Hz,1H),4.55(q,J=6.5Hz,1H),4.45(t,J=8.7Hz,2H),3. 52(s,2H),3.11(t,J=8.7Hz,2H),1.36(s,3H),1.34(s,3H).HR-MS(ESI)m / z:calcd for C 23 H 25FN7O4[M+H] + 482.1947 found 482.1947.

[0116] Example 13: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-phenoxyphenyl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0117]

[0118] The synthesis method was the same as in Example 1, with a yield of 64.8% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.57(s,1H),9.82(s,1H),9.13(s,1H),8.69(dd,J=8.8,2.2Hz,1H),8.28(s,1H),7.44–7.31(m,4H),7.18(s,1H) ,7.12(t,J=7.4Hz,1H),7.03–6.94(m,4H),6.82(s,2H),4.58(p,J=6.5Hz,1H),3.67(s,2H),1.39(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C 27 H 26 FN7O4[M+H] + 533.2091 found 533.2119.

[0119] Example 14: 5-Amino-N 3 -(2-Fluoro-5-(2-(naphth-2-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0120]

[0121] The synthesis method was the same as in Example 1, with a yield of 72.2% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.65(s,1H),9.82(s,1H),9.14(s,1H),8.70(dd,J=8.7,2.0Hz,1H),8.30(s,1H),8.01–7.79(m,4H), 7.63–7.36(m,3H),7.16(s,1H),6.82(s,2H),4.58(p,J=6.5Hz,1H),3.87(s,2H),1.39(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C25 H 24 FN7O3[MH] + 488.1851 found 488.1860.

[0122] Example 15: 5-Amino-N 3 -(2-Fluoro-5-(2-(1-methyl-1H-indol-3-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0123]

[0124] The synthesis method was the same as in Example 1, with a yield of 63.5% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.82(s,1H),9.12(s,1H),8.67(dd,J= 8.8,2.4Hz,1H),8.29(t,J=2.1Hz,1H),7.61(d,J=7.9Hz,1H),7.40(d,J=8.2 Hz,1H),7.27(s,1H),7.20–7.09(m,2H),7.07–6.94(m,1H),6.80(s,2H),4.5 8(p,J=6.5Hz,1H),3.76(s,5H),1.39(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C 24 H 25 FN8O3[M+H] + 493.2107 found 493.2124.

[0125] Example 16: 5-Amino-N 3 -(2-Fluoro-5-(2-(imidazo[1,2-a]pyridin-3-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0126]

[0127] The synthesis method was the same as in Example 1, with a yield of 66.5% and a white solid. 1H NMR (300MHz, DMSO-d6) δ10.72(s,1H),9.84(s,1H),9.11(s,1H),8.67(dd,J=8.8,2.2Hz,1H),8.43(d,J=6.8Hz,1H),8.26(s,1H),7.73–7.42(m,2H), 7.36–7.21(m,1H),7.15(s,1H),6.96(t,J=6.5Hz,1H),6.81(s,2H),4.58( p,J=6.4Hz,1H),4.17(s,2H),1.39(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 22 FN9O3[M+H] + 480.1903 found 480.1906.

[0128] Example 17: 5-Amino-N 3 -(2-Fluoro-5-(2-(thien-2-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0129]

[0130] The synthesis method was the same as in Example 1, with a yield of 61.4% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.83(s,1H),9.13(s,1H),8.68(dd,J=8.7,2.2Hz,1H),8.27(s,1H),7.40(dd,J=5.0,1.3Hz, 1H),7.16(s,1H),7.07–6.93(m,2H),6.81(s,2H),4.58(p,J=6.5Hz,1H),3.92(s,2H),1.40(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C 19 H 20 FN7O3S[M+H] + 446.1406 found 446.1431.

[0131] Example 18: 5-Amino-N 3 -(5-(2-cyclohexylacetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0132]

[0133] The synthesis method was the same as in Example 1, with a yield of 60.9% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.82(s,1H),9.13(s,1H),8.65(dd,J=8.8,2. 3Hz,1H),8.26(t,J=2.0Hz,1H),7.16(s,1H),6.81(s,2H),4.58(p,J=6.5Hz,1H),2. 21(d,J=7.1Hz,2H),1.78(ddq,J=14.3,7.0,3.6Hz,1H),1.73–1.56(m,4H),1.39(d, J=6.5Hz,6H),1.32–1.06(m,4H),0.97(q,J=10.4,9.3Hz,2H).HR-MS(ESI)m / z:calcd for C 21 H 28 FN7O3[M+H] + 446.2311 found 446.2320.

[0134] Example 19: N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-5-(methylamino)-1H-pyrazole-3,4-dicarboxamide

[0135]

[0136] Step 1: The synthesis method was the same as in Step 1 of Example 1, yielding tert-butyl(3-((5-(2-(4-chlorophenyl)acetamide)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate, in 71.2% yield, as a white solid. ESI-MS m / z: 555.2 [M+H] + .

[0137] Step 2: Dissolve tert-butyl(3-((5-(2-(4-chlorophenyl)acetamide)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate (597 mg, 0.93 mmol) in anhydrous DMF, add 60% NaH (38 mg, 0.93 mmol), stir for half an hour, then add iodomethane (58 μL, 0.93 mmol) and stir overnight at room temperature. After the reaction was complete, the reaction solution was slowly poured into 100 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (PE / EA = 4:1) to give tert-butyl(3-((5-(2-(4-chlorophenyl)acetamide)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)(methyl)carbamate, yield 67.7%, white solid. ESI-MS m / z: 569.2 [M+H] + .

[0138] Steps 3 and 4: The synthesis method is the same as steps 2 and 3 of Example 1, yielding N. 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-5-(methylamino)-1H-pyrazole-3,4-dicarboxamide, yield 79.6%, white solid. 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 10.00 (s, 1H), 8.80 (dd, J = 5.0, 1.5Hz, 1H), 8.2 5(d,J=1.5Hz,1H),7.99(q,J=3.7Hz,1H),7.67(d,J=12.4Hz,1H),7.51(d,J=12.2Hz, 1H),7.43–7.35(m,2H),7.29(dt,J=7.5,1.0Hz,2H),4.59(hept,J=6.6Hz,1H),3.74( t,J=1.0Hz,2H),3.04(d,J=3.7Hz,3H),1.45(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 23 ClFN7O3[M+H] + 487.1535 found 487.1533.

[0139] Example 20: 5-Amino-1-ethyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0140]

[0141] The synthesis method was the same as in Example 1, with a yield of 76.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.86(s,1H),9.12(s,1H),8.67(dd,J=8.7,2.5Hz,1H),8.29(t,J=2.2Hz,1H),7.46(d,J=8.6Hz, 2H),7.32(d,J=8.2Hz,2H),7.17(s,1H),6.81(s,2H),4.07(q,J=7.1Hz,2H),3.74(s,2H),1.32(t,J=7.1Hz,3H).HR-MS(ESI)m / z:calcd for C 21 H 19 F4N7O4[M+H] + 510.1508 found 510.1508.

[0142] Example 21: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-isobutyl-1H-pyrazole-3,4-dicarboxamide

[0143]

[0144] The synthesis method was the same as in Example 1, with a yield of 74.0% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),9.82(s,1H),9.11(s,1H),8.67(dd,J=8.7,2.6Hz,1H),8.28(t,J=2.2Hz,1H),7.46(d,J=8.7Hz,2H),7.32(d,J =8.1Hz,2H),7.17(s,1H),6.83(s,2H),3.85(d,J=7.4Hz,2H),3.74(s,2H),2.27–2.12(m,J=6.7Hz,1H),0.89(d,J=6.7Hz,6H).HR-MS(ESI)m / z:calcd for C 23 H 23 F4N7O4[M+H] + 538.1821 found 538.1821.

[0145] Example 22: 5-Amino-1-(tert-butyl)-N 3-(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0146]

[0147] The synthesis method was the same as in Example 1, with a yield of 70.2% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.60(s,1H),9.77(s,1H),9.22(s,1H),8.70(dd,J=8.3Hz,1H),8.27(t,J=2.3Hz,1H),7.46 (d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),7.24(s,1H),6.84(s,2H),3.74(s,2H),1.61(s,9H).HR-MS(ESI)m / z:calcd for C 23 H 23 F4N7O4[M+H] + 538.1821 found 538.1821.

[0148] Example 23: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(4-fluorophenyl)-1H-pyrazole-3,4-dicarboxamide

[0149]

[0150] The synthesis method was the same as in Example 1, with a yield of 78.5% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.61(s,1H),10.19(s,1H),9.15(s,1H),8.57(dd,J=8.7,2.5Hz,1H),8.29(t,J=2.1Hz ,1H),7.79–7.65(m,2H),7.51–7.39(m,4H),7.36–7.29(m,3H),6.90(s,2H),3.74(s,2H).HR-MS(ESI)m / z:calcd for C 25 H 18 F5N7O4[M+H] + 576.1414 found 576.1414.

[0151] Example 24: 5-Amino-N 3-(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3,4-dicarboxamide

[0152]

[0153] The synthesis method was the same as in Example 1, with a yield of 68.7% and a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.60(s,1H),9.89(s,1H),9.14(s,1H),8.64(dd,J =8.8,2.5Hz,1H),8.27(t,J=2.2Hz,1H),7.46(d,J=8.7Hz,2H),7.38–7.27( m,2H),7.19(s,1H),6.88(s,2H),4.06–3.96(m,2H),3.74(s,2H),3.57–3.4 0(m,2H),2.18–1.93(m,3H),1.83(m,J=12.6Hz,2H).HR-MS(ESI)m / z:calcd for C 24 H 23 F4N7O5[M+H] + 566.1770 found 566.1770.

[0154] Example 25: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0155]

[0156] The synthesis method was the same as in Example 1, with a yield of 60.4% and a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.63(s,1H),9.83(s,1H),9.12(s,1H),8.67(d,J=6.6Hz,1H),8.27(s,1H),7.46(d,J=8.7Hz,2H),7.33(d, J=8.0Hz,2H),7.18(s,1H),6.81(d,J=6.7Hz,2H),4.58(p,J=6.4Hz,1H),3.74(s,2H),1.39(d,J=6.5Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 21 F4N7O4[M+H] +524.1664 found 524.1683.

[0157] Example 26: 5-Amino-1-cyclopropyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0158]

[0159] The synthesis method was the same as in Example 1, with a yield of 58.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.89(s,1H),9.08(s,1H),8.61(dd,J=8.8,2.5Hz,1H),8.28(t,J=2.2Hz,1H),7.46(d,J=8.7Hz,2H),7.37–7 .29(d,2H),7.22–7.16(m,1H),6.81(s,2H),3.74(s,2H),3.47–3.40(m,1H),1.10(m,J=3.9,3.3Hz,2H),1.08–1.03(m,2H).HR-MS(ESI)m / z:calcd for C 22 H 19 F4N7O4[M+H] + 522.1508 found 522.1508.

[0160] Example 27: 5-Amino-1-cyclobutyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0161]

[0162] The synthesis method was the same as in Example 1, with a yield of 70.1% and a white solid. 1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),9.99(s,1H),9.17(s,1H),8.69(dd,J =8.6,2.6Hz,1H),8.32(s,1H),7.49(d,J=8.2Hz,2H),7.35(d,J=8.1Hz,2H) ,7.24(s,1H),6.83(s,2H),4.89(p,J=8.2Hz,1H),3.77(s,2H),2.60(q,J=1 0.0Hz,2H),2.39(q,J=8.3Hz,2H),1.92–1.72(m,2H).HR-MS(ESI)m / z:calcd for C 23 H 21 F4N7O4[M+H] + 536.1664 found 536.1664.

[0163] Example 28: 5-Amino-1-cyclopentyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0164]

[0165] The synthesis method was the same as in Example 1, with a yield of 66.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.76(s,1H),9.12(s,1H),8.70(dd,J=8.9,2. 5Hz,1H),8.27(t,J=2.1Hz,1H),7.46(d,J=8.7Hz,2H),7.38–7.22(m,2H),7.17(s,1 H),6.82(s,2H),4.71(p,J=7.0Hz,1H),3.74(s,2H),2.00(ddq,J=24.7,12.1,5.6Hz ,4H),1.90–1.81(m,2H),1.65(ddt,J=11.3,8.6,3.9Hz,2H).HR-MS(ESI)m / z:calcd for C 24 H 23 F4N7O4[M+H] + 550.1821 found 550.1821.

[0166] Example 29: 5-Amino-N 3-(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-pyrazole-3,4-dicarboxamide

[0167]

[0168] The synthesis method was the same as in Example 1, with a yield of 52.5% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),9.87(s,1H),9.10(s,1H),8.64(dd,J=8 .8,2.5Hz,1H),8.28(t,J=2.2Hz,1H),7.53–7.39(m,2H),7.33(d,J=8.2Hz,2H ),7.17(s,1H),6.89(s,2H),4.16(t,J=6.5Hz,2H),3.74(s,2H),3.57(t,J=4. 5Hz,4H),2.71(t,J=6.5Hz,2H),2.46(t,J=4.7Hz,4H).HR-MS(ESI)m / z:calcd for C 25 H 26 F4N8O5[M+H] + 595.2036 found 595.2036.

[0169] Example 30: 5-Amino-N 3 -(2-chloro-5-(2-(4-chlorophenyl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0170]

[0171] The synthesis method was the same as in Example 1, with a yield of 64.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.96(s,1H),8.73(d,J=1.5Hz,1H),8.40(d,J=1.5Hz,1H),8.06(d,J=9.1Hz,1H),7.87(d,J=9.1Hz,1H),7.60( s,2H),7.43–7.35(m,2H),7.29(dt,J=7.4,1.0Hz,2H),4.53(hept,J=6.7Hz,1H),3.74(t,J=1.0Hz,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 21 H 21Cl2N7O3[M+H] + 490.1156 found 490.1153.

[0172] Example 31: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-methylpyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0173]

[0174] The synthesis method was the same as in Example 1, with a yield of 79.6% and a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.98(s,1H),8.60(d,J=1.5Hz,1H),8.3 3(d,J=1.5Hz,1H),8.06(d,J=8.9Hz,1H),7.94(d,J=9.1Hz,1H),7.60(s,2H), 7.43–7.36(m,2H),7.29(dt,J=7.5,1.1Hz,2H),4.53(hept,J=6.7Hz,1H),3.7 2(t,J=1.0Hz,2H),2.33(s,3H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 24 ClN7O3[M+H] + 470.1702 found 470.1701.

[0175] Example 32: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-cyclopropylpyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0176]

[0177] The synthesis method was the same as in Example 1, with a yield of 77.4% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),9.85(s,1H),8.77(d,J=1.5Hz,1H),8.38(d,J=1.5Hz,1 H),8.04(d,J=9.1Hz,1H),7.87(d,J=9.1Hz,1H),7.56(d,J=12.5Hz,1H),7.47(d,J=12.4Hz,1 H),7.42–7.35(m,2H),7.29(dt,J=7.4,1.0Hz,2H),4.55(hept,J=6.8Hz,1H),3.74(t,J=1.0H z,2H),3.17(p,J=7.0Hz,1H),1.44(d,J=6.8Hz,6H),1.14–0.88(m,4H).HR-MS(ESI)m / z:calcd for C 24 H 26 ClN7O3[M+H] + 496.1858 found 496.1864.

[0178] Example 33: 5-Amino-N 3 -(5-(3-((4-chlorophenyl)amino)-3-carbonylpropionylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0179]

[0180] The synthesis method was the same as in Example 1, with a yield of 60.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 10.03 (d, J = 7.1Hz, 2H), 8.80 (dd, J = 5. 0,1.5Hz,1H),8.24(d,J=1.5Hz,1H),8.04(d,J=9.1Hz,1H),7.88(d,J=9.1Hz ,1H),7.65–7.52(m,3H),7.47(d,J=12.4Hz,1H),7.32–7.25(m,2H),4.55(he pt,J=6.8Hz,1H),3.54(s,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 22 ClFN8O4[M+H] + 517.1509 found 517.1509.

[0181] Example 34: 5-Amino-N 3-(5-(2-(4-chlorophenyl)-2-carbonylacetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0182]

[0183] The synthesis method was the same as in Example 1, with a yield of 74.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.99(d,J=12.8Hz,2H),8.84(dd,J=5.0,1.5Hz,1H),8.28(d,J=1.5Hz,1H),8.06(d,J=9.1Hz,1H),7.98–7.91(m,2H ),7.87(d,J=9.1Hz,1H),7.56(d,J=12.5Hz,1H),7.53–7.43(m,3H),4.55(hept,J=6.8Hz,1H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd forC 21 H 19 ClFN7O4[M+H] + 488.1244 found 488.1250.

[0184] Example 35: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)propionylamino)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0185]

[0186] The synthesis method was the same as in Example 1, with a yield of 71.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.01(s,1H),8.37(d,J=2.1Hz,1H),7.66(d,J=2.1Hz,1H),7.39–7.34(m,2H),7.34–7.30(m,3H ),7.20(d,J=7.5Hz,1H),6.29(s,2H),4.66(hept,J=3.6Hz,1H),4.05(qt,J=5.7,0.9Hz,1H),1.70–1.32(m,9H).HR-MS(ESI)m / z:calcd for C 22 H 23 ClFN7O3[M+H] + 488.1608 found 488.1607.

[0187] Example 36: 5-Amino-N 3 -(5-(2-(4-chloro-3-fluorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0188]

[0189] The synthesis method was the same as in Example 1, with a yield of 68.0% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 10.04 (s, 1H), 8.80 (dd, J = 5.0, 1.5Hz, 1H) ,8.25(d,J=1.5Hz,1H),8.06(d,J=9.1Hz,1H),7.87(d,J=9.1Hz,1H),7.57(d,J= 12.3Hz,1H),7.53–7.43(m,2H),7.12(ddq,J=7.6,3.4,1.2Hz,2H),4.55(hept,J =6.8Hz,1H),3.74(t,J=1.0Hz,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 21 H 20 ClF2N7O3[M+H] + 492.1357 found 492.1366.

[0190] Example 37: 5-Amino-N 3 -(5-(2-(4-chloro-3-(trifluoromethyl)phenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0191]

[0192] The synthesis method was the same as in Example 1, with a yield of 62.9% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),10.04(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.25(d,J=1.5Hz,1H),7.99(d,J=9.1Hz,1H),7.90(d,J=9.1 Hz,1H),7.60–7.43(m,4H),7.26–7.19(m,1H),4.55(hept,J=6.8Hz,1H),3.71(t,J=1.0Hz,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd forC 21 H 20 ClF2N7O3[M+H] + 492.1357 found 492.1351.

[0193] Example 38: 5-Amino-N 3 -(5-(2-(4-ethoxyphenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0194]

[0195] The synthesis method was the same as in Example 1, with a yield of 78.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),10.01(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.25(d,J=1. 5Hz,1H),8.04(d,J=9.1Hz,1H),7.87(d,J=9.1Hz,1H),7.59(d,J=12.2Hz,1H),7.47(d,J=12.4H z,1H),7.21(dt,J=7.5,1.1Hz,2H),6.91–6.84(m,2H),4.55(hept,J=6.8Hz,1H),4.02(q,J=8.0 Hz,2H),3.73(t,J=1.0Hz,2H),1.44(d,J=6.8Hz,6H),1.40–1.31(m,3H).HR-MS(ESI)m / z:calcd for C 23 H 26 ClF2N7O4[M+H] + 484.2103 found 484.2099.

[0196] Example 39: 5-Amino-N 3-(5-(2-(3,4-dimethoxyphenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0197]

[0198] The synthesis method was the same as in Example 1, with a yield of 73.6% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.27 (s, 1H), 10.04 (s, 1H), 8.80 (dd, J = 5.0, 1.5Hz, 1H), 8 .25(d,J=1.5Hz,1H),8.04(d,J=9.1Hz,1H),7.88(d,J=9.1Hz,1H),7.56(d,J=12.5H z,1H),7.47(d,J=12.4Hz,1H),6.90–6.77(m,3H),4.55(hept,J=6.8Hz,1H),3.81(d ,J=9.1Hz,6H),3.72(t,J=1.0Hz,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 23 H 26 FN7O5[M+H] + 500.2052 found 500.2052.

[0199] Example 40: 5-Amino-N 3 -(5-(2-(2,4-dimethoxyphenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0200]

[0201] The synthesis method was the same as in Example 1, with a yield of 75.3% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),10.04(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.25(d,J=1.5Hz ,1H),8.04(d,J=9.1Hz,1H),7.88(d,J=9.1Hz,1H),7.56(d,J=12.5Hz,1H),7.47(d,J=12.4Hz,1H), 7.17(dt,J=7.5,1.0Hz,1H),6.62(dd,J=7.5,1.5Hz,1H),6.54(d,J=1.5Hz,1H),4.55(hept,J=6.8H z,1H),3.82(d,J=10.8Hz,6H),3.72(d,J=1.1Hz,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 23 H 26 FN7O5[M+H] + 500.2052 found 500.2050.

[0202] Example 41: 5-Amino-N 3 -(5-(2-(4-(difluoromethoxy)phenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0203]

[0204] The synthesis method was the same as in Example 1, with a yield of 78.5% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),10.04(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.25(d ,J=1.5Hz,1H),8.04(d,J=9.1Hz,1H),7.88(d,J=9.1Hz,1H),7.56(d,J=12.5Hz,1H),7.4 7(d,J=12.4Hz,1H),7.15(dt,J=7.5,1.1Hz,2H),7.07–6.99(m,2H),6.94–6.73(m,1H),4 .55(hept,J=6.8Hz,1H),3.80–3.61(m,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 22 F3N7O4[M+H] +506.1758 found 506.1764.

[0205] Example 42: 5-Amino-N 3 -(2-Fluoro-5-(2-(naphth-1-yl)acetamido)pyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0206]

[0207] The synthesis method was the same as in Example 1, with a yield of 70.5% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.04(s,1H),8.80(dd,J=5.0,1.4Hz,1 H),8.25(d,J=1.5Hz,1H),8.07–7.97(m,2H),7.91–7.81(m,2H),7.77(dt,J=7. 3,1.7Hz,1H),7.63–7.53(m,2H),7.53–7.46(m,2H),7.46–7.38(m,2H),4.55( hept,J=6.8Hz,1H),3.81(s,2H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 25 H 24 FN7O3[M+H] + 490.1997 found 490.2003.

[0208] Example 43: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-hydroxyethyl)-1H-pyrazole-3,4-dicarboxamide

[0209]

[0210] The synthesis method was the same as in Example 1, with a yield of 64.8% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.26 (s, 1H), 10.00 (s, 1H), 8.80 (dd, J = 5.0, 1.5Hz, 1H), 8.25(d,J=1.4Hz,1H),7.96(d,J=9.1Hz,1H),7.91(d,J=9.1Hz,1H),7.42(q,J=12 .4Hz,2H),7.14(m,4H),4.88(t,J=7.6Hz,1H),4.13(t,J=7.2Hz,2H),3.83(q,J=7 .3Hz,2H),3.76(d,J=14.4Hz,1H),3.67(d,J=14.5Hz,1H).HR-MS(ESI)m / z:calcd for C 21 H 19 F4N7O5[M+H] + 526.1457 found 526.1465.

[0211] Example 44: 1-Acetyl-5-amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0212]

[0213] The synthesis method was the same as in Example 1, with a yield of 62.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7 .17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),3.82(t,J=1.0Hz,2H),2.80(s,3H).HR-MS(ESI)m / z:calcd for C 21 H 17 F4N7O5[M+H] + 524.1300 found 524.1298.

[0214] Example 45: 5-Amino-1-(But-3-yn-1-yl)-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0215]

[0216] The synthesis method was the same as in Example 1, with a yield of 79.0% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7.21–7.13(m,2H),6.9 3–6.85(m,2H),6.62(s,2H),4.84(t,J=6.5Hz,2H),3.82(t,J=1.0Hz,2H),2.74(t,J=3.0Hz,1H),2.56–2.49(m,2H).HR-MS(ESI)m / z:calcd forC 23 H 19 F4N7O4[M+H] + 534.1507 found 534.1507.

[0217] Example 46: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(piperidin-4-yl)-1H-pyrazole-3,4-dicarboxamide

[0218]

[0219] The synthesis method was the same as in Example 1, with a yield of 74.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H), 7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),4.40(p,J=7.9Hz,1H),3.82( t,J=1.0Hz,2H),3.01(ddt,J=12.0,7.3,4.6Hz,2H),2.71(ddt,J=12.2,7.3,4.6Hz,2H),2.44(p,J=4.6 Hz,1H),1.93(dtd,J=12.3,7.7,4.6Hz,2H),1.79(dtd,J=12.4,7.6,4.7Hz,2H).HR-MS(ESI)m / z:calcd for C 24 H 24 F4N8O4[M+H] +565.1929 found 565.1931.

[0220] Example 47: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-3,4-dicarboxamide

[0221]

[0222] The synthesis method was the same as in Example 1, with a yield of 68.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H), 7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),4.40(p,J=7.5Hz,1H),3.82(t ,J=1.0Hz,2H),2.97(ddd,J=12.5,8.8,6.1Hz,2H),2.57(ddd,J=12.4,8.8,6.1Hz,2H),2.25(s,3H),2. 14(dddd,J=12.5,8.7,7.5,6.2Hz,2H),1.86(dddd,J=12.4,8.9,7.5,6.2Hz,2H).HR-MS(ESI)m / z:calcd for C 25 H 26 F4N8O4[M+H] + 579.2086 found 579.2090.

[0223] Example 48: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-3,4-dicarboxamide

[0224]

[0225] The synthesis method was the same as in Example 1, with a yield of 66.4% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 9.94 (s, 1H), 9.15 (dd, J = 5.0, 2.1Hz, 1H), 8. 19(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6. 62(s,2H),4.66(t,J=7.2Hz,2H),3.82(t,J=1.0Hz,2H),3.12(t,J=7.1Hz,2H),2.8 9(dd,J=5.9,3.2Hz,4H),2.75(p,J=5.2Hz,1H),2.54(m,4H).HR-MS(ESI)m / z:calcd for C 25 H 27 F4N9O4[M+H] + 594.2195found594.2196.

[0226] Example 49: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazole-3,4-dicarboxamide

[0227]

[0228] The synthesis method was the same as in Example 1, with a yield of 65.0% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 9.94 (s, 1H), 9.15 (dd, J = 5.0, 2.1Hz, 1H), 8.1 9(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62 (s,2H),4.66(t,J=7.2Hz,2H),3.82(t,J=1.0Hz,2H),3.12(t,J=7.1Hz,2H),2.69(dd ,J=7.9,5.2Hz,4H),2.58(s,3H),2.29(dd,J=7.9,5.2Hz,4H).HR-MS(ESI)m / z:calcd for C 26 H 29 F4N9O4[M+H] + 608.2351 found 608.2348.

[0229] Example 50: 5-Amino-N 3-(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(4-hydroxycyclohexyl)-1H-pyrazole-3,4-dicarboxamide

[0230]

[0231] The synthesis method was the same as in Example 1, with a yield of 71.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6. 93–6.85(m,2H),6.62(s,2H),3.88–3.74(m,3H),3.70–3.58(m,1H),2.09– 1.91(m,2H),1.85–1.68(m,4H),1.60–1.44(m,3H).HR-MS(ESI)m / z:calcd for C 25 H 25 F4N7O5[M+H] + 580.1926 found 580.1923.

[0232] Example 51: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-morpholinoacetyl)-1H-pyrazole-3,4-dicarboxamide

[0233]

[0234] The synthesis method was the same as in Example 1, with a yield of 75.9% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6 .93–6.85(m,2H),6.62(s,2H),3.82(t,J=1.0Hz,2H),3.68(dd,J=7.5,4.8Hz,4H),3.47(s,2H),2.57(dd,J=7.4,4.7Hz,4H).HR-MS(ESI)m / z:calcd for C 25 H 24F4N8O6[M+H] + 609.1828 found 609.1825.

[0235] Example 52: 5-Amino-1-cyclohexyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0236]

[0237] The synthesis method was the same as in Example 1, with a yield of 76.0% and a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8 .19(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H) ,6.62(s,2H),3.82(t,J=1.0Hz,2H),3.64(p,J=7.3Hz,1H),2.00(dddd,J=12.0,9 .0,7.4,6.3Hz,2H),1.82–1.41(m,7H),1.27–1.13(m,1H).HR-MS(ESI)m / z:calcd for C 25 H 25 F4N7O4[M+H] + 564.1977 found 564.1977.

[0238] Example 53: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-carbonyl-2-(4-(piperazin-1-yl)piperidin-1-yl)ethyl)-1H-pyrazole-3,4-dicarboxamide

[0239]

[0240] The synthesis method was the same as in Example 1, with a yield of 62.4% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1. 9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),5.06(s,2H ),3.85–3.72(m,4H),2.80–2.61(m,5H),2.58–2.47(m,6H),2.37(p,J=7.9Hz,1H),1.81(dddd, J=12.4,9.7,7.9,7.0Hz,2H),1.25(dddd,J=12.3,9.6,7.8,6.9Hz,2H).HR-MS(ESI)m / z:calcd forC 30 H 34 F4N 10 O5[M+H] + 691.2723 found 691.2719.

[0241] Example 54: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-carbonylethyl)-1H-pyrazole-3,4-dicarboxamide

[0242]

[0243] The synthesis method was the same as in Example 1, with a yield of 61.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H) ,7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),5.06(s,2H),3.85–3.72(m, 4H),3.14–3.02(m,2H),2.78–2.60(m,4H),2.58(s,3H),2.56–2.44(m,4H),2.37(p,J=7.9Hz,1H),1.8 1(dddd,J=12.4,9.7,7.9,7.0Hz,2H),1.25(dddd,J=12.3,9.6,7.8,6.9Hz,2H).HR-MS(ESI)m / z:calcd for C31 H 36 F4N 10 O5[M+H] + 705.2879 found 705.2878.

[0244] Example 55: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-(4-morpholinopiperidin-1-yl)-2-carbonylethyl)-1H-pyrazole-3,4-dicarboxamide

[0245]

[0246] The synthesis method was the same as in Example 1, with a yield of 79.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 9.94 (s, 1H), 9.15 (dd, J = 5.0, 2.1Hz, 1H), 8.19 (d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s ,2H),5.06(s,2H),3.85–3.72(m,4H),3.56(dd,J=7.7,5.0Hz,4H),2.72(ddd,J=12.5 ,9.7,7.0Hz,2H),2.49–2.31(m,5H),1.81(m,2H),1.25(m,2H).HR-MS(ESI)m / z:calcd for C 30 H 33 F4N9O6[M+H] + 692.2563 found 692.2566.

[0247] Example 56: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-carbonylethyl)-1H-pyrazole-3,4-dicarboxamide

[0248]

[0249] The synthesis method was the same as in Example 1, with a yield of 66.8% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H) ,7.50(s,2H),7.17(dt,J=7.8,1.1Hz,2H),6.93–6.85(m,2H),6.62(s,2H),5.06(s,2H),4.29(ddd,J= 12.2,10.0,7.3Hz,2H),3.91–3.83(m,3H),3.82(t,J=1.0Hz,2H),1.83(dtd,J=12.5,10.1,7.5Hz,2H) ,1.69(dtd,J=12.5,10.1,7.5Hz,2H),1.42–1.27(m,1H),1.23(d,J=1.5Hz,6H).HR-MS(ESI)m / z:calcd for C 29 H 32 F4N8O6[M+H] + 665.2454 found 665.2461.

[0250] Example 57: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2-oxaspiro[3.5]nonane-7-yl)-1H-pyrazole-3,4-dicarboxamide

[0251]

[0252] The synthesis method was the same as in Example 1, with a yield of 63.4% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 9.94 (s, 1H), 9.15 (dd, J = 5.0, 2.1Hz, 1H), 8.19 (d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62( s,2H),4.61(s,4H),3.82(t,J=1.0Hz,2H),3.64(p,J=7.2Hz,1H),2.00(dq,J=12.2,7 .1Hz,2H),1.75(dq,J=12.4,7.2Hz,2H),1.20(t,J=7.2Hz,4H).HR-MS(ESI)m / z:calcd for C 27 H 27 F4N7O5[M+H] +606.2083 found 606.2082.

[0253] Example 58: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3,4-dicarboxamide

[0254]

[0255] The synthesis method was the same as in Example 1, with a yield of 74.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7 .21–7.13(m,2H),6.93–6.85(m,2H),6.62(s,2H),5.32(q,J=9.1Hz,2H),3.82(t,J=1.0Hz,2H).HR-MS(ESI)m / z:calcd for C 21 H 16 F7N7O4[M+H] + 564.1225 found 564.1229.

[0256] Example 59: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3,4-dicarboxamide

[0257]

[0258] The synthesis method was the same as in Example 1, with a yield of 75.2% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7.17(dt,J=7.8 ,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),5.98–5.82(m,1H),3.82(t,J=1.0Hz,2H),1.39(d,J=5.6Hz,3H).HR-MS(ESI)m / z:calcd for C 22 H18 F7N7O4[M+H] + 578.1381 found 578.1383.

[0259] Example 60: 5-Amino-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-3,4-dicarboxamide

[0260]

[0261] The synthesis method was the same as in Example 1, with a yield of 63.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.94(s,1H),9.15(dd,J=5.0,2.1Hz,1H),8.19(d,J=1.9Hz,1H),7.50(s,2H),7 .17(dt,J=7.8,1.0Hz,2H),6.93–6.85(m,2H),6.62(s,2H),3.82(t,J=1.0Hz,2H),1.25(s,6H).HR-MS(ESI)m / z:calcd for C 23 H 20 F7N7O4[M+H] + 592.1538 found 592.1546.

[0262] Example 61: 5-amino-3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0263]

[0264] Step 1: Di-tert-butyl(3-(5-bromo-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)iminodicarbonate

[0265] Under strictly anhydrous, oxygen-free, and nitrogen-protected conditions, di-tert-butyl(4-cyano-1-isopropyl-3-(methoxy(methyl)carbamoyl)-1H-pyrazol-5-yl)iminodicarbonate (500 mg, 1.14 mmol) and 3,5-dibromo-2-fluoropyridine (290.6 mg, 1.14 mmol) were dissolved in 20 mL of ultra-dry tetrahydrofuran. After cooling to -78 °C, a tetrahydrofuran solution of n-butyllithium (1.6 M, 785.7 μL, 1.26 mmol) was added, and the reaction was maintained at this temperature for 2 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with water. It was then extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EA = 4:1) to give di-tert-butyl(3-(5-bromo-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)iminodicarbonate, 35.2% yield, as a white solid. ESI-MS m / z: 551.1 [M+H] + .

[0266] Step 2: Tert-butyl(4-cyano-3-(5-((diphenylmethylene)amino)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-5-yl)carbamate

[0267] Di-tert-butyl(3-(5-bromo-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)iminodicarbonate (150 mg, 0.28 mmol) was dissolved in 20 mL of toluene, and then benzophenone imine (70.7 μL, 0.42 mmol), cesium carbonate (457.3 mg, 1.40 mmol), palladium acetate (6.3 mg, 0.01 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (17.5 mg, 0.01 mmol) were added sequentially. The reaction was carried out overnight under nitrogen protection and reflux. After the reaction was complete, toluene was evaporated to dryness, diluted with water, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (PE / EA = 8:1) to give tert-butyl(4-cyano-3-(5-((diphenylmethylene)amino)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-5-yl)carbamate, in 53.1% yield, as a pale yellow solid. ESI-MS m / z: 552.2 [M+H] + .

[0268] Step 3: Tert-butyl(3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate

[0269] 1.0 g (1.87 mmol) of tert-butyl(4-cyano-3-(5-((diphenylmethylene)amino)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-5-yl)carbamate was dissolved in a mixed solvent of 20 mL of tetrahydrofuran and 2N hydrochloric acid (v / v = 1:1) and stirred at room temperature for 2 h. After the reaction was completed, the mixture was slowly poured into 50 mL of 1N sodium hydroxide aqueous solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (PE / EA = 2:1) to obtain the intermediate. This intermediate (1.2 g, 3.23 mmol) and p-chlorophenylacetic acid (661.7 mg, 3.88 mmol) were then dissolved in 20 mL of tetrahydrofuran, and then triethylamine (1.57 mL, 11.31 mmol) and an ethyl acetate solution of T3P (50 wt.%, 5.14 g, 8.08 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was slowly poured into 100 mL of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (PE / EA = 4:1) to give tert-butyl(3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate, yield 53.1%, white solid. ESI-MS m / z: 540.2 [M+H] + .

[0270] Step 4: The synthesis method is the same as step 2 of Example 1. The protecting group of tert-butyl(3-(5-(2-(4-chlorophenyl)acetamitano)-2-fluoronicotinyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate was removed to obtain N-(5-(5-amino-4-cyano-1-isopropyl-1H-pyrazole-3-carbonyl)-6-fluoropyridin-3-yl)-2-(4-chlorophenyl)acetamide, yield 75.2%, white solid. ESI-MS m / z: 440.1 [M+H] + .

[0271] Step 5: The synthesis method is the same as step 3 of Example 1. 5-amino-3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-3-carbonyl)-6-fluoropyridin-3-yl)-2-(4-chlorophenyl)acetamide was hydrolyzed to obtain 5-amino-3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-4-carboxamide in 78.0% yield, as a white solid. 1H NMR(400MHz, DMSO-d6)δ9.94(s,1H),9.07(dd,J=5.0,2.1Hz,1H),8.55(d,J=1.9Hz,1H),7.50(s,2H),7.39–7.27( m,4H),6.62(s,2H),4.47(hept,J=3.6Hz,1H),3.82(t,J=1.0Hz,2H),1.40(d,J=3.5Hz,6H).HR-MS(ESI)m / z:calcd for C 21 H 20 ClFN6O3[M+H] + 459.1342 found 459.1347.

[0272] Example 62: 5-Amino-N 3 -(4-(2-(4-chlorophenyl)acetamido)pyridin-2-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0273]

[0274] The synthesis method was the same as in Example 1, with a yield of 66.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),9.04(s,1H),7.83(d,J=4.3Hz,1H),7.77(d,J=2.3Hz,1H),7.50(s,2H),7.40–7. 27(m,5H),6.62(s,2H),4.47(hept,J=3.6Hz,1H),3.82(t,J=1.0Hz,2H),1.40(d,J=3.5Hz,6H).HR-MS(ESI)m / z:calcd for C 21 H 22 ClN7O3[M+H] + 456.1545found456.1546.

[0275] Example 63: 5-Amino-N 3 -(2-(2-(4-chlorophenyl)acetamido)pyridin-4-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0276]

[0277] The synthesis method was the same as in Example 1, with a yield of 70.6% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.88(s,1H),8.03(d,J=4.2Hz,1H),7.52–7.43(m,3H),7.39–7.27(m,4H),6.62(s,2H) ,6.32(dd,J=4.4,2.3Hz,1H),4.47(hept,J=3.6Hz,1H),3.82(t,J=1.0Hz,2H),1.40(d,J=3.5Hz,6H).HR-MS(ESI)m / z:calcd for C 21 H 22 ClN7O3[M+H] + 456.1545found456.1541.

[0278] Example 64: 5-amino-3-(5-(2-(4-chlorophenyl)acetamido)-6-fluoronicotinyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0279]

[0280] The synthesis method was the same as in Example 1, with a yield of 80.5% and a white solid. 1 H NMR(400MHz, DMSO-d6)δ9.96(s,1H),8.44(d,J=2.1Hz,1H),8.04(d,J=2.1Hz,1H),7.43–7.35(m,2H),7.34–7.24(m,3H),7.15(d,J=7.5Hz,1H ),6.71(d,J=9.1Hz,1H),6.47(d,J=9.1Hz,1H),4.57(hept,J=3.7Hz,1H),3.59(t,J=1.0Hz,2H),1.50(d,J=3.5Hz,6H).HR-MS(ESI)m / z:calcd forC 21 H 20 ClFN6O3[M+H] + 459.1342 found 456.1348.

[0281] Example 65: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-(methoxymethyl)-1H-pyrazole-3,4-dicarboxamide

[0282]

[0283] The synthesis method was the same as in Example 1, with a yield of 72.7% and a white solid.1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.99(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.25(d,J=1.5Hz,1H),7.98(s,2H),7.53(d,J=12 .5Hz,1H),7.48–7.35(m,3H),7.29(dt,J=7.4,1.0Hz,2H),5.44(s,2H),3.72(t,J=1.0Hz,2H),3.36(s,3H).HR-MS(ESI)m / z:calcd for C 20 H 19 ClFN7O4[M+H] + 476.1244 found 456.1250.

[0284] Example 66: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-N 4 -Methyl-1H-pyrazole-3,4-dicarboxamide

[0285]

[0286] Step 1: The synthesis method was the same as in Step 1 of Example 1, yielding bis-tert-butyl(3-((5-(2-(4-chlorophenyl)acetamide)-2-fluoropyridin-3-yl)carbamoyl)-4-cyano-1-isopropyl-1H-pyrazole-5-yl)carbamate, in 61.8% yield, as a white solid. ESI-MS m / z: 655.2 [M+H] + .

[0287] Step 2: The synthesis method is the same as step 3 of Example 1, yielding bis-tert-butyl(4-carbamoyl-3-((5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)carbamoyl)-1-isopropyl-1H-pyrazole-5-yl)carbamate, in 58.4% yield, a white solid. ESI-MS m / z: 673.2 [M+H] + .

[0288] Step 3: The synthesis method is the same as step 2 of Example 19, yielding bis-tert-butyl(3-((5-(2-(4-chlorophenyl)acetamide)-2-fluoropyridin-3-yl)carbamoyl)-1-isopropyl-4-(methylcarbamoyl)-1H-pyrazole-5-yl)carbamate, in 68.2% yield, a white solid. ESI-MS m / z: 687.3 [M+H] + .

[0289] Step 4: The synthesis method is the same as step 2 of Example 1, to obtain 5-amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-isopropyl-N 4 3-Methyl-1H-pyrazole-3,4-dicarboxamide, yield 61.0%, white solid. 1 H NMR(400MHz, DMSO-d6)δ10.28(s,1H),10.00(s,1H),8.80(dd,J=5.0,1.5Hz,1H),8.28–8.20(m,2H),8.08–7.99(m,2H),7.43–7.35(m,2H),7.2 9(dt,J=7.5,1.0Hz,2H),4.55(hept,J=6.8Hz,1H),3.74(t,J=1.0Hz,2H),2.88(d,J=3.7Hz,3H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 23 ClFN7O3[M+H] + 487.1535 found 487.1538.

[0290] Example 67: 5-Amino-3-(5-(2-(4-chlorophenyl)-N-methylacetamido)-2-fluoronicotinyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0291]

[0292] The synthesis method was the same as in Example 1, with a yield of 58.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=1.4Hz,1H),8.36(d,J=9.1Hz,1H),8.26(d,J=8.9Hz,1H),7.84(dd,J=5.0,1.4Hz,1H),7.59(s,2H),7.43–7.36 (m,2H),7.30(dt,J=7.7,1.1Hz,2H),4.53(hept,J=6.7Hz,1H),3.61(t,J=1.0Hz,2H),3.20(s,3H),1.45(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 22 ClFN6O3[M+H] + 473.1499 found 473.1501.

[0293] Example 68: 5-Amino-N 3 -(5-(3-(4-chlorophenyl)propynamide)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0294]

[0295] The synthesis method was the same as in Example 1, with a yield of 66.7% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),10.01(s,1H),8.84(dd,J=5.1,1.6Hz,1H),8.27(d,J=1.5Hz,1H),8.06(d,J=9.1Hz,1H),7.87 (d,J=9.1Hz,1H),7.56(d,J=12.5Hz,1H),7.51–7.36(m,5H),4.55(hept,J=6.8Hz,1H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 19 ClFN7O3[M+H] + 484.1295 found 484.1292.

[0296] Example 69: N-(5-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazole-3-carbonyl)-6-fluoropyridin-3-yl)-4-(4-chlorophenyl)piperidine-1-carboxamide

[0297]

[0298] The synthesis method was the same as in Example 1, with a yield of 60.5% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.62–8.52(m,3H),8.42(d,J=8.9Hz,1H),8.09(dd,J=5.0 ,1.4Hz,1H),7.58(s,2H),7.36–7.28(m,2H),7.28–7.22(m,2H),4.55(hept,J=6. 8Hz,1H),3.78(dt,J=12.4,7.1Hz,2H),3.60(dt,J=12.5,7.1Hz,2H),2.86–2.75( m,1H),2.02(qq,J=12.4,7.1Hz,4H),1.45(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 25 H 27ClFN7O3[M+H] + 528.1921 found 528.1927.

[0299] Example 70: 5-Amino-N 3 -(5-(3-(4-chlorophenyl)-1,3-dimethylureo)-2-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazole-3,4-dicarboxamide

[0300]

[0301] The synthesis method was the same as in Example 1, with a yield of 59.7% and a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.11–8.01(m,2H),7.91–7.83(m,2H),7.64–7.41(m,2H),7.37–7.26 (m,4H),4.55(hept,J=6.8Hz,1H),3.48(s,3H),3.22(s,3H),1.44(d,J=6.8Hz,6H).HR-MS(ESI)m / z:calcd for C 22 H 24 ClFN8O3[M+H] + 503.1717 found 503.1719.

[0302] Example 71: 5-amino-3-(5-(2-(4-chlorophenyl)acetamido)-2-fluoronicotinyl)-1-(morpholino-4-carbonyl)-1H-pyrazole-4-carboxamide

[0303]

[0304] The synthesis method was the same as in Example 1, with a yield of 71.3% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.14(s,2H),8.60(d,J=1.5Hz,1H),8.17(dd,J=5.0,1.5Hz,1H),7.58(s,2 H),7.43–7.36(m,2H),7.29(dt,J=7.5,1.0Hz,2H),3.78–3.63(m,8H),3.55–3.43(m,2H).HR-MS(ESI)m / z:calcd for C 23 H 21 ClFN7O5[M+H] + 530.1349 found 530.1344.

[0305] Example 72: 5-Amino-N 3 -(5-(2-(4-chlorophenyl)acetamido)-2-fluoropyridin-3-yl)-1-cyclopentyl-1H-pyrazole-3,4-dicarboxamide

[0306]

[0307] The synthesis method was the same as in Example 1, with a yield of 72.1% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.85(s,1H),9.22(s,1H),8.80(dd,J=8.9,2. 5Hz,1H),8.32(t,J=2.1Hz,1H),7.55(d,J=8.7Hz,2H),7.42–7.36(m,2H),7.21(s,1 H),6.81(s,2H),4.70(p,J=7.0Hz,1H),3.78(s,2H),2.12(ddq,J=24.7,12.1,5.6Hz ,4H),1.92–1.82(m,2H),1.71(ddt,J=11.3,8.6,3.9Hz,2H).HR-MS(ESI)m / z:calcd for C 23 H 24 ClFN7O3[M+H] + 550.1608 found 550.1608.

[0308] Example 73: 5-Amino-1-cyclopentyl-N 3 -(2-Fluoro-5-(2-(4-fluorophenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0309]

[0310] The synthesis method was the same as in Example 1, with a yield of 76.9% and a white solid. 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.82(s,1H),9.23(s,1H),8.78(dd,J=8.9,2. 5Hz,1H),8.29(t,J=2.1Hz,1H),7.48(d,J=8.7Hz,2H),7.37–7.29(m,2H),7.20(s,1 H),6.78(s,2H),4.71(p,J=7.0Hz,1H),3.82(s,2H),2.18(ddq,J=24.7,12.1,5.6Hz ,4H),1.98–1.86(m,2H),1.75(ddt,J=11.3,8.6,3.9Hz,2H).HR-MS(ESI)m / z:calcd for C 23 H 24 F2N7O3[M+H] + 484.1903 found 484.1911.

[0311] Example 74: 5-Amino-1-cyclopentyl-N 3 -(2-Fluoro-5-(2-(4-(trifluoromethyl)phenyl)acetamido)pyridin-3-yl)-1H-pyrazole-3,4-dicarboxamide

[0312]

[0313] The synthesis method was the same as in Example 1, with a yield of 77.8% and a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.94(s,1H),9.35(s,1H),8.91(dd,J=8.9,2. 5Hz,1H),8.41(t,J=2.1Hz,1H),7.62(d,J=8.7Hz,2H),7.41–7.32(m,2H),7.25(s,1 H),6.87(s,2H),4.74(p,J=7.0Hz,1H),3.91(s,2H),2.31(ddq,J=24.7,12.1,5.6Hz ,4H),1.99–1.87(m,2H),1.80(ddt,J=11.3,8.6,3.9Hz,2H).HR-MS(ESI)m / z:calcd for C 24 H 24 F4N7O3[M+H] + 534.1871 found 534.1871.

[0314] Example 75: Inhibition experiment on the activity of the compound against Ba / F3-LMNA-NTRK1 and Ba / F3-LMNA-NTRK1-G667C cells

[0315] 1. Experimental materials and instruments

[0316]

[0317] 2. Experimental Procedure

[0318] (1) Compound concentration preparation: Dilute the compound to the final test concentration 20 times with growth medium.

[0319] (2) Cell seeding: Centrifuged Ba / F3-LMNA-NTRK1 and Ba / F3-LMNA-NTRK1-G667C cells were resuspended in growth medium. Cell counts were performed using a cell counter, and the cell suspension was prepared to the required density. 95 μL of cell suspension was added to each well of a 96-well plate, followed by 5 μL of drug-containing medium. Positive control, negative control, and solvent control groups were also established. Finally, the 96-well plates were incubated at 37°C and 5% CO2 for 72 h.

[0320] (3) Measurement signal: Cool the test plate to room temperature and add 50 μL to each well. The reagents were stirred on a vibrating sieve for 2 minutes to induce cell lysis, and then incubated at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was then recorded on Paradigm.

[0321] (4) Calculate the inhibition rate and drug IC of each group. 50 The application software SPSS (Staffstical Package for the Social Science) was used to calculate the IC using the probability unit weighted regression method (Bliss method). 50 .

[0322]

[0323] 3. Experimental Results

[0324] The inhibitory activities of the compounds in each example are as follows:

[0325]

[0326]

[0327] IC 50 : A≤10nM; 10nM<B≤100nM; 100nM<C≤1μM; D>1μM.

[0328] The results of the above bioactivity tests show that the TRK inhibitor of the present invention has high inhibitory activity against both wild-type Ba / F3-LMNA-NTRK1 cells and mutant Ba / F3-LMNA-NTRK1-G667C cells. In particular, its inhibitory activity against mutant Ba / F3-LMNA-NTRK1-G667C cells is significantly better than that of the positive control TRK inhibitor LOXO-101.

Claims

1. A pyrazole compound, characterized in that, Having the structure of formula (I), or a pharmaceutically acceptable salt thereof: ， in: L1 is selected from C(O)NH and carbonyl groups; A 1 For N, A 3 A 4 Independently selected from CR 6 ; A 2 Selected from CR 7 ; R 1 Selected from (CH3)2CH、(CH3)3C、CH3CH2、(CH3)2CHCH2、CH2CF3、(CH3)2CCF3、CH3CHCF3; R 2 It represents -NH2; R 3 It represents -C(O)NH2; R 4 It is H; L2 indicates a group selected from the following: CH2; R 5 Selected from ; R 6 Selected from H, halogens; R 7 Selected from fluorine, chlorine, methyl, and cyclopropyl.

2. The pyrazole compound according to claim 1, characterized in that, A in the structure 3 A 4 For CH.

3. A pyrazole compound, characterized in that, Selected from any of the following compounds, or pharmaceutically acceptable salts thereof: 。 4. The pyrazole compound according to claim 1 or 3, characterized in that, The pharmaceutically acceptable salt is a salt formed by the compound and an acid selected from the following: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and acidic amino acids.

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a pyrazole compound as described in claim 1 or 3 and a pharmaceutically acceptable carrier.

6. Use of a pyrazole compound of claim 1 or 3 or a pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of tropomyosin kinase-mediated diseases.

7. The application according to claim 6, characterized in that, The drug is a drug for the prevention and / or treatment of diseases related to abnormal function of tropomyosin-related kinase caused by gene amplification, overexpression, mutation or fusion of tropomyosin-related kinase.

8. The application according to claim 6, characterized in that, The drug is a medication for the prevention and / or treatment of pain or cancer.

9. The application according to claim 8, characterized in that, The drug is for the prevention and / or treatment of lung cancer, malignant hematological diseases, prostate cancer, breast cancer, ovarian cancer, glioma, pancreatic cancer, hepatobiliary hepatocellular carcinoma, papillary thyroid carcinoma, colon cancer, head and neck squamous cell carcinoma, and melanoma.

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